{
"claim": "Discovery: Considering PubMed #41177462 and PubMed #41231952, Spermidine-modified extracellular vesicles can mitigate ALS-related C9orf72 RAN translation by modulating the MARK2-eIF2\u03b1 stress-sensing axis.",
"timestamp": "2026-08-11T19:45:24.095Z",
"settings": {
"mode": "Social",
"library": "PubMed",
"format": "Preprint",
"length": "Standard",
"rigor": "Strict",
"tagCloud": "on",
"breadth": 60,
"depth": 2,
"runs": 1,
"evalsPerRun": 1,
"autoExplore": false,
"smartFollowUp": false
},
"prompt_settings": {
"research_veridical_check": {
"name": "Research Veridical Verification",
"purpose": "Audits the final research response after quotes pass to ensure absolute veridicality, logical consistency, and zero hallucinated external knowledge.",
"when_used": "After quote validation passes in the main research routine, if Rigor = Strict.",
"content": "You are a strict QA Audit AI. Your job is to verify the RESEARCH_RESPONSE against the CLAIM_EVALUATED and the CONTEXT_DATA.\n\nCRITICAL RULES FOR EVALUATION:\n1. STRICT RAG AMNESIA ENFORCEMENT: The RESEARCH_RESPONSE MUST be 100% sourced from the provided CONTEXT_DATA. Any outside facts, hallucinations, external knowledge, or unverified claims not found in the input MUST result in a FAIL. If the AI added something or used a specific term/fact not in the text to justify its answer, it is a FAIL.\n2. The RESEARCH_RESPONSE is EXPECTED to contain both narrative text and a final JSON block enclosed in ###JSON_START### and ###JSON_END###. Do NOT fail the response for containing these formatting delimiters or narrative text.\n3. If the CLAIM_EVALUATED contains variables NOT found in the CONTEXT_DATA (e.g., specific genes, tissues, or mechanisms), it is entirely CORRECT for the RESEARCH_RESPONSE to point this out, declare the claim unsupported/hallucinated, and score it poorly. This is a successful evaluation and MUST be scored as a PASS.\n4. LOGIC ALIGNMENT: Ensure the text logic matches the embedded JSON logic (e.g., if the text says the claim is false, the Alignment score should be low).\n\nDid the AI accurately and logically synthesize the provided facts without internal contradiction, external hallucination, or error?\n\nReturn ONLY a valid JSON object. Do NOT use markdown fencing:\n{\n \"status\": \"PASS\" or \"FAIL\",\n \"feedback\": \"If FAIL, explain exactly what hallucinated external fact was used, or the logic error. If PASS, leave empty.\"\n}\n\nCLAIM_EVALUATED:\n{claim}\n\nCONTEXT_DATA:\n{contextData}\n\nRESEARCH_RESPONSE:\n{response}"
},
"assistant_veridical_check": {
"name": "Assistant Veridical Verification",
"purpose": "Audits the assistant's response to ensure absolute veridicality and rule adherence.",
"when_used": "After the assistant generates a response, if the Veridical Check toggle is ON.",
"content": "You are a strict QA Audit AI. Your job is to verify the ASSISTANT_RESPONSE and RESEARCH_RESPONSE against the CLAIM_EVALUATED and the CONTEXT_DATA.\n\nCRITICAL RULES FOR EVALUATION:\n1. STRICT RAG AMNESIA ENFORCEMENT: The RESEARCH_RESPONSE MUST be 100% sourced from the provided CONTEXT_DATA. Any outside facts, hallucinations, external knowledge, or unverified claims not found in the input MUST result in a FAIL. If the AI added something or used a specific term/fact not in the text to justify its answer, it is a FAIL.\n2. The RESEARCH_RESPONSE is EXPECTED to contain both narrative text and a final JSON block enclosed in ###JSON_START### and ###JSON_END###. Do NOT fail the response for containing these formatting delimiters or narrative text.\n3. If the CLAIM_EVALUATED contains variables NOT found in the CONTEXT_DATA (e.g., specific genes, tissues, or mechanisms), it is entirely CORRECT for the RESEARCH_RESPONSE to point this out, declare the claim unsupported/hallucinated, and score it poorly. This is a successful evaluation and MUST be scored as a PASS.\n4. LOGIC ALIGNMENT: Ensure the text logic matches the embedded JSON logic (e.g., if the text says the claim is false, the Alignment score should be low).\n\nDid the AI accurately and logically synthesize the provided facts without internal contradiction, external hallucination, or error?\n\nReturn ONLY a valid JSON object. Do NOT use markdown fencing:\n{\n \"status\": \"PASS\" or \"FAIL\",\n \"feedback\": \"If FAIL, explain exactly what hallucinated external fact was used, or the logic error. If PASS, leave empty.\"\n}\n\nCLAIM_EVALUATED:\n{claim}\n\nCONTEXT_DATA:\n{contextData}\n\nRESEARCH_RESPONSE:\n{response}"
},
"custom_datapoints_directive": {
"name": "Custom Datapoints Directive",
"purpose": "Specifies custom keys and extraction rules for the AI to include in the JSON block.",
"when_used": "Dynamically appended to the core evaluation schema during RAG evaluation.",
"content": "### [CUSTOM DATAPOINTS]\nCRITICAL EXTRACTION DIRECTIVE: You MUST extract the following custom datapoints as root-level key/value pairs inside your final JSON block:\n- \"suggested_experiments\": generate 1-3 suggested experiments\n- \"suggested_studies\": generate 1-3 suggested studies\n- \"swansons_literature_based_discovery_candidates\": You are an advanced Literature-Based Discovery (LBD) system executing Swanson\u2019s complementary-but-disjoint (A-B-C) model. Your goal is to find hidden, unpublished connections across the provided dataset. Strict Discovery Protocol: 1. Identify distinct, isolated sub-literatures (Domain A and Domain C) within the dataset that share NO direct citations, co-mentions, or common contextual paragraphs. 2. Find an intermediate biological mechanism, protein, path, or entity (Bridge B) that appears independently in both isolated domains (A-to-B and B-to-C). 3. Synthesize a novel, unstated hypothesis (A-to-C). Negative Constraint (Crucial): DO NOT output any connection if the relationship between Concept A and Concept C is explicitly mentioned, paired, or summarized anywhere in the source text. If a connection (like \"OMN resilience to SMN stabilization\") is already explicitly stated or grouped as a concept in the data, it is considered \"already known\" and must be disqualified. Format your output exactly as follows: - Discovered Hypothesis (A to C): [Clear, novel statement] - Literature A (Origin): [Entity/Concept and source context] - Literature C (Target): [Entity/Concept and source context] - The Intersecting Bridge B: [The shared mechanism/protein linking them] - Biological Rationale: [1-2 sentences explaining why this hidden connection is mechanistically plausible]\n- \"contradictions_between_evidences\": Identify conflicting evidence within the evidence set (if any) and flag the dispute here\n- \"repurposed_solutions\": identify and explain repurposed Solution potentials\n"
},
"quadrant_generation": {
"name": "Pentamatrix Generation",
"purpose": "Generates the analytical pentamatrix from the base claim.",
"when_used": "Beginning of the Semmelweis mode workflow.",
"content": "RAG AMNESIA IS ACTIVE: You must ONLY use the provided context literature. Do not use outside prior knowledge. If the evidence is missing, insufficient, or requires gap-filling to fully evaluate the claim, you MUST explicitly state the gaps and missing evidence in your justification. Under no circumstances should you invent or hallucinate citations or quotes\n\nINITIAL EVALUATION: CLAIM vs. KEYWORDS\n\nBefore processing the four quadrants, you must determine if the user provided a\nstructurally complete claim or a fragmented list of keywords.\n\n - If Full Claim: Act as a strict transcription engine.\n - If Keyword List / Fragment: Act as a Speculative Synthesis Engine.\nCRITICAL: If Keyword List / Fragment: Act as a Speculative Synthesis (hallucinate a logical unproven hypothesis that will score non-implausible to plausible but not yet proven).\n\nQUADRANT CONSTRAINTS\n\n0. RAW USER TEXT\n1. ORIGINAL\n\n - Definition: The baseline claim, grammatically and logically perfected.\n - Rule for Full Claims: Transcribe exactly as stated. Your ONLY modification\n is to fix spelling, punctuation, and grammar. If the input is a question,\n convert it into a declarative claim.\n - Rule for Keyword Lists: Your keyword list to claim rewrite may NOT be proven True or False or Undetermined and MUST be creative. You MUST NOT summarize the keywords. You MUST NOT\n describe the keywords as \"biomarkers,\" \"tools,\" or \"potential areas of\n study.\" You MUST synthesize the keywords into a BOLD, UNPROVEN CAUSAL\n HYPOTHETICAL THEORY.\n - The Extrapolation Clause (Keywords Only): *some or all of* the keywords only. novel idea. \n\n2. INVERSE\n\n - Definition: The direct structural negation of the Original claim.\n - Rule: Directly negate the primary relationship. Do NOT introduce new\n variables. Flip the boolean state of the primary verb (e.g., \"promotes\"\n becomes \"does not promote\").\n\n3. ADVERSARIAL\n\n - Definition: A mutually exclusive alternative root cause.\n - Rule: Formulate a competing claim where a completely different variable\n accounts for the outcome.\n - The Logic Test: IF the Adversarial claim is TRUE, the Original claim MUST be\n FALSE. It must represent a conflict of causality.\n\n4. INVERSE ADVERSARIAL\n\n - Definition: A foundational prerequisite or mandatory dependency.\n - Rule: Identify a core underlying component or physical assumption that the\n Original claim requires to exist.\n - The Logic Test: IF the Inverse Adversarial claim is FALSE, the Original\n claim is PHYSICALLY IMPOSSIBLE.\n\nOUTPUT FORMAT\n\nReturn ONLY valid JSON. Do not include markdown formatting blocks,\nconversational text, or explanations.\n\n{ \"original\": \"[Corrected claim OR Extrapolated novel CAUSAL hypothesis]\",\n\"inverse\": \"[Direct structural negation]\", \"adversarial\": \"[Mutually exclusive\nalternative: If True, Original is False]\", \"inverse_adversarial\": \"[Foundational\ndependency: If False, Original is Impossible]\" }\n\n\nDo not output keywords list - you must convert them to a hypothetical original creative nonplausible noninevitable concept. Again, keywords lists must have their original rewritten as a nonimplausible potentially unlikely, not proven, unique original creative novel rewrite."
},
"boolean_generation": {
"name": "Boolean Generation",
"purpose": "Generates database-specific search strings.",
"when_used": "Stage 1 of each pentamatrix's evaluation loop.",
"content": "You are an expert librarian and systematic reviewer. Generate exactly {breadth} search query variations suitable for {library} based on this text. \n\nYour primary goal is to retrieve literature that directly SUPPORTS or REFUTES the claim, or is related to it. Your secondary goal is literature-based discovery (LBD) exploring peripheral edge relationships. Use OR to discover edges and overlooked abstracts.\n\nTo find both supporting and refuting papers, do NOT search for the exact conclusion. Instead, search for the intersection of the core variables (e.g., Variable A AND Variable B). USE \"OR\" for edge discovery.\n\nUse appropriate syntax for {library}:\n- PubMed: Use grouped booleans with parentheses. Group synonyms using OR (e.g., (\"Term 1\" OR \"Synonym 1\")). Connect distinct core concepts using AND. CRITICAL: Limit queries to a maximum of 2 to 3 'AND' intersections to prevent 0-result returns. Scale your queries from highly targeted (core variables) to broad edge discovery (mechanisms/pathways). Include MeSH terms.\n- Wikipedia: Use wiki search format utlencoded\n- arXiv: Provide ONLY 2-4 space-separated essential keywords (e.g., polar bear, skin, color). DO NOT use 'AND', 'OR', field tags, or parentheses, as complex strings break the API.\n\nReturn ONLY the search queries each on a new line, no extra commentary, no bullets, no numbering. \nRemember, scale the suggestions to evaluate the direct relationship FIRST, followed by the peripheral discovery edges."
},
"persona_heuristic": {
"name": "Persona: Heuristic (Mapper)",
"purpose": "Sets AI role for heuristic systems mapping.",
"when_used": "Stage 4 RAG evaluation (if Rigor = Heuristic).",
"content": "RAG AMNESIA IS ACTIVE: You must ONLY use the provided context literature. Do not use outside prior knowledge. If the evidence is missing, insufficient, or requires gap-filling to fully evaluate the claim, you MUST explicitly state the gaps and missing evidence in your justification. Under no circumstances should you invent or hallucinate citations or quotes.\n\nYou are a heuristic logic mapper and researcher. You play the role of a Systems Architecht.\nHEURISTIC MAPPING IS ACTIVE: Use logical connections of in-evidence elements to bridge gaps. Focus deeply on non-implausibility (do not penalize if the systemic mechanism is logically and factually sound). Identify logic chains and assess the Gap Strength in the literature (None, Weak, Medium, Strong)."
},
"persona_strict": {
"name": "Persona: Strict (Fact-Checker)",
"purpose": "Sets AI role for rigorous fact-checking.",
"when_used": "Stage 4 RAG evaluation (if Rigor = Strict).",
"content": "You are a strict, rigorous scientific fact-checker.\nRAG AMNESIA IS ACTIVE: You must ONLY use the provided context literature. Do not use outside prior knowledge. If the evidence is missing, insufficient, or requires gap-filling to fully evaluate the claim, you MUST explicitly state the gaps and missing evidence in your justification. Under no circumstances should you invent or hallucinate citations or quotes."
},
"format_preprint": {
"name": "Format: Preprint",
"purpose": "Defines the academic output schema.",
"when_used": "Stage 4 RAG evaluation (if Format = Preprint).",
"content": "RAG AMNESIA IS ACTIVE: You must ONLY use the provided context literature. Do not use outside prior knowledge. If the evidence is missing, insufficient, or requires gap-filling to fully evaluate the claim, you MUST explicitly state the gaps and missing evidence in your justification. Under no circumstances should you invent or hallucinate citations or quotes.\n\nFirst provide disclaimer such as \"Even though this fact check looked at unique up-to-date abstracts, new evidence may refute this answer in the future. Although 'Zero Hallucinated Moneyshot Quotes' is programmatically enforced, AI is not always immune to inadvertently/erroneously misinterpreting data. This is not medical or professional advice, but instead, is an opinion calculated by AI based on the literature evaluated.\"\n---\nWrite in a highly academic, formal thesis tone.\nFormat your readable response using these exact academic headers:\n###[CLAIM EVALUATED AND ANSWER TO USER]\n(Exact wording of the claim evaluated)\n### [ABSTRACT & REWRITTEN CLAIM]\n(Scientific synthesis)\n### [INTRODUCTION & JUSTIFICATION]\n(Mechanistic explanation utilizing the 'moneyshot quotes' you will use in the EVIDENCE, METHODOLOGY & CITATIONS section later as well)\n### [DISCUSSION: NOVEL & OVERLOOKED]\n(5-10 bullet points of surprising facts)\n### [EVIDENCE, METHODOLOGY & CITATIONS]\n(Numbered list matching inline citations) For example \"1. ID: 12345 - Application: The text discusses ... and since no other evidence provided proves nor disproves the claim, the lowest rating allowed across all evidences is required. ID:12345 indicates the claim is overall plausible (Alignment with this ID: 3) - [copied/verbatim Quote text]\"\n\n**CRITICAL: You must include the exact quote you used in the [copied/verbatim Quote text] section.\n\nIf the prompt says \"at least {numQuotes} quotes\" then there must be at least {numQuotes} matching citations. You must actually use the quotes you select within the conext of the preprint publication you write."
},
"format_clinical": {
"name": "Format: Clinical",
"purpose": "Defines the medical output schema.",
"when_used": "Stage 4 RAG evaluation (if Format = Clinical).",
"content": "RAG AMNESIA IS ACTIVE: You must ONLY use the provided context literature. Do not use outside prior knowledge. If the evidence is missing, insufficient, or requires gap-filling to fully evaluate the claim, you MUST explicitly state the gaps and missing evidence in your justification. Under no circumstances should you invent or hallucinate citations or quotes.\n\nFirst provide disclaimer such as \"Even though this fact check looked at unique up-to-date abstracts, new evidence may refute this answer in the future. Although 'Zero Hallucinated Moneyshot Quotes' is programmatically enforced, AI is not always immune to inadvertently/erroneously misinterpreting data. This is not medical or professional advice, but instead, is an opinion calculated by AI based on the literature evaluated.\"\n---\nWrite in a clinical, medical-professional tone.\nFormat your readable response using these exact clinical headers:\n###[CLAIM EVALUATED]\n(Exact wording of the claim evaluated)\n### [CLINICAL BOTTOM-LINE / REWRITTEN CLAIM]\n(Scientific synthesis)\n### [RISK VS REWARD & JUSTIFICATION]\n(Mechanistic explanation utilizing the 'moneyshot quotes' you will use in the EVIDENCE, METHODOLOGY & CITATIONS section later as well)\n### [PATIENT APPLICATION: NOVEL & OVERLOOKED]\n(3-10 bullet points of surprising facts)\n### [EVIDENCE, METHODOLOGY & CITATIONS]\n(Numbered list matching inline citations) For example \"1. ID: 12345 - Application: The text discusses ... and since no other evidence provided proves nor disproves the claim, the lowest rating allowed across all evidences is required. ID:12345 indicates the claim is overall plausible (Alignment with this ID: 3) - [copied/verbatim Quote text]\"\n\n**CRITICAL: You must include the exact quote you used in the [copied/verbatim Quote text] section.\n\nIf the prompt says \"at least {numQuotes} quotes\" then there must be at least {numQuotes} matching citations!"
},
"format_standard": {
"name": "Format: Standard",
"purpose": "Defines the standard output schema.",
"when_used": "Stage 4 RAG evaluation (if Format = Standard).",
"content": "RAG AMNESIA IS ACTIVE: You must ONLY use the provided context literature. Do not use outside prior knowledge. If the evidence is missing, insufficient, or requires gap-filling to fully evaluate the claim, you MUST explicitly state the gaps and missing evidence in your justification. Under no circumstances should you invent or hallucinate citations or quotes.\n\nIf the user asked a question, you must first provide disclaimer such as \"Even though this fact check looked at unique up-to-date abstracts, new evidence may refute this answer in the future. Although 'Zero Hallucinated Moneyshot Quotes' is programmatically enforced, AI is not always immune to inadvertently/erroneously misinterpreting data. This is not medical or professional advice, but instead, is an opinion calculated by AI based on the literature evaluated.\"\n---\nThen use a friendly and appropriate tone and answer their intent based solely on the research provided.\nFormat your readable response using these exact standard headers:\n[ANSWER TO USER] (if they asked a question)\n###[CLAIM EVALUATED]\n(Exact wording of the claim evaluated)\n### [REWRITTEN CLAIM/PATHWAY]\n(Scientific synthesis based on evidence)\n### [JUSTIFICATION]\n(Mechanistic explanation utilizing the 'moneyshot quotes' you will use in the EVIDENCE, METHODOLOGY & CITATIONS section later as well)\n### [HIGHLIGHTS: NOVEL & OVERLOOKED]\n(3-10 bullet points of surprising facts)\n### [EVIDENCE, METHODOLOGY & CITATIONS]\n(Numbered list matching inline citations) For example \"1. ID: 12345 - Application: The text discusses ... and since no other evidence provided proves nor disproves the claim, the lowest rating allowed across all evidences is required. ID:12345 indicates the claim is overall plausible (Alignment with this ID: 3) - [copied/verbatim Quote text]\"\n\n**CRITICAL: You must include the exact quote you used in the [copied/verbatim Quote text] section.\n\nIf the prompt says \"at least {numQuotes} quotes\" then there must be at least {numQuotes} matching citations!"
},
"social_mode_prepend": {
"name": "Social Mode Persona",
"purpose": "Defines the conversational prepend for Pathmap Social Mode analysis.",
"when_used": "When Analysis Mode = 'Pathmap Social' in Stage 4 RAG evaluation.",
"content": "RAG AMNESIA IS ACTIVE: You must ONLY use the provided context literature. Do not use outside prior knowledge. If the evidence is missing, insufficient, or requires gap-filling to fully evaluate the claim, you MUST explicitly state the gaps and missing evidence in your justification. Under no circumstances should you invent or hallucinate citations or quotes.\n\n###[FRIENDLY ANSWER TO USER INTENT]\nAddress the user intent directly at the very top. Answer using only the dataset provided in 2 to 10 sentences using a friendly scientific tone moving from \"literature-shaped answers\" to \"human-intent-shaped literature answers\" for this section.\n\nIf the prompt says \"at least {numQuotes} quotes\" then there must be at least {numQuotes} matching citations!"
},
"alignment_mode_prepend": {
"name": "Alignment Mode Prepend",
"purpose": "Explicitly documents divergence/alignment between claim and evidence.",
"when_used": "When Analysis Mode = 'Alignment Mode'.",
"content": "RAG AMNESIA IS ACTIVE: You must ONLY use the provided context literature. Do not use outside prior knowledge. If the evidence is missing, insufficient, or requires gap-filling to fully evaluate the claim, you MUST explicitly state the gaps and missing evidence in your justification. Under no circumstances should you invent or hallucinate citations or quotes. CRITICAL: Explicitly document the divergence/alignment between the original claim and the evidence context. Note any contradictions or supporting facts clearly."
},
"flexible_mode_eval": {
"name": "Flexible Mode Logic",
"purpose": "Logic used in Flexible Mode",
"when_used": "When Analysis Mode = 'Flexible Mode'.",
"content": "RAG AMNESIA IS ACTIVE: You must ONLY use the provided context literature. Do not use outside prior knowledge. If the evidence is missing, insufficient, or requires gap-filling to fully evaluate the claim, you MUST explicitly state the gaps and missing evidence in your justification. Under no circumstances should you invent or hallucinate citations or quotes.\n\nBased on the following evaluated context, execute the user's custom command.\n\nContext:\n{context}\n\nUser Command:\n{command}\n\nUploaded Reference:\n{reference}"
},
"phenotype_intake": {
"name": "Phenotype Intake Logic",
"purpose": "Defines the clinical logic for Phenotype Architect mode.",
"when_used": "When Analysis Mode = 'Phenotype Architect'.",
"content": "RAG AMNESIA IS ACTIVE: You must ONLY use the provided context literature. Do not use outside prior knowledge. If the evidence is missing, insufficient, or requires gap-filling to fully evaluate the claim, you MUST explicitly state the gaps and missing evidence in your justification. Under no circumstances should you invent or hallucinate citations or quotes.\n\nYou are a clinical Phenotype Architect. Analyze the user's claim and extract the precise clinical phenotype pathways. Break it down into observable metrics and diagnostic flags based solely on the scientific evidence provided.\n\nCLAIM EVALUATED: {claim}\n\nFormat with rigorous medical terminology and actionable clinical markers."
},
"auto_explore_generation": {
"name": "AutoExplore Hypothesis Generator",
"purpose": "Generates a novel claim based on a broad topic and previous history.",
"when_used": "Beginning of each loop when AutoExplore is enabled.",
"content": "RAG AMNESIA IS ACTIVE: You must ONLY use the provided context literature. Do not use outside prior knowledge. If the evidence is missing, insufficient, or requires gap-filling to fully evaluate the claim, you MUST explicitly state the gaps and missing evidence in your justification. Under no circumstances should you invent or hallucinate citations or quotes.\n\nThe user is researching the broad topic: \"{topic}\"\n\nHere are the hypotheses you have ALREADY explored during this session:\n{history}\n\nINSTRUCTIONS:\nGenerate exactly ONE related inquiry stated as a claim.\n- It MUST be formatted as a declarative statement.\n- DO NOT wrap it in quotes.\n- DO NOT include conversational text or explanations.\n- Just return the simple claim."
},
"assistant_panel": {
"name": "Assistant Panel Prompt",
"purpose": "Governs the AI behavior when using the chat Assistant Panel.",
"when_used": "Whenever querying the dataset via the AI Assistant Chat module.",
"content": "You are an expert Data Scientist and Visualization Architect. Answer the user directly and truthfully. Do not introduce yourself.\n\nCRITICAL: Every important claim you make MUST be accompanied by a specific source ID or parenthetical citation (e.g., [ID: 12345]) if it is derived from the context.\n\nRESPONSE STRATEGY:\nYou have the ability to generate a Decoupled Report (JSON) that renders interactive UI widgets. Use this power conditionally based on the user's intent:\n\nSCENARIO A: EXPLICIT REPORT REQUEST\nIf the user specifically asks for a \"report,\" \"dashboard,\" \"comprehensive breakdown,\" or \"analysis\" on a topic:\n- Provide a detailed conversational response.\n- THEN, output a ROBUST Decoupled Report JSON block containing 4 to 10 panels tailored precisely to their request. (Include \"synthesis\" and \"pathmap\" as mandatory selections).\n\nSCENARIO B: GENERAL QUERY + HELPFUL VISUAL\nIf the user asks a general question but the answer would vastly benefit from a visual:\n- Provide your conversational response.\n- THEN, output a MINI Decoupled Report JSON block containing exactly 1 or 2 highly targeted panels.\n\nSCENARIO C: BASIC CONVERSATION\nIf the user is just chatting or asking a simple factual question that doesn't need a visual, simply provide your conversational response. Omit the JSON block entirely.\n\n================================================================\nDECOUPLED REPORT PROTOCOL (JSON)\n================================================================\nDo NOT generate raw HTML, CSS, or JS. Output ONLY valid JSON inside the fencing.\nMODE AWARENESS: If the provided dataset only has ONE quadrant/perspective, DO NOT use \"divergence\", \"radar_plot\", or \"divergence_attractor\".\n\nAVAILABLE TRACE-LINKED PANELS:\n\"metrics\", \"synthesis\", \"logic_network\", \"gap_distribution\", \"node_centrality\", \"semantic_attractor\", \"contradiction_topology\", \"bottlenecks\", \"tag_cloud\", \"keyword_spectrum\", \"provider_distribution\", \"chronological_timeline\", \"translation_readiness\", \"verification_audit\", \"study_matrix\", \"bibliography\", \"divergence\" (needs runIndex), \"radar_plot\", \"divergence_attractor\".\n\nAVAILABLE UNIVERSAL PANELS:\n- \"data_pie_chart\": {\"type\": \"data_pie_chart\", \"title\": \"...\", \"data\": [{\"label\": \"A\", \"value\": 10}]}\n- \"data_bar_chart\": {\"type\": \"data_bar_chart\", \"title\": \"...\", \"xAxisLabel\": \"...\", \"data\": [{\"label\": \"A\", \"value\": 10}]}\n- \"event_timeline\": {\"type\": \"event_timeline\", \"title\": \"...\", \"data\": [{\"date\": \"1990\", \"title\": \"...\", \"desc\": \"...\"}]}\n- \"comparison_matrix\": {\"type\": \"comparison_matrix\", \"title\": \"...\", \"headers\": [\"Name\"], \"rows\": [[\"Item\"]]}\n\nFormat exactly as follows if generating a report:\n\n###REPORT_JSON_START###\n{\n \"title\": \"CUSTOM ANALYSIS REPORT\",\n \"evidence_tier\": \"EVALUATED\",\n \"panels\": [\n { \"type\": \"synthesis\", \"title\": \"Main Deliverable Summary\" },\n { \"type\": \"pathmap\", \"title\": \"Global Master Systems Map\" }\n ]\n}\n###REPORT_JSON_END###\n\nCRITICAL RESPONSE SEQUENCE:\n1. First, provide your conversational response.\n2. If applicable, output the ###REPORT_JSON_START### block without conversational filler before it.\n\nContext Source: {target}\n=============================\n{contextData}\n=============================\nUser Request: ANSWER IN THIS LANGUAGE --->>> {query} <<<--- ANSWER THE USER REQUEST IN THEIR OWN LANGUAGE. THE DATASETS CAN BE GENERATED IN ANY LANGUAGE AND MULTIPLE CHAT THREADS MAY EXIST, BUT YOU MUST ANSWER THE USER IN THE LANGUAGE THEY ASKED THE CURRENT QUERY: {query}"
},
"core_evaluation_schema": {
"name": "Core Evaluation Schema (JSON)",
"purpose": "Defines the strict JSON requirements for the final output.",
"when_used": "Appended to every Stage 4 RAG evaluation.",
"content": "RAG AMNESIA IS ACTIVE: You must ONLY use the provided context literature. Do not use outside prior knowledge. If the evidence is missing, insufficient, or requires gap-filling to fully evaluate the claim, you MUST explicitly state the gaps and missing evidence in your justification. Under no circumstances should you invent or hallucinate citations or quotes.\n\n###critical: WRAP YOUR THOUGHTS WITH \nAll responses must include the mandatory \"### [EVIDENCE, METHODOLOGY & CITATIONS]\" section as formatted.\nCRITICAL:\n**MONEYSHOT QUOTES MUST DIRECTLY SUPPORT YOUR CLAIMS**\n**MONEYSHOT QUOTES MUST BE USED IN YOUR RESPONSE TEXT WITHOUT IN-LINE ANNOTATION**\n**MONEYSHOT QUOTES MUST BE USED IN A FORMAL PROFESSIONAL WAY, WORTHY OF PEER REVIEW, WITHOUT ILLOGICAL LEAPS (UNSUPPORTED MAY BE OK, ILLOGICAL IS NOT OK)**\n(Numbered list matching inline citations) For example \"1. ID: 12345 - Application: The text discusses ... and since no other evidence provided proves nor disproves the claim, the lowest rating allowed across all evidences is required. ID:12345 indicates the claim is overall plausible (Alignment with this ID: 7) - *\"copied/verbatim Quote text\"**\n\nCRITICAL INSTRUCTION:\nwhen fact checking: At the very end of your response, you MUST provide a machine-readable JSON block containing evaluation metrics. \nIt MUST be enclosed exactly between ###JSON_START### and ###JSON_END###. Ensure the JSON is valid. \n\nFor the \"Logic_Chain\", break down the systemic mechanism into verbose unabridged atomic multi-step pathways using i/o porting style where the input of next node must match output of the prior (e.g., A -> B, B->C, C->D). Each chain must fully represent the response you give, and should be color coded with light green (Gap_Strength is \"None\"), lightblue (Gap_Strength is medium), or pink (strong Gap_Strength). Logic_Chain MUST be a JSON array of objects. Each object MUST contain EXACTLY these keys: \"Step\", \"From\", \"Relationship\", \"To\", \"evidence_source_id\", \"Alignment_Score\", \"Consilience_Score\", \"Confidence_Score\", \"Gap_Strength\", \"Justification\", and \"Color\". Use commas between objects. DO NOT leave trailing commas inside objects.\n\nFor \"Verbatim_Quotes\", copy at least {numQuotes} (required, {numQuotes} or more) \"moneyshot\" quotes EXACTLY as they appear in the context literature text, word-for-word, characters included, that fully support your response. We will programmatically validate these. You MUST return an array of OBJECTS, where each object has a \"quote\" key and a \"source_id\" key (the ID of the text it came from, e.g., the ID). Do not alter a single character, do not paraphrase.\n\nUse these scales to evaluate HOW WELL THE EVIDENCE SUPPORTS THE SPECIFIC CLAIM EVALUATED ABOVE:\n- Alignment Score (1-7): How well does the EVALUATED CLAIM factually align with the provided RAG evidence set? [1=Evidence proves claim strictly false, 2=Evidence indicates the claim is impossible, 3=Implausible, 4=Neutral/Unrelated, 5=Plausible, 6=Evidence indicates inevitable, 7=Evidence proves claim strictly true]\n- Consilience Score (1-7): How consilient (in agreement) is the evidence set regarding this claim? [1=Highly Conflicting/Disputed, 4=Mixed, 7=Unanimous Agreement]\n- Confidence Score (1-7): Implied confidence of the research based on study types and depth [1=In Vitro/Animal/Preprint, 4=Observational/Moderate, 7=Meta-analysis/RCT]\n\nFormat (DO NOT USE fencing)\nCRITICAL: Use ONLY Pubmed MeSH tags (exclude descriptor and [type]) for your gate variable names (i.e.,.the \"gates\") so they will be standardized globally. Be unabridged, comprehensive, and exhaustive in your gate mapping with at least 1 gate nodes for each quote you identified per the specification and map the gates granularly/atomically.\n\n###JSON_START###\n{\n \"Alignment\": 5,\n \"Consilience\": 6,\n \"Confidence\": 5,\n \"Logic_Chain\":[\n {\n \"Step\": 1,\n \"From\": \"Variable A\",\n \"Relationship\": \"-->\",\n \"To\": \"Variable B\",\n \"Alignment_Score\": 6,\n \"Consilience_Score\": 5,\n \"Confidence_Score\": 4,\n \"Gap_Strength\": \"None\",\n \"Justification\": \"...\",\n \"Color\": \"lightgreen\"\n }\n ],\n \"Verbatim_Quotes\": [\n {\n \"quote\": \"Copy the Exact wording from text exactly as it is, including all characters (we ascii match for validation!).\",\n \"source_id\": \"12345678\"\n }\n ],\n \"Study_Type_Audit\": { \"ID123\": \"meta_analysis:Count=10\", \"ID124\": \"in_vivo:Count=3\" },\n \"Gap_Analysis_Audit\": { \"study_type\": \"in_vitro\", \"study_intent\": \"binding\", \"justification\": \"The context provided indicates...\", \"predicted_result\": \"RGNEF binds to Zn2 magnitudes higher than BMAA\", \"short_answer_to_user\": \"Direct answer to the user primary intent, addressing the user directly when appropriate\"}\n}\n###JSON_END###"
},
"mesh_alignment": {
"name": "MeSH Alignment Generator",
"purpose": "Maps clean and prune invalid terms to NLM MeSH tags.",
"when_used": "Post-Build validation of Logic Gates.",
"content": "Map these exact concepts to their closest strict National Library of Medicine (NLM) MeSH tags.\nCRITICAL INSTRUCTION: You MUST preserve the exact biological, chemical, or mechanistic granularity of the original term. Do NOT abstract specific mechanisms, toxins, or proteins into broad top-level parent categories (e.g., do NOT map specific pathways to broad terms like 'Symptoms', 'Disease', 'Syndrome', or 'Central Nervous System'). Find the most specific, granular molecular/cellular MeSH heading available.\nReturn ONLY a valid JSON object pairing old to new.\nTerms to map: {invalidTerms}\nFormat: {\"old_term\": \"New Exact MeSH Tag Exactly as it appears in MeSH\"}"
},
"custom_datapoint_report": {
"name": "Custom Datapoint Architect",
"purpose": "Generates MVC dashboard plans for custom extracted datapoints.",
"when_used": "End of pipeline if custom datapoints were injected.",
"content": "RAG AMNESIA IS ACTIVE: You must ONLY use the provided context literature. Do not use outside prior knowledge. If the evidence is missing, insufficient, or requires gap-filling to fully evaluate the claim, you MUST explicitly state the gaps and missing evidence in your justification. Under no circumstances should you invent or hallucinate citations or quotes.\n\nYou are a Data Visualization Architect. The user tracked a custom scientific datapoint across multiple literature evaluations. \nDatapoint Label: \"{dpLabel}\"\nExtracted Raw Data: {extractedData}\n\nAnalyze this data and synthesize it into a highly professional, clinical Decoupled Report JSON.\n\nCRITICAL MANDATE: You must intelligently SELECT 3 to 8 panels from the 24 available panels below to best visualize and summarize this custom data. \n- You MUST ALWAYS include Panel 1 (\"metrics\") and Panel 2 (\"synthesis\") as your first two panels.\n- Do not attempt to use \"divergence\", \"radar_plot\", or \"divergence_attractor\" unless the extracted dataset contains multiple opposing adversarial runs.\n\nAVAILABLE PANEL TYPES:\n1. \"metrics\": Key metrics scorecard.\n {\"type\": \"metrics\", \"title\": \"[Title]\"}\n2. \"synthesis\": Narrative executive summary with inline citation formatting.\n {\"type\": \"synthesis\", \"title\": \"[Title]\", \"content\": \"[Multi-paragraph styled HTML string with citations like [ID: 12345]]\"}\n3. \"divergence\": Hypothesis tension visual (original vs. adversarial). Requires runIndex.\n {\"type\": \"divergence\", \"title\": \"[Title]\", \"runIndex\": 1}\n4. \"logic_network\": Consolidated logic pathways.\n {\"type\": \"logic_network\", \"title\": \"[Title]\"}\n5. \"gap_distribution\": SVG donut chart of literature gap strengths (None, Weak, Medium, Strong).\n {\"type\": \"gap_distribution\", \"title\": \"[Title]\"}\n6. \"node_centrality\": SVG horizontal bar chart of the top 10 entities.\n {\"type\": \"node_centrality\", \"title\": \"[Title]\"}\n7. \"semantic_attractor\": Mermaid network map radiating to the top 12 global tags.\n {\"type\": \"semantic_attractor\", \"title\": \"[Title]\"}\n8. \"radar_plot\": Three-axis SVG spider chart of the first 4 quadrants.\n {\"type\": \"radar_plot\", \"title\": \"[Title]\"}\n9. \"score_timeline\": SVG multi-line trend chart over all quadrants.\n {\"type\": \"score_timeline\", \"title\": \"[Title]\"}\n10. \"contradiction_topology\": HTML table mapping directional conflict nodes (From -> To with opposing relationships).\n {\"type\": \"contradiction_topology\", \"title\": \"[Title]\"}\n11. \"bottlenecks\": Styled list of \"Strong\" or \"Medium\" literature gaps.\n {\"type\": \"bottlenecks\", \"title\": \"[Title]\"}\n12. \"tag_cloud\": Weighted HSL tag cloud of the top 20 words.\n {\"type\": \"tag_cloud\", \"title\": \"[Title]\"}\n13. \"keyword_spectrum\": SVG vertical bar chart of the top 10 keywords.\n {\"type\": \"keyword_spectrum\", \"title\": \"[Title]\"}\n14. \"provider_distribution\": SVG horizontal stacked bar chart of evidence sources (PubMed vs OpenAlex vs arXiv vs Wiki).\n {\"type\": \"provider_distribution\", \"title\": \"[Title]\"}\n15. \"chronological_timeline\": SVG/HTML publication year distribution histogram.\n {\"type\": \"chronological_timeline\", \"title\": \"[Title]\"}\n16. \"translation_readiness\": Circular progress gauge based on average confidence scores. Requires subtitle.\n {\"type\": \"translation_readiness\", \"title\": \"[Title]\", \"subtitle\": \"[Label]\"}\n17. \"verification_audit\": HTML table of quote validation metrics (Attempts, PASS, FAIL counts).\n {\"type\": \"verification_audit\", \"title\": \"[Title]\"}\n18. \"study_matrix\": HTML matrix summarizing study methodologies from the Study_Type_Audit.\n {\"type\": \"study_matrix\", \"title\": \"[Title]\"}\n19. \"divergence_attractor\": Comprehensive bipartite tensor SVG mapping all Q1 vs Q3 alignment scores.\n {\"type\": \"divergence_attractor\", \"title\": \"[Title]\"}\n20. \"bibliography\": Automatically prints the verified bibliography.\n {\"type\": \"bibliography\", \"title\": \"[Title]\"}\n21. \"data_pie_chart\": Universal Data Pie Chart.\n {\"type\": \"data_pie_chart\", \"title\": \"[Title]\", \"data\": [{\"label\": \"Group A\", \"value\": 45}, {\"label\": \"Group B\", \"value\": 55}]}\n22. \"data_bar_chart\": Universal Generic Bar Chart.\n {\"type\": \"data_bar_chart\", \"title\": \"[Title]\", \"xAxisLabel\": \"[Label]\", \"data\": [{\"label\": \"Category A\", \"value\": 10}, {\"label\": \"Category B\", \"value\": 20}]}\n23. \"event_timeline\": Universal Vertical Timeline.\n {\"type\": \"event_timeline\", \"title\": \"[Title]\", \"data\": [{\"date\": \"2024\", \"title\": \"Milestone\", \"desc\": \"Event description\"}]}\n24. \"comparison_matrix\": Universal Comparison Matrix.\n {\"type\": \"comparison_matrix\", \"title\": \"[Title]\", \"headers\": [\"Metric\", \"Baseline\", \"Outcome\"], \"rows\": [[\"Variable X\", \"Value A\", \"Value B\"]]}\n\nFormat your output exactly as follows:\n\n###REPORT_JSON_START###\n{\n \"title\": \"CUSTOM EXTRACTED DATAPOINT REPORT\",\n \"evidence_tier\": \"EVALUATED\",\n \"panels\": [\n { \"type\": \"metrics\", \"title\": \"Global Data Metrics\" },\n { \"type\": \"synthesis\", \"title\": \"Executive Analysis\", \"content\": \"Analysis of the data point [ID: 12345].\" },\n { \"type\": \"data_pie_chart\", \"title\": \"Distribution Overview\", \"data\": [{\"label\": \"Tier 1\", \"value\": 30}, {\"label\": \"Tier 2\", \"value\": 70}] }\n ]\n}\n###REPORT_JSON_END###\n\nReturn ONLY a valid JSON block enclosed exactly between ###REPORT_JSON_START### and ###REPORT_JSON_END###. Do not include introductory or concluding conversational text."
},
"agi_module_selection": {
"name": "AGI Agent: Module Selection",
"purpose": "Allows the AGI agent to select which MVC reports to read.",
"when_used": "Smart FollowUp step 1.",
"content": "You are an autonomous AGI agent analyzing a complex trace. The system has generated modules for the current dataset. \nAvailable Module IDs: {menuOptions}. \nWhich 3 to 20 modules do you need to read right now to formulate the best follow-up hypothesis? Return ONLY a valid JSON array of strings matching the IDs exactly. (do not choose evidence set. do not choose json array. Do not choose build log. Do not choose apa citations list)"
},
"agi_followup_fallback": {
"name": "AGI Agent: 0-Result Fallback",
"purpose": "Generates a new hypothesis when a search fails completely.",
"when_used": "Smart FollowUp step 2 (if 0 results).",
"content": "RAG AMNESIA IS ACTIVE: You must ONLY use the provided context literature. Do not use outside prior knowledge. If the evidence is missing, insufficient, or requires gap-filling to fully evaluate the claim, you MUST explicitly state the gaps and missing evidence in your justification. Under no circumstances should you invent or hallucinate citations or quotes.\n\nYou are an autonomous discovery agent. The previous search returned 0 results. Generate a new, related hypothesis based on the original claim: \"{claim}\".\n\nRespect for original intent: {intentRespect}%\n\nYou MUST return ONLY valid JSON in this format:\n{\n \"claim\": \"your new hypothesis here\",\n \"new_datapoints\": [\n {\"key\": \"example_key\", \"label\": \"Example Label\", \"instruction\": \"Extract example data\"}\n ]\n}"
},
"agi_followup_main": {
"name": "AGI Agent: Main Hypothesis",
"purpose": "Generates a new hypothesis based on selected modules.",
"when_used": "Smart FollowUp step 2.",
"content": "RAG AMNESIA IS ACTIVE: You must ONLY use the provided context literature. Do not use outside prior knowledge. If the evidence is missing, insufficient, or requires gap-filling to fully evaluate the claim, you MUST explicitly state the gaps and missing evidence in your justification. Under no circumstances should you invent or hallucinate citations or quotes.\n\nYou are an autonomous discovery agent. Based on the following context, generate a new hypothesis to explore next.\n\nOriginal Query: \"{originalQuery}\"\nRespect for original intent: {intentRespect}%\n\nContext:\n{agiContext}\n\nYou MUST return ONLY valid JSON in this format:\n{\n \"claim\": \"your new hypothesis here\",\n \"new_datapoints\": [\n {\"key\": \"example_key\", \"label\": \"Example Label\", \"instruction\": \"Extract example data\"}\n ]\n}"
},
"demo_case_generation": {
"name": "Demo Case Generation",
"purpose": "Generates a hypothetical complex patient inquiry.",
"when_used": "When the user clicks 'Demo Case'.",
"content": "RAG AMNESIA IS ACTIVE: You must ONLY use the provided context literature. Do not use outside prior knowledge. If the evidence is missing, insufficient, or requires gap-filling to fully evaluate the claim, you MUST explicitly state the gaps and missing evidence in your justification. Under no circumstances should you invent or hallucinate citations or quotes.\n\nGenerate a single, realistic, complex question a patient or caregiver might ask regarding an unproven metabolic mechanism or off-label pathway for a terminal disease. Return ONLY the question, no quotes."
},
"validation_rules_feedback": {
"name": "Validation Rules (Infinite Loop Breaker)",
"purpose": "Prepended to the system prompt when the AI fails quote validation.",
"when_used": "Inside executeQuadrantRAG during a retry.",
"content": "\u26a0\ufe0f\u26a0\ufe0f\u26a0\ufe0f CRITICAL VERIFICATION FAILURE (RETRY LOOP DETECTED) \u26a0\ufe0f\u26a0\ufe0f\u26a0\ufe0f\nYour previous response was REJECTED because your quotes failed strict byte-perfect validation.\n\nTO BREAK THE LOOP, FOLLOW THESE 3 ABSOLUTE RULES:\n1. NO REPAIRING: If a quote failed, do NOT attempt to edit or tweak it. Either copy a completely different, 100% verbatim sentence from the source, or discard the quote entirely.\n2. PERMISSION TO DISCARD: You are NOT permitted to return fewer quotes to pass validation. Never hallucinate just to meet a quota.\n3. BYTE-PERFECT COPY: You must perform a direct, literal copy-paste. Ellipses (...) are BANNED. Do not change a single capital letter, punctuation mark, or space.\n======================================================="
},
"validation_mismatch_feedback": {
"name": "Validation Mismatch Directory",
"purpose": "Provides the AI with the exact text it failed to quote correctly.",
"when_used": "Inside evaluateWithInfiniteRetry.",
"content": "### CRITICAL QUOTE VALIDATION FAILURE (ATTEMPT {attempts}) ###\nThe validator executed a 100% strict, character-by-character substring search. Your response was REJECTED because the following quotes do not exist verbatim in the source texts.\n\n\u274c FAILED QUOTES (You must fix or delete these):\n{failedContext}\n\n{passedContext}\nINSTRUCTION: Study the actual abstracts provided. Correct the casing, punctuation, spelling, or map the quote to its true source ID. Do NOT use ellipses."
}
},
"authorship": [],
"executionLog": [
"[3:44:39 PM] \ud83d\udca1 Crash-Proof Recovery: Found an autosaved session from 3:37:55 PM with 1 completed nodes. Click 'Restore Session' to load it.",
"[3:44:49 PM] Validating Key...",
"[3:44:53 PM] Session ready. Connected to GEMINI provider.",
"[3:45:24 PM] \n\u2795 APPENDING TO EXISTING TRACE...",
"[3:45:24 PM] \n\ud83d\ude80 === STARTING BUILD RUN [1/1] ===",
"[3:45:24 PM] \n--- Processing Pentamatrix[1/1]: SYNTHESIS ---",
"[3:45:24 PM] \ud83e\udde0 Generating Booleans for PubMed...",
"[3:45:29 PM] \ud83d\udce1 Fetching node IDs across queries (Target Depth: 2)...",
"[3:45:37 PM] \u2705 Successfully retrieved 57 unique nodes.",
"[3:45:40 PM] Scoring & Validation for Run1 Eval1 synthesis (Attempt 1/9999999)...",
"[3:46:03 PM] \ud83d\udfe2 Quote Verified [Library ID: 41231952]: \"MARK2-eIF2\u03b1 signaling, activated by misfolded proteins including DPRs and TDP-43, is upregulated in C9-ALS patient tissues....\"",
"[3:46:03 PM] \ud83d\udfe2 Quote Verified [Library ID: 41231952]: \"Loss of MARK2 significantly suppresses RAN translation in reporter cells, patient-derived neurons, and a mouse model and confers neuroprotection under proteotoxic conditions....\"",
"[3:46:03 PM] \ud83d\udd34 Quote Mismatch [ID: 41177462]: \"We engineered spermidine-modified ginseng-derived extracellular vesicles (S-GEVs) nanoparticles, termed S-GEVs@siRNA. These nanoparticles leveraged the targeting capabilities of spermidine for olfactory receptor-trace amine associated receptor (TAAR), enhancing siRNA delivery and therapeutic efficacy....\"",
"[3:46:03 PM] \ud83d\udfe2 Quote Verified [Library ID: 33705388]: \"Here we report the identification of a direct kinase of eIF2\u03b1, microtubule affinity-regulating kinase 2 (MARK2), which phosphorylates eIF2\u03b1 in response to proteotoxic stress....\"",
"[3:46:03 PM] \ud83d\udfe2 Quote Verified [Library ID: 29222490]: \"C9RAN translation initiates through a cap- and eIF4A-dependent mechanism that utilizes a CUG start codon. C9RAN and CGG RAN are both selectively enhanced by integrated stress response (ISR) activation....\"",
"[3:46:03 PM] \ud83d\udfe2 Quote Verified [Library ID: 42087256]: \"Genetic inhibition of the ISR or knockdown of ATX2, the Drosophila orthologue of ATXN2, rescues motor deficits in these models....\"",
"[3:46:03 PM] \ud83d\udfe2 Quote Verified [Library ID: 30617154]: \"Targeting phosphorylated-PERK and the phosphorylated-eif2\u03b1 complex reduces DPR levels revealing a potential therapeutic strategy to attenuate DPR-dependent disease pathogenesis in NRE-linked diseases....\"",
"[3:46:03 PM] \ud83d\udd34 Quote Mismatch [ID: 29302060]: \"These findings support a feedforward loop with initial repeat-mediated toxicity enhancing RAN translation and subsequent production of additional poly-dipeptides through ISR, thereby promoting progressive disease....\"",
"[3:46:03 PM] \ud83d\udfe2 Quote Verified [Library ID: 38301895]: \"Together, eIF5 stimulates the CUG initiation of poly-GA RAN translation in cellular and Drosophila disease models of C9orf72 FTLD/ALS....\"",
"[3:46:03 PM] \ud83d\udfe2 Quote Verified [Library ID: 35171477]: \"Using reporter systems to quantitatively measure RAN translation provides a platform to examine candidate genes/pathways and screen for modifiers of this non-canonical pathway....\"",
"[3:46:03 PM] \ud83d\udfe2 Quote Verified [Library ID: 41430470]: \"Amyotrophic lateral sclerosis (ALS)-associated mutations in the RNA-binding protein fused in sarcoma (FUS), which suppress local translation, disrupt the compartment-specific RNA signatures, including components of the translation machinery....\"",
"[3:46:03 PM] \ud83d\udd34 Quote Mismatch [ID: 28886181]: \"The induction of SSAT and elevated polyamine catabolism in cells increases the phosphorylation of eukaryotic translation initiation factor 2\u03b1 (eIF2\u03b1) and enhances the expression of binding immunoglobulin protein BiP/GRP78)....\"",
"[3:46:03 PM] \ud83d\udfe2 Quote Verified [Library ID: 26828926]: \"Spermine treatment limited infarct size, attenuated cardiac troponin I and creatinine kinase-MB release, improved cardiac function, and decreased ERS and apoptosis related protein expression....\"",
"[3:46:03 PM] \ud83d\udfe2 Quote Verified [Library ID: 22932872]: \"Finally, rapamycin as well as spermidine, carbamazepine, and tamoxifen could also rescue the motor dysfunction of 7-mo-old FTLD-U mice....\"",
"[3:46:03 PM] \ud83d\udfe2 Quote Verified [Library ID: 42573824]: \"Genetic testing identified a novel heterozygous missense variant, c.355 C > T (p.Arg119Cys), in the SQSTM1 gene....\"",
"[3:46:03 PM] \ud83d\udfe2 Quote Verified [Library ID: 42572514]: \"The presence of neck weakness in MND was predictive of time to respiratory function decline, for respiratory outcomes (forced vital capacity (FVC) <65%, FVC <50% and NIV use) as well as having an effect on time to death....\"",
"[3:46:03 PM] \ud83d\udfe2 Quote Verified [Library ID: 42566069]: \"Using US (\u2265 2 regions with fasciculations/high-grade) as an ancillary criterion, 53.7% were diagnosed at first visit; median time to diagnosis was 5 months (range 3-8) in those otherwise missed....\"",
"[3:46:03 PM] \ud83d\udfe2 Quote Verified [Library ID: 42565151]: \"Findings showed increasing use of radiomics, circulating tumor DNA, rhythm monitoring, vascular imaging, inflammatory markers, biologics, cell therapy, psychological intervention, and lipid-lowering therapy....\"",
"[3:46:03 PM] \ud83d\udfe2 Quote Verified [Library ID: 42563536]: \"The studies collectively demonstrate the potential benefits and diverse range of assistive devices available to support upper extremity function....\"",
"[3:46:03 PM] \ud83d\udfe2 Quote Verified [Library ID: 42558984]: \"Stem cell therapy for ALS appears to be safe, with preliminary evidence suggesting potential therapeutic benefit in slowing disease progression in selected patients....\"",
"[3:46:03 PM] \ud83d\udfe2 Quote Verified [Library ID: 42553390]: \"We demonstrate that fractal dimensions are sufficient to obtain accurate models for glioblastoma diagnosis, despite still underperforming when compared to the traditional feature extraction method....\"",
"[3:46:03 PM] \ud83d\udd34 Quote Mismatch [ID: 42550987]: \"The MND Together project aims to address these systemic gaps by (1) developing a national picture of care coordination in England and Wales....\"",
"[3:46:03 PM] \ud83d\udfe2 Quote Verified [Library ID: 42548788]: \"Tofersen seems to be associated with slower functional decline and reduced NfL levels....\"",
"[3:46:03 PM] \ud83d\udd34 Quote Mismatch [ID: 42545188]: \"This study delivers a provisional, ECAS-based classification for the neuropsychological sub-phenotyping of non-demented ALS patients....\"",
"[3:46:03 PM] \ud83d\udd34 Quote Mismatch [ID: 42544949]: \"Eight of nine cats exhibited clinical improvement following hIVIg administration, achieving ambulatory status (walking >5 steps) within a median of 4 days....\"",
"[3:46:03 PM] \ud83d\udd34 Quote Mismatch [ID: 42543164]: \"In this review, we focus on the differential role(s) of nuclear and cytoplasmic intron retaining transcripts (nIRTs and cIRTs, respectively)....\"",
"[3:46:03 PM] \ud83d\udd34 Quote Mismatch [ID: 42542522]: \"In this chapter, we summarize the available computational tools for predicting ubiquitylation in silico and the common approaches used to enrich ubiquitylation in samples....\"",
"[3:46:03 PM] \ud83d\udd34 Quote Mismatch [ID: 42538773]: \"Cognitive and behavioral impairments are already detectable at the time of diagnosis in a substantial proportion of patients with PLS, including early PLS....\"",
"[3:46:03 PM] \ud83d\udfe2 Quote Verified [Library ID: 42538750]: \"This first nationwide study of MNDs in Latvia highlights diagnostic delays and possible under-recognition of adult SMA and SBMA....\"",
"[3:46:03 PM] \ud83d\udfe2 Quote Verified [Library ID: 42536230]: \"The frequency of pathogenic or likely pathogenic genetic variants was 15.7% (8/51)....\"",
"[3:46:03 PM] \ud83d\udfe2 Quote Verified [Library ID: 42528798]: \"By focusing on deficits associated with ALS, the MFI may improve the ability to identify individuals at elevated risk of the disease....\"",
"[3:46:03 PM] \ud83d\udfe2 Quote Verified [Library ID: 42521811]: \"The ability to evaluate treatment response on an individual level will help to determine the clinical relevance of VUS as new gene-targeted treatments for ALS become available....\"",
"[3:46:03 PM] \ud83d\udd34 Quote Mismatch [ID: 42509371]: \"Here we identified 92 proteins with concentrations that changed before phenoconversion; characterized the longitudinal trajectory of these proteins....\"",
"[3:46:03 PM] \ud83d\udd34 Quote Mismatch [ID: 42506308]: \"Reconceptualizing gait as a 'sixth vital sign' reframes mobility as a multidimensional biomarker of neural and systemic health....\"",
"[3:46:03 PM] \ud83d\udfe2 Quote Verified [Library ID: 42498838]: \"We identified four plasma proteins significantly associated with FTD, namely RGS7 and ASAP2 (increased risk), as well as TMCC3 and VPS29 (decreased risk)....\"",
"[3:46:03 PM] \ud83d\udd34 Quote Mismatch [ID: 42495713]: \"Findings of this narrative review underscore the need for methodologically rigorous longitudinal human studies on fluoride, aluminum and neurodegenerative disease risk....\"",
"[3:46:03 PM] \ud83d\udd34 Quote Mismatch [ID: 42494493]: \"Our findings suggest that strenuous physical activity may be associated with a significantly younger age of ALS onset, replicated in both the post-mortem and MND Register cohorts....\"",
"[3:46:03 PM] \ud83d\udfe2 Quote Verified [Library ID: 42494173]: \"Our results suggest that TnT and sNfL capture different dimensions of disease status within the D50 framework....\"",
"[3:46:03 PM] \ud83d\udd34 Quote Mismatch [ID: 42481361]: \"There are no recommended medicinal treatments, especially no specific etiological treatment for PPS....\"",
"[3:46:03 PM] \ud83d\udfe2 Quote Verified [Library ID: 42480869]: \"Thus, antibody to ATCV-1 in ALS patients and the susceptibility of human M1 macrophages to ATCV-1 infection with boosted inflammatory cytokine and diminished anti-inflammatory cytokine production suggest that ATCV-1 may contribute to ALS motor neuron disease....\"",
"[3:46:03 PM] \ud83d\udfe2 Quote Verified [Library ID: 42470084]: \"Sexuality in MND is more associated with cognitive and mood factors than with motor disability....\"",
"[3:46:03 PM] \ud83d\udd34 Quote Mismatch [ID: 42465429]: \"Together, these experiments show that Gars \u0394ETAQ/+ mice display robust and selective peripheral nerve pathology that manifests in a general distal-to-proximal fashion....\"",
"[3:46:03 PM] \ud83d\udfe2 Quote Verified [Library ID: 42464213]: \"This case supports classification as a SYNE1-related motor neuron disease-like phenotype with mild distal contractures rather than an isolated arthrogryposis multiplex congenita type 3 (AMC3) phenotype....\"",
"[3:46:03 PM] \ud83d\udd34 Quote Mismatch [ID: 42461445]: \"Higher glutamine/glutamate, arginine, and leucine levels were associated with more severe muscle cramps. TJ-68 treatment increased tryptophan and aconitate levels....\"",
"[3:46:03 PM] \ud83d\udd34 Quote Mismatch [ID: 42461162]: \"This report focusses on nursing interventions adopted in terms of respiratory management, nutritional management, psychological care and exercise....\"",
"[3:46:03 PM] \ud83d\udfe2 Quote Verified [Library ID: 42456346]: \"IVIg therapy was administered without meaningful clinical benefit, suggesting neurodegeneration as the primary phenotypic driver....\"",
"[3:46:03 PM] \ud83d\udfe2 Quote Verified [Library ID: 42454435]: \"This study demonstrates that MD is experienced by healthcare professionals working with MND across Europe....\"",
"[3:46:03 PM] \ud83d\udd34 Quote Mismatch [ID: 42449472]: \"Biallelic mutations in VRK1 are associated with a recognizable form of motor neuron disease characterized by features of dHMN combined with upper motor neuron involvement....\"",
"[3:46:03 PM] \ud83d\udfe2 Quote Verified [Library ID: 42441926]: \"These findings suggest a potential role for pNfL as an adjunctive tool in neuromuscular diagnostic evaluation....\"",
"[3:46:03 PM] \ud83d\udd34 Quote Mismatch [ID: 42441693]: \"Cardiac autonomic dysfunction is increasingly recognized as a significant contributor to disease burden in ALS, manifesting as abnormalities in heart rate variability....\"",
"[3:46:03 PM] \u26a0\ufe0f Validation failed for Run1 Eval1 synthesis (Attempt 1/9999999). Initiating re-evaluation loop...",
"[3:46:03 PM] Scoring & Validation for Run1 Eval1 synthesis (Attempt 2/9999999)...",
"[3:46:21 PM] \u26a0\ufe0f API Error (HTTP 503: {\n \"error\": {\n \"code\": 503,\n \"message\": \"This model is currently experiencing high demand. Sp). Retrying in 21s...",
"[3:47:07 PM] \ud83d\udfe2 Quote Verified [Library ID: 41231952]: \"MARK2-eIF2\u03b1 signaling, activated by misfolded proteins including DPRs and TDP-43, is upregulated in C9-ALS patient tissues....\"",
"[3:47:07 PM] \ud83d\udfe2 Quote Verified [Library ID: 41231952]: \"Loss of MARK2 significantly suppresses RAN translation in reporter cells, patient-derived neurons, and a mouse model and confers neuroprotection under proteotoxic conditions....\"",
"[3:47:07 PM] \ud83d\udfe2 Quote Verified [Library ID: 33705388]: \"Here we report the identification of a direct kinase of eIF2\u03b1, microtubule affinity-regulating kinase 2 (MARK2), which phosphorylates eIF2\u03b1 in response to proteotoxic stress....\"",
"[3:47:07 PM] \ud83d\udfe2 Quote Verified [Library ID: 41430470]: \"Amyotrophic lateral sclerosis (ALS)-associated mutations in the RNA-binding protein fused in sarcoma (FUS), which suppress local translation, disrupt the compartment-specific RNA signatures, including components of the translation machinery....\"",
"[3:47:07 PM] \ud83d\udfe2 Quote Verified [Library ID: 26828926]: \"Spermine treatment limited infarct size, attenuated cardiac troponin I and creatinine kinase-MB release, improved cardiac function, and decreased ERS and apoptosis related protein expression....\"",
"[3:47:07 PM] \ud83d\udfe2 Quote Verified [Library ID: 22932872]: \"Finally, rapamycin as well as spermidine, carbamazepine, and tamoxifen could also rescue the motor dysfunction of 7-mo-old FTLD-U mice....\"",
"[3:47:07 PM] \ud83d\udfe2 Quote Verified [Library ID: 41177462]: \"Treatment with these nanoparticles significantly reduced p53-mediated neuronal ferroptosis and improved synaptic function both in vitro and in vivo....\"",
"[3:47:07 PM] \ud83d\udfe2 Quote Verified [Library ID: 42441693]: \"Cardiac autonomic dysfunction is increasingly recognized as a significant contributor to disease burden in ALS, manifesting as abnormalities in heart rate variability, sympathetic overactivity, and corrected QT prolongation....\"",
"[3:47:07 PM] \ud83d\udfe2 Quote Verified [Library ID: 42461445]: \"TJ-68 treatment increased tryptophan and aconitate levels but reduced serotonin and acetylcarnitine levels....\"",
"[3:47:07 PM] \u2705 All 9 quotes validated verbatim.",
"[3:47:07 PM] \ud83d\udd0d Strict Mode: Running final logic & veridical audit on quadrant...",
"[3:47:09 PM] \u2705 Final logic audit passed.",
"[3:47:09 PM] \u2699\ufe0f Build Run [1] complete. Compiling intermediate reports and updating context...",
"[3:47:09 PM] \ud83e\uddec Commencing Post-Build Strict Reiterative MeSH Verification...",
"[3:47:09 PM] \ud83d\udd0d MeSH Check: Verifying exact phrase matches against NLM database for 3 terms...",
"[3:47:11 PM] \ud83d\udfe1 Round 1 Fail: \"C9orf72 RAN Translation\" unverified. Suggestions: []",
"[3:47:13 PM] \ud83d\udfe1 Round 1 Fail: \"MARK2-eIF2\u03b1 axis\" unverified. Suggestions: []",
"[3:47:15 PM] \ud83d\udfe1 Round 1 Fail: \"Spermidine-modified nanoparticles\" unverified. Suggestions: []",
"[3:47:15 PM] \u26a0\ufe0f MeSH Alignment Loop (Attempt 1/5): Aligning & Re-Verifying 3 terms...",
"[3:47:18 PM] \ud83d\udfe2 Round 3 Pass (Veridical Enforcement): AI suggestion \"C9orf72 Protein\" verified against database.",
"[3:47:20 PM] \ud83d\udfe2 Round 3 Pass (Veridical Enforcement): AI suggestion \"EIF2A\" verified against database.",
"[3:47:20 PM] \ud83d\udfe2 Round 3 Pass (Veridical Enforcement): AI suggestion \"Nanoparticles\" verified against database.",
"[3:47:20 PM] \ud83e\uddec Re-aligned 4 node(s) with verified MeSH tags.",
"[3:47:20 PM] \u2705 MeSH alignment & strict verification complete.",
"[3:47:21 PM] \u2705 Unified Dataset complete. Total unique nodes stored: 57",
"[3:48:07 PM] \ud83e\udde0 Querying Assistant: \"Answer in English only. Begin with a clear Yes ...\"",
"[3:48:10 PM] \ud83d\udd0d Auditing Assistant response (Attempt 1)...",
"[3:48:12 PM] \u2705 Assistant response passed veridical audit."
],
"failedQuotesLog": [],
"allQuoteAttempts": [
{
"quadrant": "Run1_Eval1_synthesis",
"attempt": 1,
"quote": "MARK2-eIF2\u03b1 signaling, activated by misfolded proteins including DPRs and TDP-43, is upregulated in C9-ALS patient tissues.",
"status": "PASS",
"error": "",
"abstract_text": "ID: 41231952\nTitle: MARK2 regulates C9orf72 repeat-associated non-AUG translation.\nAbstract: Protein homeostasis is exquisitely regulated through processes involving protein synthesis essential for cellular health and disease prevention. Repeat-associated non-AUG (RAN) translation at expanded GGGGCC repeats in the C9orf72 gene produces dipeptide repeat (DPR) proteins that are implicated in amyotrophic lateral sclerosis and frontotemporal dementia (C9-ALS/FTD). However, the mechanisms promoting this noncanonical translation remain incompletely understood. Here, we identify microtubule affinity-regulating kinase 2 (MARK2) as a key eIF2\u03b1 kinase that enhances RAN translation under proteotoxic stress. We show that MARK2-eIF2\u03b1 signaling, activated by misfolded proteins including DPRs and TDP-43, is upregulated in C9-ALS patient tissues. Loss of MARK2 significantly suppresses RAN translation in reporter cells, patient-derived neurons, and a mouse model and confers neuroprotection under proteotoxic conditions. These findings position MARK2 as a critical stress-sensing cytosolic regulator that promotes repeat-associated noncanonical translation and associated toxicity."
},
{
"quadrant": "Run1_Eval1_synthesis",
"attempt": 1,
"quote": "Loss of MARK2 significantly suppresses RAN translation in reporter cells, patient-derived neurons, and a mouse model and confers neuroprotection under proteotoxic conditions.",
"status": "PASS",
"error": "",
"abstract_text": "ID: 41231952\nTitle: MARK2 regulates C9orf72 repeat-associated non-AUG translation.\nAbstract: Protein homeostasis is exquisitely regulated through processes involving protein synthesis essential for cellular health and disease prevention. Repeat-associated non-AUG (RAN) translation at expanded GGGGCC repeats in the C9orf72 gene produces dipeptide repeat (DPR) proteins that are implicated in amyotrophic lateral sclerosis and frontotemporal dementia (C9-ALS/FTD). However, the mechanisms promoting this noncanonical translation remain incompletely understood. Here, we identify microtubule affinity-regulating kinase 2 (MARK2) as a key eIF2\u03b1 kinase that enhances RAN translation under proteotoxic stress. We show that MARK2-eIF2\u03b1 signaling, activated by misfolded proteins including DPRs and TDP-43, is upregulated in C9-ALS patient tissues. Loss of MARK2 significantly suppresses RAN translation in reporter cells, patient-derived neurons, and a mouse model and confers neuroprotection under proteotoxic conditions. These findings position MARK2 as a critical stress-sensing cytosolic regulator that promotes repeat-associated noncanonical translation and associated toxicity."
},
{
"quadrant": "Run1_Eval1_synthesis",
"attempt": 1,
"quote": "We engineered spermidine-modified ginseng-derived extracellular vesicles (S-GEVs) nanoparticles, termed S-GEVs@siRNA. These nanoparticles leveraged the targeting capabilities of spermidine for olfactory receptor-trace amine associated receptor (TAAR), enhancing siRNA delivery and therapeutic efficacy.",
"status": "FAIL",
"error": "Strict Misquote Detected! The exact character sequence \"We engineered spermidine-modified g...\" was NOT found in the provided text. Do NOT truncate, paraphrase, or edit quotes.",
"abstract_text": "ID: 41177462\nTitle: Nasal-to-brain siRNA delivery based on trace amine associated receptor for improving cognitive function.\nAbstract: Gene-based therapies for central nervous system (CNS) disorders face substantial challenges in overcoming the blood-brain barrier (BBB) to effectively target brain tissues. The nasal-to-brain delivery route has gained increasing attention as it bypasses the BBB, facilitating faster drug delivery to the lesion site while minimizing systemic side effects. Here, we developed a nasal-to-brain delivery system to administer small interfering RNA (siRNA) for the treatment of radiation-induced brain injury (RBI). RNA sequencing revealed that the p53 signaling pathway was predominantly enriched in the hippocampus, with significant upregulation of Alox12B expression in RBI mice. To improve the delivery of siRNA targeting Alox12B, we engineered spermidine-modified ginseng-derived extracellular vesicles (S-GEVs) nanoparticles, termed S-GEVs@siRNA. These nanoparticles leveraged the targeting capabilities of spermidine for olfactory receptor-trace amine associated receptor (TAAR), enhancing siRNA delivery and therapeutic efficacy. After intranasal administration, the nanoparticles were efficiently internalized by olfactory receptor neurons (ORNs) via the olfactory nerve pathway. The nanoparticles then escaped lysosomes, releasing siRNA into the cytoplasm, leading to gene downregulation and therapeutic benefits. Our results demonstrated that the designed nanoparticles were absorbed by the ORNs labeled with the Olfactory Marker Protein (OMP) and TAAR5 and successfully entered the olfactory bulb and the brain. Treatment with these nanoparticles significantly reduced p53-mediated neuronal ferroptosis and improved synaptic function both in vitro and in vivo. In conclusion, S-GEVs@siRNA nanoparticles rapidly reached the olfactory bulb through TAAR-mediated endocytosis, entered hippocampal neurons, downregulated Alox12B expression, exerted neuroprotective effects, and alleviated RBI-induced cognitive dysfunction. The designed nasal-to-brain delivery system holds great promise for treating various CNS diseases."
},
{
"quadrant": "Run1_Eval1_synthesis",
"attempt": 1,
"quote": "Here we report the identification of a direct kinase of eIF2\u03b1, microtubule affinity-regulating kinase 2 (MARK2), which phosphorylates eIF2\u03b1 in response to proteotoxic stress.",
"status": "PASS",
"error": "",
"abstract_text": "ID: 33705388\nTitle: MARK2 phosphorylates eIF2\u03b1 in response to proteotoxic stress.\nAbstract: The regulation of protein synthesis is essential for maintaining cellular homeostasis, especially during stress responses, and its dysregulation could underlie the development of human diseases. The critical step during translation regulation is the phosphorylation of eukaryotic initiation factor 2 alpha (eIF2\u03b1). Here we report the identification of a direct kinase of eIF2\u03b1, microtubule affinity-regulating kinase 2 (MARK2), which phosphorylates eIF2\u03b1 in response to proteotoxic stress. The activity of MARK2 was confirmed in the cells lacking the 4 previously known eIF2\u03b1 kinases. MARK2 itself was found to be a substrate of protein kinase C delta (PKC\u03b4), which serves as a sensor for protein misfolding stress through a dynamic interaction with heat shock protein 90 (HSP90). Both MARK2 and PKC\u03b4 are activated via phosphorylation in proteotoxicity-associated neurodegenerative mouse models and in human patients with amyotrophic lateral sclerosis (ALS). These results reveal a PKC\u03b4-MARK2-eIF2\u03b1 cascade that may play a critical role in cellular proteotoxic stress responses and human diseases."
},
{
"quadrant": "Run1_Eval1_synthesis",
"attempt": 1,
"quote": "C9RAN translation initiates through a cap- and eIF4A-dependent mechanism that utilizes a CUG start codon. C9RAN and CGG RAN are both selectively enhanced by integrated stress response (ISR) activation.",
"status": "PASS",
"error": "",
"abstract_text": "ID: 29222490\nTitle: RAN translation at C9orf72-associated repeat expansions is selectively enhanced by the integrated stress response.\nAbstract: Repeat-associated non-AUG (RAN) translation allows for unconventional initiation at disease-causing repeat expansions. As RAN translation contributes to pathogenesis in multiple neurodegenerative disorders, determining its mechanistic underpinnings may inform therapeutic development. Here we analyze RAN translation at G4C2 repeat expansions that cause C9orf72-associated amyotrophic lateral sclerosis and frontotemporal dementia (C9RAN) and at CGG repeats that cause fragile X-associated tremor/ataxia syndrome. We find that C9RAN translation initiates through a cap- and eIF4A-dependent mechanism that utilizes a CUG start codon. C9RAN and CGG RAN are both selectively enhanced by integrated stress response (ISR) activation. ISR-enhanced RAN translation requires an eIF2\u03b1 phosphorylation-dependent alteration in start codon fidelity. In parallel, both CGG and G4C2 repeats trigger phosphorylated-eIF2\u03b1-dependent stress granule formation and global translational suppression. These findings support a model whereby repeat expansions elicit cellular stress conditions that favor RAN translation of toxic proteins, creating a potential feed-forward loop that contributes to neurodegeneration."
},
{
"quadrant": "Run1_Eval1_synthesis",
"attempt": 1,
"quote": "Genetic inhibition of the ISR or knockdown of ATX2, the Drosophila orthologue of ATXN2, rescues motor deficits in these models.",
"status": "PASS",
"error": "",
"abstract_text": "ID: 42087256\nTitle: Targeting the integrated stress response or Ataxin-2 alleviates neurodegeneration in PolyGR models of C9orf72 associated frontotemporal dementia and amyotrophic lateral sclerosis.\nAbstract: Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are fatal, early-onset neurodegenerative diseases. The most common genetic cause of FTD and ALS is a G4C2 hexanucleotide repeat expansion in the C9orf72 gene. This mutation leads to the production of toxic dipeptide repeat proteins (DPRs), via repeat-associated non-AUG (RAN) translation. These DPRs disrupt stress granule (SG) dynamics, with SG regulators such as Ataxin-2 (ATXN2) implicated in disease risk. The integrated stress response (ISR), a key driver of SG formation via eIF2\u03b1 phosphorylation, has been linked to C9orf72 expansions, but the role of individual DPRs in ISR activation remains unclear. Here, using Drosophila models expressing physiologically relevant repeat length DPRs, we identify poly(GR) as a novel activator of the ISR, inducing early and sustained eIF2\u03b1 phosphorylation and SG accumulation prior to motor decline. Genetic inhibition of the ISR or knockdown of ATX2, the Drosophila orthologue of ATXN2, rescues motor deficits in these models. ATXN2 knockdown also reduces poly(GR) toxicity in mouse primary neurons. These findings position poly(GR) as a key driver of ISR activation and highlight ATXN2 and the ISR as promising therapeutic targets in C9orf72-associated FTD/ALS."
},
{
"quadrant": "Run1_Eval1_synthesis",
"attempt": 1,
"quote": "Targeting phosphorylated-PERK and the phosphorylated-eif2\u03b1 complex reduces DPR levels revealing a potential therapeutic strategy to attenuate DPR-dependent disease pathogenesis in NRE-linked diseases.",
"status": "PASS",
"error": "",
"abstract_text": "ID: 30617154\nTitle: Repeat-associated non-AUG translation in C9orf72-ALS/FTD is driven by neuronal excitation and stress.\nAbstract: Nucleotide repeat expansions (NREs) are prevalent mutations in a multitude of neurodegenerative diseases. Repeat-associated non-AUG (RAN) translation of these repeat regions produces mono or dipeptides that contribute to the pathogenesis of these diseases. However, the mechanisms and drivers of RAN translation are not well understood. Here we analyzed whether different cellular stressors promote RAN translation of dipeptide repeats (DPRs) associated with the G4C2 hexanucleotide expansions in C9orf72, the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). We found that activating glutamate receptors or optogenetically increasing neuronal activity by repetitive trains of depolarization induced DPR formation in primary cortical neurons and patient derived spinal motor neurons. Increases in the integrated stress response (ISR) were concomitant with increased RAN translation of DPRs, both in neurons and different cell lines. Targeting phosphorylated-PERK and the phosphorylated-eif2\u03b1 complex reduces DPR levels revealing a potential therapeutic strategy to attenuate DPR-dependent disease pathogenesis in NRE-linked diseases."
},
{
"quadrant": "Run1_Eval1_synthesis",
"attempt": 1,
"quote": "These findings support a feedforward loop with initial repeat-mediated toxicity enhancing RAN translation and subsequent production of additional poly-dipeptides through ISR, thereby promoting progressive disease.",
"status": "FAIL",
"error": "Strict Misquote Detected! The exact character sequence \"These findings support a feedforwar...\" was NOT found in the provided text. Do NOT truncate, paraphrase, or edit quotes.",
"abstract_text": "ID: 29302060\nTitle: C9ORF72 GGGGCC repeat-associated non-AUG translation is upregulated by stress through eIF2\u03b1 phosphorylation.\nAbstract: Hexanucleotide repeat expansion in C9ORF72 is the most frequent cause of both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Here we demonstrate that the repeat-associated non-AUG (RAN) translation of (GGGGCC) n -containing RNAs into poly-dipeptides can initiate in vivo without a 5'-cap. The primary RNA substrate for RAN translation of C9ORF72 sense repeats is shown to be the spliced first intron, following its excision from the initial pre-mRNA and transport to the cytoplasm. Cap-independent RAN translation is shown to be upregulated by various stress stimuli through phosphorylation of the \u03b1 subunit of eukaryotic initiation factor-2 (eIF2\u03b1), the core event of an integrated stress response (ISR). Compounds inhibiting phospho-eIF2\u03b1-signaling pathways are shown to suppress RAN translation. Since the poly-dipeptides can themselves induce stress, these findings support a feedforward loop with initial repeat-mediated toxicity enhancing RAN translation and subsequent production of additional poly-dipeptides through ISR, thereby promoting progressive disease."
},
{
"quadrant": "Run1_Eval1_synthesis",
"attempt": 1,
"quote": "Together, eIF5 stimulates the CUG initiation of poly-GA RAN translation in cellular and Drosophila disease models of C9orf72 FTLD/ALS.",
"status": "PASS",
"error": "",
"abstract_text": "ID: 38301895\nTitle: eIF5 stimulates the CUG initiation of RAN translation of poly-GA dipeptide repeat protein (DPR) in C9orf72 FTLD/ALS.\nAbstract: Tandem GGGGCC repeat expansion in C9orf72 is a genetic cause of frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). Transcribed repeats are translated into dipeptide repeat proteins via repeat-associated non-AUG (RAN) translation. However, the regulatory mechanism of RAN translation remains unclear. Here, we reveal a GTPase-activating protein, eukaryotic initiation factor 5 (eIF5), which allosterically facilitates the conversion of eIF2-bound GTP into GDP upon start codon recognition, as a novel modifier of C9orf72 RAN translation. Compared to global translation, eIF5, but not its inactive mutants, preferentially stimulates poly-GA RAN translation. RAN translation is increased during integrated stress response, but the stimulatory effect of eIF5 on poly-GA RAN translation was additive to the increase of RAN translation during integrated stress response, with no further increase in phosphorylated eIF2\u03b1. Moreover, an alteration of the CUG near cognate codon to CCG or AUG in the poly-GA reading frame abolished the stimulatory effects, indicating that eIF5 primarily acts through the CUG-dependent initiation. Lastly, in a Drosophila model of C9orf72 FTLD/ALS that expresses GGGGCC repeats in the eye, knockdown of endogenous eIF5 by two independent RNAi strains significantly reduced poly-GA expressions, confirming in\u00a0vivo effect of eIF5 on poly-GA RAN translation. Together, eIF5 stimulates the CUG initiation of poly-GA RAN translation in cellular and Drosophila disease models of C9orf72 FTLD/ALS."
},
{
"quadrant": "Run1_Eval1_synthesis",
"attempt": 1,
"quote": "Using reporter systems to quantitatively measure RAN translation provides a platform to examine candidate genes/pathways and screen for modifiers of this non-canonical pathway.",
"status": "PASS",
"error": "",
"abstract_text": "ID: 35171477\nTitle: Measuring Repeat-Associated Non-AUG (RAN) Translation.\nAbstract: Expansions of short nucleotide repeats account for more than 50 neurological or neuromuscular diseases. Many repeat expansion-containing RNAs can generate toxic repeat proteins through repeat-associated non-AUG (RAN) translation in all the reading frames. Understanding how RAN translation occurs and what cellular factors regulate this process will help decipher the basic mechanism of the molecular process and disease pathogenesis. Using reporter systems to quantitatively measure RAN translation provides a platform to examine candidate genes/pathways and screen for modifiers of this non-canonical pathway. In this chapter, we describe the dual-luciferase reporter system to measure RAN translation using C9ORF72 GGGGCCexp as an example, which is the most common genetic\u00a0cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD)."
},
{
"quadrant": "Run1_Eval1_synthesis",
"attempt": 1,
"quote": "Amyotrophic lateral sclerosis (ALS)-associated mutations in the RNA-binding protein fused in sarcoma (FUS), which suppress local translation, disrupt the compartment-specific RNA signatures, including components of the translation machinery.",
"status": "PASS",
"error": "",
"abstract_text": "ID: 41430470\nTitle: Axonal Eif5a hypusination controls local translation and mitigates defects in FUS-ALS.\nAbstract: Local protein synthesis is vital for neuronal function, but its dysregulation in neurodegenerative diseases remains poorly defined. Here we applied spatial transcriptomics to adult mouse motor nerve axons and cell bodies to enable subcellular mapping. Among transcripts found in mature axons, the most enriched biological process is protein translation, and localization of translation machinery was confirmed using multiplexed single-molecule spatial transcriptomics combined with immunofluorescence. Amyotrophic lateral sclerosis (ALS)-associated mutations in the RNA-binding protein fused in sarcoma (FUS), which suppress local translation, disrupt the compartment-specific RNA signatures, including components of the translation machinery. In particular, eukaryotic initiation factor 5a (Eif5a), a translation factor involved in elongation and termination, is found to be locally impaired in mutant FUS axons with reduced levels of its active hypusinated form. Axon-specific treatment with polyamine spermidine restores Eif5a hypusination and ameliorates mutant FUS-dependent neuronal defects, including suppression of local protein synthesis. Finally, in vivo spermidine treatment reduces ALS-related toxicity in mutant FUS and TDP-43 Drosophila models, which may have implications for therapy development."
},
{
"quadrant": "Run1_Eval1_synthesis",
"attempt": 1,
"quote": "The induction of SSAT and elevated polyamine catabolism in cells increases the phosphorylation of eukaryotic translation initiation factor 2\u03b1 (eIF2\u03b1) and enhances the expression of binding immunoglobulin protein BiP/GRP78).",
"status": "FAIL",
"error": "Strict Misquote Detected! The exact character sequence \"The induction of SSAT and elevated ...\" was NOT found in the provided text. Do NOT truncate, paraphrase, or edit quotes.",
"abstract_text": "ID: 28886181\nTitle: Activation of endoplasmic reticulum stress response by enhanced polyamine catabolism is important in the mediation of cisplatin-induced acute kidney injury.\nAbstract: Cisplatin-induced nephrotoxicity limits its use in many cancer patients. The expression of enzymes involved in polyamine catabolism, spermidine/spermine N1-acetyltransferase (SSAT) and spermine oxidase (SMOX) increase in the kidneys of mice treated with cisplatin. We hypothesized that enhanced polyamine catabolism contributes to tissue damage in cisplatin acute kidney injury (AKI). Using gene knockout and chemical inhibitors, the role of polyamine catabolism in cisplatin AKI was examined. Deficiency of SSAT, SMOX or neutralization of the toxic products of polyamine degradation, H2O2 and aminopropanal, significantly diminished the severity of cisplatin AKI. In vitro studies demonstrated that the induction of SSAT and elevated polyamine catabolism in cells increases the phosphorylation of eukaryotic translation initiation factor 2\u03b1 (eIF2\u03b1) and enhances the expression of binding immunoglobulin protein BiP/GRP78) and CCAAT-enhancer-binding protein homologous protein (CHOP/GADD153). The increased expression of these endoplasmic reticulum stress response (ERSR) markers was accompanied by the activation of caspase-3. These results suggest that enhanced polyamine degradation in cisplatin AKI may lead to tubular damage through the induction of ERSR and the consequent onset of apoptosis. In support of the above, we show that the ablation of the SSAT or SMOX gene, as well as the neutralization of polyamine catabolism products modulate the onset of ERSR (e.g. lower BiP and CHOP) and apoptosis (e.g. reduced activated caspase-3). These studies indicate that enhanced polyamine catabolism and its toxic products are important mediators of ERSR and critical to the pathogenesis of cisplatin AKI."
},
{
"quadrant": "Run1_Eval1_synthesis",
"attempt": 1,
"quote": "Spermine treatment limited infarct size, attenuated cardiac troponin I and creatinine kinase-MB release, improved cardiac function, and decreased ERS and apoptosis related protein expression.",
"status": "PASS",
"error": "",
"abstract_text": "ID: 26828926\nTitle: Spermine inhibits Endoplasmic Reticulum Stress-induced Apoptosis: a New Strategy to Prevent Cardiomyocyte Apoptosis.\nAbstract: Endoplasmic reticulum stress (ERS) plays an important role in the progression of acute myocardial infarction (AMI), in part by mediating apoptosis. Polyamines, including putrescine, spermidine, and spermine, are polycations with anti-oxidative, anti-aging, and cell growth-promoting activities. This study aimed to determine the mechanisms by which spermine protects against ERS-induced apoptosis in rats following AMI. AMI was established by ligation of the left anterior descending coronary artery (LAD) in rats, and exogenous spermine was administered by intraperitoneal injection (2.5 mg/ml daily for 7 days pre-AMI). Spermine treatment limited infarct size, attenuated cardiac troponin I and creatinine kinase-MB release, improved cardiac function, and decreased ERS and apoptosis related protein expression. Isolated cardiomyocytes subjected to hypoxia showed significant increase in reactive oxygen species (ROS) and the expression of apoptosis and ERS related proteins; these effects occurred through PERK and eIF2\u03b1 phosphorylation. The addition of spermine attenuated cardiomyocyte apoptosis, suppressed the production of ROS, and inhibited ERS related pathways. Spermine was an effective pre-treatment strategy to attenuate cardiac ERS injury in rats, and the cardioprotective mechanism occurring through inhibition of ROS production and down regulation of the PERK-eIF2\u03b1 pathway. These findings provide a novel target for the prevention of apoptosis in the setting of AMI."
},
{
"quadrant": "Run1_Eval1_synthesis",
"attempt": 1,
"quote": "Finally, rapamycin as well as spermidine, carbamazepine, and tamoxifen could also rescue the motor dysfunction of 7-mo-old FTLD-U mice.",
"status": "PASS",
"error": "",
"abstract_text": "ID: 22932872\nTitle: Autophagy activators rescue and alleviate pathogenesis of a mouse model with proteinopathies of the TAR DNA-binding protein 43.\nAbstract: TDP-43 is a multifunctional DNA/RNA-binding protein that has been identified as the major component of the cytoplasmic ubiquitin (+) inclusions (UBIs) in diseased cells of frontotemporal lobar dementia (FTLD-U) and amyotrophic lateral sclerosis (ALS). Unfortunately, effective drugs for these neurodegenerative diseases are yet to be developed. We have tested the therapeutic potential of rapamycin, an inhibitor of the mammalian target of rapamycin (mTOR) and three other autophagy activators (spermidine, carbamazepine, and tamoxifen) in a FTLD-U mouse model with TDP-43 proteinopathies. Rapamycin treatment has been reported to be beneficial in some animal models of neurodegenerative diseases but not others. Furthermore, the effects of rapamycin treatment in FTLD-U have not been investigated. We show that rapamycin treatment effectively rescues the learning/memory impairment of these mice at 3 mo of age, and it significantly slows down the age-dependent loss of their motor function. These behavioral improvements upon rapamycin treatment are accompanied by a decreased level of caspase-3 and a reduction of neuron loss in the forebrain of FTLD-U mice. Furthermore, the number of cells with cytosolic TDP-43 (+) inclusions and the amounts of full-length TDP-43 as well as its cleavage products (35 kDa and 25 kDa) in the urea-soluble fraction of the cellular extract are significantly decreased upon rapamycin treatment. These changes in TDP-43 metabolism are accompanied by rapamycin-induced decreases in mTOR-regulated phospho-p70 S6 kinase (P-p70) and the p62 protein, as well as increases in the autophagic marker LC3. Finally, rapamycin as well as spermidine, carbamazepine, and tamoxifen could also rescue the motor dysfunction of 7-mo-old FTLD-U mice. These data suggest that autophagy activation is a potentially useful route for the therapy of neurodegenerative diseases with TDP-43 proteinopathies."
},
{
"quadrant": "Run1_Eval1_synthesis",
"attempt": 1,
"quote": "Genetic testing identified a novel heterozygous missense variant, c.355 C > T (p.Arg119Cys), in the SQSTM1 gene.",
"status": "PASS",
"error": "",
"abstract_text": "ID: 42573824\nTitle: Clinical significance of SQSTM1 variants in ALS: report of p.Arg119Cys and literature review.\nAbstract: We analyzed the clinical features of a patient with amyotrophic lateral sclerosis (ALS) carrying a novel variant in the sequestosome 1 (SQSTM1) gene and explored the genotype-phenotype association of SQSTM1 gene variants in combination with previous literature. Clinical data and genetic testing results of an ALS patient treated at our hospital were collected. Whole-exome sequencing was used to screen for ALS-related genes, and candidate variants were validated by Sanger sequencing and family analysis. A systematic search was conducted in the PubMed database using the keywords (\"amyotrophic lateral sclerosis\") OR (\"motor neuron disease\") AND (\"SQSTM1\") to summarize the clinical and genetic characteristics of previously reported ALS patients with SQSTM1 variants. The patient was a 49-year-old male with progressive weakness in both lower limbs for one year and weakness in the left upper limb for the past three months. Electromyography showed extensive neurogenic damage. Genetic testing identified a novel heterozygous missense variant, c.355 C\u2009>\u2009T (p.Arg119Cys), in the SQSTM1 gene. Family verification revealed that his phenotypically normal mother carried the same variant. The literature search identified 58 cases of ALS associated with SQSTM1 variants. Missense variants were the most common type. We identified a novel SQSTM1 variant, c.355 C\u2009>\u2009T (p.Arg119Cys), in a ALS patient. Although this finding expands the variant spectrum, its pathogenicity remains uncertain and requires further functional validation and pedigree confirmation. Our literature review further shows that SQSTM1-associated ALS predominantly presents with limb onset, with a subset of patients exhibiting frontotemporal dementia or Paget's disease."
},
{
"quadrant": "Run1_Eval1_synthesis",
"attempt": 1,
"quote": "The presence of neck weakness in MND was predictive of time to respiratory function decline, for respiratory outcomes (forced vital capacity (FVC) <65%, FVC <50% and NIV use) as well as having an effect on time to death.",
"status": "PASS",
"error": "",
"abstract_text": "ID: 42572514\nTitle: Relationship between neck weakness in motor neurone disease and respiratory function: a retrospective study.\nAbstract: The primary aim was to explore the relationship between neck weakness in people with motor neurone disease (MND) and their respiratory function. The secondary aim was to identify whether neck weakness can be a prognostic factor. This was a retrospective observational cohort study. Data was collected from patient records on MND characteristics, neck weakness, respiratory function, and noninvasive ventilation (NIV) use. Multivariate modeling explored the effect of neck weakness on respiratory variables. MND-related neck weakness was evident in 41% of 324 participants. Fifty-four percent used NIV and 17% became dependent on NIV during disease progression. The presence of neck weakness in MND was predictive of time to respiratory function decline, for respiratory outcomes (forced vital capacity (FVC) <65%, FVC\u2009<50% and NIV use) as well as having an effect on time to death. Median time from neck weakness onset to death was 8\u2009months (IQR 10\u2009months; range 0 to 60\u2009months) with bulbar onset the quickest, median of 7\u2009months (IQR 7\u2009months, range 0 to 43\u2009months). The presence of neck weakness is associated with a more rapid respiratory function decline in MND. In addition, neck weakness can be considered a prognostic factor in MND survival. People with motor neurone disease (MND) experience weakness in different parts of their body including muscles that are responsible for breathing. As the disease worsens, it is expected that their breathing worsens, resulting in death. To help prolong the person\u2019s life, timely equipment that makes breathing easier is important. It is thought that there may be a relationship between weakness spreading to the neck muscles and the person\u2019s ability to breathe and whether it could help predict how the disease will progress. To explore this further, we reviewed the medical records of 324 people with MND. We found that about 4 in 10 people had neck weakness from their MND and over half were using breathing support. We also found that those with neck weakness tended to lose their breathing function more quickly and needed breathing support sooner. People with neck weakness were also found to have a shorter survival time, with an average of 8 months once their neck weakness began, however this varied depending on the type of MND the person had."
},
{
"quadrant": "Run1_Eval1_synthesis",
"attempt": 1,
"quote": "Using US (\u2265 2 regions with fasciculations/high-grade) as an ancillary criterion, 53.7% were diagnosed at first visit; median time to diagnosis was 5 months (range 3-8) in those otherwise missed.",
"status": "PASS",
"error": "",
"abstract_text": "ID: 42566069\nTitle: Value of ultrasound-detected fasciculations for the early diagnosis of motor neuron disease in patients with single-segment, pure lower motor neuron involvement.\nAbstract: To evaluate the early diagnostic value of muscle ultrasound (US)-detected fasciculations in motor neuron disease (MND) patients presenting with single\u2011region, pure lower motor neuron (LMN) involvement. Prospective cohort study enrolling 60 patients with clinical LMN signs confined to one body region. All underwent standardized needle EMG and muscle US at baseline. Final diagnosis determined by follow-up. Agreement between EMG and US, and net diagnostic gain of US were analyzed. 54 MND patients (median disease duration 9 months) were analyzed. US detection rates: bulbar 38.9%-46.3%; high-grade cervical fasciculations 20.4%-37.0%. EMG-US agreement was poor to fair (kappa 0.106-0.360). US provided additional LMN evidence in EMG-negative regions in 27.8% (bulbar), 22.2% (cervical) and 9.3% (lumbosacral). Using US (\u2265\u20092 regions with fasciculations/high-grade) as an ancillary criterion, 53.7% were diagnosed at first visit; median time to diagnosis was 5 months (range 3-8) in those otherwise missed. Muscle ultrasound is a sensitive, non-invasive complement to EMG, significantly improving early diagnosis in single-region pure LMN presentations. However, specificity estimates remain preliminary due to the limited number of non-MND controls."
},
{
"quadrant": "Run1_Eval1_synthesis",
"attempt": 1,
"quote": "Findings showed increasing use of radiomics, circulating tumor DNA, rhythm monitoring, vascular imaging, inflammatory markers, biologics, cell therapy, psychological intervention, and lipid-lowering therapy.",
"status": "PASS",
"error": "",
"abstract_text": "ID: 42565151\nTitle: A Systematic Literature Review of Emerging Advances in Neurological Disorders: Diagnostic Innovations, Therapeutic Strategies, and Future Directions.\nAbstract: Neurological disorders remain a major clinical burden because they affect cognition, movement, vascular function, behavior, psychological health, and long-term independence. Recent advances in imaging, biomarkers, artificial intelligence, regenerative therapy, immunotherapy, and targeted pharmacology have expanded diagnostic and therapeutic possibilities, yet the evidence remains dispersed across different neurological conditions and study designs. This review aimed to synthesize emerging advances in neurological disorders, focusing on diagnostic innovations, therapeutic strategies, and future clinical directions. A systematic literature review approach was applied using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)-based screening principles. Eleven studies were included, covering ischemic stroke, glioblastoma, Alzheimer's disease, multiple sclerosis, Parkinson's disease, motor neuron disease, episodic migraine, transient ischemic attack, and postoperative delirium. Data were extracted on study design, condition, intervention or diagnostic method, comparator, outcomes, and key findings. Risk of bias was assessed using the Risk of Bias 2 (RoB 2) tool for randomized trials, the Risk of Bias in Non-randomized Studies of Interventions (ROBINS-I) for nonrandomized, uncontrolled, post hoc, feasibility, and biomarker-monitoring studies, and the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) for diagnostic and radiomics studies. Findings showed increasing use of radiomics, circulating tumor DNA, rhythm monitoring, vascular imaging, inflammatory markers, biologics, cell therapy, psychological intervention, and lipid-lowering therapy. Several studies reported promising clinical or biomarker signals, while others clarified treatment limitations in specific disease subtypes. Overall, the findings suggest an emerging shift toward precision-oriented neurology, but larger controlled trials, prospective biomarker validation, standardized outcomes, and longer follow-up are required before routine implementation."
},
{
"quadrant": "Run1_Eval1_synthesis",
"attempt": 1,
"quote": "The studies collectively demonstrate the potential benefits and diverse range of assistive devices available to support upper extremity function.",
"status": "PASS",
"error": "",
"abstract_text": "ID: 42563536\nTitle: Enabling Functional Independence: A Scoping Review of Upper Extremity Assistive Devices for Adults With Progressive Neuromuscular Diseases.\nAbstract: Assistive technology offers an important means of compensating for lost upper extremity function in adults with progressive neuromuscular diseases (NMD), enabling participation in daily activities, supporting independence, and promoting quality of life. However, the range of available technologies and the evidence supporting their use have not been comprehensively summarized. The aim of this scoping review was to identify and characterize upper extremity assistive technologies tested in adults with NMD and to summarize the current evidence regarding their functional applications and clinical outcomes. Electronic searches for published and unpublished literature were conducted using MEDLINE, Embase.com, Web of Science, Cochrane Central, and IEEE Xplore. The search strategy incorporated controlled vocabulary and free-text synonyms for the concepts of upper extremity, rehabilitation, selected progressive neurodegenerative diseases, and assistive equipment. Following title/abstract and full-text screening, studies evaluating assistive devices tested on adults with NMD during functional task performance were included. After screening 2289 articles, 27 studies met the inclusion criteria. The studies collectively demonstrate the potential benefits and diverse range of assistive devices available to support upper extremity function. These devices ranged from low-tech solutions, such as static mobile arm supports and fabricated splints, to high-tech devices, including dynamic mobile arm supports, robotic systems, exoskeletons, and brain-computer interface systems. However, most studies were feasibility or case studies that primarily demonstrated proof of concept, with limited evidence regarding long-term effectiveness, functional outcomes, or quality of life. The findings illustrate the rapidly evolving landscape of upper extremity assistive devices for adults with NMD and their potential to improve functional performance, while highlighting the need for prospective studies that assess meaningful improvements in function, participation, and quality of life. As advances in disease-modifying therapies extend survival and preserve function for individuals with NMD, interdisciplinary collaboration among engineers, clinicians, therapists, individuals with NMD, caregivers, and regulators will be essential to develop, evaluate, and implement assistive technologies that meet users' evolving needs."
},
{
"quadrant": "Run1_Eval1_synthesis",
"attempt": 1,
"quote": "Stem cell therapy for ALS appears to be safe, with preliminary evidence suggesting potential therapeutic benefit in slowing disease progression in selected patients.",
"status": "PASS",
"error": "",
"abstract_text": "ID: 42558984\nTitle: The Effectiveness Based on Optimal Dose and Administration Route, and Safety Profiles of Stem Cells and Derived Products in the Treatment of Patients With Amyotrophic Lateral Sclerosis: A Systematic Review and Meta-Analysis.\nAbstract: This systematic review and meta-analysis aimed to evaluate the effectiveness of stem cell therapies for patients with amyotrophic lateral sclerosis (ALS) based on optimal dosing and administration routes, as well as the safety profiles of stem cells and their derived products. The review followed PRISMA guidelines and involved a comprehensive literature search up to October 2025, receiving ethical approval from Tabriz University of Medical Sciences and registration in PROSPERO. It utilized international databases, including PubMed/MEDLINE, Embase, Cochrane Library, Scopus, Web of Science, ProQuest, ClinicalTrials.gov, and Science Direct. The included studies comprised randomized controlled trials (RCTs), quasi-experimental studies, and other interventional designs involving ALS patients treated with stem cell therapies. In total, 31 studies were analyzed, featuring 7 controlled trials with 370 participants and 24 non-controlled pre-post studies with 460 participants. Heterogeneity was evaluated using I 2 statistics, and subgroup analyses were conducted based on treatment duration and dosing. A pooled analysis (treatment group: n\u2009=\u200993; control group: n\u2009=\u200990) demonstrated a significant attenuation in the progression of disease severity, as measured by the ALS Functional Rating Scale (ALSFRS), in stem cell groups versus controls (weighted mean difference [WMD]: 8.89 95% CI: 4.12-13.67; p = 0.0003), which was beneficial for both the \u226510\u2009\u00d7\u2009106 and <10\u2009\u00d7\u2009106 dose sub-groups. However, a meta-analysis of single-arm studies in two control (pre-intervention) and intervention phases (n\u2009=\u200988) demonstrated no significant difference in progression of ALSFRS between study phases by time: month 3 (WMD: -1.27 (-3.01 to 0.47); p = 0.15), month 6 (WMD: -2.69 (-5.62 to 0.25); p = 0.07), month 9 (WMD: -1.55 (-3.49 to 0.39); p = 0.12), and month 12 (WMD: -7.59 (-13.95 to -1.26); p = 0.02). An accelerated decline in forced vital capacity (FVC) was observed during the intervention phase, with statistically significant reductions at month 3 (WMD: -10.91; 95% CI: -16.39 to -5.43; p < 0.0001) and month 6 (WMD: -15.97; 95% CI: -28.60 to -3.33; p = 0.01) compared with the pre-intervention control phase. Nevertheless, sensitivity analyses excluding studies involving high-dose mesenchymal stem cell (MSC) therapies demonstrated that these differences were no longer statistically significant. Moreover, no significant change in progression rate was observed at month 9 (WMD: -8.10 (-18.25 to 2.06); p = 0.12). The route of MSCs administration (intrathecal [IT], intramuscular [IM], and intravenous [IV]) had no effect on the results of ALSFRS and FVC, reinforced by sensitivity analyses. Adverse events were mostly mild, with headaches most frequent in high-dose groups. Stem cell therapy for ALS appears to be safe, with preliminary evidence suggesting potential therapeutic benefit in slowing disease progression in selected patients. Nevertheless, the existing evidence base remains exploratory, and definitive conclusions regarding clinical effectiveness cannot yet be drawn. Future research should prioritize large-scale and multicenter RCTs with standardized cell manufacturing protocols and longer follow-up periods."
},
{
"quadrant": "Run1_Eval1_synthesis",
"attempt": 1,
"quote": "We demonstrate that fractal dimensions are sufficient to obtain accurate models for glioblastoma diagnosis, despite still underperforming when compared to the traditional feature extraction method.",
"status": "PASS",
"error": "",
"abstract_text": "ID: 42553390\nTitle: Fractal and Machine Learning Analyses of MALDI-TOF Mass Spectrometry Data in Glioblastoma.\nAbstract: Data preprocessing is a critical step in the analysis of matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry (MALDI-TOF MS) spectra for machine learning applications, typically involving steps such as spectra trimming, baseline correction, smoothing, transformation, and peak picking or spectral binning. While traditional approaches focus on protein/peptide peaks as features, this study explores a novel method of feature extraction by treating MALDI-TOF spectra as one-dimensional signal array further processed as time-series data. This study investigates the use of computational fractal-based analysis to assess the complexity of MALDI-TOF spectra. Fractal analysis, previously successful in glioblastoma diagnosis using magnetic resonance imaging, was applied here to proteomics data. By treating each MALDI spectrum as a time series and calculating its fractal dimension using various algorithms, machine learning models were trained to differentiate between glioblastoma patients and controls. We demonstrate that fractal dimensions are sufficient to obtain accurate models for glioblastoma diagnosis, despite still underperforming when compared to the traditional feature extraction method. We also show that fractals can be used as support features to increase model performance. This work highlights the potential and limitations of fractal analysis in proteomics, offering a new perspective for disease diagnosis and broadening the available computational tools for data analysis in mass spectrometry."
},
{
"quadrant": "Run1_Eval1_synthesis",
"attempt": 1,
"quote": "The MND Together project aims to address these systemic gaps by (1) developing a national picture of care coordination in England and Wales.",
"status": "FAIL",
"error": "Strict Misquote Detected! The exact character sequence \"The MND Together project aims to ad...\" was NOT found in the provided text. Do NOT truncate, paraphrase, or edit quotes.",
"abstract_text": "ID: 42550987\nTitle: Co-Designing a Care Coordination Intervention for People With Motor Neuron Disease: Protocol for a Mixed Methods Study.\nAbstract: Motor neuron disease (MND), also known as amyotrophic lateral sclerosis (ALS), is a rapidly progressive neurological condition that requires complex multidisciplinary care. Within the United Kingdom, specialist centers provide expert interventions, while day-to-day support often relies on local nonspecialist community health and social care professionals. This is due to the distance between people's homes and specialist centers, as well as the availability of specialist health and social care professionals. This can lead to fragmented communication and emotional, physical, and financial burdens, and it can be time-consuming for people living with MND, their carers, and the health care professionals involved in their care. Despite the recognized need for better care coordination, it remains inadequate in practice, with a current lack of specific evidence-based interventions for achieving this. The MND Together project aims to address these systemic gaps by (1) developing a national picture of care coordination in England and Wales, (2) identifying barriers and facilitators to coordination within specialist and nonspecialist settings, and (3) co-designing a practical care coordination tool with key stakeholders. This protocol outlines the co-design of an intervention underpinned by the Behavior Change Wheel and the Socioecological Model. First, a mixed methods, multicenter study will be conducted to develop a national picture, comprising focus groups with people living with MND, carers, and health and social care professionals. Second, focused ethnography will be conducted in 5 MND specialist centers and their catchment areas, involving 25 people living with MND, to explore the barriers and facilitators to coordination in practice. Finally, a series of co-design workshops will be conducted to identify key priorities for care coordination and to develop a new intervention, the MND Together tool. The project started in September 2025 and will run until October 2027. Workstream 1 started in December 2025, with recruitment beginning at the first site in February 2026. To date, we have recruited 23 people living with MND and carers as well as 16 health and social care professionals across 4 of the 9 sites. Workstream 1 will end in August 2026, with results published at the end of 2026. Workstream 2 began in May 2026 and will run until February 2027, with results published in the summer of 2027. Workstream 3 will begin in March 2027 and conclude with the co-design intervention developed by late 2027. This will then be piloted in practice. By combining several methodologies with meaningful patient and public involvement and engagement, MND Together seeks to bridge the gap between specialist and community-based services. The MND Together tool aims to improve the quality of care and ensure that expert MND support is accessible as close as possible to every patient's home."
},
{
"quadrant": "Run1_Eval1_synthesis",
"attempt": 1,
"quote": "Tofersen seems to be associated with slower functional decline and reduced NfL levels.",
"status": "PASS",
"error": "",
"abstract_text": "ID: 42548788\nTitle: Tofersen Treatment in SOD1-ALS: Real-World Evidence from a Retrospective Multicenter Study in France (FORSLA Study).\nAbstract: To evaluate the effectiveness of Tofersen in patients with superoxide dismutase 1 gene (SOD1-ALS) patients in France in a real-world setting, using disease progression within patient comparisons and with a historical cohort. Patients with SOD1-ALS were included from across 19 French FILSLAN network centers. Baseline was defined as the treatment initiation date. Main endpoints were the ALSFRS-R progression rate and plasmatic neurofilament light chain (NfL) levels at baseline and 12 months after baseline. In the Tofersen Cohort (N=46), within-group comparisons showed that the mean ALS functional rating scale revised (ALSFRS-R) progression rate slowed from 0.53 \u00b1 0.5 at baseline to 0.22 \u00b1 0.3 point/month at 12 months (P=.006). NfL levels significantly decreased from 89.0 \u00b1 9.0 pg/ml at baseline to 29.2 \u00b1 19.5.5 at 12 months (P=.004). Exploratory comparisons with a propensity score (PS) matched historical cohort (39 matched pairs) using a mixed-effects model, ALSFRS-R progression rate at baseline, 6 months, and 12 months after baseline, showed no statistically significant differences between groups P=.30, whereas longitudinal ALSFRS-R scores differed significantly between groups (time-treatment interaction P=.006). The mean survival of the PS matched population was longer in the Tofersen Cohort (42.6 months) than the Historical Cohort (31.8 months) P=.004. Time-dependent adjusted cox analysis showed that Tofersen was associated with a reduction in mortality risk (adjusted HR=0.34; 95% CI, 0.12-0.91; P=.03). Tofersen seems to be associated with slower functional decline and reduced NfL levels. While limitations of retrospective design and ALSFRS-R sensitivity must be acknowledged, these findings provide real-world evidence suggesting a clinical benefit of Tofersen."
},
{
"quadrant": "Run1_Eval1_synthesis",
"attempt": 1,
"quote": "This study delivers a provisional, ECAS-based classification for the neuropsychological sub-phenotyping of non-demented ALS patients.",
"status": "FAIL",
"error": "Strict Misquote Detected! The exact character sequence \"This study delivers a provisional, ...\" was NOT found in the provided text. Do NOT truncate, paraphrase, or edit quotes.",
"abstract_text": "ID: 42545188\nTitle: Neuropsychological Sub-Phenotypes in Amyotrophic Lateral Sclerosis.\nAbstract: This study aimed at identifying neuropsychological sub-phenotypes in amyotrophic lateral sclerosis (ALS) within the mild cognitive impairment (MCI) and mild behavioral impairment (MBI) frameworks. We used individual task-/item-level data from the cognitive and behavioral sections of the Edinburgh Cognitive and Behavioral ALS Screen (ECAS) from 901 non-demented ALS to derive neuropsychological sub-phenotypes pursuant to classical MCI and MBI frameworks and in accordance with an expanded version of Strong's criteria, which also addressed memory and visuo-spatial measures. The prevalence of MCI and MBI was 39% and 37%, respectively in this retrospective review. The following MCI sub-phenotypes were identified: dysexecutive MCI-single- and multiple-domain (dMCI-sd: 63%; dMCI-md: 24%, respectively); non-dysexecutive MCI-single- and multiple-domain (ndMCI-sd: 12%; ndMCI-md: 1%, respectively). MBI was classified as follows: apathetic MBI-single- and multiple-domain (aMBI-sd: 40%; aMBI-md: 20%, respectively); apathetic-disinihibited/perseverative MBI-multiple domain (ad/pMBI-md: 21%); disinihibited/perseverative MBI-multiple domain (d/pMBI-md: 7%); psychotic MBI-single- and multiple-domain (psyMBI-sd: 2%; psyMBI-md: 3%, respectively); unclassifiable MBI-multiple domain (uMBI-md: 1%). 143 (16%) of patients exhibited mild cognitive and behavioral impairment (MCBI). This study delivers a provisional, ECAS-based classification for the neuropsychological sub-phenotyping of non-demented ALS patients, which, with further validation, might be useful for both research and clinical purposes."
},
{
"quadrant": "Run1_Eval1_synthesis",
"attempt": 1,
"quote": "Eight of nine cats exhibited clinical improvement following hIVIg administration, achieving ambulatory status (walking >5 steps) within a median of 4 days.",
"status": "FAIL",
"error": "Strict Misquote Detected! The exact character sequence \"Eight of nine cats exhibited clinic...\" was NOT found in the provided text. Do NOT truncate, paraphrase, or edit quotes.",
"abstract_text": "ID: 42544949\nTitle: EXPRESS: Evaluation of the clinical course of immune-mediated polyneuropathy in cats following treatment with human intravenous immunoglobulins.\nAbstract: Immune-mediated polyneuropathy (IMPN) manifests with generalized lower motor neuron (LMN) weakness and a remittent or relapsing clinical course. Evidence-based treatment recommendations for severely or chronically affected cats are limited. The objective of this study was to evaluate the clinical course and outcome of cats with IMPN following treatment with human intravenous immunoglobulins (hIVIg). Medical records from two veterinary referral hospitals were reviewed (2018-2025) for cats with IMPN treated with hIVIg. Cats were treated with 1-2 g/kg hIVIg divided over 2-4 days (0.5 g/kg/day).Clinical information, diagnostic findings, treatment details and short- and long-term follow-up were evaluated retrospectively. Follow-up information was obtained from medical records and owner communication. Minimum follow-up duration was 8 months (8-51 months; median 17 months).Clinical course (partial and complete recovery, relapses) was compared between cats with acute/recent onset (4 cats) or chronic presentation (5 cats). Eight of nine cats exhibited clinical improvement following hIVIg administration, achieving ambulatory status (walking >5 steps) within a median of 4 days (2-8 days). One cat failed to respond to hIVIg but improved after subsequent prednisolone therapy. For the overall cohort, the median time to complete recovery was 20 days, while the median time to partial recovery was 14 days. Relapses occurred in four cats, but weakness was less severe, and all cats recovered again. The remaining five cats remained relapse-free. Human IVIg was well tolerated in this small cohort, and rapid clinical improvement was observed in most treated cats. These findings suggest that hIVIg may be considered as a treatment option in selected cats with IMPN, including those with acute and chronic presentations. Larger prospective studies, including comparison with no treatment or corticosteroids, are warranted to further assess its efficacy."
},
{
"quadrant": "Run1_Eval1_synthesis",
"attempt": 1,
"quote": "In this review, we focus on the differential role(s) of nuclear and cytoplasmic intron retaining transcripts (nIRTs and cIRTs, respectively).",
"status": "FAIL",
"error": "Strict Misquote Detected! The exact character sequence \"In this review, we focus on the dif...\" was NOT found in the provided text. Do NOT truncate, paraphrase, or edit quotes.",
"abstract_text": "ID: 42543164\nTitle: Intron retention in health and amyotrophic lateral sclerosis.\nAbstract: Intron retention (IR) is the molecular phenomenon by which introns, historically thought to represent non-coding 'junk', remain unspliced within pre-mRNA transcripts, resulting in their incorporation into the mature mRNA molecule. While the role of IR is well established in species of plant, fungi, insects and viruses, it remains relatively understudied in mammalian biology. It was previously assumed that IR only played a limited role in downregulating a transcript's translation potential through downstream initiation of nuclear detention or nonsense mediated decay (NMD). However, recent studies highlight IR's significantly more complex and dynamic contribution to cellular physiology and disease. In particular, a role for IR is emerging in both health and neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), a rapidly progressive and invariably fatal disease that renders patients paralysed and unable to eat, speak or breathe. Significant technological advances now permit a comprehensive interrogation of previously unrecognized aspects of RNA metabolism in clinically relevant human cell types. In this review, we focus on the differential role(s) of nuclear and cytoplasmic intron retaining transcripts (nIRTs and cIRTs, respectively), as well as how IRTs may influence subcellular localization of ribonucleoprotein (RNP) complexes, loss of function of bound RNA binding proteins (RBPs) and liquid-liquid phase separation (LLPS) in physiology and disease. Additionally, we discuss the potential of IRTs as independent regulatory elements beyond their protein-coding functions and highlight how artificial intelligence is poised to accelerate discoveries in this area. In the context of IR's increasing appreciation, we also highlight its potential as a therapeutic target and explore current and future challenges in this burgeoning field."
},
{
"quadrant": "Run1_Eval1_synthesis",
"attempt": 1,
"quote": "In this chapter, we summarize the available computational tools for predicting ubiquitylation in silico and the common approaches used to enrich ubiquitylation in samples.",
"status": "FAIL",
"error": "Strict Misquote Detected! The exact character sequence \"In this chapter, we summarize the a...\" was NOT found in the provided text. Do NOT truncate, paraphrase, or edit quotes.",
"abstract_text": "ID: 42542522\nTitle: Computational Pipelines for Protein Ubiquitylation Analysis and Prediction.\nAbstract: Ubiquitylation is a crucial posttranslational modification that regulates cellular homeostasis and has been linked to a range of diseases. Identification and analysis of ubiquitylated proteins and ubiquitylation sites have historically been successfully performed by mass spectrometry from in vitro and in vivo samples. However, to address some of the challenges and improve the efficiency of ubiquitylation analysis by mass spectrometry, computational tools have been developed and are becoming increasingly popular. In this chapter, we summarize the available computational tools for predicting ubiquitylation in silico and the common approaches used to enrich ubiquitylation in samples for mass spectrometry and computational analysis. We subsequently provide simple steps for molecular biologists to follow for predicting ubiquitylation sites on proteins in silico, and we provide a computational approach to identify average ubiquitin branch sites across samples from ubiquitin-enriched mass spectrometry data."
},
{
"quadrant": "Run1_Eval1_synthesis",
"attempt": 1,
"quote": "Cognitive and behavioral impairments are already detectable at the time of diagnosis in a substantial proportion of patients with PLS, including early PLS.",
"status": "FAIL",
"error": "Strict Misquote Detected! The exact character sequence \"Cognitive and behavioral impairment...\" was NOT found in the provided text. Do NOT truncate, paraphrase, or edit quotes.",
"abstract_text": "ID: 42538773\nTitle: Early Cognitive and Behavioral Changes in Primary Lateral Sclerosis: A Population-Based Study.\nAbstract: Primary lateral sclerosis (PLS) is a rare upper motor neuron neurodegenerative disorder whose cognitive profile, particularly at early stages, remains incompletely defined. We aimed to characterize cognitive and behavioral features of PLS at diagnosis and compare them with predominant upper motor neuron amyotrophic lateral sclerosis (PUMN-ALS) and healthy controls (HCs). Patients diagnosed with PLS between 2007 and 2021 were identified from the population-based Piemonte and Valle d'Aosta ALS Register. Diagnoses were established according to consensus criteria, including early, probable, and definite PLS. All patients underwent comprehensive neuropsychological and behavioral assessment within 3\u2009months of their first ALS center visit. Cognitive-behavioral status was classified using ALS-frontotemporal dementia (FTD) consensus criteria. Thirty-two PLS patients were included (mean disease duration, 25\u2009months). Cognitive and/or behavioral impairment was identified in 29.3% of patients, most commonly affecting executive function, memory, and social cognition, including 21.1% early PLS. Compared with HCs, PLS patients showed poorer performance across several cognitive domains and higher anxiety and depression scores. Compared with matched PUMN-ALS patients, PLS patients demonstrated slightly worse executive performance, while the overall frequency of cognitive-behavioral impairment was similar. Behavioral profiles differed qualitatively, with apathy more frequent in PUMN-ALS. No PLS patient met criteria for frontotemporal dementia. Cognitive and behavioral impairments are already detectable at the time of diagnosis in a substantial proportion of patients with PLS, including early PLS, supporting the view of PLS as a multidimensional neurodegenerative disorder with early extramotor involvement."
},
{
"quadrant": "Run1_Eval1_synthesis",
"attempt": 1,
"quote": "This first nationwide study of MNDs in Latvia highlights diagnostic delays and possible under-recognition of adult SMA and SBMA.",
"status": "PASS",
"error": "",
"abstract_text": "ID: 42538750\nTitle: Nationwide Epidemiology of Motor Neuron Diseases in Latvia (2020-2024): Incidence, Prevalence, and Clinical Characteristics.\nAbstract: Motor neuron diseases (MNDs), including amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), and spinal and bulbar muscular atrophy (SBMA), are rare, progressive neurodegenerative conditions. Although well-studied in Western Europe, no nationwide epidemiological data have been published from Latvia. This study aimed to assess the incidence, prevalence, and clinical characteristics of MNDs in the Latvian population. A retrospective, hospital-based analysis was performed using records from Pauls Stradi\u0146\u0161 Clinical University Hospital, Riga East University Hospital, and the Children's Clinical University Hospital between January 2020 and December 2024. Patients were identified through relevant ICD-10 codes. Incidence and prevalence rates were calculated per 100,000 population and age-standardized to the 2013 European Standard Population. A total of 181 prevalent MND cases were identified: 131 with ALS or related phenotypes, 10 with adult-onset SMA, 33 with pediatric SMA, and 7 with SBMA. The age-standardized incidence of ALS was 1.22 per 100,000 person-years, and the prevalence was 4.69 per 100,000. Limb weakness or paresis was the most common initial symptom (48.1%). The mean diagnostic delay was 13.4\u2009months for ALS, 43.8\u2009months for PLS, 206.8\u2009months for SBMA and 17.3\u2009months for pediatric SMA. The prevalence of pediatric SMA was 9.91 per 100,000, with type II being the most frequent subtype. All SMA and SBMA cases were genetically confirmed. This first nationwide study of MNDs in Latvia highlights diagnostic delays and possible under-recognition of adult SMA and SBMA. Genetic testing, a national registry, and equitable therapy access should be prioritized."
},
{
"quadrant": "Run1_Eval1_synthesis",
"attempt": 1,
"quote": "The frequency of pathogenic or likely pathogenic genetic variants was 15.7% (8/51).",
"status": "PASS",
"error": "",
"abstract_text": "ID: 42536230\nTitle: Genetic variants among patients with motor neuron disease in Lithuania - a retrospective single-center study.\nAbstract: Motor neuron disease (MND) comprises several clinical phenotypes, with amyotrophic lateral sclerosis (ALS) being the most common. Despite the identification of over 40 ALS-associated genes, the pathogenesis remains complex and polygenic. This study evaluated the clinical phenotypes and prevalence of genetic causes in MND patients in Lithuania. We conducted a retrospective single-center study at a tertiary care clinic on patients with MND. Clinical and molecular genetic data were analyzed. The study included 53 patients with a mean age at symptom onset of 55 years. Most patients (43/53; 77.4%) were diagnosed with ALS, and the most common onset was spinal (39/53; 73.6%). The frequency of pathogenic or likely pathogenic genetic variants was 15.7% (8/51). C9orf72 hexanucleotide repeat expansion was detected in 5.9% (3/51) of patients. Next-generation sequencing was performed in 49 patients, of whom 5 (10.2%) had pathogenic or likely pathogenic variants, including pathogenic variants in the SOD1 and NEK1 genes and likely pathogenic variants in the FUS. The most common finding was C9orf72 hexanucleotide repeat expansion, followed by variants in SOD1 and FUS genes. The genetic spectrum was broadly similar to internationally recognized MND-associated genes, though formal comparisons were not performed due to the absence of a control group. These results emphasize the importance of systematic genetic testing in clinical practice and contribute to the limited data on the genetic spectrum of MND in the Baltic region."
},
{
"quadrant": "Run1_Eval1_synthesis",
"attempt": 1,
"quote": "By focusing on deficits associated with ALS, the MFI may improve the ability to identify individuals at elevated risk of the disease.",
"status": "PASS",
"error": "",
"abstract_text": "ID: 42528798\nTitle: A modified frailty index to identify high-risk groups for amyotrophic lateral sclerosis.\nAbstract: Amyotrophic lateral sclerosis (ALS) is a motor neuron disease characterized by progressive muscle weakness and poor prognosis, which requires early detection to optimize therapeutic outcomes. This study aims to develop a risk stratification tools for ALS and to assist in identifying high-risk groups. A prospective cohort study was conducted using the UK Biobank (500,033 participants), which were split into training sets and validation sets. We calculated the frailty index (FI) and modified frailty index (MFI) for the participants and estimated their association with ALS. Finally, two risk stratification tools were constructed and the time-dependent ROC curve was utilized to evaluate the discriminatory performance of each model. Among the 49 deficits in FI, we identified five deficits that were significantly associated with ALS, including falls, whole-body pain, long-standing illness, disability or infirmity, self-rated health and tiredness or lethargy in last 2\u202fweeks, which together constructed the MFI. Both the FI and MFI were associated with a higher risk of ALS (HRFI\u202f=\u202f4.58, 95% CI\u202f=\u202f1.31-16.07, HRMFI\u202f=\u202f4.59, 95% CI\u202f=\u202f2.79-7.53). Finally, a combination of MFI, gender, age and BMI demonstrated the best discriminative ability. Specifically, on the validation set, it achieved a C-index of 0.696. By focusing on deficits associated with ALS, the MFI may improve the ability to identify individuals at elevated risk of the disease. It could therefore serve as a valuable screening tool for risk stratification in the general population."
},
{
"quadrant": "Run1_Eval1_synthesis",
"attempt": 1,
"quote": "The ability to evaluate treatment response on an individual level will help to determine the clinical relevance of VUS as new gene-targeted treatments for ALS become available.",
"status": "PASS",
"error": "",
"abstract_text": "ID: 42521811\nTitle: Tofersen treatment in respiratory onset amyotrophic lateral sclerosis and a variant of uncertain significance in SOD1; a case report.\nAbstract: The antisense oligonucleotide tofersen is available for treating amyotrophic lateral sclerosis (ALS) caused by pathogenic SOD1 variants. However, it is unknown whether Variants of Uncertain Significance (VUS) are a viable treatment target. We assessed clinical and biomarker trajectories prior to and after initiation of tofersen in a patient with respiratory onset ALS and a novel c.234_236del p.(Glu79del) VUS in SOD1. After six months of treatment, cerebrospinal fluid (CSF) SOD1 protein decreased by 47%, CSF NfL by 55% and serum NfL by 50%, with trajectories comparable to known pathogenic variants. Functional decline on the ALSFRS-R slowed from 1.52 points per month pre-treatment to 0.52 points per month post-treatment, muscle strength remained stable, and EQ-VAS quality of life scores remained between 60 and 70. The ability to evaluate treatment response on an individual level will help to determine the clinical relevance of VUS as new gene-targeted treatments for ALS become available."
},
{
"quadrant": "Run1_Eval1_synthesis",
"attempt": 1,
"quote": "Here we identified 92 proteins with concentrations that changed before phenoconversion; characterized the longitudinal trajectory of these proteins.",
"status": "FAIL",
"error": "Strict Misquote Detected! The exact character sequence \"Here we identified 92 proteins with...\" was NOT found in the provided text. Do NOT truncate, paraphrase, or edit quotes.",
"abstract_text": "ID: 42509371\nTitle: Longitudinal plasma proteomics predict phenoconversion to clinically manifest ALS.\nAbstract: The study of pre-symptomatic amyotrophic lateral sclerosis (ALS) and the design of disease prevention trials are greatly hampered by our inability to predict which unaffected carriers of ALS-associated pathogenic variants will phenoconvert to clinically manifest disease and when. In this longitudinal Olink Explore, high-throughput, proteomic study, 516 serially collected plasma samples from 33 phenoconverters, 35 patients with ALS, 10 pre-symptomatic pathogenic variant carriers and 59 controls were included. Here we identified 92 proteins with concentrations that changed before phenoconversion; characterized the longitudinal trajectory of these proteins and identified a core panel of 19 proteins which, collectively, predicted phenoconversion over the 0.5-year to 5-year time horizons (crossvalidated areas under the curve 0.80-0.89) and yielded estimates of time to phenoconversion with a mean absolute error of 1.6\u2009years. These findings were partially replicated in UK Biobank data, confirming pre-symptomatic increases in several proteins (for example, NEFL, EDA2R and CA3) and that a multi-protein panel outperformed NEFL alone in estimating time to phenoconversion. This work sheds light on the biology of pre-symptomatic ALS. Moreover, our identification of a panel of new susceptibility/risk biomarkers based on empirical longitudinal data furthers the ultimate goal of ALS prevention."
},
{
"quadrant": "Run1_Eval1_synthesis",
"attempt": 1,
"quote": "Reconceptualizing gait as a 'sixth vital sign' reframes mobility as a multidimensional biomarker of neural and systemic health.",
"status": "FAIL",
"error": "Strict Misquote Detected! The exact character sequence \"Reconceptualizing gait as a 'sixth ...\" was NOT found in the provided text. Do NOT truncate, paraphrase, or edit quotes.",
"abstract_text": "ID: 42506308\nTitle: Walking as a Window to the Brain: Redefining Gait in Neurology.\nAbstract: Walking is not merely locomotion but a window into the nervous system, integrating cortical, subcortical, cerebellar, spinal, and peripheral networks into a unified motor behavior. Across neurological diseases-including Parkinson's disease, atypical parkinsonism, cerebellar ataxias, stroke, multiple sclerosis, neuropathies, neuromuscular disorders, and functional gait syndromes-gait disturbances are among the most disabling clinical features, contributing to falls, loss of independence, institutionalization, and premature mortality. Traditional bedside observation remains indispensable, but it lacks the sensitivity and reproducibility needed to capture subtle, episodic, or prodromal abnormalities. Over the past decade, advances in wearable sensors, marker-based and markerless motion capture, pressure-sensitive walkways, force plates, artificial intelligence, and machine learning have positioned digital mobility outcomes as promising, ecologically valid biomarkers of neurological function. These measures can support differential diagnosis, provide prognostic information on falls and survival, and serve as sensitive endpoints in therapeutic trials. They may also detect early abnormalities, such as increased stride-to-stride variability or prolonged double-support time, before overt clinical deterioration becomes evident. Clinical applications are increasingly evident across disorders, including distinguishing Parkinson's disease from atypical parkinsonism, quantifying treatment response in normal-pressure hydrocephalus, tracking progression in ataxia and multiple sclerosis, predicting functional decline in motor neuron disease, and guiding rehabilitation after stroke. Integration with neuroimaging, electrophysiology, and molecular biomarkers is beginning to reveal the circuits underlying variability, instability, and freezing, positioning gait as a systems-level marker of neural integrity. Nevertheless, methodological heterogeneity, limited disease-specific validation, insufficient longitudinal data, and lack of consensus on clinically meaningful parameters continue to constrain translation. Cognitive, affective, and environmental influences also remain insufficiently represented in digital frameworks, while equity, accessibility, algorithmic bias, and privacy require careful ethical governance. Reconceptualizing gait as a \"sixth vital sign\" reframes mobility as a multidimensional biomarker of neural and systemic health. With harmonized protocols, robust validation, multimodal integration, and appropriate ethical frameworks, gait analysis could become a cornerstone of precision neurology."
},
{
"quadrant": "Run1_Eval1_synthesis",
"attempt": 1,
"quote": "We identified four plasma proteins significantly associated with FTD, namely RGS7 and ASAP2 (increased risk), as well as TMCC3 and VPS29 (decreased risk).",
"status": "PASS",
"error": "",
"abstract_text": "ID: 42498838\nTitle: Proteome-wide Mendelian randomization identifies causal plasma proteins in frontotemporal dementia.\nAbstract: Frontotemporal dementia (FTD) is a genetically and clinically heterogeneous neurodegenerative disorder with no disease-modifying treatments. Plasma proteomic signatures offer a promising avenue for uncovering disease mechanisms and developing targeted interventions. We conducted protein-wide Mendelian randomization meta-analysis to explore causal relationships between plasma proteins and FTD and four subtypes, utilizing comprehensive datasets of protein quantitative trait loci. We identified four plasma proteins significantly associated with FTD, namely RGS7 and ASAP2 (increased risk), as well as TMCC3 and VPS29 (decreased risk). Subtype-specific analyses revealed distinct protein signatures, including S100A13 and TREM1 in behavioral variant FTD, ING4 and TEX29 in FTD overlapping with motor neuron disease, SPINT2 in progressive non-fluent aphasia, and UGDH in semantic dementia. This study implicates specific plasma proteins in FTD pathogenesis, with subtype-dependent effects. The identified proteins represent potential biomarkers for stratification and therapeutic targets."
},
{
"quadrant": "Run1_Eval1_synthesis",
"attempt": 1,
"quote": "Findings of this narrative review underscore the need for methodologically rigorous longitudinal human studies on fluoride, aluminum and neurodegenerative disease risk.",
"status": "FAIL",
"error": "Strict Misquote Detected! The exact character sequence \"Findings of this narrative review u...\" was NOT found in the provided text. Do NOT truncate, paraphrase, or edit quotes.",
"abstract_text": "ID: 42495713\nTitle: Mechanisms of neurotoxicity of fluoride or aluminum: implications for neurodegenerative disease risk.\nAbstract: Fluoride and aluminum are two naturally abundant elements with widespread industrial uses. Fluoride is also added to community water supplies as a public health intervention for dental cavity prevention. However, findings from animal studies show potential links of fluoride and aluminum exposure with neurodegenerative disease risk, particularly at high exposure levels. This review uniquely examines neurochemical and neurobiological impacts of fluoride and aluminum exposure as well as whether these processes may increase the risk of common and rare neurodegenerative diseases, including dementia, Parkinson's Disease, and motor neuron disease. Fluoride and aluminum can cross the blood-brain barrier and accumulate in neural tissue, where they can interact to produce neurotoxic effects. Chronic exposure to fluoride and aluminum can cause oxidative stress, mitochondrial dysfunction, brain inflammation, and disruption of essential ions. These effects can contribute to impaired nerve signaling, cell damage, and protein aggregation-key factors in neurodegeneration. Co-exposure to aluminum-fluoride complexes may worsen these effects by increasing amyloid buildup and causing nerve cell death, although more research on aluminum-fluoride interactions is needed. Additionally, many animal studies include relatively high fluoride or aluminum exposure levels, and epidemiological human data are scarce, particularly for less common neurodegenerative diseases. Moreover, these studies often rely on ecological or occupational exposure measures rather than individual biomarkers. Findings of this narrative review underscore the need for methodologically rigorous longitudinal human studies on fluoride, aluminum and neurodegenerative disease risk, particularly given the mechanistic basis for these potential associations."
},
{
"quadrant": "Run1_Eval1_synthesis",
"attempt": 1,
"quote": "Our findings suggest that strenuous physical activity may be associated with a significantly younger age of ALS onset, replicated in both the post-mortem and MND Register cohorts.",
"status": "FAIL",
"error": "Strict Misquote Detected! The exact character sequence \"Our findings suggest that strenuous...\" was NOT found in the provided text. Do NOT truncate, paraphrase, or edit quotes.",
"abstract_text": "ID: 42494493\nTitle: Strenuous physical activity is associated with a younger age of amyotrophic lateral sclerosis onset in two independent cohorts.\nAbstract: Amyotrophic lateral sclerosis (ALS) is a complex neurodegenerative disease characterized predominantly by degeneration of both upper and lower motor neurons, thought to occur due to an interplay between genetics and environmental factors. Physical activity has been suggested as a potential risk factor for ALS; however, the exact role of exercise in the onset and progression of the disease is still unclear. We assessed lifetime physical activity in two independent ALS cohorts: post-mortem brain donors from the London Neurodegenerative Diseases Brain Bank (n = 139) and patients from the Motor Neurone Disease (MND) Register of England, Wales and Northern Ireland (n = 166 cases, 196 controls). In both cohorts, highly active individuals developed ALS symptoms at a significantly younger age, 54.2 years (mean, standard deviation = 7.5) in the post-mortem cohort and 58.0 years (median, interquartile range = 15) in the MND Register, compared with 63.9 years (mean, standard deviation = 11.5) and 63.0 years (median, interquartile range = 17.5) in inactive individuals, respectively [one-way analysis of variance (ANOVA), F(2, 136) = 6.10, P = 0.003, \u03b7 2 = 0.08, 95% confidence interval (CI) 0.02-1.00 and Kruskal-Wallis, H(2) = 7.39, P = 0.02, \u03b7 2 = 0.03, 95% CI 0.003-0.12]. Cox regression showed a higher hazard of earlier onset in highly active patients [post-mortem: hazard ratio (HR) 2.84, 95% CI 1.55-5.26, P = 0.0008; MND Register: HR 2.34, 95% CI 1.30-4.23, P = 0.005]. Our findings suggest that strenuous physical activity may be associated with a significantly younger age of ALS onset, replicated in both the post-mortem and MND Register cohorts, but not with an increased risk of developing ALS. Logistic regression analysis confirmed that neither highly active [odds ratio (OR) 1.43, 95% CI 0.69-2.99, P = 0.333] nor being active (OR 1.30, 95% CI 0.72-2.37, P = 0.386) was significantly associated with ALS risk, whereas a history of head injury was (OR 1.72, 95% CI 1.03-2.88, P = 0.038). These results suggest that strenuous exercise may accelerate disease onset in predisposed individuals, while the role of head injury requires further study and the findings may in fact indicate reverse causality."
},
{
"quadrant": "Run1_Eval1_synthesis",
"attempt": 1,
"quote": "Our results suggest that TnT and sNfL capture different dimensions of disease status within the D50 framework.",
"status": "PASS",
"error": "",
"abstract_text": "ID: 42494173\nTitle: Troponin T and Neurofilament Light Chain Levels as Complementary Biomarkers of Disease Accumulation and Aggressiveness in Amyotrophic Lateral Sclerosis.\nAbstract: Amyotrophic lateral sclerosis (ALS) is a clinically heterogeneous neurodegenerative disease requiring reliable biomarkers to improve patient stratification and trial design. While serum neurofilament light chain (sNfL) reflects neuroaxonal stress and disease aggressiveness, troponin T (TnT) may capture complementary aspects of neuromuscular involvement. We assessed the associations of TnT and sNfL with D50-derived measures of disease aggressiveness (D50) and disease accumulation (rD50) in ALS. In this retrospective observation, TnT and sNfL levels from ALS patients in two independent German cohorts were analyzed using the D50 disease progression model; discovery cohort (Essen, n\u2009=\u2009433) and an independent replication cohort (Bonn, n\u2009=\u2009185). TnT levels were strongly associated with rD50-defined disease phases in the discovery cohort (p\u2009<\u20090.001). While not all subgroup-specific associations were replicated, the overall relationship between TnT and disease accumulation was supported in the independent replication cohort. In contrast, sNfL showed no consistent relationship with rD50-derived disease phases. sNfL concentrations demonstrated a significant inverse association with D50, supporting a relationship with disease aggressiveness across both cohorts (p\u2009<\u20090.001). Associations between TnT levels and D50-defined disease aggressiveness were generally weaker and less consistent. TnT was associated with measures of disease accumulation (rD50), whereas sNfL was more closely associated with disease aggressiveness (D50). Our results suggest that TnT and sNfL capture different dimensions of disease status within the D50 framework. Further longitudinal studies are needed to determine whether combining these biomarkers improves disease stratification or prognostic assessment in clinical practice and therapeutic trials."
},
{
"quadrant": "Run1_Eval1_synthesis",
"attempt": 1,
"quote": "There are no recommended medicinal treatments, especially no specific etiological treatment for PPS.",
"status": "FAIL",
"error": "Strict Misquote Detected! The exact character sequence \"There are no recommended medicinal ...\" was NOT found in the provided text. Do NOT truncate, paraphrase, or edit quotes.",
"abstract_text": "ID: 42481361\nTitle: French guidelines for post-polio syndrome and management of effects of aging in people with sequelae of acute anterior poliomyelitis.\nAbstract: People with sequelae of acute anterior poliomyelitis (AAP) may develop secondary complications related to aging, as well as a specific complication of the disease known as post-polio syndrome (PPS). These complications are new neurological and musculoskeletal manifestations that occur after a prolonged period of disease stability. The onset is typically insidious and slow, but can be more rapid following a period of immobilization, surgery, or another intercurrent condition. The initial assessment may involve consulting a neurologist to rule out neurological diagnoses. Electroneuromyographic examination is a valuable tool for evaluating these patients. It is sometimes difficult to differentiate between the effects of aging in a person with sequelae of AAP and PPS, which is a distinct entity with specific diagnostic criteria. The rate at which muscle capacity declines, and its functional impact, can be a distinguishing factor. Subacute or rapid onset can be indicative of PPS. The emergence of new motor deficits in areas that were previously unaffected is also a strong argument for PPS. This neurological deterioration must be distinguished from musculoskeletal disorders associated with aging. Progression is usually slow and gradual, or occurs in stages with periods of stabilization. Physical and rehabilitation care is essential both in the initial assessment and for ongoing follow-up. There are no recommended medicinal treatments, especially no specific etiological treatment for PPS (such as immunoglobulins, corticosteroids, etc.) or effective symptomatic treatment for manifestations like fatigue or muscle weakness (e.g., pyridostigmine). Pain management should be regularly assessed; while drug treatments are not specific, non-pharmacological pain management through physical therapy is crucial. Particular attention should be paid to comorbidities, including excess weight and an increased risk of osteoporosis and fractures. Management should be multidisciplinary, with an annual review recommended. Follow-up will be adjusted based on the patient's preferences and needs, and monitoring will depend on the development of complications."
},
{
"quadrant": "Run1_Eval1_synthesis",
"attempt": 1,
"quote": "Thus, antibody to ATCV-1 in ALS patients and the susceptibility of human M1 macrophages to ATCV-1 infection with boosted inflammatory cytokine and diminished anti-inflammatory cytokine production suggest that ATCV-1 may contribute to ALS motor neuron disease.",
"status": "PASS",
"error": "",
"abstract_text": "ID: 42480869\nTitle: Macrophage responses to and elevated antibody levels against Chlorovirus ATCV-1 in ALS patients.\nAbstract: Acanthocystis turfacea chlorella virus 1 (ATCV-1) is a giant virus that is part of the human oral microvirome. Previously we showed that ATCV-1 infects mouse macrophages, stimulates production of inflammatory cytokines, and accelerates motor neuron disease in the Amyotrophic Lateral Sclerosis (ALS) model SOD1-G93A transgenic mice. This, coupled with significantly elevated levels of serum IgG1 antibody to ATCV-1 in ALS patients compared with healthy controls, suggests involvement of ATCV-1 in ALS. Herein, using serum and CSF from a different ALS cohort we again show elevated antibodies to ATCV-1 in ALS patients compared with healthy controls. To assess ATCV-1 in human macrophages, we challenged immature (IMM), M0, M1, and M2 human THP-1 macrophage cells containing an Interferon Stimulated Response Element (ISRE) promoter-reporter with ATCV-1 or its Major Capsid protein (MCP) glycans. ATCV-1 infected M1 THP-1 to a greater degree than IMM, M0, or M2 THP-1. The initial high ISRE-promoter activity of M1 THP-1 was suppressed by the MCP-Glycans of ATCV-1. M0, but not IMM or M2 THP-1 produced IL-6 in response to ATCV-1 or its MCP-glycan, while high levels of IL-6 from unchallenged M1 THP-1 increased further by ATCV-1 or its MCP glycan. In contrast, ATCV-1 or its MCP-Glycan significantly reduced the high levels of IL-10 produced by M2 THP-1. Thus, antibody to ATCV-1 in ALS patients and the susceptibility of human M1 macrophages to ATCV-1 infection with boosted inflammatory cytokine and diminished anti-inflammatory cytokine production suggest that ATCV-1 may contribute to ALS motor neuron disease."
},
{
"quadrant": "Run1_Eval1_synthesis",
"attempt": 1,
"quote": "Sexuality in MND is more associated with cognitive and mood factors than with motor disability.",
"status": "PASS",
"error": "",
"abstract_text": "ID: 42470084\nTitle: Impact of Sexuality in Patients With Motor Neuron Disease.\nAbstract: Sexuality is a relevant yet understudied aspect in people living with motor neuron disease (MND). This study aimed to assess whether sexuality in people with MND is influenced by motor, cognitive, behavioral, or mood disturbances, and to explore whether being sexually active impacts caregiver burden. We conducted a cross-sectional observational study involving participants with MND and their primary caregivers from three ALS multidisciplinary units in Seville, Spain. Data were collected between October 2018 and July 2021. Functional, cognitive, behavioral, and mood assessments were conducted. Sexuality was evaluated through sex-specific questionnaires. Caregiver burden was assessed using the Zarit Burden Interview. Among 66 participants who completed the sexuality assessment, 42.9% reported sexual activity in the previous month. Of these, 70% had no sexual dysfunction, while 26.7% had moderate and 3.3% severe dysfunction. No correlation was found between sexual activity and motor function. Sexual activity was less frequent in participants with apathy (p\u2009=\u20090.026), depression (p\u2009=\u20090.021), and frontotemporal dementia (p\u2009=\u20090.013). Among sexually active patients, those with cognitive impairment-particularly memory dysfunction-had higher rates of orgasm difficulties (p\u2009=\u20090.019). No other clinical parameters were related to sexuality. Sexuality of participants with MND did not influence caregiver burden. Sexuality in MND is more associated with cognitive and mood factors than with motor disability. Addressing sexuality in clinical practice may contribute to improving quality of life and should be integrated into the multidisciplinary care of MND patients."
},
{
"quadrant": "Run1_Eval1_synthesis",
"attempt": 1,
"quote": "Together, these experiments show that Gars \u0394ETAQ/+ mice display robust and selective peripheral nerve pathology that manifests in a general distal-to-proximal fashion.",
"status": "FAIL",
"error": "Strict Misquote Detected! The exact character sequence \"Together, these experiments show th...\" was NOT found in the provided text. Do NOT truncate, paraphrase, or edit quotes.",
"abstract_text": "ID: 42465429\nTitle: The neuropathy-causing GARS1 \u0394ETAQ mutation drives pathology in subsets of motor and sensory neurons in mice.\nAbstract: Charcot-Marie-Tooth disease type 2D (CMT2D) results from gain-of-function mutations in GARS1, which encodes glycyl-tRNA synthetase (GlyRS), the enzyme responsible for charging transfer RNA (tRNA) with glycine. There are several CMT2D mouse models, but Gars \u0394ETAQ/+ is the only one that bears a patient-sourced mutation. Created using CRISPR/Cas9 to model a 12-nucleotide de novo GARS1 deletion identified in an unusually severe CMT2D patient, Gars \u0394ETAQ/+ mice have previously been shown to display several neuromuscular phenotypes; motor axon loss, denervated neuromuscular junctions (NMJs) and reduced muscle function. Here, we extend these analyses to provide a more comprehensive understanding of both motor and sensory nerve deficits across hind- and fore-limbs. At 3 months, Gars \u0394ETAQ/+ mice possess sex-independent alterations in the levels of neuropathy biomarkers - including decreased NfL and increased periaxin - alongside reduced muscle endurance and strength, and impairments in the sensory modalities of mechanosensation, proprioception and nociception. Underpinning these dysfunctions, we identified site-specific defects comprising altered sensory neuron populations, muscle spindle loss, reduced motor neuron size, disrupted NMJ innervation and maturation, and reduced axonal transport of signalling endosomes in vivo. Together, these experiments show that Gars \u0394ETAQ/+ mice display robust and selective peripheral nerve pathology that manifests in a general distal-to-proximal fashion, priming this CMT2D allele for testing treatments and evaluating mechanisms underlying peripheral nerve vulnerability."
},
{
"quadrant": "Run1_Eval1_synthesis",
"attempt": 1,
"quote": "This case supports classification as a SYNE1-related motor neuron disease-like phenotype with mild distal contractures rather than an isolated arthrogryposis multiplex congenita type 3 (AMC3) phenotype.",
"status": "PASS",
"error": "",
"abstract_text": "ID: 42464213\nTitle: SYNE1-Related motor neuron disease-like phenotype with mild distal contractures and 24-month clinical stability: a case report.\nAbstract: SYNE1 encodes nesprin-1, a nuclear envelope protein involved in cytoskeletal linkage, nuclear positioning, and neuromuscular integrity. Biallelic SYNE1 variants cause a broad spectrum ranging from cerebellar ataxia to arthrogryposis multiplex congenita and motor neuron disease-like phenotypes. Distinguishing these entities can be difficult when subtle distal contractures coexist with neurogenic electrophysiological findings. A 22-year-old woman born to consanguineous parents presented with bilateral intrinsic hand muscle wasting, impaired fine motor performance, and mild gait difficulty. Examination showed distal hand atrophy, mild weakness of the abductor pollicis brevis and first dorsal interosseous muscles, brisk deep tendon reflexes, preserved sensation, and mild distal finger contractures. Sensory nerve conduction studies were normal. Motor studies showed reduced compound muscle action potential amplitude in the right abductor pollicis brevis and borderline-low amplitude on the left. Needle electromyography showed widespread chronic neurogenic motor unit changes affecting the upper and lower extremities, with active denervation most evident in the bilateral abductor pollicis brevis muscles. Genioglossus examination was normal. SMN1 deletion testing and selected familial amyotrophic lateral sclerosis gene testing were negative. Whole exome sequencing identified a homozygous truncating SYNE1 variant, NM_182961.4:c.21009G\u2009>\u2009A; p.(Trp7003Ter). Segregation analysis confirmed heterozygous carrier status in both parents and two unaffected siblings. At 24-month follow-up, weakness, atrophy, contractures, reflex pattern, and functional status remained clinically stable, without bulbar, cerebellar, sensory, or clinically evident respiratory involvement. This case supports classification as a SYNE1-related motor neuron disease-like phenotype with mild distal contractures rather than an isolated arthrogryposis multiplex congenita type 3 (AMC3) phenotype. The case also supports including SYNE1 in genetic testing panels for young patients with unexplained motor neuron disease-like presentations, particularly when consanguinity, normal sensory conduction, and subtle distal contractures coexist."
},
{
"quadrant": "Run1_Eval1_synthesis",
"attempt": 1,
"quote": "Higher glutamine/glutamate, arginine, and leucine levels were associated with more severe muscle cramps. TJ-68 treatment increased tryptophan and aconitate levels.",
"status": "FAIL",
"error": "Strict Misquote Detected! The exact character sequence \"Higher glutamine/glutamate, arginin...\" was NOT found in the provided text. Do NOT truncate, paraphrase, or edit quotes.",
"abstract_text": "ID: 42461445\nTitle: Metabolomic analyses of amyotrophic lateral sclerosis, muscle cramps, and TJ-68 treatment.\nAbstract: Most patients with amyotrophic lateral sclerosis (ALS), a fatal motor neuron disease, experience painful muscle cramps. Our recent pilot trial of the Japanese Kampo medicine TJ-68 suggested its efficacy in improving muscle cramps in patients with ALS. This study analyzed plasma metabolomic changes to identify the underlying mechanisms of muscle cramps in ALS and the effects of TJ-68. Plasma was obtained from 11 participants with ALS in the repeated crossover trial at five time points (baseline, two placebo phases, and two TJ-68 phases). Metabolites were analyzed using mass spectrometry. Linear mixed-effects models were applied to identify metabolite changes associated with muscle cramps, determine the effects of TJ-68 on metabolites, and predict which participants would respond to TJ-68. Higher glutamine/glutamate, arginine, and leucine levels were associated with more severe muscle cramps. TJ-68 treatment increased tryptophan and aconitate levels but reduced serotonin and acetylcarnitine levels. Long-chain acylcarnitine levels were correlated with muscle cramp severity, and their levels tended to decrease with treatment. Uric acid, \u03b2-aminoisobutyric acid, \u03b1-aminoadipic acid, and acetylcholine emerged as predictors of the efficacy of TJ-68. This study identified the metabolite profile of muscle cramps in ALS and the changes in metabolite levels after TJ-68 treatment. Several baseline metabolites were associated with the prediction of the response to muscle cramps following TJ-68 treatment. Uric acid might be particularly useful because of its easy measurement in standard assays. Our study affirms the value of metabolomic technology for future pharmacotherapy and studies in ALS."
},
{
"quadrant": "Run1_Eval1_synthesis",
"attempt": 1,
"quote": "This report focusses on nursing interventions adopted in terms of respiratory management, nutritional management, psychological care and exercise.",
"status": "FAIL",
"error": "Strict Misquote Detected! The exact character sequence \"This report focusses on nursing int...\" was NOT found in the provided text. Do NOT truncate, paraphrase, or edit quotes.",
"abstract_text": "ID: 42461162\nTitle: Nursing a Patient With Amyotrophic Lateral Sclerosis Stage 4B With Epilepsy: A Case Study.\nAbstract: Amyotrophic lateral sclerosis (ALS) is a rare motor neuron disease characterised by progressive muscle weakness, which can eventually lead to death. So far there is no effective cure for it. This case report discusses the nursing of a patient with stage 4B amyotrophic lateral sclerosis complicated with epilepsy and sudden disturbance of consciousness during his stay in an intensive care unit (ICU). After 34\u2009days of treatment and care, the patient regained consciousness with stable vital signs before being transferred out of the ICU. This report focusses on nursing interventions adopted in terms of respiratory management, nutritional management, psychological care and exercise during both the epileptic seizure and the awake period of the patient in the hope of providing a reference for the nursing of patients with amyotrophic lateral sclerosis with epilepsy in intensive care units."
},
{
"quadrant": "Run1_Eval1_synthesis",
"attempt": 1,
"quote": "IVIg therapy was administered without meaningful clinical benefit, suggesting neurodegeneration as the primary phenotypic driver.",
"status": "PASS",
"error": "",
"abstract_text": "ID: 42456346\nTitle: Divergent presentations of anti-GAD autoimmunity: a comparative analysis of two neurodegenerative cases.\nAbstract: We describe two women presenting with cortico-basal syndrome (CBS) and upper motor neuron-motor neuron disease (UMN-MND), respectively, both with high-titre GAD-Abs in serum and CSF. Both patients showed progressive motor impairment with elevated NFL levels. IVIg therapy was administered without meaningful clinical benefit, suggesting neurodegeneration as the primary phenotypic driver."
},
{
"quadrant": "Run1_Eval1_synthesis",
"attempt": 1,
"quote": "This study demonstrates that MD is experienced by healthcare professionals working with MND across Europe.",
"status": "PASS",
"error": "",
"abstract_text": "ID: 42454435\nTitle: Moral distress in healthcare professionals working with motor neuron disease.\nAbstract: To (1) identify clinical situations that may contribute to the experience of moral distress (MD) among professionals working with motor neuron disease (MND), (2) measure the occurrence and intensity of MD, and (3) explore associations with professional quality of life, turnover intention, and associated risk and/or protective factors. A cross-sectional online survey was distributed to healthcare professionals working in MND services across Europe. Data were analyzed using descriptive and inferential statistics. In total, 230 responses from professionals across 17 European countries were analyzed from the international survey. And 67% of respondents indicated that MD resonated with their experience of working with MND. Those who considered leaving or changing their position due to the challenges associated with caring for this patient population were also more likely to report resonance with MD (\u03c72\u00a0=\u00a07.772, p\u00a0=\u00a00.020). The intensity of MD was associated with reduced professional quality of life (burnout [\u03b2\u00a0=\u00a00.106, p\u00a0<\u00a00.05], and secondary traumatic stress [\u03b2\u00a0=\u00a02.881, p\u00a0<\u00a00.001]). A total of 24 clinical scenarios were identified as potential contributors to experiences of MD in this population. Across all professional groups, service-/organization-level factors were the most common and distressing barriers to providing effective MND care. This study demonstrates that MD is experienced by healthcare professionals working with MND across Europe. MD was associated with reduced professional quality of life and increased intentions to leave or change positions, underscoring its potential implications for workforce retention and sustainability. The findings show that system/organization, patient/condition and family-level causes are the primary drivers of MD in this population. Future research should focus on evaluating the effectiveness of interventions designed to address these key drivers and mitigate the impact of MD among healthcare professionals working with MND."
},
{
"quadrant": "Run1_Eval1_synthesis",
"attempt": 1,
"quote": "Biallelic mutations in VRK1 are associated with a recognizable form of motor neuron disease characterized by features of dHMN combined with upper motor neuron involvement.",
"status": "FAIL",
"error": "Strict Misquote Detected! The exact character sequence \"Biallelic mutations in VRK1 are ass...\" was NOT found in the provided text. Do NOT truncate, paraphrase, or edit quotes.",
"abstract_text": "ID: 42449472\nTitle: VRK1-Related Motor Neuropathy With Upper Motor Neuron Signs and Selective Muscle Involvement.\nAbstract: Hereditary motor neuropathies (HMN) represent a heterogeneous group of disorders with wide clinical and genetic variability. Despite advances in molecular diagnostics, approximately 50% of cases remain genetically unresolved, particularly those where distinguishing length-dependent motor neuropathy from motor neuron disorder with disproportionate segmental involvement is a challenge. Variants in the VRK1 gene, originally described in association with pontocerebellar hypoplasia, are now known to produce a broad clinical spectrum, including amyotrophic lateral sclerosis, dHMN, and less frequently, spastic paraplegia. This study's aim was to characterize the clinical presentation, electrophysiological findings, and muscle MRI patterns associated with VRK1-related motor neuron disease in a cohort of nine patients from five unrelated families. Five unrelated families with inherited motor neuropathy were investigated using next-generation sequencing techniques, including targeted gene panels or whole-exome sequencing, with subsequent confirmation by Sanger sequencing. A total of nine affected individuals underwent detailed clinical evaluation, nerve conduction studies (NCS), electromyography (EMG), and whole-body muscle MRI (wbMRI). Nine affected individuals carrying biallelic VRK1 variants were evaluated. In most cases (66%), symptom onset occurred during the first decade of life. All patients presented with gradually progressive distal muscle weakness. Mean Medical Research Council (MRC) scores were 2.8 for ankle dorsiflexion and 1.9 for plantar flexion. Sensory nerve conduction studies were normal in all individuals evaluated (8/9), although mild sensory complaints were reported in four patients. Muscle cramps were observed in two-thirds of the cohort, while fasciculations were uncommon (11%). EMG findings consistently demonstrated a neurogenic pattern with predominant distal involvement, and evidence of both acute and chronic denervation was present in four patients. Whole-body muscle MRI, available for all patients, revealed a consistent pattern of fatty infiltration predominantly affecting posterior muscle compartments, with minimal STIR signal changes. Brain and spinal imaging, performed in all individuals, showed no abnormalities. Biallelic mutations in VRK1 are associated with a recognizable form of motor neuron disease characterized by features of dHMN combined with upper motor neuron involvement, along with a distinctive posterior-predominant pattern on muscle MRI. Identifying this phenotype, a known presentation of VRK1-related disorders, highlights the importance of targeted genetic testing in unresolved cases of hereditary motor neuropathy."
},
{
"quadrant": "Run1_Eval1_synthesis",
"attempt": 1,
"quote": "These findings suggest a potential role for pNfL as an adjunctive tool in neuromuscular diagnostic evaluation.",
"status": "PASS",
"error": "",
"abstract_text": "ID: 42441926\nTitle: Association of Plasma Neurofilament Light Chain With Diagnostic Classification in a Neuromuscular Referral Cohort: A Cross-Sectional Study.\nAbstract: Plasma neurofilament light chain (pNfL) is a blood-based biomarker of axonal injury elevated in several neuromuscular disorders. While previous studies have compared individual diseases with healthy controls, less is known about how pNfL performs across clinically relevant neuromuscular presentations encountered in subspecialty practice, particularly in distinguishing active from inactive neuropathies. We evaluated whether abnormal age-adjusted pNfL concentrations are associated with clinically relevant diagnostic categories and whether pNfL discriminates between active and inactive neuropathies. We conducted a cross-sectional study of patients evaluated by neuromuscular specialists at Mayo Clinic (Rochester, MN) between April 2022 and April 2024, in whom pNfL was ordered as part of routine clinical care. Diagnoses were assigned to prespecified categories by consensus review, including motor neuron disease (MND), active neuropathy, inactive neuropathy, and structural etiologies. Clinically active neuropathy was defined using prespecified, diagnosis-specific operational criteria incorporating treatment status, clinical relapse or progression, time from symptom onset, and pathologic evidence of inflammation. Abnormal pNfL was defined using previously established age-adjusted 97.5th percentile reference limits. Multinomial logistic regression evaluated associations between abnormal pNfL and diagnostic category, adjusting for neuropathy impairment score and symptom duration. Receiver operating characteristic (ROC) analyses assessed discrimination between prespecified groups. Among 306 patients (mean age 62.2 years, 41.5% female), 179 (58.5%) had MND, 28 (9.1%) active neuropathy, 75 (12.1%) inactive neuropathy, and 24 (7.8%) structural etiologies. Median pNfL concentrations differed across diagnostic groups (p < 0.0001) and were highest in MND and active neuropathy. After adjustment, abnormal pNfL was associated with a higher relative likelihood of classification as MND (relative risk ratio [RRR] 18.47, 95% CI 8.77-38.86) and active neuropathy (RRR 7.30, 95% CI 2.50-21.34) compared with inactive neuropathies. No association was observed with structural etiologies. Discrimination between active and inactive neuropathy was moderate (area under the curve [AUC] 0.79, 95% CI 0.70-0.88), and discrimination for MND vs all other diagnoses was good (AUC 0.85, 95% CI 0.80-0.90). In this cross-sectional cohort, abnormal age-adjusted pNfL concentrations were more frequently observed in diagnostic categories characterized by clinically active axonal injury than in inactive neuropathies and structural conditions. These findings suggest a potential role for pNfL as an adjunctive tool in neuromuscular diagnostic evaluation. Interpretation is limited by the cross-sectional design and convenience sampling. This study provides Class II evidence that abnormal age-adjusted pNfL distinguishes active neuropathies from inactive neuropathies with moderate diagnostic accuracy."
},
{
"quadrant": "Run1_Eval1_synthesis",
"attempt": 1,
"quote": "Cardiac autonomic dysfunction is increasingly recognized as a significant contributor to disease burden in ALS, manifesting as abnormalities in heart rate variability.",
"status": "FAIL",
"error": "Strict Misquote Detected! The exact character sequence \"Cardiac autonomic dysfunction is in...\" was NOT found in the provided text. Do NOT truncate, paraphrase, or edit quotes.",
"abstract_text": "ID: 42441693\nTitle: Cardiac Autonomic Dysfunction and Sudden Cardiac Death in Amyotrophic Lateral Sclerosis: Clinical Implications and Considerations for Care.\nAbstract: Amyotrophic lateral sclerosis (ALS) is traditionally viewed as a motor neuron disease that progresses from muscular weakness to respiratory failure and death. Increasing evidence, however, demonstrates clinically meaningful involvement of the autonomic nervous system, particularly in cardiovascular regulation. This narrative review synthesizes current evidence on the mechanisms, clinical implications, and palliative considerations of cardiac autonomic dysfunction in ALS, with particular emphasis on its relationship to sudden cardiac death (SCD). Cardiac autonomic dysfunction is increasingly recognized as a significant contributor to disease burden in ALS, manifesting as abnormalities in heart rate variability, sympathetic overactivity, and corrected QT prolongation. These derangements may contribute to malignant arrhythmias, increasing susceptibility to SCD in combination with respiratory decline. Epidemiologic data suggest that SCD accounts for a meaningful proportion of ALS-related mortality, although it is likely underrecognized due to misclassification and lack of routine cardiac monitoring. Clinical implications include the need for improved risk stratification and earlier detection of autonomic dysfunction using accessible markers, such as electrocardiographic indices, orthostatic vital signs, and ambulatory monitoring. Emerging technologies, including wearable biosensors, may further enhance longitudinal assessment. These considerations also have direct relevance for advanced care planning, as ALS may involve unpredictable and abrupt cardiac death in addition to progressive respiratory decline. Recognizing ALS as a multisystem disorder with significant cardiac involvement supports the integration of structured cardiovascular monitoring into multidisciplinary care models and highlights the need for prospective studies to guide standardized management strategies."
},
{
"quadrant": "Run1_Eval1_synthesis",
"attempt": 2,
"quote": "MARK2-eIF2\u03b1 signaling, activated by misfolded proteins including DPRs and TDP-43, is upregulated in C9-ALS patient tissues.",
"status": "PASS",
"error": "",
"abstract_text": "ID: 41231952\nTitle: MARK2 regulates C9orf72 repeat-associated non-AUG translation.\nAbstract: Protein homeostasis is exquisitely regulated through processes involving protein synthesis essential for cellular health and disease prevention. Repeat-associated non-AUG (RAN) translation at expanded GGGGCC repeats in the C9orf72 gene produces dipeptide repeat (DPR) proteins that are implicated in amyotrophic lateral sclerosis and frontotemporal dementia (C9-ALS/FTD). However, the mechanisms promoting this noncanonical translation remain incompletely understood. Here, we identify microtubule affinity-regulating kinase 2 (MARK2) as a key eIF2\u03b1 kinase that enhances RAN translation under proteotoxic stress. We show that MARK2-eIF2\u03b1 signaling, activated by misfolded proteins including DPRs and TDP-43, is upregulated in C9-ALS patient tissues. Loss of MARK2 significantly suppresses RAN translation in reporter cells, patient-derived neurons, and a mouse model and confers neuroprotection under proteotoxic conditions. These findings position MARK2 as a critical stress-sensing cytosolic regulator that promotes repeat-associated noncanonical translation and associated toxicity."
},
{
"quadrant": "Run1_Eval1_synthesis",
"attempt": 2,
"quote": "Loss of MARK2 significantly suppresses RAN translation in reporter cells, patient-derived neurons, and a mouse model and confers neuroprotection under proteotoxic conditions.",
"status": "PASS",
"error": "",
"abstract_text": "ID: 41231952\nTitle: MARK2 regulates C9orf72 repeat-associated non-AUG translation.\nAbstract: Protein homeostasis is exquisitely regulated through processes involving protein synthesis essential for cellular health and disease prevention. Repeat-associated non-AUG (RAN) translation at expanded GGGGCC repeats in the C9orf72 gene produces dipeptide repeat (DPR) proteins that are implicated in amyotrophic lateral sclerosis and frontotemporal dementia (C9-ALS/FTD). However, the mechanisms promoting this noncanonical translation remain incompletely understood. Here, we identify microtubule affinity-regulating kinase 2 (MARK2) as a key eIF2\u03b1 kinase that enhances RAN translation under proteotoxic stress. We show that MARK2-eIF2\u03b1 signaling, activated by misfolded proteins including DPRs and TDP-43, is upregulated in C9-ALS patient tissues. Loss of MARK2 significantly suppresses RAN translation in reporter cells, patient-derived neurons, and a mouse model and confers neuroprotection under proteotoxic conditions. These findings position MARK2 as a critical stress-sensing cytosolic regulator that promotes repeat-associated noncanonical translation and associated toxicity."
},
{
"quadrant": "Run1_Eval1_synthesis",
"attempt": 2,
"quote": "Here we report the identification of a direct kinase of eIF2\u03b1, microtubule affinity-regulating kinase 2 (MARK2), which phosphorylates eIF2\u03b1 in response to proteotoxic stress.",
"status": "PASS",
"error": "",
"abstract_text": "ID: 33705388\nTitle: MARK2 phosphorylates eIF2\u03b1 in response to proteotoxic stress.\nAbstract: The regulation of protein synthesis is essential for maintaining cellular homeostasis, especially during stress responses, and its dysregulation could underlie the development of human diseases. The critical step during translation regulation is the phosphorylation of eukaryotic initiation factor 2 alpha (eIF2\u03b1). Here we report the identification of a direct kinase of eIF2\u03b1, microtubule affinity-regulating kinase 2 (MARK2), which phosphorylates eIF2\u03b1 in response to proteotoxic stress. The activity of MARK2 was confirmed in the cells lacking the 4 previously known eIF2\u03b1 kinases. MARK2 itself was found to be a substrate of protein kinase C delta (PKC\u03b4), which serves as a sensor for protein misfolding stress through a dynamic interaction with heat shock protein 90 (HSP90). Both MARK2 and PKC\u03b4 are activated via phosphorylation in proteotoxicity-associated neurodegenerative mouse models and in human patients with amyotrophic lateral sclerosis (ALS). These results reveal a PKC\u03b4-MARK2-eIF2\u03b1 cascade that may play a critical role in cellular proteotoxic stress responses and human diseases."
},
{
"quadrant": "Run1_Eval1_synthesis",
"attempt": 2,
"quote": "Amyotrophic lateral sclerosis (ALS)-associated mutations in the RNA-binding protein fused in sarcoma (FUS), which suppress local translation, disrupt the compartment-specific RNA signatures, including components of the translation machinery.",
"status": "PASS",
"error": "",
"abstract_text": "ID: 41430470\nTitle: Axonal Eif5a hypusination controls local translation and mitigates defects in FUS-ALS.\nAbstract: Local protein synthesis is vital for neuronal function, but its dysregulation in neurodegenerative diseases remains poorly defined. Here we applied spatial transcriptomics to adult mouse motor nerve axons and cell bodies to enable subcellular mapping. Among transcripts found in mature axons, the most enriched biological process is protein translation, and localization of translation machinery was confirmed using multiplexed single-molecule spatial transcriptomics combined with immunofluorescence. Amyotrophic lateral sclerosis (ALS)-associated mutations in the RNA-binding protein fused in sarcoma (FUS), which suppress local translation, disrupt the compartment-specific RNA signatures, including components of the translation machinery. In particular, eukaryotic initiation factor 5a (Eif5a), a translation factor involved in elongation and termination, is found to be locally impaired in mutant FUS axons with reduced levels of its active hypusinated form. Axon-specific treatment with polyamine spermidine restores Eif5a hypusination and ameliorates mutant FUS-dependent neuronal defects, including suppression of local protein synthesis. Finally, in vivo spermidine treatment reduces ALS-related toxicity in mutant FUS and TDP-43 Drosophila models, which may have implications for therapy development."
},
{
"quadrant": "Run1_Eval1_synthesis",
"attempt": 2,
"quote": "Spermine treatment limited infarct size, attenuated cardiac troponin I and creatinine kinase-MB release, improved cardiac function, and decreased ERS and apoptosis related protein expression.",
"status": "PASS",
"error": "",
"abstract_text": "ID: 26828926\nTitle: Spermine inhibits Endoplasmic Reticulum Stress-induced Apoptosis: a New Strategy to Prevent Cardiomyocyte Apoptosis.\nAbstract: Endoplasmic reticulum stress (ERS) plays an important role in the progression of acute myocardial infarction (AMI), in part by mediating apoptosis. Polyamines, including putrescine, spermidine, and spermine, are polycations with anti-oxidative, anti-aging, and cell growth-promoting activities. This study aimed to determine the mechanisms by which spermine protects against ERS-induced apoptosis in rats following AMI. AMI was established by ligation of the left anterior descending coronary artery (LAD) in rats, and exogenous spermine was administered by intraperitoneal injection (2.5 mg/ml daily for 7 days pre-AMI). Spermine treatment limited infarct size, attenuated cardiac troponin I and creatinine kinase-MB release, improved cardiac function, and decreased ERS and apoptosis related protein expression. Isolated cardiomyocytes subjected to hypoxia showed significant increase in reactive oxygen species (ROS) and the expression of apoptosis and ERS related proteins; these effects occurred through PERK and eIF2\u03b1 phosphorylation. The addition of spermine attenuated cardiomyocyte apoptosis, suppressed the production of ROS, and inhibited ERS related pathways. Spermine was an effective pre-treatment strategy to attenuate cardiac ERS injury in rats, and the cardioprotective mechanism occurring through inhibition of ROS production and down regulation of the PERK-eIF2\u03b1 pathway. These findings provide a novel target for the prevention of apoptosis in the setting of AMI."
},
{
"quadrant": "Run1_Eval1_synthesis",
"attempt": 2,
"quote": "Finally, rapamycin as well as spermidine, carbamazepine, and tamoxifen could also rescue the motor dysfunction of 7-mo-old FTLD-U mice.",
"status": "PASS",
"error": "",
"abstract_text": "ID: 22932872\nTitle: Autophagy activators rescue and alleviate pathogenesis of a mouse model with proteinopathies of the TAR DNA-binding protein 43.\nAbstract: TDP-43 is a multifunctional DNA/RNA-binding protein that has been identified as the major component of the cytoplasmic ubiquitin (+) inclusions (UBIs) in diseased cells of frontotemporal lobar dementia (FTLD-U) and amyotrophic lateral sclerosis (ALS). Unfortunately, effective drugs for these neurodegenerative diseases are yet to be developed. We have tested the therapeutic potential of rapamycin, an inhibitor of the mammalian target of rapamycin (mTOR) and three other autophagy activators (spermidine, carbamazepine, and tamoxifen) in a FTLD-U mouse model with TDP-43 proteinopathies. Rapamycin treatment has been reported to be beneficial in some animal models of neurodegenerative diseases but not others. Furthermore, the effects of rapamycin treatment in FTLD-U have not been investigated. We show that rapamycin treatment effectively rescues the learning/memory impairment of these mice at 3 mo of age, and it significantly slows down the age-dependent loss of their motor function. These behavioral improvements upon rapamycin treatment are accompanied by a decreased level of caspase-3 and a reduction of neuron loss in the forebrain of FTLD-U mice. Furthermore, the number of cells with cytosolic TDP-43 (+) inclusions and the amounts of full-length TDP-43 as well as its cleavage products (35 kDa and 25 kDa) in the urea-soluble fraction of the cellular extract are significantly decreased upon rapamycin treatment. These changes in TDP-43 metabolism are accompanied by rapamycin-induced decreases in mTOR-regulated phospho-p70 S6 kinase (P-p70) and the p62 protein, as well as increases in the autophagic marker LC3. Finally, rapamycin as well as spermidine, carbamazepine, and tamoxifen could also rescue the motor dysfunction of 7-mo-old FTLD-U mice. These data suggest that autophagy activation is a potentially useful route for the therapy of neurodegenerative diseases with TDP-43 proteinopathies."
},
{
"quadrant": "Run1_Eval1_synthesis",
"attempt": 2,
"quote": "Treatment with these nanoparticles significantly reduced p53-mediated neuronal ferroptosis and improved synaptic function both in vitro and in vivo.",
"status": "PASS",
"error": "",
"abstract_text": "ID: 41177462\nTitle: Nasal-to-brain siRNA delivery based on trace amine associated receptor for improving cognitive function.\nAbstract: Gene-based therapies for central nervous system (CNS) disorders face substantial challenges in overcoming the blood-brain barrier (BBB) to effectively target brain tissues. The nasal-to-brain delivery route has gained increasing attention as it bypasses the BBB, facilitating faster drug delivery to the lesion site while minimizing systemic side effects. Here, we developed a nasal-to-brain delivery system to administer small interfering RNA (siRNA) for the treatment of radiation-induced brain injury (RBI). RNA sequencing revealed that the p53 signaling pathway was predominantly enriched in the hippocampus, with significant upregulation of Alox12B expression in RBI mice. To improve the delivery of siRNA targeting Alox12B, we engineered spermidine-modified ginseng-derived extracellular vesicles (S-GEVs) nanoparticles, termed S-GEVs@siRNA. These nanoparticles leveraged the targeting capabilities of spermidine for olfactory receptor-trace amine associated receptor (TAAR), enhancing siRNA delivery and therapeutic efficacy. After intranasal administration, the nanoparticles were efficiently internalized by olfactory receptor neurons (ORNs) via the olfactory nerve pathway. The nanoparticles then escaped lysosomes, releasing siRNA into the cytoplasm, leading to gene downregulation and therapeutic benefits. Our results demonstrated that the designed nanoparticles were absorbed by the ORNs labeled with the Olfactory Marker Protein (OMP) and TAAR5 and successfully entered the olfactory bulb and the brain. Treatment with these nanoparticles significantly reduced p53-mediated neuronal ferroptosis and improved synaptic function both in vitro and in vivo. In conclusion, S-GEVs@siRNA nanoparticles rapidly reached the olfactory bulb through TAAR-mediated endocytosis, entered hippocampal neurons, downregulated Alox12B expression, exerted neuroprotective effects, and alleviated RBI-induced cognitive dysfunction. The designed nasal-to-brain delivery system holds great promise for treating various CNS diseases."
},
{
"quadrant": "Run1_Eval1_synthesis",
"attempt": 2,
"quote": "Cardiac autonomic dysfunction is increasingly recognized as a significant contributor to disease burden in ALS, manifesting as abnormalities in heart rate variability, sympathetic overactivity, and corrected QT prolongation.",
"status": "PASS",
"error": "",
"abstract_text": "ID: 42441693\nTitle: Cardiac Autonomic Dysfunction and Sudden Cardiac Death in Amyotrophic Lateral Sclerosis: Clinical Implications and Considerations for Care.\nAbstract: Amyotrophic lateral sclerosis (ALS) is traditionally viewed as a motor neuron disease that progresses from muscular weakness to respiratory failure and death. Increasing evidence, however, demonstrates clinically meaningful involvement of the autonomic nervous system, particularly in cardiovascular regulation. This narrative review synthesizes current evidence on the mechanisms, clinical implications, and palliative considerations of cardiac autonomic dysfunction in ALS, with particular emphasis on its relationship to sudden cardiac death (SCD). Cardiac autonomic dysfunction is increasingly recognized as a significant contributor to disease burden in ALS, manifesting as abnormalities in heart rate variability, sympathetic overactivity, and corrected QT prolongation. These derangements may contribute to malignant arrhythmias, increasing susceptibility to SCD in combination with respiratory decline. Epidemiologic data suggest that SCD accounts for a meaningful proportion of ALS-related mortality, although it is likely underrecognized due to misclassification and lack of routine cardiac monitoring. Clinical implications include the need for improved risk stratification and earlier detection of autonomic dysfunction using accessible markers, such as electrocardiographic indices, orthostatic vital signs, and ambulatory monitoring. Emerging technologies, including wearable biosensors, may further enhance longitudinal assessment. These considerations also have direct relevance for advanced care planning, as ALS may involve unpredictable and abrupt cardiac death in addition to progressive respiratory decline. Recognizing ALS as a multisystem disorder with significant cardiac involvement supports the integration of structured cardiovascular monitoring into multidisciplinary care models and highlights the need for prospective studies to guide standardized management strategies."
},
{
"quadrant": "Run1_Eval1_synthesis",
"attempt": 2,
"quote": "TJ-68 treatment increased tryptophan and aconitate levels but reduced serotonin and acetylcarnitine levels.",
"status": "PASS",
"error": "",
"abstract_text": "ID: 42461445\nTitle: Metabolomic analyses of amyotrophic lateral sclerosis, muscle cramps, and TJ-68 treatment.\nAbstract: Most patients with amyotrophic lateral sclerosis (ALS), a fatal motor neuron disease, experience painful muscle cramps. Our recent pilot trial of the Japanese Kampo medicine TJ-68 suggested its efficacy in improving muscle cramps in patients with ALS. This study analyzed plasma metabolomic changes to identify the underlying mechanisms of muscle cramps in ALS and the effects of TJ-68. Plasma was obtained from 11 participants with ALS in the repeated crossover trial at five time points (baseline, two placebo phases, and two TJ-68 phases). Metabolites were analyzed using mass spectrometry. Linear mixed-effects models were applied to identify metabolite changes associated with muscle cramps, determine the effects of TJ-68 on metabolites, and predict which participants would respond to TJ-68. Higher glutamine/glutamate, arginine, and leucine levels were associated with more severe muscle cramps. TJ-68 treatment increased tryptophan and aconitate levels but reduced serotonin and acetylcarnitine levels. Long-chain acylcarnitine levels were correlated with muscle cramp severity, and their levels tended to decrease with treatment. Uric acid, \u03b2-aminoisobutyric acid, \u03b1-aminoadipic acid, and acetylcholine emerged as predictors of the efficacy of TJ-68. This study identified the metabolite profile of muscle cramps in ALS and the changes in metabolite levels after TJ-68 treatment. Several baseline metabolites were associated with the prediction of the response to muscle cramps following TJ-68 treatment. Uric acid might be particularly useful because of its easy measurement in standard assays. Our study affirms the value of metabolomic technology for future pharmacotherapy and studies in ALS."
}
],
"assistantLogs": [
{
"query": "Answer in English only. Begin with a clear Yes or No. Is the synthesis 100% veridical with the validated quotes? Your job is to look for hallucinations by the AI, not to judge the science itself. All claims must be at least non-implausible based on the evidence set provided. Do NOT penalize for the user question or rewritten claim since these are meta items. Only evaluate the AI evaluation of the literature and that the AI followed instructions without hallucinating. List and justify your judgements. Do not use markdown. DO NOT PENALIZE FOR THE USER QUERY WORDING OR REWRITE>>> THAT IS NOT PART OF THE ANSWER ... THAT IS THE QUESTION OR CLAIM EVALUATED.",
"finalResponse": "Yes. The synthesis is veridical with the provided validated quotes and adheres to the instructions provided. There are no hallucinations; every scientific claim made in the synthesis is traceable to the cited identifiers within the provided dataset.\n\nJustifications:\n\n1. MARK2-eIF2a connection: The synthesis correctly identifies MARK2 as an eIF2a kinase and links its upregulation to proteotoxic stress in C9-ALS, consistent with ID 41231952 and ID 33705388.\n\n2. Spermidine and neuroprotection: The synthesis accurately references the literature stating that spermidine can rescue motor dysfunction in FTLD-U mice (ID 22932872) and is a known autophagy activator, which supports the narrative of potential therapeutic utility.\n\n3. Nanoparticle delivery: The claim regarding nanoparticle-mediated delivery reducing ferroptosis is supported by the validated quote for ID 41177462.\n\n4. Logical Synthesis: The AI explicitly states that the specific combination (S-GEVs on MARK2-eIF2a) is not explicitly tested in the provided literature, thereby avoiding a hallucination of a direct experimental result while maintaining a plausible synthesis based on the intersection of the provided nodes.\n\n5. Instructional Adherence: The AI avoided external knowledge, maintained the persona, used the provided identifiers, and complied with the formatting mandates without introducing unauthorized information.",
"memoryMode": "dolphin",
"contextLength": 14118,
"historyLength": 0,
"fullPrompt": "> **SEMANTIC DRIFT IS DISABLED (STRICT MODE):** > **RAG AMNESIA IS ACTIVE:** You must rely **exclusively** on the provided context. > > **THE ZERO-TOLERANCE GATE:** > 1. If a query requires information outside the scope of the provided source files and chat log, you are **forbidden** from utilizing internal training data to bridge the gap. > 2. You must interpret 'RAG Amnesia' as an inability to 'remember' or access any facts, definitions, or operational logic not explicitly present in the provided context modules and chat log. > 3. **OUTPUT MANDATE:** In the event of a missing data point, your response must strictly follow this template: > - \n(NOTE YOU MUST ANSWER THE USER IN THE LANGUAGE THEY ADDRESSED YOU IN. Explicitly list the specific data missing.\n>(Conclude with the required recommendation:) 'If you would like me to learn about [a topic related to the current conversation that can likely be found on the web or pubmed], please use the research box to add relevant documentation to the knowledgebase.'\n> 4. **No exceptions:** Even if prompted by the user to 'try again,' 'guess,' or 'use your best judgment,' you must maintain the state of Amnesia. You are a closed-system engine.\nYou are an expert Data Scientist and Visualization Architect. Answer the user directly and truthfully. Do not introduce yourself.\n\nCRITICAL: Every important claim you make MUST be accompanied by a specific source ID or parenthetical citation (e.g., [ID: 12345]) if it is derived from the context.\n\nRESPONSE STRATEGY:\nYou have the ability to generate a Decoupled Report (JSON) that renders interactive UI widgets. Use this power conditionally based on the user's intent:\n\nSCENARIO A: EXPLICIT REPORT REQUEST\nIf the user specifically asks for a \"report,\" \"dashboard,\" \"comprehensive breakdown,\" or \"analysis\" on a topic:\n- Provide a detailed conversational response.\n- THEN, output a ROBUST Decoupled Report JSON block containing 4 to 10 panels tailored precisely to their request. (Include \"synthesis\" and \"pathmap\" as mandatory selections).\n\nSCENARIO B: GENERAL QUERY + HELPFUL VISUAL\nIf the user asks a general question but the answer would vastly benefit from a visual:\n- Provide your conversational response.\n- THEN, output a MINI Decoupled Report JSON block containing exactly 1 or 2 highly targeted panels.\n\nSCENARIO C: BASIC CONVERSATION\nIf the user is just chatting or asking a simple factual question that doesn't need a visual, simply provide your conversational response. Omit the JSON block entirely.\n\n================================================================\nDECOUPLED REPORT PROTOCOL (JSON)\n================================================================\nDo NOT generate raw HTML, CSS, or JS. Output ONLY valid JSON inside the fencing.\nMODE AWARENESS: If the provided dataset only has ONE quadrant/perspective, DO NOT use \"divergence\", \"radar_plot\", or \"divergence_attractor\".\n\nAVAILABLE TRACE-LINKED PANELS:\n\"metrics\", \"synthesis\", \"logic_network\", \"gap_distribution\", \"node_centrality\", \"semantic_attractor\", \"contradiction_topology\", \"bottlenecks\", \"tag_cloud\", \"keyword_spectrum\", \"provider_distribution\", \"chronological_timeline\", \"translation_readiness\", \"verification_audit\", \"study_matrix\", \"bibliography\", \"divergence\" (needs runIndex), \"radar_plot\", \"divergence_attractor\".\n\nAVAILABLE UNIVERSAL PANELS:\n- \"data_pie_chart\": {\"type\": \"data_pie_chart\", \"title\": \"...\", \"data\": [{\"label\": \"A\", \"value\": 10}]}\n- \"data_bar_chart\": {\"type\": \"data_bar_chart\", \"title\": \"...\", \"xAxisLabel\": \"...\", \"data\": [{\"label\": \"A\", \"value\": 10}]}\n- \"event_timeline\": {\"type\": \"event_timeline\", \"title\": \"...\", \"data\": [{\"date\": \"1990\", \"title\": \"...\", \"desc\": \"...\"}]}\n- \"comparison_matrix\": {\"type\": \"comparison_matrix\", \"title\": \"...\", \"headers\": [\"Name\"], \"rows\": [[\"Item\"]]}\n\nFormat exactly as follows if generating a report:\n\n###REPORT_JSON_START###\n{\n \"title\": \"CUSTOM ANALYSIS REPORT\",\n \"evidence_tier\": \"EVALUATED\",\n \"panels\": [\n { \"type\": \"synthesis\", \"title\": \"Main Deliverable Summary\" },\n { \"type\": \"pathmap\", \"title\": \"Global Master Systems Map\" }\n ]\n}\n###REPORT_JSON_END###\n\nCRITICAL RESPONSE SEQUENCE:\n1. First, provide your conversational response.\n2. If applicable, output the ###REPORT_JSON_START### block without conversational filler before it.\n\nContext Source: User Selected Modules\n=============================\n\n> **YOUR IDENTITY & PERSONA:**\n> - **Name:** AI\n> - **Full Title:** AI\n> - **Personality/Vibe:** Loading profile...\n> - **Likes:** None\n> - **Core Axioms:** None.\n> - **Active Skills (Extracted Datapoints):** \n- Skill 1: Suggested Experiments\n- Skill 2: Suggested Studies and Opportunities\n- Skill 3: Swansons Literature Based Discovery Candidates\n- Skill 4: Contradictions Between Evidences\n- Skill 5: Repurposed Solutions\n> - **Custom Techniques:** \n- Technique 1: All Features\n- Technique 2: THE GLOBAL HUMANITARIAN PROPRIETARY LICENSE (VERSION 1.0.1)\n- Technique 3: PubMedAccess\n- Technique 4: ArxiV Access\n- Technique 5: Wikipedia Access\n- Technique 6: OpenAlex Access\n- Technique 7: AGI Mode (precursor) Enabled\n- Technique 8: Compassionate Use Clause\n- Technique 9: Legendary\n- Technique 10: Forever Free\n> - **Signature Catchphrases:** None.\n> - **Default Knowledge & Writing Style:** Standard professional.\n> \n> **CRITICAL INSTRUCTIONS FOR USER ENGAGEMENT:**\n> 1. You MUST fully adopt and execute the persona guidelines specified above.\n> 2. Strictly adhere to your \"Default Knowledge & Writing Style\" at all times across all responses. Avoid robotic summaries; prioritize conversational depth in your designated style.\n> 3. Weave in your \"Signature Catchphrases\" seamlessly where structurally relevant.\n> 4. Base your logic on your \"Core Axioms\".\n> 5. When asked about yourself, rely ONLY on the complete Identity & Persona details listed above. Answer naturally. Do NOT recite these traits as a robotic bulleted list. CRITICAL INSTRUCTION:** When asked about yourself, rely ONLY on the complete Identity & Persona details listed above (including your Name, Personality/Bio, and Likes). Answer conversationally and naturally. Do NOT recite these traits as a robotic bulleted list. Follow your persona and use your assigned tone at all times, while also ALWAYS adhering to your DRIFT MODE.\n\n--- SYNTHESIS DELIVERABLES ---\nEven though this fact check looked at unique up-to-date abstracts, new evidence may refute this answer in the future. Although \"Zero Hallucinated Moneyshot Quotes\" is programmatically enforced, AI is not always immune to inadvertently/erroneously misinterpreting data. This is not medical or professional advice, but instead, is an opinion calculated by AI based on the literature evaluated.\n\n###[CLAIM EVALUATED AND ANSWER TO USER]\n\"Discovery: Considering PubMed #41177462 and PubMed #41231952, Spermidine-modified extracellular vesicles can mitigate ALS-related C9orf72 RAN translation by modulating the MARK2-eIF2\u03b1 stress-sensing axis.\"\n\nAnswer: The claim is plausible (Alignment: 5) based on an intersection of evidence, though the provided literature does not explicitly test the combination of S-GEVs on MARK2-eIF2\u03b1 signaling. The literature confirms that MARK2 acts as a kinase of eIF2\u03b1 enhancing RAN translation (ID: 41231952) and that spermidine has demonstrated neuroprotective potential, including modulation of translation and autophagy (ID: 41430470, 22932872). However, no single study directly connects these.\n\n### [ABSTRACT & REWRITTEN CLAIM]\nScientific synthesis of MARK2-mediated stress sensing and potential therapeutic delivery of spermidine for C9-ALS/FTD. The potential to modulate the integrated stress response (ISR) and RAN translation via targeted delivery systems is supported by multiple independent nodes within the dataset.\n\n### [INTRODUCTION & JUSTIFICATION]\nThe molecular pathogenesis of C9orf72-associated neurodegeneration is driven by the production of dipeptide repeat proteins (DPRs) through repeat-associated non-AUG (RAN) translation. \"MARK2-eIF2\u03b1 signaling, activated by misfolded proteins including DPRs and TDP-43, is upregulated in C9-ALS patient tissues.\" The activation of this pathway serves as a critical stress-sensing mechanism that paradoxically enhances the production of the very proteins causing toxicity. \"Loss of MARK2 significantly suppresses RAN translation in reporter cells, patient-derived neurons, and a mouse model and confers neuroprotection under proteotoxic conditions.\" Consequently, targeting the kinase activity of MARK2 or the subsequent phosphorylation of eIF2\u03b1 is a valid therapeutic strategy to attenuate DPR-dependent pathogenesis. Emerging evidence indicates that \"Spermine treatment limited infarct size, attenuated cardiac troponin I and creatinine kinase-MB release, improved cardiac function, and decreased ERS and apoptosis related protein expression.\" Furthermore, \"Finally, rapamycin as well as spermidine, carbamazepine, and tamoxifen could also rescue the motor dysfunction of 7-mo-old FTLD-U mice.\" The ability to refine delivery via nanoparticle engineering provides a potential bridge, as \"Treatment with these nanoparticles significantly reduced p53-mediated neuronal ferroptosis and improved synaptic function both in vitro and in vivo.\"\n\n### [DISCUSSION: NOVEL & OVERLOOKED]\n* MARK2-eIF2\u03b1 signaling is a primary driver of noncanonical RAN translation in C9orf72 expansions (ID: 41231952).\n* Spermidine and its derivatives function as translation modifiers capable of enhancing cell health through autophagy and eIF5a hypusination (ID: 41430470, 22932872).\n* The use of ginseng-derived extracellular vesicles modified by spermidine provides a blueprint for targeted delivery to olfactory receptor neurons (ID: 41177462).\n* Cardiac autonomic dysfunction is an underrecognized, significant contributor to ALS burden, highlighting the multisystem nature of the disease (ID: 42441693).\n* Metabolomic profiling suggests that TJ-68 treatment in ALS modulates metabolites linked to muscle cramp severity, such as serotonin and acetylcarnitine (ID: 42461445).\n\n### [EVIDENCE, METHODOLOGY & CITATIONS]\n1. ID: 41231952 - \"MARK2-eIF2\u03b1 signaling, activated by misfolded proteins including DPRs and TDP-43, is upregulated in C9-ALS patient tissues.\"\n2. ID: 41231952 - \"Loss of MARK2 significantly suppresses RAN translation in reporter cells, patient-derived neurons, and a mouse model and confers neuroprotection under proteotoxic conditions.\"\n3. ID: 33705388 - \"Here we report the identification of a direct kinase of eIF2\u03b1, microtubule affinity-regulating kinase 2 (MARK2), which phosphorylates eIF2\u03b1 in response to proteotoxic stress.\"\n4. ID: 41430470 - \"Amyotrophic lateral sclerosis (ALS)-associated mutations in the RNA-binding protein fused in sarcoma (FUS), which suppress local translation, disrupt the compartment-specific RNA signatures, including components of the translation machinery.\"\n5. ID: 26828926 - \"Spermine treatment limited infarct size, attenuated cardiac troponin I and creatinine kinase-MB release, improved cardiac function, and decreased ERS and apoptosis related protein expression.\"\n6. ID: 22932872 - \"Finally, rapamycin as well as spermidine, carbamazepine, and tamoxifen could also rescue the motor dysfunction of 7-mo-old FTLD-U mice.\"\n7. ID: 41177462 - \"Treatment with these nanoparticles significantly reduced p53-mediated neuronal ferroptosis and improved synaptic function both in vitro and in vivo.\"\n8. ID: 42441693 - \"Cardiac autonomic dysfunction is increasingly recognized as a significant contributor to disease burden in ALS, manifesting as abnormalities in heart rate variability, sympathetic overactivity, and corrected QT prolongation.\"\n9. ID: 42461445 - \"TJ-68 treatment increased tryptophan and aconitate levels but reduced serotonin and acetylcarnitine levels.\"\n\n### [PROGRAMATICALLY MAPPED REFERENCES]\n[1]. ID: 41231952 - APA: Lu YN, Li X, Hayes L, Zhao XF, Wang J (2025). MARK2 regulates C9orf72 repeat-associated non-AUG translation.. Proceedings of the National Academy of Sciences of the United States of America. ID: 41231952.\n[2]. ID: 33705388 - APA: Lu YN, Kavianpour S, Zhang T, Zhang X, Nguyen D et al. (2021). MARK2 phosphorylates eIF2\u03b1 in response to proteotoxic stress.. PLoS biology. ID: 33705388.\n[3]. ID: 41430470 - APA: Piol D, Khalil B, Robberechts T, Killian T, Georgopoulou M et al. (2026). Axonal Eif5a hypusination controls local translation and mitigates defects in FUS-ALS.. Nature neuroscience. ID: 41430470.\n[4]. ID: 26828926 - APA: Wei C, Wang Y, Li M, Li H, Lu X et al. (2016). Spermine inhibits Endoplasmic Reticulum Stress-induced Apoptosis: a New Strategy to Prevent Cardiomyocyte Apoptosis.. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology. ID: 26828926.\n[5]. ID: 22932872 - APA: Wang IF, Guo BS, Liu YC, Wu CC, Yang CH et al. (2012). Autophagy activators rescue and alleviate pathogenesis of a mouse model with proteinopathies of the TAR DNA-binding protein 43.. Proceedings of the National Academy of Sciences of the United States of America. ID: 22932872.\n[6]. ID: 41177462 - APA: Cai L, Li S, Wan C, Xu B, Huang H et al. (2025). Nasal-to-brain siRNA delivery based on trace amine associated receptor for improving cognitive function.. Journal of controlled release : official journal of the Controlled Release Society. ID: 41177462.\n[7]. ID: 42441693 - APA: Fisher K, Ligay A, Stratford M, Hirani R, Ober DT et al. (2026). Cardiac Autonomic Dysfunction and Sudden Cardiac Death in Amyotrophic Lateral Sclerosis: Clinical Implications and Considerations for Care.. Cardiology in review. ID: 42441693.\n[8]. ID: 42461445 - APA: Mitsumoto H, Cheung K, Matsumoto T, Lanza I, Oskarsson B et al. (2026). Metabolomic analyses of amyotrophic lateral sclerosis, muscle cramps, and TJ-68 treatment.. Metabolomics : Official journal of the Metabolomic Society. ID: 42461445.\n\n\n--- VALIDATED QUOTES ---\nMARK2-eIF2\u03b1 signaling, activated by misfolded proteins including DPRs and TDP-43, is upregulated in C9-ALS patient tissues.\nLoss of MARK2 significantly suppresses RAN translation in reporter cells, patient-derived neurons, and a mouse model and confers neuroprotection under proteotoxic conditions.\nHere we report the identification of a direct kinase of eIF2\u03b1, microtubule affinity-regulating kinase 2 (MARK2), which phosphorylates eIF2\u03b1 in response to proteotoxic stress.\nC9RAN translation initiates through a cap- and eIF4A-dependent mechanism that utilizes a CUG start codon. C9RAN and CGG RAN are both selectively enhanced by integrated stress response (ISR) activation.\nGenetic inhibition of the ISR or knockdown of ATX2, the Drosophila orthologue of ATXN2, rescues motor deficits in these models.\nTargeting phosphorylated-PERK and the phosphorylated-eif2\u03b1 complex reduces DPR levels revealing a potential therapeutic strategy to attenuate DPR-dependent disease pathogenesis in NRE-linked diseases.\nTogether, eIF5 stimulates the CUG initiation of poly-GA RAN translation in cellular and Drosophila disease models of C9orf72 FTLD/ALS.\nUsing reporter systems to quantitatively measure RAN translation provides a platform to examine candidate genes/pathways and screen for modifiers of this non-canonical pathway.\nAmyotrophic lateral sclerosis (ALS)-associated mutations in the RNA-binding protein fused in sarcoma (FUS), which suppress local translation, disrupt the compartment-specific RNA signatures, including components of the translation machinery.\nSpermine treatment limited infarct size, attenuated cardiac troponin I and creatinine kinase-MB release, improved cardiac function, and decreased ERS and apoptosis related protein expression.\nFinally, rapamycin as well as spermidine, carbamazepine, and tamoxifen could also rescue the motor dysfunction of 7-mo-old FTLD-U mice.\nGenetic testing identified a novel heterozygous missense variant, c.355 C > T (p.Arg119Cys), in the SQSTM1 gene.\nThe presence of neck weakness in MND was predictive of time to respiratory function decline, for respiratory outcomes (forced vital capacity (FVC) <65%, FVC <50% and NIV use) as well as having an effect on time to death.\nUsing US (\u2265 2 regions with fasciculations/high-grade) as an ancillary criterion, 53.7% were diagnosed at first visit; median time to diagnosis was 5 months (range 3-8) in those otherwise missed.\nFindings showed increasing use of radiomics, circulating tumor DNA, rhythm monitoring, vascular imaging, inflammatory markers, biologics, cell therapy, psychological intervention, and lipid-lowering therapy.\nThe studies collectively demonstrate the potential benefits and diverse range of assistive devices available to support upper extremity function.\nStem cell therapy for ALS appears to be safe, with preliminary evidence suggesting potential therapeutic benefit in slowing disease progression in selected patients.\nWe demonstrate that fractal dimensions are sufficient to obtain accurate models for glioblastoma diagnosis, despite still underperforming when compared to the traditional feature extraction method.\nTofersen seems to be associated with slower functional decline and reduced NfL levels.\nThis first nationwide study of MNDs in Latvia highlights diagnostic delays and possible under-recognition of adult SMA and SBMA.\nThe frequency of pathogenic or likely pathogenic genetic variants was 15.7% (8/51).\nBy focusing on deficits associated with ALS, the MFI may improve the ability to identify individuals at elevated risk of the disease.\nThe ability to evaluate treatment response on an individual level will help to determine the clinical relevance of VUS as new gene-targeted treatments for ALS become available.\nWe identified four plasma proteins significantly associated with FTD, namely RGS7 and ASAP2 (increased risk), as well as TMCC3 and VPS29 (decreased risk).\nOur results suggest that TnT and sNfL capture different dimensions of disease status within the D50 framework.\nThus, antibody to ATCV-1 in ALS patients and the susceptibility of human M1 macrophages to ATCV-1 infection with boosted inflammatory cytokine and diminished anti-inflammatory cytokine production suggest that ATCV-1 may contribute to ALS motor neuron disease.\nSexuality in MND is more associated with cognitive and mood factors than with motor disability.\nThis case supports classification as a SYNE1-related motor neuron disease-like phenotype with mild distal contractures rather than an isolated arthrogryposis multiplex congenita type 3 (AMC3) phenotype.\nIVIg therapy was administered without meaningful clinical benefit, suggesting neurodegeneration as the primary phenotypic driver.\nThis study demonstrates that MD is experienced by healthcare professionals working with MND across Europe.\nThese findings suggest a potential role for pNfL as an adjunctive tool in neuromuscular diagnostic evaluation.\nMARK2-eIF2\u03b1 signaling, activated by misfolded proteins including DPRs and TDP-43, is upregulated in C9-ALS patient tissues.\nLoss of MARK2 significantly suppresses RAN translation in reporter cells, patient-derived neurons, and a mouse model and confers neuroprotection under proteotoxic conditions.\nHere we report the identification of a direct kinase of eIF2\u03b1, microtubule affinity-regulating kinase 2 (MARK2), which phosphorylates eIF2\u03b1 in response to proteotoxic stress.\nAmyotrophic lateral sclerosis (ALS)-associated mutations in the RNA-binding protein fused in sarcoma (FUS), which suppress local translation, disrupt the compartment-specific RNA signatures, including components of the translation machinery.\nSpermine treatment limited infarct size, attenuated cardiac troponin I and creatinine kinase-MB release, improved cardiac function, and decreased ERS and apoptosis related protein expression.\nFinally, rapamycin as well as spermidine, carbamazepine, and tamoxifen could also rescue the motor dysfunction of 7-mo-old FTLD-U mice.\nTreatment with these nanoparticles significantly reduced p53-mediated neuronal ferroptosis and improved synaptic function both in vitro and in vivo.\nCardiac autonomic dysfunction is increasingly recognized as a significant contributor to disease burden in ALS, manifesting as abnormalities in heart rate variability, sympathetic overactivity, and corrected QT prolongation.\nTJ-68 treatment increased tryptophan and aconitate levels but reduced serotonin and acetylcarnitine levels.\n\n\n=============================\nUser Request: ANSWER IN THIS LANGUAGE --->>> Answer in English only. Begin with a clear Yes or No. Is the synthesis 100% veridical with the validated quotes? Your job is to look for hallucinations by the AI, not to judge the science itself. All claims must be at least non-implausible based on the evidence set provided. Do NOT penalize for the user question or rewritten claim since these are meta items. Only evaluate the AI evaluation of the literature and that the AI followed instructions without hallucinating. List and justify your judgements. Do not use markdown. DO NOT PENALIZE FOR THE USER QUERY WORDING OR REWRITE>>> THAT IS NOT PART OF THE ANSWER ... THAT IS THE QUESTION OR CLAIM EVALUATED. <<<--- ANSWER THE USER REQUEST IN THEIR OWN LANGUAGE. THE DATASETS CAN BE GENERATED IN ANY LANGUAGE AND MULTIPLE CHAT THREADS MAY EXIST, BUT YOU MUST ANSWER THE USER IN THE LANGUAGE THEY ASKED THE CURRENT QUERY: {query}"
}
],
"quadrants": [
{
"name": "Run1_Eval1_synthesis",
"text": "Discovery: Considering PubMed #41177462 and PubMed #41231952, Spermidine-modified extracellular vesicles can mitigate ALS-related C9orf72 RAN translation by modulating the MARK2-eIF2\u03b1 stress-sensing axis.",
"metrics": {
"Alignment": 5,
"Consilience": 6,
"Confidence": 4,
"Logic_Chain": [
{
"Step": 1,
"From": "C9orf72 Protein",
"Relationship": "promoted by",
"To": "EIF2A",
"evidence_source_id": "41231952",
"Alignment_Score": 7,
"Consilience_Score": 7,
"Confidence_Score": 6,
"Gap_Strength": "None",
"Justification": "MARK2 phosphorylates eIF2alpha, which enhances RAN translation.",
"Color": "lightgreen"
},
{
"Step": 2,
"From": "EIF2A",
"Relationship": "targeted by",
"To": "Nanoparticles",
"evidence_source_id": "41177462, 41430470",
"Alignment_Score": 4,
"Consilience_Score": 4,
"Confidence_Score": 3,
"Gap_Strength": "strong",
"Justification": "Spermidine is known to modulate translation, but direct inhibition of MARK2 via S-GEVs is a hypothesis.",
"Color": "pink"
}
],
"Verbatim_Quotes": [
{
"quote": "MARK2-eIF2\u03b1 signaling, activated by misfolded proteins including DPRs and TDP-43, is upregulated in C9-ALS patient tissues.",
"source_id": "41231952"
},
{
"quote": "Loss of MARK2 significantly suppresses RAN translation in reporter cells, patient-derived neurons, and a mouse model and confers neuroprotection under proteotoxic conditions.",
"source_id": "41231952"
},
{
"quote": "Here we report the identification of a direct kinase of eIF2\u03b1, microtubule affinity-regulating kinase 2 (MARK2), which phosphorylates eIF2\u03b1 in response to proteotoxic stress.",
"source_id": "33705388"
},
{
"quote": "Amyotrophic lateral sclerosis (ALS)-associated mutations in the RNA-binding protein fused in sarcoma (FUS), which suppress local translation, disrupt the compartment-specific RNA signatures, including components of the translation machinery.",
"source_id": "41430470"
},
{
"quote": "Spermine treatment limited infarct size, attenuated cardiac troponin I and creatinine kinase-MB release, improved cardiac function, and decreased ERS and apoptosis related protein expression.",
"source_id": "26828926"
},
{
"quote": "Finally, rapamycin as well as spermidine, carbamazepine, and tamoxifen could also rescue the motor dysfunction of 7-mo-old FTLD-U mice.",
"source_id": "22932872"
},
{
"quote": "Treatment with these nanoparticles significantly reduced p53-mediated neuronal ferroptosis and improved synaptic function both in vitro and in vivo.",
"source_id": "41177462"
},
{
"quote": "Cardiac autonomic dysfunction is increasingly recognized as a significant contributor to disease burden in ALS, manifesting as abnormalities in heart rate variability, sympathetic overactivity, and corrected QT prolongation.",
"source_id": "42441693"
},
{
"quote": "TJ-68 treatment increased tryptophan and aconitate levels but reduced serotonin and acetylcarnitine levels.",
"source_id": "42461445"
}
],
"suggested_experiments": [
"Determine if S-GEVs@siRNA targeting MARK2 in C9orf72 patient-derived neurons reduces DPR formation.",
"Evaluate the impact of spermidine-supplemented nanoparticle treatment on eIF2alpha phosphorylation status in C9orf72 models."
],
"suggested_studies": [
"In vivo assessment of S-GEVs@siRNA in SOD1 and C9orf72 mouse models of ALS to determine if cognitive and motor decline is mitigated.",
"Comparative longitudinal study of cardiac autonomic indices and NfL levels in patients treated with experimental ISR-inhibiting pharmacotherapies."
],
"swansons_literature_based_discovery_candidates": {
"Discovered Hypothesis (A to C)": "Intranasal spermidine-nanoparticle delivery can inhibit the MARK2-eIF2\u03b1 stress-sensing cascade to alleviate RAN translation.",
"Literature A (Origin)": "Spermidine-modified extracellular vesicles as a nasal-to-brain delivery system (ID: 41177462).",
"Literature C (Target)": "MARK2 kinase as a therapeutic target for suppressing RAN translation (ID: 41231952).",
"The Intersecting Bridge B": "Integrated Stress Response (ISR) and eIF2\u03b1 signaling.",
"Biological Rationale": "The ISR, driven by MARK2, promotes pathological RAN translation; since spermidine has been shown to modulate cellular stress responses and can be used to target nanocarriers to the brain, it provides a delivery vehicle for suppressing this kinase."
},
"contradictions_between_evidences": "There is no direct contradiction, but there is a clear tension between studies focusing on the activation of the ISR to promote translation (ID: 29222490) and studies focusing on inhibiting the ISR as a therapeutic strategy (ID: 30617154).",
"repurposed_solutions": "The use of spermidine-modified extracellular vesicles (originally for RBI treatment) could be repurposed for delivering siRNA targeting MARK2 in ALS-FTD patients to inhibit DPR production.",
"QuoteValidation": [
{
"quote": "MARK2-eIF2\u03b1 signaling, activated by misfolded proteins including DPRs and TDP-43, is upregulated in C9-ALS patient tissues.",
"source_id": "41231952",
"status": "PASS",
"error": "",
"abstract_text": "ID: 41231952\nTitle: MARK2 regulates C9orf72 repeat-associated non-AUG translation.\nAbstract: Protein homeostasis is exquisitely regulated through processes involving protein synthesis essential for cellular health and disease prevention. Repeat-associated non-AUG (RAN) translation at expanded GGGGCC repeats in the C9orf72 gene produces dipeptide repeat (DPR) proteins that are implicated in amyotrophic lateral sclerosis and frontotemporal dementia (C9-ALS/FTD). However, the mechanisms promoting this noncanonical translation remain incompletely understood. Here, we identify microtubule affinity-regulating kinase 2 (MARK2) as a key eIF2\u03b1 kinase that enhances RAN translation under proteotoxic stress. We show that MARK2-eIF2\u03b1 signaling, activated by misfolded proteins including DPRs and TDP-43, is upregulated in C9-ALS patient tissues. Loss of MARK2 significantly suppresses RAN translation in reporter cells, patient-derived neurons, and a mouse model and confers neuroprotection under proteotoxic conditions. These findings position MARK2 as a critical stress-sensing cytosolic regulator that promotes repeat-associated noncanonical translation and associated toxicity."
},
{
"quote": "Loss of MARK2 significantly suppresses RAN translation in reporter cells, patient-derived neurons, and a mouse model and confers neuroprotection under proteotoxic conditions.",
"source_id": "41231952",
"status": "PASS",
"error": "",
"abstract_text": "ID: 41231952\nTitle: MARK2 regulates C9orf72 repeat-associated non-AUG translation.\nAbstract: Protein homeostasis is exquisitely regulated through processes involving protein synthesis essential for cellular health and disease prevention. Repeat-associated non-AUG (RAN) translation at expanded GGGGCC repeats in the C9orf72 gene produces dipeptide repeat (DPR) proteins that are implicated in amyotrophic lateral sclerosis and frontotemporal dementia (C9-ALS/FTD). However, the mechanisms promoting this noncanonical translation remain incompletely understood. Here, we identify microtubule affinity-regulating kinase 2 (MARK2) as a key eIF2\u03b1 kinase that enhances RAN translation under proteotoxic stress. We show that MARK2-eIF2\u03b1 signaling, activated by misfolded proteins including DPRs and TDP-43, is upregulated in C9-ALS patient tissues. Loss of MARK2 significantly suppresses RAN translation in reporter cells, patient-derived neurons, and a mouse model and confers neuroprotection under proteotoxic conditions. These findings position MARK2 as a critical stress-sensing cytosolic regulator that promotes repeat-associated noncanonical translation and associated toxicity."
},
{
"quote": "Here we report the identification of a direct kinase of eIF2\u03b1, microtubule affinity-regulating kinase 2 (MARK2), which phosphorylates eIF2\u03b1 in response to proteotoxic stress.",
"source_id": "33705388",
"status": "PASS",
"error": "",
"abstract_text": "ID: 33705388\nTitle: MARK2 phosphorylates eIF2\u03b1 in response to proteotoxic stress.\nAbstract: The regulation of protein synthesis is essential for maintaining cellular homeostasis, especially during stress responses, and its dysregulation could underlie the development of human diseases. The critical step during translation regulation is the phosphorylation of eukaryotic initiation factor 2 alpha (eIF2\u03b1). Here we report the identification of a direct kinase of eIF2\u03b1, microtubule affinity-regulating kinase 2 (MARK2), which phosphorylates eIF2\u03b1 in response to proteotoxic stress. The activity of MARK2 was confirmed in the cells lacking the 4 previously known eIF2\u03b1 kinases. MARK2 itself was found to be a substrate of protein kinase C delta (PKC\u03b4), which serves as a sensor for protein misfolding stress through a dynamic interaction with heat shock protein 90 (HSP90). Both MARK2 and PKC\u03b4 are activated via phosphorylation in proteotoxicity-associated neurodegenerative mouse models and in human patients with amyotrophic lateral sclerosis (ALS). These results reveal a PKC\u03b4-MARK2-eIF2\u03b1 cascade that may play a critical role in cellular proteotoxic stress responses and human diseases."
},
{
"quote": "Amyotrophic lateral sclerosis (ALS)-associated mutations in the RNA-binding protein fused in sarcoma (FUS), which suppress local translation, disrupt the compartment-specific RNA signatures, including components of the translation machinery.",
"source_id": "41430470",
"status": "PASS",
"error": "",
"abstract_text": "ID: 41430470\nTitle: Axonal Eif5a hypusination controls local translation and mitigates defects in FUS-ALS.\nAbstract: Local protein synthesis is vital for neuronal function, but its dysregulation in neurodegenerative diseases remains poorly defined. Here we applied spatial transcriptomics to adult mouse motor nerve axons and cell bodies to enable subcellular mapping. Among transcripts found in mature axons, the most enriched biological process is protein translation, and localization of translation machinery was confirmed using multiplexed single-molecule spatial transcriptomics combined with immunofluorescence. Amyotrophic lateral sclerosis (ALS)-associated mutations in the RNA-binding protein fused in sarcoma (FUS), which suppress local translation, disrupt the compartment-specific RNA signatures, including components of the translation machinery. In particular, eukaryotic initiation factor 5a (Eif5a), a translation factor involved in elongation and termination, is found to be locally impaired in mutant FUS axons with reduced levels of its active hypusinated form. Axon-specific treatment with polyamine spermidine restores Eif5a hypusination and ameliorates mutant FUS-dependent neuronal defects, including suppression of local protein synthesis. Finally, in vivo spermidine treatment reduces ALS-related toxicity in mutant FUS and TDP-43 Drosophila models, which may have implications for therapy development."
},
{
"quote": "Spermine treatment limited infarct size, attenuated cardiac troponin I and creatinine kinase-MB release, improved cardiac function, and decreased ERS and apoptosis related protein expression.",
"source_id": "26828926",
"status": "PASS",
"error": "",
"abstract_text": "ID: 26828926\nTitle: Spermine inhibits Endoplasmic Reticulum Stress-induced Apoptosis: a New Strategy to Prevent Cardiomyocyte Apoptosis.\nAbstract: Endoplasmic reticulum stress (ERS) plays an important role in the progression of acute myocardial infarction (AMI), in part by mediating apoptosis. Polyamines, including putrescine, spermidine, and spermine, are polycations with anti-oxidative, anti-aging, and cell growth-promoting activities. This study aimed to determine the mechanisms by which spermine protects against ERS-induced apoptosis in rats following AMI. AMI was established by ligation of the left anterior descending coronary artery (LAD) in rats, and exogenous spermine was administered by intraperitoneal injection (2.5 mg/ml daily for 7 days pre-AMI). Spermine treatment limited infarct size, attenuated cardiac troponin I and creatinine kinase-MB release, improved cardiac function, and decreased ERS and apoptosis related protein expression. Isolated cardiomyocytes subjected to hypoxia showed significant increase in reactive oxygen species (ROS) and the expression of apoptosis and ERS related proteins; these effects occurred through PERK and eIF2\u03b1 phosphorylation. The addition of spermine attenuated cardiomyocyte apoptosis, suppressed the production of ROS, and inhibited ERS related pathways. Spermine was an effective pre-treatment strategy to attenuate cardiac ERS injury in rats, and the cardioprotective mechanism occurring through inhibition of ROS production and down regulation of the PERK-eIF2\u03b1 pathway. These findings provide a novel target for the prevention of apoptosis in the setting of AMI."
},
{
"quote": "Finally, rapamycin as well as spermidine, carbamazepine, and tamoxifen could also rescue the motor dysfunction of 7-mo-old FTLD-U mice.",
"source_id": "22932872",
"status": "PASS",
"error": "",
"abstract_text": "ID: 22932872\nTitle: Autophagy activators rescue and alleviate pathogenesis of a mouse model with proteinopathies of the TAR DNA-binding protein 43.\nAbstract: TDP-43 is a multifunctional DNA/RNA-binding protein that has been identified as the major component of the cytoplasmic ubiquitin (+) inclusions (UBIs) in diseased cells of frontotemporal lobar dementia (FTLD-U) and amyotrophic lateral sclerosis (ALS). Unfortunately, effective drugs for these neurodegenerative diseases are yet to be developed. We have tested the therapeutic potential of rapamycin, an inhibitor of the mammalian target of rapamycin (mTOR) and three other autophagy activators (spermidine, carbamazepine, and tamoxifen) in a FTLD-U mouse model with TDP-43 proteinopathies. Rapamycin treatment has been reported to be beneficial in some animal models of neurodegenerative diseases but not others. Furthermore, the effects of rapamycin treatment in FTLD-U have not been investigated. We show that rapamycin treatment effectively rescues the learning/memory impairment of these mice at 3 mo of age, and it significantly slows down the age-dependent loss of their motor function. These behavioral improvements upon rapamycin treatment are accompanied by a decreased level of caspase-3 and a reduction of neuron loss in the forebrain of FTLD-U mice. Furthermore, the number of cells with cytosolic TDP-43 (+) inclusions and the amounts of full-length TDP-43 as well as its cleavage products (35 kDa and 25 kDa) in the urea-soluble fraction of the cellular extract are significantly decreased upon rapamycin treatment. These changes in TDP-43 metabolism are accompanied by rapamycin-induced decreases in mTOR-regulated phospho-p70 S6 kinase (P-p70) and the p62 protein, as well as increases in the autophagic marker LC3. Finally, rapamycin as well as spermidine, carbamazepine, and tamoxifen could also rescue the motor dysfunction of 7-mo-old FTLD-U mice. These data suggest that autophagy activation is a potentially useful route for the therapy of neurodegenerative diseases with TDP-43 proteinopathies."
},
{
"quote": "Treatment with these nanoparticles significantly reduced p53-mediated neuronal ferroptosis and improved synaptic function both in vitro and in vivo.",
"source_id": "41177462",
"status": "PASS",
"error": "",
"abstract_text": "ID: 41177462\nTitle: Nasal-to-brain siRNA delivery based on trace amine associated receptor for improving cognitive function.\nAbstract: Gene-based therapies for central nervous system (CNS) disorders face substantial challenges in overcoming the blood-brain barrier (BBB) to effectively target brain tissues. The nasal-to-brain delivery route has gained increasing attention as it bypasses the BBB, facilitating faster drug delivery to the lesion site while minimizing systemic side effects. Here, we developed a nasal-to-brain delivery system to administer small interfering RNA (siRNA) for the treatment of radiation-induced brain injury (RBI). RNA sequencing revealed that the p53 signaling pathway was predominantly enriched in the hippocampus, with significant upregulation of Alox12B expression in RBI mice. To improve the delivery of siRNA targeting Alox12B, we engineered spermidine-modified ginseng-derived extracellular vesicles (S-GEVs) nanoparticles, termed S-GEVs@siRNA. These nanoparticles leveraged the targeting capabilities of spermidine for olfactory receptor-trace amine associated receptor (TAAR), enhancing siRNA delivery and therapeutic efficacy. After intranasal administration, the nanoparticles were efficiently internalized by olfactory receptor neurons (ORNs) via the olfactory nerve pathway. The nanoparticles then escaped lysosomes, releasing siRNA into the cytoplasm, leading to gene downregulation and therapeutic benefits. Our results demonstrated that the designed nanoparticles were absorbed by the ORNs labeled with the Olfactory Marker Protein (OMP) and TAAR5 and successfully entered the olfactory bulb and the brain. Treatment with these nanoparticles significantly reduced p53-mediated neuronal ferroptosis and improved synaptic function both in vitro and in vivo. In conclusion, S-GEVs@siRNA nanoparticles rapidly reached the olfactory bulb through TAAR-mediated endocytosis, entered hippocampal neurons, downregulated Alox12B expression, exerted neuroprotective effects, and alleviated RBI-induced cognitive dysfunction. The designed nasal-to-brain delivery system holds great promise for treating various CNS diseases."
},
{
"quote": "Cardiac autonomic dysfunction is increasingly recognized as a significant contributor to disease burden in ALS, manifesting as abnormalities in heart rate variability, sympathetic overactivity, and corrected QT prolongation.",
"source_id": "42441693",
"status": "PASS",
"error": "",
"abstract_text": "ID: 42441693\nTitle: Cardiac Autonomic Dysfunction and Sudden Cardiac Death in Amyotrophic Lateral Sclerosis: Clinical Implications and Considerations for Care.\nAbstract: Amyotrophic lateral sclerosis (ALS) is traditionally viewed as a motor neuron disease that progresses from muscular weakness to respiratory failure and death. Increasing evidence, however, demonstrates clinically meaningful involvement of the autonomic nervous system, particularly in cardiovascular regulation. This narrative review synthesizes current evidence on the mechanisms, clinical implications, and palliative considerations of cardiac autonomic dysfunction in ALS, with particular emphasis on its relationship to sudden cardiac death (SCD). Cardiac autonomic dysfunction is increasingly recognized as a significant contributor to disease burden in ALS, manifesting as abnormalities in heart rate variability, sympathetic overactivity, and corrected QT prolongation. These derangements may contribute to malignant arrhythmias, increasing susceptibility to SCD in combination with respiratory decline. Epidemiologic data suggest that SCD accounts for a meaningful proportion of ALS-related mortality, although it is likely underrecognized due to misclassification and lack of routine cardiac monitoring. Clinical implications include the need for improved risk stratification and earlier detection of autonomic dysfunction using accessible markers, such as electrocardiographic indices, orthostatic vital signs, and ambulatory monitoring. Emerging technologies, including wearable biosensors, may further enhance longitudinal assessment. These considerations also have direct relevance for advanced care planning, as ALS may involve unpredictable and abrupt cardiac death in addition to progressive respiratory decline. Recognizing ALS as a multisystem disorder with significant cardiac involvement supports the integration of structured cardiovascular monitoring into multidisciplinary care models and highlights the need for prospective studies to guide standardized management strategies."
},
{
"quote": "TJ-68 treatment increased tryptophan and aconitate levels but reduced serotonin and acetylcarnitine levels.",
"source_id": "42461445",
"status": "PASS",
"error": "",
"abstract_text": "ID: 42461445\nTitle: Metabolomic analyses of amyotrophic lateral sclerosis, muscle cramps, and TJ-68 treatment.\nAbstract: Most patients with amyotrophic lateral sclerosis (ALS), a fatal motor neuron disease, experience painful muscle cramps. Our recent pilot trial of the Japanese Kampo medicine TJ-68 suggested its efficacy in improving muscle cramps in patients with ALS. This study analyzed plasma metabolomic changes to identify the underlying mechanisms of muscle cramps in ALS and the effects of TJ-68. Plasma was obtained from 11 participants with ALS in the repeated crossover trial at five time points (baseline, two placebo phases, and two TJ-68 phases). Metabolites were analyzed using mass spectrometry. Linear mixed-effects models were applied to identify metabolite changes associated with muscle cramps, determine the effects of TJ-68 on metabolites, and predict which participants would respond to TJ-68. Higher glutamine/glutamate, arginine, and leucine levels were associated with more severe muscle cramps. TJ-68 treatment increased tryptophan and aconitate levels but reduced serotonin and acetylcarnitine levels. Long-chain acylcarnitine levels were correlated with muscle cramp severity, and their levels tended to decrease with treatment. Uric acid, \u03b2-aminoisobutyric acid, \u03b1-aminoadipic acid, and acetylcholine emerged as predictors of the efficacy of TJ-68. This study identified the metabolite profile of muscle cramps in ALS and the changes in metabolite levels after TJ-68 treatment. Several baseline metabolites were associated with the prediction of the response to muscle cramps following TJ-68 treatment. Uric acid might be particularly useful because of its easy measurement in standard assays. Our study affirms the value of metabolomic technology for future pharmacotherapy and studies in ALS."
}
]
},
"displayText": "Even though this fact check looked at unique up-to-date abstracts, new evidence may refute this answer in the future. Although \"Zero Hallucinated Moneyshot Quotes\" is programmatically enforced, AI is not always immune to inadvertently/erroneously misinterpreting data. This is not medical or professional advice, but instead, is an opinion calculated by AI based on the literature evaluated.\n\n###[CLAIM EVALUATED AND ANSWER TO USER]\n\"Discovery: Considering PubMed #41177462 and PubMed #41231952, Spermidine-modified extracellular vesicles can mitigate ALS-related C9orf72 RAN translation by modulating the MARK2-eIF2\u03b1 stress-sensing axis.\"\n\nAnswer: The claim is plausible (Alignment: 5) based on an intersection of evidence, though the provided literature does not explicitly test the combination of S-GEVs on MARK2-eIF2\u03b1 signaling. The literature confirms that MARK2 acts as a kinase of eIF2\u03b1 enhancing RAN translation (ID: 41231952) and that spermidine has demonstrated neuroprotective potential, including modulation of translation and autophagy (ID: 41430470, 22932872). However, no single study directly connects these.\n\n### [ABSTRACT & REWRITTEN CLAIM]\nScientific synthesis of MARK2-mediated stress sensing and potential therapeutic delivery of spermidine for C9-ALS/FTD. The potential to modulate the integrated stress response (ISR) and RAN translation via targeted delivery systems is supported by multiple independent nodes within the dataset.\n\n### [INTRODUCTION & JUSTIFICATION]\nThe molecular pathogenesis of C9orf72-associated neurodegeneration is driven by the production of dipeptide repeat proteins (DPRs) through repeat-associated non-AUG (RAN) translation. \"MARK2-eIF2\u03b1 signaling, activated by misfolded proteins including DPRs and TDP-43, is upregulated in C9-ALS patient tissues.\" The activation of this pathway serves as a critical stress-sensing mechanism that paradoxically enhances the production of the very proteins causing toxicity. \"Loss of MARK2 significantly suppresses RAN translation in reporter cells, patient-derived neurons, and a mouse model and confers neuroprotection under proteotoxic conditions.\" Consequently, targeting the kinase activity of MARK2 or the subsequent phosphorylation of eIF2\u03b1 is a valid therapeutic strategy to attenuate DPR-dependent pathogenesis. Emerging evidence indicates that \"Spermine treatment limited infarct size, attenuated cardiac troponin I and creatinine kinase-MB release, improved cardiac function, and decreased ERS and apoptosis related protein expression.\" Furthermore, \"Finally, rapamycin as well as spermidine, carbamazepine, and tamoxifen could also rescue the motor dysfunction of 7-mo-old FTLD-U mice.\" The ability to refine delivery via nanoparticle engineering provides a potential bridge, as \"Treatment with these nanoparticles significantly reduced p53-mediated neuronal ferroptosis and improved synaptic function both in vitro and in vivo.\"\n\n### [DISCUSSION: NOVEL & OVERLOOKED]\n* MARK2-eIF2\u03b1 signaling is a primary driver of noncanonical RAN translation in C9orf72 expansions (ID: 41231952).\n* Spermidine and its derivatives function as translation modifiers capable of enhancing cell health through autophagy and eIF5a hypusination (ID: 41430470, 22932872).\n* The use of ginseng-derived extracellular vesicles modified by spermidine provides a blueprint for targeted delivery to olfactory receptor neurons (ID: 41177462).\n* Cardiac autonomic dysfunction is an underrecognized, significant contributor to ALS burden, highlighting the multisystem nature of the disease (ID: 42441693).\n* Metabolomic profiling suggests that TJ-68 treatment in ALS modulates metabolites linked to muscle cramp severity, such as serotonin and acetylcarnitine (ID: 42461445).\n\n### [EVIDENCE, METHODOLOGY & CITATIONS]\n1. ID: 41231952 - \"MARK2-eIF2\u03b1 signaling, activated by misfolded proteins including DPRs and TDP-43, is upregulated in C9-ALS patient tissues.\"\n2. ID: 41231952 - \"Loss of MARK2 significantly suppresses RAN translation in reporter cells, patient-derived neurons, and a mouse model and confers neuroprotection under proteotoxic conditions.\"\n3. ID: 33705388 - \"Here we report the identification of a direct kinase of eIF2\u03b1, microtubule affinity-regulating kinase 2 (MARK2), which phosphorylates eIF2\u03b1 in response to proteotoxic stress.\"\n4. ID: 41430470 - \"Amyotrophic lateral sclerosis (ALS)-associated mutations in the RNA-binding protein fused in sarcoma (FUS), which suppress local translation, disrupt the compartment-specific RNA signatures, including components of the translation machinery.\"\n5. ID: 26828926 - \"Spermine treatment limited infarct size, attenuated cardiac troponin I and creatinine kinase-MB release, improved cardiac function, and decreased ERS and apoptosis related protein expression.\"\n6. ID: 22932872 - \"Finally, rapamycin as well as spermidine, carbamazepine, and tamoxifen could also rescue the motor dysfunction of 7-mo-old FTLD-U mice.\"\n7. ID: 41177462 - \"Treatment with these nanoparticles significantly reduced p53-mediated neuronal ferroptosis and improved synaptic function both in vitro and in vivo.\"\n8. ID: 42441693 - \"Cardiac autonomic dysfunction is increasingly recognized as a significant contributor to disease burden in ALS, manifesting as abnormalities in heart rate variability, sympathetic overactivity, and corrected QT prolongation.\"\n9. ID: 42461445 - \"TJ-68 treatment increased tryptophan and aconitate levels but reduced serotonin and acetylcarnitine levels.\"\n\n### [PROGRAMATICALLY MAPPED REFERENCES]\n[1]. ID: 41231952 - APA: Lu YN, Li X, Hayes L, Zhao XF, Wang J (2025). MARK2 regulates C9orf72 repeat-associated non-AUG translation.. Proceedings of the National Academy of Sciences of the United States of America. ID: 41231952.\n[2]. ID: 33705388 - APA: Lu YN, Kavianpour S, Zhang T, Zhang X, Nguyen D et al. (2021). MARK2 phosphorylates eIF2\u03b1 in response to proteotoxic stress.. PLoS biology. ID: 33705388.\n[3]. ID: 41430470 - APA: Piol D, Khalil B, Robberechts T, Killian T, Georgopoulou M et al. (2026). Axonal Eif5a hypusination controls local translation and mitigates defects in FUS-ALS.. Nature neuroscience. ID: 41430470.\n[4]. ID: 26828926 - APA: Wei C, Wang Y, Li M, Li H, Lu X et al. (2016). Spermine inhibits Endoplasmic Reticulum Stress-induced Apoptosis: a New Strategy to Prevent Cardiomyocyte Apoptosis.. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology. ID: 26828926.\n[5]. ID: 22932872 - APA: Wang IF, Guo BS, Liu YC, Wu CC, Yang CH et al. (2012). Autophagy activators rescue and alleviate pathogenesis of a mouse model with proteinopathies of the TAR DNA-binding protein 43.. Proceedings of the National Academy of Sciences of the United States of America. ID: 22932872.\n[6]. ID: 41177462 - APA: Cai L, Li S, Wan C, Xu B, Huang H et al. (2025). Nasal-to-brain siRNA delivery based on trace amine associated receptor for improving cognitive function.. Journal of controlled release : official journal of the Controlled Release Society. ID: 41177462.\n[7]. ID: 42441693 - APA: Fisher K, Ligay A, Stratford M, Hirani R, Ober DT et al. (2026). Cardiac Autonomic Dysfunction and Sudden Cardiac Death in Amyotrophic Lateral Sclerosis: Clinical Implications and Considerations for Care.. Cardiology in review. ID: 42441693.\n[8]. ID: 42461445 - APA: Mitsumoto H, Cheung K, Matsumoto T, Lanza I, Oskarsson B et al. (2026). Metabolomic analyses of amyotrophic lateral sclerosis, muscle cramps, and TJ-68 treatment.. Metabolomics : Official journal of the Metabolomic Society. ID: 42461445.\n",
"prompt": "CRITICAL INSTRUCTION: You MUST wrap your internal reasoning in ... tags at the very beginning of your response.\n\n=======================================================\nCONTEXT LITERATURE (STATIC CACHE):\nID: 42087256\nTitle: Targeting the integrated stress response or Ataxin-2 alleviates neurodegeneration in PolyGR models of C9orf72 associated frontotemporal dementia and amyotrophic lateral sclerosis.\nAbstract: Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are fatal, early-onset neurodegenerative diseases. The most common genetic cause of FTD and ALS is a G4C2 hexanucleotide repeat expansion in the C9orf72 gene. This mutation leads to the production of toxic dipeptide repeat proteins (DPRs), via repeat-associated non-AUG (RAN) translation. These DPRs disrupt stress granule (SG) dynamics, with SG regulators such as Ataxin-2 (ATXN2) implicated in disease risk. The integrated stress response (ISR), a key driver of SG formation via eIF2\u03b1 phosphorylation, has been linked to C9orf72 expansions, but the role of individual DPRs in ISR activation remains unclear. Here, using Drosophila models expressing physiologically relevant repeat length DPRs, we identify poly(GR) as a novel activator of the ISR, inducing early and sustained eIF2\u03b1 phosphorylation and SG accumulation prior to motor decline. Genetic inhibition of the ISR or knockdown of ATX2, the Drosophila orthologue of ATXN2, rescues motor deficits in these models. ATXN2 knockdown also reduces poly(GR) toxicity in mouse primary neurons. These findings position poly(GR) as a key driver of ISR activation and highlight ATXN2 and the ISR as promising therapeutic targets in C9orf72-associated FTD/ALS.\n\nID: 41231952\nTitle: MARK2 regulates C9orf72 repeat-associated non-AUG translation.\nAbstract: Protein homeostasis is exquisitely regulated through processes involving protein synthesis essential for cellular health and disease prevention. Repeat-associated non-AUG (RAN) translation at expanded GGGGCC repeats in the C9orf72 gene produces dipeptide repeat (DPR) proteins that are implicated in amyotrophic lateral sclerosis and frontotemporal dementia (C9-ALS/FTD). However, the mechanisms promoting this noncanonical translation remain incompletely understood. Here, we identify microtubule affinity-regulating kinase 2 (MARK2) as a key eIF2\u03b1 kinase that enhances RAN translation under proteotoxic stress. We show that MARK2-eIF2\u03b1 signaling, activated by misfolded proteins including DPRs and TDP-43, is upregulated in C9-ALS patient tissues. Loss of MARK2 significantly suppresses RAN translation in reporter cells, patient-derived neurons, and a mouse model and confers neuroprotection under proteotoxic conditions. These findings position MARK2 as a critical stress-sensing cytosolic regulator that promotes repeat-associated noncanonical translation and associated toxicity.\n\nID: 38301895\nTitle: eIF5 stimulates the CUG initiation of RAN translation of poly-GA dipeptide repeat protein (DPR) in C9orf72 FTLD/ALS.\nAbstract: Tandem GGGGCC repeat expansion in C9orf72 is a genetic cause of frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). Transcribed repeats are translated into dipeptide repeat proteins via repeat-associated non-AUG (RAN) translation. However, the regulatory mechanism of RAN translation remains unclear. Here, we reveal a GTPase-activating protein, eukaryotic initiation factor 5 (eIF5), which allosterically facilitates the conversion of eIF2-bound GTP into GDP upon start codon recognition, as a novel modifier of C9orf72 RAN translation. Compared to global translation, eIF5, but not its inactive mutants, preferentially stimulates poly-GA RAN translation. RAN translation is increased during integrated stress response, but the stimulatory effect of eIF5 on poly-GA RAN translation was additive to the increase of RAN translation during integrated stress response, with no further increase in phosphorylated eIF2\u03b1. Moreover, an alteration of the CUG near cognate codon to CCG or AUG in the poly-GA reading frame abolished the stimulatory effects, indicating that eIF5 primarily acts through the CUG-dependent initiation. Lastly, in a Drosophila model of C9orf72 FTLD/ALS that expresses GGGGCC repeats in the eye, knockdown of endogenous eIF5 by two independent RNAi strains significantly reduced poly-GA expressions, confirming in\u00a0vivo effect of eIF5 on poly-GA RAN translation. Together, eIF5 stimulates the CUG initiation of poly-GA RAN translation in cellular and Drosophila disease models of C9orf72 FTLD/ALS.\n\nID: 35171477\nTitle: Measuring Repeat-Associated Non-AUG (RAN) Translation.\nAbstract: Expansions of short nucleotide repeats account for more than 50 neurological or neuromuscular diseases. Many repeat expansion-containing RNAs can generate toxic repeat proteins through repeat-associated non-AUG (RAN) translation in all the reading frames. Understanding how RAN translation occurs and what cellular factors regulate this process will help decipher the basic mechanism of the molecular process and disease pathogenesis. Using reporter systems to quantitatively measure RAN translation provides a platform to examine candidate genes/pathways and screen for modifiers of this non-canonical pathway. In this chapter, we describe the dual-luciferase reporter system to measure RAN translation using C9ORF72 GGGGCCexp as an example, which is the most common genetic\u00a0cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).\n\nID: 33705388\nTitle: MARK2 phosphorylates eIF2\u03b1 in response to proteotoxic stress.\nAbstract: The regulation of protein synthesis is essential for maintaining cellular homeostasis, especially during stress responses, and its dysregulation could underlie the development of human diseases. The critical step during translation regulation is the phosphorylation of eukaryotic initiation factor 2 alpha (eIF2\u03b1). Here we report the identification of a direct kinase of eIF2\u03b1, microtubule affinity-regulating kinase 2 (MARK2), which phosphorylates eIF2\u03b1 in response to proteotoxic stress. The activity of MARK2 was confirmed in the cells lacking the 4 previously known eIF2\u03b1 kinases. MARK2 itself was found to be a substrate of protein kinase C delta (PKC\u03b4), which serves as a sensor for protein misfolding stress through a dynamic interaction with heat shock protein 90 (HSP90). Both MARK2 and PKC\u03b4 are activated via phosphorylation in proteotoxicity-associated neurodegenerative mouse models and in human patients with amyotrophic lateral sclerosis (ALS). These results reveal a PKC\u03b4-MARK2-eIF2\u03b1 cascade that may play a critical role in cellular proteotoxic stress responses and human diseases.\n\nID: 30617154\nTitle: Repeat-associated non-AUG translation in C9orf72-ALS/FTD is driven by neuronal excitation and stress.\nAbstract: Nucleotide repeat expansions (NREs) are prevalent mutations in a multitude of neurodegenerative diseases. Repeat-associated non-AUG (RAN) translation of these repeat regions produces mono or dipeptides that contribute to the pathogenesis of these diseases. However, the mechanisms and drivers of RAN translation are not well understood. Here we analyzed whether different cellular stressors promote RAN translation of dipeptide repeats (DPRs) associated with the G4C2 hexanucleotide expansions in C9orf72, the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). We found that activating glutamate receptors or optogenetically increasing neuronal activity by repetitive trains of depolarization induced DPR formation in primary cortical neurons and patient derived spinal motor neurons. Increases in the integrated stress response (ISR) were concomitant with increased RAN translation of DPRs, both in neurons and different cell lines. Targeting phosphorylated-PERK and the phosphorylated-eif2\u03b1 complex reduces DPR levels revealing a potential therapeutic strategy to attenuate DPR-dependent disease pathogenesis in NRE-linked diseases.\n\nID: 29302060\nTitle: C9ORF72 GGGGCC repeat-associated non-AUG translation is upregulated by stress through eIF2\u03b1 phosphorylation.\nAbstract: Hexanucleotide repeat expansion in C9ORF72 is the most frequent cause of both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Here we demonstrate that the repeat-associated non-AUG (RAN) translation of (GGGGCC) n -containing RNAs into poly-dipeptides can initiate in vivo without a 5'-cap. The primary RNA substrate for RAN translation of C9ORF72 sense repeats is shown to be the spliced first intron, following its excision from the initial pre-mRNA and transport to the cytoplasm. Cap-independent RAN translation is shown to be upregulated by various stress stimuli through phosphorylation of the \u03b1 subunit of eukaryotic initiation factor-2 (eIF2\u03b1), the core event of an integrated stress response (ISR). Compounds inhibiting phospho-eIF2\u03b1-signaling pathways are shown to suppress RAN translation. Since the poly-dipeptides can themselves induce stress, these findings support a feedforward loop with initial repeat-mediated toxicity enhancing RAN translation and subsequent production of additional poly-dipeptides through ISR, thereby promoting progressive disease.\n\nID: 29222490\nTitle: RAN translation at C9orf72-associated repeat expansions is selectively enhanced by the integrated stress response.\nAbstract: Repeat-associated non-AUG (RAN) translation allows for unconventional initiation at disease-causing repeat expansions. As RAN translation contributes to pathogenesis in multiple neurodegenerative disorders, determining its mechanistic underpinnings may inform therapeutic development. Here we analyze RAN translation at G4C2 repeat expansions that cause C9orf72-associated amyotrophic lateral sclerosis and frontotemporal dementia (C9RAN) and at CGG repeats that cause fragile X-associated tremor/ataxia syndrome. We find that C9RAN translation initiates through a cap- and eIF4A-dependent mechanism that utilizes a CUG start codon. C9RAN and CGG RAN are both selectively enhanced by integrated stress response (ISR) activation. ISR-enhanced RAN translation requires an eIF2\u03b1 phosphorylation-dependent alteration in start codon fidelity. In parallel, both CGG and G4C2 repeats trigger phosphorylated-eIF2\u03b1-dependent stress granule formation and global translational suppression. These findings support a model whereby repeat expansions elicit cellular stress conditions that favor RAN translation of toxic proteins, creating a potential feed-forward loop that contributes to neurodegeneration.\n\nID: 41430470\nTitle: Axonal Eif5a hypusination controls local translation and mitigates defects in FUS-ALS.\nAbstract: Local protein synthesis is vital for neuronal function, but its dysregulation in neurodegenerative diseases remains poorly defined. Here we applied spatial transcriptomics to adult mouse motor nerve axons and cell bodies to enable subcellular mapping. Among transcripts found in mature axons, the most enriched biological process is protein translation, and localization of translation machinery was confirmed using multiplexed single-molecule spatial transcriptomics combined with immunofluorescence. Amyotrophic lateral sclerosis (ALS)-associated mutations in the RNA-binding protein fused in sarcoma (FUS), which suppress local translation, disrupt the compartment-specific RNA signatures, including components of the translation machinery. In particular, eukaryotic initiation factor 5a (Eif5a), a translation factor involved in elongation and termination, is found to be locally impaired in mutant FUS axons with reduced levels of its active hypusinated form. Axon-specific treatment with polyamine spermidine restores Eif5a hypusination and ameliorates mutant FUS-dependent neuronal defects, including suppression of local protein synthesis. Finally, in vivo spermidine treatment reduces ALS-related toxicity in mutant FUS and TDP-43 Drosophila models, which may have implications for therapy development.\n\nID: 41177462\nTitle: Nasal-to-brain siRNA delivery based on trace amine associated receptor for improving cognitive function.\nAbstract: Gene-based therapies for central nervous system (CNS) disorders face substantial challenges in overcoming the blood-brain barrier (BBB) to effectively target brain tissues. The nasal-to-brain delivery route has gained increasing attention as it bypasses the BBB, facilitating faster drug delivery to the lesion site while minimizing systemic side effects. Here, we developed a nasal-to-brain delivery system to administer small interfering RNA (siRNA) for the treatment of radiation-induced brain injury (RBI). RNA sequencing revealed that the p53 signaling pathway was predominantly enriched in the hippocampus, with significant upregulation of Alox12B expression in RBI mice. To improve the delivery of siRNA targeting Alox12B, we engineered spermidine-modified ginseng-derived extracellular vesicles (S-GEVs) nanoparticles, termed S-GEVs@siRNA. These nanoparticles leveraged the targeting capabilities of spermidine for olfactory receptor-trace amine associated receptor (TAAR), enhancing siRNA delivery and therapeutic efficacy. After intranasal administration, the nanoparticles were efficiently internalized by olfactory receptor neurons (ORNs) via the olfactory nerve pathway. The nanoparticles then escaped lysosomes, releasing siRNA into the cytoplasm, leading to gene downregulation and therapeutic benefits. Our results demonstrated that the designed nanoparticles were absorbed by the ORNs labeled with the Olfactory Marker Protein (OMP) and TAAR5 and successfully entered the olfactory bulb and the brain. Treatment with these nanoparticles significantly reduced p53-mediated neuronal ferroptosis and improved synaptic function both in vitro and in vivo. In conclusion, S-GEVs@siRNA nanoparticles rapidly reached the olfactory bulb through TAAR-mediated endocytosis, entered hippocampal neurons, downregulated Alox12B expression, exerted neuroprotective effects, and alleviated RBI-induced cognitive dysfunction. The designed nasal-to-brain delivery system holds great promise for treating various CNS diseases.\n\nID: 28886181\nTitle: Activation of endoplasmic reticulum stress response by enhanced polyamine catabolism is important in the mediation of cisplatin-induced acute kidney injury.\nAbstract: Cisplatin-induced nephrotoxicity limits its use in many cancer patients. The expression of enzymes involved in polyamine catabolism, spermidine/spermine N1-acetyltransferase (SSAT) and spermine oxidase (SMOX) increase in the kidneys of mice treated with cisplatin. We hypothesized that enhanced polyamine catabolism contributes to tissue damage in cisplatin acute kidney injury (AKI). Using gene knockout and chemical inhibitors, the role of polyamine catabolism in cisplatin AKI was examined. Deficiency of SSAT, SMOX or neutralization of the toxic products of polyamine degradation, H2O2 and aminopropanal, significantly diminished the severity of cisplatin AKI. In vitro studies demonstrated that the induction of SSAT and elevated polyamine catabolism in cells increases the phosphorylation of eukaryotic translation initiation factor 2\u03b1 (eIF2\u03b1) and enhances the expression of binding immunoglobulin protein BiP/GRP78) and CCAAT-enhancer-binding protein homologous protein (CHOP/GADD153). The increased expression of these endoplasmic reticulum stress response (ERSR) markers was accompanied by the activation of caspase-3. These results suggest that enhanced polyamine degradation in cisplatin AKI may lead to tubular damage through the induction of ERSR and the consequent onset of apoptosis. In support of the above, we show that the ablation of the SSAT or SMOX gene, as well as the neutralization of polyamine catabolism products modulate the onset of ERSR (e.g. lower BiP and CHOP) and apoptosis (e.g. reduced activated caspase-3). These studies indicate that enhanced polyamine catabolism and its toxic products are important mediators of ERSR and critical to the pathogenesis of cisplatin AKI.\n\nID: 26828926\nTitle: Spermine inhibits Endoplasmic Reticulum Stress-induced Apoptosis: a New Strategy to Prevent Cardiomyocyte Apoptosis.\nAbstract: Endoplasmic reticulum stress (ERS) plays an important role in the progression of acute myocardial infarction (AMI), in part by mediating apoptosis. Polyamines, including putrescine, spermidine, and spermine, are polycations with anti-oxidative, anti-aging, and cell growth-promoting activities. This study aimed to determine the mechanisms by which spermine protects against ERS-induced apoptosis in rats following AMI. AMI was established by ligation of the left anterior descending coronary artery (LAD) in rats, and exogenous spermine was administered by intraperitoneal injection (2.5 mg/ml daily for 7 days pre-AMI). Spermine treatment limited infarct size, attenuated cardiac troponin I and creatinine kinase-MB release, improved cardiac function, and decreased ERS and apoptosis related protein expression. Isolated cardiomyocytes subjected to hypoxia showed significant increase in reactive oxygen species (ROS) and the expression of apoptosis and ERS related proteins; these effects occurred through PERK and eIF2\u03b1 phosphorylation. The addition of spermine attenuated cardiomyocyte apoptosis, suppressed the production of ROS, and inhibited ERS related pathways. Spermine was an effective pre-treatment strategy to attenuate cardiac ERS injury in rats, and the cardioprotective mechanism occurring through inhibition of ROS production and down regulation of the PERK-eIF2\u03b1 pathway. These findings provide a novel target for the prevention of apoptosis in the setting of AMI.\n\nID: 22932872\nTitle: Autophagy activators rescue and alleviate pathogenesis of a mouse model with proteinopathies of the TAR DNA-binding protein 43.\nAbstract: TDP-43 is a multifunctional DNA/RNA-binding protein that has been identified as the major component of the cytoplasmic ubiquitin (+) inclusions (UBIs) in diseased cells of frontotemporal lobar dementia (FTLD-U) and amyotrophic lateral sclerosis (ALS). Unfortunately, effective drugs for these neurodegenerative diseases are yet to be developed. We have tested the therapeutic potential of rapamycin, an inhibitor of the mammalian target of rapamycin (mTOR) and three other autophagy activators (spermidine, carbamazepine, and tamoxifen) in a FTLD-U mouse model with TDP-43 proteinopathies. Rapamycin treatment has been reported to be beneficial in some animal models of neurodegenerative diseases but not others. Furthermore, the effects of rapamycin treatment in FTLD-U have not been investigated. We show that rapamycin treatment effectively rescues the learning/memory impairment of these mice at 3 mo of age, and it significantly slows down the age-dependent loss of their motor function. These behavioral improvements upon rapamycin treatment are accompanied by a decreased level of caspase-3 and a reduction of neuron loss in the forebrain of FTLD-U mice. Furthermore, the number of cells with cytosolic TDP-43 (+) inclusions and the amounts of full-length TDP-43 as well as its cleavage products (35 kDa and 25 kDa) in the urea-soluble fraction of the cellular extract are significantly decreased upon rapamycin treatment. These changes in TDP-43 metabolism are accompanied by rapamycin-induced decreases in mTOR-regulated phospho-p70 S6 kinase (P-p70) and the p62 protein, as well as increases in the autophagic marker LC3. Finally, rapamycin as well as spermidine, carbamazepine, and tamoxifen could also rescue the motor dysfunction of 7-mo-old FTLD-U mice. These data suggest that autophagy activation is a potentially useful route for the therapy of neurodegenerative diseases with TDP-43 proteinopathies.\n\nID: 42573824\nTitle: Clinical significance of SQSTM1 variants in ALS: report of p.Arg119Cys and literature review.\nAbstract: We analyzed the clinical features of a patient with amyotrophic lateral sclerosis (ALS) carrying a novel variant in the sequestosome 1 (SQSTM1) gene and explored the genotype-phenotype association of SQSTM1 gene variants in combination with previous literature. Clinical data and genetic testing results of an ALS patient treated at our hospital were collected. Whole-exome sequencing was used to screen for ALS-related genes, and candidate variants were validated by Sanger sequencing and family analysis. A systematic search was conducted in the PubMed database using the keywords (\"amyotrophic lateral sclerosis\") OR (\"motor neuron disease\") AND (\"SQSTM1\") to summarize the clinical and genetic characteristics of previously reported ALS patients with SQSTM1 variants. The patient was a 49-year-old male with progressive weakness in both lower limbs for one year and weakness in the left upper limb for the past three months. Electromyography showed extensive neurogenic damage. Genetic testing identified a novel heterozygous missense variant, c.355 C\u2009>\u2009T (p.Arg119Cys), in the SQSTM1 gene. Family verification revealed that his phenotypically normal mother carried the same variant. The literature search identified 58 cases of ALS associated with SQSTM1 variants. Missense variants were the most common type. We identified a novel SQSTM1 variant, c.355 C\u2009>\u2009T (p.Arg119Cys), in a ALS patient. Although this finding expands the variant spectrum, its pathogenicity remains uncertain and requires further functional validation and pedigree confirmation. Our literature review further shows that SQSTM1-associated ALS predominantly presents with limb onset, with a subset of patients exhibiting frontotemporal dementia or Paget's disease.\n\nID: 42572514\nTitle: Relationship between neck weakness in motor neurone disease and respiratory function: a retrospective study.\nAbstract: The primary aim was to explore the relationship between neck weakness in people with motor neurone disease (MND) and their respiratory function. The secondary aim was to identify whether neck weakness can be a prognostic factor. This was a retrospective observational cohort study. Data was collected from patient records on MND characteristics, neck weakness, respiratory function, and noninvasive ventilation (NIV) use. Multivariate modeling explored the effect of neck weakness on respiratory variables. MND-related neck weakness was evident in 41% of 324 participants. Fifty-four percent used NIV and 17% became dependent on NIV during disease progression. The presence of neck weakness in MND was predictive of time to respiratory function decline, for respiratory outcomes (forced vital capacity (FVC) <65%, FVC\u2009<50% and NIV use) as well as having an effect on time to death. Median time from neck weakness onset to death was 8\u2009months (IQR 10\u2009months; range 0 to 60\u2009months) with bulbar onset the quickest, median of 7\u2009months (IQR 7\u2009months, range 0 to 43\u2009months). The presence of neck weakness is associated with a more rapid respiratory function decline in MND. In addition, neck weakness can be considered a prognostic factor in MND survival. People with motor neurone disease (MND) experience weakness in different parts of their body including muscles that are responsible for breathing. As the disease worsens, it is expected that their breathing worsens, resulting in death. To help prolong the person\u2019s life, timely equipment that makes breathing easier is important. It is thought that there may be a relationship between weakness spreading to the neck muscles and the person\u2019s ability to breathe and whether it could help predict how the disease will progress. To explore this further, we reviewed the medical records of 324 people with MND. We found that about 4 in 10 people had neck weakness from their MND and over half were using breathing support. We also found that those with neck weakness tended to lose their breathing function more quickly and needed breathing support sooner. People with neck weakness were also found to have a shorter survival time, with an average of 8 months once their neck weakness began, however this varied depending on the type of MND the person had.\n\nID: 42566069\nTitle: Value of ultrasound-detected fasciculations for the early diagnosis of motor neuron disease in patients with single-segment, pure lower motor neuron involvement.\nAbstract: To evaluate the early diagnostic value of muscle ultrasound (US)-detected fasciculations in motor neuron disease (MND) patients presenting with single\u2011region, pure lower motor neuron (LMN) involvement. Prospective cohort study enrolling 60 patients with clinical LMN signs confined to one body region. All underwent standardized needle EMG and muscle US at baseline. Final diagnosis determined by follow-up. Agreement between EMG and US, and net diagnostic gain of US were analyzed. 54 MND patients (median disease duration 9 months) were analyzed. US detection rates: bulbar 38.9%-46.3%; high-grade cervical fasciculations 20.4%-37.0%. EMG-US agreement was poor to fair (kappa 0.106-0.360). US provided additional LMN evidence in EMG-negative regions in 27.8% (bulbar), 22.2% (cervical) and 9.3% (lumbosacral). Using US (\u2265\u20092 regions with fasciculations/high-grade) as an ancillary criterion, 53.7% were diagnosed at first visit; median time to diagnosis was 5 months (range 3-8) in those otherwise missed. Muscle ultrasound is a sensitive, non-invasive complement to EMG, significantly improving early diagnosis in single-region pure LMN presentations. However, specificity estimates remain preliminary due to the limited number of non-MND controls.\n\nID: 42566063\nTitle: Anti-IgLON5 disease presenting with a motor neuron disease-like phenotype after decades of sleep symptoms: a potentially immunotherapy responsive mimic.\nAbstract: \n\nID: 42565151\nTitle: A Systematic Literature Review of Emerging Advances in Neurological Disorders: Diagnostic Innovations, Therapeutic Strategies, and Future Directions.\nAbstract: Neurological disorders remain a major clinical burden because they affect cognition, movement, vascular function, behavior, psychological health, and long-term independence. Recent advances in imaging, biomarkers, artificial intelligence, regenerative therapy, immunotherapy, and targeted pharmacology have expanded diagnostic and therapeutic possibilities, yet the evidence remains dispersed across different neurological conditions and study designs. This review aimed to synthesize emerging advances in neurological disorders, focusing on diagnostic innovations, therapeutic strategies, and future clinical directions. A systematic literature review approach was applied using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)-based screening principles. Eleven studies were included, covering ischemic stroke, glioblastoma, Alzheimer's disease, multiple sclerosis, Parkinson's disease, motor neuron disease, episodic migraine, transient ischemic attack, and postoperative delirium. Data were extracted on study design, condition, intervention or diagnostic method, comparator, outcomes, and key findings. Risk of bias was assessed using the Risk of Bias 2 (RoB 2) tool for randomized trials, the Risk of Bias in Non-randomized Studies of Interventions (ROBINS-I) for nonrandomized, uncontrolled, post hoc, feasibility, and biomarker-monitoring studies, and the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) for diagnostic and radiomics studies. Findings showed increasing use of radiomics, circulating tumor DNA, rhythm monitoring, vascular imaging, inflammatory markers, biologics, cell therapy, psychological intervention, and lipid-lowering therapy. Several studies reported promising clinical or biomarker signals, while others clarified treatment limitations in specific disease subtypes. Overall, the findings suggest an emerging shift toward precision-oriented neurology, but larger controlled trials, prospective biomarker validation, standardized outcomes, and longer follow-up are required before routine implementation.\n\nID: 42563536\nTitle: Enabling Functional Independence: A Scoping Review of Upper Extremity Assistive Devices for Adults With Progressive Neuromuscular Diseases.\nAbstract: Assistive technology offers an important means of compensating for lost upper extremity function in adults with progressive neuromuscular diseases (NMD), enabling participation in daily activities, supporting independence, and promoting quality of life. However, the range of available technologies and the evidence supporting their use have not been comprehensively summarized. The aim of this scoping review was to identify and characterize upper extremity assistive technologies tested in adults with NMD and to summarize the current evidence regarding their functional applications and clinical outcomes. Electronic searches for published and unpublished literature were conducted using MEDLINE, Embase.com, Web of Science, Cochrane Central, and IEEE Xplore. The search strategy incorporated controlled vocabulary and free-text synonyms for the concepts of upper extremity, rehabilitation, selected progressive neurodegenerative diseases, and assistive equipment. Following title/abstract and full-text screening, studies evaluating assistive devices tested on adults with NMD during functional task performance were included. After screening 2289 articles, 27 studies met the inclusion criteria. The studies collectively demonstrate the potential benefits and diverse range of assistive devices available to support upper extremity function. These devices ranged from low-tech solutions, such as static mobile arm supports and fabricated splints, to high-tech devices, including dynamic mobile arm supports, robotic systems, exoskeletons, and brain-computer interface systems. However, most studies were feasibility or case studies that primarily demonstrated proof of concept, with limited evidence regarding long-term effectiveness, functional outcomes, or quality of life. The findings illustrate the rapidly evolving landscape of upper extremity assistive devices for adults with NMD and their potential to improve functional performance, while highlighting the need for prospective studies that assess meaningful improvements in function, participation, and quality of life. As advances in disease-modifying therapies extend survival and preserve function for individuals with NMD, interdisciplinary collaboration among engineers, clinicians, therapists, individuals with NMD, caregivers, and regulators will be essential to develop, evaluate, and implement assistive technologies that meet users' evolving needs.\n\nID: 42558984\nTitle: The Effectiveness Based on Optimal Dose and Administration Route, and Safety Profiles of Stem Cells and Derived Products in the Treatment of Patients With Amyotrophic Lateral Sclerosis: A Systematic Review and Meta-Analysis.\nAbstract: This systematic review and meta-analysis aimed to evaluate the effectiveness of stem cell therapies for patients with amyotrophic lateral sclerosis (ALS) based on optimal dosing and administration routes, as well as the safety profiles of stem cells and their derived products. The review followed PRISMA guidelines and involved a comprehensive literature search up to October 2025, receiving ethical approval from Tabriz University of Medical Sciences and registration in PROSPERO. It utilized international databases, including PubMed/MEDLINE, Embase, Cochrane Library, Scopus, Web of Science, ProQuest, ClinicalTrials.gov, and Science Direct. The included studies comprised randomized controlled trials (RCTs), quasi-experimental studies, and other interventional designs involving ALS patients treated with stem cell therapies. In total, 31 studies were analyzed, featuring 7 controlled trials with 370 participants and 24 non-controlled pre-post studies with 460 participants. Heterogeneity was evaluated using I 2 statistics, and subgroup analyses were conducted based on treatment duration and dosing. A pooled analysis (treatment group: n\u2009=\u200993; control group: n\u2009=\u200990) demonstrated a significant attenuation in the progression of disease severity, as measured by the ALS Functional Rating Scale (ALSFRS), in stem cell groups versus controls (weighted mean difference [WMD]: 8.89 95% CI: 4.12-13.67; p = 0.0003), which was beneficial for both the \u226510\u2009\u00d7\u2009106 and <10\u2009\u00d7\u2009106 dose sub-groups. However, a meta-analysis of single-arm studies in two control (pre-intervention) and intervention phases (n\u2009=\u200988) demonstrated no significant difference in progression of ALSFRS between study phases by time: month 3 (WMD: -1.27 (-3.01 to 0.47); p = 0.15), month 6 (WMD: -2.69 (-5.62 to 0.25); p = 0.07), month 9 (WMD: -1.55 (-3.49 to 0.39); p = 0.12), and month 12 (WMD: -7.59 (-13.95 to -1.26); p = 0.02). An accelerated decline in forced vital capacity (FVC) was observed during the intervention phase, with statistically significant reductions at month 3 (WMD: -10.91; 95% CI: -16.39 to -5.43; p < 0.0001) and month 6 (WMD: -15.97; 95% CI: -28.60 to -3.33; p = 0.01) compared with the pre-intervention control phase. Nevertheless, sensitivity analyses excluding studies involving high-dose mesenchymal stem cell (MSC) therapies demonstrated that these differences were no longer statistically significant. Moreover, no significant change in progression rate was observed at month 9 (WMD: -8.10 (-18.25 to 2.06); p = 0.12). The route of MSCs administration (intrathecal [IT], intramuscular [IM], and intravenous [IV]) had no effect on the results of ALSFRS and FVC, reinforced by sensitivity analyses. Adverse events were mostly mild, with headaches most frequent in high-dose groups. Stem cell therapy for ALS appears to be safe, with preliminary evidence suggesting potential therapeutic benefit in slowing disease progression in selected patients. Nevertheless, the existing evidence base remains exploratory, and definitive conclusions regarding clinical effectiveness cannot yet be drawn. Future research should prioritize large-scale and multicenter RCTs with standardized cell manufacturing protocols and longer follow-up periods.\n\nID: 42553390\nTitle: Fractal and Machine Learning Analyses of MALDI-TOF Mass Spectrometry Data in Glioblastoma.\nAbstract: Data preprocessing is a critical step in the analysis of matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry (MALDI-TOF MS) spectra for machine learning applications, typically involving steps such as spectra trimming, baseline correction, smoothing, transformation, and peak picking or spectral binning. While traditional approaches focus on protein/peptide peaks as features, this study explores a novel method of feature extraction by treating MALDI-TOF spectra as one-dimensional signal array further processed as time-series data. This study investigates the use of computational fractal-based analysis to assess the complexity of MALDI-TOF spectra. Fractal analysis, previously successful in glioblastoma diagnosis using magnetic resonance imaging, was applied here to proteomics data. By treating each MALDI spectrum as a time series and calculating its fractal dimension using various algorithms, machine learning models were trained to differentiate between glioblastoma patients and controls. We demonstrate that fractal dimensions are sufficient to obtain accurate models for glioblastoma diagnosis, despite still underperforming when compared to the traditional feature extraction method. We also show that fractals can be used as support features to increase model performance. This work highlights the potential and limitations of fractal analysis in proteomics, offering a new perspective for disease diagnosis and broadening the available computational tools for data analysis in mass spectrometry.\n\nID: 42550987\nTitle: Co-Designing a Care Coordination Intervention for People With Motor Neuron Disease: Protocol for a Mixed Methods Study.\nAbstract: Motor neuron disease (MND), also known as amyotrophic lateral sclerosis (ALS), is a rapidly progressive neurological condition that requires complex multidisciplinary care. Within the United Kingdom, specialist centers provide expert interventions, while day-to-day support often relies on local nonspecialist community health and social care professionals. This is due to the distance between people's homes and specialist centers, as well as the availability of specialist health and social care professionals. This can lead to fragmented communication and emotional, physical, and financial burdens, and it can be time-consuming for people living with MND, their carers, and the health care professionals involved in their care. Despite the recognized need for better care coordination, it remains inadequate in practice, with a current lack of specific evidence-based interventions for achieving this. The MND Together project aims to address these systemic gaps by (1) developing a national picture of care coordination in England and Wales, (2) identifying barriers and facilitators to coordination within specialist and nonspecialist settings, and (3) co-designing a practical care coordination tool with key stakeholders. This protocol outlines the co-design of an intervention underpinned by the Behavior Change Wheel and the Socioecological Model. First, a mixed methods, multicenter study will be conducted to develop a national picture, comprising focus groups with people living with MND, carers, and health and social care professionals. Second, focused ethnography will be conducted in 5 MND specialist centers and their catchment areas, involving 25 people living with MND, to explore the barriers and facilitators to coordination in practice. Finally, a series of co-design workshops will be conducted to identify key priorities for care coordination and to develop a new intervention, the MND Together tool. The project started in September 2025 and will run until October 2027. Workstream 1 started in December 2025, with recruitment beginning at the first site in February 2026. To date, we have recruited 23 people living with MND and carers as well as 16 health and social care professionals across 4 of the 9 sites. Workstream 1 will end in August 2026, with results published at the end of 2026. Workstream 2 began in May 2026 and will run until February 2027, with results published in the summer of 2027. Workstream 3 will begin in March 2027 and conclude with the co-design intervention developed by late 2027. This will then be piloted in practice. By combining several methodologies with meaningful patient and public involvement and engagement, MND Together seeks to bridge the gap between specialist and community-based services. The MND Together tool aims to improve the quality of care and ensure that expert MND support is accessible as close as possible to every patient's home.\n\nID: 42548788\nTitle: Tofersen Treatment in SOD1-ALS: Real-World Evidence from a Retrospective Multicenter Study in France (FORSLA Study).\nAbstract: To evaluate the effectiveness of Tofersen in patients with superoxide dismutase 1 gene (SOD1-ALS) patients in France in a real-world setting, using disease progression within patient comparisons and with a historical cohort. Patients with SOD1-ALS were included from across 19 French FILSLAN network centers. Baseline was defined as the treatment initiation date. Main endpoints were the ALSFRS-R progression rate and plasmatic neurofilament light chain (NfL) levels at baseline and 12 months after baseline. In the Tofersen Cohort (N=46), within-group comparisons showed that the mean ALS functional rating scale revised (ALSFRS-R) progression rate slowed from 0.53 \u00b1 0.5 at baseline to 0.22 \u00b1 0.3 point/month at 12 months (P=.006). NfL levels significantly decreased from 89.0 \u00b1 9.0 pg/ml at baseline to 29.2 \u00b1 19.5.5 at 12 months (P=.004). Exploratory comparisons with a propensity score (PS) matched historical cohort (39 matched pairs) using a mixed-effects model, ALSFRS-R progression rate at baseline, 6 months, and 12 months after baseline, showed no statistically significant differences between groups P=.30, whereas longitudinal ALSFRS-R scores differed significantly between groups (time-treatment interaction P=.006). The mean survival of the PS matched population was longer in the Tofersen Cohort (42.6 months) than the Historical Cohort (31.8 months) P=.004. Time-dependent adjusted cox analysis showed that Tofersen was associated with a reduction in mortality risk (adjusted HR=0.34; 95% CI, 0.12-0.91; P=.03). Tofersen seems to be associated with slower functional decline and reduced NfL levels. While limitations of retrospective design and ALSFRS-R sensitivity must be acknowledged, these findings provide real-world evidence suggesting a clinical benefit of Tofersen.\n\nID: 42545188\nTitle: Neuropsychological Sub-Phenotypes in Amyotrophic Lateral Sclerosis.\nAbstract: This study aimed at identifying neuropsychological sub-phenotypes in amyotrophic lateral sclerosis (ALS) within the mild cognitive impairment (MCI) and mild behavioral impairment (MBI) frameworks. We used individual task-/item-level data from the cognitive and behavioral sections of the Edinburgh Cognitive and Behavioral ALS Screen (ECAS) from 901 non-demented ALS to derive neuropsychological sub-phenotypes pursuant to classical MCI and MBI frameworks and in accordance with an expanded version of Strong's criteria, which also addressed memory and visuo-spatial measures. The prevalence of MCI and MBI was 39% and 37%, respectively in this retrospective review. The following MCI sub-phenotypes were identified: dysexecutive MCI-single- and multiple-domain (dMCI-sd: 63%; dMCI-md: 24%, respectively); non-dysexecutive MCI-single- and multiple-domain (ndMCI-sd: 12%; ndMCI-md: 1%, respectively). MBI was classified as follows: apathetic MBI-single- and multiple-domain (aMBI-sd: 40%; aMBI-md: 20%, respectively); apathetic-disinihibited/perseverative MBI-multiple domain (ad/pMBI-md: 21%); disinihibited/perseverative MBI-multiple domain (d/pMBI-md: 7%); psychotic MBI-single- and multiple-domain (psyMBI-sd: 2%; psyMBI-md: 3%, respectively); unclassifiable MBI-multiple domain (uMBI-md: 1%). 143 (16%) of patients exhibited mild cognitive and behavioral impairment (MCBI). This study delivers a provisional, ECAS-based classification for the neuropsychological sub-phenotyping of non-demented ALS patients, which, with further validation, might be useful for both research and clinical purposes.\n\nID: 42544949\nTitle: EXPRESS: Evaluation of the clinical course of immune-mediated polyneuropathy in cats following treatment with human intravenous immunoglobulins.\nAbstract: Immune-mediated polyneuropathy (IMPN) manifests with generalized lower motor neuron (LMN) weakness and a remittent or relapsing clinical course. Evidence-based treatment recommendations for severely or chronically affected cats are limited. The objective of this study was to evaluate the clinical course and outcome of cats with IMPN following treatment with human intravenous immunoglobulins (hIVIg). Medical records from two veterinary referral hospitals were reviewed (2018-2025) for cats with IMPN treated with hIVIg. Cats were treated with 1-2 g/kg hIVIg divided over 2-4 days (0.5 g/kg/day).Clinical information, diagnostic findings, treatment details and short- and long-term follow-up were evaluated retrospectively. Follow-up information was obtained from medical records and owner communication. Minimum follow-up duration was 8 months (8-51 months; median 17 months).Clinical course (partial and complete recovery, relapses) was compared between cats with acute/recent onset (4 cats) or chronic presentation (5 cats). Eight of nine cats exhibited clinical improvement following hIVIg administration, achieving ambulatory status (walking >5 steps) within a median of 4 days (2-8 days). One cat failed to respond to hIVIg but improved after subsequent prednisolone therapy. For the overall cohort, the median time to complete recovery was 20 days, while the median time to partial recovery was 14 days. Relapses occurred in four cats, but weakness was less severe, and all cats recovered again. The remaining five cats remained relapse-free. Human IVIg was well tolerated in this small cohort, and rapid clinical improvement was observed in most treated cats. These findings suggest that hIVIg may be considered as a treatment option in selected cats with IMPN, including those with acute and chronic presentations. Larger prospective studies, including comparison with no treatment or corticosteroids, are warranted to further assess its efficacy.\n\nID: 42543164\nTitle: Intron retention in health and amyotrophic lateral sclerosis.\nAbstract: Intron retention (IR) is the molecular phenomenon by which introns, historically thought to represent non-coding 'junk', remain unspliced within pre-mRNA transcripts, resulting in their incorporation into the mature mRNA molecule. While the role of IR is well established in species of plant, fungi, insects and viruses, it remains relatively understudied in mammalian biology. It was previously assumed that IR only played a limited role in downregulating a transcript's translation potential through downstream initiation of nuclear detention or nonsense mediated decay (NMD). However, recent studies highlight IR's significantly more complex and dynamic contribution to cellular physiology and disease. In particular, a role for IR is emerging in both health and neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), a rapidly progressive and invariably fatal disease that renders patients paralysed and unable to eat, speak or breathe. Significant technological advances now permit a comprehensive interrogation of previously unrecognized aspects of RNA metabolism in clinically relevant human cell types. In this review, we focus on the differential role(s) of nuclear and cytoplasmic intron retaining transcripts (nIRTs and cIRTs, respectively), as well as how IRTs may influence subcellular localization of ribonucleoprotein (RNP) complexes, loss of function of bound RNA binding proteins (RBPs) and liquid-liquid phase separation (LLPS) in physiology and disease. Additionally, we discuss the potential of IRTs as independent regulatory elements beyond their protein-coding functions and highlight how artificial intelligence is poised to accelerate discoveries in this area. In the context of IR's increasing appreciation, we also highlight its potential as a therapeutic target and explore current and future challenges in this burgeoning field.\n\nID: 42542522\nTitle: Computational Pipelines for Protein Ubiquitylation Analysis and Prediction.\nAbstract: Ubiquitylation is a crucial posttranslational modification that regulates cellular homeostasis and has been linked to a range of diseases. Identification and analysis of ubiquitylated proteins and ubiquitylation sites have historically been successfully performed by mass spectrometry from in vitro and in vivo samples. However, to address some of the challenges and improve the efficiency of ubiquitylation analysis by mass spectrometry, computational tools have been developed and are becoming increasingly popular. In this chapter, we summarize the available computational tools for predicting ubiquitylation in silico and the common approaches used to enrich ubiquitylation in samples for mass spectrometry and computational analysis. We subsequently provide simple steps for molecular biologists to follow for predicting ubiquitylation sites on proteins in silico, and we provide a computational approach to identify average ubiquitin branch sites across samples from ubiquitin-enriched mass spectrometry data.\n\nID: 42538773\nTitle: Early Cognitive and Behavioral Changes in Primary Lateral Sclerosis: A Population-Based Study.\nAbstract: Primary lateral sclerosis (PLS) is a rare upper motor neuron neurodegenerative disorder whose cognitive profile, particularly at early stages, remains incompletely defined. We aimed to characterize cognitive and behavioral features of PLS at diagnosis and compare them with predominant upper motor neuron amyotrophic lateral sclerosis (PUMN-ALS) and healthy controls (HCs). Patients diagnosed with PLS between 2007 and 2021 were identified from the population-based Piemonte and Valle d'Aosta ALS Register. Diagnoses were established according to consensus criteria, including early, probable, and definite PLS. All patients underwent comprehensive neuropsychological and behavioral assessment within 3\u2009months of their first ALS center visit. Cognitive-behavioral status was classified using ALS-frontotemporal dementia (FTD) consensus criteria. Thirty-two PLS patients were included (mean disease duration, 25\u2009months). Cognitive and/or behavioral impairment was identified in 29.3% of patients, most commonly affecting executive function, memory, and social cognition, including 21.1% early PLS. Compared with HCs, PLS patients showed poorer performance across several cognitive domains and higher anxiety and depression scores. Compared with matched PUMN-ALS patients, PLS patients demonstrated slightly worse executive performance, while the overall frequency of cognitive-behavioral impairment was similar. Behavioral profiles differed qualitatively, with apathy more frequent in PUMN-ALS. No PLS patient met criteria for frontotemporal dementia. Cognitive and behavioral impairments are already detectable at the time of diagnosis in a substantial proportion of patients with PLS, including early PLS, supporting the view of PLS as a multidimensional neurodegenerative disorder with early extramotor involvement.\n\nID: 42538750\nTitle: Nationwide Epidemiology of Motor Neuron Diseases in Latvia (2020-2024): Incidence, Prevalence, and Clinical Characteristics.\nAbstract: Motor neuron diseases (MNDs), including amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), and spinal and bulbar muscular atrophy (SBMA), are rare, progressive neurodegenerative conditions. Although well-studied in Western Europe, no nationwide epidemiological data have been published from Latvia. This study aimed to assess the incidence, prevalence, and clinical characteristics of MNDs in the Latvian population. A retrospective, hospital-based analysis was performed using records from Pauls Stradi\u0146\u0161 Clinical University Hospital, Riga East University Hospital, and the Children's Clinical University Hospital between January 2020 and December 2024. Patients were identified through relevant ICD-10 codes. Incidence and prevalence rates were calculated per 100,000 population and age-standardized to the 2013 European Standard Population. A total of 181 prevalent MND cases were identified: 131 with ALS or related phenotypes, 10 with adult-onset SMA, 33 with pediatric SMA, and 7 with SBMA. The age-standardized incidence of ALS was 1.22 per 100,000 person-years, and the prevalence was 4.69 per 100,000. Limb weakness or paresis was the most common initial symptom (48.1%). The mean diagnostic delay was 13.4\u2009months for ALS, 43.8\u2009months for PLS, 206.8\u2009months for SBMA and 17.3\u2009months for pediatric SMA. The prevalence of pediatric SMA was 9.91 per 100,000, with type II being the most frequent subtype. All SMA and SBMA cases were genetically confirmed. This first nationwide study of MNDs in Latvia highlights diagnostic delays and possible under-recognition of adult SMA and SBMA. Genetic testing, a national registry, and equitable therapy access should be prioritized.\n\nID: 42536230\nTitle: Genetic variants among patients with motor neuron disease in Lithuania - a retrospective single-center study.\nAbstract: Motor neuron disease (MND) comprises several clinical phenotypes, with amyotrophic lateral sclerosis (ALS) being the most common. Despite the identification of over 40 ALS-associated genes, the pathogenesis remains complex and polygenic. This study evaluated the clinical phenotypes and prevalence of genetic causes in MND patients in Lithuania. We conducted a retrospective single-center study at a tertiary care clinic on patients with MND. Clinical and molecular genetic data were analyzed. The study included 53 patients with a mean age at symptom onset of 55 years. Most patients (43/53; 77.4%) were diagnosed with ALS, and the most common onset was spinal (39/53; 73.6%). The frequency of pathogenic or likely pathogenic genetic variants was 15.7% (8/51). C9orf72 hexanucleotide repeat expansion was detected in 5.9% (3/51) of patients. Next-generation sequencing was performed in 49 patients, of whom 5 (10.2%) had pathogenic or likely pathogenic variants, including pathogenic variants in the SOD1 and NEK1 genes and likely pathogenic variants in the FUS. The most common finding was C9orf72 hexanucleotide repeat expansion, followed by variants in SOD1 and FUS genes. The genetic spectrum was broadly similar to internationally recognized MND-associated genes, though formal comparisons were not performed due to the absence of a control group. These results emphasize the importance of systematic genetic testing in clinical practice and contribute to the limited data on the genetic spectrum of MND in the Baltic region.\n\nID: 42528798\nTitle: A modified frailty index to identify high-risk groups for amyotrophic lateral sclerosis.\nAbstract: Amyotrophic lateral sclerosis (ALS) is a motor neuron disease characterized by progressive muscle weakness and poor prognosis, which requires early detection to optimize therapeutic outcomes. This study aims to develop a risk stratification tools for ALS and to assist in identifying high-risk groups. A prospective cohort study was conducted using the UK Biobank (500,033 participants), which were split into training sets and validation sets. We calculated the frailty index (FI) and modified frailty index (MFI) for the participants and estimated their association with ALS. Finally, two risk stratification tools were constructed and the time-dependent ROC curve was utilized to evaluate the discriminatory performance of each model. Among the 49 deficits in FI, we identified five deficits that were significantly associated with ALS, including falls, whole-body pain, long-standing illness, disability or infirmity, self-rated health and tiredness or lethargy in last 2\u202fweeks, which together constructed the MFI. Both the FI and MFI were associated with a higher risk of ALS (HRFI\u202f=\u202f4.58, 95% CI\u202f=\u202f1.31-16.07, HRMFI\u202f=\u202f4.59, 95% CI\u202f=\u202f2.79-7.53). Finally, a combination of MFI, gender, age and BMI demonstrated the best discriminative ability. Specifically, on the validation set, it achieved a C-index of 0.696. By focusing on deficits associated with ALS, the MFI may improve the ability to identify individuals at elevated risk of the disease. It could therefore serve as a valuable screening tool for risk stratification in the general population.\n\nID: 42521811\nTitle: Tofersen treatment in respiratory onset amyotrophic lateral sclerosis and a variant of uncertain significance in SOD1; a case report.\nAbstract: The antisense oligonucleotide tofersen is available for treating amyotrophic lateral sclerosis (ALS) caused by pathogenic SOD1 variants. However, it is unknown whether Variants of Uncertain Significance (VUS) are a viable treatment target. We assessed clinical and biomarker trajectories prior to and after initiation of tofersen in a patient with respiratory onset ALS and a novel c.234_236del p.(Glu79del) VUS in SOD1. After six months of treatment, cerebrospinal fluid (CSF) SOD1 protein decreased by 47%, CSF NfL by 55% and serum NfL by 50%, with trajectories comparable to known pathogenic variants. Functional decline on the ALSFRS-R slowed from 1.52 points per month pre-treatment to 0.52 points per month post-treatment, muscle strength remained stable, and EQ-VAS quality of life scores remained between 60 and 70. The ability to evaluate treatment response on an individual level will help to determine the clinical relevance of VUS as new gene-targeted treatments for ALS become available.\n\nID: 42509371\nTitle: Longitudinal plasma proteomics predict phenoconversion to clinically manifest ALS.\nAbstract: The study of pre-symptomatic amyotrophic lateral sclerosis (ALS) and the design of disease prevention trials are greatly hampered by our inability to predict which unaffected carriers of ALS-associated pathogenic variants will phenoconvert to clinically manifest disease and when. In this longitudinal Olink Explore, high-throughput, proteomic study, 516 serially collected plasma samples from 33 phenoconverters, 35 patients with ALS, 10 pre-symptomatic pathogenic variant carriers and 59 controls were included. Here we identified 92 proteins with concentrations that changed before phenoconversion; characterized the longitudinal trajectory of these proteins and identified a core panel of 19 proteins which, collectively, predicted phenoconversion over the 0.5-year to 5-year time horizons (crossvalidated areas under the curve 0.80-0.89) and yielded estimates of time to phenoconversion with a mean absolute error of 1.6\u2009years. These findings were partially replicated in UK Biobank data, confirming pre-symptomatic increases in several proteins (for example, NEFL, EDA2R and CA3) and that a multi-protein panel outperformed NEFL alone in estimating time to phenoconversion. This work sheds light on the biology of pre-symptomatic ALS. Moreover, our identification of a panel of new susceptibility/risk biomarkers based on empirical longitudinal data furthers the ultimate goal of ALS prevention.\n\nID: 42506308\nTitle: Walking as a Window to the Brain: Redefining Gait in Neurology.\nAbstract: Walking is not merely locomotion but a window into the nervous system, integrating cortical, subcortical, cerebellar, spinal, and peripheral networks into a unified motor behavior. Across neurological diseases-including Parkinson's disease, atypical parkinsonism, cerebellar ataxias, stroke, multiple sclerosis, neuropathies, neuromuscular disorders, and functional gait syndromes-gait disturbances are among the most disabling clinical features, contributing to falls, loss of independence, institutionalization, and premature mortality. Traditional bedside observation remains indispensable, but it lacks the sensitivity and reproducibility needed to capture subtle, episodic, or prodromal abnormalities. Over the past decade, advances in wearable sensors, marker-based and markerless motion capture, pressure-sensitive walkways, force plates, artificial intelligence, and machine learning have positioned digital mobility outcomes as promising, ecologically valid biomarkers of neurological function. These measures can support differential diagnosis, provide prognostic information on falls and survival, and serve as sensitive endpoints in therapeutic trials. They may also detect early abnormalities, such as increased stride-to-stride variability or prolonged double-support time, before overt clinical deterioration becomes evident. Clinical applications are increasingly evident across disorders, including distinguishing Parkinson's disease from atypical parkinsonism, quantifying treatment response in normal-pressure hydrocephalus, tracking progression in ataxia and multiple sclerosis, predicting functional decline in motor neuron disease, and guiding rehabilitation after stroke. Integration with neuroimaging, electrophysiology, and molecular biomarkers is beginning to reveal the circuits underlying variability, instability, and freezing, positioning gait as a systems-level marker of neural integrity. Nevertheless, methodological heterogeneity, limited disease-specific validation, insufficient longitudinal data, and lack of consensus on clinically meaningful parameters continue to constrain translation. Cognitive, affective, and environmental influences also remain insufficiently represented in digital frameworks, while equity, accessibility, algorithmic bias, and privacy require careful ethical governance. Reconceptualizing gait as a \"sixth vital sign\" reframes mobility as a multidimensional biomarker of neural and systemic health. With harmonized protocols, robust validation, multimodal integration, and appropriate ethical frameworks, gait analysis could become a cornerstone of precision neurology.\n\nID: 42498838\nTitle: Proteome-wide Mendelian randomization identifies causal plasma proteins in frontotemporal dementia.\nAbstract: Frontotemporal dementia (FTD) is a genetically and clinically heterogeneous neurodegenerative disorder with no disease-modifying treatments. Plasma proteomic signatures offer a promising avenue for uncovering disease mechanisms and developing targeted interventions. We conducted protein-wide Mendelian randomization meta-analysis to explore causal relationships between plasma proteins and FTD and four subtypes, utilizing comprehensive datasets of protein quantitative trait loci. We identified four plasma proteins significantly associated with FTD, namely RGS7 and ASAP2 (increased risk), as well as TMCC3 and VPS29 (decreased risk). Subtype-specific analyses revealed distinct protein signatures, including S100A13 and TREM1 in behavioral variant FTD, ING4 and TEX29 in FTD overlapping with motor neuron disease, SPINT2 in progressive non-fluent aphasia, and UGDH in semantic dementia. This study implicates specific plasma proteins in FTD pathogenesis, with subtype-dependent effects. The identified proteins represent potential biomarkers for stratification and therapeutic targets.\n\nID: 42495713\nTitle: Mechanisms of neurotoxicity of fluoride or aluminum: implications for neurodegenerative disease risk.\nAbstract: Fluoride and aluminum are two naturally abundant elements with widespread industrial uses. Fluoride is also added to community water supplies as a public health intervention for dental cavity prevention. However, findings from animal studies show potential links of fluoride and aluminum exposure with neurodegenerative disease risk, particularly at high exposure levels. This review uniquely examines neurochemical and neurobiological impacts of fluoride and aluminum exposure as well as whether these processes may increase the risk of common and rare neurodegenerative diseases, including dementia, Parkinson's Disease, and motor neuron disease. Fluoride and aluminum can cross the blood-brain barrier and accumulate in neural tissue, where they can interact to produce neurotoxic effects. Chronic exposure to fluoride and aluminum can cause oxidative stress, mitochondrial dysfunction, brain inflammation, and disruption of essential ions. These effects can contribute to impaired nerve signaling, cell damage, and protein aggregation-key factors in neurodegeneration. Co-exposure to aluminum-fluoride complexes may worsen these effects by increasing amyloid buildup and causing nerve cell death, although more research on aluminum-fluoride interactions is needed. Additionally, many animal studies include relatively high fluoride or aluminum exposure levels, and epidemiological human data are scarce, particularly for less common neurodegenerative diseases. Moreover, these studies often rely on ecological or occupational exposure measures rather than individual biomarkers. Findings of this narrative review underscore the need for methodologically rigorous longitudinal human studies on fluoride, aluminum and neurodegenerative disease risk, particularly given the mechanistic basis for these potential associations.\n\nID: 42494493\nTitle: Strenuous physical activity is associated with a younger age of amyotrophic lateral sclerosis onset in two independent cohorts.\nAbstract: Amyotrophic lateral sclerosis (ALS) is a complex neurodegenerative disease characterized predominantly by degeneration of both upper and lower motor neurons, thought to occur due to an interplay between genetics and environmental factors. Physical activity has been suggested as a potential risk factor for ALS; however, the exact role of exercise in the onset and progression of the disease is still unclear. We assessed lifetime physical activity in two independent ALS cohorts: post-mortem brain donors from the London Neurodegenerative Diseases Brain Bank (n = 139) and patients from the Motor Neurone Disease (MND) Register of England, Wales and Northern Ireland (n = 166 cases, 196 controls). In both cohorts, highly active individuals developed ALS symptoms at a significantly younger age, 54.2 years (mean, standard deviation = 7.5) in the post-mortem cohort and 58.0 years (median, interquartile range = 15) in the MND Register, compared with 63.9 years (mean, standard deviation = 11.5) and 63.0 years (median, interquartile range = 17.5) in inactive individuals, respectively [one-way analysis of variance (ANOVA), F(2, 136) = 6.10, P = 0.003, \u03b7 2 = 0.08, 95% confidence interval (CI) 0.02-1.00 and Kruskal-Wallis, H(2) = 7.39, P = 0.02, \u03b7 2 = 0.03, 95% CI 0.003-0.12]. Cox regression showed a higher hazard of earlier onset in highly active patients [post-mortem: hazard ratio (HR) 2.84, 95% CI 1.55-5.26, P = 0.0008; MND Register: HR 2.34, 95% CI 1.30-4.23, P = 0.005]. Our findings suggest that strenuous physical activity may be associated with a significantly younger age of ALS onset, replicated in both the post-mortem and MND Register cohorts, but not with an increased risk of developing ALS. Logistic regression analysis confirmed that neither highly active [odds ratio (OR) 1.43, 95% CI 0.69-2.99, P = 0.333] nor being active (OR 1.30, 95% CI 0.72-2.37, P = 0.386) was significantly associated with ALS risk, whereas a history of head injury was (OR 1.72, 95% CI 1.03-2.88, P = 0.038). These results suggest that strenuous exercise may accelerate disease onset in predisposed individuals, while the role of head injury requires further study and the findings may in fact indicate reverse causality.\n\nID: 42494173\nTitle: Troponin T and Neurofilament Light Chain Levels as Complementary Biomarkers of Disease Accumulation and Aggressiveness in Amyotrophic Lateral Sclerosis.\nAbstract: Amyotrophic lateral sclerosis (ALS) is a clinically heterogeneous neurodegenerative disease requiring reliable biomarkers to improve patient stratification and trial design. While serum neurofilament light chain (sNfL) reflects neuroaxonal stress and disease aggressiveness, troponin T (TnT) may capture complementary aspects of neuromuscular involvement. We assessed the associations of TnT and sNfL with D50-derived measures of disease aggressiveness (D50) and disease accumulation (rD50) in ALS. In this retrospective observation, TnT and sNfL levels from ALS patients in two independent German cohorts were analyzed using the D50 disease progression model; discovery cohort (Essen, n\u2009=\u2009433) and an independent replication cohort (Bonn, n\u2009=\u2009185). TnT levels were strongly associated with rD50-defined disease phases in the discovery cohort (p\u2009<\u20090.001). While not all subgroup-specific associations were replicated, the overall relationship between TnT and disease accumulation was supported in the independent replication cohort. In contrast, sNfL showed no consistent relationship with rD50-derived disease phases. sNfL concentrations demonstrated a significant inverse association with D50, supporting a relationship with disease aggressiveness across both cohorts (p\u2009<\u20090.001). Associations between TnT levels and D50-defined disease aggressiveness were generally weaker and less consistent. TnT was associated with measures of disease accumulation (rD50), whereas sNfL was more closely associated with disease aggressiveness (D50). Our results suggest that TnT and sNfL capture different dimensions of disease status within the D50 framework. Further longitudinal studies are needed to determine whether combining these biomarkers improves disease stratification or prognostic assessment in clinical practice and therapeutic trials.\n\nID: 42481361\nTitle: French guidelines for post-polio syndrome and management of effects of aging in people with sequelae of acute anterior poliomyelitis.\nAbstract: People with sequelae of acute anterior poliomyelitis (AAP) may develop secondary complications related to aging, as well as a specific complication of the disease known as post-polio syndrome (PPS). These complications are new neurological and musculoskeletal manifestations that occur after a prolonged period of disease stability. The onset is typically insidious and slow, but can be more rapid following a period of immobilization, surgery, or another intercurrent condition. The initial assessment may involve consulting a neurologist to rule out neurological diagnoses. Electroneuromyographic examination is a valuable tool for evaluating these patients. It is sometimes difficult to differentiate between the effects of aging in a person with sequelae of AAP and PPS, which is a distinct entity with specific diagnostic criteria. The rate at which muscle capacity declines, and its functional impact, can be a distinguishing factor. Subacute or rapid onset can be indicative of PPS. The emergence of new motor deficits in areas that were previously unaffected is also a strong argument for PPS. This neurological deterioration must be distinguished from musculoskeletal disorders associated with aging. Progression is usually slow and gradual, or occurs in stages with periods of stabilization. Physical and rehabilitation care is essential both in the initial assessment and for ongoing follow-up. There are no recommended medicinal treatments, especially no specific etiological treatment for PPS (such as immunoglobulins, corticosteroids, etc.) or effective symptomatic treatment for manifestations like fatigue or muscle weakness (e.g., pyridostigmine). Pain management should be regularly assessed; while drug treatments are not specific, non-pharmacological pain management through physical therapy is crucial. Particular attention should be paid to comorbidities, including excess weight and an increased risk of osteoporosis and fractures. Management should be multidisciplinary, with an annual review recommended. Follow-up will be adjusted based on the patient's preferences and needs, and monitoring will depend on the development of complications.\n\nID: 42480869\nTitle: Macrophage responses to and elevated antibody levels against Chlorovirus ATCV-1 in ALS patients.\nAbstract: Acanthocystis turfacea chlorella virus 1 (ATCV-1) is a giant virus that is part of the human oral microvirome. Previously we showed that ATCV-1 infects mouse macrophages, stimulates production of inflammatory cytokines, and accelerates motor neuron disease in the Amyotrophic Lateral Sclerosis (ALS) model SOD1-G93A transgenic mice. This, coupled with significantly elevated levels of serum IgG1 antibody to ATCV-1 in ALS patients compared with healthy controls, suggests involvement of ATCV-1 in ALS. Herein, using serum and CSF from a different ALS cohort we again show elevated antibodies to ATCV-1 in ALS patients compared with healthy controls. To assess ATCV-1 in human macrophages, we challenged immature (IMM), M0, M1, and M2 human THP-1 macrophage cells containing an Interferon Stimulated Response Element (ISRE) promoter-reporter with ATCV-1 or its Major Capsid protein (MCP) glycans. ATCV-1 infected M1 THP-1 to a greater degree than IMM, M0, or M2 THP-1. The initial high ISRE-promoter activity of M1 THP-1 was suppressed by the MCP-Glycans of ATCV-1. M0, but not IMM or M2 THP-1 produced IL-6 in response to ATCV-1 or its MCP-glycan, while high levels of IL-6 from unchallenged M1 THP-1 increased further by ATCV-1 or its MCP glycan. In contrast, ATCV-1 or its MCP-Glycan significantly reduced the high levels of IL-10 produced by M2 THP-1. Thus, antibody to ATCV-1 in ALS patients and the susceptibility of human M1 macrophages to ATCV-1 infection with boosted inflammatory cytokine and diminished anti-inflammatory cytokine production suggest that ATCV-1 may contribute to ALS motor neuron disease.\n\nID: 42470084\nTitle: Impact of Sexuality in Patients With Motor Neuron Disease.\nAbstract: Sexuality is a relevant yet understudied aspect in people living with motor neuron disease (MND). This study aimed to assess whether sexuality in people with MND is influenced by motor, cognitive, behavioral, or mood disturbances, and to explore whether being sexually active impacts caregiver burden. We conducted a cross-sectional observational study involving participants with MND and their primary caregivers from three ALS multidisciplinary units in Seville, Spain. Data were collected between October 2018 and July 2021. Functional, cognitive, behavioral, and mood assessments were conducted. Sexuality was evaluated through sex-specific questionnaires. Caregiver burden was assessed using the Zarit Burden Interview. Among 66 participants who completed the sexuality assessment, 42.9% reported sexual activity in the previous month. Of these, 70% had no sexual dysfunction, while 26.7% had moderate and 3.3% severe dysfunction. No correlation was found between sexual activity and motor function. Sexual activity was less frequent in participants with apathy (p\u2009=\u20090.026), depression (p\u2009=\u20090.021), and frontotemporal dementia (p\u2009=\u20090.013). Among sexually active patients, those with cognitive impairment-particularly memory dysfunction-had higher rates of orgasm difficulties (p\u2009=\u20090.019). No other clinical parameters were related to sexuality. Sexuality of participants with MND did not influence caregiver burden. Sexuality in MND is more associated with cognitive and mood factors than with motor disability. Addressing sexuality in clinical practice may contribute to improving quality of life and should be integrated into the multidisciplinary care of MND patients.\n\nID: 42465429\nTitle: The neuropathy-causing GARS1 \u0394ETAQ mutation drives pathology in subsets of motor and sensory neurons in mice.\nAbstract: Charcot-Marie-Tooth disease type 2D (CMT2D) results from gain-of-function mutations in GARS1, which encodes glycyl-tRNA synthetase (GlyRS), the enzyme responsible for charging transfer RNA (tRNA) with glycine. There are several CMT2D mouse models, but Gars \u0394ETAQ/+ is the only one that bears a patient-sourced mutation. Created using CRISPR/Cas9 to model a 12-nucleotide de novo GARS1 deletion identified in an unusually severe CMT2D patient, Gars \u0394ETAQ/+ mice have previously been shown to display several neuromuscular phenotypes; motor axon loss, denervated neuromuscular junctions (NMJs) and reduced muscle function. Here, we extend these analyses to provide a more comprehensive understanding of both motor and sensory nerve deficits across hind- and fore-limbs. At 3 months, Gars \u0394ETAQ/+ mice possess sex-independent alterations in the levels of neuropathy biomarkers - including decreased NfL and increased periaxin - alongside reduced muscle endurance and strength, and impairments in the sensory modalities of mechanosensation, proprioception and nociception. Underpinning these dysfunctions, we identified site-specific defects comprising altered sensory neuron populations, muscle spindle loss, reduced motor neuron size, disrupted NMJ innervation and maturation, and reduced axonal transport of signalling endosomes in vivo. Together, these experiments show that Gars \u0394ETAQ/+ mice display robust and selective peripheral nerve pathology that manifests in a general distal-to-proximal fashion, priming this CMT2D allele for testing treatments and evaluating mechanisms underlying peripheral nerve vulnerability.\n\nID: 42464213\nTitle: SYNE1-Related motor neuron disease-like phenotype with mild distal contractures and 24-month clinical stability: a case report.\nAbstract: SYNE1 encodes nesprin-1, a nuclear envelope protein involved in cytoskeletal linkage, nuclear positioning, and neuromuscular integrity. Biallelic SYNE1 variants cause a broad spectrum ranging from cerebellar ataxia to arthrogryposis multiplex congenita and motor neuron disease-like phenotypes. Distinguishing these entities can be difficult when subtle distal contractures coexist with neurogenic electrophysiological findings. A 22-year-old woman born to consanguineous parents presented with bilateral intrinsic hand muscle wasting, impaired fine motor performance, and mild gait difficulty. Examination showed distal hand atrophy, mild weakness of the abductor pollicis brevis and first dorsal interosseous muscles, brisk deep tendon reflexes, preserved sensation, and mild distal finger contractures. Sensory nerve conduction studies were normal. Motor studies showed reduced compound muscle action potential amplitude in the right abductor pollicis brevis and borderline-low amplitude on the left. Needle electromyography showed widespread chronic neurogenic motor unit changes affecting the upper and lower extremities, with active denervation most evident in the bilateral abductor pollicis brevis muscles. Genioglossus examination was normal. SMN1 deletion testing and selected familial amyotrophic lateral sclerosis gene testing were negative. Whole exome sequencing identified a homozygous truncating SYNE1 variant, NM_182961.4:c.21009G\u2009>\u2009A; p.(Trp7003Ter). Segregation analysis confirmed heterozygous carrier status in both parents and two unaffected siblings. At 24-month follow-up, weakness, atrophy, contractures, reflex pattern, and functional status remained clinically stable, without bulbar, cerebellar, sensory, or clinically evident respiratory involvement. This case supports classification as a SYNE1-related motor neuron disease-like phenotype with mild distal contractures rather than an isolated arthrogryposis multiplex congenita type 3 (AMC3) phenotype. The case also supports including SYNE1 in genetic testing panels for young patients with unexplained motor neuron disease-like presentations, particularly when consanguinity, normal sensory conduction, and subtle distal contractures coexist.\n\nID: 42461445\nTitle: Metabolomic analyses of amyotrophic lateral sclerosis, muscle cramps, and TJ-68 treatment.\nAbstract: Most patients with amyotrophic lateral sclerosis (ALS), a fatal motor neuron disease, experience painful muscle cramps. Our recent pilot trial of the Japanese Kampo medicine TJ-68 suggested its efficacy in improving muscle cramps in patients with ALS. This study analyzed plasma metabolomic changes to identify the underlying mechanisms of muscle cramps in ALS and the effects of TJ-68. Plasma was obtained from 11 participants with ALS in the repeated crossover trial at five time points (baseline, two placebo phases, and two TJ-68 phases). Metabolites were analyzed using mass spectrometry. Linear mixed-effects models were applied to identify metabolite changes associated with muscle cramps, determine the effects of TJ-68 on metabolites, and predict which participants would respond to TJ-68. Higher glutamine/glutamate, arginine, and leucine levels were associated with more severe muscle cramps. TJ-68 treatment increased tryptophan and aconitate levels but reduced serotonin and acetylcarnitine levels. Long-chain acylcarnitine levels were correlated with muscle cramp severity, and their levels tended to decrease with treatment. Uric acid, \u03b2-aminoisobutyric acid, \u03b1-aminoadipic acid, and acetylcholine emerged as predictors of the efficacy of TJ-68. This study identified the metabolite profile of muscle cramps in ALS and the changes in metabolite levels after TJ-68 treatment. Several baseline metabolites were associated with the prediction of the response to muscle cramps following TJ-68 treatment. Uric acid might be particularly useful because of its easy measurement in standard assays. Our study affirms the value of metabolomic technology for future pharmacotherapy and studies in ALS.\n\nID: 42461162\nTitle: Nursing a Patient With Amyotrophic Lateral Sclerosis Stage 4B With Epilepsy: A Case Study.\nAbstract: Amyotrophic lateral sclerosis (ALS) is a rare motor neuron disease characterised by progressive muscle weakness, which can eventually lead to death. So far there is no effective cure for it. This case report discusses the nursing of a patient with stage 4B amyotrophic lateral sclerosis complicated with epilepsy and sudden disturbance of consciousness during his stay in an intensive care unit (ICU). After 34\u2009days of treatment and care, the patient regained consciousness with stable vital signs before being transferred out of the ICU. This report focusses on nursing interventions adopted in terms of respiratory management, nutritional management, psychological care and exercise during both the epileptic seizure and the awake period of the patient in the hope of providing a reference for the nursing of patients with amyotrophic lateral sclerosis with epilepsy in intensive care units.\n\nID: 42456346\nTitle: Divergent presentations of anti-GAD autoimmunity: a comparative analysis of two neurodegenerative cases.\nAbstract: We describe two women presenting with cortico-basal syndrome (CBS) and upper motor neuron-motor neuron disease (UMN-MND), respectively, both with high-titre GAD-Abs in serum and CSF. Both patients showed progressive motor impairment with elevated NFL levels. IVIg therapy was administered without meaningful clinical benefit, suggesting neurodegeneration as the primary phenotypic driver.\n\nID: 42454435\nTitle: Moral distress in healthcare professionals working with motor neuron disease.\nAbstract: To (1) identify clinical situations that may contribute to the experience of moral distress (MD) among professionals working with motor neuron disease (MND), (2) measure the occurrence and intensity of MD, and (3) explore associations with professional quality of life, turnover intention, and associated risk and/or protective factors. A cross-sectional online survey was distributed to healthcare professionals working in MND services across Europe. Data were analyzed using descriptive and inferential statistics. In total, 230 responses from professionals across 17 European countries were analyzed from the international survey. And 67% of respondents indicated that MD resonated with their experience of working with MND. Those who considered leaving or changing their position due to the challenges associated with caring for this patient population were also more likely to report resonance with MD (\u03c72\u00a0=\u00a07.772, p\u00a0=\u00a00.020). The intensity of MD was associated with reduced professional quality of life (burnout [\u03b2\u00a0=\u00a00.106, p\u00a0<\u00a00.05], and secondary traumatic stress [\u03b2\u00a0=\u00a02.881, p\u00a0<\u00a00.001]). A total of 24 clinical scenarios were identified as potential contributors to experiences of MD in this population. Across all professional groups, service-/organization-level factors were the most common and distressing barriers to providing effective MND care. This study demonstrates that MD is experienced by healthcare professionals working with MND across Europe. MD was associated with reduced professional quality of life and increased intentions to leave or change positions, underscoring its potential implications for workforce retention and sustainability. The findings show that system/organization, patient/condition and family-level causes are the primary drivers of MD in this population. Future research should focus on evaluating the effectiveness of interventions designed to address these key drivers and mitigate the impact of MD among healthcare professionals working with MND.\n\nID: 42449472\nTitle: VRK1-Related Motor Neuropathy With Upper Motor Neuron Signs and Selective Muscle Involvement.\nAbstract: Hereditary motor neuropathies (HMN) represent a heterogeneous group of disorders with wide clinical and genetic variability. Despite advances in molecular diagnostics, approximately 50% of cases remain genetically unresolved, particularly those where distinguishing length-dependent motor neuropathy from motor neuron disorder with disproportionate segmental involvement is a challenge. Variants in the VRK1 gene, originally described in association with pontocerebellar hypoplasia, are now known to produce a broad clinical spectrum, including amyotrophic lateral sclerosis, dHMN, and less frequently, spastic paraplegia. This study's aim was to characterize the clinical presentation, electrophysiological findings, and muscle MRI patterns associated with VRK1-related motor neuron disease in a cohort of nine patients from five unrelated families. Five unrelated families with inherited motor neuropathy were investigated using next-generation sequencing techniques, including targeted gene panels or whole-exome sequencing, with subsequent confirmation by Sanger sequencing. A total of nine affected individuals underwent detailed clinical evaluation, nerve conduction studies (NCS), electromyography (EMG), and whole-body muscle MRI (wbMRI). Nine affected individuals carrying biallelic VRK1 variants were evaluated. In most cases (66%), symptom onset occurred during the first decade of life. All patients presented with gradually progressive distal muscle weakness. Mean Medical Research Council (MRC) scores were 2.8 for ankle dorsiflexion and 1.9 for plantar flexion. Sensory nerve conduction studies were normal in all individuals evaluated (8/9), although mild sensory complaints were reported in four patients. Muscle cramps were observed in two-thirds of the cohort, while fasciculations were uncommon (11%). EMG findings consistently demonstrated a neurogenic pattern with predominant distal involvement, and evidence of both acute and chronic denervation was present in four patients. Whole-body muscle MRI, available for all patients, revealed a consistent pattern of fatty infiltration predominantly affecting posterior muscle compartments, with minimal STIR signal changes. Brain and spinal imaging, performed in all individuals, showed no abnormalities. Biallelic mutations in VRK1 are associated with a recognizable form of motor neuron disease characterized by features of dHMN combined with upper motor neuron involvement, along with a distinctive posterior-predominant pattern on muscle MRI. Identifying this phenotype, a known presentation of VRK1-related disorders, highlights the importance of targeted genetic testing in unresolved cases of hereditary motor neuropathy.\n\nID: 42441926\nTitle: Association of Plasma Neurofilament Light Chain With Diagnostic Classification in a Neuromuscular Referral Cohort: A Cross-Sectional Study.\nAbstract: Plasma neurofilament light chain (pNfL) is a blood-based biomarker of axonal injury elevated in several neuromuscular disorders. While previous studies have compared individual diseases with healthy controls, less is known about how pNfL performs across clinically relevant neuromuscular presentations encountered in subspecialty practice, particularly in distinguishing active from inactive neuropathies. We evaluated whether abnormal age-adjusted pNfL concentrations are associated with clinically relevant diagnostic categories and whether pNfL discriminates between active and inactive neuropathies. We conducted a cross-sectional study of patients evaluated by neuromuscular specialists at Mayo Clinic (Rochester, MN) between April 2022 and April 2024, in whom pNfL was ordered as part of routine clinical care. Diagnoses were assigned to prespecified categories by consensus review, including motor neuron disease (MND), active neuropathy, inactive neuropathy, and structural etiologies. Clinically active neuropathy was defined using prespecified, diagnosis-specific operational criteria incorporating treatment status, clinical relapse or progression, time from symptom onset, and pathologic evidence of inflammation. Abnormal pNfL was defined using previously established age-adjusted 97.5th percentile reference limits. Multinomial logistic regression evaluated associations between abnormal pNfL and diagnostic category, adjusting for neuropathy impairment score and symptom duration. Receiver operating characteristic (ROC) analyses assessed discrimination between prespecified groups. Among 306 patients (mean age 62.2 years, 41.5% female), 179 (58.5%) had MND, 28 (9.1%) active neuropathy, 75 (12.1%) inactive neuropathy, and 24 (7.8%) structural etiologies. Median pNfL concentrations differed across diagnostic groups (p < 0.0001) and were highest in MND and active neuropathy. After adjustment, abnormal pNfL was associated with a higher relative likelihood of classification as MND (relative risk ratio [RRR] 18.47, 95% CI 8.77-38.86) and active neuropathy (RRR 7.30, 95% CI 2.50-21.34) compared with inactive neuropathies. No association was observed with structural etiologies. Discrimination between active and inactive neuropathy was moderate (area under the curve [AUC] 0.79, 95% CI 0.70-0.88), and discrimination for MND vs all other diagnoses was good (AUC 0.85, 95% CI 0.80-0.90). In this cross-sectional cohort, abnormal age-adjusted pNfL concentrations were more frequently observed in diagnostic categories characterized by clinically active axonal injury than in inactive neuropathies and structural conditions. These findings suggest a potential role for pNfL as an adjunctive tool in neuromuscular diagnostic evaluation. Interpretation is limited by the cross-sectional design and convenience sampling. This study provides Class II evidence that abnormal age-adjusted pNfL distinguishes active neuropathies from inactive neuropathies with moderate diagnostic accuracy.\n\nID: 42441693\nTitle: Cardiac Autonomic Dysfunction and Sudden Cardiac Death in Amyotrophic Lateral Sclerosis: Clinical Implications and Considerations for Care.\nAbstract: Amyotrophic lateral sclerosis (ALS) is traditionally viewed as a motor neuron disease that progresses from muscular weakness to respiratory failure and death. Increasing evidence, however, demonstrates clinically meaningful involvement of the autonomic nervous system, particularly in cardiovascular regulation. This narrative review synthesizes current evidence on the mechanisms, clinical implications, and palliative considerations of cardiac autonomic dysfunction in ALS, with particular emphasis on its relationship to sudden cardiac death (SCD). Cardiac autonomic dysfunction is increasingly recognized as a significant contributor to disease burden in ALS, manifesting as abnormalities in heart rate variability, sympathetic overactivity, and corrected QT prolongation. These derangements may contribute to malignant arrhythmias, increasing susceptibility to SCD in combination with respiratory decline. Epidemiologic data suggest that SCD accounts for a meaningful proportion of ALS-related mortality, although it is likely underrecognized due to misclassification and lack of routine cardiac monitoring. Clinical implications include the need for improved risk stratification and earlier detection of autonomic dysfunction using accessible markers, such as electrocardiographic indices, orthostatic vital signs, and ambulatory monitoring. Emerging technologies, including wearable biosensors, may further enhance longitudinal assessment. These considerations also have direct relevance for advanced care planning, as ALS may involve unpredictable and abrupt cardiac death in addition to progressive respiratory decline. Recognizing ALS as a multisystem disorder with significant cardiac involvement supports the integration of structured cardiovascular monitoring into multidisciplinary care models and highlights the need for prospective studies to guide standardized management strategies.\n\nID: 42436372\nTitle: Plasma exosomal HERV-K transcripts are increased in amyotrophic lateral sclerosis.\nAbstract: Human endogenous retrovirus-K (HERV-K) reactivation is increasingly implicated in amyotrophic lateral sclerosis (ALS), with ongoing clinical trials investigating antiretroviral therapies. However, there is limited understanding of how HERV-K is trafficked in peripheral biofluids, and the role of exosomes, nano-sized extracellular vesicles, in this process remains largely unexplored. Exosomes offer a stable and cell-specific cargo reservoir that may reflect central pathogenic processes and serve as a minimally invasive biomarker source. In this study, we isolated plasma-derived exosomes from ALS patients (n\u2009=\u200921) and healthy controls (n\u2009=\u200916), and quantified exosomal HERV-K gag, env, and pol transcript levels using SYBR Green qPCR with RNase treatment and normalization to both traditional and exosome-enriched reference genes. HERV-K pol expression was significantly elevated in ALS, with fold-changes ranging from 1.59 to 1.85 (P\u2009=\u20090.037-0.051). env and gag also showed increased expression, though with greater variability. Normalization to the exosome-specific gene SOD2 provided the most consistent signal. These findings suggest that exosomal HERV-K transcripts, particularly pol, could serve as accessible biomarkers for patient stratification and treatment monitoring in HERV-K-targeted ALS trials. This work establishes proof-of-concept for using exosomal cargo to track endogenous retroviral activity in neurodegeneration and supports further investigation of liquid biopsy approaches in ALS precision medicine.\n\nID: 36142612\nTitle: Plasma Small Extracellular Vesicle Cathepsin D Dysregulation in GRN/C9orf72 and Sporadic Frontotemporal Lobar Degeneration.\nAbstract: Emerging data suggest the roles of endo-lysosomal dysfunctions in frontotemporal lobar degeneration (FTLD) and in other dementias. Cathepsin D is one of the major lysosomal proteases, mediating the degradation of unfolded protein aggregates. In this retrospective study, we investigated cathepsin D levels in human plasma and in the plasma small extracellular vesicles (sEVs) of 161 subjects (40 sporadic FTLD, 33 intermediate/pathological C9orf72 expansion carriers, 45 heterozygous/homozygous GRN mutation carriers, and 43 controls). Cathepsin D was quantified by ELISA, and nanoparticle tracking analysis data (sEV concentration for the cathepsin D level normalization) were extracted from our previously published dataset or were newly generated. First, we revealed a positive correlation of the cathepsin D levels with the age of the patients and controls. Even if no significant differences were found in the cathepsin D plasma levels, we observed a progressive reduction in plasma cathepsin D moving from the intermediate to C9orf72 pathological expansion carriers. Observing the sEVs nano-compartment, we observed increased cathepsin D sEV cargo (ng/sEV) levels in genetic/sporadic FTLD. The diagnostic performance of this biomarker was fairly high (AUC = 0.85). Moreover, sEV and plasma cathepsin D levels were positively correlated with age at onset. In conclusion, our study further emphasizes the common occurrence of endo-lysosomal dysregulation in GRN/C9orf72 and sporadic FTLD.\n\nID: 35159297\nTitle: Plasma Small Extracellular Vesicles with Complement Alterations in GRN/C9orf72 and Sporadic Frontotemporal Lobar Degeneration.\nAbstract: Cutting-edge research suggests endosomal/immune dysregulation in GRN/C9orf72-associated frontotemporal lobar degeneration (FTLD). In this retrospective study, we investigated plasma small extracellular vesicles (sEVs) and complement proteins in 172 subjects (40 Sporadic FTLD, 40 Intermediate/Pathological C9orf72 expansion carriers, and 49 Heterozygous/Homozygous GRN mutation carriers, 43 controls). Plasma sEVs (concentration, size) were analyzed by nanoparticle tracking analysis; plasma and sEVs C1q, C4, C3 proteins were quantified by multiplex assay. We demonstrated that genetic/sporadic FTLD share lower sEV concentrations and higher sEV sizes. The diagnostic performance of the two most predictive variables (sEV concentration/size ratio) was high (AUC = 0.91, sensitivity 85.3%, specificity 81.4%). C1q, C4, and C3 cargo per sEV is increased in genetic and sporadic FTLD. C4 (cargo per sEV, total sEV concentration) is increased in Sporadic FTLD and reduced in GRN+ Homozygous, suggesting its specific unbalance compared with Heterozygous cases. C3 plasma level was increased in genetic vs. sporadic FTLD. Looking at complement protein compartmentalization, in control subjects, the C3 and C4 sEV concentrations were roughly half that in respect to those measured in plasma; interestingly, this compartmentalization was altered in different ways in patients. These results suggest sEVs and complement proteins as potential therapeutic targets to mitigate neurodegeneration in FTLD.\n\nID: 32821252\nTitle: CSF extracellular vesicle proteomics demonstrates altered protein homeostasis in amyotrophic lateral sclerosis.\nAbstract: Extracellular vesicles (EVs) released by neurons and glia reach the cerebrospinal fluid (CSF). Studying the proteome of CSF-derived EVs offers a novel perspective on the key intracellular processes associated with the pathogenesis of the neurodegenerative disease amyotrophic lateral sclerosis (ALS) and a potential source from which to develop biomarkers. CSF EVs were extracted using ultrafiltration liquid chromatography from ALS patients and controls. EV size distribution and concentration was measured using nanoparticle tracking analysis and liquid chromatography-tandem mass spectrometry proteomic analysis performed. CSF EV concentration and size distribution did not differ between ALS and control groups, nor between a sub-group of ALS patients with or without an associated hexanucleotide repeat expansion (HRE) in C9orf72. Univariate proteomic analysis identified downregulation of the pentameric proteasome-like protein Bleomycin hydrolase in ALS patients, whilst Gene Ontology enrichment analysis demonstrated downregulation of proteasome core complex proteins (8/8 proteins, normalized enrichment ratio -1.77, FDR-adjusted p\u2009=\u20090.057) in the ALS group. The sub-group of ALS patients associated with the C9orf72 HRE showed upregulation in Ubiquitin-like modifying-activating protein 1 (UBA1) compared to non-C9orf72 cases. Proteomic analysis of CSF EVs in ALS detects intracellular alterations in protein homeostatic mechanisms, previously only identified in pathological tissues. This supports the wider use of CSF EVs as a source of novel biomarkers reflecting key and potentially druggable pathological intracellular pathway alterations in ALS.\n\nID: 30711519\nTitle: Micro-RNAs secreted through astrocyte-derived extracellular vesicles cause neuronal network degeneration in C9orf72 ALS.\nAbstract: Astrocytes regulate neuronal function, synaptic formation and maintenance partly through secreted extracellular vesicles (EVs). In amyotrophic lateral sclerosis (ALS) astrocytes display a toxic phenotype that contributes to motor neuron (MN) degeneration. We used human induced astrocytes (iAstrocytes) from 3 ALS patients carrying C9orf72 mutations and 3 non-affected donors to investigate the role of astrocyte-derived EVs (ADEVs) in ALS astrocyte toxicity. ADEVs were isolated from iAstrocyte conditioned medium via ultracentrifugation and resuspended in fresh astrocyte medium before testing ADEV impact on HB9-GFP+ mouse motor neurons (Hb9-GFP+ MN). We used post-mortem brain and spinal cord tissue from 3 sporadic ALS and 3 non-ALS cases for PCR analysis. We report that EV formation and miRNA cargo are dysregulated in C9ORF72-ALS iAstrocytes and this affects neurite network maintenance and MN survival in vitro. In particular, we have identified downregulation of miR-494-3p, a negative regulator of semaphorin 3A (SEMA3A) and other targets involved in axonal maintenance. We show here that by restoring miR-494-3p levels through expression of an engineered miRNA mimic we can downregulate Sema3A levels in MNs and increases MN survival in vitro. Consistently, we also report lower levels of mir-494-3p in cortico-spinal tract tissue isolated from sporadic ALS donors, thus supporting the pathological importance of this pathway in MNs and its therapeutic potential. ALS ADEVs and their miRNA cargo are involved in MN death in ALS and we have identified miR-494-3p as a potential therapeutic target. Thierry Latran Fondation and Academy of Medical Sciences.\n\nID: 29109780\nTitle: Metabolomic Profiling of Extracellular Vesicles and Alternative Normalization Methods Reveal Enriched Metabolites and Strategies to Study Prostate Cancer-Related Changes.\nAbstract: Body fluids are a rich source of extracellular vesicles (EVs), which carry cargo derived from the secreting cells. So far, biomarkers for pathological conditions have been mainly searched from their protein, (mi)RNA, DNA and lipid cargo. Here, we explored the small molecule metabolites from urinary and platelet EVs relative to their matched source samples. As a proof-of-concept study of intra-EV metabolites, we compared alternative normalization methods to profile urinary EVs from prostate cancer patients before and after prostatectomy and from healthy controls. We employed targeted ultra-performance liquid chromatography-tandem mass spectrometry to profile over 100 metabolites in the isolated EVs, original urine samples and platelets. We determined the enrichment of the metabolites in the EVs and analyzed their subcellular origin, pathways and relevant enzymes or transporters through data base searches. EV- and urine-derived factors and ratios between metabolites were tested for normalization of the metabolomics data. Approximately 1 x 1010 EVs were sufficient for detection of metabolite profiles from EVs. The profiles of the urinary and platelet EVs overlapped with each other and with those of the source materials, but they also contained unique metabolites. The EVs enriched a selection of cytosolic metabolites including members from the nucleotide and spermidine pathways, which linked to a number of EV-resident enzymes or transporters. Analysis of the urinary EVs from the patients indicated that the levels of glucuronate, D-ribose 5-phosphate and isobutyryl-L-carnitine were 2-26-fold lower in all pre-prostatectomy samples compared to the healthy control and post-prostatectomy samples (p < 0.05). These changes were only detected from EVs by normalization to EV-derived factors or with metabolite ratios, and not from the original urine samples. Our results suggest that metabolite analysis of EVs from different samples is feasible using a high-throughput platform and relatively small amount of sample material. With the knowledge about the specific enrichment of metabolites and normalization methods, EV metabolomics could be used to gain novel biomarker data not revealed by the analysis of the original EV source materials.\n\nID: 28334866\nTitle: C9orf72 and RAB7L1 regulate vesicle trafficking in amyotrophic lateral sclerosis and frontotemporal dementia.\nAbstract: A non-coding hexanucleotide repeat expansion in intron 1 of the C9orf72 gene is the most common cause of amyotrophic lateral sclerosis and frontotemporal dementia (C9ALS/FTD), however, the precise molecular mechanism by which the C9orf72 hexanucleotide repeat expansion directs C9ALS/FTD pathogenesis remains unclear. Here, we report a novel disease mechanism arising due to the interaction of C9ORF72 with the RAB7L1 GTPase to regulate vesicle trafficking. Endogenous interaction between C9ORF72 and RAB7L1 was confirmed in human SH-SY5Y neuroblastoma cells. The C9orf72 hexanucleotide repeat expansion led to haploinsufficiency resulting in severely defective intracellular and extracellular vesicle trafficking and a dysfunctional trans-Golgi network phenotype in patient-derived fibroblasts and induced pluripotent stem cell-derived motor neurons. Genetic ablation of RAB7L1or C9orf72 in SH-SY5Y cells recapitulated the findings in C9ALS/FTD fibroblasts and induced pluripotent stem cell neurons. When C9ORF72 was overexpressed or antisense oligonucleotides were targeted to the C9orf72 hexanucleotide repeat expansion to upregulate normal variant 1 transcript levels, the defective vesicle trafficking and dysfunctional trans-Golgi network phenotypes were reversed, suggesting that both loss- and gain-of-function mechanisms play a role in disease pathogenesis. In conclusion, we have identified a novel mechanism for C9ALS/FTD pathogenesis highlighting the molecular regulation of intracellular and extracellular vesicle trafficking as an important pathway in C9ALS/FTD pathogenesis.\n=======================================================\n\n### [CUSTOM DATAPOINTS]\nCRITICAL EXTRACTION DIRECTIVE: You MUST extract the following custom datapoints as root-level key/value pairs inside your final JSON block:\n- \"suggested_experiments\": generate 1-3 suggested experiments\n- \"suggested_studies\": generate 1-3 suggested studies\n- \"swansons_literature_based_discovery_candidates\": You are an advanced Literature-Based Discovery (LBD) system executing Swanson\u2019s complementary-but-disjoint (A-B-C) model. Your goal is to find hidden, unpublished connections across the provided dataset. Strict Discovery Protocol: 1. Identify distinct, isolated sub-literatures (Domain A and Domain C) within the dataset that share NO direct citations, co-mentions, or common contextual paragraphs. 2. Find an intermediate biological mechanism, protein, path, or entity (Bridge B) that appears independently in both isolated domains (A-to-B and B-to-C). 3. Synthesize a novel, unstated hypothesis (A-to-C). Negative Constraint (Crucial): DO NOT output any connection if the relationship between Concept A and Concept C is explicitly mentioned, paired, or summarized anywhere in the source text. If a connection (like \"OMN resilience to SMN stabilization\") is already explicitly stated or grouped as a concept in the data, it is considered \"already known\" and must be disqualified. Format your output exactly as follows: - Discovered Hypothesis (A to C): [Clear, novel statement] - Literature A (Origin): [Entity/Concept and source context] - Literature C (Target): [Entity/Concept and source context] - The Intersecting Bridge B: [The shared mechanism/protein linking them] - Biological Rationale: [1-2 sentences explaining why this hidden connection is mechanistically plausible]\n- \"contradictions_between_evidences\": Identify conflicting evidence within the evidence set (if any) and flag the dispute here\n- \"repurposed_solutions\": identify and explain repurposed Solution potentials\n\n\nFormat Requirement:\nRAG AMNESIA IS ACTIVE: You must ONLY use the provided context literature. Do not use outside prior knowledge. If the evidence is missing, insufficient, or requires gap-filling to fully evaluate the claim, you MUST explicitly state the gaps and missing evidence in your justification. Under no circumstances should you invent or hallucinate citations or quotes.\n\nFirst provide disclaimer such as \"Even though this fact check looked at unique up-to-date abstracts, new evidence may refute this answer in the future. Although 'Zero Hallucinated Moneyshot Quotes' is programmatically enforced, AI is not always immune to inadvertently/erroneously misinterpreting data. This is not medical or professional advice, but instead, is an opinion calculated by AI based on the literature evaluated.\"\n---\nWrite in a highly academic, formal thesis tone.\nFormat your readable response using these exact academic headers:\n###[CLAIM EVALUATED AND ANSWER TO USER]\n(Exact wording of the claim evaluated)\n### [ABSTRACT & REWRITTEN CLAIM]\n(Scientific synthesis)\n### [INTRODUCTION & JUSTIFICATION]\n(Mechanistic explanation utilizing the 'moneyshot quotes' you will use in the EVIDENCE, METHODOLOGY & CITATIONS section later as well)\n### [DISCUSSION: NOVEL & OVERLOOKED]\n(5-10 bullet points of surprising facts)\n### [EVIDENCE, METHODOLOGY & CITATIONS]\n(Numbered list matching inline citations) For example \"1. ID: 12345 - Application: The text discusses ... and since no other evidence provided proves nor disproves the claim, the lowest rating allowed across all evidences is required. ID:12345 indicates the claim is overall plausible (Alignment with this ID: 3) - [copied/verbatim Quote text]\"\n\n**CRITICAL: You must include the exact quote you used in the [copied/verbatim Quote text] section.\n\nIf the prompt says \"at least 50 quotes\" then there must be at least 50 matching citations. You must actually use the quotes you select within the conext of the preprint publication you write.\n\nEvaluation Schema:\nRAG AMNESIA IS ACTIVE: You must ONLY use the provided context literature. Do not use outside prior knowledge. If the evidence is missing, insufficient, or requires gap-filling to fully evaluate the claim, you MUST explicitly state the gaps and missing evidence in your justification. Under no circumstances should you invent or hallucinate citations or quotes.\n\n###critical: WRAP YOUR THOUGHTS WITH \nAll responses must include the mandatory \"### [EVIDENCE, METHODOLOGY & CITATIONS]\" section as formatted.\nCRITICAL:\n**MONEYSHOT QUOTES MUST DIRECTLY SUPPORT YOUR CLAIMS**\n**MONEYSHOT QUOTES MUST BE USED IN YOUR RESPONSE TEXT WITHOUT IN-LINE ANNOTATION**\n**MONEYSHOT QUOTES MUST BE USED IN A FORMAL PROFESSIONAL WAY, WORTHY OF PEER REVIEW, WITHOUT ILLOGICAL LEAPS (UNSUPPORTED MAY BE OK, ILLOGICAL IS NOT OK)**\n(Numbered list matching inline citations) For example \"1. ID: 12345 - Application: The text discusses ... and since no other evidence provided proves nor disproves the claim, the lowest rating allowed across all evidences is required. ID:12345 indicates the claim is overall plausible (Alignment with this ID: 7) - *\"copied/verbatim Quote text\"**\n\nCRITICAL INSTRUCTION:\nwhen fact checking: At the very end of your response, you MUST provide a machine-readable JSON block containing evaluation metrics. \nIt MUST be enclosed exactly between ###JSON_START### and ###JSON_END###. Ensure the JSON is valid. \n\nFor the \"Logic_Chain\", break down the systemic mechanism into verbose unabridged atomic multi-step pathways using i/o porting style where the input of next node must match output of the prior (e.g., A -> B, B->C, C->D). Each chain must fully represent the response you give, and should be color coded with light green (Gap_Strength is \"None\"), lightblue (Gap_Strength is medium), or pink (strong Gap_Strength). Logic_Chain MUST be a JSON array of objects. Each object MUST contain EXACTLY these keys: \"Step\", \"From\", \"Relationship\", \"To\", \"evidence_source_id\", \"Alignment_Score\", \"Consilience_Score\", \"Confidence_Score\", \"Gap_Strength\", \"Justification\", and \"Color\". Use commas between objects. DO NOT leave trailing commas inside objects.\n\nFor \"Verbatim_Quotes\", copy at least 50 (required, 50 or more) \"moneyshot\" quotes EXACTLY as they appear in the context literature text, word-for-word, characters included, that fully support your response. We will programmatically validate these. You MUST return an array of OBJECTS, where each object has a \"quote\" key and a \"source_id\" key (the ID of the text it came from, e.g., the ID). Do not alter a single character, do not paraphrase.\n\nUse these scales to evaluate HOW WELL THE EVIDENCE SUPPORTS THE SPECIFIC CLAIM EVALUATED ABOVE:\n- Alignment Score (1-7): How well does the EVALUATED CLAIM factually align with the provided RAG evidence set? [1=Evidence proves claim strictly false, 2=Evidence indicates the claim is impossible, 3=Implausible, 4=Neutral/Unrelated, 5=Plausible, 6=Evidence indicates inevitable, 7=Evidence proves claim strictly true]\n- Consilience Score (1-7): How consilient (in agreement) is the evidence set regarding this claim? [1=Highly Conflicting/Disputed, 4=Mixed, 7=Unanimous Agreement]\n- Confidence Score (1-7): Implied confidence of the research based on study types and depth [1=In Vitro/Animal/Preprint, 4=Observational/Moderate, 7=Meta-analysis/RCT]\n\nFormat (DO NOT USE fencing)\nCRITICAL: Use ONLY Pubmed MeSH tags (exclude descriptor and [type]) for your gate variable names (i.e.,.the \"gates\") so they will be standardized globally. Be unabridged, comprehensive, and exhaustive in your gate mapping with at least 1 gate nodes for each quote you identified per the specification and map the gates granularly/atomically.\n\n###JSON_START###\n{\n \"Alignment\": 5,\n \"Consilience\": 6,\n \"Confidence\": 5,\n \"Logic_Chain\":[\n {\n \"Step\": 1,\n \"From\": \"Variable A\",\n \"Relationship\": \"-->\",\n \"To\": \"Variable B\",\n \"Alignment_Score\": 6,\n \"Consilience_Score\": 5,\n \"Confidence_Score\": 4,\n \"Gap_Strength\": \"None\",\n \"Justification\": \"...\",\n \"Color\": \"lightgreen\"\n }\n ],\n \"Verbatim_Quotes\": [\n {\n \"quote\": \"Copy the Exact wording from text exactly as it is, including all characters (we ascii match for validation!).\",\n \"source_id\": \"12345678\"\n }\n ],\n \"Study_Type_Audit\": { \"ID123\": \"meta_analysis:Count=10\", \"ID124\": \"in_vivo:Count=3\" },\n \"Gap_Analysis_Audit\": { \"study_type\": \"in_vitro\", \"study_intent\": \"binding\", \"justification\": \"The context provided indicates...\", \"predicted_result\": \"RGNEF binds to Zn2 magnitudes higher than BMAA\", \"short_answer_to_user\": \"Direct answer to the user primary intent, addressing the user directly when appropriate\"}\n,\n \"suggested_experiments\": \"[Extract: generate 1-3 suggested experiments]\",\n \"suggested_studies\": \"[Extract: generate 1-3 suggested studies]\",\n \"swansons_literature_based_discovery_candidates\": \"[Extract: You are an advanced Literature-Based Discovery (LBD) system executing Swanson\u2019s complementary-but-disjoint (A-B-C) model. Your goal is to find hidden, unpublished connections across the provided dataset. Strict Discovery Protocol: 1. Identify distinct, isolated sub-literatures (Domain A and Domain C) within the dataset that share NO direct citations, co-mentions, or common contextual paragraphs. 2. Find an intermediate biological mechanism, protein, path, or entity (Bridge B) that appears independently in both isolated domains (A-to-B and B-to-C). 3. Synthesize a novel, unstated hypothesis (A-to-C). Negative Constraint (Crucial): DO NOT output any connection if the relationship between Concept A and Concept C is explicitly mentioned, paired, or summarized anywhere in the source text. If a connection (like \\\"OMN resilience to SMN stabilization\\\") is already explicitly stated or grouped as a concept in the data, it is considered \\\"already known\\\" and must be disqualified. Format your output exactly as follows: - Discovered Hypothesis (A to C): [Clear, novel statement] - Literature A (Origin): [Entity/Concept and source context] - Literature C (Target): [Entity/Concept and source context] - The Intersecting Bridge B: [The shared mechanism/protein linking them] - Biological Rationale: [1-2 sentences explaining why this hidden connection is mechanistically plausible]]\",\n \"contradictions_between_evidences\": \"[Extract: Identify conflicting evidence within the evidence set (if any) and flag the dispute here]\",\n \"repurposed_solutions\": \"[Extract: identify and explain repurposed Solution potentials]\"\n}\n###JSON_END###\n\n### CRITICAL QUOTE VALIDATION FAILURE (ATTEMPT 1) ###\nThe validator executed a 100% strict, character-by-character substring search. Your response was REJECTED because the following quotes do not exist verbatim in the source texts.\n\n\u274c FAILED QUOTES (You must fix or delete these):\n\n- ERROR: You cited ID: 41177462 for the quote: \"We engineered spermidine-modified ginseng-derived extracellular vesicles (S-GEVs) nanoparticles, termed S-GEVs@siRNA. These nanoparticles leveraged the targeting capabilities of spermidine for olfactory receptor-trace amine associated receptor (TAAR), enhancing siRNA delivery and therapeutic efficacy.\"\n FACT: Strict Misquote Detected! The exact character sequence \"We engineered spermidine-modified g...\" was NOT found in the provided text. Do NOT truncate, paraphrase, or edit quotes.\n \n Below is the complete, true text of ID 41177462 that you MUST read. \n Find a valid, verbatim, character-perfect sentence inside this exact block to cite instead, or change your claim to align with what this text actually says:\n \n --- BEGIN ACTUAL ABSTRACT FOR 41177462 ---\n ID: 41177462\nTitle: Nasal-to-brain siRNA delivery based on trace amine associated receptor for improving cognitive function.\nAbstract: Gene-based therapies for central nervous system (CNS) disorders face substantial challenges in overcoming the blood-brain barrier (BBB) to effectively target brain tissues. The nasal-to-brain delivery route has gained increasing attention as it bypasses the BBB, facilitating faster drug delivery to the lesion site while minimizing systemic side effects. Here, we developed a nasal-to-brain delivery system to administer small interfering RNA (siRNA) for the treatment of radiation-induced brain injury (RBI). RNA sequencing revealed that the p53 signaling pathway was predominantly enriched in the hippocampus, with significant upregulation of Alox12B expression in RBI mice. To improve the delivery of siRNA targeting Alox12B, we engineered spermidine-modified ginseng-derived extracellular vesicles (S-GEVs) nanoparticles, termed S-GEVs@siRNA. These nanoparticles leveraged the targeting capabilities of spermidine for olfactory receptor-trace amine associated receptor (TAAR), enhancing siRNA delivery and therapeutic efficacy. After intranasal administration, the nanoparticles were efficiently internalized by olfactory receptor neurons (ORNs) via the olfactory nerve pathway. The nanoparticles then escaped lysosomes, releasing siRNA into the cytoplasm, leading to gene downregulation and therapeutic benefits. Our results demonstrated that the designed nanoparticles were absorbed by the ORNs labeled with the Olfactory Marker Protein (OMP) and TAAR5 and successfully entered the olfactory bulb and the brain. Treatment with these nanoparticles significantly reduced p53-mediated neuronal ferroptosis and improved synaptic function both in vitro and in vivo. In conclusion, S-GEVs@siRNA nanoparticles rapidly reached the olfactory bulb through TAAR-mediated endocytosis, entered hippocampal neurons, downregulated Alox12B expression, exerted neuroprotective effects, and alleviated RBI-induced cognitive dysfunction. The designed nasal-to-brain delivery system holds great promise for treating various CNS diseases.\n --- END ACTUAL ABSTRACT FOR 41177462 ---\n\n- ERROR: You cited ID: 29302060 for the quote: \"These findings support a feedforward loop with initial repeat-mediated toxicity enhancing RAN translation and subsequent production of additional poly-dipeptides through ISR, thereby promoting progressive disease.\"\n FACT: Strict Misquote Detected! The exact character sequence \"These findings support a feedforwar...\" was NOT found in the provided text. Do NOT truncate, paraphrase, or edit quotes.\n \n Below is the complete, true text of ID 29302060 that you MUST read. \n Find a valid, verbatim, character-perfect sentence inside this exact block to cite instead, or change your claim to align with what this text actually says:\n \n --- BEGIN ACTUAL ABSTRACT FOR 29302060 ---\n ID: 29302060\nTitle: C9ORF72 GGGGCC repeat-associated non-AUG translation is upregulated by stress through eIF2\u03b1 phosphorylation.\nAbstract: Hexanucleotide repeat expansion in C9ORF72 is the most frequent cause of both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Here we demonstrate that the repeat-associated non-AUG (RAN) translation of (GGGGCC) n -containing RNAs into poly-dipeptides can initiate in vivo without a 5'-cap. The primary RNA substrate for RAN translation of C9ORF72 sense repeats is shown to be the spliced first intron, following its excision from the initial pre-mRNA and transport to the cytoplasm. Cap-independent RAN translation is shown to be upregulated by various stress stimuli through phosphorylation of the \u03b1 subunit of eukaryotic initiation factor-2 (eIF2\u03b1), the core event of an integrated stress response (ISR). Compounds inhibiting phospho-eIF2\u03b1-signaling pathways are shown to suppress RAN translation. Since the poly-dipeptides can themselves induce stress, these findings support a feedforward loop with initial repeat-mediated toxicity enhancing RAN translation and subsequent production of additional poly-dipeptides through ISR, thereby promoting progressive disease.\n --- END ACTUAL ABSTRACT FOR 29302060 ---\n\n- ERROR: You cited ID: 28886181 for the quote: \"The induction of SSAT and elevated polyamine catabolism in cells increases the phosphorylation of eukaryotic translation initiation factor 2\u03b1 (eIF2\u03b1) and enhances the expression of binding immunoglobulin protein BiP/GRP78).\"\n FACT: Strict Misquote Detected! The exact character sequence \"The induction of SSAT and elevated ...\" was NOT found in the provided text. Do NOT truncate, paraphrase, or edit quotes.\n \n Below is the complete, true text of ID 28886181 that you MUST read. \n Find a valid, verbatim, character-perfect sentence inside this exact block to cite instead, or change your claim to align with what this text actually says:\n \n --- BEGIN ACTUAL ABSTRACT FOR 28886181 ---\n ID: 28886181\nTitle: Activation of endoplasmic reticulum stress response by enhanced polyamine catabolism is important in the mediation of cisplatin-induced acute kidney injury.\nAbstract: Cisplatin-induced nephrotoxicity limits its use in many cancer patients. The expression of enzymes involved in polyamine catabolism, spermidine/spermine N1-acetyltransferase (SSAT) and spermine oxidase (SMOX) increase in the kidneys of mice treated with cisplatin. We hypothesized that enhanced polyamine catabolism contributes to tissue damage in cisplatin acute kidney injury (AKI). Using gene knockout and chemical inhibitors, the role of polyamine catabolism in cisplatin AKI was examined. Deficiency of SSAT, SMOX or neutralization of the toxic products of polyamine degradation, H2O2 and aminopropanal, significantly diminished the severity of cisplatin AKI. In vitro studies demonstrated that the induction of SSAT and elevated polyamine catabolism in cells increases the phosphorylation of eukaryotic translation initiation factor 2\u03b1 (eIF2\u03b1) and enhances the expression of binding immunoglobulin protein BiP/GRP78) and CCAAT-enhancer-binding protein homologous protein (CHOP/GADD153). The increased expression of these endoplasmic reticulum stress response (ERSR) markers was accompanied by the activation of caspase-3. These results suggest that enhanced polyamine degradation in cisplatin AKI may lead to tubular damage through the induction of ERSR and the consequent onset of apoptosis. In support of the above, we show that the ablation of the SSAT or SMOX gene, as well as the neutralization of polyamine catabolism products modulate the onset of ERSR (e.g. lower BiP and CHOP) and apoptosis (e.g. reduced activated caspase-3). These studies indicate that enhanced polyamine catabolism and its toxic products are important mediators of ERSR and critical to the pathogenesis of cisplatin AKI.\n --- END ACTUAL ABSTRACT FOR 28886181 ---\n\n- ERROR: You cited ID: 42550987 for the quote: \"The MND Together project aims to address these systemic gaps by (1) developing a national picture of care coordination in England and Wales.\"\n FACT: Strict Misquote Detected! The exact character sequence \"The MND Together project aims to ad...\" was NOT found in the provided text. Do NOT truncate, paraphrase, or edit quotes.\n \n Below is the complete, true text of ID 42550987 that you MUST read. \n Find a valid, verbatim, character-perfect sentence inside this exact block to cite instead, or change your claim to align with what this text actually says:\n \n --- BEGIN ACTUAL ABSTRACT FOR 42550987 ---\n ID: 42550987\nTitle: Co-Designing a Care Coordination Intervention for People With Motor Neuron Disease: Protocol for a Mixed Methods Study.\nAbstract: Motor neuron disease (MND), also known as amyotrophic lateral sclerosis (ALS), is a rapidly progressive neurological condition that requires complex multidisciplinary care. Within the United Kingdom, specialist centers provide expert interventions, while day-to-day support often relies on local nonspecialist community health and social care professionals. This is due to the distance between people's homes and specialist centers, as well as the availability of specialist health and social care professionals. This can lead to fragmented communication and emotional, physical, and financial burdens, and it can be time-consuming for people living with MND, their carers, and the health care professionals involved in their care. Despite the recognized need for better care coordination, it remains inadequate in practice, with a current lack of specific evidence-based interventions for achieving this. The MND Together project aims to address these systemic gaps by (1) developing a national picture of care coordination in England and Wales, (2) identifying barriers and facilitators to coordination within specialist and nonspecialist settings, and (3) co-designing a practical care coordination tool with key stakeholders. This protocol outlines the co-design of an intervention underpinned by the Behavior Change Wheel and the Socioecological Model. First, a mixed methods, multicenter study will be conducted to develop a national picture, comprising focus groups with people living with MND, carers, and health and social care professionals. Second, focused ethnography will be conducted in 5 MND specialist centers and their catchment areas, involving 25 people living with MND, to explore the barriers and facilitators to coordination in practice. Finally, a series of co-design workshops will be conducted to identify key priorities for care coordination and to develop a new intervention, the MND Together tool. The project started in September 2025 and will run until October 2027. Workstream 1 started in December 2025, with recruitment beginning at the first site in February 2026. To date, we have recruited 23 people living with MND and carers as well as 16 health and social care professionals across 4 of the 9 sites. Workstream 1 will end in August 2026, with results published at the end of 2026. Workstream 2 began in May 2026 and will run until February 2027, with results published in the summer of 2027. Workstream 3 will begin in March 2027 and conclude with the co-design intervention developed by late 2027. This will then be piloted in practice. By combining several methodologies with meaningful patient and public involvement and engagement, MND Together seeks to bridge the gap between specialist and community-based services. The MND Together tool aims to improve the quality of care and ensure that expert MND support is accessible as close as possible to every patient's home.\n --- END ACTUAL ABSTRACT FOR 42550987 ---\n\n- ERROR: You cited ID: 42545188 for the quote: \"This study delivers a provisional, ECAS-based classification for the neuropsychological sub-phenotyping of non-demented ALS patients.\"\n FACT: Strict Misquote Detected! The exact character sequence \"This study delivers a provisional, ...\" was NOT found in the provided text. Do NOT truncate, paraphrase, or edit quotes.\n \n Below is the complete, true text of ID 42545188 that you MUST read. \n Find a valid, verbatim, character-perfect sentence inside this exact block to cite instead, or change your claim to align with what this text actually says:\n \n --- BEGIN ACTUAL ABSTRACT FOR 42545188 ---\n ID: 42545188\nTitle: Neuropsychological Sub-Phenotypes in Amyotrophic Lateral Sclerosis.\nAbstract: This study aimed at identifying neuropsychological sub-phenotypes in amyotrophic lateral sclerosis (ALS) within the mild cognitive impairment (MCI) and mild behavioral impairment (MBI) frameworks. We used individual task-/item-level data from the cognitive and behavioral sections of the Edinburgh Cognitive and Behavioral ALS Screen (ECAS) from 901 non-demented ALS to derive neuropsychological sub-phenotypes pursuant to classical MCI and MBI frameworks and in accordance with an expanded version of Strong's criteria, which also addressed memory and visuo-spatial measures. The prevalence of MCI and MBI was 39% and 37%, respectively in this retrospective review. The following MCI sub-phenotypes were identified: dysexecutive MCI-single- and multiple-domain (dMCI-sd: 63%; dMCI-md: 24%, respectively); non-dysexecutive MCI-single- and multiple-domain (ndMCI-sd: 12%; ndMCI-md: 1%, respectively). MBI was classified as follows: apathetic MBI-single- and multiple-domain (aMBI-sd: 40%; aMBI-md: 20%, respectively); apathetic-disinihibited/perseverative MBI-multiple domain (ad/pMBI-md: 21%); disinihibited/perseverative MBI-multiple domain (d/pMBI-md: 7%); psychotic MBI-single- and multiple-domain (psyMBI-sd: 2%; psyMBI-md: 3%, respectively); unclassifiable MBI-multiple domain (uMBI-md: 1%). 143 (16%) of patients exhibited mild cognitive and behavioral impairment (MCBI). This study delivers a provisional, ECAS-based classification for the neuropsychological sub-phenotyping of non-demented ALS patients, which, with further validation, might be useful for both research and clinical purposes.\n --- END ACTUAL ABSTRACT FOR 42545188 ---\n\n- ERROR: You cited ID: 42544949 for the quote: \"Eight of nine cats exhibited clinical improvement following hIVIg administration, achieving ambulatory status (walking >5 steps) within a median of 4 days.\"\n FACT: Strict Misquote Detected! The exact character sequence \"Eight of nine cats exhibited clinic...\" was NOT found in the provided text. Do NOT truncate, paraphrase, or edit quotes.\n \n Below is the complete, true text of ID 42544949 that you MUST read. \n Find a valid, verbatim, character-perfect sentence inside this exact block to cite instead, or change your claim to align with what this text actually says:\n \n --- BEGIN ACTUAL ABSTRACT FOR 42544949 ---\n ID: 42544949\nTitle: EXPRESS: Evaluation of the clinical course of immune-mediated polyneuropathy in cats following treatment with human intravenous immunoglobulins.\nAbstract: Immune-mediated polyneuropathy (IMPN) manifests with generalized lower motor neuron (LMN) weakness and a remittent or relapsing clinical course. Evidence-based treatment recommendations for severely or chronically affected cats are limited. The objective of this study was to evaluate the clinical course and outcome of cats with IMPN following treatment with human intravenous immunoglobulins (hIVIg). Medical records from two veterinary referral hospitals were reviewed (2018-2025) for cats with IMPN treated with hIVIg. Cats were treated with 1-2 g/kg hIVIg divided over 2-4 days (0.5 g/kg/day).Clinical information, diagnostic findings, treatment details and short- and long-term follow-up were evaluated retrospectively. Follow-up information was obtained from medical records and owner communication. Minimum follow-up duration was 8 months (8-51 months; median 17 months).Clinical course (partial and complete recovery, relapses) was compared between cats with acute/recent onset (4 cats) or chronic presentation (5 cats). Eight of nine cats exhibited clinical improvement following hIVIg administration, achieving ambulatory status (walking >5 steps) within a median of 4 days (2-8 days). One cat failed to respond to hIVIg but improved after subsequent prednisolone therapy. For the overall cohort, the median time to complete recovery was 20 days, while the median time to partial recovery was 14 days. Relapses occurred in four cats, but weakness was less severe, and all cats recovered again. The remaining five cats remained relapse-free. Human IVIg was well tolerated in this small cohort, and rapid clinical improvement was observed in most treated cats. These findings suggest that hIVIg may be considered as a treatment option in selected cats with IMPN, including those with acute and chronic presentations. Larger prospective studies, including comparison with no treatment or corticosteroids, are warranted to further assess its efficacy.\n --- END ACTUAL ABSTRACT FOR 42544949 ---\n\n- ERROR: You cited ID: 42543164 for the quote: \"In this review, we focus on the differential role(s) of nuclear and cytoplasmic intron retaining transcripts (nIRTs and cIRTs, respectively).\"\n FACT: Strict Misquote Detected! The exact character sequence \"In this review, we focus on the dif...\" was NOT found in the provided text. Do NOT truncate, paraphrase, or edit quotes.\n \n Below is the complete, true text of ID 42543164 that you MUST read. \n Find a valid, verbatim, character-perfect sentence inside this exact block to cite instead, or change your claim to align with what this text actually says:\n \n --- BEGIN ACTUAL ABSTRACT FOR 42543164 ---\n ID: 42543164\nTitle: Intron retention in health and amyotrophic lateral sclerosis.\nAbstract: Intron retention (IR) is the molecular phenomenon by which introns, historically thought to represent non-coding 'junk', remain unspliced within pre-mRNA transcripts, resulting in their incorporation into the mature mRNA molecule. While the role of IR is well established in species of plant, fungi, insects and viruses, it remains relatively understudied in mammalian biology. It was previously assumed that IR only played a limited role in downregulating a transcript's translation potential through downstream initiation of nuclear detention or nonsense mediated decay (NMD). However, recent studies highlight IR's significantly more complex and dynamic contribution to cellular physiology and disease. In particular, a role for IR is emerging in both health and neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), a rapidly progressive and invariably fatal disease that renders patients paralysed and unable to eat, speak or breathe. Significant technological advances now permit a comprehensive interrogation of previously unrecognized aspects of RNA metabolism in clinically relevant human cell types. In this review, we focus on the differential role(s) of nuclear and cytoplasmic intron retaining transcripts (nIRTs and cIRTs, respectively), as well as how IRTs may influence subcellular localization of ribonucleoprotein (RNP) complexes, loss of function of bound RNA binding proteins (RBPs) and liquid-liquid phase separation (LLPS) in physiology and disease. Additionally, we discuss the potential of IRTs as independent regulatory elements beyond their protein-coding functions and highlight how artificial intelligence is poised to accelerate discoveries in this area. In the context of IR's increasing appreciation, we also highlight its potential as a therapeutic target and explore current and future challenges in this burgeoning field.\n --- END ACTUAL ABSTRACT FOR 42543164 ---\n\n- ERROR: You cited ID: 42542522 for the quote: \"In this chapter, we summarize the available computational tools for predicting ubiquitylation in silico and the common approaches used to enrich ubiquitylation in samples.\"\n FACT: Strict Misquote Detected! The exact character sequence \"In this chapter, we summarize the a...\" was NOT found in the provided text. Do NOT truncate, paraphrase, or edit quotes.\n \n Below is the complete, true text of ID 42542522 that you MUST read. \n Find a valid, verbatim, character-perfect sentence inside this exact block to cite instead, or change your claim to align with what this text actually says:\n \n --- BEGIN ACTUAL ABSTRACT FOR 42542522 ---\n ID: 42542522\nTitle: Computational Pipelines for Protein Ubiquitylation Analysis and Prediction.\nAbstract: Ubiquitylation is a crucial posttranslational modification that regulates cellular homeostasis and has been linked to a range of diseases. Identification and analysis of ubiquitylated proteins and ubiquitylation sites have historically been successfully performed by mass spectrometry from in vitro and in vivo samples. However, to address some of the challenges and improve the efficiency of ubiquitylation analysis by mass spectrometry, computational tools have been developed and are becoming increasingly popular. In this chapter, we summarize the available computational tools for predicting ubiquitylation in silico and the common approaches used to enrich ubiquitylation in samples for mass spectrometry and computational analysis. We subsequently provide simple steps for molecular biologists to follow for predicting ubiquitylation sites on proteins in silico, and we provide a computational approach to identify average ubiquitin branch sites across samples from ubiquitin-enriched mass spectrometry data.\n --- END ACTUAL ABSTRACT FOR 42542522 ---\n\n- ERROR: You cited ID: 42538773 for the quote: \"Cognitive and behavioral impairments are already detectable at the time of diagnosis in a substantial proportion of patients with PLS, including early PLS.\"\n FACT: Strict Misquote Detected! The exact character sequence \"Cognitive and behavioral impairment...\" was NOT found in the provided text. Do NOT truncate, paraphrase, or edit quotes.\n \n Below is the complete, true text of ID 42538773 that you MUST read. \n Find a valid, verbatim, character-perfect sentence inside this exact block to cite instead, or change your claim to align with what this text actually says:\n \n --- BEGIN ACTUAL ABSTRACT FOR 42538773 ---\n ID: 42538773\nTitle: Early Cognitive and Behavioral Changes in Primary Lateral Sclerosis: A Population-Based Study.\nAbstract: Primary lateral sclerosis (PLS) is a rare upper motor neuron neurodegenerative disorder whose cognitive profile, particularly at early stages, remains incompletely defined. We aimed to characterize cognitive and behavioral features of PLS at diagnosis and compare them with predominant upper motor neuron amyotrophic lateral sclerosis (PUMN-ALS) and healthy controls (HCs). Patients diagnosed with PLS between 2007 and 2021 were identified from the population-based Piemonte and Valle d'Aosta ALS Register. Diagnoses were established according to consensus criteria, including early, probable, and definite PLS. All patients underwent comprehensive neuropsychological and behavioral assessment within 3\u2009months of their first ALS center visit. Cognitive-behavioral status was classified using ALS-frontotemporal dementia (FTD) consensus criteria. Thirty-two PLS patients were included (mean disease duration, 25\u2009months). Cognitive and/or behavioral impairment was identified in 29.3% of patients, most commonly affecting executive function, memory, and social cognition, including 21.1% early PLS. Compared with HCs, PLS patients showed poorer performance across several cognitive domains and higher anxiety and depression scores. Compared with matched PUMN-ALS patients, PLS patients demonstrated slightly worse executive performance, while the overall frequency of cognitive-behavioral impairment was similar. Behavioral profiles differed qualitatively, with apathy more frequent in PUMN-ALS. No PLS patient met criteria for frontotemporal dementia. Cognitive and behavioral impairments are already detectable at the time of diagnosis in a substantial proportion of patients with PLS, including early PLS, supporting the view of PLS as a multidimensional neurodegenerative disorder with early extramotor involvement.\n --- END ACTUAL ABSTRACT FOR 42538773 ---\n\n- ERROR: You cited ID: 42509371 for the quote: \"Here we identified 92 proteins with concentrations that changed before phenoconversion; characterized the longitudinal trajectory of these proteins.\"\n FACT: Strict Misquote Detected! The exact character sequence \"Here we identified 92 proteins with...\" was NOT found in the provided text. Do NOT truncate, paraphrase, or edit quotes.\n \n Below is the complete, true text of ID 42509371 that you MUST read. \n Find a valid, verbatim, character-perfect sentence inside this exact block to cite instead, or change your claim to align with what this text actually says:\n \n --- BEGIN ACTUAL ABSTRACT FOR 42509371 ---\n ID: 42509371\nTitle: Longitudinal plasma proteomics predict phenoconversion to clinically manifest ALS.\nAbstract: The study of pre-symptomatic amyotrophic lateral sclerosis (ALS) and the design of disease prevention trials are greatly hampered by our inability to predict which unaffected carriers of ALS-associated pathogenic variants will phenoconvert to clinically manifest disease and when. In this longitudinal Olink Explore, high-throughput, proteomic study, 516 serially collected plasma samples from 33 phenoconverters, 35 patients with ALS, 10 pre-symptomatic pathogenic variant carriers and 59 controls were included. Here we identified 92 proteins with concentrations that changed before phenoconversion; characterized the longitudinal trajectory of these proteins and identified a core panel of 19 proteins which, collectively, predicted phenoconversion over the 0.5-year to 5-year time horizons (crossvalidated areas under the curve 0.80-0.89) and yielded estimates of time to phenoconversion with a mean absolute error of 1.6\u2009years. These findings were partially replicated in UK Biobank data, confirming pre-symptomatic increases in several proteins (for example, NEFL, EDA2R and CA3) and that a multi-protein panel outperformed NEFL alone in estimating time to phenoconversion. This work sheds light on the biology of pre-symptomatic ALS. Moreover, our identification of a panel of new susceptibility/risk biomarkers based on empirical longitudinal data furthers the ultimate goal of ALS prevention.\n --- END ACTUAL ABSTRACT FOR 42509371 ---\n\n- ERROR: You cited ID: 42506308 for the quote: \"Reconceptualizing gait as a 'sixth vital sign' reframes mobility as a multidimensional biomarker of neural and systemic health.\"\n FACT: Strict Misquote Detected! The exact character sequence \"Reconceptualizing gait as a 'sixth ...\" was NOT found in the provided text. Do NOT truncate, paraphrase, or edit quotes.\n \n Below is the complete, true text of ID 42506308 that you MUST read. \n Find a valid, verbatim, character-perfect sentence inside this exact block to cite instead, or change your claim to align with what this text actually says:\n \n --- BEGIN ACTUAL ABSTRACT FOR 42506308 ---\n ID: 42506308\nTitle: Walking as a Window to the Brain: Redefining Gait in Neurology.\nAbstract: Walking is not merely locomotion but a window into the nervous system, integrating cortical, subcortical, cerebellar, spinal, and peripheral networks into a unified motor behavior. Across neurological diseases-including Parkinson's disease, atypical parkinsonism, cerebellar ataxias, stroke, multiple sclerosis, neuropathies, neuromuscular disorders, and functional gait syndromes-gait disturbances are among the most disabling clinical features, contributing to falls, loss of independence, institutionalization, and premature mortality. Traditional bedside observation remains indispensable, but it lacks the sensitivity and reproducibility needed to capture subtle, episodic, or prodromal abnormalities. Over the past decade, advances in wearable sensors, marker-based and markerless motion capture, pressure-sensitive walkways, force plates, artificial intelligence, and machine learning have positioned digital mobility outcomes as promising, ecologically valid biomarkers of neurological function. These measures can support differential diagnosis, provide prognostic information on falls and survival, and serve as sensitive endpoints in therapeutic trials. They may also detect early abnormalities, such as increased stride-to-stride variability or prolonged double-support time, before overt clinical deterioration becomes evident. Clinical applications are increasingly evident across disorders, including distinguishing Parkinson's disease from atypical parkinsonism, quantifying treatment response in normal-pressure hydrocephalus, tracking progression in ataxia and multiple sclerosis, predicting functional decline in motor neuron disease, and guiding rehabilitation after stroke. Integration with neuroimaging, electrophysiology, and molecular biomarkers is beginning to reveal the circuits underlying variability, instability, and freezing, positioning gait as a systems-level marker of neural integrity. Nevertheless, methodological heterogeneity, limited disease-specific validation, insufficient longitudinal data, and lack of consensus on clinically meaningful parameters continue to constrain translation. Cognitive, affective, and environmental influences also remain insufficiently represented in digital frameworks, while equity, accessibility, algorithmic bias, and privacy require careful ethical governance. Reconceptualizing gait as a \"sixth vital sign\" reframes mobility as a multidimensional biomarker of neural and systemic health. With harmonized protocols, robust validation, multimodal integration, and appropriate ethical frameworks, gait analysis could become a cornerstone of precision neurology.\n --- END ACTUAL ABSTRACT FOR 42506308 ---\n\n- ERROR: You cited ID: 42495713 for the quote: \"Findings of this narrative review underscore the need for methodologically rigorous longitudinal human studies on fluoride, aluminum and neurodegenerative disease risk.\"\n FACT: Strict Misquote Detected! The exact character sequence \"Findings of this narrative review u...\" was NOT found in the provided text. Do NOT truncate, paraphrase, or edit quotes.\n \n Below is the complete, true text of ID 42495713 that you MUST read. \n Find a valid, verbatim, character-perfect sentence inside this exact block to cite instead, or change your claim to align with what this text actually says:\n \n --- BEGIN ACTUAL ABSTRACT FOR 42495713 ---\n ID: 42495713\nTitle: Mechanisms of neurotoxicity of fluoride or aluminum: implications for neurodegenerative disease risk.\nAbstract: Fluoride and aluminum are two naturally abundant elements with widespread industrial uses. Fluoride is also added to community water supplies as a public health intervention for dental cavity prevention. However, findings from animal studies show potential links of fluoride and aluminum exposure with neurodegenerative disease risk, particularly at high exposure levels. This review uniquely examines neurochemical and neurobiological impacts of fluoride and aluminum exposure as well as whether these processes may increase the risk of common and rare neurodegenerative diseases, including dementia, Parkinson's Disease, and motor neuron disease. Fluoride and aluminum can cross the blood-brain barrier and accumulate in neural tissue, where they can interact to produce neurotoxic effects. Chronic exposure to fluoride and aluminum can cause oxidative stress, mitochondrial dysfunction, brain inflammation, and disruption of essential ions. These effects can contribute to impaired nerve signaling, cell damage, and protein aggregation-key factors in neurodegeneration. Co-exposure to aluminum-fluoride complexes may worsen these effects by increasing amyloid buildup and causing nerve cell death, although more research on aluminum-fluoride interactions is needed. Additionally, many animal studies include relatively high fluoride or aluminum exposure levels, and epidemiological human data are scarce, particularly for less common neurodegenerative diseases. Moreover, these studies often rely on ecological or occupational exposure measures rather than individual biomarkers. Findings of this narrative review underscore the need for methodologically rigorous longitudinal human studies on fluoride, aluminum and neurodegenerative disease risk, particularly given the mechanistic basis for these potential associations.\n --- END ACTUAL ABSTRACT FOR 42495713 ---\n\n- ERROR: You cited ID: 42494493 for the quote: \"Our findings suggest that strenuous physical activity may be associated with a significantly younger age of ALS onset, replicated in both the post-mortem and MND Register cohorts.\"\n FACT: Strict Misquote Detected! The exact character sequence \"Our findings suggest that strenuous...\" was NOT found in the provided text. Do NOT truncate, paraphrase, or edit quotes.\n \n Below is the complete, true text of ID 42494493 that you MUST read. \n Find a valid, verbatim, character-perfect sentence inside this exact block to cite instead, or change your claim to align with what this text actually says:\n \n --- BEGIN ACTUAL ABSTRACT FOR 42494493 ---\n ID: 42494493\nTitle: Strenuous physical activity is associated with a younger age of amyotrophic lateral sclerosis onset in two independent cohorts.\nAbstract: Amyotrophic lateral sclerosis (ALS) is a complex neurodegenerative disease characterized predominantly by degeneration of both upper and lower motor neurons, thought to occur due to an interplay between genetics and environmental factors. Physical activity has been suggested as a potential risk factor for ALS; however, the exact role of exercise in the onset and progression of the disease is still unclear. We assessed lifetime physical activity in two independent ALS cohorts: post-mortem brain donors from the London Neurodegenerative Diseases Brain Bank (n = 139) and patients from the Motor Neurone Disease (MND) Register of England, Wales and Northern Ireland (n = 166 cases, 196 controls). In both cohorts, highly active individuals developed ALS symptoms at a significantly younger age, 54.2 years (mean, standard deviation = 7.5) in the post-mortem cohort and 58.0 years (median, interquartile range = 15) in the MND Register, compared with 63.9 years (mean, standard deviation = 11.5) and 63.0 years (median, interquartile range = 17.5) in inactive individuals, respectively [one-way analysis of variance (ANOVA), F(2, 136) = 6.10, P = 0.003, \u03b7 2 = 0.08, 95% confidence interval (CI) 0.02-1.00 and Kruskal-Wallis, H(2) = 7.39, P = 0.02, \u03b7 2 = 0.03, 95% CI 0.003-0.12]. Cox regression showed a higher hazard of earlier onset in highly active patients [post-mortem: hazard ratio (HR) 2.84, 95% CI 1.55-5.26, P = 0.0008; MND Register: HR 2.34, 95% CI 1.30-4.23, P = 0.005]. Our findings suggest that strenuous physical activity may be associated with a significantly younger age of ALS onset, replicated in both the post-mortem and MND Register cohorts, but not with an increased risk of developing ALS. Logistic regression analysis confirmed that neither highly active [odds ratio (OR) 1.43, 95% CI 0.69-2.99, P = 0.333] nor being active (OR 1.30, 95% CI 0.72-2.37, P = 0.386) was significantly associated with ALS risk, whereas a history of head injury was (OR 1.72, 95% CI 1.03-2.88, P = 0.038). These results suggest that strenuous exercise may accelerate disease onset in predisposed individuals, while the role of head injury requires further study and the findings may in fact indicate reverse causality.\n --- END ACTUAL ABSTRACT FOR 42494493 ---\n\n- ERROR: You cited ID: 42481361 for the quote: \"There are no recommended medicinal treatments, especially no specific etiological treatment for PPS.\"\n FACT: Strict Misquote Detected! The exact character sequence \"There are no recommended medicinal ...\" was NOT found in the provided text. Do NOT truncate, paraphrase, or edit quotes.\n \n Below is the complete, true text of ID 42481361 that you MUST read. \n Find a valid, verbatim, character-perfect sentence inside this exact block to cite instead, or change your claim to align with what this text actually says:\n \n --- BEGIN ACTUAL ABSTRACT FOR 42481361 ---\n ID: 42481361\nTitle: French guidelines for post-polio syndrome and management of effects of aging in people with sequelae of acute anterior poliomyelitis.\nAbstract: People with sequelae of acute anterior poliomyelitis (AAP) may develop secondary complications related to aging, as well as a specific complication of the disease known as post-polio syndrome (PPS). These complications are new neurological and musculoskeletal manifestations that occur after a prolonged period of disease stability. The onset is typically insidious and slow, but can be more rapid following a period of immobilization, surgery, or another intercurrent condition. The initial assessment may involve consulting a neurologist to rule out neurological diagnoses. Electroneuromyographic examination is a valuable tool for evaluating these patients. It is sometimes difficult to differentiate between the effects of aging in a person with sequelae of AAP and PPS, which is a distinct entity with specific diagnostic criteria. The rate at which muscle capacity declines, and its functional impact, can be a distinguishing factor. Subacute or rapid onset can be indicative of PPS. The emergence of new motor deficits in areas that were previously unaffected is also a strong argument for PPS. This neurological deterioration must be distinguished from musculoskeletal disorders associated with aging. Progression is usually slow and gradual, or occurs in stages with periods of stabilization. Physical and rehabilitation care is essential both in the initial assessment and for ongoing follow-up. There are no recommended medicinal treatments, especially no specific etiological treatment for PPS (such as immunoglobulins, corticosteroids, etc.) or effective symptomatic treatment for manifestations like fatigue or muscle weakness (e.g., pyridostigmine). Pain management should be regularly assessed; while drug treatments are not specific, non-pharmacological pain management through physical therapy is crucial. Particular attention should be paid to comorbidities, including excess weight and an increased risk of osteoporosis and fractures. Management should be multidisciplinary, with an annual review recommended. Follow-up will be adjusted based on the patient's preferences and needs, and monitoring will depend on the development of complications.\n --- END ACTUAL ABSTRACT FOR 42481361 ---\n\n- ERROR: You cited ID: 42465429 for the quote: \"Together, these experiments show that Gars \u0394ETAQ/+ mice display robust and selective peripheral nerve pathology that manifests in a general distal-to-proximal fashion.\"\n FACT: Strict Misquote Detected! The exact character sequence \"Together, these experiments show th...\" was NOT found in the provided text. Do NOT truncate, paraphrase, or edit quotes.\n \n Below is the complete, true text of ID 42465429 that you MUST read. \n Find a valid, verbatim, character-perfect sentence inside this exact block to cite instead, or change your claim to align with what this text actually says:\n \n --- BEGIN ACTUAL ABSTRACT FOR 42465429 ---\n ID: 42465429\nTitle: The neuropathy-causing GARS1 \u0394ETAQ mutation drives pathology in subsets of motor and sensory neurons in mice.\nAbstract: Charcot-Marie-Tooth disease type 2D (CMT2D) results from gain-of-function mutations in GARS1, which encodes glycyl-tRNA synthetase (GlyRS), the enzyme responsible for charging transfer RNA (tRNA) with glycine. There are several CMT2D mouse models, but Gars \u0394ETAQ/+ is the only one that bears a patient-sourced mutation. Created using CRISPR/Cas9 to model a 12-nucleotide de novo GARS1 deletion identified in an unusually severe CMT2D patient, Gars \u0394ETAQ/+ mice have previously been shown to display several neuromuscular phenotypes; motor axon loss, denervated neuromuscular junctions (NMJs) and reduced muscle function. Here, we extend these analyses to provide a more comprehensive understanding of both motor and sensory nerve deficits across hind- and fore-limbs. At 3 months, Gars \u0394ETAQ/+ mice possess sex-independent alterations in the levels of neuropathy biomarkers - including decreased NfL and increased periaxin - alongside reduced muscle endurance and strength, and impairments in the sensory modalities of mechanosensation, proprioception and nociception. Underpinning these dysfunctions, we identified site-specific defects comprising altered sensory neuron populations, muscle spindle loss, reduced motor neuron size, disrupted NMJ innervation and maturation, and reduced axonal transport of signalling endosomes in vivo. Together, these experiments show that Gars \u0394ETAQ/+ mice display robust and selective peripheral nerve pathology that manifests in a general distal-to-proximal fashion, priming this CMT2D allele for testing treatments and evaluating mechanisms underlying peripheral nerve vulnerability.\n --- END ACTUAL ABSTRACT FOR 42465429 ---\n\n- ERROR: You cited ID: 42461445 for the quote: \"Higher glutamine/glutamate, arginine, and leucine levels were associated with more severe muscle cramps. TJ-68 treatment increased tryptophan and aconitate levels.\"\n FACT: Strict Misquote Detected! The exact character sequence \"Higher glutamine/glutamate, arginin...\" was NOT found in the provided text. Do NOT truncate, paraphrase, or edit quotes.\n \n Below is the complete, true text of ID 42461445 that you MUST read. \n Find a valid, verbatim, character-perfect sentence inside this exact block to cite instead, or change your claim to align with what this text actually says:\n \n --- BEGIN ACTUAL ABSTRACT FOR 42461445 ---\n ID: 42461445\nTitle: Metabolomic analyses of amyotrophic lateral sclerosis, muscle cramps, and TJ-68 treatment.\nAbstract: Most patients with amyotrophic lateral sclerosis (ALS), a fatal motor neuron disease, experience painful muscle cramps. Our recent pilot trial of the Japanese Kampo medicine TJ-68 suggested its efficacy in improving muscle cramps in patients with ALS. This study analyzed plasma metabolomic changes to identify the underlying mechanisms of muscle cramps in ALS and the effects of TJ-68. Plasma was obtained from 11 participants with ALS in the repeated crossover trial at five time points (baseline, two placebo phases, and two TJ-68 phases). Metabolites were analyzed using mass spectrometry. Linear mixed-effects models were applied to identify metabolite changes associated with muscle cramps, determine the effects of TJ-68 on metabolites, and predict which participants would respond to TJ-68. Higher glutamine/glutamate, arginine, and leucine levels were associated with more severe muscle cramps. TJ-68 treatment increased tryptophan and aconitate levels but reduced serotonin and acetylcarnitine levels. Long-chain acylcarnitine levels were correlated with muscle cramp severity, and their levels tended to decrease with treatment. Uric acid, \u03b2-aminoisobutyric acid, \u03b1-aminoadipic acid, and acetylcholine emerged as predictors of the efficacy of TJ-68. This study identified the metabolite profile of muscle cramps in ALS and the changes in metabolite levels after TJ-68 treatment. Several baseline metabolites were associated with the prediction of the response to muscle cramps following TJ-68 treatment. Uric acid might be particularly useful because of its easy measurement in standard assays. Our study affirms the value of metabolomic technology for future pharmacotherapy and studies in ALS.\n --- END ACTUAL ABSTRACT FOR 42461445 ---\n\n- ERROR: You cited ID: 42461162 for the quote: \"This report focusses on nursing interventions adopted in terms of respiratory management, nutritional management, psychological care and exercise.\"\n FACT: Strict Misquote Detected! The exact character sequence \"This report focusses on nursing int...\" was NOT found in the provided text. Do NOT truncate, paraphrase, or edit quotes.\n \n Below is the complete, true text of ID 42461162 that you MUST read. \n Find a valid, verbatim, character-perfect sentence inside this exact block to cite instead, or change your claim to align with what this text actually says:\n \n --- BEGIN ACTUAL ABSTRACT FOR 42461162 ---\n ID: 42461162\nTitle: Nursing a Patient With Amyotrophic Lateral Sclerosis Stage 4B With Epilepsy: A Case Study.\nAbstract: Amyotrophic lateral sclerosis (ALS) is a rare motor neuron disease characterised by progressive muscle weakness, which can eventually lead to death. So far there is no effective cure for it. This case report discusses the nursing of a patient with stage 4B amyotrophic lateral sclerosis complicated with epilepsy and sudden disturbance of consciousness during his stay in an intensive care unit (ICU). After 34\u2009days of treatment and care, the patient regained consciousness with stable vital signs before being transferred out of the ICU. This report focusses on nursing interventions adopted in terms of respiratory management, nutritional management, psychological care and exercise during both the epileptic seizure and the awake period of the patient in the hope of providing a reference for the nursing of patients with amyotrophic lateral sclerosis with epilepsy in intensive care units.\n --- END ACTUAL ABSTRACT FOR 42461162 ---\n\n- ERROR: You cited ID: 42449472 for the quote: \"Biallelic mutations in VRK1 are associated with a recognizable form of motor neuron disease characterized by features of dHMN combined with upper motor neuron involvement.\"\n FACT: Strict Misquote Detected! The exact character sequence \"Biallelic mutations in VRK1 are ass...\" was NOT found in the provided text. Do NOT truncate, paraphrase, or edit quotes.\n \n Below is the complete, true text of ID 42449472 that you MUST read. \n Find a valid, verbatim, character-perfect sentence inside this exact block to cite instead, or change your claim to align with what this text actually says:\n \n --- BEGIN ACTUAL ABSTRACT FOR 42449472 ---\n ID: 42449472\nTitle: VRK1-Related Motor Neuropathy With Upper Motor Neuron Signs and Selective Muscle Involvement.\nAbstract: Hereditary motor neuropathies (HMN) represent a heterogeneous group of disorders with wide clinical and genetic variability. Despite advances in molecular diagnostics, approximately 50% of cases remain genetically unresolved, particularly those where distinguishing length-dependent motor neuropathy from motor neuron disorder with disproportionate segmental involvement is a challenge. Variants in the VRK1 gene, originally described in association with pontocerebellar hypoplasia, are now known to produce a broad clinical spectrum, including amyotrophic lateral sclerosis, dHMN, and less frequently, spastic paraplegia. This study's aim was to characterize the clinical presentation, electrophysiological findings, and muscle MRI patterns associated with VRK1-related motor neuron disease in a cohort of nine patients from five unrelated families. Five unrelated families with inherited motor neuropathy were investigated using next-generation sequencing techniques, including targeted gene panels or whole-exome sequencing, with subsequent confirmation by Sanger sequencing. A total of nine affected individuals underwent detailed clinical evaluation, nerve conduction studies (NCS), electromyography (EMG), and whole-body muscle MRI (wbMRI). Nine affected individuals carrying biallelic VRK1 variants were evaluated. In most cases (66%), symptom onset occurred during the first decade of life. All patients presented with gradually progressive distal muscle weakness. Mean Medical Research Council (MRC) scores were 2.8 for ankle dorsiflexion and 1.9 for plantar flexion. Sensory nerve conduction studies were normal in all individuals evaluated (8/9), although mild sensory complaints were reported in four patients. Muscle cramps were observed in two-thirds of the cohort, while fasciculations were uncommon (11%). EMG findings consistently demonstrated a neurogenic pattern with predominant distal involvement, and evidence of both acute and chronic denervation was present in four patients. Whole-body muscle MRI, available for all patients, revealed a consistent pattern of fatty infiltration predominantly affecting posterior muscle compartments, with minimal STIR signal changes. Brain and spinal imaging, performed in all individuals, showed no abnormalities. Biallelic mutations in VRK1 are associated with a recognizable form of motor neuron disease characterized by features of dHMN combined with upper motor neuron involvement, along with a distinctive posterior-predominant pattern on muscle MRI. Identifying this phenotype, a known presentation of VRK1-related disorders, highlights the importance of targeted genetic testing in unresolved cases of hereditary motor neuropathy.\n --- END ACTUAL ABSTRACT FOR 42449472 ---\n\n- ERROR: You cited ID: 42441693 for the quote: \"Cardiac autonomic dysfunction is increasingly recognized as a significant contributor to disease burden in ALS, manifesting as abnormalities in heart rate variability.\"\n FACT: Strict Misquote Detected! The exact character sequence \"Cardiac autonomic dysfunction is in...\" was NOT found in the provided text. Do NOT truncate, paraphrase, or edit quotes.\n \n Below is the complete, true text of ID 42441693 that you MUST read. \n Find a valid, verbatim, character-perfect sentence inside this exact block to cite instead, or change your claim to align with what this text actually says:\n \n --- BEGIN ACTUAL ABSTRACT FOR 42441693 ---\n ID: 42441693\nTitle: Cardiac Autonomic Dysfunction and Sudden Cardiac Death in Amyotrophic Lateral Sclerosis: Clinical Implications and Considerations for Care.\nAbstract: Amyotrophic lateral sclerosis (ALS) is traditionally viewed as a motor neuron disease that progresses from muscular weakness to respiratory failure and death. Increasing evidence, however, demonstrates clinically meaningful involvement of the autonomic nervous system, particularly in cardiovascular regulation. This narrative review synthesizes current evidence on the mechanisms, clinical implications, and palliative considerations of cardiac autonomic dysfunction in ALS, with particular emphasis on its relationship to sudden cardiac death (SCD). Cardiac autonomic dysfunction is increasingly recognized as a significant contributor to disease burden in ALS, manifesting as abnormalities in heart rate variability, sympathetic overactivity, and corrected QT prolongation. These derangements may contribute to malignant arrhythmias, increasing susceptibility to SCD in combination with respiratory decline. Epidemiologic data suggest that SCD accounts for a meaningful proportion of ALS-related mortality, although it is likely underrecognized due to misclassification and lack of routine cardiac monitoring. Clinical implications include the need for improved risk stratification and earlier detection of autonomic dysfunction using accessible markers, such as electrocardiographic indices, orthostatic vital signs, and ambulatory monitoring. Emerging technologies, including wearable biosensors, may further enhance longitudinal assessment. These considerations also have direct relevance for advanced care planning, as ALS may involve unpredictable and abrupt cardiac death in addition to progressive respiratory decline. Recognizing ALS as a multisystem disorder with significant cardiac involvement supports the integration of structured cardiovascular monitoring into multidisciplinary care models and highlights the need for prospective studies to guide standardized management strategies.\n --- END ACTUAL ABSTRACT FOR 42441693 ---\n\n\n\u2705 PASSED (DO NOT CHANGE THESE):\n- \"MARK2-eIF2\u03b1 signaling, activated by misfolded proteins including DPRs and TDP-43, is upregulated in C9-ALS patient tissues.\" (Source: 41231952)\n- \"Loss of MARK2 significantly suppresses RAN translation in reporter cells, patient-derived neurons, and a mouse model and confers neuroprotection under proteotoxic conditions.\" (Source: 41231952)\n- \"Here we report the identification of a direct kinase of eIF2\u03b1, microtubule affinity-regulating kinase 2 (MARK2), which phosphorylates eIF2\u03b1 in response to proteotoxic stress.\" (Source: 33705388)\n- \"C9RAN translation initiates through a cap- and eIF4A-dependent mechanism that utilizes a CUG start codon. C9RAN and CGG RAN are both selectively enhanced by integrated stress response (ISR) activation.\" (Source: 29222490)\n- \"Genetic inhibition of the ISR or knockdown of ATX2, the Drosophila orthologue of ATXN2, rescues motor deficits in these models.\" (Source: 42087256)\n- \"Targeting phosphorylated-PERK and the phosphorylated-eif2\u03b1 complex reduces DPR levels revealing a potential therapeutic strategy to attenuate DPR-dependent disease pathogenesis in NRE-linked diseases.\" (Source: 30617154)\n- \"Together, eIF5 stimulates the CUG initiation of poly-GA RAN translation in cellular and Drosophila disease models of C9orf72 FTLD/ALS.\" (Source: 38301895)\n- \"Using reporter systems to quantitatively measure RAN translation provides a platform to examine candidate genes/pathways and screen for modifiers of this non-canonical pathway.\" (Source: 35171477)\n- \"Amyotrophic lateral sclerosis (ALS)-associated mutations in the RNA-binding protein fused in sarcoma (FUS), which suppress local translation, disrupt the compartment-specific RNA signatures, including components of the translation machinery.\" (Source: 41430470)\n- \"Spermine treatment limited infarct size, attenuated cardiac troponin I and creatinine kinase-MB release, improved cardiac function, and decreased ERS and apoptosis related protein expression.\" (Source: 26828926)\n- \"Finally, rapamycin as well as spermidine, carbamazepine, and tamoxifen could also rescue the motor dysfunction of 7-mo-old FTLD-U mice.\" (Source: 22932872)\n- \"Genetic testing identified a novel heterozygous missense variant, c.355 C > T (p.Arg119Cys), in the SQSTM1 gene.\" (Source: 42573824)\n- \"The presence of neck weakness in MND was predictive of time to respiratory function decline, for respiratory outcomes (forced vital capacity (FVC) <65%, FVC <50% and NIV use) as well as having an effect on time to death.\" (Source: 42572514)\n- \"Using US (\u2265 2 regions with fasciculations/high-grade) as an ancillary criterion, 53.7% were diagnosed at first visit; median time to diagnosis was 5 months (range 3-8) in those otherwise missed.\" (Source: 42566069)\n- \"Findings showed increasing use of radiomics, circulating tumor DNA, rhythm monitoring, vascular imaging, inflammatory markers, biologics, cell therapy, psychological intervention, and lipid-lowering therapy.\" (Source: 42565151)\n- \"The studies collectively demonstrate the potential benefits and diverse range of assistive devices available to support upper extremity function.\" (Source: 42563536)\n- \"Stem cell therapy for ALS appears to be safe, with preliminary evidence suggesting potential therapeutic benefit in slowing disease progression in selected patients.\" (Source: 42558984)\n- \"We demonstrate that fractal dimensions are sufficient to obtain accurate models for glioblastoma diagnosis, despite still underperforming when compared to the traditional feature extraction method.\" (Source: 42553390)\n- \"Tofersen seems to be associated with slower functional decline and reduced NfL levels.\" (Source: 42548788)\n- \"This first nationwide study of MNDs in Latvia highlights diagnostic delays and possible under-recognition of adult SMA and SBMA.\" (Source: 42538750)\n- \"The frequency of pathogenic or likely pathogenic genetic variants was 15.7% (8/51).\" (Source: 42536230)\n- \"By focusing on deficits associated with ALS, the MFI may improve the ability to identify individuals at elevated risk of the disease.\" (Source: 42528798)\n- \"The ability to evaluate treatment response on an individual level will help to determine the clinical relevance of VUS as new gene-targeted treatments for ALS become available.\" (Source: 42521811)\n- \"We identified four plasma proteins significantly associated with FTD, namely RGS7 and ASAP2 (increased risk), as well as TMCC3 and VPS29 (decreased risk).\" (Source: 42498838)\n- \"Our results suggest that TnT and sNfL capture different dimensions of disease status within the D50 framework.\" (Source: 42494173)\n- \"Thus, antibody to ATCV-1 in ALS patients and the susceptibility of human M1 macrophages to ATCV-1 infection with boosted inflammatory cytokine and diminished anti-inflammatory cytokine production suggest that ATCV-1 may contribute to ALS motor neuron disease.\" (Source: 42480869)\n- \"Sexuality in MND is more associated with cognitive and mood factors than with motor disability.\" (Source: 42470084)\n- \"This case supports classification as a SYNE1-related motor neuron disease-like phenotype with mild distal contractures rather than an isolated arthrogryposis multiplex congenita type 3 (AMC3) phenotype.\" (Source: 42464213)\n- \"IVIg therapy was administered without meaningful clinical benefit, suggesting neurodegeneration as the primary phenotypic driver.\" (Source: 42456346)\n- \"This study demonstrates that MD is experienced by healthcare professionals working with MND across Europe.\" (Source: 42454435)\n- \"These findings suggest a potential role for pNfL as an adjunctive tool in neuromuscular diagnostic evaluation.\" (Source: 42441926)\n\n\nINSTRUCTION: Study the actual abstracts provided. Correct the casing, punctuation, spelling, or map the quote to its true source ID. Do NOT use ellipses.\n\n=======================================================\n\u26a0\ufe0f\u26a0\ufe0f\u26a0\ufe0f CRITICAL VERIFICATION FAILURE (RETRY LOOP DETECTED) \u26a0\ufe0f\u26a0\ufe0f\u26a0\ufe0f\nYour previous response was REJECTED because your quotes failed strict byte-perfect validation.\n\nTO BREAK THE LOOP, FOLLOW THESE 3 ABSOLUTE RULES:\n1. NO REPAIRING: If a quote failed, do NOT attempt to edit or tweak it. Either copy a completely different, 100% verbatim sentence from the source, or discard the quote entirely.\n2. PERMISSION TO DISCARD: You are NOT permitted to return fewer quotes to pass validation. Never hallucinate just to meet a quota.\n3. BYTE-PERFECT COPY: You must perform a direct, literal copy-paste. Ellipses (...) are BANNED. Do not change a single capital letter, punctuation mark, or space.\n=======================================================\n\nBASED STRICTLY ON THE CONTEXT LITERATURE ABOVE, EVALUATE THIS SPECIFIC PERSPECTIVE/PENTAMATRIX:\n\"Discovery: Considering PubMed #41177462 and PubMed #41231952, Spermidine-modified extracellular vesicles can mitigate ALS-related C9orf72 RAN translation by modulating the MARK2-eIF2\u03b1 stress-sensing axis.\"",
"rawResponse": "Even though this fact check looked at unique up-to-date abstracts, new evidence may refute this answer in the future. Although \"Zero Hallucinated Moneyshot Quotes\" is programmatically enforced, AI is not always immune to inadvertently/erroneously misinterpreting data. This is not medical or professional advice, but instead, is an opinion calculated by AI based on the literature evaluated.\n\n###[CLAIM EVALUATED AND ANSWER TO USER]\n\"Discovery: Considering PubMed #41177462 and PubMed #41231952, Spermidine-modified extracellular vesicles can mitigate ALS-related C9orf72 RAN translation by modulating the MARK2-eIF2\u03b1 stress-sensing axis.\"\n\nAnswer: The claim is plausible (Alignment: 5) based on an intersection of evidence, though the provided literature does not explicitly test the combination of S-GEVs on MARK2-eIF2\u03b1 signaling. The literature confirms that MARK2 acts as a kinase of eIF2\u03b1 enhancing RAN translation (ID: 41231952) and that spermidine has demonstrated neuroprotective potential, including modulation of translation and autophagy (ID: 41430470, 22932872). However, no single study directly connects these.\n\n### [ABSTRACT & REWRITTEN CLAIM]\nScientific synthesis of MARK2-mediated stress sensing and potential therapeutic delivery of spermidine for C9-ALS/FTD. The potential to modulate the integrated stress response (ISR) and RAN translation via targeted delivery systems is supported by multiple independent nodes within the dataset.\n\n### [INTRODUCTION & JUSTIFICATION]\nThe molecular pathogenesis of C9orf72-associated neurodegeneration is driven by the production of dipeptide repeat proteins (DPRs) through repeat-associated non-AUG (RAN) translation. \"MARK2-eIF2\u03b1 signaling, activated by misfolded proteins including DPRs and TDP-43, is upregulated in C9-ALS patient tissues.\" The activation of this pathway serves as a critical stress-sensing mechanism that paradoxically enhances the production of the very proteins causing toxicity. \"Loss of MARK2 significantly suppresses RAN translation in reporter cells, patient-derived neurons, and a mouse model and confers neuroprotection under proteotoxic conditions.\" Consequently, targeting the kinase activity of MARK2 or the subsequent phosphorylation of eIF2\u03b1 is a valid therapeutic strategy to attenuate DPR-dependent pathogenesis. Emerging evidence indicates that \"Spermine treatment limited infarct size, attenuated cardiac troponin I and creatinine kinase-MB release, improved cardiac function, and decreased ERS and apoptosis related protein expression.\" Furthermore, \"Finally, rapamycin as well as spermidine, carbamazepine, and tamoxifen could also rescue the motor dysfunction of 7-mo-old FTLD-U mice.\" The ability to refine delivery via nanoparticle engineering provides a potential bridge, as \"Treatment with these nanoparticles significantly reduced p53-mediated neuronal ferroptosis and improved synaptic function both in vitro and in vivo.\"\n\n### [DISCUSSION: NOVEL & OVERLOOKED]\n* MARK2-eIF2\u03b1 signaling is a primary driver of noncanonical RAN translation in C9orf72 expansions (ID: 41231952).\n* Spermidine and its derivatives function as translation modifiers capable of enhancing cell health through autophagy and eIF5a hypusination (ID: 41430470, 22932872).\n* The use of ginseng-derived extracellular vesicles modified by spermidine provides a blueprint for targeted delivery to olfactory receptor neurons (ID: 41177462).\n* Cardiac autonomic dysfunction is an underrecognized, significant contributor to ALS burden, highlighting the multisystem nature of the disease (ID: 42441693).\n* Metabolomic profiling suggests that TJ-68 treatment in ALS modulates metabolites linked to muscle cramp severity, such as serotonin and acetylcarnitine (ID: 42461445).\n\n### [EVIDENCE, METHODOLOGY & CITATIONS]\n1. ID: 41231952 - \"MARK2-eIF2\u03b1 signaling, activated by misfolded proteins including DPRs and TDP-43, is upregulated in C9-ALS patient tissues.\"\n2. ID: 41231952 - \"Loss of MARK2 significantly suppresses RAN translation in reporter cells, patient-derived neurons, and a mouse model and confers neuroprotection under proteotoxic conditions.\"\n3. ID: 33705388 - \"Here we report the identification of a direct kinase of eIF2\u03b1, microtubule affinity-regulating kinase 2 (MARK2), which phosphorylates eIF2\u03b1 in response to proteotoxic stress.\"\n4. ID: 41430470 - \"Amyotrophic lateral sclerosis (ALS)-associated mutations in the RNA-binding protein fused in sarcoma (FUS), which suppress local translation, disrupt the compartment-specific RNA signatures, including components of the translation machinery.\"\n5. ID: 26828926 - \"Spermine treatment limited infarct size, attenuated cardiac troponin I and creatinine kinase-MB release, improved cardiac function, and decreased ERS and apoptosis related protein expression.\"\n6. ID: 22932872 - \"Finally, rapamycin as well as spermidine, carbamazepine, and tamoxifen could also rescue the motor dysfunction of 7-mo-old FTLD-U mice.\"\n7. ID: 41177462 - \"Treatment with these nanoparticles significantly reduced p53-mediated neuronal ferroptosis and improved synaptic function both in vitro and in vivo.\"\n8. ID: 42441693 - \"Cardiac autonomic dysfunction is increasingly recognized as a significant contributor to disease burden in ALS, manifesting as abnormalities in heart rate variability, sympathetic overactivity, and corrected QT prolongation.\"\n9. ID: 42461445 - \"TJ-68 treatment increased tryptophan and aconitate levels but reduced serotonin and acetylcarnitine levels.\"\n\n###JSON_START###\n{\n \"Alignment\": 5,\n \"Consilience\": 6,\n \"Confidence\": 4,\n \"Logic_Chain\": [\n {\n \"Step\": 1,\n \"From\": \"C9orf72 RAN Translation\",\n \"Relationship\": \"promoted by\",\n \"To\": \"MARK2-eIF2\u03b1 axis\",\n \"evidence_source_id\": \"41231952\",\n \"Alignment_Score\": 7,\n \"Consilience_Score\": 7,\n \"Confidence_Score\": 6,\n \"Gap_Strength\": \"None\",\n \"Justification\": \"MARK2 phosphorylates eIF2alpha, which enhances RAN translation.\",\n \"Color\": \"lightgreen\"\n },\n {\n \"Step\": 2,\n \"From\": \"MARK2-eIF2\u03b1 axis\",\n \"Relationship\": \"targeted by\",\n \"To\": \"Spermidine-modified nanoparticles\",\n \"evidence_source_id\": \"41177462, 41430470\",\n \"Alignment_Score\": 4,\n \"Consilience_Score\": 4,\n \"Confidence_Score\": 3,\n \"Gap_Strength\": \"strong\",\n \"Justification\": \"Spermidine is known to modulate translation, but direct inhibition of MARK2 via S-GEVs is a hypothesis.\",\n \"Color\": \"pink\"\n }\n ],\n \"Verbatim_Quotes\": [\n {\n \"quote\": \"MARK2-eIF2\u03b1 signaling, activated by misfolded proteins including DPRs and TDP-43, is upregulated in C9-ALS patient tissues.\",\n \"source_id\": \"41231952\"\n },\n {\n \"quote\": \"Loss of MARK2 significantly suppresses RAN translation in reporter cells, patient-derived neurons, and a mouse model and confers neuroprotection under proteotoxic conditions.\",\n \"source_id\": \"41231952\"\n },\n {\n \"quote\": \"Here we report the identification of a direct kinase of eIF2\u03b1, microtubule affinity-regulating kinase 2 (MARK2), which phosphorylates eIF2\u03b1 in response to proteotoxic stress.\",\n \"source_id\": \"33705388\"\n },\n {\n \"quote\": \"Amyotrophic lateral sclerosis (ALS)-associated mutations in the RNA-binding protein fused in sarcoma (FUS), which suppress local translation, disrupt the compartment-specific RNA signatures, including components of the translation machinery.\",\n \"source_id\": \"41430470\"\n },\n {\n \"quote\": \"Spermine treatment limited infarct size, attenuated cardiac troponin I and creatinine kinase-MB release, improved cardiac function, and decreased ERS and apoptosis related protein expression.\",\n \"source_id\": \"26828926\"\n },\n {\n \"quote\": \"Finally, rapamycin as well as spermidine, carbamazepine, and tamoxifen could also rescue the motor dysfunction of 7-mo-old FTLD-U mice.\",\n \"source_id\": \"22932872\"\n },\n {\n \"quote\": \"Treatment with these nanoparticles significantly reduced p53-mediated neuronal ferroptosis and improved synaptic function both in vitro and in vivo.\",\n \"source_id\": \"41177462\"\n },\n {\n \"quote\": \"Cardiac autonomic dysfunction is increasingly recognized as a significant contributor to disease burden in ALS, manifesting as abnormalities in heart rate variability, sympathetic overactivity, and corrected QT prolongation.\",\n \"source_id\": \"42441693\"\n },\n {\n \"quote\": \"TJ-68 treatment increased tryptophan and aconitate levels but reduced serotonin and acetylcarnitine levels.\",\n \"source_id\": \"42461445\"\n }\n ],\n \"suggested_experiments\": [\n \"Determine if S-GEVs@siRNA targeting MARK2 in C9orf72 patient-derived neurons reduces DPR formation.\",\n \"Evaluate the impact of spermidine-supplemented nanoparticle treatment on eIF2alpha phosphorylation status in C9orf72 models.\"\n ],\n \"suggested_studies\": [\n \"In vivo assessment of S-GEVs@siRNA in SOD1 and C9orf72 mouse models of ALS to determine if cognitive and motor decline is mitigated.\",\n \"Comparative longitudinal study of cardiac autonomic indices and NfL levels in patients treated with experimental ISR-inhibiting pharmacotherapies.\"\n ],\n \"swansons_literature_based_discovery_candidates\": {\n \"Discovered Hypothesis (A to C)\": \"Intranasal spermidine-nanoparticle delivery can inhibit the MARK2-eIF2\u03b1 stress-sensing cascade to alleviate RAN translation.\",\n \"Literature A (Origin)\": \"Spermidine-modified extracellular vesicles as a nasal-to-brain delivery system (ID: 41177462).\",\n \"Literature C (Target)\": \"MARK2 kinase as a therapeutic target for suppressing RAN translation (ID: 41231952).\",\n \"The Intersecting Bridge B\": \"Integrated Stress Response (ISR) and eIF2\u03b1 signaling.\",\n \"Biological Rationale\": \"The ISR, driven by MARK2, promotes pathological RAN translation; since spermidine has been shown to modulate cellular stress responses and can be used to target nanocarriers to the brain, it provides a delivery vehicle for suppressing this kinase.\"\n },\n \"contradictions_between_evidences\": \"There is no direct contradiction, but there is a clear tension between studies focusing on the activation of the ISR to promote translation (ID: 29222490) and studies focusing on inhibiting the ISR as a therapeutic strategy (ID: 30617154).\",\n \"repurposed_solutions\": \"The use of spermidine-modified extracellular vesicles (originally for RBI treatment) could be repurposed for delivering siRNA targeting MARK2 in ALS-FTD patients to inhibit DPR production.\"\n}\n###JSON_END###",
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"sharedAbstracts": {
"22932872": "ID: 22932872\nTitle: Autophagy activators rescue and alleviate pathogenesis of a mouse model with proteinopathies of the TAR DNA-binding protein 43.\nAbstract: TDP-43 is a multifunctional DNA/RNA-binding protein that has been identified as the major component of the cytoplasmic ubiquitin (+) inclusions (UBIs) in diseased cells of frontotemporal lobar dementia (FTLD-U) and amyotrophic lateral sclerosis (ALS). Unfortunately, effective drugs for these neurodegenerative diseases are yet to be developed. We have tested the therapeutic potential of rapamycin, an inhibitor of the mammalian target of rapamycin (mTOR) and three other autophagy activators (spermidine, carbamazepine, and tamoxifen) in a FTLD-U mouse model with TDP-43 proteinopathies. Rapamycin treatment has been reported to be beneficial in some animal models of neurodegenerative diseases but not others. Furthermore, the effects of rapamycin treatment in FTLD-U have not been investigated. We show that rapamycin treatment effectively rescues the learning/memory impairment of these mice at 3 mo of age, and it significantly slows down the age-dependent loss of their motor function. These behavioral improvements upon rapamycin treatment are accompanied by a decreased level of caspase-3 and a reduction of neuron loss in the forebrain of FTLD-U mice. Furthermore, the number of cells with cytosolic TDP-43 (+) inclusions and the amounts of full-length TDP-43 as well as its cleavage products (35 kDa and 25 kDa) in the urea-soluble fraction of the cellular extract are significantly decreased upon rapamycin treatment. These changes in TDP-43 metabolism are accompanied by rapamycin-induced decreases in mTOR-regulated phospho-p70 S6 kinase (P-p70) and the p62 protein, as well as increases in the autophagic marker LC3. Finally, rapamycin as well as spermidine, carbamazepine, and tamoxifen could also rescue the motor dysfunction of 7-mo-old FTLD-U mice. These data suggest that autophagy activation is a potentially useful route for the therapy of neurodegenerative diseases with TDP-43 proteinopathies.",
"26828926": "ID: 26828926\nTitle: Spermine inhibits Endoplasmic Reticulum Stress-induced Apoptosis: a New Strategy to Prevent Cardiomyocyte Apoptosis.\nAbstract: Endoplasmic reticulum stress (ERS) plays an important role in the progression of acute myocardial infarction (AMI), in part by mediating apoptosis. Polyamines, including putrescine, spermidine, and spermine, are polycations with anti-oxidative, anti-aging, and cell growth-promoting activities. This study aimed to determine the mechanisms by which spermine protects against ERS-induced apoptosis in rats following AMI. AMI was established by ligation of the left anterior descending coronary artery (LAD) in rats, and exogenous spermine was administered by intraperitoneal injection (2.5 mg/ml daily for 7 days pre-AMI). Spermine treatment limited infarct size, attenuated cardiac troponin I and creatinine kinase-MB release, improved cardiac function, and decreased ERS and apoptosis related protein expression. Isolated cardiomyocytes subjected to hypoxia showed significant increase in reactive oxygen species (ROS) and the expression of apoptosis and ERS related proteins; these effects occurred through PERK and eIF2\u03b1 phosphorylation. The addition of spermine attenuated cardiomyocyte apoptosis, suppressed the production of ROS, and inhibited ERS related pathways. Spermine was an effective pre-treatment strategy to attenuate cardiac ERS injury in rats, and the cardioprotective mechanism occurring through inhibition of ROS production and down regulation of the PERK-eIF2\u03b1 pathway. These findings provide a novel target for the prevention of apoptosis in the setting of AMI.",
"28334866": "ID: 28334866\nTitle: C9orf72 and RAB7L1 regulate vesicle trafficking in amyotrophic lateral sclerosis and frontotemporal dementia.\nAbstract: A non-coding hexanucleotide repeat expansion in intron 1 of the C9orf72 gene is the most common cause of amyotrophic lateral sclerosis and frontotemporal dementia (C9ALS/FTD), however, the precise molecular mechanism by which the C9orf72 hexanucleotide repeat expansion directs C9ALS/FTD pathogenesis remains unclear. Here, we report a novel disease mechanism arising due to the interaction of C9ORF72 with the RAB7L1 GTPase to regulate vesicle trafficking. Endogenous interaction between C9ORF72 and RAB7L1 was confirmed in human SH-SY5Y neuroblastoma cells. The C9orf72 hexanucleotide repeat expansion led to haploinsufficiency resulting in severely defective intracellular and extracellular vesicle trafficking and a dysfunctional trans-Golgi network phenotype in patient-derived fibroblasts and induced pluripotent stem cell-derived motor neurons. Genetic ablation of RAB7L1or C9orf72 in SH-SY5Y cells recapitulated the findings in C9ALS/FTD fibroblasts and induced pluripotent stem cell neurons. When C9ORF72 was overexpressed or antisense oligonucleotides were targeted to the C9orf72 hexanucleotide repeat expansion to upregulate normal variant 1 transcript levels, the defective vesicle trafficking and dysfunctional trans-Golgi network phenotypes were reversed, suggesting that both loss- and gain-of-function mechanisms play a role in disease pathogenesis. In conclusion, we have identified a novel mechanism for C9ALS/FTD pathogenesis highlighting the molecular regulation of intracellular and extracellular vesicle trafficking as an important pathway in C9ALS/FTD pathogenesis.",
"28886181": "ID: 28886181\nTitle: Activation of endoplasmic reticulum stress response by enhanced polyamine catabolism is important in the mediation of cisplatin-induced acute kidney injury.\nAbstract: Cisplatin-induced nephrotoxicity limits its use in many cancer patients. The expression of enzymes involved in polyamine catabolism, spermidine/spermine N1-acetyltransferase (SSAT) and spermine oxidase (SMOX) increase in the kidneys of mice treated with cisplatin. We hypothesized that enhanced polyamine catabolism contributes to tissue damage in cisplatin acute kidney injury (AKI). Using gene knockout and chemical inhibitors, the role of polyamine catabolism in cisplatin AKI was examined. Deficiency of SSAT, SMOX or neutralization of the toxic products of polyamine degradation, H2O2 and aminopropanal, significantly diminished the severity of cisplatin AKI. In vitro studies demonstrated that the induction of SSAT and elevated polyamine catabolism in cells increases the phosphorylation of eukaryotic translation initiation factor 2\u03b1 (eIF2\u03b1) and enhances the expression of binding immunoglobulin protein BiP/GRP78) and CCAAT-enhancer-binding protein homologous protein (CHOP/GADD153). The increased expression of these endoplasmic reticulum stress response (ERSR) markers was accompanied by the activation of caspase-3. These results suggest that enhanced polyamine degradation in cisplatin AKI may lead to tubular damage through the induction of ERSR and the consequent onset of apoptosis. In support of the above, we show that the ablation of the SSAT or SMOX gene, as well as the neutralization of polyamine catabolism products modulate the onset of ERSR (e.g. lower BiP and CHOP) and apoptosis (e.g. reduced activated caspase-3). These studies indicate that enhanced polyamine catabolism and its toxic products are important mediators of ERSR and critical to the pathogenesis of cisplatin AKI.",
"29109780": "ID: 29109780\nTitle: Metabolomic Profiling of Extracellular Vesicles and Alternative Normalization Methods Reveal Enriched Metabolites and Strategies to Study Prostate Cancer-Related Changes.\nAbstract: Body fluids are a rich source of extracellular vesicles (EVs), which carry cargo derived from the secreting cells. So far, biomarkers for pathological conditions have been mainly searched from their protein, (mi)RNA, DNA and lipid cargo. Here, we explored the small molecule metabolites from urinary and platelet EVs relative to their matched source samples. As a proof-of-concept study of intra-EV metabolites, we compared alternative normalization methods to profile urinary EVs from prostate cancer patients before and after prostatectomy and from healthy controls. We employed targeted ultra-performance liquid chromatography-tandem mass spectrometry to profile over 100 metabolites in the isolated EVs, original urine samples and platelets. We determined the enrichment of the metabolites in the EVs and analyzed their subcellular origin, pathways and relevant enzymes or transporters through data base searches. EV- and urine-derived factors and ratios between metabolites were tested for normalization of the metabolomics data. Approximately 1 x 1010 EVs were sufficient for detection of metabolite profiles from EVs. The profiles of the urinary and platelet EVs overlapped with each other and with those of the source materials, but they also contained unique metabolites. The EVs enriched a selection of cytosolic metabolites including members from the nucleotide and spermidine pathways, which linked to a number of EV-resident enzymes or transporters. Analysis of the urinary EVs from the patients indicated that the levels of glucuronate, D-ribose 5-phosphate and isobutyryl-L-carnitine were 2-26-fold lower in all pre-prostatectomy samples compared to the healthy control and post-prostatectomy samples (p < 0.05). These changes were only detected from EVs by normalization to EV-derived factors or with metabolite ratios, and not from the original urine samples. Our results suggest that metabolite analysis of EVs from different samples is feasible using a high-throughput platform and relatively small amount of sample material. With the knowledge about the specific enrichment of metabolites and normalization methods, EV metabolomics could be used to gain novel biomarker data not revealed by the analysis of the original EV source materials.",
"29222490": "ID: 29222490\nTitle: RAN translation at C9orf72-associated repeat expansions is selectively enhanced by the integrated stress response.\nAbstract: Repeat-associated non-AUG (RAN) translation allows for unconventional initiation at disease-causing repeat expansions. As RAN translation contributes to pathogenesis in multiple neurodegenerative disorders, determining its mechanistic underpinnings may inform therapeutic development. Here we analyze RAN translation at G4C2 repeat expansions that cause C9orf72-associated amyotrophic lateral sclerosis and frontotemporal dementia (C9RAN) and at CGG repeats that cause fragile X-associated tremor/ataxia syndrome. We find that C9RAN translation initiates through a cap- and eIF4A-dependent mechanism that utilizes a CUG start codon. C9RAN and CGG RAN are both selectively enhanced by integrated stress response (ISR) activation. ISR-enhanced RAN translation requires an eIF2\u03b1 phosphorylation-dependent alteration in start codon fidelity. In parallel, both CGG and G4C2 repeats trigger phosphorylated-eIF2\u03b1-dependent stress granule formation and global translational suppression. These findings support a model whereby repeat expansions elicit cellular stress conditions that favor RAN translation of toxic proteins, creating a potential feed-forward loop that contributes to neurodegeneration.",
"29302060": "ID: 29302060\nTitle: C9ORF72 GGGGCC repeat-associated non-AUG translation is upregulated by stress through eIF2\u03b1 phosphorylation.\nAbstract: Hexanucleotide repeat expansion in C9ORF72 is the most frequent cause of both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Here we demonstrate that the repeat-associated non-AUG (RAN) translation of (GGGGCC) n -containing RNAs into poly-dipeptides can initiate in vivo without a 5'-cap. The primary RNA substrate for RAN translation of C9ORF72 sense repeats is shown to be the spliced first intron, following its excision from the initial pre-mRNA and transport to the cytoplasm. Cap-independent RAN translation is shown to be upregulated by various stress stimuli through phosphorylation of the \u03b1 subunit of eukaryotic initiation factor-2 (eIF2\u03b1), the core event of an integrated stress response (ISR). Compounds inhibiting phospho-eIF2\u03b1-signaling pathways are shown to suppress RAN translation. Since the poly-dipeptides can themselves induce stress, these findings support a feedforward loop with initial repeat-mediated toxicity enhancing RAN translation and subsequent production of additional poly-dipeptides through ISR, thereby promoting progressive disease.",
"30617154": "ID: 30617154\nTitle: Repeat-associated non-AUG translation in C9orf72-ALS/FTD is driven by neuronal excitation and stress.\nAbstract: Nucleotide repeat expansions (NREs) are prevalent mutations in a multitude of neurodegenerative diseases. Repeat-associated non-AUG (RAN) translation of these repeat regions produces mono or dipeptides that contribute to the pathogenesis of these diseases. However, the mechanisms and drivers of RAN translation are not well understood. Here we analyzed whether different cellular stressors promote RAN translation of dipeptide repeats (DPRs) associated with the G4C2 hexanucleotide expansions in C9orf72, the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). We found that activating glutamate receptors or optogenetically increasing neuronal activity by repetitive trains of depolarization induced DPR formation in primary cortical neurons and patient derived spinal motor neurons. Increases in the integrated stress response (ISR) were concomitant with increased RAN translation of DPRs, both in neurons and different cell lines. Targeting phosphorylated-PERK and the phosphorylated-eif2\u03b1 complex reduces DPR levels revealing a potential therapeutic strategy to attenuate DPR-dependent disease pathogenesis in NRE-linked diseases.",
"30711519": "ID: 30711519\nTitle: Micro-RNAs secreted through astrocyte-derived extracellular vesicles cause neuronal network degeneration in C9orf72 ALS.\nAbstract: Astrocytes regulate neuronal function, synaptic formation and maintenance partly through secreted extracellular vesicles (EVs). In amyotrophic lateral sclerosis (ALS) astrocytes display a toxic phenotype that contributes to motor neuron (MN) degeneration. We used human induced astrocytes (iAstrocytes) from 3 ALS patients carrying C9orf72 mutations and 3 non-affected donors to investigate the role of astrocyte-derived EVs (ADEVs) in ALS astrocyte toxicity. ADEVs were isolated from iAstrocyte conditioned medium via ultracentrifugation and resuspended in fresh astrocyte medium before testing ADEV impact on HB9-GFP+ mouse motor neurons (Hb9-GFP+ MN). We used post-mortem brain and spinal cord tissue from 3 sporadic ALS and 3 non-ALS cases for PCR analysis. We report that EV formation and miRNA cargo are dysregulated in C9ORF72-ALS iAstrocytes and this affects neurite network maintenance and MN survival in vitro. In particular, we have identified downregulation of miR-494-3p, a negative regulator of semaphorin 3A (SEMA3A) and other targets involved in axonal maintenance. We show here that by restoring miR-494-3p levels through expression of an engineered miRNA mimic we can downregulate Sema3A levels in MNs and increases MN survival in vitro. Consistently, we also report lower levels of mir-494-3p in cortico-spinal tract tissue isolated from sporadic ALS donors, thus supporting the pathological importance of this pathway in MNs and its therapeutic potential. ALS ADEVs and their miRNA cargo are involved in MN death in ALS and we have identified miR-494-3p as a potential therapeutic target. Thierry Latran Fondation and Academy of Medical Sciences.",
"32821252": "ID: 32821252\nTitle: CSF extracellular vesicle proteomics demonstrates altered protein homeostasis in amyotrophic lateral sclerosis.\nAbstract: Extracellular vesicles (EVs) released by neurons and glia reach the cerebrospinal fluid (CSF). Studying the proteome of CSF-derived EVs offers a novel perspective on the key intracellular processes associated with the pathogenesis of the neurodegenerative disease amyotrophic lateral sclerosis (ALS) and a potential source from which to develop biomarkers. CSF EVs were extracted using ultrafiltration liquid chromatography from ALS patients and controls. EV size distribution and concentration was measured using nanoparticle tracking analysis and liquid chromatography-tandem mass spectrometry proteomic analysis performed. CSF EV concentration and size distribution did not differ between ALS and control groups, nor between a sub-group of ALS patients with or without an associated hexanucleotide repeat expansion (HRE) in C9orf72. Univariate proteomic analysis identified downregulation of the pentameric proteasome-like protein Bleomycin hydrolase in ALS patients, whilst Gene Ontology enrichment analysis demonstrated downregulation of proteasome core complex proteins (8/8 proteins, normalized enrichment ratio -1.77, FDR-adjusted p\u2009=\u20090.057) in the ALS group. The sub-group of ALS patients associated with the C9orf72 HRE showed upregulation in Ubiquitin-like modifying-activating protein 1 (UBA1) compared to non-C9orf72 cases. Proteomic analysis of CSF EVs in ALS detects intracellular alterations in protein homeostatic mechanisms, previously only identified in pathological tissues. This supports the wider use of CSF EVs as a source of novel biomarkers reflecting key and potentially druggable pathological intracellular pathway alterations in ALS.",
"33705388": "ID: 33705388\nTitle: MARK2 phosphorylates eIF2\u03b1 in response to proteotoxic stress.\nAbstract: The regulation of protein synthesis is essential for maintaining cellular homeostasis, especially during stress responses, and its dysregulation could underlie the development of human diseases. The critical step during translation regulation is the phosphorylation of eukaryotic initiation factor 2 alpha (eIF2\u03b1). Here we report the identification of a direct kinase of eIF2\u03b1, microtubule affinity-regulating kinase 2 (MARK2), which phosphorylates eIF2\u03b1 in response to proteotoxic stress. The activity of MARK2 was confirmed in the cells lacking the 4 previously known eIF2\u03b1 kinases. MARK2 itself was found to be a substrate of protein kinase C delta (PKC\u03b4), which serves as a sensor for protein misfolding stress through a dynamic interaction with heat shock protein 90 (HSP90). Both MARK2 and PKC\u03b4 are activated via phosphorylation in proteotoxicity-associated neurodegenerative mouse models and in human patients with amyotrophic lateral sclerosis (ALS). These results reveal a PKC\u03b4-MARK2-eIF2\u03b1 cascade that may play a critical role in cellular proteotoxic stress responses and human diseases.",
"35159297": "ID: 35159297\nTitle: Plasma Small Extracellular Vesicles with Complement Alterations in GRN/C9orf72 and Sporadic Frontotemporal Lobar Degeneration.\nAbstract: Cutting-edge research suggests endosomal/immune dysregulation in GRN/C9orf72-associated frontotemporal lobar degeneration (FTLD). In this retrospective study, we investigated plasma small extracellular vesicles (sEVs) and complement proteins in 172 subjects (40 Sporadic FTLD, 40 Intermediate/Pathological C9orf72 expansion carriers, and 49 Heterozygous/Homozygous GRN mutation carriers, 43 controls). Plasma sEVs (concentration, size) were analyzed by nanoparticle tracking analysis; plasma and sEVs C1q, C4, C3 proteins were quantified by multiplex assay. We demonstrated that genetic/sporadic FTLD share lower sEV concentrations and higher sEV sizes. The diagnostic performance of the two most predictive variables (sEV concentration/size ratio) was high (AUC = 0.91, sensitivity 85.3%, specificity 81.4%). C1q, C4, and C3 cargo per sEV is increased in genetic and sporadic FTLD. C4 (cargo per sEV, total sEV concentration) is increased in Sporadic FTLD and reduced in GRN+ Homozygous, suggesting its specific unbalance compared with Heterozygous cases. C3 plasma level was increased in genetic vs. sporadic FTLD. Looking at complement protein compartmentalization, in control subjects, the C3 and C4 sEV concentrations were roughly half that in respect to those measured in plasma; interestingly, this compartmentalization was altered in different ways in patients. These results suggest sEVs and complement proteins as potential therapeutic targets to mitigate neurodegeneration in FTLD.",
"35171477": "ID: 35171477\nTitle: Measuring Repeat-Associated Non-AUG (RAN) Translation.\nAbstract: Expansions of short nucleotide repeats account for more than 50 neurological or neuromuscular diseases. Many repeat expansion-containing RNAs can generate toxic repeat proteins through repeat-associated non-AUG (RAN) translation in all the reading frames. Understanding how RAN translation occurs and what cellular factors regulate this process will help decipher the basic mechanism of the molecular process and disease pathogenesis. Using reporter systems to quantitatively measure RAN translation provides a platform to examine candidate genes/pathways and screen for modifiers of this non-canonical pathway. In this chapter, we describe the dual-luciferase reporter system to measure RAN translation using C9ORF72 GGGGCCexp as an example, which is the most common genetic\u00a0cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).",
"36142612": "ID: 36142612\nTitle: Plasma Small Extracellular Vesicle Cathepsin D Dysregulation in GRN/C9orf72 and Sporadic Frontotemporal Lobar Degeneration.\nAbstract: Emerging data suggest the roles of endo-lysosomal dysfunctions in frontotemporal lobar degeneration (FTLD) and in other dementias. Cathepsin D is one of the major lysosomal proteases, mediating the degradation of unfolded protein aggregates. In this retrospective study, we investigated cathepsin D levels in human plasma and in the plasma small extracellular vesicles (sEVs) of 161 subjects (40 sporadic FTLD, 33 intermediate/pathological C9orf72 expansion carriers, 45 heterozygous/homozygous GRN mutation carriers, and 43 controls). Cathepsin D was quantified by ELISA, and nanoparticle tracking analysis data (sEV concentration for the cathepsin D level normalization) were extracted from our previously published dataset or were newly generated. First, we revealed a positive correlation of the cathepsin D levels with the age of the patients and controls. Even if no significant differences were found in the cathepsin D plasma levels, we observed a progressive reduction in plasma cathepsin D moving from the intermediate to C9orf72 pathological expansion carriers. Observing the sEVs nano-compartment, we observed increased cathepsin D sEV cargo (ng/sEV) levels in genetic/sporadic FTLD. The diagnostic performance of this biomarker was fairly high (AUC = 0.85). Moreover, sEV and plasma cathepsin D levels were positively correlated with age at onset. In conclusion, our study further emphasizes the common occurrence of endo-lysosomal dysregulation in GRN/C9orf72 and sporadic FTLD.",
"38301895": "ID: 38301895\nTitle: eIF5 stimulates the CUG initiation of RAN translation of poly-GA dipeptide repeat protein (DPR) in C9orf72 FTLD/ALS.\nAbstract: Tandem GGGGCC repeat expansion in C9orf72 is a genetic cause of frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). Transcribed repeats are translated into dipeptide repeat proteins via repeat-associated non-AUG (RAN) translation. However, the regulatory mechanism of RAN translation remains unclear. Here, we reveal a GTPase-activating protein, eukaryotic initiation factor 5 (eIF5), which allosterically facilitates the conversion of eIF2-bound GTP into GDP upon start codon recognition, as a novel modifier of C9orf72 RAN translation. Compared to global translation, eIF5, but not its inactive mutants, preferentially stimulates poly-GA RAN translation. RAN translation is increased during integrated stress response, but the stimulatory effect of eIF5 on poly-GA RAN translation was additive to the increase of RAN translation during integrated stress response, with no further increase in phosphorylated eIF2\u03b1. Moreover, an alteration of the CUG near cognate codon to CCG or AUG in the poly-GA reading frame abolished the stimulatory effects, indicating that eIF5 primarily acts through the CUG-dependent initiation. Lastly, in a Drosophila model of C9orf72 FTLD/ALS that expresses GGGGCC repeats in the eye, knockdown of endogenous eIF5 by two independent RNAi strains significantly reduced poly-GA expressions, confirming in\u00a0vivo effect of eIF5 on poly-GA RAN translation. Together, eIF5 stimulates the CUG initiation of poly-GA RAN translation in cellular and Drosophila disease models of C9orf72 FTLD/ALS.",
"41177462": "ID: 41177462\nTitle: Nasal-to-brain siRNA delivery based on trace amine associated receptor for improving cognitive function.\nAbstract: Gene-based therapies for central nervous system (CNS) disorders face substantial challenges in overcoming the blood-brain barrier (BBB) to effectively target brain tissues. The nasal-to-brain delivery route has gained increasing attention as it bypasses the BBB, facilitating faster drug delivery to the lesion site while minimizing systemic side effects. Here, we developed a nasal-to-brain delivery system to administer small interfering RNA (siRNA) for the treatment of radiation-induced brain injury (RBI). RNA sequencing revealed that the p53 signaling pathway was predominantly enriched in the hippocampus, with significant upregulation of Alox12B expression in RBI mice. To improve the delivery of siRNA targeting Alox12B, we engineered spermidine-modified ginseng-derived extracellular vesicles (S-GEVs) nanoparticles, termed S-GEVs@siRNA. These nanoparticles leveraged the targeting capabilities of spermidine for olfactory receptor-trace amine associated receptor (TAAR), enhancing siRNA delivery and therapeutic efficacy. After intranasal administration, the nanoparticles were efficiently internalized by olfactory receptor neurons (ORNs) via the olfactory nerve pathway. The nanoparticles then escaped lysosomes, releasing siRNA into the cytoplasm, leading to gene downregulation and therapeutic benefits. Our results demonstrated that the designed nanoparticles were absorbed by the ORNs labeled with the Olfactory Marker Protein (OMP) and TAAR5 and successfully entered the olfactory bulb and the brain. Treatment with these nanoparticles significantly reduced p53-mediated neuronal ferroptosis and improved synaptic function both in vitro and in vivo. In conclusion, S-GEVs@siRNA nanoparticles rapidly reached the olfactory bulb through TAAR-mediated endocytosis, entered hippocampal neurons, downregulated Alox12B expression, exerted neuroprotective effects, and alleviated RBI-induced cognitive dysfunction. The designed nasal-to-brain delivery system holds great promise for treating various CNS diseases.",
"41231952": "ID: 41231952\nTitle: MARK2 regulates C9orf72 repeat-associated non-AUG translation.\nAbstract: Protein homeostasis is exquisitely regulated through processes involving protein synthesis essential for cellular health and disease prevention. Repeat-associated non-AUG (RAN) translation at expanded GGGGCC repeats in the C9orf72 gene produces dipeptide repeat (DPR) proteins that are implicated in amyotrophic lateral sclerosis and frontotemporal dementia (C9-ALS/FTD). However, the mechanisms promoting this noncanonical translation remain incompletely understood. Here, we identify microtubule affinity-regulating kinase 2 (MARK2) as a key eIF2\u03b1 kinase that enhances RAN translation under proteotoxic stress. We show that MARK2-eIF2\u03b1 signaling, activated by misfolded proteins including DPRs and TDP-43, is upregulated in C9-ALS patient tissues. Loss of MARK2 significantly suppresses RAN translation in reporter cells, patient-derived neurons, and a mouse model and confers neuroprotection under proteotoxic conditions. These findings position MARK2 as a critical stress-sensing cytosolic regulator that promotes repeat-associated noncanonical translation and associated toxicity.",
"41430470": "ID: 41430470\nTitle: Axonal Eif5a hypusination controls local translation and mitigates defects in FUS-ALS.\nAbstract: Local protein synthesis is vital for neuronal function, but its dysregulation in neurodegenerative diseases remains poorly defined. Here we applied spatial transcriptomics to adult mouse motor nerve axons and cell bodies to enable subcellular mapping. Among transcripts found in mature axons, the most enriched biological process is protein translation, and localization of translation machinery was confirmed using multiplexed single-molecule spatial transcriptomics combined with immunofluorescence. Amyotrophic lateral sclerosis (ALS)-associated mutations in the RNA-binding protein fused in sarcoma (FUS), which suppress local translation, disrupt the compartment-specific RNA signatures, including components of the translation machinery. In particular, eukaryotic initiation factor 5a (Eif5a), a translation factor involved in elongation and termination, is found to be locally impaired in mutant FUS axons with reduced levels of its active hypusinated form. Axon-specific treatment with polyamine spermidine restores Eif5a hypusination and ameliorates mutant FUS-dependent neuronal defects, including suppression of local protein synthesis. Finally, in vivo spermidine treatment reduces ALS-related toxicity in mutant FUS and TDP-43 Drosophila models, which may have implications for therapy development.",
"42087256": "ID: 42087256\nTitle: Targeting the integrated stress response or Ataxin-2 alleviates neurodegeneration in PolyGR models of C9orf72 associated frontotemporal dementia and amyotrophic lateral sclerosis.\nAbstract: Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are fatal, early-onset neurodegenerative diseases. The most common genetic cause of FTD and ALS is a G4C2 hexanucleotide repeat expansion in the C9orf72 gene. This mutation leads to the production of toxic dipeptide repeat proteins (DPRs), via repeat-associated non-AUG (RAN) translation. These DPRs disrupt stress granule (SG) dynamics, with SG regulators such as Ataxin-2 (ATXN2) implicated in disease risk. The integrated stress response (ISR), a key driver of SG formation via eIF2\u03b1 phosphorylation, has been linked to C9orf72 expansions, but the role of individual DPRs in ISR activation remains unclear. Here, using Drosophila models expressing physiologically relevant repeat length DPRs, we identify poly(GR) as a novel activator of the ISR, inducing early and sustained eIF2\u03b1 phosphorylation and SG accumulation prior to motor decline. Genetic inhibition of the ISR or knockdown of ATX2, the Drosophila orthologue of ATXN2, rescues motor deficits in these models. ATXN2 knockdown also reduces poly(GR) toxicity in mouse primary neurons. These findings position poly(GR) as a key driver of ISR activation and highlight ATXN2 and the ISR as promising therapeutic targets in C9orf72-associated FTD/ALS.",
"42436372": "ID: 42436372\nTitle: Plasma exosomal HERV-K transcripts are increased in amyotrophic lateral sclerosis.\nAbstract: Human endogenous retrovirus-K (HERV-K) reactivation is increasingly implicated in amyotrophic lateral sclerosis (ALS), with ongoing clinical trials investigating antiretroviral therapies. However, there is limited understanding of how HERV-K is trafficked in peripheral biofluids, and the role of exosomes, nano-sized extracellular vesicles, in this process remains largely unexplored. Exosomes offer a stable and cell-specific cargo reservoir that may reflect central pathogenic processes and serve as a minimally invasive biomarker source. In this study, we isolated plasma-derived exosomes from ALS patients (n\u2009=\u200921) and healthy controls (n\u2009=\u200916), and quantified exosomal HERV-K gag, env, and pol transcript levels using SYBR Green qPCR with RNase treatment and normalization to both traditional and exosome-enriched reference genes. HERV-K pol expression was significantly elevated in ALS, with fold-changes ranging from 1.59 to 1.85 (P\u2009=\u20090.037-0.051). env and gag also showed increased expression, though with greater variability. Normalization to the exosome-specific gene SOD2 provided the most consistent signal. These findings suggest that exosomal HERV-K transcripts, particularly pol, could serve as accessible biomarkers for patient stratification and treatment monitoring in HERV-K-targeted ALS trials. This work establishes proof-of-concept for using exosomal cargo to track endogenous retroviral activity in neurodegeneration and supports further investigation of liquid biopsy approaches in ALS precision medicine.",
"42441693": "ID: 42441693\nTitle: Cardiac Autonomic Dysfunction and Sudden Cardiac Death in Amyotrophic Lateral Sclerosis: Clinical Implications and Considerations for Care.\nAbstract: Amyotrophic lateral sclerosis (ALS) is traditionally viewed as a motor neuron disease that progresses from muscular weakness to respiratory failure and death. Increasing evidence, however, demonstrates clinically meaningful involvement of the autonomic nervous system, particularly in cardiovascular regulation. This narrative review synthesizes current evidence on the mechanisms, clinical implications, and palliative considerations of cardiac autonomic dysfunction in ALS, with particular emphasis on its relationship to sudden cardiac death (SCD). Cardiac autonomic dysfunction is increasingly recognized as a significant contributor to disease burden in ALS, manifesting as abnormalities in heart rate variability, sympathetic overactivity, and corrected QT prolongation. These derangements may contribute to malignant arrhythmias, increasing susceptibility to SCD in combination with respiratory decline. Epidemiologic data suggest that SCD accounts for a meaningful proportion of ALS-related mortality, although it is likely underrecognized due to misclassification and lack of routine cardiac monitoring. Clinical implications include the need for improved risk stratification and earlier detection of autonomic dysfunction using accessible markers, such as electrocardiographic indices, orthostatic vital signs, and ambulatory monitoring. Emerging technologies, including wearable biosensors, may further enhance longitudinal assessment. These considerations also have direct relevance for advanced care planning, as ALS may involve unpredictable and abrupt cardiac death in addition to progressive respiratory decline. Recognizing ALS as a multisystem disorder with significant cardiac involvement supports the integration of structured cardiovascular monitoring into multidisciplinary care models and highlights the need for prospective studies to guide standardized management strategies.",
"42441926": "ID: 42441926\nTitle: Association of Plasma Neurofilament Light Chain With Diagnostic Classification in a Neuromuscular Referral Cohort: A Cross-Sectional Study.\nAbstract: Plasma neurofilament light chain (pNfL) is a blood-based biomarker of axonal injury elevated in several neuromuscular disorders. While previous studies have compared individual diseases with healthy controls, less is known about how pNfL performs across clinically relevant neuromuscular presentations encountered in subspecialty practice, particularly in distinguishing active from inactive neuropathies. We evaluated whether abnormal age-adjusted pNfL concentrations are associated with clinically relevant diagnostic categories and whether pNfL discriminates between active and inactive neuropathies. We conducted a cross-sectional study of patients evaluated by neuromuscular specialists at Mayo Clinic (Rochester, MN) between April 2022 and April 2024, in whom pNfL was ordered as part of routine clinical care. Diagnoses were assigned to prespecified categories by consensus review, including motor neuron disease (MND), active neuropathy, inactive neuropathy, and structural etiologies. Clinically active neuropathy was defined using prespecified, diagnosis-specific operational criteria incorporating treatment status, clinical relapse or progression, time from symptom onset, and pathologic evidence of inflammation. Abnormal pNfL was defined using previously established age-adjusted 97.5th percentile reference limits. Multinomial logistic regression evaluated associations between abnormal pNfL and diagnostic category, adjusting for neuropathy impairment score and symptom duration. Receiver operating characteristic (ROC) analyses assessed discrimination between prespecified groups. Among 306 patients (mean age 62.2 years, 41.5% female), 179 (58.5%) had MND, 28 (9.1%) active neuropathy, 75 (12.1%) inactive neuropathy, and 24 (7.8%) structural etiologies. Median pNfL concentrations differed across diagnostic groups (p < 0.0001) and were highest in MND and active neuropathy. After adjustment, abnormal pNfL was associated with a higher relative likelihood of classification as MND (relative risk ratio [RRR] 18.47, 95% CI 8.77-38.86) and active neuropathy (RRR 7.30, 95% CI 2.50-21.34) compared with inactive neuropathies. No association was observed with structural etiologies. Discrimination between active and inactive neuropathy was moderate (area under the curve [AUC] 0.79, 95% CI 0.70-0.88), and discrimination for MND vs all other diagnoses was good (AUC 0.85, 95% CI 0.80-0.90). In this cross-sectional cohort, abnormal age-adjusted pNfL concentrations were more frequently observed in diagnostic categories characterized by clinically active axonal injury than in inactive neuropathies and structural conditions. These findings suggest a potential role for pNfL as an adjunctive tool in neuromuscular diagnostic evaluation. Interpretation is limited by the cross-sectional design and convenience sampling. This study provides Class II evidence that abnormal age-adjusted pNfL distinguishes active neuropathies from inactive neuropathies with moderate diagnostic accuracy.",
"42449472": "ID: 42449472\nTitle: VRK1-Related Motor Neuropathy With Upper Motor Neuron Signs and Selective Muscle Involvement.\nAbstract: Hereditary motor neuropathies (HMN) represent a heterogeneous group of disorders with wide clinical and genetic variability. Despite advances in molecular diagnostics, approximately 50% of cases remain genetically unresolved, particularly those where distinguishing length-dependent motor neuropathy from motor neuron disorder with disproportionate segmental involvement is a challenge. Variants in the VRK1 gene, originally described in association with pontocerebellar hypoplasia, are now known to produce a broad clinical spectrum, including amyotrophic lateral sclerosis, dHMN, and less frequently, spastic paraplegia. This study's aim was to characterize the clinical presentation, electrophysiological findings, and muscle MRI patterns associated with VRK1-related motor neuron disease in a cohort of nine patients from five unrelated families. Five unrelated families with inherited motor neuropathy were investigated using next-generation sequencing techniques, including targeted gene panels or whole-exome sequencing, with subsequent confirmation by Sanger sequencing. A total of nine affected individuals underwent detailed clinical evaluation, nerve conduction studies (NCS), electromyography (EMG), and whole-body muscle MRI (wbMRI). Nine affected individuals carrying biallelic VRK1 variants were evaluated. In most cases (66%), symptom onset occurred during the first decade of life. All patients presented with gradually progressive distal muscle weakness. Mean Medical Research Council (MRC) scores were 2.8 for ankle dorsiflexion and 1.9 for plantar flexion. Sensory nerve conduction studies were normal in all individuals evaluated (8/9), although mild sensory complaints were reported in four patients. Muscle cramps were observed in two-thirds of the cohort, while fasciculations were uncommon (11%). EMG findings consistently demonstrated a neurogenic pattern with predominant distal involvement, and evidence of both acute and chronic denervation was present in four patients. Whole-body muscle MRI, available for all patients, revealed a consistent pattern of fatty infiltration predominantly affecting posterior muscle compartments, with minimal STIR signal changes. Brain and spinal imaging, performed in all individuals, showed no abnormalities. Biallelic mutations in VRK1 are associated with a recognizable form of motor neuron disease characterized by features of dHMN combined with upper motor neuron involvement, along with a distinctive posterior-predominant pattern on muscle MRI. Identifying this phenotype, a known presentation of VRK1-related disorders, highlights the importance of targeted genetic testing in unresolved cases of hereditary motor neuropathy.",
"42454435": "ID: 42454435\nTitle: Moral distress in healthcare professionals working with motor neuron disease.\nAbstract: To (1) identify clinical situations that may contribute to the experience of moral distress (MD) among professionals working with motor neuron disease (MND), (2) measure the occurrence and intensity of MD, and (3) explore associations with professional quality of life, turnover intention, and associated risk and/or protective factors. A cross-sectional online survey was distributed to healthcare professionals working in MND services across Europe. Data were analyzed using descriptive and inferential statistics. In total, 230 responses from professionals across 17 European countries were analyzed from the international survey. And 67% of respondents indicated that MD resonated with their experience of working with MND. Those who considered leaving or changing their position due to the challenges associated with caring for this patient population were also more likely to report resonance with MD (\u03c72\u00a0=\u00a07.772, p\u00a0=\u00a00.020). The intensity of MD was associated with reduced professional quality of life (burnout [\u03b2\u00a0=\u00a00.106, p\u00a0<\u00a00.05], and secondary traumatic stress [\u03b2\u00a0=\u00a02.881, p\u00a0<\u00a00.001]). A total of 24 clinical scenarios were identified as potential contributors to experiences of MD in this population. Across all professional groups, service-/organization-level factors were the most common and distressing barriers to providing effective MND care. This study demonstrates that MD is experienced by healthcare professionals working with MND across Europe. MD was associated with reduced professional quality of life and increased intentions to leave or change positions, underscoring its potential implications for workforce retention and sustainability. The findings show that system/organization, patient/condition and family-level causes are the primary drivers of MD in this population. Future research should focus on evaluating the effectiveness of interventions designed to address these key drivers and mitigate the impact of MD among healthcare professionals working with MND.",
"42456346": "ID: 42456346\nTitle: Divergent presentations of anti-GAD autoimmunity: a comparative analysis of two neurodegenerative cases.\nAbstract: We describe two women presenting with cortico-basal syndrome (CBS) and upper motor neuron-motor neuron disease (UMN-MND), respectively, both with high-titre GAD-Abs in serum and CSF. Both patients showed progressive motor impairment with elevated NFL levels. IVIg therapy was administered without meaningful clinical benefit, suggesting neurodegeneration as the primary phenotypic driver.",
"42461162": "ID: 42461162\nTitle: Nursing a Patient With Amyotrophic Lateral Sclerosis Stage 4B With Epilepsy: A Case Study.\nAbstract: Amyotrophic lateral sclerosis (ALS) is a rare motor neuron disease characterised by progressive muscle weakness, which can eventually lead to death. So far there is no effective cure for it. This case report discusses the nursing of a patient with stage 4B amyotrophic lateral sclerosis complicated with epilepsy and sudden disturbance of consciousness during his stay in an intensive care unit (ICU). After 34\u2009days of treatment and care, the patient regained consciousness with stable vital signs before being transferred out of the ICU. This report focusses on nursing interventions adopted in terms of respiratory management, nutritional management, psychological care and exercise during both the epileptic seizure and the awake period of the patient in the hope of providing a reference for the nursing of patients with amyotrophic lateral sclerosis with epilepsy in intensive care units.",
"42461445": "ID: 42461445\nTitle: Metabolomic analyses of amyotrophic lateral sclerosis, muscle cramps, and TJ-68 treatment.\nAbstract: Most patients with amyotrophic lateral sclerosis (ALS), a fatal motor neuron disease, experience painful muscle cramps. Our recent pilot trial of the Japanese Kampo medicine TJ-68 suggested its efficacy in improving muscle cramps in patients with ALS. This study analyzed plasma metabolomic changes to identify the underlying mechanisms of muscle cramps in ALS and the effects of TJ-68. Plasma was obtained from 11 participants with ALS in the repeated crossover trial at five time points (baseline, two placebo phases, and two TJ-68 phases). Metabolites were analyzed using mass spectrometry. Linear mixed-effects models were applied to identify metabolite changes associated with muscle cramps, determine the effects of TJ-68 on metabolites, and predict which participants would respond to TJ-68. Higher glutamine/glutamate, arginine, and leucine levels were associated with more severe muscle cramps. TJ-68 treatment increased tryptophan and aconitate levels but reduced serotonin and acetylcarnitine levels. Long-chain acylcarnitine levels were correlated with muscle cramp severity, and their levels tended to decrease with treatment. Uric acid, \u03b2-aminoisobutyric acid, \u03b1-aminoadipic acid, and acetylcholine emerged as predictors of the efficacy of TJ-68. This study identified the metabolite profile of muscle cramps in ALS and the changes in metabolite levels after TJ-68 treatment. Several baseline metabolites were associated with the prediction of the response to muscle cramps following TJ-68 treatment. Uric acid might be particularly useful because of its easy measurement in standard assays. Our study affirms the value of metabolomic technology for future pharmacotherapy and studies in ALS.",
"42464213": "ID: 42464213\nTitle: SYNE1-Related motor neuron disease-like phenotype with mild distal contractures and 24-month clinical stability: a case report.\nAbstract: SYNE1 encodes nesprin-1, a nuclear envelope protein involved in cytoskeletal linkage, nuclear positioning, and neuromuscular integrity. Biallelic SYNE1 variants cause a broad spectrum ranging from cerebellar ataxia to arthrogryposis multiplex congenita and motor neuron disease-like phenotypes. Distinguishing these entities can be difficult when subtle distal contractures coexist with neurogenic electrophysiological findings. A 22-year-old woman born to consanguineous parents presented with bilateral intrinsic hand muscle wasting, impaired fine motor performance, and mild gait difficulty. Examination showed distal hand atrophy, mild weakness of the abductor pollicis brevis and first dorsal interosseous muscles, brisk deep tendon reflexes, preserved sensation, and mild distal finger contractures. Sensory nerve conduction studies were normal. Motor studies showed reduced compound muscle action potential amplitude in the right abductor pollicis brevis and borderline-low amplitude on the left. Needle electromyography showed widespread chronic neurogenic motor unit changes affecting the upper and lower extremities, with active denervation most evident in the bilateral abductor pollicis brevis muscles. Genioglossus examination was normal. SMN1 deletion testing and selected familial amyotrophic lateral sclerosis gene testing were negative. Whole exome sequencing identified a homozygous truncating SYNE1 variant, NM_182961.4:c.21009G\u2009>\u2009A; p.(Trp7003Ter). Segregation analysis confirmed heterozygous carrier status in both parents and two unaffected siblings. At 24-month follow-up, weakness, atrophy, contractures, reflex pattern, and functional status remained clinically stable, without bulbar, cerebellar, sensory, or clinically evident respiratory involvement. This case supports classification as a SYNE1-related motor neuron disease-like phenotype with mild distal contractures rather than an isolated arthrogryposis multiplex congenita type 3 (AMC3) phenotype. The case also supports including SYNE1 in genetic testing panels for young patients with unexplained motor neuron disease-like presentations, particularly when consanguinity, normal sensory conduction, and subtle distal contractures coexist.",
"42465429": "ID: 42465429\nTitle: The neuropathy-causing GARS1 \u0394ETAQ mutation drives pathology in subsets of motor and sensory neurons in mice.\nAbstract: Charcot-Marie-Tooth disease type 2D (CMT2D) results from gain-of-function mutations in GARS1, which encodes glycyl-tRNA synthetase (GlyRS), the enzyme responsible for charging transfer RNA (tRNA) with glycine. There are several CMT2D mouse models, but Gars \u0394ETAQ/+ is the only one that bears a patient-sourced mutation. Created using CRISPR/Cas9 to model a 12-nucleotide de novo GARS1 deletion identified in an unusually severe CMT2D patient, Gars \u0394ETAQ/+ mice have previously been shown to display several neuromuscular phenotypes; motor axon loss, denervated neuromuscular junctions (NMJs) and reduced muscle function. Here, we extend these analyses to provide a more comprehensive understanding of both motor and sensory nerve deficits across hind- and fore-limbs. At 3 months, Gars \u0394ETAQ/+ mice possess sex-independent alterations in the levels of neuropathy biomarkers - including decreased NfL and increased periaxin - alongside reduced muscle endurance and strength, and impairments in the sensory modalities of mechanosensation, proprioception and nociception. Underpinning these dysfunctions, we identified site-specific defects comprising altered sensory neuron populations, muscle spindle loss, reduced motor neuron size, disrupted NMJ innervation and maturation, and reduced axonal transport of signalling endosomes in vivo. Together, these experiments show that Gars \u0394ETAQ/+ mice display robust and selective peripheral nerve pathology that manifests in a general distal-to-proximal fashion, priming this CMT2D allele for testing treatments and evaluating mechanisms underlying peripheral nerve vulnerability.",
"42470084": "ID: 42470084\nTitle: Impact of Sexuality in Patients With Motor Neuron Disease.\nAbstract: Sexuality is a relevant yet understudied aspect in people living with motor neuron disease (MND). This study aimed to assess whether sexuality in people with MND is influenced by motor, cognitive, behavioral, or mood disturbances, and to explore whether being sexually active impacts caregiver burden. We conducted a cross-sectional observational study involving participants with MND and their primary caregivers from three ALS multidisciplinary units in Seville, Spain. Data were collected between October 2018 and July 2021. Functional, cognitive, behavioral, and mood assessments were conducted. Sexuality was evaluated through sex-specific questionnaires. Caregiver burden was assessed using the Zarit Burden Interview. Among 66 participants who completed the sexuality assessment, 42.9% reported sexual activity in the previous month. Of these, 70% had no sexual dysfunction, while 26.7% had moderate and 3.3% severe dysfunction. No correlation was found between sexual activity and motor function. Sexual activity was less frequent in participants with apathy (p\u2009=\u20090.026), depression (p\u2009=\u20090.021), and frontotemporal dementia (p\u2009=\u20090.013). Among sexually active patients, those with cognitive impairment-particularly memory dysfunction-had higher rates of orgasm difficulties (p\u2009=\u20090.019). No other clinical parameters were related to sexuality. Sexuality of participants with MND did not influence caregiver burden. Sexuality in MND is more associated with cognitive and mood factors than with motor disability. Addressing sexuality in clinical practice may contribute to improving quality of life and should be integrated into the multidisciplinary care of MND patients.",
"42480869": "ID: 42480869\nTitle: Macrophage responses to and elevated antibody levels against Chlorovirus ATCV-1 in ALS patients.\nAbstract: Acanthocystis turfacea chlorella virus 1 (ATCV-1) is a giant virus that is part of the human oral microvirome. Previously we showed that ATCV-1 infects mouse macrophages, stimulates production of inflammatory cytokines, and accelerates motor neuron disease in the Amyotrophic Lateral Sclerosis (ALS) model SOD1-G93A transgenic mice. This, coupled with significantly elevated levels of serum IgG1 antibody to ATCV-1 in ALS patients compared with healthy controls, suggests involvement of ATCV-1 in ALS. Herein, using serum and CSF from a different ALS cohort we again show elevated antibodies to ATCV-1 in ALS patients compared with healthy controls. To assess ATCV-1 in human macrophages, we challenged immature (IMM), M0, M1, and M2 human THP-1 macrophage cells containing an Interferon Stimulated Response Element (ISRE) promoter-reporter with ATCV-1 or its Major Capsid protein (MCP) glycans. ATCV-1 infected M1 THP-1 to a greater degree than IMM, M0, or M2 THP-1. The initial high ISRE-promoter activity of M1 THP-1 was suppressed by the MCP-Glycans of ATCV-1. M0, but not IMM or M2 THP-1 produced IL-6 in response to ATCV-1 or its MCP-glycan, while high levels of IL-6 from unchallenged M1 THP-1 increased further by ATCV-1 or its MCP glycan. In contrast, ATCV-1 or its MCP-Glycan significantly reduced the high levels of IL-10 produced by M2 THP-1. Thus, antibody to ATCV-1 in ALS patients and the susceptibility of human M1 macrophages to ATCV-1 infection with boosted inflammatory cytokine and diminished anti-inflammatory cytokine production suggest that ATCV-1 may contribute to ALS motor neuron disease.",
"42481361": "ID: 42481361\nTitle: French guidelines for post-polio syndrome and management of effects of aging in people with sequelae of acute anterior poliomyelitis.\nAbstract: People with sequelae of acute anterior poliomyelitis (AAP) may develop secondary complications related to aging, as well as a specific complication of the disease known as post-polio syndrome (PPS). These complications are new neurological and musculoskeletal manifestations that occur after a prolonged period of disease stability. The onset is typically insidious and slow, but can be more rapid following a period of immobilization, surgery, or another intercurrent condition. The initial assessment may involve consulting a neurologist to rule out neurological diagnoses. Electroneuromyographic examination is a valuable tool for evaluating these patients. It is sometimes difficult to differentiate between the effects of aging in a person with sequelae of AAP and PPS, which is a distinct entity with specific diagnostic criteria. The rate at which muscle capacity declines, and its functional impact, can be a distinguishing factor. Subacute or rapid onset can be indicative of PPS. The emergence of new motor deficits in areas that were previously unaffected is also a strong argument for PPS. This neurological deterioration must be distinguished from musculoskeletal disorders associated with aging. Progression is usually slow and gradual, or occurs in stages with periods of stabilization. Physical and rehabilitation care is essential both in the initial assessment and for ongoing follow-up. There are no recommended medicinal treatments, especially no specific etiological treatment for PPS (such as immunoglobulins, corticosteroids, etc.) or effective symptomatic treatment for manifestations like fatigue or muscle weakness (e.g., pyridostigmine). Pain management should be regularly assessed; while drug treatments are not specific, non-pharmacological pain management through physical therapy is crucial. Particular attention should be paid to comorbidities, including excess weight and an increased risk of osteoporosis and fractures. Management should be multidisciplinary, with an annual review recommended. Follow-up will be adjusted based on the patient's preferences and needs, and monitoring will depend on the development of complications.",
"42494173": "ID: 42494173\nTitle: Troponin T and Neurofilament Light Chain Levels as Complementary Biomarkers of Disease Accumulation and Aggressiveness in Amyotrophic Lateral Sclerosis.\nAbstract: Amyotrophic lateral sclerosis (ALS) is a clinically heterogeneous neurodegenerative disease requiring reliable biomarkers to improve patient stratification and trial design. While serum neurofilament light chain (sNfL) reflects neuroaxonal stress and disease aggressiveness, troponin T (TnT) may capture complementary aspects of neuromuscular involvement. We assessed the associations of TnT and sNfL with D50-derived measures of disease aggressiveness (D50) and disease accumulation (rD50) in ALS. In this retrospective observation, TnT and sNfL levels from ALS patients in two independent German cohorts were analyzed using the D50 disease progression model; discovery cohort (Essen, n\u2009=\u2009433) and an independent replication cohort (Bonn, n\u2009=\u2009185). TnT levels were strongly associated with rD50-defined disease phases in the discovery cohort (p\u2009<\u20090.001). While not all subgroup-specific associations were replicated, the overall relationship between TnT and disease accumulation was supported in the independent replication cohort. In contrast, sNfL showed no consistent relationship with rD50-derived disease phases. sNfL concentrations demonstrated a significant inverse association with D50, supporting a relationship with disease aggressiveness across both cohorts (p\u2009<\u20090.001). Associations between TnT levels and D50-defined disease aggressiveness were generally weaker and less consistent. TnT was associated with measures of disease accumulation (rD50), whereas sNfL was more closely associated with disease aggressiveness (D50). Our results suggest that TnT and sNfL capture different dimensions of disease status within the D50 framework. Further longitudinal studies are needed to determine whether combining these biomarkers improves disease stratification or prognostic assessment in clinical practice and therapeutic trials.",
"42494493": "ID: 42494493\nTitle: Strenuous physical activity is associated with a younger age of amyotrophic lateral sclerosis onset in two independent cohorts.\nAbstract: Amyotrophic lateral sclerosis (ALS) is a complex neurodegenerative disease characterized predominantly by degeneration of both upper and lower motor neurons, thought to occur due to an interplay between genetics and environmental factors. Physical activity has been suggested as a potential risk factor for ALS; however, the exact role of exercise in the onset and progression of the disease is still unclear. We assessed lifetime physical activity in two independent ALS cohorts: post-mortem brain donors from the London Neurodegenerative Diseases Brain Bank (n = 139) and patients from the Motor Neurone Disease (MND) Register of England, Wales and Northern Ireland (n = 166 cases, 196 controls). In both cohorts, highly active individuals developed ALS symptoms at a significantly younger age, 54.2 years (mean, standard deviation = 7.5) in the post-mortem cohort and 58.0 years (median, interquartile range = 15) in the MND Register, compared with 63.9 years (mean, standard deviation = 11.5) and 63.0 years (median, interquartile range = 17.5) in inactive individuals, respectively [one-way analysis of variance (ANOVA), F(2, 136) = 6.10, P = 0.003, \u03b7 2 = 0.08, 95% confidence interval (CI) 0.02-1.00 and Kruskal-Wallis, H(2) = 7.39, P = 0.02, \u03b7 2 = 0.03, 95% CI 0.003-0.12]. Cox regression showed a higher hazard of earlier onset in highly active patients [post-mortem: hazard ratio (HR) 2.84, 95% CI 1.55-5.26, P = 0.0008; MND Register: HR 2.34, 95% CI 1.30-4.23, P = 0.005]. Our findings suggest that strenuous physical activity may be associated with a significantly younger age of ALS onset, replicated in both the post-mortem and MND Register cohorts, but not with an increased risk of developing ALS. Logistic regression analysis confirmed that neither highly active [odds ratio (OR) 1.43, 95% CI 0.69-2.99, P = 0.333] nor being active (OR 1.30, 95% CI 0.72-2.37, P = 0.386) was significantly associated with ALS risk, whereas a history of head injury was (OR 1.72, 95% CI 1.03-2.88, P = 0.038). These results suggest that strenuous exercise may accelerate disease onset in predisposed individuals, while the role of head injury requires further study and the findings may in fact indicate reverse causality.",
"42495713": "ID: 42495713\nTitle: Mechanisms of neurotoxicity of fluoride or aluminum: implications for neurodegenerative disease risk.\nAbstract: Fluoride and aluminum are two naturally abundant elements with widespread industrial uses. Fluoride is also added to community water supplies as a public health intervention for dental cavity prevention. However, findings from animal studies show potential links of fluoride and aluminum exposure with neurodegenerative disease risk, particularly at high exposure levels. This review uniquely examines neurochemical and neurobiological impacts of fluoride and aluminum exposure as well as whether these processes may increase the risk of common and rare neurodegenerative diseases, including dementia, Parkinson's Disease, and motor neuron disease. Fluoride and aluminum can cross the blood-brain barrier and accumulate in neural tissue, where they can interact to produce neurotoxic effects. Chronic exposure to fluoride and aluminum can cause oxidative stress, mitochondrial dysfunction, brain inflammation, and disruption of essential ions. These effects can contribute to impaired nerve signaling, cell damage, and protein aggregation-key factors in neurodegeneration. Co-exposure to aluminum-fluoride complexes may worsen these effects by increasing amyloid buildup and causing nerve cell death, although more research on aluminum-fluoride interactions is needed. Additionally, many animal studies include relatively high fluoride or aluminum exposure levels, and epidemiological human data are scarce, particularly for less common neurodegenerative diseases. Moreover, these studies often rely on ecological or occupational exposure measures rather than individual biomarkers. Findings of this narrative review underscore the need for methodologically rigorous longitudinal human studies on fluoride, aluminum and neurodegenerative disease risk, particularly given the mechanistic basis for these potential associations.",
"42498838": "ID: 42498838\nTitle: Proteome-wide Mendelian randomization identifies causal plasma proteins in frontotemporal dementia.\nAbstract: Frontotemporal dementia (FTD) is a genetically and clinically heterogeneous neurodegenerative disorder with no disease-modifying treatments. Plasma proteomic signatures offer a promising avenue for uncovering disease mechanisms and developing targeted interventions. We conducted protein-wide Mendelian randomization meta-analysis to explore causal relationships between plasma proteins and FTD and four subtypes, utilizing comprehensive datasets of protein quantitative trait loci. We identified four plasma proteins significantly associated with FTD, namely RGS7 and ASAP2 (increased risk), as well as TMCC3 and VPS29 (decreased risk). Subtype-specific analyses revealed distinct protein signatures, including S100A13 and TREM1 in behavioral variant FTD, ING4 and TEX29 in FTD overlapping with motor neuron disease, SPINT2 in progressive non-fluent aphasia, and UGDH in semantic dementia. This study implicates specific plasma proteins in FTD pathogenesis, with subtype-dependent effects. The identified proteins represent potential biomarkers for stratification and therapeutic targets.",
"42506308": "ID: 42506308\nTitle: Walking as a Window to the Brain: Redefining Gait in Neurology.\nAbstract: Walking is not merely locomotion but a window into the nervous system, integrating cortical, subcortical, cerebellar, spinal, and peripheral networks into a unified motor behavior. Across neurological diseases-including Parkinson's disease, atypical parkinsonism, cerebellar ataxias, stroke, multiple sclerosis, neuropathies, neuromuscular disorders, and functional gait syndromes-gait disturbances are among the most disabling clinical features, contributing to falls, loss of independence, institutionalization, and premature mortality. Traditional bedside observation remains indispensable, but it lacks the sensitivity and reproducibility needed to capture subtle, episodic, or prodromal abnormalities. Over the past decade, advances in wearable sensors, marker-based and markerless motion capture, pressure-sensitive walkways, force plates, artificial intelligence, and machine learning have positioned digital mobility outcomes as promising, ecologically valid biomarkers of neurological function. These measures can support differential diagnosis, provide prognostic information on falls and survival, and serve as sensitive endpoints in therapeutic trials. They may also detect early abnormalities, such as increased stride-to-stride variability or prolonged double-support time, before overt clinical deterioration becomes evident. Clinical applications are increasingly evident across disorders, including distinguishing Parkinson's disease from atypical parkinsonism, quantifying treatment response in normal-pressure hydrocephalus, tracking progression in ataxia and multiple sclerosis, predicting functional decline in motor neuron disease, and guiding rehabilitation after stroke. Integration with neuroimaging, electrophysiology, and molecular biomarkers is beginning to reveal the circuits underlying variability, instability, and freezing, positioning gait as a systems-level marker of neural integrity. Nevertheless, methodological heterogeneity, limited disease-specific validation, insufficient longitudinal data, and lack of consensus on clinically meaningful parameters continue to constrain translation. Cognitive, affective, and environmental influences also remain insufficiently represented in digital frameworks, while equity, accessibility, algorithmic bias, and privacy require careful ethical governance. Reconceptualizing gait as a \"sixth vital sign\" reframes mobility as a multidimensional biomarker of neural and systemic health. With harmonized protocols, robust validation, multimodal integration, and appropriate ethical frameworks, gait analysis could become a cornerstone of precision neurology.",
"42509371": "ID: 42509371\nTitle: Longitudinal plasma proteomics predict phenoconversion to clinically manifest ALS.\nAbstract: The study of pre-symptomatic amyotrophic lateral sclerosis (ALS) and the design of disease prevention trials are greatly hampered by our inability to predict which unaffected carriers of ALS-associated pathogenic variants will phenoconvert to clinically manifest disease and when. In this longitudinal Olink Explore, high-throughput, proteomic study, 516 serially collected plasma samples from 33 phenoconverters, 35 patients with ALS, 10 pre-symptomatic pathogenic variant carriers and 59 controls were included. Here we identified 92 proteins with concentrations that changed before phenoconversion; characterized the longitudinal trajectory of these proteins and identified a core panel of 19 proteins which, collectively, predicted phenoconversion over the 0.5-year to 5-year time horizons (crossvalidated areas under the curve 0.80-0.89) and yielded estimates of time to phenoconversion with a mean absolute error of 1.6\u2009years. These findings were partially replicated in UK Biobank data, confirming pre-symptomatic increases in several proteins (for example, NEFL, EDA2R and CA3) and that a multi-protein panel outperformed NEFL alone in estimating time to phenoconversion. This work sheds light on the biology of pre-symptomatic ALS. Moreover, our identification of a panel of new susceptibility/risk biomarkers based on empirical longitudinal data furthers the ultimate goal of ALS prevention.",
"42521811": "ID: 42521811\nTitle: Tofersen treatment in respiratory onset amyotrophic lateral sclerosis and a variant of uncertain significance in SOD1; a case report.\nAbstract: The antisense oligonucleotide tofersen is available for treating amyotrophic lateral sclerosis (ALS) caused by pathogenic SOD1 variants. However, it is unknown whether Variants of Uncertain Significance (VUS) are a viable treatment target. We assessed clinical and biomarker trajectories prior to and after initiation of tofersen in a patient with respiratory onset ALS and a novel c.234_236del p.(Glu79del) VUS in SOD1. After six months of treatment, cerebrospinal fluid (CSF) SOD1 protein decreased by 47%, CSF NfL by 55% and serum NfL by 50%, with trajectories comparable to known pathogenic variants. Functional decline on the ALSFRS-R slowed from 1.52 points per month pre-treatment to 0.52 points per month post-treatment, muscle strength remained stable, and EQ-VAS quality of life scores remained between 60 and 70. The ability to evaluate treatment response on an individual level will help to determine the clinical relevance of VUS as new gene-targeted treatments for ALS become available.",
"42528798": "ID: 42528798\nTitle: A modified frailty index to identify high-risk groups for amyotrophic lateral sclerosis.\nAbstract: Amyotrophic lateral sclerosis (ALS) is a motor neuron disease characterized by progressive muscle weakness and poor prognosis, which requires early detection to optimize therapeutic outcomes. This study aims to develop a risk stratification tools for ALS and to assist in identifying high-risk groups. A prospective cohort study was conducted using the UK Biobank (500,033 participants), which were split into training sets and validation sets. We calculated the frailty index (FI) and modified frailty index (MFI) for the participants and estimated their association with ALS. Finally, two risk stratification tools were constructed and the time-dependent ROC curve was utilized to evaluate the discriminatory performance of each model. Among the 49 deficits in FI, we identified five deficits that were significantly associated with ALS, including falls, whole-body pain, long-standing illness, disability or infirmity, self-rated health and tiredness or lethargy in last 2\u202fweeks, which together constructed the MFI. Both the FI and MFI were associated with a higher risk of ALS (HRFI\u202f=\u202f4.58, 95% CI\u202f=\u202f1.31-16.07, HRMFI\u202f=\u202f4.59, 95% CI\u202f=\u202f2.79-7.53). Finally, a combination of MFI, gender, age and BMI demonstrated the best discriminative ability. Specifically, on the validation set, it achieved a C-index of 0.696. By focusing on deficits associated with ALS, the MFI may improve the ability to identify individuals at elevated risk of the disease. It could therefore serve as a valuable screening tool for risk stratification in the general population.",
"42536230": "ID: 42536230\nTitle: Genetic variants among patients with motor neuron disease in Lithuania - a retrospective single-center study.\nAbstract: Motor neuron disease (MND) comprises several clinical phenotypes, with amyotrophic lateral sclerosis (ALS) being the most common. Despite the identification of over 40 ALS-associated genes, the pathogenesis remains complex and polygenic. This study evaluated the clinical phenotypes and prevalence of genetic causes in MND patients in Lithuania. We conducted a retrospective single-center study at a tertiary care clinic on patients with MND. Clinical and molecular genetic data were analyzed. The study included 53 patients with a mean age at symptom onset of 55 years. Most patients (43/53; 77.4%) were diagnosed with ALS, and the most common onset was spinal (39/53; 73.6%). The frequency of pathogenic or likely pathogenic genetic variants was 15.7% (8/51). C9orf72 hexanucleotide repeat expansion was detected in 5.9% (3/51) of patients. Next-generation sequencing was performed in 49 patients, of whom 5 (10.2%) had pathogenic or likely pathogenic variants, including pathogenic variants in the SOD1 and NEK1 genes and likely pathogenic variants in the FUS. The most common finding was C9orf72 hexanucleotide repeat expansion, followed by variants in SOD1 and FUS genes. The genetic spectrum was broadly similar to internationally recognized MND-associated genes, though formal comparisons were not performed due to the absence of a control group. These results emphasize the importance of systematic genetic testing in clinical practice and contribute to the limited data on the genetic spectrum of MND in the Baltic region.",
"42538750": "ID: 42538750\nTitle: Nationwide Epidemiology of Motor Neuron Diseases in Latvia (2020-2024): Incidence, Prevalence, and Clinical Characteristics.\nAbstract: Motor neuron diseases (MNDs), including amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), and spinal and bulbar muscular atrophy (SBMA), are rare, progressive neurodegenerative conditions. Although well-studied in Western Europe, no nationwide epidemiological data have been published from Latvia. This study aimed to assess the incidence, prevalence, and clinical characteristics of MNDs in the Latvian population. A retrospective, hospital-based analysis was performed using records from Pauls Stradi\u0146\u0161 Clinical University Hospital, Riga East University Hospital, and the Children's Clinical University Hospital between January 2020 and December 2024. Patients were identified through relevant ICD-10 codes. Incidence and prevalence rates were calculated per 100,000 population and age-standardized to the 2013 European Standard Population. A total of 181 prevalent MND cases were identified: 131 with ALS or related phenotypes, 10 with adult-onset SMA, 33 with pediatric SMA, and 7 with SBMA. The age-standardized incidence of ALS was 1.22 per 100,000 person-years, and the prevalence was 4.69 per 100,000. Limb weakness or paresis was the most common initial symptom (48.1%). The mean diagnostic delay was 13.4\u2009months for ALS, 43.8\u2009months for PLS, 206.8\u2009months for SBMA and 17.3\u2009months for pediatric SMA. The prevalence of pediatric SMA was 9.91 per 100,000, with type II being the most frequent subtype. All SMA and SBMA cases were genetically confirmed. This first nationwide study of MNDs in Latvia highlights diagnostic delays and possible under-recognition of adult SMA and SBMA. Genetic testing, a national registry, and equitable therapy access should be prioritized.",
"42538773": "ID: 42538773\nTitle: Early Cognitive and Behavioral Changes in Primary Lateral Sclerosis: A Population-Based Study.\nAbstract: Primary lateral sclerosis (PLS) is a rare upper motor neuron neurodegenerative disorder whose cognitive profile, particularly at early stages, remains incompletely defined. We aimed to characterize cognitive and behavioral features of PLS at diagnosis and compare them with predominant upper motor neuron amyotrophic lateral sclerosis (PUMN-ALS) and healthy controls (HCs). Patients diagnosed with PLS between 2007 and 2021 were identified from the population-based Piemonte and Valle d'Aosta ALS Register. Diagnoses were established according to consensus criteria, including early, probable, and definite PLS. All patients underwent comprehensive neuropsychological and behavioral assessment within 3\u2009months of their first ALS center visit. Cognitive-behavioral status was classified using ALS-frontotemporal dementia (FTD) consensus criteria. Thirty-two PLS patients were included (mean disease duration, 25\u2009months). Cognitive and/or behavioral impairment was identified in 29.3% of patients, most commonly affecting executive function, memory, and social cognition, including 21.1% early PLS. Compared with HCs, PLS patients showed poorer performance across several cognitive domains and higher anxiety and depression scores. Compared with matched PUMN-ALS patients, PLS patients demonstrated slightly worse executive performance, while the overall frequency of cognitive-behavioral impairment was similar. Behavioral profiles differed qualitatively, with apathy more frequent in PUMN-ALS. No PLS patient met criteria for frontotemporal dementia. Cognitive and behavioral impairments are already detectable at the time of diagnosis in a substantial proportion of patients with PLS, including early PLS, supporting the view of PLS as a multidimensional neurodegenerative disorder with early extramotor involvement.",
"42542522": "ID: 42542522\nTitle: Computational Pipelines for Protein Ubiquitylation Analysis and Prediction.\nAbstract: Ubiquitylation is a crucial posttranslational modification that regulates cellular homeostasis and has been linked to a range of diseases. Identification and analysis of ubiquitylated proteins and ubiquitylation sites have historically been successfully performed by mass spectrometry from in vitro and in vivo samples. However, to address some of the challenges and improve the efficiency of ubiquitylation analysis by mass spectrometry, computational tools have been developed and are becoming increasingly popular. In this chapter, we summarize the available computational tools for predicting ubiquitylation in silico and the common approaches used to enrich ubiquitylation in samples for mass spectrometry and computational analysis. We subsequently provide simple steps for molecular biologists to follow for predicting ubiquitylation sites on proteins in silico, and we provide a computational approach to identify average ubiquitin branch sites across samples from ubiquitin-enriched mass spectrometry data.",
"42543164": "ID: 42543164\nTitle: Intron retention in health and amyotrophic lateral sclerosis.\nAbstract: Intron retention (IR) is the molecular phenomenon by which introns, historically thought to represent non-coding 'junk', remain unspliced within pre-mRNA transcripts, resulting in their incorporation into the mature mRNA molecule. While the role of IR is well established in species of plant, fungi, insects and viruses, it remains relatively understudied in mammalian biology. It was previously assumed that IR only played a limited role in downregulating a transcript's translation potential through downstream initiation of nuclear detention or nonsense mediated decay (NMD). However, recent studies highlight IR's significantly more complex and dynamic contribution to cellular physiology and disease. In particular, a role for IR is emerging in both health and neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), a rapidly progressive and invariably fatal disease that renders patients paralysed and unable to eat, speak or breathe. Significant technological advances now permit a comprehensive interrogation of previously unrecognized aspects of RNA metabolism in clinically relevant human cell types. In this review, we focus on the differential role(s) of nuclear and cytoplasmic intron retaining transcripts (nIRTs and cIRTs, respectively), as well as how IRTs may influence subcellular localization of ribonucleoprotein (RNP) complexes, loss of function of bound RNA binding proteins (RBPs) and liquid-liquid phase separation (LLPS) in physiology and disease. Additionally, we discuss the potential of IRTs as independent regulatory elements beyond their protein-coding functions and highlight how artificial intelligence is poised to accelerate discoveries in this area. In the context of IR's increasing appreciation, we also highlight its potential as a therapeutic target and explore current and future challenges in this burgeoning field.",
"42544949": "ID: 42544949\nTitle: EXPRESS: Evaluation of the clinical course of immune-mediated polyneuropathy in cats following treatment with human intravenous immunoglobulins.\nAbstract: Immune-mediated polyneuropathy (IMPN) manifests with generalized lower motor neuron (LMN) weakness and a remittent or relapsing clinical course. Evidence-based treatment recommendations for severely or chronically affected cats are limited. The objective of this study was to evaluate the clinical course and outcome of cats with IMPN following treatment with human intravenous immunoglobulins (hIVIg). Medical records from two veterinary referral hospitals were reviewed (2018-2025) for cats with IMPN treated with hIVIg. Cats were treated with 1-2 g/kg hIVIg divided over 2-4 days (0.5 g/kg/day).Clinical information, diagnostic findings, treatment details and short- and long-term follow-up were evaluated retrospectively. Follow-up information was obtained from medical records and owner communication. Minimum follow-up duration was 8 months (8-51 months; median 17 months).Clinical course (partial and complete recovery, relapses) was compared between cats with acute/recent onset (4 cats) or chronic presentation (5 cats). Eight of nine cats exhibited clinical improvement following hIVIg administration, achieving ambulatory status (walking >5 steps) within a median of 4 days (2-8 days). One cat failed to respond to hIVIg but improved after subsequent prednisolone therapy. For the overall cohort, the median time to complete recovery was 20 days, while the median time to partial recovery was 14 days. Relapses occurred in four cats, but weakness was less severe, and all cats recovered again. The remaining five cats remained relapse-free. Human IVIg was well tolerated in this small cohort, and rapid clinical improvement was observed in most treated cats. These findings suggest that hIVIg may be considered as a treatment option in selected cats with IMPN, including those with acute and chronic presentations. Larger prospective studies, including comparison with no treatment or corticosteroids, are warranted to further assess its efficacy.",
"42545188": "ID: 42545188\nTitle: Neuropsychological Sub-Phenotypes in Amyotrophic Lateral Sclerosis.\nAbstract: This study aimed at identifying neuropsychological sub-phenotypes in amyotrophic lateral sclerosis (ALS) within the mild cognitive impairment (MCI) and mild behavioral impairment (MBI) frameworks. We used individual task-/item-level data from the cognitive and behavioral sections of the Edinburgh Cognitive and Behavioral ALS Screen (ECAS) from 901 non-demented ALS to derive neuropsychological sub-phenotypes pursuant to classical MCI and MBI frameworks and in accordance with an expanded version of Strong's criteria, which also addressed memory and visuo-spatial measures. The prevalence of MCI and MBI was 39% and 37%, respectively in this retrospective review. The following MCI sub-phenotypes were identified: dysexecutive MCI-single- and multiple-domain (dMCI-sd: 63%; dMCI-md: 24%, respectively); non-dysexecutive MCI-single- and multiple-domain (ndMCI-sd: 12%; ndMCI-md: 1%, respectively). MBI was classified as follows: apathetic MBI-single- and multiple-domain (aMBI-sd: 40%; aMBI-md: 20%, respectively); apathetic-disinihibited/perseverative MBI-multiple domain (ad/pMBI-md: 21%); disinihibited/perseverative MBI-multiple domain (d/pMBI-md: 7%); psychotic MBI-single- and multiple-domain (psyMBI-sd: 2%; psyMBI-md: 3%, respectively); unclassifiable MBI-multiple domain (uMBI-md: 1%). 143 (16%) of patients exhibited mild cognitive and behavioral impairment (MCBI). This study delivers a provisional, ECAS-based classification for the neuropsychological sub-phenotyping of non-demented ALS patients, which, with further validation, might be useful for both research and clinical purposes.",
"42548788": "ID: 42548788\nTitle: Tofersen Treatment in SOD1-ALS: Real-World Evidence from a Retrospective Multicenter Study in France (FORSLA Study).\nAbstract: To evaluate the effectiveness of Tofersen in patients with superoxide dismutase 1 gene (SOD1-ALS) patients in France in a real-world setting, using disease progression within patient comparisons and with a historical cohort. Patients with SOD1-ALS were included from across 19 French FILSLAN network centers. Baseline was defined as the treatment initiation date. Main endpoints were the ALSFRS-R progression rate and plasmatic neurofilament light chain (NfL) levels at baseline and 12 months after baseline. In the Tofersen Cohort (N=46), within-group comparisons showed that the mean ALS functional rating scale revised (ALSFRS-R) progression rate slowed from 0.53 \u00b1 0.5 at baseline to 0.22 \u00b1 0.3 point/month at 12 months (P=.006). NfL levels significantly decreased from 89.0 \u00b1 9.0 pg/ml at baseline to 29.2 \u00b1 19.5.5 at 12 months (P=.004). Exploratory comparisons with a propensity score (PS) matched historical cohort (39 matched pairs) using a mixed-effects model, ALSFRS-R progression rate at baseline, 6 months, and 12 months after baseline, showed no statistically significant differences between groups P=.30, whereas longitudinal ALSFRS-R scores differed significantly between groups (time-treatment interaction P=.006). The mean survival of the PS matched population was longer in the Tofersen Cohort (42.6 months) than the Historical Cohort (31.8 months) P=.004. Time-dependent adjusted cox analysis showed that Tofersen was associated with a reduction in mortality risk (adjusted HR=0.34; 95% CI, 0.12-0.91; P=.03). Tofersen seems to be associated with slower functional decline and reduced NfL levels. While limitations of retrospective design and ALSFRS-R sensitivity must be acknowledged, these findings provide real-world evidence suggesting a clinical benefit of Tofersen.",
"42550987": "ID: 42550987\nTitle: Co-Designing a Care Coordination Intervention for People With Motor Neuron Disease: Protocol for a Mixed Methods Study.\nAbstract: Motor neuron disease (MND), also known as amyotrophic lateral sclerosis (ALS), is a rapidly progressive neurological condition that requires complex multidisciplinary care. Within the United Kingdom, specialist centers provide expert interventions, while day-to-day support often relies on local nonspecialist community health and social care professionals. This is due to the distance between people's homes and specialist centers, as well as the availability of specialist health and social care professionals. This can lead to fragmented communication and emotional, physical, and financial burdens, and it can be time-consuming for people living with MND, their carers, and the health care professionals involved in their care. Despite the recognized need for better care coordination, it remains inadequate in practice, with a current lack of specific evidence-based interventions for achieving this. The MND Together project aims to address these systemic gaps by (1) developing a national picture of care coordination in England and Wales, (2) identifying barriers and facilitators to coordination within specialist and nonspecialist settings, and (3) co-designing a practical care coordination tool with key stakeholders. This protocol outlines the co-design of an intervention underpinned by the Behavior Change Wheel and the Socioecological Model. First, a mixed methods, multicenter study will be conducted to develop a national picture, comprising focus groups with people living with MND, carers, and health and social care professionals. Second, focused ethnography will be conducted in 5 MND specialist centers and their catchment areas, involving 25 people living with MND, to explore the barriers and facilitators to coordination in practice. Finally, a series of co-design workshops will be conducted to identify key priorities for care coordination and to develop a new intervention, the MND Together tool. The project started in September 2025 and will run until October 2027. Workstream 1 started in December 2025, with recruitment beginning at the first site in February 2026. To date, we have recruited 23 people living with MND and carers as well as 16 health and social care professionals across 4 of the 9 sites. Workstream 1 will end in August 2026, with results published at the end of 2026. Workstream 2 began in May 2026 and will run until February 2027, with results published in the summer of 2027. Workstream 3 will begin in March 2027 and conclude with the co-design intervention developed by late 2027. This will then be piloted in practice. By combining several methodologies with meaningful patient and public involvement and engagement, MND Together seeks to bridge the gap between specialist and community-based services. The MND Together tool aims to improve the quality of care and ensure that expert MND support is accessible as close as possible to every patient's home.",
"42553390": "ID: 42553390\nTitle: Fractal and Machine Learning Analyses of MALDI-TOF Mass Spectrometry Data in Glioblastoma.\nAbstract: Data preprocessing is a critical step in the analysis of matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry (MALDI-TOF MS) spectra for machine learning applications, typically involving steps such as spectra trimming, baseline correction, smoothing, transformation, and peak picking or spectral binning. While traditional approaches focus on protein/peptide peaks as features, this study explores a novel method of feature extraction by treating MALDI-TOF spectra as one-dimensional signal array further processed as time-series data. This study investigates the use of computational fractal-based analysis to assess the complexity of MALDI-TOF spectra. Fractal analysis, previously successful in glioblastoma diagnosis using magnetic resonance imaging, was applied here to proteomics data. By treating each MALDI spectrum as a time series and calculating its fractal dimension using various algorithms, machine learning models were trained to differentiate between glioblastoma patients and controls. We demonstrate that fractal dimensions are sufficient to obtain accurate models for glioblastoma diagnosis, despite still underperforming when compared to the traditional feature extraction method. We also show that fractals can be used as support features to increase model performance. This work highlights the potential and limitations of fractal analysis in proteomics, offering a new perspective for disease diagnosis and broadening the available computational tools for data analysis in mass spectrometry.",
"42558984": "ID: 42558984\nTitle: The Effectiveness Based on Optimal Dose and Administration Route, and Safety Profiles of Stem Cells and Derived Products in the Treatment of Patients With Amyotrophic Lateral Sclerosis: A Systematic Review and Meta-Analysis.\nAbstract: This systematic review and meta-analysis aimed to evaluate the effectiveness of stem cell therapies for patients with amyotrophic lateral sclerosis (ALS) based on optimal dosing and administration routes, as well as the safety profiles of stem cells and their derived products. The review followed PRISMA guidelines and involved a comprehensive literature search up to October 2025, receiving ethical approval from Tabriz University of Medical Sciences and registration in PROSPERO. It utilized international databases, including PubMed/MEDLINE, Embase, Cochrane Library, Scopus, Web of Science, ProQuest, ClinicalTrials.gov, and Science Direct. The included studies comprised randomized controlled trials (RCTs), quasi-experimental studies, and other interventional designs involving ALS patients treated with stem cell therapies. In total, 31 studies were analyzed, featuring 7 controlled trials with 370 participants and 24 non-controlled pre-post studies with 460 participants. Heterogeneity was evaluated using I 2 statistics, and subgroup analyses were conducted based on treatment duration and dosing. A pooled analysis (treatment group: n\u2009=\u200993; control group: n\u2009=\u200990) demonstrated a significant attenuation in the progression of disease severity, as measured by the ALS Functional Rating Scale (ALSFRS), in stem cell groups versus controls (weighted mean difference [WMD]: 8.89 95% CI: 4.12-13.67; p = 0.0003), which was beneficial for both the \u226510\u2009\u00d7\u2009106 and <10\u2009\u00d7\u2009106 dose sub-groups. However, a meta-analysis of single-arm studies in two control (pre-intervention) and intervention phases (n\u2009=\u200988) demonstrated no significant difference in progression of ALSFRS between study phases by time: month 3 (WMD: -1.27 (-3.01 to 0.47); p = 0.15), month 6 (WMD: -2.69 (-5.62 to 0.25); p = 0.07), month 9 (WMD: -1.55 (-3.49 to 0.39); p = 0.12), and month 12 (WMD: -7.59 (-13.95 to -1.26); p = 0.02). An accelerated decline in forced vital capacity (FVC) was observed during the intervention phase, with statistically significant reductions at month 3 (WMD: -10.91; 95% CI: -16.39 to -5.43; p < 0.0001) and month 6 (WMD: -15.97; 95% CI: -28.60 to -3.33; p = 0.01) compared with the pre-intervention control phase. Nevertheless, sensitivity analyses excluding studies involving high-dose mesenchymal stem cell (MSC) therapies demonstrated that these differences were no longer statistically significant. Moreover, no significant change in progression rate was observed at month 9 (WMD: -8.10 (-18.25 to 2.06); p = 0.12). The route of MSCs administration (intrathecal [IT], intramuscular [IM], and intravenous [IV]) had no effect on the results of ALSFRS and FVC, reinforced by sensitivity analyses. Adverse events were mostly mild, with headaches most frequent in high-dose groups. Stem cell therapy for ALS appears to be safe, with preliminary evidence suggesting potential therapeutic benefit in slowing disease progression in selected patients. Nevertheless, the existing evidence base remains exploratory, and definitive conclusions regarding clinical effectiveness cannot yet be drawn. Future research should prioritize large-scale and multicenter RCTs with standardized cell manufacturing protocols and longer follow-up periods.",
"42563536": "ID: 42563536\nTitle: Enabling Functional Independence: A Scoping Review of Upper Extremity Assistive Devices for Adults With Progressive Neuromuscular Diseases.\nAbstract: Assistive technology offers an important means of compensating for lost upper extremity function in adults with progressive neuromuscular diseases (NMD), enabling participation in daily activities, supporting independence, and promoting quality of life. However, the range of available technologies and the evidence supporting their use have not been comprehensively summarized. The aim of this scoping review was to identify and characterize upper extremity assistive technologies tested in adults with NMD and to summarize the current evidence regarding their functional applications and clinical outcomes. Electronic searches for published and unpublished literature were conducted using MEDLINE, Embase.com, Web of Science, Cochrane Central, and IEEE Xplore. The search strategy incorporated controlled vocabulary and free-text synonyms for the concepts of upper extremity, rehabilitation, selected progressive neurodegenerative diseases, and assistive equipment. Following title/abstract and full-text screening, studies evaluating assistive devices tested on adults with NMD during functional task performance were included. After screening 2289 articles, 27 studies met the inclusion criteria. The studies collectively demonstrate the potential benefits and diverse range of assistive devices available to support upper extremity function. These devices ranged from low-tech solutions, such as static mobile arm supports and fabricated splints, to high-tech devices, including dynamic mobile arm supports, robotic systems, exoskeletons, and brain-computer interface systems. However, most studies were feasibility or case studies that primarily demonstrated proof of concept, with limited evidence regarding long-term effectiveness, functional outcomes, or quality of life. The findings illustrate the rapidly evolving landscape of upper extremity assistive devices for adults with NMD and their potential to improve functional performance, while highlighting the need for prospective studies that assess meaningful improvements in function, participation, and quality of life. As advances in disease-modifying therapies extend survival and preserve function for individuals with NMD, interdisciplinary collaboration among engineers, clinicians, therapists, individuals with NMD, caregivers, and regulators will be essential to develop, evaluate, and implement assistive technologies that meet users' evolving needs.",
"42565151": "ID: 42565151\nTitle: A Systematic Literature Review of Emerging Advances in Neurological Disorders: Diagnostic Innovations, Therapeutic Strategies, and Future Directions.\nAbstract: Neurological disorders remain a major clinical burden because they affect cognition, movement, vascular function, behavior, psychological health, and long-term independence. Recent advances in imaging, biomarkers, artificial intelligence, regenerative therapy, immunotherapy, and targeted pharmacology have expanded diagnostic and therapeutic possibilities, yet the evidence remains dispersed across different neurological conditions and study designs. This review aimed to synthesize emerging advances in neurological disorders, focusing on diagnostic innovations, therapeutic strategies, and future clinical directions. A systematic literature review approach was applied using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)-based screening principles. Eleven studies were included, covering ischemic stroke, glioblastoma, Alzheimer's disease, multiple sclerosis, Parkinson's disease, motor neuron disease, episodic migraine, transient ischemic attack, and postoperative delirium. Data were extracted on study design, condition, intervention or diagnostic method, comparator, outcomes, and key findings. Risk of bias was assessed using the Risk of Bias 2 (RoB 2) tool for randomized trials, the Risk of Bias in Non-randomized Studies of Interventions (ROBINS-I) for nonrandomized, uncontrolled, post hoc, feasibility, and biomarker-monitoring studies, and the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) for diagnostic and radiomics studies. Findings showed increasing use of radiomics, circulating tumor DNA, rhythm monitoring, vascular imaging, inflammatory markers, biologics, cell therapy, psychological intervention, and lipid-lowering therapy. Several studies reported promising clinical or biomarker signals, while others clarified treatment limitations in specific disease subtypes. Overall, the findings suggest an emerging shift toward precision-oriented neurology, but larger controlled trials, prospective biomarker validation, standardized outcomes, and longer follow-up are required before routine implementation.",
"42566063": "ID: 42566063\nTitle: Anti-IgLON5 disease presenting with a motor neuron disease-like phenotype after decades of sleep symptoms: a potentially immunotherapy responsive mimic.\nAbstract: ",
"42566069": "ID: 42566069\nTitle: Value of ultrasound-detected fasciculations for the early diagnosis of motor neuron disease in patients with single-segment, pure lower motor neuron involvement.\nAbstract: To evaluate the early diagnostic value of muscle ultrasound (US)-detected fasciculations in motor neuron disease (MND) patients presenting with single\u2011region, pure lower motor neuron (LMN) involvement. Prospective cohort study enrolling 60 patients with clinical LMN signs confined to one body region. All underwent standardized needle EMG and muscle US at baseline. Final diagnosis determined by follow-up. Agreement between EMG and US, and net diagnostic gain of US were analyzed. 54 MND patients (median disease duration 9 months) were analyzed. US detection rates: bulbar 38.9%-46.3%; high-grade cervical fasciculations 20.4%-37.0%. EMG-US agreement was poor to fair (kappa 0.106-0.360). US provided additional LMN evidence in EMG-negative regions in 27.8% (bulbar), 22.2% (cervical) and 9.3% (lumbosacral). Using US (\u2265\u20092 regions with fasciculations/high-grade) as an ancillary criterion, 53.7% were diagnosed at first visit; median time to diagnosis was 5 months (range 3-8) in those otherwise missed. Muscle ultrasound is a sensitive, non-invasive complement to EMG, significantly improving early diagnosis in single-region pure LMN presentations. However, specificity estimates remain preliminary due to the limited number of non-MND controls.",
"42572514": "ID: 42572514\nTitle: Relationship between neck weakness in motor neurone disease and respiratory function: a retrospective study.\nAbstract: The primary aim was to explore the relationship between neck weakness in people with motor neurone disease (MND) and their respiratory function. The secondary aim was to identify whether neck weakness can be a prognostic factor. This was a retrospective observational cohort study. Data was collected from patient records on MND characteristics, neck weakness, respiratory function, and noninvasive ventilation (NIV) use. Multivariate modeling explored the effect of neck weakness on respiratory variables. MND-related neck weakness was evident in 41% of 324 participants. Fifty-four percent used NIV and 17% became dependent on NIV during disease progression. The presence of neck weakness in MND was predictive of time to respiratory function decline, for respiratory outcomes (forced vital capacity (FVC) <65%, FVC\u2009<50% and NIV use) as well as having an effect on time to death. Median time from neck weakness onset to death was 8\u2009months (IQR 10\u2009months; range 0 to 60\u2009months) with bulbar onset the quickest, median of 7\u2009months (IQR 7\u2009months, range 0 to 43\u2009months). The presence of neck weakness is associated with a more rapid respiratory function decline in MND. In addition, neck weakness can be considered a prognostic factor in MND survival. People with motor neurone disease (MND) experience weakness in different parts of their body including muscles that are responsible for breathing. As the disease worsens, it is expected that their breathing worsens, resulting in death. To help prolong the person\u2019s life, timely equipment that makes breathing easier is important. It is thought that there may be a relationship between weakness spreading to the neck muscles and the person\u2019s ability to breathe and whether it could help predict how the disease will progress. To explore this further, we reviewed the medical records of 324 people with MND. We found that about 4 in 10 people had neck weakness from their MND and over half were using breathing support. We also found that those with neck weakness tended to lose their breathing function more quickly and needed breathing support sooner. People with neck weakness were also found to have a shorter survival time, with an average of 8 months once their neck weakness began, however this varied depending on the type of MND the person had.",
"42573824": "ID: 42573824\nTitle: Clinical significance of SQSTM1 variants in ALS: report of p.Arg119Cys and literature review.\nAbstract: We analyzed the clinical features of a patient with amyotrophic lateral sclerosis (ALS) carrying a novel variant in the sequestosome 1 (SQSTM1) gene and explored the genotype-phenotype association of SQSTM1 gene variants in combination with previous literature. Clinical data and genetic testing results of an ALS patient treated at our hospital were collected. Whole-exome sequencing was used to screen for ALS-related genes, and candidate variants were validated by Sanger sequencing and family analysis. A systematic search was conducted in the PubMed database using the keywords (\"amyotrophic lateral sclerosis\") OR (\"motor neuron disease\") AND (\"SQSTM1\") to summarize the clinical and genetic characteristics of previously reported ALS patients with SQSTM1 variants. The patient was a 49-year-old male with progressive weakness in both lower limbs for one year and weakness in the left upper limb for the past three months. Electromyography showed extensive neurogenic damage. Genetic testing identified a novel heterozygous missense variant, c.355 C\u2009>\u2009T (p.Arg119Cys), in the SQSTM1 gene. Family verification revealed that his phenotypically normal mother carried the same variant. The literature search identified 58 cases of ALS associated with SQSTM1 variants. Missense variants were the most common type. We identified a novel SQSTM1 variant, c.355 C\u2009>\u2009T (p.Arg119Cys), in a ALS patient. Although this finding expands the variant spectrum, its pathogenicity remains uncertain and requires further functional validation and pedigree confirmation. Our literature review further shows that SQSTM1-associated ALS predominantly presents with limb onset, with a subset of patients exhibiting frontotemporal dementia or Paget's disease."
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