{
"claim": "Exploration: The gut microbial metabolite 3-indolepropionic acid as a functional neuroprotective agent against intracerebral hemorrhage: integrating epidemiological screening with in vivo validation.",
"timestamp": "2026-08-12T01:46:37.890Z",
"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 ... tags at the very beginning of your response.\n\n=======================================================\nCONTEXT LITERATURE (STATIC CACHE):\nID: 42530713\nTitle: Integrative Analysis Reveals Interactions Between Gut Microbiota-Derived Metabolites and the Brain in Parkinson's Disease.\nAbstract: Parkinson's disease (PD) is a neurodegenerative disorder increasingly associated with gut microbiota alterations, yet the mechanisms by which microbial metabolites influence PD remain unclear. Here, we applied an integrative computational and experimental strategy to identify key gut microbial metabolites and host genes potentially involved in PD. Differentially abundant gut microbes were obtained from the gutMDisorder database and their corresponding metabolites from gutMGene, with predicted protein targets generated using the Similarity Ensemble Approach. Transcriptomic data from PD brain tissues were analyzed to identify differentially expressed genes, which were intersected with metabolite targets, followed by enrichment and protein-protein interaction analyses. Three machine learning algorithms were applied for gene prioritization, while molecular docking evaluated metabolite-gene binding affinities and ProTox3.0 predicted toxicity and blood-brain barrier permeability. In vitro assays further assessed the functional effects of 3-indolepropionic acid in a rotenone-induced SH-SY5Y cell model. Our analyses identified 44 PD-associated microbial taxa linked to 77 metabolites and 905 predicted target genes, with 29 overlapping differentially expressed genes enriched in synaptic signaling and dopaminergic pathways. Dopamine receptor D2 (DRD2) emerged as a central hub gene, with strong docking interactions predicted for two indole metabolites, 3-(1H-indol-3-yl)propanoate and 3-indolepropionic acid. Functional validation showed that 3-indolepropionic acid improved cell viability, reduced apoptosis, and preserved DRD2 expression under neurotoxic stress. Together, these findings suggest that specific gut microbial metabolites may modulate host dopaminergic signaling via DRD2, offering new insights into the microbiota-brain axis and potential targets for further PD research.\n\nID: 42360541\nTitle: The gut microbial metabolite 3-indolepropionic acid as a functional neuroprotective agent against intracerebral hemorrhage: integrating epidemiological screening with in vivo validation.\nAbstract: Intracerebral hemorrhage (ICH) is a severe stroke subtype with limited therapeutic options. Emerging evidence highlights the diet-gut-brain axis in neurological outcomes, yet the specific metabolic mediators remain elusive. This study integrated epidemiological, genetic, and experimental approaches to investigate the potential neuroprotective role of gut-derived metabolites in ICH. Utilizing Global Burden of Disease data and Mendelian randomization analysis, we explored the associations between dietary habits and ICH, and investigated putative causal relationships between specific gut microbiota and disease risk. Subsequent network pharmacology analysis predicted that 3-indolepropionic acid (3-IPA) might exert neuroprotective effects primarily through anti-apoptotic pathways. To evaluate these findings in vivo, we established a mouse model of ICH. Administration of 3-IPA significantly ameliorated neurological deficits and improved cognitive memory in the Morris water maze test. Furthermore, immunofluorescence and Western blot analyses indicated that 3-IPA treatment was associated with the upregulation of the anti-apoptotic protein BCL2 and the reduction of pro-apoptotic markers in the peri-hematomal region. In conclusion, our multidisciplinary study outlines a potential biological pathway linking dietary patterns, gut microbial metabolism, and brain injury recovery. Our findings suggest that the gut microbial metabolite 3-IPA protects against ICH-induced secondary brain injury, potentially by attenuating neuronal apoptosis, highlighting it as a promising metabolic intervention target for ICH therapy.\n\nID: 41774153\nTitle: Restoring Firmicutes-Associated Metabolites: A Gut-Brain Axis Approach to Alleviate Neuroinflammation and Oxidative Stress in Intracerebral Hemorrhage.\nAbstract: Intracerebral hemorrhage (ICH), a lethal stroke subtype, lacks therapies targeting gut-brain axis dysregulation. While gut microbiota influences ischemic stroke outcomes, how ICH perturbs microbial-metabolite interactions via the microbiota-gut-brain axis (MGBA) remains unknown. We combined a collagenase-induced ICH mouse model with multi-omics (16S rRNA sequencing, metabolomics) and functional assays (BV2 microglia) to investigate gut dysbiosis and metabolite alterations. Intestinal barrier integrity, neuroinflammation, and oxidative stress were assessed. At the phylum level, the control (CON) group exhibited a microbiome dominated by Firmicutes, Actinobacteriota, and Campylobacterota. In stark contrast, the ICH group displayed a pathological shift toward Bacteroidota, Cyanobacteria, and Proteobacteria. These dysbiotic alterations corresponded to intestinal barrier compromise marked by reduced expression of zonula occludens-1 (ZO-1), occludin, and mucin 2 (MUC2), systemic elevation of pro-inflammatory cytokines including interleukin-1\u03b2 (Il-1\u03b2) and tumor necrosis factor-\u03b1 (Tnf-\u03b1), and depletion of neuroprotective metabolites\u2013specifically oleoyl ethanolamide, linoleoyl ethanolamide, and L-valine\u2013whose levels positively correlated with Firmicutes abundance. Mechanistically, in vitro experiments demonstrated that these metabolites collectively suppressed neuroinflammation and neuronal apoptosis, with l-valine exhibiting unique antioxidant activity through Reactive oxygen species scavenging. Molecular docking studies have shown that linoleoyl ethanolamide (LEA) and oleoylethanolamide (OEA) can inhibit the levels of inflammatory cytokines interleukin-6 (Il-6) and tumor necrosis Tnf-\u03b1 by binding to key sites. Our findings underscore the critical role of gut microbiota-metabolite crosstalk in ICH pathogenesis and identify microbial metabolites as potential therapeutic targets for preserving gut-brain axis homeostasis.\n\nID: 36389714\nTitle: Gut microbes in cerebrovascular diseases: Gut flora imbalance, potential impact mechanisms and promising treatment strategies.\nAbstract: The high morbidity, mortality, and disability rates associated with cerebrovascular disease (CeVD) pose a severe danger to human health. Gut bacteria significantly affect the onset, progression, and prognosis of CeVD. Gut microbes play a critical role in gut-brain interactions, and the gut-brain axis is essential for communication in CeVD. The reflection of changes in the gut and brain caused by gut bacteria makes it possible to investigate early warning biomarkers and potential treatment targets. We primarily discussed the following three levels of brain-gut interactions in a systematic review of the connections between gut microbiota and several cerebrovascular conditions, including ischemic stroke, intracerebral hemorrhage, intracranial aneurysm, cerebral small vessel disease, and cerebral cavernous hemangioma. First, we studied the gut microbes in conjunction with CeVD and examined alterations in the core microbiota. This enabled us to identify the focus of gut microbes and determine the focus for CeVD prevention and treatment. Second, we discussed the pathological mechanisms underlying the involvement of gut microbes in CeVD occurrence and development, including immune-mediated inflammatory responses, variations in intestinal barrier function, and reciprocal effects of microbial metabolites. Finally, based on the aforementioned proven mechanisms, we assessed the effectiveness and potential applications of the current therapies, such as dietary intervention, fecal bacterial transplantation, traditional Chinese medicine, and antibiotic therapy.\n\nID: 27885969\nTitle: 36th International Symposium on Intensive Care and Emergency Medicine : Brussels, Belgium. 15-18 March 2016.\nAbstract: P001 - Sepsis impairs the capillary response within hypoxic capillaries and decreases erythrocyte oxygen-dependent ATP efflux R. M. Bateman, M. D. Sharpe, J. E. Jagger, C. G. Ellis P002 - Lower serum immunoglobulin G2 level does not predispose to severe flu. J. Sol\u00e9-Viol\u00e1n, M. L\u00f3pez-Rodr\u00edguez, E. Herrera-Ramos, J. Ru\u00edz-Hern\u00e1ndez, L. Border\u00edas, J. Horcajada, N. Gonz\u00e1lez-Quevedo, O. Rajas, M. Briones, F. Rodr\u00edguez de Castro, C. Rodr\u00edguez Gallego P003 - Brain protective effects of intravenous immunoglobulin through inhibition of complement activation and apoptosis in a rat model of sepsis F. Esen, G. Orhun, P. Ergin Ozcan, E. Senturk, C. Ugur Yilmaz, N. Orhan, N. Arican, M. Kaya, M. Kucukerden, M. Giris, U. Akcan, S. Bilgic Gazioglu, E. Tuzun P004 - Adenosine a1 receptor dysfunction is associated with leukopenia: A possible mechanism for sepsis-induced leukopenia R. Riff, O. Naamani, A. Douvdevani P005 - Analysis of neutrophil by hyper spectral imaging - A preliminary report R. Takegawa, H. Yoshida, T. Hirose, N. Yamamoto, H. Hagiya, M. Ojima, Y. Akeda, O. Tasaki, K. Tomono, T. Shimazu P006 - Chemiluminescent intensity assessed by eaa predicts the incidence of postoperative infectious complications following gastrointestinal surgery S. Ono, T. Kubo, S. Suda, T. Ueno, T. Ikeda P007 - Serial change of c1 inhibitor in patients with sepsis \u2013 A prospective observational study T. Hirose, H. Ogura, H. Takahashi, M. Ojima, J. Kang, Y. Nakamura, T. Kojima, T. Shimazu P008 - Comparison of bacteremia and sepsis on sepsis related biomarkers T. Ikeda, S. Suda, Y. Izutani, T. Ueno, S. Ono P009 - The changes of procalcitonin levels in critical patients with abdominal septic shock during blood purification T. Taniguchi, M. O P010 - Validation of a new sensitive point of care device for rapid measurement of procalcitonin C. Dinter, J. Lotz, B. Eilers, C. Wissmann, R. Lott P011 - Infection biomarkers in primary care patients with acute respiratory tract infections \u2013 Comparison of procalcitonin and C-reactive protein M. M. Meili, P. S. Schuetz P012 - Do we need a lower procalcitonin cut off? H. Hawa, M. Sharshir, M. Aburageila, N. Salahuddin P013 - The predictive role of C-reactive protein and procalcitonin biomarkers in central nervous system infections with extensively drug resistant bacteria V. Chantziara, S. Georgiou, A. Tsimogianni, P. Alexandropoulos, A. Vassi, F. Lagiou, M. Valta, G. Micha, E. Chinou, G. Michaloudis P014 - Changes in endotoxin activity assay and procalcitonin levels after direct hemoperfusion with polymyxin-b immobilized fiber A. Kodaira, T. Ikeda, S. Ono, T. Ueno, S. Suda, Y. Izutani, H. Imaizumi P015 - Diagnostic usefullness of combination biomarkers on ICU admission M. V. De la Torre-Prados, A. Garcia-De la Torre, A. Enguix-Armada, A. Puerto-Morlan, V. Perez-Valero, A. Garcia-Alcantara P016 - Platelet function analysis utilising the PFA-100 does not predict infection, bacteraemia, sepsis or outcome in critically ill patients N. Bolton, J. Dudziak, S. Bonney, A. Tridente, P. Nee P017 - Extracellular histone H3 levels are inversely correlated with antithrombin levels and platelet counts and are associated with mortality in sepsis patients G. Nicolaes, M. Wiewel, M. Schultz, K. Wildhagen, J. Horn, R. Schrijver, T. Van der Poll, C. Reutelingsperger P018 - Il-8: is this a more reliable biomarker for sepsis severity than CRP, Procalcitonin, E-selectin, IL-6 and TNF-[alpha] S. Pillai, G. Davies, G. Mills, R. Aubrey, K. Morris, P. Williams, P. Evans P019 - Relation between adrenomedullin and short-term outcome in ICU patients: Results from the frog ICU study E. G. Gayat, J. Struck, A. Cariou, N. Deye, B. Guidet, S. Jabert, J. Launay, M. Legrand, M. L\u00e9one, M. Resche-Rigon, E. Vicaut, A. Vieillard-Baron, A. Mebazaa P020 - Impact of disease severity assessment on performance of heparin-binding protein for the prediction of septic shock R. Arnold, M. Capan, A. Linder, P. Akesson P021 - Kinetics and prognostic value of presepsin (sCD14) in septic patients. A pilot study M. Popescu, D. Tomescu P022 - Comparison of CD64 levels performed by the facs and accellix systems C. L. Sprung, R. Calderon Morales, G. Munteanu, E. Orenbuch-Harroch, P. Levin, H. Kasdan, A. Reiter, T. Volker, Y. Himmel, Y. Cohen, J. Meissonnier P023 - Diagnosing sepsis in 5\u00a0minutes: Nanofluidic technology study with pancreatic-stone protein (PSP/ reg) L. Girard, F. Rebeaud P024 - How nanotechnology-based approaches could contribute to sepsis prevention, diagnosis and treatment I. Herrmann P025 - Il7r transcriptional expression analysis during septic shock B. Delwarde, E. Peronnet, E. Cerrato, F. Venet, A. Lepape, T. Rimmel\u00e9, G. Monneret, J. Textoris P026 - Disbalance of microbial metabolites of aromatic acids affects the severity in critically ill patients N. Beloborodova, V. Moroz, A. Osipov, A. Bedova, Y. Sarshor, A. Pautova, A. Sergeev, E. Chernevskaya P027 - Copeptin predicts 10-year all-cause mortality in community patients J. Odermatt, R. Bolliger, L. Hersberger, M. Ottiger, M. Christ-Crain, B. Mueller, P. Schuetz P028 - Identification of differential proteomic response in septic patients secondary to community and hospital acquired pneumonia N. K. Sharma, A. K. Tashima, M. K. Brunialti, F. R. Machado, M. Assuncao, O. Rigato, R. Salomao P029 - Monocyte HLA-DR expression in community-acquired bacteremic sepsis - dynamics associated to aetiology and prediction of secondary sepsis S. C. Cajander, G. Rasmussen, E. Tina, B. S\u00f6derquist, J. K\u00e4llman, K. Str\u00e5lin P030 - Soluble B- and T-lymphocyte attenuator: A possible prognostic marker in sepsis A. L. Lange, J. S. Sund\u00e9n-Cullberg, A. M. Magnuson, O. H. Hultgren P031 - Fractal dimension: A new biomarker for quantifying clot microstructure in patients across the sepsis spectrum G. Davies, S. Pillai, G. Mills, R. Aubrey, K. Morris, P. Williams, P. Evans P032 - Comparison between the new biomarker for coagulation, clot microstructure (Df) with rotational thromboelastometry (ROTEM) in patients across the sepsis spectrum S. Pillai, G. Davies, G. Mills, R. Aubrey, K. Morris, P. Williams, P. Evans P033 - Changes in fibrinolysis across the sepsis spectrum: The use of rotational thromboelastometry (ROTEM) lysis index (LI60) and D-Dimer concentration S. Pillai, G. Davies, G. Mills, R. Aubrey, K. Morris, P. Williams, P. Evans P034 - The intensive care infection score \u2013 a promising marker for the prediction of infection and its severity. P. Van der Geest, M. Mohseni, J. Linssen, R. De Jonge, S. Duran, J. Groeneveld P035 - Challenges in the clinical diagnosis of sepsis R. Miller III, B. K. Lopansri, L. C. McHugh, A. Seldon, J. P. Burke P036 - Does zero heat flux thermometry more accurately identify sepsis on intensive care? J. Johnston, R. Reece-Anthony, A. Bond, A. Molokhia P037 - Advancing quality (AQ) sepsis programme: Improving early identification & treatment of sepsis in North West England. C. Mcgrath, E. Nsutebu P038 - Prehospital transport of acute septic patients P. Bank Pedersen, D. Pilsgaard Henriksen, S. Mikkelsen, A. Touborg Lassen P039 - Vasodilatory plant extracts gel as an alternative treatment for fever in critically ill patients R. Tincu, C. Cobilinschi, D. Tomescu, Z. Ghiorghiu, R. Macovei P040 - Host response and outcome of hypothermic sepsis M. A. Wiewel, M. B. Harmon, L. A. Van Vught, B. P. Scicluna, A. J. Hoogendijk, J. Horn, A. H. Zwinderman, O. L. Cremer, M. J. Bonten, M. J. Schultz, T. Van der Poll, N. P. Juffermans, W. J. Wiersinga P041 - Septic shock alert over SIRS criteria has an impact on outcome but needs to be revised G. Eren, Y Tekdos, M. Dogan, O. Acicbe, E. Kaya, O. Hergunsel P042 - Association between previous prescription of \u03b2blockers and mortality rate among septic patients: A retrospective observational study S. Alsolamy, G. Ghamdi, L. Alswaidan, S. Alharbi, F. Alenezi, Y. Arabi P043 - Recognition and treatment of sepsis on labour ward\u2013 teaching & information resources can improve knowledge J. Heaton, A. Boyce, L. Nolan, J. Johnston, A. Dukoff-Gordon, A. Dean, A. Molokhia P044 - Culture negative sepsis in the ICU \u2013 what is unique to this patient population? T. Mann Ben Yehudah P045 - Organ dysfunction in severe sepsis patients identified in administrative data in Germany, 2007-2013 C. Fleischmann, D. Thomas-Rueddel, C. Haas, U. Dennler, K. Reinhart P046 - A comparison of residents\u2019 knowledge regarding; the Surviving Sepsis Campaign 2012 guideline O. Suntornlohanakul, B. Khwannimit P047 - Effectiveness of a septic shock bundle to improve outcomes in the ICU F. Breckenridge, A. Puxty P048 - Dose of norepinephrine in the first 24\u00a0hours as a parameter evaluating the effectiveness of treatment in patients with severe sepsis and septic shock P. Szturz, P. Folwarzcny, J. Svancara, R. Kula, P. Sevcik P049 - Norepinephrine or vasopressin\u2009+\u2009norepinephrine in septic shock. A retrospective series of 39 patients L. Caneva, A. Casazza, E. Bellazzi, S. Marra, L. Pagani, M. Vetere, R. Vanzino, D. Ciprandi, R. Preda, R. Boschi, L. Carnevale P050 - Methylene blue effectiveness as contributory treatment in patients with septic shock V. Lopez, M. Aguilar Arzapalo, L. Barradas, A. Escalante, J. Gongora, M. Cetina P051 - Coagulation disorders in patients with severe sepsis and DIC evaluated with thromboelastometry. B Adamik, D Jakubczyk, A K\u00fcbler P052 - Frequency and outcome of early sepsis-associated coagulopathy A. Radford, T. Lee, J. Singer, J. Boyd, D. Fineberg, M. Williams, J. Russell P053 - Assessment of coagulopathy in cancer patients with severe sepsis or septic shock. A case-control pilot study E. Scarlatescu, D. Tomescu, G. Droc, S. Arama P054 - Thromboelastometry in critically ill patients with disseminated intravascular coagulation M. M\u00fcller, M. Straat, S. S. Zeerleder, N. P. Juffermans P055 - Cessation of a preexisting chronic antiplatelet therapy is associated with increased mortality rates in severe sepsis and septic shock C. F. Fuchs, C. S. Scheer, S. W. Wauschkuhn, M. V. Vollmer, K. M. Meissner, S. K. Kuhn, K. H. Hahnenkamp, S. R. Rehberg, M. G. Gr\u00fcndling P056 - Neutrophil Extracellular Traps (NETs) production under hypoxic condition N. Yamamoto, M. Ojima, S. Hamaguchi, T. Hirose, Y. Akeda, R. Takegawa, O. Tasaki, T. Shimazu, K. Tomono P057 - Impact of ultraviolet air sterilizer in intensive care unit room, and clinical outcomes of patients E. G\u00f3mez-S\u00e1nchez, M. Heredia-Rodr\u00edguez, E. \u00c1lvarez-Fuente, M. Lorenzo-L\u00f3pez, E. G\u00f3mez-Pesquera, M. Arag\u00f3n-Camino, P. Liu-Zhu, A. S\u00e1nchez-L\u00f3pez, A. Hern\u00e1ndez-Lozano, M. T. Pel\u00e1ez-Jare\u00f1o, E. Tamayo P058 - Focus of infection in severe sepsis - comparison of administrative data and prospective cohorts from Germany D. O. Thomas-R\u00fcddel, C. Fleischmann, C. Haas, U. Dennler, K. Reinhart P059 - \u201cZero CLABSI\u201d \u2013 can we get there? Obstacles on the 4\u00a0year journey and our strategies to overcome them \u2013 experience from an Indian ICU V. Adora, A. Kar, A. Chakraborty, S. Roy, A. Bandyopadhyay, M. Das P060 - Novel molecular techniques to identify central venous catheter (CVC) associated blood stream infections (BSIs) T. Mann Ben Yehudah, G. Ben Yehudah, M. Salim, N. Kumar, L. Arabi, T. Burger, P. Lephart, E. Toth-martin P061 - Zero clabsi\u201d \u2013 can we get there? Obstacles on the 4\u00a0year journey and our strategies to overcome them \u2013 experience from an Indian ICU R. Rao, A. Kar, A. Chakraborty P062 - Prevention of central line-associated bloodstream infections in intensive care units: An international online survey C. Valencia, N. Hammami, S. Blot, J. L. Vincent, M. L. Lambert P063 - 30\u00a0days antimicrobial efficacy of non-leaching central venous catheters J. Brunke, T. Riemann, I. Roschke P064 - Efficacy of noble metal alloy-coated catheter in prevention of bacteriuria R. Tincu, C. Cobilinschi, D. Tomescu, Z. Ghiorghiu, R. Macovei P065 - Predicting bacteremic urinary tract infection in community setting: A prospective observational study S. Nimitvilai, K. Jintanapramote, S. Jarupongprapa P066 - Eight-year analysis of acinetobacter spp. monobacteremia in surgical and medical intensive care units at university hospital in Lithuania D. Adukauskiene, D. Valanciene P067 - Group A and group B streptococcal infections in intensive care unit \u2013 our experience in a tertiary centre G. Bose, V. Lostarakos, B. Carr P068 - Improved detection of spontaneous bacterial peritonitis by uritop\u2009+\u2009tm strip test and inoculation of blood culture bottles with ascitic fluid S. Khedher, A. Maaoui, A. Ezzamouri, M. Salem P069 - Increased risk of cellulitis in patients with congestive heart failure: a population based cohort study J. Chen P070 - Outcomes of severe cellulitis and necrotizing fasciitis in the critically ill D. R. Cranendonk, L. A. Van Vught, M. A. Wiewel, O. L. Cremer, J. Horn, M. J. Bonten, M. J. Schultz, T. Van der Poll, W. J. Wiersinga P071 - Botulism outbreak associated with people who inject drugs (PWIDs) in Scotland. M. Day, G. Penrice, K. Roy, P. Robertson, G. Godbole, B. Jones, M. Booth, L. Donaldson P072 - Surveillance of ESBL-producing enterobacteriaceae fecal carriers in the ICU Y. Kawano, H. Ishikura P073 - Prevalence of ESBL and carbapenemase producing uropathogens in a newly opened hospital in south India S. Sreevidya, N. Brahmananda Reddy, P. Muraray Govind, R. Pratheema, J. Devachandran Apollo Speciality Hospital - OMR, Chennai, India P074 - Prevalence, risk factors and outcomes of methicillin-resistant staphylococcus aureus nasal colonization in critically ill patients H. Al-Dorzi, M. Almutairi, B. Alhamadi, A. Crizaldo Toledo, R. Khan, B. Al Raiy, Y. Arabi P075 - Multidrug-resistant Acinetobacter baumannii infection in intensive care unit patients in a hospital with building construction: Is there an association? H. Talaie P076 - Multidrug-resistant organisms in a Dutch ICU J. A. Van Oers, A. Harts, E. Nieuwkoop, P. Vos P077 - Epidemiology and risk factors of ICU acquired infections caused by multidrug-resistant gram negative bacilli Y. Boussarsar, F. Boutouta, S. Kamoun, I. Mezghani, S. Koubaji, A. Ben Souissi, A. Riahi, M. S. Mebazaa P078 - Improving outcomes of severe infections by multidrug-resistant pathogens with polyclonal IgM-enriched immunoglobulins E. Giamarellos-Bourboulis, N. Tziolos, C. Routsi, C. Katsenos, I. Tsangaris, I. Pneumatikos, G. Vlachogiannis, V. Theodorou, A. Prekates, E. Antypa, V. Koulouras, N. Kapravelos, C. Gogos, E. Antoniadou, K. Mandragos, A. Armaganidis P079 - Must change the medical practice in ICU? A. R. Robles Caballero, B. Civantos, J. C. Figueira, J. L\u00f3pez P080 - Mediterranean spotted fever in an infectious diseases intensive care unit A. Silva-Pinto, F. Ceia, A. Sarmento, L. Santos P081 - Clinical features and outcomes of patients with Middle East respiratory syndrome requiring admission to a saudi intensive care unit: A retrospective analysis of 31 cases G. Almekhlafi, Y. Sakr P082 - The ICU response to a hospital outbreak of Middle East respiratory syndrome coronavirus infection H. Al-Dorzi, R. Khan, S. Baharoon, A. Aldawood, A. Matroud, J. Alchin, S. Al Johani, H. Balkhy, Y. Arabi P083 - Middle East respiratory syndrome: Surveillance data analysis S. Alsolamy, S. Y. Yousif, B. O. Alotabi, A. S. Alsaawi P085 - Use of Taqman array card molecular diagnostics in severe pneumonia: A case series J. Ang, MD Curran, D. Enoch, V. Navapurkar, A. Conway Morris P086 - \u2018BUNS\u2019: An investigation protocol improves the ICU management of pneumonia R. Sharvill, J. Astin P087 - Pneumonia in patients following secondary peritonitis: epidemiological features and impact on mortality M. Heredia-Rodr\u00edguez, E. G\u00f3mez-S\u00e1nchez, M. T. Pel\u00e1ez-Jare\u00f1o, E. G\u00f3mez-Pesquera, M. Lorenzo-L\u00f3pez, P. Liu-Zhu, M. Arag\u00f3n-Camino, A. Hern\u00e1ndez-Lozano, A. S\u00e1nchez-L\u00f3pez, E. \u00c1lvarez-Fuente, E. Tamayo P088 - The use of the \u201cCURB-65 score\u201d by emergency room clinicians in a large teaching hospital J. Patel, C. Kruger P089 - Incidence of community acquired pneumonia with viral infection in mechanically ventilated patients in the medical intensive care unit J. O\u2019Neal, H. Rhodes, J. Jancik P090 - The SAATELLITE Study: Prevention of S aureus Nosocomial Pneumonia (NP) with MEDI4893, a Human Monoclonal Antibody (mAb) Against S aureus B. Fran\u00e7ois, P. F. Laterre, P. Eggimann, A. Torres, M. S\u00e1nchez, P. F. Dequin, G. L. Bassi, J. Chastre, H. S. Jafri P091 - Risk factors and microbiological profile for nosocomial infections in trauma patients M. Ben Romdhane, Z. Douira, S. Kamoun, M. Bousselmi, A. Ben Souissi, Y. Boussarsar, A. Riahi, M.S. Mebazaa P092 - Correlation between percentages of ventilated patients developed vap and use of antimicrobial agents in ICU patients. A. Vakalos, V. Avramidis P093 - A comparison of two ventilator associated pneumonia surveillance techniques T. H. Craven, G. Wojcik, K. Kefala, J. McCoubrey, J. Reilly, R. Paterson, D. Inverarity, I. Laurenson, T. S. Walsh P094 - Lung ultrasound before and after fiberbronchoscopy - modifications may improve ventilator-associated pneumonia diagnosis S. Mongodi, B. Bouhemad, A. Orlando, A. Stella, G. Via, G. Iotti, A. Braschi, F. Mojoli P095 - Comparing the accuracy of predictors of mortality in ventilator-associated pneumonia M. Haliloglu, B. Bilgili, U. Kasapoglu, I. Sayan, M. S\u00fczer Aslan, A. Yalc\u0131n, I. Cinel P096 - Impact of pRBCs transfusion on percentage of ventilated patients developed VAP in ICU patients A. Vakalos, V. Avramidis P097 - The impact of a series of interventions on the rate of ventilator associated pneumonia in a large teaching hospital H. E. Ellis, K. Bauchmuller, D. Miller, A Temple P098 - The EVADE study: Prevention of Nosocomial Pneumonia (NP) caused by P aeruginosa with MEDI3902, a Novel Bispecific Monoclonal Antibody, against P aeruginosa virulence factors J. Chastre, B. Fran\u00e7ois, A. Torres, C. E. Luyt, M. S\u00e1nchez, M. Singer, H. S. Jafri P099 - Short-term inhaled colistin adjunctive therapy for ventilator-associated pneumonia Y. Nassar, M. S. Ayad P100 - Effect of aerosolised colistin on weaning from mechanical ventilation A. Trifi, S. Abdellatif, F. Daly, R. Nasri, S. Ben Lakhal P101 - Septic shock is an independent risk factor for colistin-induced severe acute kidney injury: a retrospective cohort study B. Bilgili, M. Haliloglu, F. Gul, I. Cinel P102 - Nosocomial pneumonia - emphasis on inhaled tobramycin A. Kuzovlev, A. Shabanov, S. Polovnikov, V. Moroz P103 - In vitro evaluation of amikacin inhale and commercial nebulizers in a mechanical ventilator N. Kadrichu, T. Dang, K. Corkery, P. Challoner P104 - The effects of nebulized amikacin/fosfomycin and systemic meropenem on severe amikacin-resistant meropenem-susceptible P.aeruginosa pneumonia G. Li Bassi, E. Aguilera, C. Chiurazzi, C. Travierso, A. Motos, L. Fernandez, R. Amaro, T. Senussi, F. Idone, J. Bobi, M. Rigol, A. Torres P105 - Optimization of gentamicin peak concentrations in critically ill patients C. J. Hodiamont, N. P. Juffermans, J. M. Janssen, C. S. Bouman, R. A. Math\u00f4t, M. D. De Jong, R. M. Van Hest P106 - Systematic review of cefepime induced neurotoxicity L. Payne, G. L. Fraser P107 - Unasyn\u00ae causes QT prolongation during treatment of intensive care patients B. Tudor, M. Lahner, G. Roth, C. Krenn P108 - Comparative study between teicoplanin and vancomycin in methicillin-resistant staphylococcus aureus (mrsa) infectious of toxicological intensive care unit (ticu) patients \u2013 Tehran, Iran H. Talaie P109 - Phage therapy against antimicrobial resistance, design of the first clinical study phagoburn P. Jault, J. Gabard, T. Leclerc, S. Jennes, Y. Que, A. Rousseau, F. Ravat P110 - Antibiotic dosing errors in critically ill patients with severe sepsis or septic shock H. Al-Dorzi, A. Eissa, S. Al-Harbi, T. Aldabbagh, R. Khan, Y. Arabi P111 - Does empiric antifungal therapy improve survival in septic critically ill patients? (immunocompromised excluded) A. Trifi, S. Abdellatif, F. Daly, R. Nasri, S. Ben Lakhal P112 - Neurocysticercosis-Qatar experience F. Paramba, N. Purayil, V. Naushad, O. Mohammad, V. Negi, P. Chandra P113 - Early indicators in acute haemorrhagic shock A. Kleinsasser P114 - Filtering of red blood cells reduces the inflammatory response of pulmonary cells in an in vitro model of mechanical ventilation M. R. Witrz, J. F. Buchner-Doeven, A. M. Tuip-de Boer, J. C. Goslings, N. P. Juffermans P115 - Microparticles from red blood cell transfusion induce a pro-coagulant and pro-inflammatory endothelial cell response M. Van Hezel, M. Straat, A Boing, R Van Bruggen, N Juffermans P116 - The contribution of cytokines on thrombosis development during hospitalization in ICU D. Markopoulou, K. Venetsanou, V. Kaldis, D. Koutete, D. Chroni, I. Alamanos P117 - Prophylactic enoxaparin dosing and adjustment through anti-xa monitoring in an inpatient burn unit L. Koch, J. Jancik, H. Rhodes, E. Walter P118 - Determination of optimal cut-off values of haemoglobin, platelet count and fibrinogen at 24\u00a0hours after injury associated with mortality in trauma patients K. Maekawa, M. Hayakawa, S. Kushimoto, A. Shiraishi, H. Kato, J. Sasaki, H. Ogura, T. Matauoka, T. Uejima, N. Morimura, H. Ishikura, A. Hagiwara, M. Takeda P119 - Trauma-induced coagulopathy - prothrombin complex concentrate vs fresh frozen plasma O. Tarabrin, S. Shcherbakow, D. Gavrychenko, G. Mazurenko, V. Ivanova, O. Chystikov P120 - First study to prove the superiority of prothrombin complex concentrates on mortality rate over fresh frozen plasma in patients with acute bleeding C. Plourde, J. Lessard, J. Chauny, R. Daoust P121 - Prothrombin complex concentrate vs fresh frozen plasma in obstetric massive bleeding S. Shcherbakow, O. Tarabrin, D. Gavrychenko, G. Mazurenko, O. Chystikov P122 - Impact of FFP transfusion on VAP in ICU patients A. Vakalos, V. Avramidis P123 - Preoperative platelet function test and the thrombin generation assay are predictive for blood loss after cardiac surgery L. Kropman, L. In het Panhuis, J. Konings, D. Huskens, E. Schurgers, M. Roest, B. De Laat, M. Lance P124 - Rotational thromboelastometry versus standard coagulation tests before surgical interventions M. Durila, P. Lukas, M. Astraverkhava, J. Jonas P125 - Correction of impaired clot quality and stability by fibrinogen and activated prothrombin complex concentrate in a model of severe thrombocytopenia I. Budnik, B. Shenkman P126 - Assessment of point-of-care prothrombin time analyzer as a monitor after cardiopulmonary bypass H. Hayami, Y. Koide, T. Goto P127 - Disseminated intravascular coagulation (dic) is underdiagnosed in critically ill patients: do we need d-dimer measurements? R. Iqbal, Y. Alhamdi, N. Venugopal, S. Abrams, C. Downey, C. H. Toh, I. D. Welters P128 - Validity of the age-adjusted d-dimer cutoff in patients with COPD B. Bombay, J. M. Chauny, R. D. Daoust, J. L. Lessard, M. M. Marquis, J. P. Paquet P129 - A scoping review of strategies for prevention and management of bleeding following paediatric cardiopulmonary bypass surgery K. Siemens, D. Sangaran, B. J. Hunt, A. Durward, A. Nyman, I. A. Murdoch, S. M. Tibby P130 - Nadir hemoglobulin during cardiopulmonary bypass: impact on postoperative morbidity and mortality F. Ampatzidou, D. Moisidou, E. Dalampini, M. Nastou, E. Vasilarou, V. Kalaizi, H. Chatzikostenoglou, G. Drossos P131 - Red blood cell transfusion do not influence the prognostic value of RDW in critically ill patients S. Spadaro, A. Fogagnolo, T. Fiore, A. Schiavi, V. Fontana, F. Taccone, C. Volta P132 - Reasons for admission in the paediatric intensive care unit and the need for blood and blood products transfusions E. Chochliourou, E. Volakli, A. Violaki, E. Samkinidou, G. Evlavis, V. Panagiotidou, M. Sdougka P133 - The implementation of a massive haemorrhage protocol (mhp) for the management of major trauma: a ten year, single-centre study R. Mothukuri, C. Battle, K. Guy, G. Mills, P. Evans P134 - An integrated major haemorrhage protocol for pre-hospital and retrieval medical teams J. Wijesuriya, S. Keogh P135 - The impact of transfusion thresholds on mortality and cardiovascular events in patients with cardiovascular disease (non-cardiac surgery): a systematic review and meta-analysis A. Docherty, R. O\u2019Donnell, S. Brunskill, M. Trivella, C. Doree, L. Holst, M. Parker, M. Gregersen, J. Almeida, T. Walsh, S. Stanworth P136 - The relationship between poor pre-operative immune status and outcome from cardiac surgery is specific to the peri-operative antigenic threat S. Moravcova, J. Mansell, A. Rogers, R. A. Smith, C. Hamilton-Davies P137 - Impact of simple clinical practice guidelines for reducing post-operative atrial fibrillation after cardiac surgery. A. Omar, M. Allam, O. Bilala, A. Kindawi, H. Ewila P138 - Dexamethasone administration during cardiopulmonary bypass has no beneficial effects on elective postoperative cardiac surgery patients F. Ampatzidou, D. Moisidou, M. Nastou, E. Dalampini, A. Malamas, E. Vasilarou, G. Drossos P139 - Intra-aortic balloon counterpulsation in patients undergoing cardiac surgery (IABCS): preliminary results G. Ferreira, J. Caldas, J. Fukushima, E. A. Osawa, E. Arita, L. Camara, S. Zeferino, J. Jardim, F. Gaioto, L. Dallan, F. B. Jatene, R. Kalil Filho, .F Galas, L. A. Hajjar P140 - Effects of low-dose atrial natriuretic peptide infusion on cardiac surgery-associated acute kidney injury C. Mitaka, T. Ohnuma, T. Murayama, F. Kunimoto, M. Nagashima, T. Takei, M. Tomita P141 - Acute kidney injury influence on high sensitive troponin measurements after cardiac surgery A. Omar, K. Mahmoud, S. Hanoura, S. Sudarsanan, P. Sivadasan, H. Othamn, Y. Shouman, R. Singh, A. Al Khulaifi P142 - Complex evaluation of endothelial dysfunction markers for prognosis of outcomes in patients undergoing cardiac surgery I. Mandel, S. Mikheev, I. Suhodolo, V. Kiselev, Y. Svirko, Y. Podoksenov P143 - New-onset atrial fibrillation in intensive care: incidence, management and outcome S. A. Jenkins, R. Griffin P144 - One single spot measurement of the sublingual microcirculation during acute pulmonary hypertension in a pig model of shock M. S. Tovar Doncel, A. Lima, C. Aldecoa, C. Ince P145 - Assessment of levosimendan as a therapeutic option to recruit the microcirculation in cardiogenic shock \u2013 initial experience in cardiac ICU A. Taha, A. Shafie, M. Mostafa, N. Syed, H. Hon P146 - Terlipressin vs. norepinephrine in the Potential Multiorgan Donor(PMD) F. Righetti, E. Colombaroli, G. Castellano P147 - Echocardiography in the potential heart donor exposed to substitution hormonotherapy F. Righetti, E. Colombaroli P148 - Machine learning can reduce rate of monitor alarms M. Hravnak, L. C. Chen, A. D. Dubrawski, G. C. Clermont, M. R. Pinsky P149 - Peripherally inserted central catheters placed in the ICU S. Gonzalez, D. Macias, J. Acosta, P. Jimenez, A. Loza, A. Lesmes, F. Lucena, C. Leon P150 - Recordings of abnormal central venous pressure waveform morphology during an episode of pulmonary hypertension in a porcine shock model M. S. Tovar Doncel, C. Ince, C. Aldecoa, A. Lima P151 - Ultrasound guided central venous access technique among French intensivists M. Bastide, J. Richecoeur, E. Frenoy, C. Lemaire, B. Sauneuf, F. Tamion, S. Nseir, D. Du Cheyron, H. Dupont, J. Maizel P152 - Predictive ability of the Pv-aCO2 gap in patients with shock M. Shaban, R. Kolko, N. Salahuddin, M. Sharshir, M. AbuRageila, A. AlHussain P153 - Comparison of echocardiography and pulmonary artery catheter measurements of hemodynamic parameters in critical ill patients P. Mercado, J. Maizel, L. Kontar, D. Titeca, F. Brazier, A. Riviere, M. Joris, T. Soupison, B. De Cagny, M. Slama P154 - The volume clamp method for noninvasive cardiac output measurement in postoperative cardiothoracic surgery patients: a comparison with intermittent pulmonary artery thermodilution J. Wagner, A. K\u00f6rner, M. Kubik, S. Kluge, D. Reuter, B. Saugel P155 - Hemodynamic monitoring in patients with septic shock (SS) \u2013 CPCCO (continuous pulse contour cardiac output) vs. TEE (transesophageal echocardiography) E. Colombaroli, F. Righetti, G. Castellano P156 - Cardiac output measurement with transthoracic echocardiography in critically ill patients: a pragmatic clinical study T. Tran, D. De Bels, A. Cudia, M. Strachinaru, P. Ghottignies, J. Devriendt, C. Pierrakos P157 - Left ventricular outflow tract velocity time integral correlates with stroke volume index in mechanically ventilated patients \u00d3. Mart\u00ednez Gonz\u00e1lez, R. Blancas, J. Luj\u00e1n, D. Ballesteros, C. Mart\u00ednez D\u00edaz, A. N\u00fa\u00f1ez, C. Mart\u00edn Parra, B. L\u00f3pez Matamala, M. Alonso Fern\u00e1ndez, M. Chana P158 - Transpulmonary thermodilution (TPTD) derived from femoral vs. jugular central venous catheter: validation of a previously published correction formula and a proprietary correction formula for global end-diastolic volume index (GEDVI) W. Huber, M. Eckmann, F. Elkmann, A. Gruber, I. Klein, R. M. Schmid, T. Lahmer P160 - Dynamic arterial elastance calculated with lidcoplus monitor does not predict changes in arterial pressure after a fluid challenge in postsurgical patients D. Bastoni, H. Aya, L. Toscani, L. Pigozzi, A. Rhodes, M. Cecconi P159 - Venous return driving pressure and resistance in acute blood volume changes P. W. Moller, S. Sondergaard, S. M. Jakob, J. Takala, D. Berger P160 - Dynamic arterial elastance calculated with lidcoplus monitor does not predict changes in arterial pressure after a fluid challenge in postsurgical patients D. Bastoni, H. Aya, L. Toscani, L. Pigozzi, A. Rhodes, M. Cecconi P161 - Analysis of duration of post-operative goal-directed therapy protocol C. Ostrowska, H. Aya, A. Abbas, J. Mellinghoff, C. Ryan, D. Dawson, A. Rhodes, M. Cecconi P162 - Hemodynamic optimization \u2013 back to square one? M. Cronhjort, O. Wall, E. Nyberg, R. Zeng, C. Svensen, J. M\u00e5rtensson, E. Joelsson-Alm P163 - Effectiveness of fluid thoracic content measurement by bioimpedance guiding intravascular volume optimization in patients with septic shock M. Aguilar Arzapalo, L. Barradas, V. Lopez, M. Cetina P164 - A systematic review on the role of internal jugular vein ultrasound measurements in assessment of volume status in critical shock patients N. Parenti, C. Palazzi, L. A. Amidei, F. B. Borrelli, S. C. Campanale, F. T. Tagliazucchi, G. S. Sedoni, D. L. Lucchesi, E. C. Carella, A. L Luciani P165 - Importance of recognizing dehydration in medical Intensive Care Unit M. Mackovic, N. Maric, M. Bakula P166 - Effect of volume for a fluid challenge in septic patients H. Aya, A. Rhodes, R. M. Grounds, N. Fletcher, M. Cecconi P167 - Fluid bolus practices in a large Australian intensive care unit B. Avard, P. Zhang P168 - Liberal late fluid management is associated with longer ventilation duration and worst outcome in severe trauma patients: a retrospective cohort of 294 patients M. Mezidi, J. Charbit, M. Ould-Chikh, P. Deras, C. Maury, O. Martinez, X. Capdevila P169 - Association of fluids and outcomes in emergency department patients hospitalized with community-acquired pneumonia P. Hou, W. Z. Linde-Zwirble, I. D. Douglas, N. S. Shapiro P170 - Association of positive fluid balance with poor outcome in medicosurgical ICU patients A. Ben Souissi, I. Mezghani, Y. Ben Aicha, S. Kamoun, B. Laribi, B. Jeribi, A. Riahi, M. S. Mebazaa P171 - Impact of fluid balance to organ dysfunction in critically ill patients C. Pereira, R. Marinho, R. Antunes, A. Marinho P172 - Volume bolus in ICU patients: do we need to balance our crystalloids? M. Crivits, M. Raes, J. Decruyenaere, E. Hoste P173 - The use of 6\u00a0% HES solution do not reduce total fluid requirement in the therapy of patients with burn shock V. Bagin, V. Rudnov, A. Savitsky, M. Astafyeva, I. Korobko, V. Vein P174 - Electron microscopic assessment of acute kidney injury in septic sheep resuscitated with crystalloids or different colloids T. Kampmeier , P. Arnemann, M. Hessler, A. Wald, K. Bockbreder, A. Morelli, H. Van Aken, S. Rehberg, C. Ertmer P175 - Alterations of conjunctival microcirculation in a sheep model of haemorrhagic shock and resuscitation with 0.9\u00a0% saline or balanced tetrastarch P. Arnemann, M. Hessler, T. Kampmeier, S. Rehberg, H. Van Aken, C. Ince, C. Ertmer P176 - A single centre nested pilot study investigating the effect of using 0.9\u00a0% saline or Plasma-Lyte 148 \u00ae as crystalloid fluid therapy on gastrointestinal feeding intolerance in mechanically ventilated patients receiving nasogastric enteral nutrition S. Reddy, M. Bailey, R. Beasley, R. Bellomo, D. Mackle, A. Psirides, P. Young P177 - A single centre nested pilot study investigating the effect on post-operative bleeding of using 0.9\u00a0% saline or Plasma-Lyte\u00ae 148 as crystalloid fluid therapy in adults in ICU after heart surgery S. Reddy, M. Bailey, R. Beasley, R. Bellomo, D. Mackle, P. Young P178 - Extreme hypernatremia and sepsis in a patient with Huntington\u2019s dementia: a conundrum in fluid management H. Venkatesh, S. Ramachandran, A. Basu, H. Nair P179 - Diagnosis and management of severe hypernatraemia in the critical care setting S. Egan, J. Bates P180 - Correlation between arterial blood gas and electrolyte disturbances during hospitalization and outcome in critically ill patients S. Oliveira, N. R. Rangel Neto, F. Q. Reis P181 - Missing the \u201cI\u201d in MUDPILES \u2013 a rare cause of high anion gap metabolic acidosis (HAGMA) C. P. Lee, X. L. Lin, C. Choong , K. M. Eu, W. Y. Sim , K. S. Tee, J. Pau , J. Abisheganaden P182 - Plasma NGAL and urinary output: potential parameters for early initiation of renal replacement therapy K. Maas, H. De Geus P183 - Renal replacement therapy for critically ill patients: an intermittent continuity E. Lafuente, R. Marinho, J. Moura, R. Antunes, A. Marinho P184 - A survey of practices related to renal replacement therapy in critically ill patients in the north of England. T. E. Doris, D. Monkhouse, T. Shipley, S. Kardasz, I Gonzalez P185 - High initiation creatinine associated with lower 28-day mortality in critically ill patients necessitating continuous renal replacement therapy S. Stads, A. J. Groeneveld P186 - The impact of Karnofsky performance scale on outcomes in acute kidney injury patients receiving renal replacement therapy on the intensive care unit I. Elsayed, N. Ward, A. Tridente, A. Raithatha P187 - Severe hypophosphatemia during citrate-anticoagulated CRRT A. Steuber, C. Pelletier, S. Schroeder, E. Michael, T. Slowinski, D. Kindgen-Milles P188 - Citrate regional anticoagulation for post dilution continuous renal replacement therapy S. Ghabina P189 - Citrate 18\u00a0mmol/l improves anticoagulation during RRT with adsorbing filters F. Turani, A. Belli, S. Busatti, G. Barettin, F. Candidi, F. Gargano, R. Barchetta, M. Falco P190 - Calcium gluconate instead of calcium chloride in citrate-anticoagulated CVVHD O. Demirkiran, M. Kosuk, S. Bozbay P191 - Enhanced clearance of interleukin-6 with continuous veno-venous haemodialysis (CVVHD) using Ultraflux EMiC2 vs. Ultraflux AV1000S V. Weber, J. Hartmann, S. Harm, I. Linsberger, T. Eichhorn, G. Valicek, G. Miestinger, C. Hoermann P192 - Removal of bilirubin with a new adsorbent system: in vitro kinetics S. Faenza, D. Ricci, E. Mancini, C. Gemelli, A. Cuoghi, S. Magnani, M. Atti P193 - Case series of patients with severe sepsis and septic shock treated with a new extracorporeal sorbent T. Laddomada, A. Doronzio, B. Balicco P194 - In vitro adsorption of a broad spectrum of inflammatory mediators with CytoSorb\u00ae hemoadsorbent polymer beads M. C. Gruda, P. O\u2019Sullivan, V. P. Dan, T. Guliashvili, A. Scheirer, T. D. Golobish, V. J. Capponi, P. P. Chan P195 - Observations in early vs. late use of cytosorb therapy in critically ill patients K. Kogelmann, M. Dr\u00fcner, D. Jarczak P196 - Oxiris membrane decreases endotoxin during rrt in septic patients with basal EAA\u2009>\u20090,6 F. Turani, A. B. Belli, S. M. Martni, V. C. Cotticelli, F. Mounajergi, R. Barchetta P197 - An observational prospective study on the onset of augmented renal clearance: the first report S. Morimoto, H. Ishikura P198 - An ultrasound- guided algorithm for the management of oliguria in severe sepsis I. Hussain, N. Salahuddin, A. Nadeem, K. Ghorab, K. Maghrabi P199 - Ultrasound in acute kidney injury (aki). First findings of farius, an education-programme in structural ultrasonography S. K. Kloesel, C. Goldfuss, A. Stieglitz, A. S. Stieglitz, L. Krstevska, G. Albuszies P200 - Effectiveness of renal angina index score predicting acute kidney injury on critically ill patients M. Aguilar Arzapalo, L. Barradas, V. Lopez, A. Escalante, G. Jimmy, M. Cetina P201 - Time length below blood pressure thresholds and progression of acute kidney injury in critically ill patients with or without sepsis: a retrospective, exploratory cohort study J. Izawa, T. Iwami, S. Uchino, M. Takinami, T. Kitamura, T. Kawamura P202 - Anaemia does not affect renal recovery in acute kidney injury J. G. Powell-Tuck, S. Crichton, M. Raimundo, L. Camporota, D. Wyncoll, M. Ostermann P203 - Estimated glomerular filtration rate based on serum creatinine: actual practice in Dutch ICU\u2019s A. Hana, H. R. De Geus P204 - Comparison of estimated glomerular filtration rate calculated by mdrd, ckd-epi-serum-creatinine and ckd-epi-cystatin-c in adult critically ill patients H. R. De Geus, A. Hana P205 - Early diagnosis of septic acute kidney injury in medical critical care patients with a urine cell cycle arrest marker: insulin like growth factor binding protein-7 (IGFBP-7) M. Aydogdu, N. Boyaci, S. Yuksel, G. Gursel, A. B. Cayci Sivri P206 - Urinary neutrophil gelatinase-associated lipocalin as early biomarker of severe acute kidney injury in intensive care J. Meza-M\u00e1rquez, J. Nava-L\u00f3pez, R. Carrillo-Esper P207 - Shrunken pore syndrome is associated with a sharp rise in mortality in patients undergoing elective coronary artery bypass grafting A. Dardashti, A. Grubb P208 - The biomarker nephrocheck\u2122 can discriminate the septic shock patients with an akin 1 or 2 acute renal failure who will not progress toward the akin 3 level J. Maizel, M. Wetzstein, D. Titeca, L. Kontar, F. Brazier, B. De Cagny, A. Riviere, T. Soupison, M. Joris, M. Slama P209 - A worldwide multicentre evaluation of acute kidney injury in septic and non-septic critically ill patients: the intensive care over nations (icon) audit E. Peters, H. Njimi, P. Pickkers, J. L. Vincent P210 - Does enhanced recovery after surgery reduce the incidence of acute kidney injury in those undergoing major gynae-oncological surgery? M. Waraich , J. Doyle, T. Samuels, L. Forni P211 - Identification of risk factors for the development of acute kidney injury after lower limb arthroplasty N. Desai, R. Baumber, P. Gunning, A. Sell P212 - Incidences and associations of acute kidney injury after major trauma S. Lin, H. Torrence, M. O\u2019Dwyer, C. Kirwan, J. Prowle P213 - Acute kidney injury of major trauma patients T Kim P214 - Trajectory of serum creatinine after major surgery and the diagnosis of acute kidney injury M. E. O\u2019Connor, R. W. Hewson, C. J. Kirwan, R. M. Pearse, J. Prowle P215 - Epidemiology of acute kidney injury after cardiac surgery. A single center retrospective study S. Hanoura , A. Omar, H. Othamn, S. Sudarsanan , M. Allam, M. Maksoud, R. Singh, A. Al Khulaifi P216 - Post-operative acute kidney injury after major non-cardiac surgery and its association with death in the following year M. E. O\u2019Connor, R. W. Hewson, C. J. Kirwan, R. M. Pearse, J. Prowle P217 - Factors affecting acute renal failure in intensive care unit and effect of these factors on mortality O. Uzundere, D. Memis , M. \u00ddnal, A. , N. Turan P218 - Results of the live kidney transplantations according to national data of turkish organ and tissue information system M. A. Aydin, H. Basar, I. Sencan, A. Kapuagasi, M. Ozturk, Z. Uzundurukan, D. Gokmen, A. Ozcan, C. Kaymak P219 - Anaesthesia procedure and intensive therapy in patients with neck phlegmon V. A. Artemenko, A. Budnyuk P220 - Nasal high flow oygen for acute respiratory failure: a systematic review R. Pugh , S. Bhandari P221 - Setting optimal flow rate during high flow nasal cannula support: preliminary results T. Mauri, C. Turrini, T. Langer, P. Taccone, C. A. Volta, C. Marenghi, L. Gattinoni, A. Pesenti P222 - Dose to dose consistency across two different gas flow rates using cystic fibrosis and normal adult breathing profiles during nasal high flow oxygen therapy L. Sweeney, A . O\u2019 Sullivan, P. Kelly, E. Mukeria, R. MacLoughlin P223 - Final results of an evaluation of airway medix closed suction system compared to a standard closed suction system M. Pfeffer, J. T. Thomas, G. B. Bregman, G. K. Karp, E. K. Kishinevsky, D. S. Stavi, N. A. Adi P224 - Different cuff materials and different leak tests - one size does not fit all T. Poropat, R. Knafelj P225 - Observational study on the value of the cuff-leak test and the onset of upper airway obstruction after extubation E. Llopart, M. Batlle, C. De Haro, J. Mesquida, A. Artigas P226 - A device for emergency transtracheal lung ventilation D. Pavlovic, L. Lewerentz, A. Spassov, R. Schneider P227 - Long-term outcome and health-related quality of life in patients discharged from the intensive care unit with a tracheostomy and with or without prolonged mechanical ventilation S. De Smet, S. De Raedt, E. Derom, P Depuydt, S. Oeyen, D. Benoit, J. Decruyenaere P228 - Ultrasound-guided percutaneous dilational tracheostomy versus bronchoscopy-guided percutaneous dilational tracheostomy in critically ill patients (trachus): a randomized clinical trial A. Gobatto, B. Bese, P. Tierno, L. Melro, P. Mendes, F. Cadamuro, M. Park, L. M. Malbouisson P229 - Is it safe to discharge patients with tracheostomy from the ICU to the ward? B. C. Civanto, J. L. Lopez, A. Robles, J. Figueira, S. Yus, A. Garcia P230 - The application of tracheostomy in children in ICU A. Oglinda, G. Ciobanu, C. Oglinda, L. Schirca, T. Sertinean, V. Lupu P231 - The impact of passive humidifiers on aerosol drug delivery during mechanical ventilation P. Kelly, A. O\u2019Sullivan, L. Sweeney, R. MacLoughlin P232 - Evaluation of vibrating mesh and jet nebuliser performance at two different attachment setups in line with a humidifier nebuliser system A. O\u2019Sullivan, P. Kelly, L. Sweeney, E. Mukeria, M. Wolny , R. MacLoughlin P233 - Psv-niv versus cpap in the treatment of acute cardiogenic pulmonary edema A. Pagano, F. Numis, G. Vison, L. Saldamarco, T. Russo, G. Porta, F. Paladino P234 - Noninvasive ventilation in patients with haematologic malignancy: a retrospective review C. Bell, J. Liu, J. Debacker, C. Lee, E. Tamberg, V. Campbell, S. Mehta P235 - Use of non-invasive ventilation in infectious diseases besides classical indications A. Silva-Pinto, A. Sarmento, L. Santos P236 - The impact of fragility on noninvasive mechanical ventilation application and results in the ICU \u00dd. Kara, F. Y\u00fdld\u00fdr\u00fdm, A. Zerman, Z. G\u00fcll\u00fc, N. Boyac\u00fd, B. Basar\u00fdk Aydogan, \u00dc. Gayg\u00fds\u00fdz, K. G\u00f6nderen, G. Ar\u00fdk, M. Turkoglu, M. Aydogdu, G. Aygencel, Z. \u00dclger, G. Gursel P237 - Effects of metabolic alkalosis on noninvasive ventilation success and ICU outcome in patients with hypercapnic respiratory failure N. Boyac\u00fd, Z. Is\u00fdkdogan, \u00d6. \u00d6zdedeoglu, Z. G\u00fcll\u00fc, M. Badoglu, U. Gayg\u00fds\u00fdz, M. Aydogdu, G. Gursel P238 - Asynchrony index and breathing patterns of acute exacerbation copd patients assisted with noninvasive pressure support ventilation and neurally adjusted ventilatory assist N. Kongpolprom, C. Sittipunt P239 - High frequency jet ventilation for severe acute hypoxemia A. Eden, Y. Kokhanovsky, S. Bursztein \u2013 De Myttenaere, R. Pizov P240 - HFOV revisited: a 7\u00a0year retrospective analysis of patients receiving HFOV who met oscillate trial entry criteria L. Neilans, N. MacIntyre P241 - Implementation of a goal-directed mechanical ventilation order set driven by respiratory therapists can improve compliance with best practices for mechanical ventilation M. Radosevich, B. Wanta, V. Weber, T. Meyer, N. Smischney, D. Brown, D. Diedrich P242 - A reduction in tidal volumes for ventilated patients on ICU calculated from IBW. can it minimise mortality in comparison to traditional strategies? A . Fuller, P. McLindon, K. Sim P243 - Predictive value of lung aeration scoring using lung ultrasound in weaning failure M. Shoaeir, K. Noeam, A. Mahrous, R. Matsa, A. Ali P244 - Conventional versus automated weaning from mechanical ventilation using SmartCare\u2122 C. Dridi, S. Koubaji, S. Kamoun, F. Haddad, A. Ben Souissi, B. Laribi, A. Riahi, M. S. Mebazaa P245 - Ultrasonographic evaluation protocol for weaning from mechanichal ventilation A. P\u00e9rez-Calatayud, R. Carrillo-Esper, A. Zepeda-Mendoza, M. Diaz-Carrillo, E. Arch-Tirado P246 - Diaphragm ultrasonography: a method for weaning patients from mechanical ventilation S. Carbognin, L. Pelacani, F. Zannoni, A. Agnoli, G. Gagliardi P247 - Dorsal diaphragmatic excursion tracks transpulmonary pressure in ventilated ARDS patients: a potential non-invasive indicator of lung recruitment? R. Cho, A. Adams , S. Lunos, S. Ambur, R. Shapiro, M. Prekker P248 - Pulse oximetry in the icu patient: is the perfusion index of any value? M. Thijssen, L. Janssen, N. Foudraine P249 - Ventilation is a better assessment of respiratory status than EtCO2 C. J. Voscopoulos, J. Freeman P250 - Evaluation of the relationship between non-invasive minute ventilation and end-tidal CO2 in patients undergoing general vs spinal anesthesia C. J. Voscopoulos, J. Freeman, E. George P251 - Respiratory volume monitoring provides early warning of respiratory depression and can be used to reduce false alarms in non-intubated patients C. J. Voscopoulos, D. Eversole, J. Freeman, E. 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Windisch P257 - Transpulmonary pressure in a model with elastic recoiling lung and expanding chest wall P. Persson, S. Lundin, O. Stenqvist P258 - Lactate in pleural and abdominal effusion G. Porta, F. Numis, C. S. Serra, A. P. Pagano, M. M. Masarone, L. R. Rinaldi, A. A. Amelia, M. F. Fascione, L. A. Adinolfi, E. R. Ruggiero P259 - Outcome of patients admitted to the intensive care with pulmonary fibrosis F. Asota, K. O\u2019Rourke, S. Ranjan, P. Morgan P260 - Sedation and analgesia practice in extra-corporeal membrane oxygenation (ECMO)-treated patients with acute respiratory distress syndrome (ARDS): a retrospective study J. W. DeBacker, E. Tamberg, L. O\u2019Neill, L. Munshi, L. Burry, E. Fan, S. Mehta P261 - Characteristics and outcomes of patients deemed not eligible when referred for veno-venous extracorporeal membrane oxygenation (vv-ECMO) S. Poo, K. Mahendran, J. Fowles, C. Gerrard, A. Vuylsteke P262 - The SAVE SMR for veno-arterial ECMO R. Loveridge, C. Chaddock, S. Patel, V. Kakar, C. Willars, T. Hurst, C. Park, T. Best, A. Vercueil, G. Auzinger P263 - A simplified score to predict early (48\u00a0h) mortality in patients being considered for VA-ECMO A. Borgman, A. G. Proudfoot, E. Grins, K. E. Emiley, J. Schuitema, S. J. Fitch, G. Marco, J. Sturgill, M. G. Dickinson, M. Strueber, A. Khaghani, P. Wilton, S. M. Jovinge P264 - Lung function six months post extra corporeal membrane oxygenation (ECMO) for severe acute respiratory failure in adult survivors C. Sampson, S. Harris-Fox P265 - Bicarbonate dialysis removes carbon dioxide in hypoventilated rodents. M. E. Cove, L. H. Vu, A. Sen, W. J. Federspiel, J. A. Kellum P266 - Procalcitonin as predictor of primary graft dysfunction and mortality in post-lung transplantation C. Mazo Torre, J. Riera, S. Ramirez, B. Borgatta, L. Lagunes, J. Rello P267 - New molecular biomarkers of acute respiratory distress syndrome in abdominal sepsis A. K. Kuzovlev, V. Moroz, A. Goloubev, S. Polovnikov, S. Nenchuk P268 - Tight junction\u2019s proteins claudin -5 and regulation by tnf in experimental murine lung injury model of ali/ards V. Karavana, C. Glynos, A. Asimakos, K. Pappas, C. Vrettou, M. Magkou, E. Ischaki, G. Stathopoulos, S. Zakynthinos P269 - Cell counts in endobronchial aspirate to assess airway inflammation in ARDS patients: a pilot study S. Spadaro, I. Kozhevnikova, F. Dalla Corte, S. Grasso, P. Casolari, G. Caramori, C. Volta P270 - Epidemiological and clinical profile of patients with acute respiratory distress syndrome in the surgical intensive care unit surgical, hospital JRA, Antananarivo T. Andrianjafiarinoa, T. Randriamandrato, T. Rajaonera P271 - Effect of high PEEP after recruitment maneuver on right ventricular function in ARDS. Is it good for the lung and for the heart? S. El-Dash, ELV Costa, MR Tucci, F Leleu, L Kontar, B. De Cagny, F. Brazier, D. Titeca, G. Bacari-Risal, J. Maizel, M. Amato, M. Slama P272 - Effect of recruitment maneuver on left ventricular systolic strain P. Mercado, J. Maizel, L. Kontar, D. Titeca, F. Brazier, A. Riviere, M. Joris, T. Soupison, B. De Cagny, S. El Dash, M. Slama P273 - Inhaled nitric oxide \u2013 is switching supplier cost effective? Remmington, A. Fischer, S. Squire, M. Boichat P274 - Epidemiological study of severe acute pancreatitis in Japan, comparison of the etiology and the patient outcomes on 1159 patients. H. Honzawa, H. Yasuda, T. Adati, S. Suzaki, M. Horibe, M. Sasaki, M. Sanui P275 - Extracorporeal liver support therapy. Experience in an intensive care unit R. Marinho, J. Daniel, H. Miranda, A. Marinho P276 - Accuracy of mortality prediction models in acute versus acute-on-chronic liver failure in the intensive care setting K. Milinis, M. Cooper, G. R. Williams, E. McCarron, S. Simants, I. Patanwala, I. Welters P277 - Risk of coronary artery disease in patients with chronic liver disease: a population based cohort study Y. 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Dias, S. L. Fernandes P284 - Can ventilator derived energy expenditure measurements replace indirect calorimetry? T. Oshima, S. Graf, C. Heidegger, L. Genton, V. Karsegard, Y. Dupertuis, C. Pichard P285 - Revisiting the refeeding syndrome: results of a systematic review N. Friedli, Z. Stanga, B. Mueller, P. Schuetz P286 - Compliance with the new protocol for parenteral nutrition in our ICU L. Vandersteen, B. Stessel, S. Evers, A. Van Assche, L. Jamaer, J. Dubois P287 - Nutrition may be another treatment in the intensive care unit where less is more? R. Marinho, H. Castro, J. Moura, J. Valente, P. Martins, P. Casteloes, C. Magalhaes, S. Cabral, M. Santos, B. Oliveira, A. Salgueiro, A. Marinho P288 - Should we provide more protein to critically ill patients? R. Marinho, M. Santos, E. Lafuente, H. Castro, S. Cabral, J. Moura, P. Martins, B. Oliveira, A. Salgueiro, S. Duarte, S. Castro, M. Melo, P. Casteloes, A. Marinho P289 Protein provision in an adult intensive care unit S. Gray P290 - Prevalence and clinical outcomes of vitamin d deficiency in the medical critically ill patients in Songklanagarind hospital K. Maipang, R. Bhurayanontachai P291 - Vitamin d deficiency strongly predicts adverse medical outcome across different medical inpatient populations: results from a prospective study L. G. Gr\u00e4del, P. Sch\u00fctz P292 - Omega-3 fatty acids in patients undergoing cardiac surgery: a systematic review and meta-analysis P. Langlois, W. Manzanares P293 - Can 5-hydroxytriptophan prevent post-traumatic stress disorder in critically ill patients? R. Tincu, C. Cobilinschi, D. Tomescu, Z. Ghiorghiu, R. Macovei P294 - Parenteral selenium in the critically ill: an updated systematic review and meta-analysis W. Manzanares, P. Langlois, M. Lemieux, G. Elke, F. Bloos, K. Reinhart, D. Heyland P295 - Probiotics in the critically ill: an updated systematic review and meta-analysis P. Langlois, M. Lemieux, I. Aramendi, D. Heyland, W. Manzanares P296 - Diabetes with hyperglycemic crisis episodes may be associated with higher risk of pancreatic cancer: a population-based cohort study Y. Su P297 - Incidence of hypoglycemia in an intensive care unit depending on insulin protocol R. Marinho, N. Babo, A. Marinho P298 - Severity of the diseases is two-dimensionally correlated to blood glucose, including blood glucose variability, especially in moderately to severely ill patients with glucose intolerance. M. Hoshino, Y. Haraguchi, S. Kajiwara, T. Mitsuhashi, T. Tsubata, M. Aida P299 - A study of glycemic control by subcutaneous glargine injection transition from continuous regular insulin infusion in critically ill patients T. Rattanapraphat, R. Bhurayanontachai, C. Kongkamol, B. Khwannimit P300 - Glycemic control in Portuguese intensive care unit R. Marinho, M. Santos, H. Castro, E. Lafuente, A. Salgueiro, S. Cabral, P. Martins, J. Moura, B. Oliveira, M. Melo, B. Xavier, J. Valente, C. Magalhaes, P. Casteloes, A. Marinho P301 - Impact of hyperglycemia duration on the day of operation on short-term outcome of cardiac surgery patients D. Moisidou, F. Ampatzidou, C. Koutsogiannidis, M. Moschopoulou, G. Drossos P302 - Lactate levels in diabetic ketoacidosis patients at ICU admissions G. Taskin, M. \u00c7akir, AK G\u00fcler, A. Taskin, N. \u00d6cal, S. \u00d6zer, L. Yamanel P303 - Intensive care implications of merging heart attack centre units in London J. M. Wong, C. Fitton, S. Anwar, S. Stacey P304 - Special characteristics of in-hospital cardiac arrests M. Aggou, B. Fyntanidou, S. Patsatzakis, E. Oloktsidou, K. Lolakos, E. Papapostolou, V. Grosomanidis P305 - Clinical evaluation of ICU-admitted patients who were resuscitated in the general medicine ward S. Suda , T. Ikeda, S. Ono, T. Ueno, Y. Izutani P306 - Serious game evaluation of a one-hour training basic life support session for secondary school students: new tools for future bystanders S. Gaudry, V. Desailly, P. Pasquier, PB Brun, AT Tesnieres, JD Ricard, D. Dreyfuss, A. Mignon P307 - Public and clinical staff perceptions and knowledge of CPR compared to local and national data J. C White, A. Molokhia, A. Dean, A. Stilwell, G. Friedlaender P308 Dispatcher-assisted telephone cardiopulmonary resuscitation using a French-language compression-ventilation pediatric protocol M. Peters, S. Stipulante, A. Delfosse, AF Donneau, A. Ghuysen P309 Dantrolene versus amiodarone for resuscitation \u2013 an experimental study C. Feldmann, D. Freitag, W. Dersch, M. Irqsusi, D. Eschbach, T. Steinfeldt, H. Wulf, T. Wiesmann P310 Long term survival and functional neurological outcome in comatose survivors undergoing therapeutic hypothermia N. Kongpolprom, J. Cholkraisuwat P311 Impact of kidney disease on mortality and neurological outcome in out-of-hospital cardiac arrest: a prospective observational study S. Beitland , E. Nakstad, H. St\u00e6r-Jensen , T. Dr\u00e6gni , G. Andersen , D. Jacobsen , C. Brunborg, B. Waldum-Grevbo , K. Sunde P312 ICU dependency of patients admitted after primary percutaneous coronary intervention (PPCI) following out of the hospital cardiac arrest K. Hoyland, D. Pandit P313 Prognostic indicators and outcome prediction model for patients with return of spontaneous circulation from cardiopulmonary arrest: comprehensive registry of in-hospital intensive care on OHCA survival (critical) study in Osaka, Japan K. Hayakawa P314 Cerebral oxygen saturation during resuscitation in a porcine model of cardiac arrest E. Oloktsidou, K. Kotzampassi, B. Fyntanidou, S. Patsatzakis, L. Loukipoudi, E. Doumaki, V. Grosomanidis P315 Presumption of cardiopulmonary resuscitation for sustaining cerebral oxidation using regional cerebral saturation of oxygen: observational cohort study (press study) H. Yasuda P316 EEG reactivity in patients after cardiac arrest: a close look at stimuli MM Admiraal, M. Van Assen, MJ Van Putten, M. Tjepkema-Cloostermans, AF Van Rootselaar, J. 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Shin P328 Failure in neuroprotection of remote limb ischemic post conditioning in the hippocampus of a gerbil model of transient cerebral ischemia J. Cho, J. B. Moon, C. W. Park, T. G. Ohk, M. C. Shin P329 Brain death and admission diagnosis in neurologic intensive care unit, a correlation? A Marudi, S Baroni, A Gaspari, E Bertellini P330 Brain magnetic resonance imaging findings in patients with septic shock G. Orhun, E. Senturk, P. E. Ozcan, S. Sencer, C. Ulusoy, E. Tuzun, F . Esen P331 Benefits of L-carnitine in valproic acid induced encephalopathy R. Tincu, C. Cobilinschi, D. Tomescu, Z. Ghiorghiu, R. Macovei P332Automatic analysis of EEG reactivity in comatose patients M. Van Assen, M. M. Admiraal, M. J. Van Putten, M. Tjepkema-Cloostermans, A. F. Van Rootselaar, J. Horn P333 Usefulness of common ICU severity scoring systems in predicting outcome after spontaneous intracerebral hemorrhage M. Fallenius, M. B. Skrifvars, M. Reinikainen, S. Bendel, R. Raj P334 Evalution of patients with suspected subarachnoid haemorrhage and negative ct imaging M. Abu-Habsa, C. Hymers, A. Borowska, H. Sivadhas, S. Sahiba, S. Perkins P335 Timing of endovascular and surgical treatment for aneurysmal subarachnoid haemorrhage: early but not so fast. J. Rubio, J. A. Rubio, R. Sierra P336 Red blood cell transfusion in aneurysmal subarachnoid hemorrhage \u2013 the Sahara cohort study S. English, M. Chasse, A. Turgeon, F. Lauzier, D. Griesdale, A. Garland, D. Fergusson, R. Zarychanski, A. Tinmouth, C. Van Walraven, K. Montroy, J. Ziegler, R. Dupont Chouinard, R. Carignan, A. Dhaliwal, C. Lum, J. Sinclair, G. Pagliarello, L. McIntyre P337 - Aneurysmal subarachnoid hemorrhage and anemia: a canadian multi-centre retrospective cohort study S. English, M. Chasse, A. Turgeon, F. Lauzier, D. Griesdale, A. Garland, D. Fergusson, R. Zarychanski, A. Tinmouth, C. Van Walraven, K. Montroy, J. Ziegler, R. Dupont Chouinard, R. Carignan, A. Dhaliwal, C. Lum, J. Sinclair, G. Pagliarello, L. McIntyre P338 - Does the neutrophil-to-lymphocyte (NLR) ratio predict symptomatic vasospasm or delayed cerebral ischemia (DCI) after aneurysmal subarachnoid haemorrhage (SAH)? T. Groza, N. Moreau, D. Castanares-Zapatero, P. Hantson P339 - ICU-acquired infections in aneurysmal subarachnoid hemorrhage patients: impact on ICU and hospital length of stay M. Carbonara , F. Ortolano, T. Zoerle, S. Magnoni, S. Pifferi, V. Conte, N. Stocchetti P340 - Cerebral metabolic effects of normobaric hyperoxia during the acute phase of aneurysmal subarachnoid hemorrhage L. Carteron, T. Suys, C. Patet, H. Quintard, M. Oddo P341 - Postoperative care for elective craniotomy: where is best done? J. A. Rubio, J. Rubio, R. Sierra P342 - 5-year follow-up of patients after transplantation of organs from donors from neurocritical care V. Spatenkova, E. Pokorna, P. Suchomel P343 - Evaluation of levetiracetam pharmacokinetics after severe traumatic brain injury in neurocritical care patients at a level one trauma center N. Ebert, J. Jancik, H. Rhodes P344 - Model based time series cluster analysis to determine unique patient states in traumatic brain injury T. Bylinski, C. Hawthorne, M. Shaw, I. Piper, J. Kinsella P345 - Brain compartment monitoring capabilities from ICP to BI (bioimpedance) during HS (hypertonic saline) administration. State of art simulation outcome depending on brain swelling type A. K. Kink , I. R. R\u00e4tsep P346 - Transfusion of red blood cells in patients with traumatic brain injury admitted to Canadian trauma health centers: a multicenter cohort study A. Boutin, L. Moore, M. Chasse, R. Zarychanski, F. Lauzier, S. English, L. McIntyre, J. Lacroix, D. Griesdale, P. Lessard-Bonaventure, A. F. Turgeon P347 - Hemoglobin thresholds and red blood cell transfusions in adult patients with moderate or severe traumatic brain injury: a retrospective cohort study A. Boutin, L. Moore, R. Green, P. Lessard-Bonaventure, M. Erdogan, M. Butler, F. Lauzier, M. Chasse, S. English, L. McIntyre, R. Zarychanski, J. Lacroix, D. Griesdale, P. Desjardins, D. A. Fergusson, A. F. Turgeon P348 - Characteristics of patients with gunshot wounds to the head - an observational Brazilian study B. Goncalves, B. Vidal, C. Valdez, A. C. Rodrigues, L. Miguez, G. Moralez P349 - Base excess as predictor for ICU admission and the injury severity in blunt trauma patients T. Hong P350 - Enhancement of usual emergency department care with proadrenomedullin to improve outcome prediction - Results from the multi-national, prospective, observational TRIAGE study A. Kutz, P. Hausfater, D. Amin, T. Struja, S. Haubitz, A. Huber, B. Mueller, P. Schuetz P351 - Developing an innovative emergency medicine point-of-care simulation programme T. Brown, J. Collinson, C. Pritchett, T. Slade P352 - The InSim program: an in situ simulation program for junior trainees in intensive care M. Le Guen, S. Hellings, R. Ramsaran P353 - Impact of excessive and inappropriate troponin testing in the emergency setting how good are we A. Alsheikhly P354 - The development of time tracking monitor at emergency department T. Abe P355 - Role of focussed echocardiography in emergency assessment of syncope L. Kanapeckaite, M. Abu-Habsa, R. Bahl P356 - Insertion of an open-ended 14-gauge catheter through the chest wall causes a significant pneumothorax in a self-ventilating swine model M. Q Russell, K. J. Real, M. Abu-Habsa , R. M. Lyon, N. P. Oveland P357 - Ez-io\u00ae intraosseous access teaching in the workplace using a mobile \u2018tea trolley\u2019 training method J. Penketh, M. Mcdonald, F. 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Hughes P382 - Systemic inflammatory response syndrome criteria and hospital mortality prediction in a brazilian cohort of critically ill patients L. U. Taniguchi, E. M. Siqueira, J. M. Vieira Jr, L. C. Azevedo P383 - Evaluating the efficacy of a risk predictor panel in identifying patients at elevated risk of morbidity following emergency admission A. N. Ahmad, M. Abu-Habsa, R. Bahl, E. Helme, S. Hadfield, R. Loveridge P384 - A retrospective comparison of outcomes for elective surgical patients admitted post-operatively to the critical care unit or general ward J. Shak, C. Senver, R. Howard-Griffin P385 - Effect of obesity on mortality in surgical critically ill patients. P. Wacharasint, P. Fuengfoo, N. Sukcharoen, R. Rangsin P386 - The national early warning score (news) reliably improves adverse clinical outcome prediction in community-acquired pneumonia - results from a 6\u00a0year follow-up D. Sbiti-Rohr, P. Schuetz P387 - Clinical usefulness of the charlson\u00a1\u00afs weighted index of comorbidities _as prognostic factor in patients with prolonged acute mechanical ventilation H. Na, S. Song, S. Lee, E. Jeong, K. Lee P388 - Comparison of mortality prediction scoring systems in patients with cirrhosis admitted to general intensive care unit M. Cooper, K. Milinis, G. Williams, E. McCarron, S. Simants, I. Patanwala, I. D. Welters P389 - Impact of admission source and time of admission on outcome of pediatric intensive care patients: retrospective 15\u00a0years study E. Zoumpelouli, EA Volakli, V. Chrysohoidou, S. Georgiou, K. Charisopoulou, E. Kotzapanagiotou, V. Panagiotidou, K. Manavidou, Z. Stathi, M. Sdougka P390 - Heart rate variability and outcomes prediction in critical illness N. Salahuddin, B. AlGhamdi, Q. Marashly, K. Zaza, M. Sharshir, M. Khurshid, Z. Ali, M. Malgapo, M. Jamil, A. Shafquat, M. Shoukri, M. Hijazi P391 - The incidence and outcome of hyperlactatemia in the post anaesthesia care unit T. Abe, S. Uchino, M. Takinami P392 - Correlation between arterial blood gas disturbances and arterial lactate levels during hospitalization and outcome in critically septic patients N. R. Rangel Neto, S. Oliveira, F. Q. Reis, F. A. Rocha P393 - External validation of saps 3 and mpm iii scores in 48,816 patients from 72 brazilian icus G. Moralez, K. Ebecken, L. S. Rabello, M. F. Lima, R. Hatum, F. V. De Marco, A. Alves, J. E. Pinto, M. Godoy, P. E. Brasil, F. A. Bozza, J. I. Salluh, M. Soares P394 - The frailty penalty: pre-admission functional status confounds mortality prediction models in critically ill patients J. Krinsley, G. Kang P395 - \u2018sooner rather than later\u201d: how delayed discharge from critical care leads to increased out of hours discharges and subsequent increase in in-hospital mortality. J. Perry, H. Hines P396 - Identifying poor outcome patient groups in a resource-constrained critical care unit K. M. Wilkinson, C. Tordoff, B. Sloan, M. C. Bellamy P397 - Effects of icu weekend admission and discharge on mortality. E. Moreira, F. Verga, M. Barbato, G. Burghi P398 - Organizational factors, outcomes and resource use in 9,946 cancer patients admitted to 70 ICUs M Soares, U. V. Silva, L. C. Azevedo, A. P. Torelly, J. M. Kahn, D. C. Angus, M. F. Knibel, P. E. Brasil, F. A. Bozza, J. I. Salluh P399 - Evaluation of oncological critically ill patients, severity score and outcome compared to not oncological in a particular hospital cti. M. B. Velasco, D. M. Dalcomune P400 - Outcomes of patients admitted to a large uk critical care department with palliative oncological diagnoses R. Marshall, T. Gilpin, A. Tridente, A. Raithatha P401 - Predictors of mortality in febrile neutropenic patients with haematological malignancies admitted to an intensive care unit of a cancer center D. Mota, B. Loureiro, J. Dias, O. Afonso, F. Coelho, A. Martins, F. Faria P402 - Patients with hematologic malignancies requiring invasive mechanical ventilation: characteristics and predictors of mortality H. Al-Dorzi, H. Al Orainni , F. AlEid, H. Tlaygeh, A. Itani, A. Hejazi, Y. Arabi P403 - Patient-important outcomes in randomized controlled trials in critically ill patients: a systematic review S. Gaudry, J. Messika, J. D. Ricard, S. Guillo, B. Pasquet, E. Dubief, D. Dreyfuss, F. Tubach P404 - Alopecia in survivors of critical illness: a qualitative study C . Battle, K. James, P. Temblett P405 - The impact of mental health on icu admission L. Davies, C. Battle, C. Lynch P406 - Cognitive impairment 5\u00a0years after ICU discharge S. Pereira, S. Cavaco, J. Fernandes, I. Moreira, E. Almeida, F. Seabra Pereira, M. Malheiro, F. Cardoso, I. Arag\u00e3o, T. Cardoso P407 - Apache ii versus apache iv for octagenerians in medical icu M. Fister, R. Knafelj P408 - Outcomes of octagenarians in an indian icu P. Muraray Govind, N. Brahmananda Reddy, R. Pratheema, E. D. Arul, J. Devachandran P409 - Mortality and outcomes in elderly patients 80\u00a0years of age or older admitted to the icu M. B. Velasco , D. M. Dalcomune P410 - Octagenerians in medical icu - adding days to life or life to days? R. Knafelj, M. Fister P411 - The very elderly admitted to intensive care unit: outcomes and economic evaluation N. Chin-Yee, G. D\u2019Egidio, K. Thavorn, D. Heyland, K. Kyeremanteng P412 - The very elderly in intensive care: relationship between acuity of illness and long-term mortality A. G. Murchison, K. Swalwell, J. Mandeville, D. Stott P413 - Acquired weakness in an oncological intensive care unit I. Guerreiro P414 - Musculoskeletal problems in intensive care unit (ICU) patients post-discharge H. Devine, P. MacTavish, J. McPeake, T. Quasim, J. Kinsella, M. Daniel P415 - Premorbid obesity, but not nutrition, prevents critical illness-induced muscle wasting and weakness C. Goossens M. B. Marques, S. Derde, S. Vander Perre, T. Dufour, S. E. Thiessen, F. G\u00fciza, T. Janssens, G. Hermans, I. Vanhorebeek, K. De Bock, G. Van den Berghe, L. Langouche P416 - Physical outcome measures for critical care patients following intensive care unit (icu) discharge H. Devine, P. MacTavish, T. Quasim, J. Kinsella, M. Daniel, J. McPeake P417 - Improving active mobilisation in a general intensive care unit B. Miles , S. Madden, H. Devine P418 - Mobilization in patients on vasoactive drugs use \u2013 a pilot study. M. Weiler, P. Marques, C. Rodrigues, M. Boeira, K. Brenner, C. Le\u00e3es, A. Machado, R. Townsend, J. Andrade P419 - Pharmacy intervention at an intensive care rehabilitation clinic P. MacTavish, J. McPeake, H. Devine, J. Kinsella, M. Daniel, R. Kishore, C. Fenlon, T. Quasim P420 - Interactive gaming is feasible and potentially increases icu patients\u2019 motivation to be engaged in rehabilitation programs T. Fiks, A. Ruijter, M. Te Raa, P. Spronk P421 - Simulation-based design of a robust stopping rule to ensure patient safety Y. S. Chiew, P. Docherty, J. Dickson, E. Moltchanova, C. Scarrot, C. Pretty, G. M. Shaw, J. G. Chase P422 - Are daily blood tests on the intensive care unit necessary? T. Hall, W. C. Ngu, J. M. Jack, P. Morgan P423 - Measuring urine output in ward patients: is it helpful? B. Avard, A. Pavli, X. Gee P424 - The incidence of pressure ulcers in an adult mixed intensive care unit in turkey C . Bor, E. Akin Korhan, K. Demirag, M. Uyar P425 - Intensivist/patient ratios in closed ICUs in Alexandria, Egypt; an overview M. Shirazy, A. Fayed P426 - Eicu (electronic intensive care unit): impact on ALOS (average length of stay) in a developing country like India S. Gupta, A. Kaushal, S. Dewan, A. Varma P427 - Predicting deterioration in general ward using early deterioration indicator E. Ghosh, L. Yang, L. Eshelman, B. Lord, E. Carlson P428 - High impact enhanced critical care outreach - the imobile service: making a difference E. Helme, R. Broderick, S. Hadfield, R. Loveridge P429 - Impact of bed availability and cognitive load on intensive care unit (ICU) bed allocation: a vignette-based trial J. Ramos, D. Forte P430 - Characteristics of critically ill patients admitted through the emergency department F. Yang, P. Hou P431 - Admission to critical care: the quantification of functional reserve J. Dudziak, J. Feeney, K. Wilkinson, K. Bauchmuller, K. Shuker, M. Faulds, A. Raithatha, D. Bryden, L. England, N. Bolton, A. Tridente P432 - Admission to critical care: the importance of frailty K. Bauchmuller, K Shuker, A Tridente, M Faulds, A Matheson, J. Gaynor, D Bryden, S South Yorkshire Hospitals Research Collaboration P433 - Development of an instrument to aid triage decisions for intensive care unit admission J. Ramos, B. Peroni, R. Daglius-Dias, L. Miranda, C. Cohen, C. Carvalho, I . Velasco, D. Forte P434 - Using selective serotonin re-uptake inhibitors and serotonin-norepinephrine re-uptake inhibitors in critical care: a systematic review of the evidence for benefit or harm J. M. Kelly, A. Neill, G. Rubenfeld, N. Masson, A. Min P435 - Measuring adaptive coping of hospitalized patients with a severe medical condition:the sickness insight in coping questionnaire (sicq) E. Boezeman, J. Hofhuis , A. Hovingh, R. De Vries, P. Spronk P436 - Results of a national survey regarding intensive care medicine training G. Cabral-Campello, I. Arag\u00e3o, T. Cardoso P437 - Work engagement among healthcare professionals in the intensive care unit M. Van Mol, M. Nijkamp, E . Kompanje P438 - Empowering the intensive care practitioners. is it a burnout ameliorating intervention? P. Ostrowski, A. Omar P439 - Icu patients suffer from circadian rhythm desynchronisation K. Kiss , B. K\u00f6ves, V. Csernus, Z. Moln\u00e1r P440 - Noise reduction in the ICU: feasible ? Y. Hoydonckx, S. Vanwing, B. Stessel, A. Van Assche, L. Jamaer, J. Dubois P441 - Accidental removal of invasive devices in the critical patient into the bed-washing. does the presence of professional nurse modify his incidence? V. Medo, R. Galvez, J. P. Miranda P442 - Deprivation of liberty safeguards (dols): audit of compliance in a of a 16-bed specialist cancer critical care unit. C. Stone, T. Wigmore P443 - Use of a modified cristal score to predict futility of critical care in the elderly Y. Arunan, A. Wheeler, K. Bauchmuller, D. Bryden P444 - Improvement of Referral Rate to Palliative Care for Patients with Poor Prognosis in Neurosurgical Intensive Care Unit Y. Wong, C. Poi, C. Gu P445 - Factors associated with limitation of life supporting care (lsc) in a medico-surgical intermediate care unit, and outcome of patients with lsc limitation: a monocentric, six-month study. P. Molmy, N. Van Grunderbeeck, O. Nigeon, M. Lemyze, D. Thevenin, J. Mallat P446 - Palliative care consultation and intensive care unit admission request: a cohort study J. Ramos, M. Correa, R. T. Carvalho, D. Forte P447 - Nursing and medicine together in postsurgical intensive care unit: situations of prognostic conflict at the end of life. our critical care nurses suffer with our medical activism? A. Fernandez, C. McBride P448 - End of life who may decide E. Koonthalloor, C. Walsh P449 - Correctly diagnosing death A. Webber, M. Ashe, K. Smith, P. Jeanrenaud P450 - Skin procurement performed by intensive care physicians: yes, we can. A. Marudi , S. Baroni, F. Ragusa, E. Bertellini P451 - Death analysis in pediatric intensive care patients E. A. Volakli , E. Chochliourou, M. Dimitriadou, A. Violaki, P. Mantzafleri, E. Samkinidou, O. Vrani, A. Arbouti, T. Varsami, M. Sdougka P452 - The potential impact of euthanasia on organ donation: analysis of data from belgium J. A. Bollen, T. C. Van Smaalen, W. C. De Jongh, M. M. Ten Hoopen, D. Ysebaert, L. W. Van Heurn, W. N. Van Mook P453 - Communication within an intensive care setting K. Sim, A. Fuller P454 - Development and implementation of a longitudinal communication curriculum for critical care medicine fellows A. Roze des Ordons, P. Couillard, C. Doig P455 - Staff-family conflict in a multi-ethnic intensive care unit R. V. Van Keer, R. D. Deschepper, A. F. Francke, L. H. Huyghens, J. B. Bilsen P456 - Does the source of admission to critical care affect family satisfaction? B. Nyamaizi, C. Dalrymple, A. Molokhia, A. Dobru P457 - A simple alternative to the family satisfaction survey (fs-icu) E. Marrinan, A. Ankuli, A. Molokhia P458 - A study to explore the experiences of patient and family volunteers in a critical care environment: a phenomenological analysis J. McPeake, R. Struthers, R. Crawford , H. Devine , P. Mactavish , T. Quasim P459 - Prevalence and risk factors of anxiety and depression in relatives of burn patients. P. Morelli, M. Degiovanangelo, F. Lemos, V. MArtinez, F. Verga, J. Cabrera, G. Burghi P460 - Guidance of visiting children at an adult intensive care unit (icu) A. Rutten , S. Van Ieperen, S. De Geer, M. Van Vugt, E. Der Kinderen P461 - Visiting policies in Italian pediatric ICUs: an update A. Giannini, G Miccinesi, T Marchesi, E Prandi\n\nID: 42074996\nTitle: The Effect of Pediococcus Lactis and Postbiotics on Gut Health and Intestinal Metabolic Profiles.\nAbstract: To investigate the effects of probiotics and their postbiotics on mouse health, this study utilized healthy mice randomly assigned to a control group (CK, n = 6), a probiotic group (L, n = 6, oral gavage 200 \u03bcL Pediococcus lactis), and a postbiotic group (PL, n = 6, oral gavage 200 \u03bcL Pediococcus lactis postbiotic). Following 21 days of continuous intervention, changes in gut metabolic profiles, microbial community structure, tissue morphology, and tight junction protein expression were systematically analyzed using metabolomics, 16S rRNA sequencing, hematoxylin and eosin (HE) staining, and immunohistochemistry techniques. The results revealed that screening for significantly altered endogenous metabolites identified core differences concentrated in metabolites related to intestinal barrier repair, anti-inflammation, and antioxidant activity (e.g., 3-indolepropionic acid, astaxanthin, hydroxybenzoic acid). 16S rRNA sequencing revealed that the overall community structure was relatively stable according to principal component analysis, although differences were detected in specific taxa. However, LEfSe analysis identified significantly enriched functional microbial groups at multiple taxonomic levels in the PL group: phylum: Actinomycetota; class: Coriobacteriia; order: Coriobacteriales, Erysipelotrichales; family: Erysipelotrichaceae, Eggerthellaceae; genus: norank_Erysipelotrichaceae, Intestinimonas. These results suggest that although the overall community structure remained relatively stable, specific taxa may have differed between groups. Hematoxylin and eosin staining revealed no pathological lesions in intestinal tissues from either group, with intact mucosal architecture. Immunohistochemistry demonstrated significantly elevated expression of intestinal tight junction proteins Claudin 1, MUC-2, Occludin, and ZO-1 in the PL group compared to the CK group (p < 0.001). In summary, this probiotic (Pediococcus lactis) and its postbiotic showed promising effects, which may be related to changes in specific microbiota taxa, intestinal metabolic profiles, and tight junction protein expression. Beyond maintaining gut microbiota and tissue homeostasis, it enhances intestinal barrier function, suppresses latent inflammation, and boosts antioxidant capacity. Postbiotics may exhibit superior efficacy compared to probiotics. This provides robust experimental evidence for its development and application in gut health products for healthy populations. However, these findings still require further validation in studies with longer intervention periods and in disease models.\n\nID: 42019018\nTitle: Three Low-Dose Antihypertensive Agents in a Single Pill after Intracerebral Hemorrhage.\nAbstract: Blood-pressure reduction is the only proven treatment to prevent stroke. Whether a single pill that combines three antihypertensive drugs at low doses, in addition to standard antihypertensive treatment, can lower blood pressure more than standard care alone and reduce the risk of recurrent stroke after intracerebral hemorrhage is uncertain. We conducted a multinational, double-blind, randomized, placebo-controlled trial involving patients with a history of intracerebral hemorrhage. Patients were eligible for the trial if they had a systolic blood pressure of 130 to 160 mm Hg at baseline and were in clinically stable condition. After a 2-week active run-in phase during which all the patients received a once-daily pill containing three antihypertensive agents at low doses (telmisartan at 20 mg, amlodipine at 2.5 mg, and indapamide at 1.25 mg; the triple pill), the patients were randomly assigned to continue receiving the triple pill or to receive matching placebo. The primary outcome was the first recurrent stroke. Secondary outcomes included blood-pressure control, major cardiovascular events, death from cardiovascular causes, and safety. Of 1670 patients who underwent randomization, 833 were assigned to receive the triple pill and 837 to receive placebo. The mean age of the patients was 58 years. At a median follow-up of 2.5 years, recurrent stroke had occurred in 38 patients (4.6%) in the triple-pill group and 62 (7.4%) in the placebo group (hazard ratio, 0.61; 95% confidence interval [CI], 0.41 to 0.92; P\u2009=\u20090.02). The mean systolic blood pressure during follow-up was 127 mm Hg and 138 mm Hg, respectively. The incidence of major cardiovascular events was lower with the triple pill than with placebo (6.6% vs. 9.8%; P\u2009=\u20090.04). Serious adverse events occurred in 23.2% of the patients in the triple-pill group and 26.0% of those in the placebo group. Early discontinuation of the trial regimen due to an adverse event occurred in 13.6% and 6.0%, respectively. The most common adverse event leading to discontinuation was an increase of 20% or more in the serum creatinine level. Among patients with intracerebral hemorrhage, treatment with a combination of three low-dose antihypertensive agents in a single pill, in addition to standard care, was associated with a lower incidence of recurrent stroke and major cardiovascular events than placebo. (Funded by the National Health and Medical Research Council of Australia and the Brazilian Ministry of Health; TRIDENT ClinicalTrials.gov number, NCT02699645; Australian New Zealand Clinical Trials Registry number, ACTRN12616000327482.).\n\nID: 41772831\nTitle: Neuroprotection From Intracerebral Hemorrhage Following Pharmacological Inhibition of GSK3\u03b2 Depends on HFE Gene Status.\nAbstract: Iron release from hemoglobin breakdown following an intracerebral hemorrhage (ICH) is a key mediator in stroke-induced cytotoxicity. We have previously demonstrated that mice carrying the H67D mutation in the homeostatic iron regulatory gene (HFE) experience marked neuroprotection following ICH. This improvement is likely due to an endogenous upregulation in the Nrf2 antioxidant system. Prior studies in H67D mice discovered decreased activity in GSK3\u03b2, a kinase that functions to break down Nrf2. Interestingly, pharmacological inhibition of GSK3\u03b2 has been shown to vastly improve outcomes in ICH animal models. However, it remains unclear whether this pathway is responsible for the enhanced antioxidant response in H67D animals. In this study, H67D and WT mice received daily injections of intraperitoneal SB216763, a selective inhibitor of GSK3\u03b2, 14\u2009days prior to ICH. The functional motor recovery of each animal was assessed by rotarod and neurodegeneration was measured using Fluorojade-B. Immunoblotting assessed the antioxidant response and GSK3\u03b2 activity through Nrf2, GPX4, FTH1, and \u03b2-Catenin. At 3\u2009days post-ICH, SB216763-treated WT mice display enhanced functional recovery, decreased degenerated neurons, and increased brain levels of Nrf2 and GPX4 compared to WT-Vehicle-Controls. Further, SB216763 treatment in H67D mice did not result in any significant changes in measured outcomes compared to H67D-Vehicle-Controls. In conclusion, WT mice benefit from GSK3\u03b2 inhibition following ICH whereas H67D animals do not. This suggests that the regulation of the antioxidant response may have reached its biological limit in H67D animals. Importantly, these data suggest that clinical trials aimed towards improving ICH outcomes, especially through GSK3\u03b2 inhibition, must take into account HFE genotype as this mutation, present in nearly 20% of individuals worldwide, may alter ICH recovery regardless of therapy.\n\nID: 41387160\nTitle: Sunitinib attenuates secondary injury via the regulation of peri-hematomal microglia at the acute phase of intracerebral hemorrhage.\nAbstract: Intracerebral hemorrhage (ICH) is a highly fatal stroke subtype with limited treatment options, where pathological activation of peri-hematomal microglia drives acute secondary injury. Colony-stimulating factor 1 receptor (CSF-1R), highly expressed in microglia, is a potential therapeutic target. This study evaluated the effects of short-term administration of sunitinib, a clinically used CSF-1R inhibitor, in a collagenase-induced mouse ICH model and an in vitro hemoglobin (Hb)-treated BV2 microglial model. Sunitinib significantly improved motor functions, reduced myelin damage, and attenuated microglial activation and neuroinflammation in peri-hematomal tissue. RNA sequencing revealed that sunitinib might modulate lipid metabolism, phagocytosis, and immune response. In BV2 cells, sunitinib inhibited Hb-induced lipid droplet accumulation, phagocytic reduction, and pro-inflammatory cytokine production, effects mirrored by CSF-1R knockdown. These findings suggest that sunitinib alleviates acute ICH injury by modulating microglial functions, likely through inhibition of the CSF-1R axis, supporting its potential repurposing for central nervous system disorders like ICH.\n\nID: 40994248\nTitle: Network Pharmacology-Based and Experimental Validation Elucidate the Target Mechanism of Vinorine in Ameliorating Secondary Brain Injury After Intracerebral Hemorrhage.\nAbstract: Intracerebral hemorrhage (ICH) is a severe stroke subtype associated with high mortality and long-term disability, for which no effective treatment currently exists. Vinorine (Vin), a monoterpene indole alkaloid derived from Rauvolfia reflexa, has been traditionally used for age-related neurological disorders, yet its therapeutic potential and mechanisms in ICH remain unclear. An ICH mouse model was established via intracranial collagenase injection. Vin was administered intraperitoneally at varying doses, and its effects on motor function, sensory deficits, and neural regeneration were evaluated. Network pharmacology was employed to predict potential targets and pathways, followed by validation through molecular docking, in\u00a0vivo experiments, and in\u00a0vitro assays. Network pharmacology identified four core targets and 35 related pathways, with JAK2 as a central node. In\u00a0vivo, Vin significantly improved motor deficits, reduced cerebral edema, preserved blood-brain barrier integrity, and promoted hematoma resolution. These effects were mediated through modulation of the CXCR2-JAK-STAT axis and suppression of JAK2 phosphorylation. In\u00a0vitro, Vin inhibited JAK-STAT activation in microglia, downregulated MMP expression, and facilitated the transition from M1 to M2 phenotypic polarization. Additionally, Vin enhanced the expression of neuronal markers (NF200, PSD95, GAP43) and reduced neuronal apoptosis. Vin attenuates neurological deficits after ICH likely by inhibiting MMP expression in microglia via regulation of the CXCR2-JAK-STAT pathway. These findings highlight the therapeutic potential of Vin and provide mechanistic support for its further development as a treatment for ICH.\n\nID: 40526280\nTitle: Melatonin and necroptosis: therapeutic aspects based on cellular mechanisms.\nAbstract: Necroptosis is a regulated form of programmed cell death. It is integral to the development of various diseases, such as neurological disorders, lung injuries, liver fibrosis, and testicular toxicity. This process is orchestrated by essential molecular pathways that involve receptor-interacting protein kinases (RIP1/RIP3) and mixed lineage kinase domain-like protein (MLKL), which lead to membrane disruption, the release of damage-associated molecular patterns (DAMPs), and subsequent inflammation. Melatonin, recognized for its potent antioxidant and anti-inflammatory properties, has emerged as a promising therapeutic agent that can inhibit necroptosis through various mechanisms. In neurological diseases such as intracerebral hemorrhage, traumatic brain injury, and cerebral ischemia-reperfusion, melatonin suppresses necroptosis by downregulating RIP1/RIP3/MLKL signaling, upregulating A20 (TNFAIP3), and inhibiting the HMGB1/TLR4/NF-\u03baB pathway. In lung disorders, melatonin attenuates cadmium- and LPS-induced necroptosis by modulating the Ang-II axis, reducing TNF-\u03b1-mediated signaling, and acting through MT1/MT2 receptors. In liver fibrosis models, melatonin inhibits RIP1-RIP3 necrosome formation, reduces oxidative stress, and decreases DAMPs-mediated immune responses. Similarly, in testicular toxicity induced by tetrabromobisphenol A (TBBPA), melatonin suppresses necroptosis by inhibiting the several pathways and reducing ROS overproduction. These findings highlight melatonin's ability to modulate necroptosis across diverse tissues, offering protection against inflammation, oxidative stress, and cell death. By targeting necroptosis-related pathways, melatonin presents a versatile therapeutic strategy for treating diseases characterized by excessive cell death and inflammation, including stroke, myocardial infarction, pancreatitis, and autoimmune disorders. This review underscores the potential of melatonin as a novel intervention for necroptosis-related pathologies, emphasizing its role in restoring cellular homeostasis and mitigating tissue damage.\n\nID: 40505632\nTitle: Diagnostic Values of the \"To and Fro\" Conflict Sign on Intraoperative Indocyanine Green Video Angiography as a Warning Sign of the Focal Cerebral Hyperperfusion and Watershed Shift Phenomenon after Superficial Temporal Artery-Middle Cerebral Artery Bypass for Adult Patients with Moyamoya Disease.\nAbstract: Introduction: The focal cerebral hyperperfusion (CHP) is a potential complication after superficial temporal artery-middle cerebral artery (STA-MCA) bypass for moyamoya disease (MMD) that can result in delayed intracerebral hemorrhage and/or neurological deterioration. The focal CHP could accompany hemodynamic ischemia due to the \"watershed shift (WS) phenomenon.\" Preoperative prediction of the focal CHP and WS phenomenon remains challenging. Here, we aimed to assess the diagnostic value of the \"to and fro\" conflict sign, conflicting blood flow around the vascular territory of the recipient arteries on an indocyanine green video angiography (ICG-VA) for predicting the focal CHP and WS phenomenon. Ninety-seven consecutive adult patients with MMD, undergoing 106 surgeries, were enrolled. Serial quantitative analysis of cerebral blood flow was routinely conducted using n -isopropyl-p-[123I] iodoamphetamine single-photon emission computed tomography preoperatively and postoperative day 1 and 7 after STA-MCA bypass. The association between the \"to and fro\" conflict sign on ICG-VA and the focal CHP/WS phenomenon incidence was then analyzed. The incidence of the focal CHP and WS phenomenon was 29.2% (31/106) and 10.4% (11/106), respectively. The \"to and fro\" conflict sign was evident in 35.5% (11/31) and 54.5% (6/11) of MMD patients with the focal CHP and WS phenomenon, respectively. The \"to and fro\" conflict sign was significantly associated with both the focal CHP and WS phenomena. The \"to and fro\" conflict sign on ICG-VA may serve as an intraoperative warning sign of the focal CHP and WS phenomenon after STA-MCA bypass in adult patients with MMD, providing neurosurgeons with a valuable tool for early detection.
.\n\nID: 39981743\nTitle: Melatonin Regulates Glymphatic Function to Affect Cognitive Deficits, Behavioral Issues, and Blood-Brain Barrier Damage in Mice After Intracerebral Hemorrhage: Potential Links to Circadian Rhythms.\nAbstract: Intracerebral hemorrhage (ICH) is a life-threatening cerebrovascular disorder with no specific pharmacological treatment. ICH causes significant behavioral deficits and cognitive impairments. Recent research suggests that circadian rhythm regulation could be a promising therapeutic strategy for ICH. Melatonin has been shown to alleviate glymphatic system (GS) dysfunction by regulating circadian rhythms, thereby improving depressive-like behaviors and postoperative sleep disorders in mice. However, its application in ICH treatment and specific mechanisms are not well understood. ICH models were created in 8-to-10-week-old mice using collagenase injection. Circadian rhythm modulation was tested with melatonin and luzindole. Behavioral and cognitive impairments were assessed with the modified neurological severity score, corner test, and novel object recognition test. Brain water content was measured by the dry/wet weight method, and cerebral perfusion was assessed by cerebral blood flow measurements. GS function was evaluated using RITC-dextran and Evans blue assays. Immunofluorescence and western blotting were used to analyze GS function and BBB permeability. Melatonin restored GS transport after ICH, promoting hematoma and edema absorption, reducing BBB damage, and improving cognitive and behavioral outcomes. However, luzindole partially blocked these benefits and reversed the neuroprotective effects. Melatonin and luzindole treatment affect GS function, BBB permeability, and cognitive-behavioral outcomes in mice with ICH. The underlying mechanism may involve the regulation of circadian rhythms.\n\nID: 39746523\nTitle: Liangxue Tongyu Prescription exerts neuroprotection by regulating the microbiota-gut-brain axis of rats with acute intracerebral hemorrhage.\nAbstract: Liangxue Tongyu Prescription (LTP) is a classic herbal formula for treating acute intracerebral hemorrhage (AICH) in China. Previous studies have shown that LTP significantly ameliorates neurological impairments and gastrointestinal dysfunction in patients with AICH. However, the underlying molecular mechanism remains unclear. The aim of this study is to investigate whether LTP exerts its neuroprotective effect on AICH rats through the microbiota-gut-brain axis and explore its potential underlying mechanism. In the current study, AICH models were established by injecting autologous whole blood into the right caudate nucleus of rats. Behavioural and pathological evaluations demonstrated that LTP ameliorated neuronal and intestinal damage in AICH rats. Analysis via western blot, quantitative real-time PCR, immunohistochemistry (IHC) and tunel staining indicated that LTP upregulated the expression of brain-derived neurotrophic factor (BDNF) and nerve growth factor(NGF) and reduced neuronal cell apoptosis. Additionally, 16S rDNA sequencing revealed that LTP mitigated dysbiosis of intestinal microbiota in AICH rats. LTP increased the levels of noradrenaline (NA), dopamine (DA), glutamate (GLU) and modulated brain-gut peptides such as gastrin (GAS), motilin (MTL), ghrelin in AICH rats. Furthermore, LTP enhanced vagus nerve discharge. In summary, this research provides evidence suggesting that LTP's influence on AICH may involve modulation of the microbiota-gut-brain axis, offering a potential scientific rationale for its therapeutic efficacy in improving outcomes of AICH.\n\nID: 39742937\nTitle: Harmine-induced disruption of the blood-brain barrier via excessive mitophagy in zebrafish.\nAbstract: Stroke is a serious condition with sudden onset, high severity, and significant rates of mortality and disability, ranking as the second leading cause of death globally at 11.6%. Hemorrhagic stroke, characterized by non-traumatic rupture of cerebral vessels, can cause secondary brain injury such as neurotoxicity, inflammation, reactive oxygen species, and blood-brain barrier (BBB) damage. The integrity of the BBB plays a crucial role in stroke outcomes, as its disruption can exacerbate injury. Harmine, a natural \u03b2-carboline alkaloid, has been studied for various pharmacological effects, including its potential benefits in protecting cardiac and cognitive functions. However, its impact on cerebrovascular conditions, particularly in the context of stroke, remains underexplored. This study investigates harmine's effects on BBB integrity and its role in inducing cerebral hemorrhage in zebrafish. We found that harmine disrupts BBB permeability, leading to cerebral hemorrhage through modulation of tight junction protein Claudin-5 and cytoskeletal protein F-actin expression. Furthermore, harmine altered mitochondrial morphology, causing structural imbalance, excessive mitophagy, and cell death. Together, these data indicate that harmine can induce BBB damage and intracerebral hemorrhage in zebrafish, and provide a possible mechanism and explanation for this effect.\n\nID: 39594991\nTitle: Early Metabolomic Profiling as a Predictor of Renal Function Six Months After Kidney Transplantation.\nAbstract: Kidney transplantation is the therapy of choice for patients with advanced chronic kidney disease; however, predicting graft outcomes remains a significant challenge. Early identification of reliable biomarkers could enhance post-transplant management and improve long-term outcomes. This study aimed to identify metabolomic biomarkers within the first week after kidney transplantation that predict renal function at six months. We conducted a prospective study involving 50 adult patients who received deceased donor kidney transplants. Plasma samples collected one week after transplant were analyzed using liquid chromatography-mass spectrometry in a semi-targeted metabolomic approach. A Partial Least Squares-Discriminant Analysis (PLS-DA) model identified metabolites associated with serum creatinine > 1.5 mg/dL at six months. Metabolites were selected based on a Variable Importance in Projection (VIP) score > 1.5, which was used to optimize model performance. The PLS-DA model demonstrated strong predictive performance with an area under the curve (AUC) of 0.958. The metabolites negatively associated with serum creatinine > 1.5 mg/dL were 3-methylindole, guaiacol, histidine, 3-indolepropionic acid, and \u03b1-lipoic acid. Conversely, the metabolites positively associated with worse kidney graft outcomes included homocarnosine, 5-methylcytosine, xanthosine, choline, phenylalanine, kynurenic acid, and L-kynurenine. Early metabolomic profiling after transplantation shows promise in predicting renal function. Identifying metabolites with antioxidant and anti-inflammatory properties, as well as those that are harmful and could be targeted therapeutically, underscores their potential clinical significance. The link between several metabolites and the tryptophan pathway suggests that further specific evaluation of this pathway is warranted. These biomarkers can enhance patient management and graft survival.\n\nID: 39578855\nTitle: Polydopamine(PDA)-coated diselenide-bridged mesoporous silica-based nanoplatform for neuroprotection by reducing oxidative stress and targeting neuroinflammation in intracerebral hemorrhage.\nAbstract: Oxidative stress (OS) and neuroinflammation are critical pathological processes in secondary brain injury (SBI) after intracerebral hemorrhage(ICH), and their intimate interactions initiate and aggravate brain damage. Thus, targeting oxidative stress and neuroinflammation could be a promising therapeutic strategy for ICH treatment. Here, we report a high-performance platform using polydopamine (PDA)-coated diselenide bridged mesoporous silica nanoparticle (PDA-DSeMSN) as a smart ROS scavenger and ROS-responsive drug delivery system. Caffeic acid phenethyl ester (CAPE) was blocked in the pore of DSeMSN by covering the pore with PDA as a gatekeeper. PDA-DSeMSN @CAPE maintained high stability and underwent reactive oxygen species (ROS)-responsive degradation and drug release. The intelligent nanomaterial effectively eliminated ROS, promoted M1 to M2 microglial conversion and suppressed neuroinflammation in vitro and in vivo. Importantly, intravenous administration of PDA-DSeMSN@CAPE specifically accumulated in perihematomal sites and demonstrated robust neuroprotection in an ICH mouse model with high biological safety. Taking together, the synergistic effect of ROS-responsive drug delivery ability and ROS scavenging ability of PDA-DSeMSN makes it a powerful drug delivery platform and provided new considerations into the therapeutic action to improve ICH-induce brain injury.\n\nID: 39359199\nTitle: Melatonin alleviates heme-induced ferroptosis via activating the Nrf2/HO-1 pathway in neurons.\nAbstract: Ferroptosis of neurons is a significant cause of brain injury following intracerebral hemorrhage (ICH). As an iron-containing compound in hemoglobin, heme contributes to nerve injury post-ICH. Melatonin has been shown to mitigate the effects of ICH, yet its specific functions remain largely elusive. In this study, we aimed to explore the roles and mechanisms of melatonin in heme-induced ferroptosis subsequent to ICH. C57BL/6 mice were intracranially injected with heme and then treated with melatonin. Behavior tests [modified neurological severity score (mNSS), forelimb placing, and corner turn tests], H&E staining, Nissl staining, and Prussian blue staining were used to evaluate mouse brain tissue injury. In vitro, HT-22 cells were stimulated with heme and cell viability was determined by crystal violet staining. The iron contents were determined in heme-treated brains and cells, and the levels of 4-hydroxynonenal (4-HNE) and malonaldehyde (MDA) were assessed by ELISA. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was used to investigate the mRNA levels of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1). Immunoblotting was used to analyze the protein expression of glutathione peroxidase 4 (GPX4), solute carrier family 7 member 11 (SLC7A11), Nrf2, and HO-1. Finally, small interfering RNA (siRNA) was used to knock down Nrf2 in HT-22 cells. Melatonin treatment alleviated heme-induced injuries to neural function, as indicated by improved behavior in the mice. Moreover, melatonin decreased cell death and iron concentrations, increased MDA and 4-HNE levels, and reversed the decreases in GPX4, SLC7A11, Nrf2, and HO-1 induced by heme in vitro and in vivo. These results indicated that melatonin could improve the ferroptosis induced by heme. In addition, we found that Nrf2 knockdown attenuated the therapeutic effect of melatonin on neuronal ferroptosis induced by heme. In general, melatonin alleviates heme-induced ferroptosis by activating the Nrf2/HO-1 pathway, which implies that melatonin is a promising treatment for ferroptosis in ICH.\n\nID: 39047081\nTitle: Diselenide-Bridged Mesoporous Silica-Based Nanoplatform with a Triple ROS-Scavenging Effect for Intracerebral Hemorrhage Treatment.\nAbstract: Oxidative stress (OS) is a major mediator of secondary brain injury following intracerebral hemorrhage (ICH). Thus, antioxidant therapy is emerging as an attractive strategy to combat ICH. To achieve both reactive oxygen species (ROS) scavenging ability and on-demand drug release ability, we constructed a novel polydopamine (PDA)-coated diselenide-bridged mesoporous silica nanoparticle (DSeMSN) drug delivery system (PDA-DSeMSN). Edaravone (Eda) was blocked in the pores of DSeMSN by covering the pores with PDA as a gatekeeper. The drug maintained nearly \"zero release\" before reaching the lesion site, while in the ROS-enriched circumstances, the PDA shell went through degradation and the doped diselenide bonds broke up, triggering the disintegration of nanoparticles and leading to Eda release. Interestingly, the ROS-degradable property of the PDA shell and diselenide bond endowed the system with enhanced ROS-eliminating capacity. The synergistic effect of ROS-responsive drug delivery and ROS-scavenging PDA-DSeMSN showed efficient antioxidative and mitochondria protective performance without apparent toxicity in vitro. Importantly, PDA-DSeMSN@Eda through intravenous administration specifically accumulated in perihematomal sites and demonstrated robust neuroprotection in an ICH mouse model through antioxidative and antiapoptotic effects with high biological safety. Thus, the PDA-DSeMSN platform holds tremendous potential as an excellent carrier for on-demand delivery of drugs and provides a new and effective strategy for the clinical treatment of ICH.\n\nID: 37477660\nTitle: 3-Indolepropionic acid mitigates sub-acute toxicity in the cardiomyocytes of epirubicin-treated female rats.\nAbstract: Epirubicin (EPI) is an effective chemotherapeutic against breast cancer, though EPI-related cardiotoxicity limits its usage. Endogenously derived 3-indolepropionic acid (3-IPA) from tryptophan metabolism is of interest due to its antioxidant capabilities which may have cardioprotective effects. Supplementation with 3-IPA may abate EPI's cardiotoxicity, and herein we studied the possibility of lessening EPI-induced cardiotoxicity in Wistar rats. Experimental rats (n\u2009=\u200930; BW 180-200\u00a0g) were randomly distributed in five cohorts (A-E; n\u2009=\u20096 each). Group A (control), Group B (EPI 2.5\u00a0mg/mL), and group C (3-IPA 40\u00a0mg/kg) while Groups D and E were co-treated with EPI (2.5\u00a0mg/mL) together with 3-IPA (D: 20 and E: 40\u00a0mg/kg). Following sacrifice, oxidative status, lipid profile, transaminases relevant to cardiac function, and inflammatory biomarkers were analysed. Also, 8-hydroxyl-2'-deoxyguanosine (8-OHdG) and cardiac troponin T (cTnT) levels were assessed using an enzyme-linked immunosorbent assay (ELISA). EPI-initiated increases in cardiotoxicity biomarkers were significantly (p\u2009<\u20090.05) reduced by 3-IPA supplementation. Decreased antioxidant and increases in reactive oxygen and nitrogen species (RONS), 8-OHdG and lipid peroxidation were lessened (p\u2009<\u20090.05) in rat hearts co-treated with 3-IPA. EPI-induced increases in nitric oxide and myeloperoxidase were reduced (p\u2009<\u20090.05) by 3-IPA co-treatment. In addition, 3-IPA reversed EPI-mediated alterations in alanine aminotransferase (ALT), aspartate amino transaminases (AST), lactate dehydrogenase (LDH), cardiac troponin T (cTnT), and serum lipid profile including total cholesterol and triglycerides. Microscopic examination of the cardiac tissues showed that histopathological lesions severity induced by EPI was lesser in 3-IPA co-treated rats. Our findings demonstrate that supplementing endogenously derived 3-IPA can enhance antioxidant protection in the cardiac tissue susceptible to EPI toxicity in female rats. These findings may benefit breast cancer patients undergoing chemotherapy by further validating these experimental data.\n\nID: 37310885\nTitle: Platelet-Membrane-Coated Polydopamine Nanoparticles for Neuroprotection by Reducing Oxidative Stress and Repairing Damaged Vessels in Intracerebral Hemorrhage.\nAbstract: Intracerebral hemorrhage (ICH) has a high morbidity and mortality rate. Excessive reactive oxygen species (ROS) caused by primary and second brain injury can induce neuron death and inhibit neurological functional recovery after ICH. Therefore, exploring an effective way to noninvasively target hemorrhage sites to scavenge ROS is urgently needed. Inspired by the biological function of platelets to target injury vessel and repair injury blood vessels, platelet-membrane-modified polydopamine (Menp@PLT) nanoparticles are developed with targeting to hemorrhage sites of ICH. Results demonstrate that Menp@PLT nanoparticles can effectively achieve targeting to the location of intracranial hematoma. Furthermore, Menp@PLT with excellent anti-ROS properties can scavenge ROS and improve neuroinflammation microenvironment of ICH. In addition, Menp@PLT may play a role in decreasing hemorrhage volume by repairing injury blood vessels. Combining platelet membrane and anti-ROS nanoparticles for targeting brain hemorrhage sites provide a promising strategy for efficiently treating ICH.\n\nID: 37138816\nTitle: Selective HDAC6 inhibitor TubA offers neuroprotection after intracerebral hemorrhage via inhibiting neuronal apoptosis.\nAbstract: A large body of evidence has demonstrated that neuronal apoptosis is involved in the pathological process of secondary brain injury following intracerebral hemorrhage (ICH). Additionally, our previous studies determined that the inhibition of HDAC6 activity by tubacin or specific shRNA can attenuate neuronal apoptosis in an oxygen-glucose deprivation reperfusion model. However, whether the pharmacological inhibition of HDAC6-attenuated neuronal apoptosis in ICH remains unclear. In this study, we used hemin-induced SH-SY5Y cells to simulate a hemorrhage state in vitro and adopted a collagenase-induced ICH rat model in vivo to assess the effect of the HDAC6 inhibition. We found a significant increase in HDAC6 during the early stages of ICH. As expected, the acetylated \u03b1-tubulin significantly decreased in correlation with the expression of HDAC6. Medium and high doses (25, 40 mg/kg) of TubA, a selective inhibitor of HDAC6, both reduced neurological impairments, histological impairments, and ipsilateral brain edema in vivo. TubA or HDAC6 siRNA both alleviated neuronal apoptosis in vivo and in vitro. Finally, HDAC6 inhibition increased the level of acetylated \u03b1-tubulin and Bcl-2 and lowered the expression of Bax and cleaved caspase-3 post-ICH. In general, these results suggested that the pharmacological inhibition of HDAC6 may act as a novel and promising therapeutic target for ICH therapy by up-regulating acetylated \u03b1-tubulin and reducing neuronal apoptosis.\n\nID: 37099039\nTitle: Mesenchymal Stem Cell-Derived Exosomal miR-150-3p Affects Intracerebral Hemorrhage By Regulating TRAF6/NF-\u03baB Axis, Gut Microbiota and Metabolism.\nAbstract: Intracerebral hemorrhage (ICH) is a severe subtype of stroke for which there is no effective treatment. Stem cell and exosome (Exo) therapies have great potential as new approaches for neuroprotection and neurorestoration in treating ICH. We aimed to investigate whether Exo affects ICH by regulating the ecology of gut microbiota and metabolism and the mechanisms involved. First, differential miRNAs in ICH were screened by bioinformatics and verified by qRT-PCR. Then, Exo was extracted from mouse bone marrow mesenchymal stem cells (MSCs) and identified. Dual-luciferase reporter gene assay was utilized to verify the binding relationship between miR-150-3p and TRAF6. A mouse ICH model was constructed and treated with Exo. Next, we knocked down miR-150-3p and performed fecal microbiota transplantation (FMT). Then changes in gut microbiota and differential metabolites were detected by 16S rRNA sequencing and metabolomics analysis. We found that miR-150-3p expression was lowest in the brain tissue of the ICH group compared to the Sham group. Besides, low miR-150-3p level in ICH was encapsulated by MSC-derived Exo. Moreover, miR-150-3p bound to TRAF6 and was negatively correlated. With the addition of ExomiR-150-3p inhibitor, we found that MSC-derived exosomal miR-150-3p may affect ICH injury via TRAF6/NLRP3 axis. MSC-derived exosomal miR-150-3p caused changes in gut microbiota, including Proteobacteria, Muribaculaceae, Lachnospiraceae_NK4A136_group, and Acinetobacter. Moreover, MSC-derived exosomal miR-150-3p caused changes in metabolism. After further FMT, gut microbiota-mediated MSC-derived Exo affected ICH with reduced apoptosis and reduced levels of inflammatory factors. In conclusion, MSC-derived exosomal miR-150-3p affected ICH by regulating TRAF6/NF-\u03baB axis, gut microbiota and metabolism.\n\nID: 37097396\nTitle: Epirubicin Treatment Induces Neurobehavioral, Oxido-Inflammatory and Neurohistology Alterations in Rats: Protective Effect of the Endogenous Metabolite of\u00a0Tryptophan -\u20093-Indolepropionic Acid.\nAbstract: Epirubicin's (EPI) efficacy as a chemotherapeutic agent against breast cancer is limited by EPI's neurotoxicity associated with increased oxidative and inflammatory stressors. 3-Indolepropionic acid (3-IPA) derived from in vivo metabolism of tryptophan is reported to possess antioxidative properties devoid of pro-oxidant activity. In this regard, we investigated the effect of 3-IPA on EPI-mediated neurotoxicity in forty female rats (180-200\u00a0g; five cohorts (n\u2009=\u20096) treated as follows: Untreated control; EPI alone (2.5\u00a0mg/Kg); 3-IPA alone (40\u00a0mg/Kg body weight); EPI (2.5\u00a0mg/Kg)\u2009+\u20093-IPA (20\u00a0mg/Kg) and EPI (2.5\u00a0mg/Kg)\u2009+\u20093-IPA (40\u00a0mg/Kg) for 28 days. Experimental rats were treated with EPI via intraperitoneal injection thrice weekly or co-treated with 3-IPA daily by gavage. Subsequently, the rat's locomotor activities were measured as endpoints of neurobehavioural status. After sacrifice, inflammation, oxidative stress and DNA damage biomarkers were assessed in rats' cerebrum and cerebellum alongside histopathology. Our results demonstrated that locomotor and exploratory deficits were pronounced in EPI-alone treated rats and improved in the presence of 3-IPA co-treatment. EPI-mediated decreases in tissue antioxidant status, increases in reactive oxygen and nitrogen species (RONS), as well as in lipid peroxidation (LPO) and xanthine oxidase (XO) were lessened in the cerebrum and cerebellum of 3-IPA co-treated rats. Increases in nitric oxide (NO) and 8-hydroxydeguanosin (8-OHdG) levels and myeloperoxidase MPO activity were also abated by 3-IPA. Light microscopic examination of the cerebrum and cerebellum revealed EPI-precipitated histopathological lesions were subsequently alleviated in rats co-treated with 3-IPA. Our findings demonstrate that supplementing endogenously derived 3-IPA from tryptophan metabolism enhances tissue antioxidant status, protects against EPI-mediated neuronal toxicity, and improves neurobehavioural and cognitive levels in experimental rats. These findings may benefit breast cancer patients undergoing Epirubicin chemotherapy.\n\nID: 36822302\nTitle: Epirubicin toxicity in rat's ovary and uterus: A protective role of 3-Indolepropionic acid supplementation.\nAbstract: The \"anthracycline, Epirubicin (EPI),\" in managing breast cancer, is highly cytotoxic. Tryptophan-derived 3-indolepropionic acid (3-IPA) decreases oxidative damage, and its prospect of alleviating EPI-induced cytotoxicity was examined in rats' hypothalamus-ovary-uterus axis. Female rats: Control, EPI (2.5\u00a0mg/kg), 3-IPA alone (40\u00a0mg/kg), EPI+3-IPA (2.5\u00a0mg/kg\u00a0+\u00a020\u00a0mg/kg), EPI\u00a0+\u00a03-IPA2 (2.5\u00a0mg/kg\u00a0+\u00a040\u00a0mg/kg) were treated for 28 days. Subsequently, reproductive hormones, oxidative and inflammatory stress biomarkers, and tissue histology were examined. 3-IPA prevented EPI-induced decreases in the follicle-stimulating hormone, estradiol, progesterone and prolactin levels. EPI-mediated reduction in antioxidant enzymes, reduced glutathione and total sulfhydryl groups were partially counteracted by 3-IPA co-treatment. Increased oxidative and inflammatory stress biomarkers caused by treatment with EPI alone were lessened by 3-IPA co-treatment. Also, 3-IPA reduced histological damage in the examined tissues. Conclusively, 3-IPA ameliorated biochemical markers and tissue injury caused by EPI treatment alone via an antioxidative and anti-inflammatory mechanism while stabilising serum hormone dynamics.\n\nID: 36819779\nTitle: P7C3-A20 Attenuates Microglial Inflammation and Brain Injury after ICH through Activating the NAD+/Sirt3 Pathway.\nAbstract: Intracerebral hemorrhage (ICH) is lethal but lacks effective therapies. Nicotinamide adenine dinucleotide (NAD+) is a central metabolite indispensable for a broader range of fundamental intracellular biological functions. Reduction of NAD+ usually occurs after acute brain insults, and supplementation of NAD+ has been proven neuroprotective. P7C3-A20 is a novel compound featuring its ability to facilitate the flux of NAD+. In this study, we sought to determine the potential therapeutic value of P7C3-A20 in ICH. In collagenase-induced ICH mouse models, we found that P7C3-A20 treatment could diminish lesion volume, reduce blood-brain barrier (BBB) damage, mitigate brain edema, attenuate neural apoptosis, and improve neurological outcomes after ICH. Further, RNA sequencing and subsequent experiments revealed that ICH-induced neuroinflammation and microglial proinflammatory activities were significantly suppressed following P7C3-A20 treatment. Mitochondrial damage is an important trigger of inflammatory response. We examined mitochondrial morphology and function and found that P7C3-A20 could attenuate OxyHb-induced impairment of mitochondrial dynamics and functions in vitro. Mechanistically, Sirt3, an NAD+-dependent deacetylase located in mitochondria, was then found to play a vital role in the protection of P7C3-A20 against mitochondrial damage and inflammatory response. In rescue experiments, P7C3-A20 failed to exert those protective effects in microglia-specific Sirt3 conditional knockout (CKO) mice. Finally, preclinical research revealed a correlation between the plasma NAD+ level and the neurological outcome in ICH patients. These results demonstrate that P7C3-A20 is a promising therapeutic agent for neuroinflammatory injury after ICH and exerts protective actions, at least partly, in a Sirt3-dependent manner.\n\nID: 36753496\nTitle: Indoleamine 2, 3-dioxygenase is responsible for low stress tolerance after intracerebral hemorrhage.\nAbstract: In the chronic phase after intracerebral hemorrhage (ICH), the aftereffect-associated lowering of motivation burdens many patients; however, the pathogenic mechanism is unclear. Here, we revealed for the first time that indoleamine 2, 3-dioxygenase (IDO) expression and enzyme activity are increased in the collagenase-induced murine ICH model. IDO is a rate-limiting enzyme situated at the beginning of the kynurenine pathway and converts tryptophan, a source of serotonin (5-hydroxytryptamine; 5-HT), to kynurenine. In this study, we showed that IDO is localized in 5-HTergic neurons. After ICH, the synaptosomal 5-HT level decreased, but this effect was neutralized by subcutaneous injections of 1-methyl tryptophan (MT), a specific IDO inhibitor. These results suggest that ICH-induced IDO weakens the activity of 5-HTergic neurons. Accordingly, we next investigated whether the IDO increase contributes to the depression-like behaviors of ICH mice. The immobility times of tail suspension and forced swimming tests were significantly prolonged after ICH but shortened by the administration of 1-MT. In conclusion, the increased IDO after ICH was found to decrease 5-HT levels and subsequently reduce stress tolerance. These findings indicate that IDO is a novel therapeutic target for the ICH aftereffect-associated lowering of motivation.\n\nID: 36642502\nTitle: Usefulness of 4K-resolution Indocyanine Green Endoscope for the Removal of Spontaneous Intracerebral Hematomas.\nAbstract: Indocyanine green (ICG) is a cyanine dye useful for visualizing blood vessels; it has been developed for endoscopy and is used in skull base surgery. Endoscopy is widely used for hematoma removal after an intracerebral hemorrhage since it is minimally invasive and has a shorter operation time than craniotomy. However, with this technique the surgical field is limited and it is difficult to obtain an adequate orientation; thus, it is challenging to locate the bleeding point, and postoperative rebleeding has been reported. We performed intraoperative ICG near-infrared fluorescence imaging to locate the bleeding point. This purpose of this study was to evaluate the usefulness of ICG angiography during endoscopic hematoma removal in two patients, using two endoscope types and comparing their visualization of perforating branches during the procedure. ICG angiography was performed in two different cases of putaminal hemorrhage, using the SPIES NIR/ICG-System and IMAGE1 S Rubina (both KARL STORZ, Tuttlingen, Germany) at the intraoperative bleeding site. The intraoperative use of ICG allowed the clear visualization of the perforating branches and real-time confirmation of active bleeding. We could also distinguish an old hematoma from the active bleeding point. The IMAGE1 S Rubina has adequate brightness for contrast enhancement, allowing surgical manipulation simultaneously to the enhancement phase.ICG fluorescence angiography is useful to identify the damaged vessel and perform hemostasis. We expect other similar devices to be developed in the future, accompanied by flexible and thin rigid endoscopes.\n\nID: 36214208\nTitle: The protective effect of 3-indolepropanoic acid on aflatoxin B1-induced systemic perturbation of the liver and kidney function in rats.\nAbstract: Aflatoxin B1 (AFB1) is known to derange the hepatorenal system by redox, DNA adduct formation and apoptotic networks. Endogenous 3-indole propionic acid (3-IPA) is a metabolite of tryptophan metabolism by gut microbiota that can protect against redox imbalance, inflammation and cellular lipid damage. We investigated the beneficial effect of 3-IPA against AFB1-mediated organ toxicity in male rats post 28\u2009days of consecutive treatment. The 3-IPA (25 and 50\u2009mg/kg) was orally administered alongside AFB1 (50\u2009\u03bcg/kg) treatment. Biochemical and enzyme-linked immunosorbent assays were utilised to examine biomarkers of hepatorenal function, oxidative status and inflammation. DNA damage and apoptosis were also assessed, and histological staining techniques were used to investigate hepatorenal tissues for pathological indicators. The 3-IPA supplementation abated AFB1-mediated increases in biomarkers of hepatic and renal dysfunction in rat serum. Co-administration of 3-IPA further reduced AFB1-induced redox imbalance (by upregulating antioxidant mediators and enzymes [GSH, TSH, Trx, Trx-R, SOD, CAT, GPx and GST]; reducing reactive oxygen species, lipid peroxidation and DNA adduct [RONS, LPO and 8-OH-dG] formation; suppressing pro-inflammatory and apoptotic mediators [XO, MPO, NO, IL-1\u03b2 and Casp -9 and -3]; and upregulating the level of interleukin 10 (IL-10). Moreover, treatment with 3-IPA lessened hepatorenal tissue injuries. These findings suggest that augmenting 3-IPA endogenously from tryptophan metabolism may provide a novel strategy to forestall xenobiotics-mediated hepatorenal toxicity, including AFB1.\n\nID: 35773404\nTitle: A Nurr1 ligand C-DIM12 attenuates brain inflammation and improves functional recovery after intracerebral hemorrhage in mice.\nAbstract: We have previously reported that amodiaquine, a compound that binds to the ligand-binding domain of a nuclear receptor Nurr1, attenuates inflammatory responses and neurological deficits after intracerebral hemorrhage (ICH) in mice. 1,1-Bis(3'-indolyl)-1-(p-chlorophenyl)methane (C-DIM12) is another Nurr1 ligand that recognizes a domain of Nurr1 different from the ligand-binding domain. In the present study, mice were treated daily with C-DIM12 (50 or 100\u00a0mg/kg, p.o.) or amodiaquine (40\u00a0mg/kg, i.p.), or twice daily with 1400\u00a0W (20\u00a0mg/kg, i.p.), an inducible nitric oxide synthase (iNOS) inhibitor, from 3\u00a0h after ICH induction by microinjection of collagenase into the striatum. C-DIM12 improved the recovery of neurological function and prevented neuron loss in the hematoma, while suppressed activation of microglia/macrophages and expression of inflammatory mediators interleukin-6 and CC chemokine ligand 2. In addition, C-DIM12 as well as amodiaquine preserved axonal structures in the internal capsule and axonal transport function. We also found that C-DIM12 and amodiaquine suppressed the increases of iNOS mRNA expression after ICH. Moreover, 1400\u00a0W improved neurological function and prevented neuron loss, activation of microglia/macrophages and axonal transport dysfunction. These results suggest that suppression of iNOS induction contributes to several features of the therapeutic effects of Nurr1 ligands.\n\nID: 35644820\nTitle: 3-Indolepropionic acid prevented chlorpyrifos-induced hepatorenal toxicities in rats by improving anti-inflammatory, antioxidant, and pro-apoptotic responses and abating DNA damage.\nAbstract: The application of chlorpyrifos (CPF), an organophosphorus pesticide to control insects, is associated with oxidative stress and reduced quality of life in humans and animals. Indole-3-propionic acid (IPA) is a by-product of tryptophan metabolism with high antioxidant capacity and has the potential to curb CPF-mediated toxicities in the hepatorenal system of rats. It is against this background that we explored the subacute exposure of CPF and the effect of IPA in the liver and kidney of thirty rats using five cohort experimental designs (n\u2009=\u20096) consisting of control (corn oil 2\u00a0mL/kg body weight), CPF alone (5\u00a0mg/kg), IPA alone (50\u00a0mg/kg), CPF\u2009+\u2009IPA1 (5\u00a0mg/kg\u2009+\u200925\u00a0mg/kg), and CPF\u2009+\u2009IPA2 (5\u00a0mg/kg\u2009+\u200950\u00a0mg/kg). Subsequently, we evaluated biomarkers of hepatorenal damage, oxidative and nitrosative stress, inflammation, DNA damage, and apoptosis by spectrophotometric and enzyme-linked immunosorbent assay methods. Our results showed that co-treatment with IPA decreased CPF-upregulated serum hepatic transaminases, creatinine, and urea; reversed CPF downregulation of SOD, CAT, GPx, GST, GSH, Trx, TRx-R, and TSH; and abated CPF upregulation of XO, MPO, RONS, and LPO. Co-treatment with IPA decreased CPF-upregulated IL-1\u03b2 and 8-OHdG levels, caspase-9 and caspase-3 activities, and increased IL-10. In addition, IPA averts CPF-induced histological changes in the liver and kidney of rats. Our results demonstrate that co-dosing CPF-exposed rats with IPA can significantly decrease CPF-induced oxidative stress, pro-inflammatory responses, DNA damage, and subsequent pro-apoptotic responses in rats' liver and kidneys. Therefore, supplementing tryptophan-derived endogenous IPA from exogenous sources may help avert toxicity occasioned by inadvertent exposure to harmful chemicals, including CPF-induced systemic perturbation of liver and kidney function.\n\nID: 34678318\nTitle: 3-Indolepropionic acid upturned male reproductive function by reducing oxido-inflammatory responses and apoptosis along the hypothalamic-pituitary-gonadal axis of adult rats exposed to chlorpyrifos.\nAbstract: We examined the effect of 3-Indolepropionic acid (3-IPA), an antioxidant on the organophosphorus pesticide chlorpyrifos (CPF)-induced reproductive toxicity in rats. The five experimental rat cohorts were treated per os for 14 consecutive days as follows: Control (Corn oil 2 mL/kg body weight), CPF alone (5 mg/kg), 3-IPA alone (40 mg/kg) and the co-treated rat cohorts (CPF:5 mg/kg + 3-IPA: 20 or 40 mg/kg). Biomarkers of testicular and epididymal function, oxidative stress, myeloperoxidase (MPO) activity and the levels of nitric oxide (NO), reactive oxygen and nitrogen (RONS) species and lipid peroxidation (LPO) were assessed. Also, tumour necrosis factor-alpha (TNF-\u03b1), Bcl-2-associated X (Bax) and B cell lymphoma 2 (Bcl-2) proteins were estimated, and tissue histology was microscopically examined. CPF alone significantly (p < 0.05) increased biomarkers of reproductive toxicities were averted in rats co-treated 3-IPA. Decreases in antioxidants and increases in lipid peroxidation and reactive oxygen and nitrogen species were lessened (p < 0.05) in CPF and 3-IPA co-treated rats. CPF mediated increases in TNF-\u03b1, NO, Bax, and MPO activity was reduced (p < 0.05) in the epididymis, testes, and hypothalamus of rats co-treated with 3-IPA. In addition, Bcl-2 expression was increased in rats co-treated with 3-IPA dose-dependently. Histopathological examination revealed severe lesions induced by CPF were prevented in rats co-treated with 3-IPA. Our findings demonstrate that exogenous 3-IPA reduced CPF-induced oxidative stress, inflammation, and apoptosis in the epididymis and testes of male rats.\n\nID: 42465542\nTitle: LC-MS-based serum metabolomics reveals distinct metabolic signatures in patients with intracerebral Hemorrhage.\nAbstract: Intracerebral hemorrhage (ICH) is a severe neurological disease with high mortality and disability, profoundly affecting patients' neurological function, daily activities, and quality of life. This study aimed to characterize the serum metabolic profile of patients with ICH and identify potential metabolic biomarkers associated with disease pathogenesis. Liquid chromatography-mass spectrometry (LC-MS) was employed to systematically analyze serum metabolite profiles and class distributions in 20 patients with and without ICH. Data quality was evaluated using quality control samples, while orthogonal partial least squares-discriminant analysis (OPLS-DA), differential metabolite analysis, KEGG pathway enrichment, Human Metabolome Database (HMDB), Metabolite Set Enrichment Analysis (MSEA), and receiver operating characteristic (ROC) analyses were performed. A total of 3,178 metabolites were identified. In patients with ICH, benzene and substituted derivatives were the most abundant metabolite class (15.63%), followed by organic acids (12.47%), amino acids and their metabolites (12.41%), and heterocyclic compounds (12.07%). Quality assessment demonstrated low variability in control samples (CV < 0.3), and OPLS-DA showed significant separation between the ICH and control groups (p < 0.01). Differential expression analysis revealed increased levels of benzene and substituted derivatives and organic acids, accompanied by decreased amino acids and lipid metabolites. KEGG pathway enrichment indicated significant involvement of linoleic acid, \u03b1-linolenic acid, arachidonic acid, retrograde endocannabinoid, choline metabolism in cancer, and glycerophospholipid metabolism. HMDB and MSEA analyses further demonstrated associations between differential metabolites and multiple metabolic diseases and physiological or pathological states. ROC analysis showed excellent diagnostic performance for several metabolites, with Dibutyl phthalate (AUC = 0.980), Octadecanamide (AUC = 0.960), Hypoxanthine (AUC = 0.840), and Lenticin (AUC = 0.810). These findings demonstrate distinct alterations in the serum metabolomic profile of patients with ICH and provide new insights into the metabolic mechanisms underlying ICH. The identified differential metabolites may serve as promising biomarkers for the diagnosis and investigation of ICH.\n\nID: 42332755\nTitle: Gut microbiota-derived metabolites as potential therapeutic agents for intervertebral disc degeneration: insights from network pharmacology and molecular docking.\nAbstract: Increasing evidence highlights the critical role of gut microbiota diversity in maintaining systemic homeostasis; however, the mechanisms by which microbiota-derived metabolites regulate host targets remain incompletely understood. Intervertebral disc degeneration (IDD) is strongly associated with chronic inflammation and metabolic dysregulation. This study employed a network pharmacology approach to elucidate metabolite-target interactions underlying the gut-disc axis. Gut microbiota-derived metabolites were retrieved from the gutMGene database, and their potential targets were predicted using the Similarity Ensemble Approach and SwissTargetPrediction. IDD-related genes were collected from GeneCards and OMIM databases. Overlapping targets were identified to construct a protein-protein interaction (PPI) network and screen core genes. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed using R software. A gut microbiota-metabolites-targets (G-M-T) network was established, followed by molecular docking to assess metabolite-target binding affinities. Twenty-two overlapping targets were identified, among which nine key candidates were initially screened. Network analysis revealed IL6, TLR4, CXCL8, and JUN as core targets due to their high connectivity. Enrichment analyses indicated that these targets were mainly involved in inflammatory responses, oxidative stress, apoptosis, extracellular matrix metabolism, and IL-17- and lipid-related pathways. The G-M-T network highlighted butyrate, propionate, acetate, succinate, trimethylamine oxide, and 3-indolepropionic acid as core metabolites. Molecular docking suggested favorable binding affinities, with 3-indolepropionic acid exhibiting the strongest interactions. Gut microbiota-derived metabolites, particularly 3-indolepropionic acid, may modulate IDD progression by targeting IL6, TLR4, CXCL8, and JUN through inflammation- and lipid-related pathways, providing mechanistic insights into the gut-disc axis.\n\nID: 42329535\nTitle: Age-related metabolomic signatures and stroke susceptibility in a population-based cohort.\nAbstract: Aging-related metabolic dysregulation and vascular vulnerability contribute substantially to stroke susceptibility, yet subtype-specific metabolic signatures remain incompletely characterized. Employing a nested case-control design within the Taizhou Longitudinal Study, we quantified 296 lipoprotein parameters and 54 metabolites in 1208 stroke-control pairs using nuclear magnetic resonance. Logistic regression estimated subtype-specific associations, and machine learning constructed prediction models for ischemic stroke (IS) and intracerebral hemorrhage (ICH). Distinct metabolic profiles were observed across stroke subtypes. Triglyceride-enriched lipoproteins and several low-molecular-weight metabolites were positively associated with both IS and ICH, whereas apolipoprotein A-related components showed inverse associations, with generally stronger effects observed for IS than for ICH. Age-stratified and interaction analyses revealed age-dependent heterogeneity, especially among histidine and lipoprotein composition measures. To further characterize systemic metabolic vulnerability, we constructed a weighted metabolic risk score (MRS), which was associated with age and statistically accounted for part of the age-stroke association (average causal mediation effects: 0.020 for IS; 0.025 for ICH). MRSs were also positively correlated with age and inflammatory markers, particularly for IS (both P\u2009<\u20090.001). Metabolite-based models improved risk discrimination beyond traditional risk factors for both IS and ICH. These findings identify subtype-specific metabolic signatures of stroke and suggest that circulating metabolomic profiles reflect age-associated metabolic alterations relevant to stroke susceptibility beyond traditional cardiometabolic risk factors.\n\nID: 42283270\nTitle: Identification of traumatic intracerebral hemorrhage associated metabolites using untargeted metabolomics.\nAbstract: Traumatic intracerebral hemorrhage (TICH) is a severe neurological emergency whose metabolic mechanisms remain largely unresolved. This study used serum metabolomics analysis to compare the metabolic profiles of TICH patients (n\u2009=\u200910) with non-TICH controls (n\u2009=\u200910). LC-MS/MS analysis identified a total of 3183 metabolites. The relative abundances of benzene and its derivatives, organic acids and their derivatives were significantly increased in the serum of ICH patients, while fatty acid, glycerophospholipid, and sphingomyelin metabolites were generally decreased. Multidimensional statistical methods were used to screen for significantly differentially expressed metabolites. Metabolite regulatory networks revealed the potential roles of amino acid metabolism, lipid metabolism (GP/SP/FA), and aromatic compounds (benzenes) in regulating TICH metabolism. Enrichment analysis revealed that these metabolites were highly enriched in lipid metabolism, amino acid metabolism, and neural signaling pathways, and were significantly associated with inflammatory drug pathways. The differentially expressed metabolites were further mapped to the Human Metabolite Database (HMDB) and subjected to metabolic-disease association analysis, suggesting that these metabolites may be closely related to the pathogenesis of TICH. ROC analysis demonstrated good diagnostic performance of five key metabolites in both discovery and validation cohorts (AUC > 0.70), with hypoxanthine and L-histidine showing the highest accuracy (AUC > 0.93). Correlation analysis indicated that key metabolites were associated with hematoma volume, NIHSS and GCS scores. In vitro experiments further confirmed that, under conditions of neuronal injury, the changes in these metabolites exhibit consistency. This study provides a theoretical basis for the development of potential biomarkers and precise intervention strategies.\n\nID: 42163413\nTitle: Gut microbiota-derived indole-3-propionic acid promotes lymph node metastasis in gastric cancer via the aryl-hydrocarbon receptor signaling pathway.\nAbstract: Gut microbiota (GM) regulates the tumor microenvironment through microbial metabolites. Indole 3-propionic acid (3-IPA) is one such metabolite that regulates gastrointestinal barrier function. In this study, we investigated the effects of 3-IPA on the progression of lymph node metastasis of gastric cancer (GC) and the molecular mechanisms that underlie them. The microbial metabolites were identified using a fecal metabolomic assay in GC patients. Lymphangiogenesis was evaluated using tube formation and wound healing assays in vitro. The expression of aryl hydrocarbon receptor (AHR), CYP1A1, and vascular endothelial growth factor receptor 3 (VEGFR3) were assayed using quantitative real-time PCR (qRT-PCR) and western blot (WB) analyses. Matrigel plug and popliteal lymph node metastasis model were employed to validate the influence on lymphangiogenesis and lymph node metastasis in vivo. Fecal metabolomic and microbiome profiling was drastically different between GC patients with lymph node metastasis (GC-LM) and those without metastasis. The GC-LM group showed high 3-IPA expression in the feces; 3-IPA had no significant effect on GC cells; Human lymphatic endothelial cells showed greater tube formation and promoted migration after 3-IPA administration. Also, upregulation of AHR, CYP1A1, and VEGFR3 was observed. Moreover, administration of the AHR inhibitor suppressed tube formation and lymph node metastasis both in vitro and in vivo. Our findings suggest that gut microbiota-derived 3-IPA functions as a lymph node metastasis promoter through the AHR/CYP1A1-VEGFR3 axis in GC. 3-IPA could serve as a prognostic biomarker and conceivably a therapeutic target for GC lymph node metastasis.\n\nID: 42105993\nTitle: Multifaceted mechanisms of 4-hydroxybenzaldehyde in reducing hemorrhagic transformation in ischemic stroke ameliorating based on transcriptomics and metabolomics.\nAbstract: The PI3K-AKT signaling pathway has emerged as a central modulator in the pathophysiology of hemorrhagic transformation (HT). Gastrodia elata Blume, a classic neuroprotective herb used in Traditional Chinese Medicine, traditionally believed to \"calm endogenous wind\" and \"unblock meridians\". Although phenolic compounds are recognized as key neuroprotective constituents, their anti-hemorrhagic mechanisms remain. This study aimed to validate 4-hydroxybenzaldehyde (4-HBd), a major phenolic component of G. elata, as a therapeutic candidate against ischemic stroke (IS)-associated HT, with a focus on its modulation of PI3K-AKT signaling. A rat model of transient middle cerebral artery occlusion with induced HT (tMCAO-HT) was established and treated with 4-HBd (20\u00a0mg/kg) for assessment of intracerebral hemorrhage and neurological function. Integrated transcriptomic and metabolomic profiling identified 214 differentially expressed genes and 38 differential metabolites. Molecular docking simulations evaluated 4-HBd binding to PI3K and AKT, and in vitro validation was performed in hypoxia-exposed PC12\u00a0cells using viability assays and western blot analysis. 4-HBd administration significantly attenuated cerebral hemorrhage (P\u00a0<\u00a00.01) and improved neurological function (P\u00a0<\u00a00.01). Multi-omics analysis revealed convergent enrichment of the PI3K-AKT pathway (KEGG: hsa04151), supported by high-affinity docking to both PI3K (\u0394G\u00a0=\u00a0-5.7\u00a0kcal/mol) and AKT (\u0394G\u00a0=\u00a0-5.3\u00a0kcal/mol). Treatment enhanced p-PI3K and p-AKT expression (P\u00a0<\u00a00.01), rescuing PC12\u00a0cells viability under hypoxic conditions (P\u00a0<\u00a00.05). 4-HBd exerts protective effects against HT by restoring PI3K-AKT signaling.\n\nID: 41825730\nTitle: Lactobacillus johnsonii and 3-indolepropionic acid improve the depression-like behaviors via inhibiting neuroinflammation.\nAbstract: Gut microbiota-derived metabolites play a crucial role in depression. This study aimed to elucidate the role of tryptophan metabolites herein. In a CSDS mouse model, we identified eight differential species, twelve altered neurotransmitters, and two up-regulated inflammatory factors (IL-6 and IL-1\u03b2). Notably, 3-indolepropionic acid (IPA) levels were consistently reduced in feces, colon, blood, and hippocampus of CSDS mice. The decreased abundance of Lactobacillus johnsonii (L. johnsonii) was correlated closely with depression-like behaviors (DLBs), reduced fecal IPA, and elevated IL-6 and IL-1\u03b2. Both L. johnsonii and IPA supplementation alleviated DLBs, along with up-regulated AhR and down-regulated NF-\u03baB, NLRP3, IL-6, and IL-1\u03b2 in hippocampus. Moreover, both treatments significantly elevated IPA levels in peripheral and central samples, and improved the mRNA levels of AhR and NF-\u03baB p65 in hippocampus. Critically, the antidepressant effects of L. johnsonii and IPA were counteracted by AhR antagonist CH223191. Independent experimental results showed that CH223191 had no significant effects on behaviors of CSDS mice. To our knowledge, this was the first study to report reduced IPA levels in both peripheral and central samples of CSDS mice. We also provided the first demonstration that the antidepressant effects of L. johnsonii and IPA were mediated, at least in part, through the inhibition of neuroinflammation via AhR pathway, accompanied by the restoration of IPA levels in gut-brain axis. These findings positioned L. johnsonii and IPA as promising therapeutic candidates for depression.\n\nID: 41264131\nTitle: The role of metabolomics in stroke: biomarkers of diagnosis and therapy.\nAbstract: Stroke is a neurological condition caused by an acute focal injury to the central nervous system, typically resulting from vascular events such as cerebral infarction, intracerebral hemorrhage, or subarachnoid hemorrhage. It is associated with high rates of incidence, disability, recurrence, and mortality. To reduce stroke-related mortality, researchers worldwide have developed various in vitro and in vivo models to study molecular mechanisms at different levels, including genes, microRNAs, and proteins, to identify biomarkers for improved diagnosis, treatment, and prognosis. Metabolomics, an emerging field derived from genomics and proteomics, plays a crucial role in understanding stroke pathophysiology. Changes in the metabolome can reflect the body's physiological state following a stroke. Numerous studies have identified biomarkers that aid in stroke diagnosis and treatment by analyzing metabolic alterations in vivo or in vitro stroke models. This article reviews the causes, diagnosis, and treatment of stroke, the role of metabolomics in stroke research, and the clinical significance of some biomarkers discovered by metabolomics for clinical work.\n\nID: 41231628\nTitle: Molecular biomarkers for intracerebral hemorrhage: bridging pathophysiology and precision medicines.\nAbstract: Intracerebral hemorrhage (ICH) is a highly destructive subtype of stroke, characterized by high mortality and disability rates, and remains a major clinical challenge due to limited effective treatments, hyperacute diagnostic tools, and insufficient prognostic strategies. Current approaches, primarily based on clinical symptoms and neuroimaging, effectively identify location but lack sensitivity for early risk assessment and dynamic disease monitoring. Molecular biomarkers have shown great promise in elucidating ICH pathogenesis, enhancing diagnostic sensitivity, enabling dynamic disease tracking, and improving outcome prediction. However, clinical translation remains hindered by challenges in standardization, specificity, and validation frameworks. This review systematically summarizes recent advances in biomarker research related to ICH, with a particular focus on key etiological mechanisms such as hypertension and cerebral amyloid angiopathy, as well as critical pathophysiological processes including hematoma expansion, perihematomal edema, neuroinflammation, and oxidative stress. We further explore the emerging role of multi-omics technologies, including genomics, transcriptomics, proteomics, and metabolomics, in identifying ICH specific molecular signatures. Emphasis is placed on the potential clinical utility of these biomarkers in high-risk population screening, early diagnosis, disease monitoring, and outcome prediction. Moreover, we propose the development of a disease-specific, multidimensional biomarker panel that integrates advanced neuroimaging and artificial intelligence-based analytical strategies. This approach aims to accelerate the clinical translation of biomarkers into precision medicine, supporting personalized therapeutic decision-making, preventing the onset of ICH, and improving outcomes. It further promotes a paradigm shift in ICH management from passive treatment to proactive prevention and control.\n\nID: 40750967\nTitle: Gut Microbial Metabolite Crosstalk in Crohn's Disease: Network Pharmacology Unveils Dual-Axis Pathogenesis and Therapeutic Targets.\nAbstract: Crohn's disease (CD), a chronic inflammatory bowel disorder, is driven by dysregulated interactions between gut microbiota and host metabolism. Here, we developed a computational framework integrating multiomics profiling, network pharmacology, and molecular dynamics simulations to systematically map microbiota-metabolite-target-signaling (M-M-T-S) networks and identify therapeutic candidates. By analyzing gut microbial metabolomics and CD-associated targets (via SwissTargetPrediction [STP]/SEA), we constructed a protein-protein interaction (PPI) network enriched for 50 intestinal hub targets (IL6, AKT1, PPARG; degree centrality [CD]\u2009>\u200919.4), which orchestrate inflammatory (TNF/IL-17/TLR, FDR\u2009=\u20093.8\u2009\u00d7\u200910-12) and metabolic (PPAR, FDR\u2009=\u20091.5\u2009\u00d7\u200910-10) pathways. Structure-based screening (AutoDock Vina/AMBER20) revealed 3-indolepropionic acid (IPA) as a high-affinity AKT1 binder (\u0394G\u2009=\u2009-67.4\u2009kJ/mol), while Genipin exhibited robust binding to PTGS2, both validated by 100-ns dynamics simulations (RMSD\u2009<\u20093.8\u2009\u00c5). Mechanistic network analysis uncovered a dual-axis regulatory paradigm: a pro-inflammatory axis (Clostridiumspp.-derived LPS aggravates Th17 polarization via TLR4/IL-17 signaling) and a reparative axis (Faecalibacterium prausnitzii-produced butyrate enhances barrier integrity through PPAR\u03b3-mediated NF-\u03baB suppression). Phylogenetic analysis linked microbial functional traits (e.g., LPS/SCFA synthesis) to evolutionary conservation, highlighting clade-specific roles in CD progression. Drug-likeness evaluation (SwissADME/ADMETlab 2.0) prioritized IPA as a lead candidate due to its superior solubility (7.65\u2009mg/mL), nonhepatotoxic profile, and AhR agonism, outperforming Genipin. This study establishes IL6/AKT1/PPARG as central therapeutic hubs and positions IPA for clinical translation. Our framework bridges multiomics integration with precision medicine, offering a scalable strategy to decode microbiome-driven pathologies and accelerate metabolite-based therapeutics.\n\nID: 40571216\nTitle: Novel aryl hydrocarbon receptor agonists as potential anti-inflammatory therapeutics: Identification and validation through drug repurposing.\nAbstract: The aryl hydrocarbon receptor (AhR) was shown to be an important regulator of inflammatory processes at epithelial barriers, and is thus considered a therapeutic target for several chronic inflammatory diseases, such as inflammatory bowel disease. We aimed to identify and validate new AhR agonists that sustainably attenuate intestinal inflammation. Using a high-throughput luciferase reporter gene assay, 90 AhR ligands were identified out of 7448 approved and investigational drugs. Out of these, 15 AhR ligands were selected based on substance class, half maximal effective concentration, known toxicity and pharmacokinetic/pharmacodynamic profiles, and preclinical/clinical evaluation status for other indications. While Febuxostat, Nitazoxanide, Rabeprazole, 2-(1'H-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester, 3-Indolepropionic acid, and Indirubin, were already known as AhR agonists, Nabumetone, Teriflunomide, Timapiprant/OC000459, and Caffeic acid phenylethyl ester have not yet been directly described in this context. Six compounds (Daidzein/Equol, as well as compounds no. 19, 22, 49, and 64, not yet disclosed due to pending patent applications) were newly described as AhR agonists. Hit compounds were studied in silico for their molecular interactions with AhR and in vitro for potential immunotoxicity and their ability to induce interleukin (IL)-10 and/or to suppress IL-1\u03b2 in murine macrophages without significant cytochrome P450 1A1 induction in Caco-2 cells. Five compounds that met these criteria were functionally tested using organoid-based Transwell\u00ae-like models derived from gut biopsies. Five candidates restored the epithelial barrier, as evidenced by increased transepithelial electrical resistance and induction of the tight junction proteins claudin-1/-2 and occludin, while exhibiting anti-inflammatory effects, i.e., decreased expression of toll-like receptor 4. Out of these, one compound was selected for future in vivo preclinical studies.\n\nID: 40532744\nTitle: Indole-3 propionate inhibits NF-\u03baB/NLRP3-mediated osteoclastogenesis and improves bone quality in high-fat-diet induced obese mice.\nAbstract: Obesity is a global health issue that causes altered gut microbiota and a wide variety of diseases, such as osteoporosis. The association between altered gut microbiota metabolites and high-fat diet (HFD)-induced osteoporosis has not been thoroughly investigated. 3-Indolepropionic acid (IPA) is a gut microbiota metabolite that is deficient in obese mice. The purpose of this study is to examine wheter IPA affects osteoporosis in HFD-induced obese mice. Mice were fed with HFD for 12\u00a0weeks, during which IPA or vancomycin was administered. Micro-computed tomography, hematoxylin and eosin (H&E) staining, and tartrate-resistant acid phosphatase (TRAP) staining were used to evaluate osteoporosis and osteoclast activation in vivo. Cultured bone marrow macrophages were used to examine osteoclast activation in vitro. Western blot, immunohistochemical staining, and immunofluorescence staining were used to investigate the nuclear factor kappa B (NF-\u03baB) and NLRP3 signaling pathways. Reduced bone mass and noticeable osteoclast activation were observed in mice fed with HFD and vancomycin. IPA supplementation alleviated systemic inflammatory response, inhibited osteoclast activation, and improved bone mass in mice. Mechanistically, IPA inhibited the phosphorylation of NF-\u03baB, thus, reducing the expression levels of NLRP3, caspase-1, and apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) and inhibiting osteoclast activation. These findings suggest that IPA-induced inhibition of osteoclast activation in the HFD environment was mediated via the NF-\u03baB/NLRP3 pathway. Our study suggests that IPA consumption may help manage obesity-induced osteoporosis.\n\nID: 40297859\nTitle: Metabolomic analysis reveals trimethylamine N-oxide as a biomarker for poor outcome of severe spontaneous intracerebral hemorrhage patients receiving surgical treatment.\nAbstract: Patients suffering from severe spontaneous intracerebral hemorrhage (SSICH) are at high risk of cardiocerebrovascular diseases postoperatively, which hugely affect patients' long-term outcomes. Metabolic features could reflect the pathological change of the cardiocerebrovascular system and might serve as biomarkers for evaluating the risk of poor outcomes in SSICH patients. The current study aimed to find the early-warning biomarkers for poor outcomes in SSICH patients after surgery. Severe spontaneous intracerebral hemorrhage patients receiving surgical treatment from a referring hospital were prospectively included and formed the primary cohort after propensity score matching. The primary outcome is poor 180\u202fdays after hemorrhage (modified Rankin scale \u22654). Metabolomics analysis on 3-, 7-, and 30-day serum and cerebrospinal fluid samples after surgery revealed the dysregulated metabolites of SSICH patients within the primary cohort. Within the validation cohort of SSICH patients receiving surgical treatment from a multicenter, prospective cohort, dysregulated metabolites were validated and evaluated to see whether they could serve as biomarkers for 180-day poor outcomes by area under the curve (AUC). The primary cohort included 20 SSICH patients with good 180-day outcome and 20 with poor outcome. Untargeted metabolomics analysis found 25 co-dysregulated metabolites, including trimethylamine N-oxide (TMAO), among 3-day, 7-day, and 30-day metabolism features between SSICH patients with poor outcome and good outcome after surgery. A good correlation was found in TMAO between serum and cerebrospinal fluid on 3rd day after surgery. Based on the validation cohort of 794 SSICH patients (147 patients had 180-day poor outcome), the targeted metabolomics analysis revealed increasing TMAO on 3rd day after surgery as a risk factor of poor outcomes (odds ratio, 4.7; 95%CI, 3.6-6.2; p\u202f<\u202f0.001), with a good predictive value (AUC, 0.81). This study demonstrated increasing serum TMAO level as an early-warning biomarker for 180-day poor outcomes of SSICH patients receiving surgical treatment. Chinese Clinical Trial Registry, ChiCTR1900024406, https://www.chictr.org.cn/showproj.html?proj=40640.\n\nID: 40174685\nTitle: Fusobacterium nucleatum-derived 3-indolepropionic acid promotes colorectal cancer progression via aryl hydrocarbon receptor activation in macrophages.\nAbstract: An increasing body of research indicates that Fusobacterium nucleatum (F. nucleatum) significantly influences the onset and progression of colorectal cancer (CRC). Our previous study has shown that F. nucleatum exerts pro-tumorigenic effects through aryl hydrocarbon receptor (AhR) activation. However, the role of its microbial metabolites in regulating immune responses remains unclear. Here, we report for the first time that F. nucleatum-derived 3-Indolepropionic acid (IPA) activates AhR in macrophages, driving M2 polarization and tumor-promoting immunosuppression. We discovered that culture supernatant of F. nucleatum (CSF) robustly activates AhR in macrophages. In co-culture systems, CSF upregulated the expression of the M2 marker CD206 and elevated mRNA levels of CD163, TGF-\u03b2, IL-10, and VEGF. In a subcutaneous allograft model, CSF induced an elevated number of CD206+ macrophages and decreased presence of CD8+ T cells within the tumor microenvironment, thereby promoting tumor growth. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) revealed IPA as a novel major AhR-activating metabolite in CSF. Strikingly, IPA recapitulated CSF's effects in promoting tumor cell migration and immunosuppression, both in vitro and in vivo. Critically, the AhR inhibitor CH223191 abolished both IPA-mediated M2 polarization and tumor growth. Our study revealed a novel mechanism by which F. nucleatum-derived IPA reprograms macrophages through AhR activation to fuel CRC progression, providing potential therapeutic targets for CRC treatment and prognosis improvement.\n\nID: 40069432\nTitle: Influx of Metabolites into Cerebrospinal Fluid in Intracerebral Hemorrhage is Associated with Increased Central Inflammation: a Retrospective Observational Study.\nAbstract: Intracerebral hemorrhage (ICH) is characterized by the rupture of blood vessels, allowing components from peripheral circulation to infiltrate the brain and impair central immune functions. This study employs non-targeted metabolomics to compare cerebrospinal fluid (CSF) metabolites between acute-phase and recovery-phase of ICH, aiming to identify metabolites associated with ICH central inflammation. CSF and plasma samples were collected from a retrospective observational cohort of participants with ICH (n\u2009=\u200938). Additionally, we obtained CSF samples from patients who underwent lower limb surgery due to accidental injuries, serving as healthy controls (n\u2009=\u200912). Non-targeted metabolomics analysis was performed, and inflammatory factors in the CSF were measured. The association between these metabolites and inflammation in the CSF was validated using a collagenase-induced ICH mouse model and microglial cultures in vitro. Our results demonstrate that the levels of certain metabolites in the cerebrospinal fluid of ICH patients changed significantly from the acute phase to the recovery phase (P\u2009<\u20090.05, VIP\u2009>\u20091). Furthermore, the concentration of inflammatory factors in the acute-phase CSF was significantly higher compared to both the recovery phase of ICH and healthy control levels. Correlation analyses of inflammatory factors and the patients' CSF metabolites revealed several metabolites associated with central inflammation. Notably, kynurenic acid (Kyna) exhibited a positive correlation with central inflammation and a negative correlation with the Glasgow Coma Scale (GCS). In the collagenase-induced ICH mouse model, elevated levels of Kyna were also associated with increased inflammation in the CSF. Additionally, in vitro studies demonstrated that Kyna regulates inflammatory cytokines by activating microglia. Our study highlights a significant relationship between metabolites in the CSF of ICH patients and central inflammation. Specifically, Kyna promotes inflammation by activating microglia, suggesting its potential as a promising target for therapeutic intervention in ICH central inflammation. Registration: 2023-KY-155-02.\n\nID: 39845950\nTitle: Rat models of postintracerebral hemorrhage pneumonia induced by nasal inoculation with Klebsiella pneumoniae or intratracheal inoculation with LPS.\nAbstract: A stable and reproducible experimental bacterial pneumonia model postintracerebral hemorrhage (ICH) is necessary to help investigating the pathogenesis and novel treatments of Stroke-associated pneumonia (SAP). To establish a Gram-negative bacterial pneumonia-complicating ICH rat model and an acute lung injury (ALI)-complicating ICH rat model. We established two standardized models of post-ICH pneumonia by nasal inoculation with Klebsiella pneumoniae (Kp) or intratracheal inoculation with lipopolysaccharide (LPS). Survival and neurological scores were monitored. Magnetic resonance imaging was performed to evaluate hematoma volume. Abdominal aortic blood was collected for leukocyte counting, serum was isolated to determine concentrations of S100\u03b2 and proinflammatory cytokines using ELISAs. Histopathological changes of brain, lung and gut were assessed using hematoxylin-eosin staining. Lung was isolated for immunofluorescence staining for myeloperoxidase (MPO). Bronchoalveolar lavage fluid was collected for leukocyte counting, and supernatant was prepared to measure MPO activity. Ileum was isolated for immunofluorescence staining for tight junction proteins ZO-1 and \u03b3\u03b4 TCRs/IL-17A and for Alcian blue-nuclear fast red staining of acidic mucins. Feces were collected, 16S rRNA sequencing, untargeted metabolomics and Spearman's correlation analyses were performed to explore changes of gut microbiota, metabolites and their interactions. In Kp-induced bacterial pneumonia-complicating ICH rats, we demonstrated that Kp challenge caused more severe neurological deficits, brain damage, neuroinflammation, and aggravated pneumonia and lung injury. Disruptions of the intestinal structure and gut barrier and the reductions of the protective intestinal IL-17A-producing \u03b3\u03b4T cells were also observed. Kp challenge exacerbated the gut microbiota dysbiosis and fecal metabolic profile disorders, which were characterized by abnormal sphingolipid metabolism especially elevated ceramide levels; increased levels of neurotoxic quinolinic acid and an upregulation of tryptophan (Trp)-serotonin-melatonin pathway. Spearman's correlation analyses further revealed that the reduction or depletion of some beneficial bacteria, such as Allobaculum and Faecalitalea, and the blooming of some opportunistic pathogens, such as Turicibacter, Dietzia, Corynebacterium and Clostridium_sensu_stricto_1 in Kp-induced SAP rats were associated with the disordered sphingolipid and Trp metabolism. Using an LPS-induced ALI complicating ICH model, we also characterized SAP-induced brain, lung and gut histopathology injuries; peripheral immune disorders and intense pulmonary inflammatory responses. These two models may be highly useful for investigating the pathogenesis and screening and optimizing potential treatments for SAP. Moreover, the differential genera and sphingolipid or Trp metabolites identified above seem to be promising therapeutic targets.\n\nID: 39247810\nTitle: Interaction Between the PERK/ATF4 Branch of the Endoplasmic Reticulum Stress and Mitochondrial One-Carbon Metabolism Regulates Neuronal Survival After Intracerebral Hemorrhage.\nAbstract: Recent investigations have revealed that oxidative stress can lead to neuronal damage and disrupt mitochondrial and endoplasmic reticulum functions after intracerebral hemorrhage (ICH). However, there is limited evidence elucidating their role in maintaining neuronal homeostasis. Metabolomics analysis, RNA sequencing, and CUT&Tag-seq were performed to investigate the mechanism underlying the interaction between the PERK/ATF4 branch of the endoplasmic reticulum stress (ERS) and mitochondrial one-carbon (1C) metabolism during neuronal resistance to oxidative stress. The association between mitochondrial 1C metabolism and the PERK/ATF4 branch of the ERS after ICH was investigated using transcription factor motif analysis and co-immunoprecipitation. The findings revealed interactions between the GRP78/PERK/ATF4 and mitochondrial 1C metabolism, which are important in preserving neuronal homeostasis after ICH. ATF4 is an upstream transcription factor that directly regulates the expression of 1C metabolism genes. Additionally, the GRP78/PERK/ATF4 forms a negative regulatory loop with MTHFD2 because of the interaction between GRP78 and MTHFD2. This study presents evidence of disrupted 1C metabolism and the occurrence of ERS in neurons post-ICH. Supplementing exogenous NADPH or interfering with the PERK/ATF4 could reduce symptoms related to neuronal injuries, suggesting new therapeutic prospects for ICH.\n\nID: 38809507\nTitle: Jingfang granules protects against intracerebral hemorrhage by inhibiting neuroinflammation and protecting blood-brain barrier damage.\nAbstract: Intracerebral hemorrhage (ICH) can induce intensive oxidative stress, neuroinflammation, and brain cell apoptosis. However, conventional methods for ICH treatment have many disadvantages. There is an urgent need for alternative, effective therapies with minimal side effects. Pharmacodynamics experiment, molecular docking, network pharmacology, and metabolomics were adopted to investigate the treatment and its mechanism of Jingfang Granules (JFG) in ICH. In this study, we investigated the therapeutic effects of JFG on ICH using behavioral, brain water content and Magnetic resonance imaging experiments. However, the key active component and targets of JFG remain unknown. Here we verified that JFG was beneficial to improve brain injury after ICH. A network pharmacology analysis revealed that the anti-inflammatory effect of JFG is predominantly mediated by its activation of the phosphatidylinositol 3-kinase (PI3K)/AKT pathway through Luteolin, (+)-Anomalin and Phaseol and their targeting of AKT1, tumor necrosis factor\u03b1 (TNF-\u03b1), and interleukin-1\u03b2 (IL-1\u03b2). Molecular docking analyses revealed an average affinity of -8.633 kcal/mol, indicating a binding strength of less than -5 kcal/mol. Metabolomic analysis showed that JFG exerted its therapeutic effect on ICH by regulating metabolic pathways, such as the metabolism of taurine and hypotaurine, biosynthesis of valine, leucine, and isoleucine. In conclusion, we demonstrated that JFG attenuated neuroinflammation and BBB injury subsequent to ICH by activating the PI3K/Akt signaling pathway.\n\nID: 38066208\nTitle: Injury-specific factors in the cerebrospinal fluid regulate astrocyte plasticity in the human brain.\nAbstract: The glial environment influences neurological disease progression, yet much of our knowledge still relies on preclinical animal studies, especially regarding astrocyte heterogeneity. In murine models of traumatic brain injury, beneficial functions of proliferating reactive astrocytes on disease outcome have been unraveled, but little is known regarding if and when they are present in human brain pathology. Here we examined a broad spectrum of pathologies with and without intracerebral hemorrhage and found a striking correlation between lesions involving blood-brain barrier rupture and astrocyte proliferation that was further corroborated in an assay probing for neural stem cell potential. Most importantly, proteomic analysis unraveled a crucial signaling pathway regulating this astrocyte plasticity with GALECTIN3 as a novel marker for proliferating astrocytes and the GALECTIN3-binding protein LGALS3BP as a functional hub mediating astrocyte proliferation and neurosphere formation. Taken together, this work identifies a therapeutically relevant astrocyte response and their molecular regulators in different pathologies affecting the human cerebral cortex.\n\nID: 37892146\nTitle: Gut Microbiota Metabolite 3-Indolepropionic Acid Directly Activates Hepatic Stellate Cells by ROS/JNK/p38 Signaling Pathways.\nAbstract: There has been a growing interest in studying the communication of gut microbial metabolites between the gut and the liver as liver fibrosis progresses. Although 3-Indolepropionic acid (IPA) is regarded as a clinically valuable gut metabolite for the treatment of certain chronic diseases, the effects of oral administration of IPA on hepatic fibrosis in different animal models have been conflicting. While some mechanisms have been proposed to explain these contradictory effects, the direct impact of IPA on hepatic fibrosis remains unclear. In this study, we found that IPA could directly activate LX-2 human hepatic stellate cells in vitro. IPA upregulated the expression of fibrogenic marker genes and promoted the features associated with HSCs activation, including proliferation and contractility. IPA also increased reactive oxygen species (ROS) in mitochondria and the expression of inflammation-related genes in LX-2 cells. However, when a ROS-blocking agent was used, these effects were reduced. p38 and JNK, the downstream signaling cascades of ROS, were found to be required for the activation of LX-2 induced by IPA. These findings suggest that IPA can directly activate hepatic stellate cells through ROS-induced JNK and p38 signaling pathways.\n\nID: 37598880\nTitle: Multi-time point metabolomics reveals key metabolic features from the ultra-early stage of intracerebral hemorrhage in mice.\nAbstract: Despite decades of intensive research, there are still very limited options for the effective treatment of intracerebral hemorrhage (ICH). Recently, mounting evidence has indicated that the ultra-early stage (<3\u00a0h), serving as the primary phase of ICH, plays a pivotal role and may even surpass other stages in terms of its significance. Therefore, uncovering the metabolic alterations induced by ICH in the ultra-early stage is of crucial importance. To investigate this, the collagenase ICH mouse model was employed in this study. ICH or sham-operated mice were euthanized at the ultra-early stage of 3\u00a0h and the acute stage of 24\u00a0h and 72\u00a0h after the operation. Then, the metabolic changes in the perihematomal tissues were detected by liquid chromatography coupled with tandem mass spectrometry. In total, alterations in the levels of 465 metabolites were detected. A total of 136 metabolites were significantly changed at 3\u00a0h. At 24\u00a0h and 72\u00a0h, the amounts were 132 and 126, respectively. Additionally, the key corresponding metabolic pathways for these time points were analyzed through KEGG. To gather additional information, quantitative real-time transcription polymerase chain reaction, enzyme-linked immunosorbent assay and Western blots were performed to validate the metabolic changes. Overall, ICH significantly alters important physiological functions such as cysteine metabolism, purine metabolism, synaptic alterations, the synaptic vesicle cycle, and the ATP-binding cassette transporter system. These might be the key pathologic mechanisms of the ultra-early stage induced by ICH.\n\nID: 37367902\nTitle: Metabolomic Analysis in Neurocritical Care Patients.\nAbstract: Metabolomics is the analytical study of metabolites in biological matrices using high-throughput profiling. Traditionally, the metabolome has been studied to identify various biomarkers for the diagnosis and pathophysiology of disease. Over the last decade, metabolomic research has grown to include the identification of prognostic markers, the development of novel treatment strategies, and the prediction of disease severity. In this review, we summarized the available evidence on the use of metabolome profiling in neurocritical care populations. Specifically, we focused on aneurysmal subarachnoid hemorrhage, traumatic brain injury, and intracranial hemorrhage to identify the gaps in the current literature and to provide direction for future studies. A primary literature search of the Medline and EMBASE databases was conducted. Upon removing duplicate studies, abstract screening and full-text screening were performed. We screened 648 studies and extracted data from 17 studies. Based on the current evidence, the utility of metabolomic profiling has been limited due to inconsistencies amongst studies and a lack of reproducible data. Studies identified various biomarkers for diagnosis, prognosis, and treatment modification. However, studies evaluated and identified different metabolites, resulting in an inability to compare the study results. Future research towards addressing the gaps in the current literature, including reproducing data on the use of specific metabolite panels, is needed.\n\nID: 37232423\nTitle: Glutathione Depleting a Chemoselective Novel Pro-oxidant Nano Metal-Organic Framework Induced G2/M Arrest and ROS-Mediated Apoptotic Cell Death in a Human Triple-Negative Breast Cancer Cell Line.\nAbstract: The progression of a new class of compounds to inhibit the uncontrolled proliferation of carcinoma cells has become one of the most powerful weapons to combat \"cancer\". To this end, a new Mn(II)-based metal-organic framework, namely, [{Mn(5N3-IPA)(3-pmh)}(H2O)]\u03b1 (5N3H2-IPA = 5-azidoisophthalic acid and 3-pmh = (3-pyridylmethylene)hydrazone), has been synthesized adopting a mixed ligand approach and exploited as a successful anticancer agent via systematic in vitro and in vivo studies. Single-crystal X-ray diffraction analyses depict that MOF 1 exhibits a 2D pillar-layer structure consisting of water molecules in each 2D void space. Due to the insolubility of the as-synthesized MOF 1, a green hand grinding methodology has been adopted to scale down the particle size to the nanoregime keeping its structural integrity intact. The nanoscale metal-organic framework (NMOF 1) adopts a discrete spherical morphology as affirmed by scanning electron microscopic analysis. The photoluminescence studies revealed that NMOF 1 is highly luminescent, enhancing its biomedical proficiency. Initially, the affinity of the synthesized NMOF 1 for GSH-reduced has been evaluated by various physicochemical techniques. NMOF 1 constrains the proliferation of cancer cells in vitro by inducing G2/M seizure and accordingly leads to apoptotic cell death. More significantly, compared to cancer cells, NMOF 1 exhibits less cytotoxicity against normal cells. It has been demonstrated that NMOF 1 interacts with GSH, causing a drop in cellular GSH levels and the production of intercellular ROS. It is quite intriguing that we discovered that NMOF 1-mediated ROS generation aids in significantly modifying the mitochondrial redox status, which is a crucial factor in apoptosis. According to mechanistic research, NMOF 1 increases the production of proapoptotic proteins and lowers the expression of antiapoptotic proteins, which significantly aids in activating caspase 3 and the subsequent cleavage of PARP1 and cell death via intrinsic apoptotic pathways. Finally, an in vivo investigation using immuno-competent syngeneic mice demonstrates that NMOF 1 can stop tumor growth without causing adverse side effects.\n\nID: 37152968\nTitle: Potential preventive markers in the intracerebral hemorrhage process are revealed by serum untargeted metabolomics in mice using hypertensive cerebral microbleeds.\nAbstract: Hypertensive cerebral microbleeds (HCMB) may be the early stage of hypertensive intracerebral hemorrhage (HICH), which is a serious threat to health due to its high mortality and disability rates. The early clinical symptoms of HCMB may not be significant. Moreover, it is difficult to achieve early diagnosis and intervention for targeted prevention of HICH. Although hypertension (HTN) is a predisposition for HCMB, it remains unclear whether there is any difference between hypertensive patients with or without HCMB. Therefore, we carried out liquid chromatography-mass spectrometry (LC-MS) to analyze early biomarkers for HCMB in mice with hypertension and to lay the foundation for early prevention of HICH in hypertensive patients. In total, 18 C57 male mice were randomly divided into the HCMB (n = 6), HTN (n = 6), and control groups (CON, n = 6). Hematoxylin-eosin and diaminobenzidine staining were used to assess the reliability of the model. The metabolite expression level and sample category stability were tested using the displacement test of orthogonal partial least squares discriminant analysis (OPLS-DA). Significant differences in metabolites were screened out using variable importance in the projection (VIP > 1), which were determined using the OPLS-DA model and the P-value of the t-test (P < 0.05) combined with the nonparametric rank-sum test. With an area under the curve (AUC) > 0.85 and a P-value of 0.05, the receiver operating characteristic curve (ROC) was used to further screen the distinct metabolites of HCMB. Compared with the HTN and CON groups, the HCMB group had significantly higher blood pressure and lower average body weight (P < 0.05). Through untargeted LC-MS analysis, 93 distinct metabolites were identified in the HCMB (P < 0.05, VIP > 1) group. Among these potential biomarkers, six significantly decreased and eight significantly increased differential metabolites were found. Meanwhile, we found that the HCMB group had statistically distinct arginine and purine metabolism pathways (P < 0.05), and citrulline may be the most significant possible biomarker of HCMB (AUC > 0.85, P < 0.05). All of these potential biomarkers may serve as early biomarkers for HICH in hypertension.\n\nID: 42575875\nTitle: Progression to Dementia in Very Late-Onset Schizophrenia-Like Psychosis Stratified by Alzheimer's Disease and Lewy Body Disease Biomarkers: A Retrospective Cohort Study.\nAbstract: Very late-onset schizophrenia-like psychosis (VLOSLP) is clinically heterogeneous, and its relationship with dementia-related neurodegenerative disease remains unresolved. We examined whether Alzheimer's disease (AD) and Lewy body disease (LBD) biomarker status were associated with dementia progression in VLOSLP. We retrospectively identified patients who visited the University of Osaka Hospital between January 2018 and December 2023 and met criteria for VLOSLP. Twenty-two participants with AD and/or LBD biomarker data and at least one follow-up assessment within 775\u2009days were classified as biomarker-negative (BMs-neg; n\u2009=\u20097) or biomarker-positive (BMs-pos; n\u2009=\u200915). Group comparisons were performed using Mann-Whitney U tests and Fisher's exact tests. The BMs-pos group showed older onset age and lower memory scores than the BMs-neg group. Dementia progression was more frequent in the BMs-pos group than in the BMs-neg group, although the difference was not statistically significant (8/15 [53.3%] vs. 1/7 [14.3%]; p\u2009=\u20090.165; odds ratio 6.31; 95% CI 0.55-353.18). Five of eight participants with AD biomarker positivity progressed to AD dementia. Three of seven participants with LBD biomarker positivity progressed to dementia, including two diagnosed with dementia with Lewy bodies. Follow-up MMSE, CDR, and CDR-SB scores differed significantly between groups. AD and/or LBD biomarker-positive VLOSLP may be associated with greater dementia progression and cognitive decline, although findings should be interpreted cautiously given the small sample size and retrospective design. These results support the clinical value of considering neurodegenerative biomarkers when evaluating the prognosis and underlying pathology of VLOSLP.\n\nID: 42570991\nTitle: Activated microglial phenotypes in the hippocampal CA2 subfield are implicated in Lewy body disease progression.\nAbstract: Histopathologic staging models of neuronal \u03b1-synuclein pathology (n-asyn) in Lewy body disease (LBD) seldom evaluate brain regions with direct synaptic connectivity to model the role of microglial processes. We address this gap by testing the hypothesis that, within the well-defined synaptic connectivity of the intrahippocampal circuit, n-asyn is associated with activated microglial phenotypes. We selected a cohort of autopsy-confirmed LBD patients and minimal age-related copathologies (n\u2009=\u200962) and a control cohort of cognitively healthy patients with isolated hippocampal tau accumulation (i.e., primary age-related tauopathy, PART; n\u2009=\u200912), to control for neurodegenerative pathology without amyloid plaques. We immunostained consecutive hippocampal sections for n-asyn and established markers of activated microglial phenotypes, Iba1, HLA-DR, and CD68. With validated digital histology methods, we measured percent area occupied (%AO) of each marker in 6 hippocampal subfields to compare and correlate microglial morphologic and proteomic activation phenotypes between cohorts and used linear mixed effects models to compare the %AO between subfields while covariying for demographics. We also constructed groups of n-asyn restricted to the cornu ammonis (CA) 2-3 subfields (Focal Subtype) or widespread n-asyn within additional subfields (Widespread Subtype) to model hypothesized n-asyn spread within the intrahippocampal circuit. LBD patients exhibited increased HLA-DR and CD68%AO in most hippocampal subfields compared with PART. In LBD patients, all microglial markers were the highest in the CA2. CA2 n-asyn correlated with HLA-DR and CD68 but not Iba1%AO. Patients classified as Widespread Subtype had worse cognitive impairment and increased CA2 HLA-DR and CD68%AO. CA2 HLA-DR and CD68%AO correlated with distal n-asyn in retrograde, but not anterograde connected subfields. Our data show that activated microglial phenotypes in the CA2 of LBD patients are associated with worse clinical outcomes and retrograde n-asyn transmission. These data suggest that measures of microglial states can refine LBD histopathological progression models.\n\nID: 42569517\nTitle: Fine-scale individualized gyral folding-based cortical similarity networks reveal distinct organizational patterns in Alzheimer's disease and Lewy body dementia.\nAbstract: Alzheimer's disease (AD) and Lewy body dementia (LBD) are common neurodegenerative dementias with overlapping clinical presentations, making differential diagnosis challenging. While structural magnetic resonance imaging (MRI) has revealed characteristic regional atrophy patterns, regional morphometric measures alone may not fully capture distributed cortical alterations. Morphometric similarity networks (MSNs) offer a systems-level framework to characterize coordinated structural organization, but existing approaches typically rely on atlas-based parcellations that may obscure individual-specific cortical folding geometry. Here, we propose a fine-scale, folding-informed cortical similarity network framework based on automatically detected three-hinge gyral (3HG) landmarks. Using a thickness-constrained arealization strategy in native surface space, we define individualized cortical regions and construct subject-specific MSNs without cross-subject registration. We then investigate how network topology relates to landmark-defined node count and how these properties differ between AD and LBD. We find that several graph theoretical metrics, particularly global efficiency and characteristic path length, exhibit clear associations with the number of detected landmarks, indicating that topology in individualized networks is partly shaped by node availability. When accounting for landmark count, several apparent group differences in global topology are attenuated, whereas multiple heterogeneity-related metrics remain significant, indicating that node-count scaling substantially influences the interpretation of individualized network topology. Nevertheless, multivariate topological patterns remain informative for AD/LBD classification after residualizing for node count, and landmark count itself provides modest diagnostic information. These findings highlight node-count scaling as a key methodological consideration in individualized structural networks and suggest that folding-based MSNs capture disease-related variation in cortical network organization between AD and LBD.\n\nID: 42568211\nTitle: Artificial intelligence-based 3D segmentation of tangle-associated TDP-43 in neurodegeneration.\nAbstract: TAR DNA-binding protein 43 (TDP-43) inclusions are often associated with hyperphosphorylated tau, thus neurofibrillary tangles as the hallmark of Alzheimer's disease (AD) and primary age-related tauopathy (PART). TDP-43 in AD is associated with cognitive impairment, and while staging is known, the localization, cellular and inclusion characteristics of TDP-43 are yet to be elucidated. We investigate relationships between TDP-43 inclusions and the tangle maturation continuum in AD, PART, and co-pathologies by multiplex immunostaining combined with artificial intelligence (AI)-based segmentation via object recognition, reconstruction, and quantification. We performed anti-phosphorylated TDP-43 immunofluorescence with phosphorylated tau labeling different stages and modifications of tangles (AT8, pS396, TauC3, MN423, GT38) in three controls, three cases with PART and TDP-43 (PART-TDP), five cases with high likelihood AD and TDP-43 (AD-TDP), and four cases of high likelihood AD with TDP-43 and Lewy Body disease (AD-TDP-LBD). Confocal imaging was taken from eight regions: amygdala (amygdala-BL and amygdala-CM) and hippocampus (Cornu Ammonis (CA)-1, CA2/3, CA4, dentate gyrus (DG), subiculum (SUB)), and entorhinal cortex (ERC) and quantified with AI segmentation to identify 3D spatial relations, thus the maturity of neurofibrillary tangle associated TDP-43 (TAT) inclusions. TATs, which were either identified by pTDP-43 and AT8 or pTDP-43 and pS396 double positivity, were also investigated by Thioflavin S (ThioS) histochemistry. We found pS396 labeled mature TATs predominated in PART and AD in every region. Basolateral and centromedial amygdala displayed overall greatest number of pre-TATs and mature TATs. Mature TATs were homogenously distributed among hippocampal subfields whereas CA4 and DG had the greatest mature TAT composition. ERC revealed closer numbers of pre-TATs and mature TATs yet mature TATs predominated all groups. Unbiased AI-based object identification, reconstruction, and TAT maturation analysis pipeline in conjunction with TDP-43, tau, and ThioS multiplex immunostaining demonstrated unique aggregation and maturation patterns, highlighting region-specific dynamics in the neurodegenerative processes of PART and AD.\n\nID: 42562944\nTitle: Which chemical features are captured by ChemBERTa's attention?\nAbstract: Transformer-based models such as ChemBERTa have demonstrated strong performance across a wide range of molecular prediction tasks by learning contextual representations from SMILES strings. Despite this success, the internal organization of the chemical and structural information learned by these models remains poorly understood. In this work, we investigate which chemical concepts, functional groups, and structural features are captured by ChemBERTa's attention mechanisms across layers and heads. To address this question, we formulate the Attention Matrix Pattern Capture (AMPC) problem and introduce two complementary algorithms: AMPC-Chem-FG, which assesses whether attention patterns reflect predefined chemical concepts and functional groups, and AMPC-Struct, which evaluates the alignment between attention patterns and three-dimensional molecular structure represented by Coulomb matrices. Using a curated dataset derived from the ZINC database, our framework identifies specialized layer-head pairs that consistently emerge as statistical outliers and exhibit strong associations with chemically meaningful features. The results reveal specialized attention patterns related to ring structures, bond types, chirality, and functional groups. Furthermore, a layer-head pair achieves approximately 65% similarity to Coulomb-matrix representations, suggesting that ChemBERTa can capture information related to three-dimensional molecular organization despite being trained solely on SMILES strings. Finally, we demonstrate that embeddings constructed from AMPC-identified attention heads can improve downstream prediction performance compared with randomly selected heads and conventional ChemBERTa representations, highlighting the practical utility of the discovered specialization. Together, these findings provide new insights into how molecular transformers organize chemical information and offer a pathway toward more interpretable and task-informed molecular representations.\n\nID: 42556722\nTitle: Distinct competitive and allosteric binding modes of nanobodies targeting EphA4.\nAbstract: EphA4 signaling is a key negative regulator of axonal regeneration and a genetic modifier of amyotrophic lateral sclerosis (ALS), making EphA4 an attractive but mechanistically underexplored therapeutic target. Although EphA4-targeting nanobodies have shown inhibitory potential, the structural principles governing their binding and inhibitory mechanisms remain largely unknown. Here, we report high-resolution crystal structures of the EphA4 ligand-binding domain (LBD) in complex with four nanobodies (Nb50, Nb53, Nb57, and Nb60), resolved at 1.34-2.21 \u00c5. Nb50, Nb53, and Nb57 competitively engage the canonical ephrin-binding pocket through deep CDR3 insertion, directly mimicking ephrin recognition. In contrast, Nb60 adopts a previously unrecognized binding mode, contacting two EphA4 molecules at noncanonical sites in the crystal structure through framework-dominated interactions and supporting a structural model for steric and allosteric restriction of ephrin access. Integrated biophysical analyses reveal distinct thermodynamic and kinetic signatures underlying these binding mechanisms. Together, our findings uncover unexpected structural diversity in nanobody-mediated EphA4 recognition and provide a framework for rational development of EphA4-targeted modulators for ALS and related neurodegenerative conditions.\n\nID: 42556137\nTitle: Data-driven trajectories of atrophy explain clinical heterogeneity across Lewy body diseases.\nAbstract: Lewy body diseases (LBD) collectively share \u03b1-synuclein Lewy pathology, yet present wide clinical heterogeneity, with overlapping motor and non-motor features and progression patterns that challenge traditional diagnostic boundaries. To resolve this spatiotemporal heterogeneity at the biological level, we applied a data-driven atrophy progression framework to MRI data from 833 individuals across Parkinson's disease, dementia with Lewy bodies, and prodromal isolated REM sleep behaviour disorder using the Subtype and Stage Inference algorithm. Four transdiagnostic subtypes (A: Early cortico-limbic/late basal ganglia, B: Early basal ganglia/late limbic, C: Early temporo-limbic/late basal ganglia, and D: Early basal ganglia-cingulate/late cortex) emerged, each defined by a distinct spatiotemporal progression of atrophy that explained cognitive, motor, and psychiatric variability. An early cortico-limbic/late basal ganglia subtype represented a dementia-prone subtype across clinical diagnoses, with limbic involvement associating with the emergence of visual hallucinations. These biologically relevant spatiotemporal atrophy subtypes provide an interpretable stratification of patients with LBD, with the potential to refine prognosis, improve clinical trial stratification, and guide precision therapeutic approaches. This work was made possible by an Ignition grant from the University of Sydney and University College London (Global Engagement Fund).\n\nID: 42543729\nTitle: PagCOBL5 Integrates Transcriptional and Spatial Cues to Confer G-Layer Deposition in Poplar.\nAbstract: Angiosperm trees reorient their stems by producing tension wood (TW), a specialised xylem that generates contractile force. TW fibres develop a gelatinous (G) layer rich in cellulose, yet the molecular mechanisms governing G-layer formation remain poorly understood. COBRA-like genes encode glycosylphosphatidylinositol (GPI)-anchored proteins known to regulate cellulose deposition. Here, we functionally characterised PagCOBL5 in hybrid poplar (Populus alba \u00d7 P. glandulosa) by identifying its upstream regulator and interaction partner. PagCOBL5 was preferentially expressed in mature xylem fibres, with high abundance in TW. Under mechanical stress, cobl5 knockout mutants exhibited impaired negative gravitropism and significantly thinner G-layer-phenotypes that were reversed in PagCOBL5-overexpressing lines. Furthermore, we found that the transcription factors PagLBD21 and PagLBD25 participate in the upstream negative regulation of PagCOBL5 expression, with the lbd21 lbd25/+ mutant exhibiting an enhanced gravitropic response and altered xylem cell differentiation. At the protein level, PagCOBL5 directly interacted with the cellulose synthase subunits PagCESA8b. This interaction positions PagCOBL5 as a key component recruited and spatially organised by the directionally moving cellulose synthase complex (CSC). Together, these results reveal a sophisticated regulatory and protein-interaction framework centred on PagCOBL5, providing pivotal molecular insights into how transcriptional modulation and cellulose synthase complexes coordinate G-layer formation and mechanical force generation during the gravitropic response.\n\nID: 42539784\nTitle: Pharmacologic targeting of midasin (MDN1) reveals a potential therapeutic vulnerability in ESR1-mutant breast cancer.\nAbstract: Although most cases of estrogen receptor-positive (ER+) breast cancer initially respond to endocrine therapy, many patients ultimately develop resistance. A major contributor to endocrine resistance in metastatic disease is the acquisition of constitutively active somatic mutations in the estrogen receptor ligand-binding domain (LBD). We previously identified midasin (MDN1), a ribosome biogenesis protein, as significantly overexpressed in letrozole-resistant MCF-7 cells. Because these cells are ERlow/- and represent only a subset of endocrine-resistant tumors, we hypothesized that ESR1 mutations cooperate with MDN1 dysregulation to confer a survival advantage. To address this, the cBioPortal database was queried to assess correlations between breast cancer subtypes and MDN1 expression levels. MCF-7 cell lines harboring ER point mutations were evaluated by RNA sequencing and immunoblot analysis to measure ER and MDN1 expression. To identify pharmacologic inhibitors of midasin, computational docking analyses were performed using a panel of ribozinoindole (Rbin) analogs, followed by biological evaluation studies. Initial analyses demonstrated that MDN1 expression is elevated in human breast cancer tumors, including luminal, HER2+, and triple-negative breast cancer. RNA sequencing of parental MCF-7 cells and ESR1-mutant derivatives, MCF-7 Y537S and MCF-7 D538G, revealed comparable MDN1 transcript levels across all cell lines. In contrast, immunoblot analysis showed mutation-dependent differences in MDN1 protein expression, with the highest levels observed in MCF-7 D538G cells, followed by MCF-7 Y537S cells and then parental MCF-7 cells. Computational docking analyses of Rbin analogs led to the selection of Rbin-1 and Rbin-2 for biological evaluation. Viability assays revealed minimal activity for Rbin-1, whereas Rbin-2 reduced proliferation by 30%-55% across all three cell lines, with the most pronounced effects observed in MCF-7 D538G cells at 24 and 48 h. Consistent with these findings, Rbin-2 treatment decreased MDN1 protein expression by approximately 50% in all cell lines, while ER levels remained largely unchanged. Collectively, these results establish the feasibility of pharmacologically targeting midasin in mammalian cell lines and support a functional link between MDN1 expression and ESR1 mutation-driven endocrine resistance. This work provides a foundation for future mechanistic studies of midasin as a potential therapeutic vulnerability in ER-mutant breast cancer.\n\nID: 42534654\nTitle: Tryptophan metabolism in liver transplantation immune tolerance.\nAbstract: Liver transplantation is a life-saving treatment for end-stage liver disease, but long-term outcomes are limited by complications of lifelong immunosuppression. Inducing immune tolerance has become a major research priority. Tryptophan (Trp) metabolism, particularly the kynurenine pathway, is a key endogenous regulator of peripheral tolerance. This review moves beyond a simple description of metabolic routes and provides a critical, integrated analysis. We systematically compare the non-redundant immunosuppressive roles of indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO2) in liver transplant immunity, dissect the Trp/kynurenine/AhR pathways that reprograms immune cell function, and incorporate gut-microbiota-dependent indole metabolism as an upstream gut-liver axis node. Clinical evidence is stratified by level, and major translational barriers, including safety risks, delivery challenges, and lack of validated biomarkers are discussed. Current data suggest that combined metabolite panels may outperform single markers, but therapeutic targeting of Trp metabolism remains a preclinical research direction rather than an established therapy.\n\nID: 42529077\nTitle: Shotgun metagenomic analysis reveals taxonomic and functional alterations in the gut microbiome across prodromal and symptomatic Lewy body disease.\nAbstract: Lewy body disease (LBD) is a progressive neurodegenerative a-synucleinopathy, whereas isolated REM sleep behavior disorder (iRBD) is recognized as a prodromal stage of LBD. Although growing evidence implicates the gut-brain axis in neurodegeneration, the taxonomic and functional roles of the gut microbiome across the prodromal-to-symptomatic LBD continuum remain poorly defined. Here, we performed shotgun metagenomic sequencing on stool samples from 25 patients with LBD (10 mild cognitive impairment due to LBD [MCI-LB] and 15 dementia with Lewy bodies [DLB]), 10 individuals with iRBD, and their household matched cohabitant controls to characterize disease-associated microbial alterations while minimizing environmental confounding. Despite no significant differences in global microbial diversity, we identified convergent shifts in microbial taxa, metabolic pathways, and gene families across disease stages. Both LBD and iRBD showed increased abundance of microbial taxa potentially associated with gut barrier disruption, as well as higher abundance of functional pathways related to lipopolysaccharide biosynthesis. LBD showed lower abundance of pathways related to complex carbohydrate fermentation, and both groups showed lower abundance of pathways associated with neurotransmitter-related metabolism. In particular, pathways and gene families associated with starch degradation were reduced in LBD, and those associated with histidine-to-glutamate/ GABA metabolism were reduced in both groups. These exploratory findings represent the first high-resolution, shotgun metagenomic characterization of gut microbiome alterations across the LBD continuum, highlighting functional patterns that may serve as candidate markers of disease progression in future longitudinal and mechanistic studies.\n\nID: 42518955\nTitle: Neuropsychiatric symptom profile in neurocognitive disorders and their relationship with functional decline.\nAbstract: Neuropsychiatric symptoms (NPS) are common in neurocognitive disorders (NCD) and are known to negatively impact patient's functional abilities. However, our understanding of the relationship between individual NPS and functional decline in patients with NCD across the spectrum of cognitive impairment is limited. Here we examine the relationship between specific NPS to characterize their effects on patient's function within and across different etiologies. Longitudinal observational study using the National Alzheimer's Coordinating Center Uniform Data Set (NACCUDS). We examined NPS as characterized by expert clinicians and report its impact on the outcome of functional decline, measured by the Functional Assessment Questionnaire (FAQ), a standardized assessment of activities of daily living, by dementia etiology (Alzheimer's disease (AD, N\u202f=\u202f11,044), Lewy Body Disease (LBD, N\u202f=\u202f921), and behavioral variant frontal temporal lobe dementia (bvFTD, N\u202f=\u202f933)). We find apathy was the most commonly endorsed and the most persistent symptom across dementia types in all groups and was associated with more rapid functional decline in AD and bvFTD. On the contrary, depression, occurring in 40% or more of all groups, was not associated with worsening functional impairment in any group. We identified patterns that indicated higher rates of disinhibition and persistent disinhibition in bvFTD compared to AD and LBD. Psychosis had unique impact on functional decline in AD and LBD as did agitation in AD. Differential impact of individual NPS across dementia etiologies and their impact on functional decline may have important consequences for clinical trial designs for the treatment of these symptoms.\n\nID: 42502242\nTitle: Comparative Screening of Alzheimer's Disease, Lewy Body Dementia, and Frontotemporal Dementia Using miRNA and Machine Learning.\nAbstract: Current dementia diagnostic methods can be costly, invasive, or limited in their ability to distinguish between disorders with overlapping clinical symptoms. Dysregulated microRNAs (miRNAs) have emerged as promising noninvasive biomarkers for neurodegenerative disease, but individual miRNA changes alone may not capture the complex molecular patterns needed for accurate disease classification. Machine learning provides a way to integrate multiple layers of miRNA-derived information and identify disease-specific biomarker signatures. In this study, we developed machine learning models to classify dysregulated miRNAs associated with Alzheimer's disease dementia (AD), Lewy body dementia (LBD), and frontotemporal dementia (FTD). Each miRNA was represented using sequence-derived descriptors, predicted gene targets, and KEGG pathway features. The highest-performing models trained on AD, LBD, and FTD achieved 10-fold cross-validation accuracies of 90.6%, 92.9%, and 100%, respectively. When evaluated on independent datasets, the AD, LBD, and FTD models achieved accuracies of 88.9%, 77.8%, and 90.9%, respectively. Cross-disease testing showed reduced performance when models were applied across dementia types, suggesting partially disease-specific miRNA patterns while also indicating overlap among the molecular signatures of AD, LBD, and FTD. These results suggest that machine learning-based integration of miRNA sequence, target-gene, and pathway information can improve the identification of dementia-associated biomarker signatures and may support the future development of noninvasive diagnostic tools for dementia.\n\nID: 42495784\nTitle: Genetically encoded tools for tracking metabolites in live cells.\nAbstract: Biosensors enable the in situ measurement of metabolites in living systems over time and space. Fully genetically encoded metabolite biosensors (fGEMBs) use fluorescent proteins (FPs) linked to ligand binding domains (LBDs) to transduce the ligand binding event to a measurable change in the fluorescence behavior of the FP. Because these sensors are genetically encoded, they can be expressed in cells using standard protein expression approaches, and the fluorescence changes are quantified using fluorimetry, fluorescence microscopy, and/or flow cytometry. While there are general sensor design principles to follow, an fGEMB must be engineered for each metabolite based on a particular LBD. This development process can be slow, but there are strategies emerging to increase testing throughput and improve structure-guided design. While genetically-encoded FPs remain popular, there are now numerous chemigenetic and nucleic acid-based metabolite sensors (cGEMBs) that incorporate small molecule fluorophores. De novo design of LBDs is rapidly advancing as well, and the field may soon exhibit a shift away from relying on nature's catalog of LBDs. Despite the engineering challenges, the metabolite biosensor field has expanded significantly in recent years to meet the demand for new and better-performing sensors that visualize metabolites within their cellular environments.\n\nID: 42491938\nTitle: Dynamic, state-dependent characteristics of cognitive fluctuations in Lewy body dementia: a magnetoencephalography study.\nAbstract: Cognitive fluctuations are a hallmark clinical feature of Lewy body dementia (LBD), yet their underlying neural mechanisms remain poorly understood. This study aimed to identify dynamic, state-dependent neural signatures of cognitive fluctuations in LBD using magnetoencephalography and dynamic functional connectivity based on hidden Markov modelling. Resting-state magnetoencephalography data were acquired from individuals with LBD, Parkinson's disease without dementia and cognitively normal controls. Hidden Markov modelling was used to identify transient brain states followed by spectral analyses across regions and states. Additionally, associations between regional spectral power and cognitive fluctuations severity, measured by the Clinician Assessment of Fluctuation, were assessed. Patients with LBD exhibited a distinct pattern of brain dynamics, particularly in two states (States 2 and 6), characterized by increased fractional occupancy of State 2 and markedly reduced occupancy of State 6, contrasting with the more distributed state engagement observed in Parkinson's disease and normal controls. Spectral analyses revealed widespread slowing in LBD, with elevated theta/beta power ratios in frontal, parietal and visual cortices-most pronounced in States 2 and 6. Region-specific theta/beta power ratio elevations were identified in the anterior cingulate, medial prefrontal cortex, posterior cingulate, dorsal visual stream and auditory cortex. Critically, Clinician Assessment of Fluctuation scores correlated positively with spectral power in low frequency (\u03b4 and \u03b8) and negatively with power in the high frequency (\u03b1 and \u03b2), particularly in the ventral visual stream, default mode network hubs and sensorimotor regions. These findings reveal dynamic and spatially specific electrophysiological abnormalities in LBD closely linked to cognitive fluctuations severity, suggesting that magnetoencephalography-hidden-Markov-model characteristics hold promise as biomarkers for diagnosis, monitoring and therapeutic targeting in LBD.\n\nID: 42486521\nTitle: Cross-sectional analysis of variation in diagnosis of Lewy body dementia in three English regions: data from the DETERMIND programme.\nAbstract: We aimed to examine regional differences in the relationship between core clinical features assessed using the Improving the DIAgnosis and Management Of Neurodegenerative Dementias of Lewy body type in the NHS (DIAMOND-Lewy) dementia with Lewy bodies (DLB) Assessment Toolkit and memory service diagnoses of Lewy body dementia (LBD). Secondary analysis of a multicentre observational study. Memory clinics in three sites across England (North East, London and South East) from July 2019 to March 2023. 935 individuals with a new memory service diagnosis of dementia enrolled in the DETERMinants of quality of life, care and costs, and consequences of INequalities in people with Dementia and their carers (DETERMIND) programme. Core clinical features of DLB were assessed using the DLB Assessment Toolkit. The relationship between core clinical features and memory service diagnosis of LBD was examined using Bayesian probit models. There were higher rates of LBD diagnosis from memory services in the cohort in North East England compared with the London and South East centres (11% vs 4%; risk ratio (RR)=1.72 (1.35-2.08)) and evidence of a regional moderating effect on the relationship between clinical features and LBD diagnosis (RR=1.73 (1.26-2.40)).All core clinical features of DLB were associated with LBD diagnosis in North East England, whereas visual hallucinations were the most influential diagnostic feature in London and the South East (RR=3.18 (2.29-4.02)). Regional differences in LBD diagnosis in UK memory services appear to reflect different rates of recognition of specific LBD clinical features. Routinely using a standardised DLB Assessment Toolkit and improving awareness of non-hallucination features in LBD could help to address this disparity.\n\nID: 42483926\nTitle: Phytochemical-based Neuroprotection and In-silico Docking-driven Identification of Active Natural Compounds to Combat Neuropathy.\nAbstract: Neuropathic pain, a devastating neurological disorder attributed to impairment or malfunctioning of the somatosensory system, affecting 10% of the world population. Current therapy emphasizes symptomatic management, featuring high-order side effects. Phytocompounds as neuroprotective agents are of growing interest, and can be screened using structure-based docking, and can act upon a variety of pathways with fewer adverse effects. A comprehensive literature survey was conducted covering studies published between 2000 and 2022 using scientific databases including PubMed, Scopus, Web of Science, ScienceDirect, and Google Scholar. The neuroprotective potential of medicinal plants and their bioactive phytochemicals was screened using in silico experiments targeting neuropathy-related molecular targets, followed by the evaluation of in vitro and in vivo activities. The studies showed that phytochemicals have multitarget neuroprotective activities, including antioxidant activity, modulation of neurotransmitter signaling, inhibition of inflammatory mediators, and modulation of neuropathic signaling ion channels. Several phytochemicals demonstrated notable binding affinities in docking studies, including icariin with NMDA receptors (-12.646 kcal/mol), aegeline with MAO-A (-10.06 kcal/mol) and MAO-B (-10.09 kcal/mol), and zerumbone with cannabinoid receptors CB1 (-7.80 kcal/mol) and CB2 (-9.40 kcal/mol). Other compounds, such as chlorogenic acid, myricetin, rutin, and piperine, also exhibited significant interactions with key neuropathic targets involved in neuroinflammation and pain signaling pathways. Docking studies identified that icariin, aegeline, and zerumbone are predicted lead molecules because they can interact with targets of interest, including NMDA, MAO, and CB receptors. Phytochemical neuroprotective drugs offer a promising approach to managing neuropathy. Integration of molecular docking approaches with experimental pharmacological studies provides a powerful strategy for identifying bioactive natural compounds with therapeutic potential. These findings support advancing phytochemicals as lead candidates for the development of safer, more effective treatments for neuropathy and neuropathic pain.\n\nID: 42477717\nTitle: Amygdalar nuclei vulnerability to protein aggregates in Lewy body diseases.\nAbstract: The amygdala is highly vulnerable to protein aggregation and heavily affected in Lewy body diseases (LBDs). However, vulnerability might vary per amygdalar nucleus and it is unclear if the pattern of vulnerability across the nuclei differs between types of protein aggregation and between LBDs. In this study, we aimed to assess the vulnerability of amygdalar nuclei to multiple types of protein aggregation across LBDs. Post-mortem amygdala tissue of donors with incidental LBD (iLBD, n\u2009=\u20096), Parkinson's disease (PD; n\u2009=\u200918), dementia with Lewy bodies (DLB; n\u2009=\u20099) and Alzheimer's disease with Lewy bodies (AD\u2009+\u2009LB; n\u2009=\u200915) was immunostained with antibodies against alpha-synuclein (aSyn; EP1536Y and 5G4), amyloid beta (A\u03b2; 4G8), phosphorylated tau (p-tau; AT8) and phosphorylated TDP-43 (p-TDP-43; 11-9), and quantitatively analyzed using QuPath. Neuronal and astrocytic aSyn pathology were most pronounced in the parahippocampal-amygdaloid transition area (PHA) and the basal nucleus, a pattern shared by all disease groups. Vulnerability to A\u03b2 pathology varied per group but was highest in the PHA in AD\u2009+\u2009LB, whereas diffuse plaques were most common in the accessory basal nucleus. The PHA of DLB and both the basal and accessory basal nucleus of AD\u2009+\u2009LB cases were most susceptible to p-tau pathology, with fine granular cytoplasmic neuronal tau inclusions being mostly observed in the basal nucleus and neurofibrillary tangles in the accessory basal nucleus. The nuclei in the ventromedial part of the amygdala (PHA, ventral part of the basal nucleus, and cortical nucleus) were found to be hotspots for protein aggregation across LBDs. aSyn pathology in these nuclei predominantly correlated with dementia, hallucinations and anxiety. Our results show that amygdalar nuclei vulnerability differs per protein aggregate and disease entity, although the PHA, basal nucleus and cortical nucleus are generally more vulnerable. Together, our study provides a deeper insight into the selective vulnerability of amygdalar nuclei to protein aggregates and their relation to clinical characteristics in LBDs.\n\nID: 42475839\nTitle: Genomic identification and functional characterization of the nuclear receptor gene family in relation to sex determination and gonad development in the Pacific oyster (Crassostrea gigas).\nAbstract: Nuclear receptors (NRs) are a large superfamily of transcription factors that control a wide range of physiological processes by modulating the expression of downstream target genes. Numerous studies have confirmed that NR family members play critical and conserved roles in sex determination and gonadal development across metazoans. However, in mollusks, systematic characterization of NRs and their potential functions in gonadal regulation remain largely unexplored. In this study, 46 NR gene family members in the Pacific oyster (Crassostrea gigas) were identified and assigned to eight subfamilies. All NR family members contain at least one of the two core domains (DNA-binding domain, DBD; ligand-binding domain, LBD), and conserved exon-intron structures were observed within the same subgroup, indicating their evolutionary conservation. Furthermore, expression profiling revealed high expression of CgNR2F, CgNR5A1-1, and CgNR0B1 in undifferentiated gonads, suggesting their potential involvement in sex determination. CgNR1A and CgNR2E5 were specifically expressed in female gonads and exhibited female-biased expression patterns, indicating a putative role in ovarian development. Moreover, CgNR3A and CgNR3B showed high expression levels during the undifferentiated stage and early male development stage, implying their possible participation in male gonadal development and gametogenesis. These results expand the understanding of the NR gene family in C. gigas and help elucidate the potential functions of NR genes in sex determination and gonadal development.\n\nID: 42475381\nTitle: Neuropsychiatric Diagnostic and Treatment Conundrums: Case Study of an Inpatient With a Complex Illness Presenting With Overlapping Features of Frontotemporal and Lewy Body Dementia.\nAbstract: Frontotemporal dementia (FTD) and Lewy body dementia (LBD) are distinct neurodegenerative disorders that rarely co-occur. However, their overlapping features can obscure diagnosis and complicate management. We present the case of a 65-year-old man with a history of alcohol use disorder, diabetes, and blindness who developed acute behavioral changes, catatonia, and fluctuating mental status. He exhibited signs consistent with a behavioral variant FTD, including disinhibition, executive dysfunction, and hypersexuality, as well as features associated with LBD, including visual hallucinations, autonomic instability, and waxing-and-waning impairment in cognition. His hospital course was marked by episodic disorientation, variable language use, and persecutory delusions. Neuroimaging, cerebrospinal fluid analysis, and serial neuropsychological testing yielded mixed and inconclusive results, contributing to the diagnostic ambiguity. Treatment included lorazepam, which improved catatonic symptoms but was discontinued due to risk of delirium, and aripiprazole, which was tapered due to suspected neuroleptic sensitivity. The patient was ultimately discharged to memory care with a diagnosis of an unspecified dementia. This case underscores the challenges of diagnosing and managing patients with overlapping features of multiple neurodegenerative disorders. Recognizing points of overlap between syndromes like FTD and LBD is key to tailoring interventions and avoiding harm. Serial cognitive assessments, functional neuroimaging, and biomarker analysis may improve diagnostic accuracy, although these tools have limitations. A deeper understanding of the pathophysiology of overlapping dementia syndromes is crucial for improving diagnostic clarity and guiding treatment strategies.\n\nID: 42465922\nTitle: Data-driven trajectories of atrophy explain clinical heterogeneity across Lewy body diseases.\nAbstract: Lewy body diseases (LBD) collectively share \u03b1-synuclein Lewy pathology, yet present wide clinical heterogeneity, with overlapping motor and non-motor features and progression patterns that challenge traditional diagnostic boundaries. To resolve this spatiotemporal heterogeneity at the biological level, we applied a data-driven atrophy progression framework to MRI data from 833 individuals across Parkinson's disease (PD), dementia with Lewy bodies (DLB), and prodromal idiopathic REM sleep behaviour disorder (iRBD) using the Subtype and Stage Inference (SuStaIn) algorithm. Four transdiagnostic subtypes (A: Early cortico-limbic/late basal ganglia, B: Early basal ganglia/late limbic, C: Early temporo-limbic/late basal ganglia, and D: Early basal ganglia-cingulate/late cortex) emerged, each defined by a distinct spatiotemporal progression of atrophy that explained cognitive, motor, and psychiatric variability. An early cortico-limbic/late basal ganglia subtype represented a dementia-prone subtype across clinical diagnoses, with limbic involvement associating with the emergence of visual hallucinations. These biologically relevant spatiotemporal atrophy subtypes provide an interpretable stratification of patients with LBD, with potential to refine prognosis, improve clinical trial stratification, and guide precision therapeutic approaches. This work was made possible by an Ignition grant from the University of Sydney and University College London (Global Engagement Fund). Evidence before this study: Parkinson's disease (PD), dementia with Lewy bodies (DLB), and isolated REM sleep behaviour disorder (iRBD), sit on a Lewy body disease spectrum with overlapping clinical features but marked heterogeneity in symptom profile, timing, and progression. Neuroimaging and neuropathological studies report diverse patterns of neurodegeneration within each syndrome, with partial overlap across the broader spectrum. Recent, large-scale subtyping work suggests at least two spatiotemporal neurodegeneration trajectories. However, in vivo imaging subtyping which has particularly strong translational relevance, has largely focused on a single syndrome or has included limited representation of the full Lewy body disease continuum. Added value of this study: This study includes a large, balanced cohort spanning PD, DLB and prodromal iRBD with detailed clinical and neuropsychological phenotyping. Using MRI-derived atrophy, we identified four transdiagnostic subtypes that capture clinically meaningful variability beyond syndromic diagnosis. We found that stage, an indicator of accumulated atrophy better addresses the between-syndromic differences in disease duration. We also show that certain subtypes with early limbic degeneration are associated with visual hallucinations, and are linked to amygdalar atrophy, and that subtype plus stage improves prediction of hallucinations beyond amygdalar volume alone. Longitudinal analysis further identified a subset of patients with PD with earlier cortico-limbic degeneration as being at higher risk of cognitive impairment.Implications of all the available evidence: The current field of LBD is moving towards a biologically grounded stratification and staging criteria that better reflects clinical heterogeneity. These transdiagnostic subtypes alongside stage, provide complementary information that can inform emerging LBD staging frameworks and enable more targeted clinical trial design through improved stratification and risk enrichment.\n\nID: 42464166\nTitle: Integrated transcriptomic and metabolomic analyses reveal phytohormone signaling mechanisms underlying differential regeneration potential in microspore-derived calli from hulled and hulless barley.\nAbstract: Isolated microspore culture (IMC) is an effective model for investigating plant cell totipotency and is widely used in plant breeding programs to rapidly produce doubled haploid lines. However, the limited regeneration capacity of hulless barely restricts the broader application of IMC in breeding improvement and research. In this study, two hulled barley genotypes (Hua30 and L07) exhibiting high regeneration capability and two hulless barley genotypes (Zangqing2000 and Ximala22) with poor regeneration capability were selected to comparatively evaluate the regeneration potential of microspore-derived calli generated via IMC through integrated metabolomic and transcriptomic analyses. The regeneration capability of the two hulled genotypes exceeded 200 green plantlets per 100\u00a0mg microspore-derived callus, whereas that of the hulless genotypes was nearly absent. A total of 2,647 differentially expressed genes (DEGs) and 128 differentially accumulated metabolites (DAMs) were identified in microspore-derived callus from hulled genotypes relative to hulless genotypes. Integrative analysis of transcriptomic and metabolomic datasets indicated that phytohormone signaling pathways play a central role in regulating regeneration competence acquisition. Hulled barley exhibited enhanced hormonal homeostasis and comparatively lower levels of jasmonic acid (JA) and brassinosteroids (BR), which are critical determinants of regeneration capacity in microspore calli. The exogenous application of JA and BR to the induction media markedly inhibited the subsequent regeneration of plantlets in hulled barley. Several transcription factors (TFs) associated with plant regeneration, including WOX7, BBM2, and LBD, showed differential expression patterns between hulled and hulless barley, suggesting their potential functions in regulating regeneration capacity. In addition, the hulled/hulless caryopsis phenotype may be closely associated with the regeneration potential of the microspore-derived callus. These findings provide mechanistic insights into the molecular mechanisms underlying plant regeneration in barley.\n\nID: 42460153\nTitle: Disease-predominant loci across Alzheimer's disease, Parkinson's disease and Lewy body dementia: evidence from the UK Biobank prospective cohort, conditional GWAS and colocalization.\nAbstract: Alzheimer's disease (AD), Parkinson's disease (PD) and Lewy body dementia (LBD) overlap clinically, pathologically and genetically, complicating interpretation of cross-disorder genome-wide association study (GWAS) signals. We analysed 322,963 UK Biobank participants with bidirectional time-varying Cox models, one-year and two-year lag analyses, and competing-risk sensitivity models to quantify AD-PD clinical co-occurrence. We then analysed European-ancestry AD, PD and LBD GWAS summary statistics using linkage disequilibrium score regression (LDSC), GCTA-mtCOJO/GSMR, MAGMA, stratified LDSC, brain eQTL/mQTL SMR with HEIDI filtering, and Bayesian colocalization for selected methylation probes. Conditional loci were compared with original GWAS loci to separate shared liability from retained disorder-predominant associations. PD was associated with subsequent AD (fully adjusted HR 2.27, 95% CI 1.94-2.65; P = 6.40E-25), and AD was associated with subsequent PD (HR 3.14, 95% CI 2.56-3.85; P = 2.10E-28). Lag and competing-risk sensitivity analyses remained concordant. LDSC estimated positive genetic correlations for AD-PD (rg = 0.20; P = 0.0086) and PD-LBD (rg = 0.61; P = 0.0005). Conditioning reduced genome-wide significant loci from 14 to 9 for AD, from 24 to 21 for PD and from 5 to 2 for LBD. Retained loci included AD signals near CR1, BIN1, CLU, SPI1, MS4A, PICALM, ABCA7 and APOE; PD signals near GBA, NUCKS1, TMEM163, STK39, GAK/TMEM175, BST1, SNCA, LRRK2, MAPT and RIT2; and LBD signals near SNCA/MMRN1 and APOE. MAGMA and S-LDSC highlighted amyloid, lipid, immune, synaptic-vesicle and brain-tissue enrichment patterns. Brain QTL analyses prioritized retained eQTL and mQTL signals, and colocalization supported shared PD-GWAS/mQTL signals at HLA-DRB5, ARHGAP27, CRHR1, MAPT and KANSL1. AD and PD show bidirectional clinical co-occurrence, whereas conditional genetic analyses retain a smaller set of disease-predominant loci and regulatory signals across AD, PD and LBD. These findings refine cross-disorder interpretation and nominate loci for independent genetic and functional validation.\n\nID: 42456112\nTitle: Hydraulic architecture traits influence the co-optimization of efficiency and safety in cycads.\nAbstract: As a present-day relict lineage, cycads possess key anatomical traits for understanding the evolution of plant hydraulics; however, how their hydraulic architecture influences the co-optimization of hydraulic safety and efficiency under drought remains unclear. We examined rachis cross-sectional anatomy traits in 20 cycad species and analyzed correlations between hydraulic construction design, tissue fractions, tissue connectivity, and hydraulic function. Additionally, we quantified the distance of cycads from the global hydraulic safety-efficiency trade-off boundary line (LBD) and assessed anatomical contributions to this distance. We found that cycad rachises resembled fern rhizomes, in that most histological and architectural traits did not correlate with embolism vulnerability, except that greater architectural dissection increased vulnerability at the water potential corresponding to 88% embolism. Cycads with higher conduit lumen fractions (Flx) and conduit-phloem connectivity (Ccphl), and lower conduit-parenchyma connectivity (Ccpar), exhibited greater embolism resistance. Notably, cycads showed a longer LBD compared with ferns, noncycad gymnosperms, and angiosperms, and this distance was shortened by larger pit membrane area and fraction and by higher phloem fraction and Flx. Species in Cycadaceae and Zamiaceae exhibited distinct hydraulic architectures. Cycadaceae species, which typically occupy wetter habitats, showed higher Flx and Ccphl, whereas Zamiaceae species from more arid habitats exhibited greater architectural dissection, higher conduit wall fractions (Fwx) and higher Ccpar. These differences reflect contrasting ecological strategies underlying cycad adaptation to divergent environments. Our findings demonstrate that xylem tissue fraction and connectivity play a central role in maintaining hydraulic function under drought, providing insight into water-stress regulation in ancient plant lineages.\n\nID: 42451089\nTitle: Effects of Probiotic-Phytonutrient Blends on Defecation, Intestinal Barrier Function, and Gut Microbiota: A Randomized, Placebo-Controlled Trial.\nAbstract: Background/Objectives: Probiotic interventions are widely used to improve intestinal health; however, comparative evidence on multi-strain formulations with different potencies, particularly when combined with plant-based complexes, remains limited. This study evaluated the effects of two probiotic blends containing phytonutrients: PBP1, comprising Lacticaseibacillus strains, and PBP2, comprising Lacticaseibacillus, Lactobacillus, and Bifidobacterium strains. The effects on bowel function, microbial metabolites, and gut barrier-related markers were investigated. Methods: In this randomized, double-blind, placebo-controlled trial, participants received PBP1, PBP2, or placebo for 8 weeks. Stool patterns (7-day Bristol Stool Form Scale (BSFS) diary), fecal short-chain fatty acids (SCFAs), tryptophan metabolites, zonulin, and gut microbiota were assessed at baseline and Week 8. Efficacy was evaluated by comparing each intervention group with the placebo group. Results: Both PBP1 and PBP2 significantly increased the proportion of normal stool types (BSFS types 3-5) compared with placebo (p < 0.05). Fecal SCFA levels, including acetate, propionate, and butyrate, were significantly increased in both intervention groups. Notably, butyrate levels were significantly elevated compared with placebo. Fecal tryptophan levels decreased, while indole metabolites showed increasing trends, with an inverse correlation observed between tryptophan and indole, particularly in the PBP2 group. Fecal zonulin showed a decreasing trend, with significant reductions in participants with 25.0 \u2264 BMI < 30.0 kg/m2. Microbiome analysis revealed preserved alpha diversity with selective compositional shifts, including enrichment of Lactobacillus-related taxa. Conclusions: Supplementation with PBP1 and PBP2 improved bowel function and was associated with changes in microbiome-derived metabolites, including SCFAs and tryptophan-indole metabolism, with BMI-dependent changes in barrier markers. These findings suggest a potential role of microbiome-mediated metabolic modulation in intestinal health.\n\nID: 42443803\nTitle: Metabolomic profiling reveals key metabolic pathway alterations in monochorionic diamniotic twins with selective intrauterine growth restriction.\nAbstract: Selective intrauterine growth restricted (sIUGR) is a major cause of stillbirth and adverse pregnancy outcomes in monochorionic diamniotic (MCDA) twins. However, the underlying pathophysiologic mechanism of sIUGR remains poorly understood. The study aims to investigate the metabolite perturbations and metabolic mechanisms of sIUGR fetuses through a metabolomics study. Umbilical cord blood was collected from 30 pairs of MCDA sIUGR twin fetuses and 11 pairs of MCDA preterm (PT) twins, followed by non-targeted metabolomics using gas chromatography-mass spectrometry. Data were further analyzed using partial least squares discriminant analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, and Spearman correlation analysis. Our results revealed significant metabolic differences in the umbilical cord blood among small for gestational age, appropriate for gestational age and PT fetuses, potentially linked to abnormalities in carbohydrate, amino acid, and lipid metabolism. A total of 156 metabolites were identified, of which 53 showed significant differences between the groups. Specifically, tryptophan levels were higher in the sIUGR group, while glutamic acid and palmitic acid levels were lower. Based on the KEGG enrichment analysis and the correlation analysis, we hypothesize that the tryptophan-indole metabolism pathway, which may impact immune regulation and neurodevelopment, requires further attention. Other key metabolic pathways, such as arginine metabolism and the citrate cycle were also altered. Our findings offer valuable insights into the biochemical disruptions associated with sIUGR. These results enhance our understanding of the metabolic mechanisms underlying sIUGR and pave the way for future research on potential diagnostic and therapeutic strategies.\n\nID: 42439654\nTitle: Emerging New Pathways in Malignant Neoplasms and Neurodegenerative Disorders: Perspectives for Therapeutics.\nAbstract: Neurodegenerative disorders such as Alzheimer's disease (AD) and malignant neoplasms are among the most prevalent age-associated diseases worldwide. Although cancer is characterized by uncontrolled proliferation, resistance to apoptosis, and metabolic reprogramming, AD and other neurodegenerative disorders such as Lewy body disease (LBD) including Parkinson's Disease (PD) and fronto-temporal lobar degeneration (FTLD) are defined by synaptic dysfunction, neuronal loss, neuroinflammation, and impaired proteostasis with misfolded protein aggregates. Despite these contrasting phenotypes, converging epidemiological and molecular data support an inverse relationship between cancer and neurodegenerative disorders, whereby a history of cancer is associated with reduced AD risk, whereas AD is linked to a lower incidence of multiple malignancies. These observations suggest that oncogenesis and neurodegeneration may represent divergent outcomes of shared biological processes dysregulated during aging. This conundrum likely reflects differential regulation of core cellular pathways governing cell survival, stress responses, metabolism, and genomic integrity but could also reflect the differential influence of aging pathways and secreted growth factors. Pro-survival and proliferative signaling pathways commonly activated in cancer, including PI3K-AKT-mTOR signaling, altered p53 function, enhanced DNA damage tolerance, and anabolic metabolism, are often impaired in AD, LBD and FTLD, where neurons exhibit heightened vulnerability to stress, mitochondrial dysfunction, defective autophagy, and activation of pro-apoptotic cascades. Conversely, tumor-suppressive mechanisms that restrain proliferation may protect against malignancy but increase susceptibility to degeneration in post-mitotic neurons. Aging-related processes such as cellular senescence, immune dysregulation, and loss of proteostasis may further exert divergent effects in oncogenesis and neurodegeneration. This review aims to clarify associations between specific cancer types and neurodegenerative disorders, examine shared and opposing selected molecular mechanisms linking specific cancers and neurodegeneration, and contextualize these relationships within broader aging pathways (e.g., cell senescence, proteostasis). By integrating epidemiological, mechanistic, and therapeutic perspectives, we highlight unifying biological principles and translational opportunities at the intersection of cancer, neurodegeneration, and aging.\n\nID: 42437599\nTitle: Blood Biochemistry Age Clock - An interpretable estimate of biological age and predictor of all-cause-mortality derived from routinely ordered blood biomarkers.\nAbstract: \"Omic\" aging clocks(ACs) represent an established predictor of biological-age(BA)/all-cause mortality(ACM); however, they are expensive and lack interpretability/explainability. We developed a Blood-Biochemistry Age Clock (BBAC) composed of 11 routine blood biomarkers. The AC functions by transforming the individual's levels of blood biomarkers to years added/subtracted according to \"biomarker-ACM risk-profile\". The BBAC and PhenoAge were calculated for individuals of the UKB cohort and the results were associated with ACM and disease incidence (eight common chronic diseases) using univariant/multivariate Cox mortality analysis. The BBAC calculation procedure was further optimised. Mortality analysis was likewise performed on NHANES dataset with additional ACs (PCAge/LinAge) serving as predictors. Comparisons between ACs were done using Akaike Information Criterion (AIC). In univariate ACM prediction on UKB cohort BBAC outperformed PhenoAge (AIC - 910749.6 vs. 912914.9). Similarly, BBAC was a better univariate disease incidence predictor(lower AIC). In multivariate ACM prediction PhenoAge exceeded BBAC (AIC - 890855.6 vs. 893294.4). Nevertheless, the optimised version of BBAC was better in predicting ACM in uni (BBAC/PhenoAge AIC - 154165.7/155217.6) as well as in multivariant setting (BBAC/PhenoAge AIC - 151006.9/151031.9). For multivariant disease incidence prediction the results were mixed. On the NHANES cohort BBAC and PhenoAge performed similarly, while PCAge and LinAge achieved the best mortality prediction power. BBAC is an explainable/interpretable AC with good ACM prediction ability.\n\nID: 42579828\nTitle: Distal Vessel Occlusions in Acute Ischemic Stroke: Reframing Patient Selection and Reperfusion Strategies.\nAbstract: Mechanical thrombectomy (MT) has revolutionized the treatment of acute ischemic stroke because of large vessel occlusion (LVO), but distal and medium vessel occlusions (DMVOs) remain a gray zone. DMVOs account for a substantial proportion of ischemic strokes and can cause long-term disability or death despite often presenting with only mild to moderate symptoms. Their biologic and anatomic diversity-including small vessel caliber, variable perfusion territories, collateral dependence, and complex access pathways-creates distinct patterns of natural history, treatment responsiveness, and procedural risk compared with proximal LVO. Recent randomized trials and meta-analyses, conducted in broadly defined DMVO populations, did not demonstrate functional benefit of endovascular therapy (EVT) over best medical therapy (BMT) and observed numerically higher rates of intracranial hemorrhage with MT. These neutral results have fueled skepticism and guideline recommendations against routine EVT for DMVO stroke; however, they coexist with emerging trial data suggesting that treatment effects may depend on refined patient selection and optimized, distal-specific techniques, as well as with registry findings indicating that many patients with DMVO remain disabled despite BMT. In this narrative, we provide an interpretative synthesis of the available evidence to argue that the apparent discrepancy between biologic plausibility and neutral trial results reflects, at least in part, heterogeneity of DMVO definitions and phenotypes, limitations of severity and outcome scales, anatomy- and device-related safety constraints, and the unique mechanics and biology of small vessel thrombus retrieval rather than an absence of biologic efficacy. We highlight clinical, imaging, anatomic, and thrombus-related features which may help identify subgroups more likely to benefit from distal reperfusion and discuss emerging technical and pharmacologic strategies-including DMVO-specific device adaptations, intraarterial thrombolysis, and hybrid reperfusion approaches-which aim to reduce mechanical trauma while preserving the advantages of timely recanalization. Together, these considerations support a shift from viewing distal MT as a failed extension of proximal EVT to recognizing DMVO stroke as a distinct syndrome that requires tailored selection, techniques, and outcome assessment.\n\nID: 42579823\nTitle: Clinical Significance of the Hyperintense Reperfusion Marker and Ocular Gadolinium Leakage After Thrombectomy: A Retrospective ETIS Study.\nAbstract: Despite successful recanalization after mechanical thrombectomy for acute ischemic stroke, a substantial proportion of patients experience early neurologic deterioration or infarct progression. Early blood-brain barrier disruption, visualized on post-contrast fluid-attenuated inversion recovery (pcFLAIR) imaging as hyperintense acute reperfusion marker (HARM) or gadolinium leakage in ocular structures (GLOS), has been proposed as a marker of reperfusion injury, but its determinants and prognostic significance in thrombectomy cohorts remain uncertain. We aimed to evaluate whether HARM and GLOS are associated with poor clinical outcomes after mechanical thrombectomy. Secondary objectives included their association with poor radiologic outcomes and the identification of baseline and procedural predictors. We retrospectively analyzed data from the French Endovascular Treatment in Ischemic Stroke (ETIS) registry (2010-2021), including consecutive patients admitted to Versailles and Foch Hospital. All patients underwent mechanical thrombectomy at Foch Hospital and pcFLAIR imaging within 4-48 hours postgadolinium administration. Independent predictors of HARM and GLOS were identified through multivariable logistic regression, and their associations with early neurologic deterioration, poor 3-month functional outcome, infarct growth, and hemorrhagic transformation (HT) outcomes were evaluated. Among 229 patients (mean age 69.7 \u00b1 14.9 years, 52.0% female), HARM was observed in 48.9% and GLOS in 41.9%. Overall, 60.3% of patients had either HARM or GLOS, including 29.3% with both markers, 19.7% with isolated HARM, and 11.4% with isolated GLOS. HARM was independently associated with early neurologic deterioration (adjusted odds ratio [aOR] 3.45; 95% CI 1.33-8.95) and infarct growth (aOR 2.46; 95% CI 1.22-4.95), but not with HT or 3-month functional outcome. GLOS was not independently associated with clinical or radiologic outcomes. Older age, higher creatinine, and a shorter interval between the first and second FLAIR were common predictors of both HARM and GLOS, whereas single-pass recanalization was an independent predictor of HARM only. In this large thrombectomy cohort, HARM was independently associated with early neurologic deterioration and infarct progression after thrombectomy, supporting its role as an imaging marker of early blood-brain barrier disruption. GLOS, although frequent, was not independently associated with clinical or radiologic outcomes. Prospective studies with early and serial imaging are required to clarify the prognostic relevance of HARM. NCT03776877 (ETIS registry).\n\nID: 42579790\nTitle: Ultrastructural neuroprotection by intrathecal interleukin-6 antagonism in a rat model of permanent focal cerebral ischemia.\nAbstract: This study aimed to determine whether intrathecal administration of an interleukin-6 (IL-6) neutralizing antibody could reduce ultrastructural neuronal and vascular damage in a rat model of permanent middle cerebral artery occlusion (MCAO). Forty male Wistar rats were randomly assigned to four groups: Control, Sham-operated, Occlusion (MCAO\u2009+\u2009saline), and Treatment (MCAO\u2009+\u2009anti-rat IL-6 antibody). One week later, ischemic core brain tissue was processed for transmission electron microscopy to evaluate neuronal, axonal, and microvascular integrity. The Occlusion group showed severe ischemic injury, including mitochondrial swelling with cristolysis, cytoplasmic vacuolization, axonal edema, endothelial swelling, and perivascular astrocyte edema. By contrast, the Treatment group demonstrated marked ultrastructural preservation. Endothelial swelling and perivascular edema were reduced, neuronal nuclei were more preserved, and myelin sheath separation in white matter fibers was less pronounced than in the Occlusion group. Direct intrathecal IL-6 blockade was associated with qualitative cellular-level neuroprotection after permanent focal cerebral ischemia. The treatment attenuated inflammatory vascular injury and white matter damage, supporting IL-6 as a potential therapeutic target for limiting secondary stroke injury.\n\nID: 42579394\nTitle: Engineered Brain-Targeted Exosomes Delivering FGF1 for Sustained Glycemic Regulation and Multitarget Neurovascular Protection in Diabetic Stroke.\nAbstract: Diabetic stroke is characterized by a hyperglycemic and pro-inflammatory microenvironment that exacerbates neurovascular dysfunction. However, the blood-brain barrier (BBB) remains a formidable obstacle, restricting the delivery of most therapeutic molecules. To address this, we developed a non-invasive treatment strategy using engineered exosomes. Specifically, we fabricated FGF1-loaded exosomes functionalized with the rabies virus glycoprotein (RVG) peptide (FGF1-RVG Exo). This platform facilitates selective, neuron-targeted delivery of FGF1 to the ischemic penumbra via RVG-mediated transcytosis. In a diabetic stroke mouse model, FGF1-RVG Exo exhibited superior pharmacological efficacy compared to free FGF1, achieving robust therapeutic outcomes with only once-weekly administration. Notably, a single dose during the acute phase elicited a sustained hypoglycemic effect lasting up to two weeks and effectively ameliorated systemic insulin resistance. Locally, the accumulation of exosomes within the lesion led to a significant reduction in infarct volume and cell apoptosis, while promoting neovascularization and the recovery of motor and cognitive functions. This brain-targeted strategy achieves a peripheral-central synergistic modulation, addressing the multi-target requirements of diabetic stroke management. Collectively, our findings provide a novel paradigm for treating diabetic ischemic stroke and a potent strategy for the targeted delivery of growth factors to the central nervous system.\n\nID: 42579302\nTitle: Reply to the Letter to the Editor: 'Stress Hyperglycemia Ratio Is Associated with Intracardiac Thrombus in Acute Ischemic Stroke'.\nAbstract: \n\nID: 42579199\nTitle: Astrocyte-Microglia Crosstalk in Post-Hemorrhagic Neurovascular Microenvironment: Mechanistic Nodes, Cross-Stroke Comparisons, and Therapeutic Reprogramming.\nAbstract: Intracerebral hemorrhage (ICH) produces a rapidly evolving and spatially heterogeneous neurovascular microenvironment in which secondary injury is shaped not only by hematoma volume and location, but also by the interaction of blood-derived toxins, blood-brain barrier disruption, edema, oxidative stress, protease activity, and glial responses. Increasing evidence suggests that these processes are better understood as dynamic network events rather than isolated inflammatory pathways. This review applies a network-centered framework to astrocyte-microglia coupling, viewing it as a critical control layer that may either support injury containment and hematoma resolution or drive persistent neurotoxicity and failed repair. Comparisons with ischemic stroke are used to distinguish shared inflammatory modules from hemorrhage-specific drivers, including heme, hemoglobin, iron overload, thrombin, fibrinogen, and clot-associated protease signaling. Integrating findings from single-cell and spatially resolved studies, the review summarizes the temporal and spatial organization of post-hemorrhagic microenvironment remodeling and discusses astrocyte-dependent regulation of barrier function, edema dynamics, immunometabolism, redox buffering, and synaptic homeostasis. It also examines how astrocyte-derived cues influence microglial state transitions through danger sensing, inflammasome signaling, cyclic GMP-AMP synthase-stimulator of interferon (IFN) genes signaling, phagocytic containment, iron-handling programs, complement-mediated synaptic vulnerability, and interaction with infiltrating myeloid cells. Recurring astrocyte-microglia network motifs are further evaluated as therapeutic control points, with emphasis on how lesion stage and spatial compartmentalization shape intervention windows for purinergic, chemokine, cytokine, IFN, complement-coagulation, and lipid/iron signaling pathways. Translational priorities, limitations, and therapeutic opportunities are discussed across hematoma-toxicity reduction, barrier and edema repair, network reprogramming, and regenerative microenvironment shaping. Meaningful improvement in ICH outcome will likely depend on biomarker-guided and stage-specific reprogramming of astrocyte-microglia network dynamics to restore microenvironmental balance, rather than on nonspecific suppression of neuroinflammation.\n\nID: 42578435\nTitle: Diagnostic Performance of Mobile Low-Field MRI and CT for Acute Headache as the Isolated Clinical Manifestation in the Neurology Emergency Department.\nAbstract: Headache may manifest as the sole or predominant presenting symptom of various types of acute stroke. While mobile low-field magnetic resonance imaging (mLF-MRI) shows promise for rapid and accurate diagnosis in the emergency department (ED), its diagnostic concordance using computed tomography (CT) as the reference standard requires clarification. This prospective study included 199 patients who presented to the ED of Beijing Tiantan Hospital with headache within 72\u2009h of onset, without Face-Arm-Speech Test (FAST) symptoms, and who underwent 0.23-T mLF-MRI between January and July 2024. This study evaluated the diagnostic utility of 0.23-T mLF-MRI in emergency patients presenting with an isolated acute headache. We specifically compared the consistency of mLF-MRI and CT in detecting subarachnoid hemorrhage (SAH) and other causes. Of the 199 patients with headache who did not have FAST symptoms, 71 (35.68%) were diagnosed with stroke, including 60 cases of SAH and 2 patients with intracerebral hemorrhage (ICH). Notably, 9 patients presenting with headaches but without FAST symptoms were diagnosed with acute ischemic stroke. The diagnostic concordance between the fluid-attenuated inversion recovery (FLAIR) sequence of mLF-MRI and CT for SAH was excellent (\u03ba\u2009=\u20090.99). The mLF-MRI provided short scanning times and offered a portable, low-power diagnostic tool. For emergency patients with headaches as the initial and isolated clinical manifestation, mLF-MRI may serve as a supplementary diagnostic imaging modality that provides additional diagnostic information in selected ED settings. mLF-MRI, especially FLAIR sequences, demonstrated high CT-referenced diagnostic concordance for SAH and may also detect early ischemic lesions.\n\nID: 42578421\nTitle: Cholesterol Drives IFITM3+ Microglia Activation and Induces STING Mediated Neuroinflammation After Ischemic Stroke.\nAbstract: Cerebral ischemic stroke triggers extensive neuronal membrane breakdown, releasing a massive load of cholesterol that overwhelms resident microglia. Dysregulated microglial cholesterol metabolism has been implicated in post-stroke neuroinflammation, yet the specific pathogenic microglial subpopulations, their molecular signatures, and the downstream inflammatory cascades remain poorly defined. We employed a permanent distal middle cerebral artery occlusion (dMCAO) model combined with single-cell RNA sequencing (scRNA-seq) to profile immune cell transcriptomes and identify cholesterol-associated microglial markers. Cholesterol dynamics, lipid droplet accumulation, and inflammatory marker expression were quantified via immunofluorescence and transmission electron microscopy. Therapeutic interventions included pharmacological cholesterol mobilization with 2-hydroxypropyl-\u03b2-cyclodextrin (H\u03b2CD), pharmacological STING inhibition with C-176, and microglia-targeted STING knockdown using AAV9 vectors. Cerebral injury and neurological function were assessed through infarct volume measurement, white matter integrity analysis, and behavioral assays (rotarod and grip strength) in dMCAO, tMCAO, and perioperative stroke (PIS) models. Using scRNA-seq, we identified interferon-induced transmembrane protein 3 (IFITM3) as a specific marker for a microglial subpopulation that was characterized by upregulated ACAT1, enhanced cholesterol esterification, and accumulation of cholesterol crystals and lipid droplets. This IFITM3+ microglia population peaked at 7\u2009days post-stroke and correlated with NLRP3 inflammasome activation and STING signaling. Pharmacological reduction of cholesterol burden with H\u03b2CD attenuated lipid droplet formation, suppressed mitochondrial DNA leakage, and inhibited STING pathway activation. Correspondingly, H\u03b2CD and C-176 administration significantly reduced cerebral infarct size, mitigated white matter demyelination, and improved motor function in dMCAO and tMCAO models. We further found that AAV-mediated STING knockdown recapitulated the above protective effects in H\u03b2CD and C-176 treated stroke mice. Furthermore, H\u03b2CD treatment ameliorated microglial inflammation and improved functional outcomes in a PIS model. IFITM3+ microglia is a pro-inflammatory and cholesterol-laden subpopulation that exacerbates post-stroke cerebral ischemic brain injury. Targeting the microglial cholesterol axis by H\u03b2CD or inhibiting the STING pathway represents a promising therapeutic strategy to mitigate ischemic brain injury and improve neurological function.\n\nID: 42578227\nTitle: Application of Acute Physical Therapy in Respiratory Failure Secondary to Bilateral Medial Medullary Infarction and Long-Term Follow-Up: A Case Report.\nAbstract: Bilateral medial bulbar infarction (BMMI) represents a rare yet critical form of posterior circulation ischemic stroke encountered in clinical practice. The condition progresses rapidly and is associated with a heightened risk of secondary central respiratory failure, severe pulmonary infection, and multiple systemic functional impairments, including dysphagia, limb paralysis, and sensory abnormalities. Consequently, both the disability and mortality rates remain elevated. Currently, systematic clinical studies focusing on early physical intervention, phased rehabilitation programs, and long-term prognosis follow-up for patients with BMMI during the acute phase are relatively limited. This report reviews the clinical diagnosis and treatment, early acute physical therapy, and two-year long-term rehabilitation follow-up data of a 53-year-old male patient with BMMI, who presented with acute central respiratory failure, severe pulmonary infection, and pronounced bulbar palsy. It summarizes the clinical progression characteristics, stepwise rehabilitation intervention strategies, and prognostic patterns associated with this condition. The objective is to provide a clinical reference for early rehabilitation interventions, the formulation of individualized treatment plans, and the assessment of long-term prognosis for patients with BMMI complicated by severe multi-system dysfunction.\n\nID: 42578001\nTitle: Associations of Different Inflammatory Markers with Neurological Deficit Severity and Short-Term Prognosis in Young Patients with Ischemic Stroke.\nAbstract: To investigate the correlation between inflammatory markers and neurological deficit severity in young ischemic stroke (YIS) patients, and to evaluate their predictive value for short\u2011term prognosis. We retrospectively collected clinical data from 196 YIS patients at Nanjing Brain Hospital between January 2022 and December 2025. Patients were divided into mild stroke (MIS) and moderate\u2011to\u2011severe stroke (MSS) groups based on the National Institutes of Health Stroke Scale (NIHSS) scores assessed within 24\u00a0hours of admission. Short-term prognosis at 3 months was evaluated using the modified Rankin Scale (mRS), and patients were classified into good and poor outcome groups. Correlation analysis was used to evaluate the relationships between inflammatory markers and NIHSS scores. LASSO regression was conducted to screen variables, followed by Firth's penalized logistic regression to correct for small-sample bias. Receiver operating characteristic curves were generated to evaluate predictive performance. The systemic inflammatory response index (SIRI), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and monocyte-to-lymphocyte ratio (MLR) were markedly elevated in the MSS group and positively correlated with NIHSS scores. SIRI, PLR, and MLR were significantly higher in the poor outcome group. LASSO identified D\u2011dimer (D-D), low-density lipoprotein cholesterol (LDL\u2011C), and NLR as independent predictors of poor outcomes. The area under the curve (AUC) for NLR was 0.592, whereas the combined model (D-D + LDL-C + NLR) yielded an AUC of 0.734. PLR exhibited the strongest correlation with neurological deficit severity. The combined model may provide a more accurate laboratory\u2011based tool for risk stratification in YIS patients.\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 Introduction: The focal cerebral hyperperfusion (CHP) is a potential complication after superficial temporal artery-middle cerebral artery (STA-MCA) bypass for moyamoya disease (MMD) that can result in delayed intracerebral hemorrhage and/or neurological deterioration. The focal CHP could accompany hemodynamic ischemia due to the \"watershed shift (WS) phenomenon.\" Preoperative prediction of the focal CHP and WS phenomenon remains challenging. Here, we aimed to assess the diagnostic value of the \"to and fro\" conflict sign, conflicting blood flow around the vascular territory of the recipient arteries on an indocyanine green video angiography (ICG-VA) for predicting the focal CHP and WS phenomenon. Ninety-seven consecutive adult patients with MMD, undergoing 106 surgeries, were enrolled. Serial quantitative analysis of cerebral blood flow was routinely conducted using n -isopropyl-p-[123I] iodoamphetamine single-photon emission computed tomography preoperatively and postoperative day 1 and 7 after STA-MCA bypass. The association between the \"to and fro\" conflict sign on ICG-VA and the focal CHP/WS phenomenon incidence was then analyzed. The incidence of the focal CHP and WS phenomenon was 29.2% (31/106) and 10.4% (11/106), respectively. The \"to and fro\" conflict sign was evident in 35.5% (11/31) and 54.5% (6/11) of MMD patients with the focal CHP and WS phenomenon, respectively. The \"to and fro\" conflict sign was significantly associated with both the focal CHP and WS phenomena. The \"to and fro\" conflict sign on ICG-VA may serve as an intraoperative warning sign of the focal CHP and WS phenomenon after STA-MCA bypass in adult patients with MMD, providing neurosurgeons with a valuable tool for early detection.
.",
"40526280": "ID: 40526280\nTitle: Melatonin and necroptosis: therapeutic aspects based on cellular mechanisms.\nAbstract: Necroptosis is a regulated form of programmed cell death. It is integral to the development of various diseases, such as neurological disorders, lung injuries, liver fibrosis, and testicular toxicity. This process is orchestrated by essential molecular pathways that involve receptor-interacting protein kinases (RIP1/RIP3) and mixed lineage kinase domain-like protein (MLKL), which lead to membrane disruption, the release of damage-associated molecular patterns (DAMPs), and subsequent inflammation. Melatonin, recognized for its potent antioxidant and anti-inflammatory properties, has emerged as a promising therapeutic agent that can inhibit necroptosis through various mechanisms. In neurological diseases such as intracerebral hemorrhage, traumatic brain injury, and cerebral ischemia-reperfusion, melatonin suppresses necroptosis by downregulating RIP1/RIP3/MLKL signaling, upregulating A20 (TNFAIP3), and inhibiting the HMGB1/TLR4/NF-\u03baB pathway. In lung disorders, melatonin attenuates cadmium- and LPS-induced necroptosis by modulating the Ang-II axis, reducing TNF-\u03b1-mediated signaling, and acting through MT1/MT2 receptors. In liver fibrosis models, melatonin inhibits RIP1-RIP3 necrosome formation, reduces oxidative stress, and decreases DAMPs-mediated immune responses. Similarly, in testicular toxicity induced by tetrabromobisphenol A (TBBPA), melatonin suppresses necroptosis by inhibiting the several pathways and reducing ROS overproduction. These findings highlight melatonin's ability to modulate necroptosis across diverse tissues, offering protection against inflammation, oxidative stress, and cell death. By targeting necroptosis-related pathways, melatonin presents a versatile therapeutic strategy for treating diseases characterized by excessive cell death and inflammation, including stroke, myocardial infarction, pancreatitis, and autoimmune disorders. This review underscores the potential of melatonin as a novel intervention for necroptosis-related pathologies, emphasizing its role in restoring cellular homeostasis and mitigating tissue damage.",
"40532744": "ID: 40532744\nTitle: Indole-3 propionate inhibits NF-\u03baB/NLRP3-mediated osteoclastogenesis and improves bone quality in high-fat-diet induced obese mice.\nAbstract: Obesity is a global health issue that causes altered gut microbiota and a wide variety of diseases, such as osteoporosis. The association between altered gut microbiota metabolites and high-fat diet (HFD)-induced osteoporosis has not been thoroughly investigated. 3-Indolepropionic acid (IPA) is a gut microbiota metabolite that is deficient in obese mice. The purpose of this study is to examine wheter IPA affects osteoporosis in HFD-induced obese mice. Mice were fed with HFD for 12\u00a0weeks, during which IPA or vancomycin was administered. Micro-computed tomography, hematoxylin and eosin (H&E) staining, and tartrate-resistant acid phosphatase (TRAP) staining were used to evaluate osteoporosis and osteoclast activation in vivo. Cultured bone marrow macrophages were used to examine osteoclast activation in vitro. Western blot, immunohistochemical staining, and immunofluorescence staining were used to investigate the nuclear factor kappa B (NF-\u03baB) and NLRP3 signaling pathways. Reduced bone mass and noticeable osteoclast activation were observed in mice fed with HFD and vancomycin. IPA supplementation alleviated systemic inflammatory response, inhibited osteoclast activation, and improved bone mass in mice. Mechanistically, IPA inhibited the phosphorylation of NF-\u03baB, thus, reducing the expression levels of NLRP3, caspase-1, and apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) and inhibiting osteoclast activation. These findings suggest that IPA-induced inhibition of osteoclast activation in the HFD environment was mediated via the NF-\u03baB/NLRP3 pathway. Our study suggests that IPA consumption may help manage obesity-induced osteoporosis.",
"40571216": "ID: 40571216\nTitle: Novel aryl hydrocarbon receptor agonists as potential anti-inflammatory therapeutics: Identification and validation through drug repurposing.\nAbstract: The aryl hydrocarbon receptor (AhR) was shown to be an important regulator of inflammatory processes at epithelial barriers, and is thus considered a therapeutic target for several chronic inflammatory diseases, such as inflammatory bowel disease. We aimed to identify and validate new AhR agonists that sustainably attenuate intestinal inflammation. Using a high-throughput luciferase reporter gene assay, 90 AhR ligands were identified out of 7448 approved and investigational drugs. Out of these, 15 AhR ligands were selected based on substance class, half maximal effective concentration, known toxicity and pharmacokinetic/pharmacodynamic profiles, and preclinical/clinical evaluation status for other indications. While Febuxostat, Nitazoxanide, Rabeprazole, 2-(1'H-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester, 3-Indolepropionic acid, and Indirubin, were already known as AhR agonists, Nabumetone, Teriflunomide, Timapiprant/OC000459, and Caffeic acid phenylethyl ester have not yet been directly described in this context. Six compounds (Daidzein/Equol, as well as compounds no. 19, 22, 49, and 64, not yet disclosed due to pending patent applications) were newly described as AhR agonists. Hit compounds were studied in silico for their molecular interactions with AhR and in vitro for potential immunotoxicity and their ability to induce interleukin (IL)-10 and/or to suppress IL-1\u03b2 in murine macrophages without significant cytochrome P450 1A1 induction in Caco-2 cells. Five compounds that met these criteria were functionally tested using organoid-based Transwell\u00ae-like models derived from gut biopsies. Five candidates restored the epithelial barrier, as evidenced by increased transepithelial electrical resistance and induction of the tight junction proteins claudin-1/-2 and occludin, while exhibiting anti-inflammatory effects, i.e., decreased expression of toll-like receptor 4. Out of these, one compound was selected for future in vivo preclinical studies.",
"40750967": "ID: 40750967\nTitle: Gut Microbial Metabolite Crosstalk in Crohn's Disease: Network Pharmacology Unveils Dual-Axis Pathogenesis and Therapeutic Targets.\nAbstract: Crohn's disease (CD), a chronic inflammatory bowel disorder, is driven by dysregulated interactions between gut microbiota and host metabolism. Here, we developed a computational framework integrating multiomics profiling, network pharmacology, and molecular dynamics simulations to systematically map microbiota-metabolite-target-signaling (M-M-T-S) networks and identify therapeutic candidates. By analyzing gut microbial metabolomics and CD-associated targets (via SwissTargetPrediction [STP]/SEA), we constructed a protein-protein interaction (PPI) network enriched for 50 intestinal hub targets (IL6, AKT1, PPARG; degree centrality [CD]\u2009>\u200919.4), which orchestrate inflammatory (TNF/IL-17/TLR, FDR\u2009=\u20093.8\u2009\u00d7\u200910-12) and metabolic (PPAR, FDR\u2009=\u20091.5\u2009\u00d7\u200910-10) pathways. Structure-based screening (AutoDock Vina/AMBER20) revealed 3-indolepropionic acid (IPA) as a high-affinity AKT1 binder (\u0394G\u2009=\u2009-67.4\u2009kJ/mol), while Genipin exhibited robust binding to PTGS2, both validated by 100-ns dynamics simulations (RMSD\u2009<\u20093.8\u2009\u00c5). Mechanistic network analysis uncovered a dual-axis regulatory paradigm: a pro-inflammatory axis (Clostridiumspp.-derived LPS aggravates Th17 polarization via TLR4/IL-17 signaling) and a reparative axis (Faecalibacterium prausnitzii-produced butyrate enhances barrier integrity through PPAR\u03b3-mediated NF-\u03baB suppression). Phylogenetic analysis linked microbial functional traits (e.g., LPS/SCFA synthesis) to evolutionary conservation, highlighting clade-specific roles in CD progression. Drug-likeness evaluation (SwissADME/ADMETlab 2.0) prioritized IPA as a lead candidate due to its superior solubility (7.65\u2009mg/mL), nonhepatotoxic profile, and AhR agonism, outperforming Genipin. This study establishes IL6/AKT1/PPARG as central therapeutic hubs and positions IPA for clinical translation. Our framework bridges multiomics integration with precision medicine, offering a scalable strategy to decode microbiome-driven pathologies and accelerate metabolite-based therapeutics.",
"40994248": "ID: 40994248\nTitle: Network Pharmacology-Based and Experimental Validation Elucidate the Target Mechanism of Vinorine in Ameliorating Secondary Brain Injury After Intracerebral Hemorrhage.\nAbstract: Intracerebral hemorrhage (ICH) is a severe stroke subtype associated with high mortality and long-term disability, for which no effective treatment currently exists. Vinorine (Vin), a monoterpene indole alkaloid derived from Rauvolfia reflexa, has been traditionally used for age-related neurological disorders, yet its therapeutic potential and mechanisms in ICH remain unclear. An ICH mouse model was established via intracranial collagenase injection. Vin was administered intraperitoneally at varying doses, and its effects on motor function, sensory deficits, and neural regeneration were evaluated. Network pharmacology was employed to predict potential targets and pathways, followed by validation through molecular docking, in\u00a0vivo experiments, and in\u00a0vitro assays. Network pharmacology identified four core targets and 35 related pathways, with JAK2 as a central node. In\u00a0vivo, Vin significantly improved motor deficits, reduced cerebral edema, preserved blood-brain barrier integrity, and promoted hematoma resolution. These effects were mediated through modulation of the CXCR2-JAK-STAT axis and suppression of JAK2 phosphorylation. In\u00a0vitro, Vin inhibited JAK-STAT activation in microglia, downregulated MMP expression, and facilitated the transition from M1 to M2 phenotypic polarization. Additionally, Vin enhanced the expression of neuronal markers (NF200, PSD95, GAP43) and reduced neuronal apoptosis. Vin attenuates neurological deficits after ICH likely by inhibiting MMP expression in microglia via regulation of the CXCR2-JAK-STAT pathway. These findings highlight the therapeutic potential of Vin and provide mechanistic support for its further development as a treatment for ICH.",
"41231628": "ID: 41231628\nTitle: Molecular biomarkers for intracerebral hemorrhage: bridging pathophysiology and precision medicines.\nAbstract: Intracerebral hemorrhage (ICH) is a highly destructive subtype of stroke, characterized by high mortality and disability rates, and remains a major clinical challenge due to limited effective treatments, hyperacute diagnostic tools, and insufficient prognostic strategies. Current approaches, primarily based on clinical symptoms and neuroimaging, effectively identify location but lack sensitivity for early risk assessment and dynamic disease monitoring. Molecular biomarkers have shown great promise in elucidating ICH pathogenesis, enhancing diagnostic sensitivity, enabling dynamic disease tracking, and improving outcome prediction. However, clinical translation remains hindered by challenges in standardization, specificity, and validation frameworks. This review systematically summarizes recent advances in biomarker research related to ICH, with a particular focus on key etiological mechanisms such as hypertension and cerebral amyloid angiopathy, as well as critical pathophysiological processes including hematoma expansion, perihematomal edema, neuroinflammation, and oxidative stress. We further explore the emerging role of multi-omics technologies, including genomics, transcriptomics, proteomics, and metabolomics, in identifying ICH specific molecular signatures. Emphasis is placed on the potential clinical utility of these biomarkers in high-risk population screening, early diagnosis, disease monitoring, and outcome prediction. Moreover, we propose the development of a disease-specific, multidimensional biomarker panel that integrates advanced neuroimaging and artificial intelligence-based analytical strategies. This approach aims to accelerate the clinical translation of biomarkers into precision medicine, supporting personalized therapeutic decision-making, preventing the onset of ICH, and improving outcomes. It further promotes a paradigm shift in ICH management from passive treatment to proactive prevention and control.",
"41264131": "ID: 41264131\nTitle: The role of metabolomics in stroke: biomarkers of diagnosis and therapy.\nAbstract: Stroke is a neurological condition caused by an acute focal injury to the central nervous system, typically resulting from vascular events such as cerebral infarction, intracerebral hemorrhage, or subarachnoid hemorrhage. It is associated with high rates of incidence, disability, recurrence, and mortality. To reduce stroke-related mortality, researchers worldwide have developed various in vitro and in vivo models to study molecular mechanisms at different levels, including genes, microRNAs, and proteins, to identify biomarkers for improved diagnosis, treatment, and prognosis. Metabolomics, an emerging field derived from genomics and proteomics, plays a crucial role in understanding stroke pathophysiology. Changes in the metabolome can reflect the body's physiological state following a stroke. Numerous studies have identified biomarkers that aid in stroke diagnosis and treatment by analyzing metabolic alterations in vivo or in vitro stroke models. This article reviews the causes, diagnosis, and treatment of stroke, the role of metabolomics in stroke research, and the clinical significance of some biomarkers discovered by metabolomics for clinical work.",
"41387160": "ID: 41387160\nTitle: Sunitinib attenuates secondary injury via the regulation of peri-hematomal microglia at the acute phase of intracerebral hemorrhage.\nAbstract: Intracerebral hemorrhage (ICH) is a highly fatal stroke subtype with limited treatment options, where pathological activation of peri-hematomal microglia drives acute secondary injury. Colony-stimulating factor 1 receptor (CSF-1R), highly expressed in microglia, is a potential therapeutic target. This study evaluated the effects of short-term administration of sunitinib, a clinically used CSF-1R inhibitor, in a collagenase-induced mouse ICH model and an in vitro hemoglobin (Hb)-treated BV2 microglial model. Sunitinib significantly improved motor functions, reduced myelin damage, and attenuated microglial activation and neuroinflammation in peri-hematomal tissue. RNA sequencing revealed that sunitinib might modulate lipid metabolism, phagocytosis, and immune response. In BV2 cells, sunitinib inhibited Hb-induced lipid droplet accumulation, phagocytic reduction, and pro-inflammatory cytokine production, effects mirrored by CSF-1R knockdown. These findings suggest that sunitinib alleviates acute ICH injury by modulating microglial functions, likely through inhibition of the CSF-1R axis, supporting its potential repurposing for central nervous system disorders like ICH.",
"41772831": "ID: 41772831\nTitle: Neuroprotection From Intracerebral Hemorrhage Following Pharmacological Inhibition of GSK3\u03b2 Depends on HFE Gene Status.\nAbstract: Iron release from hemoglobin breakdown following an intracerebral hemorrhage (ICH) is a key mediator in stroke-induced cytotoxicity. We have previously demonstrated that mice carrying the H67D mutation in the homeostatic iron regulatory gene (HFE) experience marked neuroprotection following ICH. This improvement is likely due to an endogenous upregulation in the Nrf2 antioxidant system. Prior studies in H67D mice discovered decreased activity in GSK3\u03b2, a kinase that functions to break down Nrf2. Interestingly, pharmacological inhibition of GSK3\u03b2 has been shown to vastly improve outcomes in ICH animal models. However, it remains unclear whether this pathway is responsible for the enhanced antioxidant response in H67D animals. In this study, H67D and WT mice received daily injections of intraperitoneal SB216763, a selective inhibitor of GSK3\u03b2, 14\u2009days prior to ICH. The functional motor recovery of each animal was assessed by rotarod and neurodegeneration was measured using Fluorojade-B. Immunoblotting assessed the antioxidant response and GSK3\u03b2 activity through Nrf2, GPX4, FTH1, and \u03b2-Catenin. At 3\u2009days post-ICH, SB216763-treated WT mice display enhanced functional recovery, decreased degenerated neurons, and increased brain levels of Nrf2 and GPX4 compared to WT-Vehicle-Controls. Further, SB216763 treatment in H67D mice did not result in any significant changes in measured outcomes compared to H67D-Vehicle-Controls. In conclusion, WT mice benefit from GSK3\u03b2 inhibition following ICH whereas H67D animals do not. This suggests that the regulation of the antioxidant response may have reached its biological limit in H67D animals. Importantly, these data suggest that clinical trials aimed towards improving ICH outcomes, especially through GSK3\u03b2 inhibition, must take into account HFE genotype as this mutation, present in nearly 20% of individuals worldwide, may alter ICH recovery regardless of therapy.",
"41774153": "ID: 41774153\nTitle: Restoring Firmicutes-Associated Metabolites: A Gut-Brain Axis Approach to Alleviate Neuroinflammation and Oxidative Stress in Intracerebral Hemorrhage.\nAbstract: Intracerebral hemorrhage (ICH), a lethal stroke subtype, lacks therapies targeting gut-brain axis dysregulation. While gut microbiota influences ischemic stroke outcomes, how ICH perturbs microbial-metabolite interactions via the microbiota-gut-brain axis (MGBA) remains unknown. We combined a collagenase-induced ICH mouse model with multi-omics (16S rRNA sequencing, metabolomics) and functional assays (BV2 microglia) to investigate gut dysbiosis and metabolite alterations. Intestinal barrier integrity, neuroinflammation, and oxidative stress were assessed. At the phylum level, the control (CON) group exhibited a microbiome dominated by Firmicutes, Actinobacteriota, and Campylobacterota. In stark contrast, the ICH group displayed a pathological shift toward Bacteroidota, Cyanobacteria, and Proteobacteria. These dysbiotic alterations corresponded to intestinal barrier compromise marked by reduced expression of zonula occludens-1 (ZO-1), occludin, and mucin 2 (MUC2), systemic elevation of pro-inflammatory cytokines including interleukin-1\u03b2 (Il-1\u03b2) and tumor necrosis factor-\u03b1 (Tnf-\u03b1), and depletion of neuroprotective metabolites\u2013specifically oleoyl ethanolamide, linoleoyl ethanolamide, and L-valine\u2013whose levels positively correlated with Firmicutes abundance. Mechanistically, in vitro experiments demonstrated that these metabolites collectively suppressed neuroinflammation and neuronal apoptosis, with l-valine exhibiting unique antioxidant activity through Reactive oxygen species scavenging. Molecular docking studies have shown that linoleoyl ethanolamide (LEA) and oleoylethanolamide (OEA) can inhibit the levels of inflammatory cytokines interleukin-6 (Il-6) and tumor necrosis Tnf-\u03b1 by binding to key sites. Our findings underscore the critical role of gut microbiota-metabolite crosstalk in ICH pathogenesis and identify microbial metabolites as potential therapeutic targets for preserving gut-brain axis homeostasis.",
"41825730": "ID: 41825730\nTitle: Lactobacillus johnsonii and 3-indolepropionic acid improve the depression-like behaviors via inhibiting neuroinflammation.\nAbstract: Gut microbiota-derived metabolites play a crucial role in depression. This study aimed to elucidate the role of tryptophan metabolites herein. In a CSDS mouse model, we identified eight differential species, twelve altered neurotransmitters, and two up-regulated inflammatory factors (IL-6 and IL-1\u03b2). Notably, 3-indolepropionic acid (IPA) levels were consistently reduced in feces, colon, blood, and hippocampus of CSDS mice. The decreased abundance of Lactobacillus johnsonii (L. johnsonii) was correlated closely with depression-like behaviors (DLBs), reduced fecal IPA, and elevated IL-6 and IL-1\u03b2. Both L. johnsonii and IPA supplementation alleviated DLBs, along with up-regulated AhR and down-regulated NF-\u03baB, NLRP3, IL-6, and IL-1\u03b2 in hippocampus. Moreover, both treatments significantly elevated IPA levels in peripheral and central samples, and improved the mRNA levels of AhR and NF-\u03baB p65 in hippocampus. Critically, the antidepressant effects of L. johnsonii and IPA were counteracted by AhR antagonist CH223191. Independent experimental results showed that CH223191 had no significant effects on behaviors of CSDS mice. To our knowledge, this was the first study to report reduced IPA levels in both peripheral and central samples of CSDS mice. We also provided the first demonstration that the antidepressant effects of L. johnsonii and IPA were mediated, at least in part, through the inhibition of neuroinflammation via AhR pathway, accompanied by the restoration of IPA levels in gut-brain axis. These findings positioned L. johnsonii and IPA as promising therapeutic candidates for depression.",
"42019018": "ID: 42019018\nTitle: Three Low-Dose Antihypertensive Agents in a Single Pill after Intracerebral Hemorrhage.\nAbstract: Blood-pressure reduction is the only proven treatment to prevent stroke. Whether a single pill that combines three antihypertensive drugs at low doses, in addition to standard antihypertensive treatment, can lower blood pressure more than standard care alone and reduce the risk of recurrent stroke after intracerebral hemorrhage is uncertain. We conducted a multinational, double-blind, randomized, placebo-controlled trial involving patients with a history of intracerebral hemorrhage. Patients were eligible for the trial if they had a systolic blood pressure of 130 to 160 mm Hg at baseline and were in clinically stable condition. After a 2-week active run-in phase during which all the patients received a once-daily pill containing three antihypertensive agents at low doses (telmisartan at 20 mg, amlodipine at 2.5 mg, and indapamide at 1.25 mg; the triple pill), the patients were randomly assigned to continue receiving the triple pill or to receive matching placebo. The primary outcome was the first recurrent stroke. Secondary outcomes included blood-pressure control, major cardiovascular events, death from cardiovascular causes, and safety. Of 1670 patients who underwent randomization, 833 were assigned to receive the triple pill and 837 to receive placebo. The mean age of the patients was 58 years. At a median follow-up of 2.5 years, recurrent stroke had occurred in 38 patients (4.6%) in the triple-pill group and 62 (7.4%) in the placebo group (hazard ratio, 0.61; 95% confidence interval [CI], 0.41 to 0.92; P\u2009=\u20090.02). The mean systolic blood pressure during follow-up was 127 mm Hg and 138 mm Hg, respectively. The incidence of major cardiovascular events was lower with the triple pill than with placebo (6.6% vs. 9.8%; P\u2009=\u20090.04). Serious adverse events occurred in 23.2% of the patients in the triple-pill group and 26.0% of those in the placebo group. Early discontinuation of the trial regimen due to an adverse event occurred in 13.6% and 6.0%, respectively. The most common adverse event leading to discontinuation was an increase of 20% or more in the serum creatinine level. Among patients with intracerebral hemorrhage, treatment with a combination of three low-dose antihypertensive agents in a single pill, in addition to standard care, was associated with a lower incidence of recurrent stroke and major cardiovascular events than placebo. (Funded by the National Health and Medical Research Council of Australia and the Brazilian Ministry of Health; TRIDENT ClinicalTrials.gov number, NCT02699645; Australian New Zealand Clinical Trials Registry number, ACTRN12616000327482.).",
"42074996": "ID: 42074996\nTitle: The Effect of Pediococcus Lactis and Postbiotics on Gut Health and Intestinal Metabolic Profiles.\nAbstract: To investigate the effects of probiotics and their postbiotics on mouse health, this study utilized healthy mice randomly assigned to a control group (CK, n = 6), a probiotic group (L, n = 6, oral gavage 200 \u03bcL Pediococcus lactis), and a postbiotic group (PL, n = 6, oral gavage 200 \u03bcL Pediococcus lactis postbiotic). Following 21 days of continuous intervention, changes in gut metabolic profiles, microbial community structure, tissue morphology, and tight junction protein expression were systematically analyzed using metabolomics, 16S rRNA sequencing, hematoxylin and eosin (HE) staining, and immunohistochemistry techniques. The results revealed that screening for significantly altered endogenous metabolites identified core differences concentrated in metabolites related to intestinal barrier repair, anti-inflammation, and antioxidant activity (e.g., 3-indolepropionic acid, astaxanthin, hydroxybenzoic acid). 16S rRNA sequencing revealed that the overall community structure was relatively stable according to principal component analysis, although differences were detected in specific taxa. However, LEfSe analysis identified significantly enriched functional microbial groups at multiple taxonomic levels in the PL group: phylum: Actinomycetota; class: Coriobacteriia; order: Coriobacteriales, Erysipelotrichales; family: Erysipelotrichaceae, Eggerthellaceae; genus: norank_Erysipelotrichaceae, Intestinimonas. These results suggest that although the overall community structure remained relatively stable, specific taxa may have differed between groups. Hematoxylin and eosin staining revealed no pathological lesions in intestinal tissues from either group, with intact mucosal architecture. Immunohistochemistry demonstrated significantly elevated expression of intestinal tight junction proteins Claudin 1, MUC-2, Occludin, and ZO-1 in the PL group compared to the CK group (p < 0.001). In summary, this probiotic (Pediococcus lactis) and its postbiotic showed promising effects, which may be related to changes in specific microbiota taxa, intestinal metabolic profiles, and tight junction protein expression. Beyond maintaining gut microbiota and tissue homeostasis, it enhances intestinal barrier function, suppresses latent inflammation, and boosts antioxidant capacity. Postbiotics may exhibit superior efficacy compared to probiotics. This provides robust experimental evidence for its development and application in gut health products for healthy populations. However, these findings still require further validation in studies with longer intervention periods and in disease models.",
"42105993": "ID: 42105993\nTitle: Multifaceted mechanisms of 4-hydroxybenzaldehyde in reducing hemorrhagic transformation in ischemic stroke ameliorating based on transcriptomics and metabolomics.\nAbstract: The PI3K-AKT signaling pathway has emerged as a central modulator in the pathophysiology of hemorrhagic transformation (HT). Gastrodia elata Blume, a classic neuroprotective herb used in Traditional Chinese Medicine, traditionally believed to \"calm endogenous wind\" and \"unblock meridians\". Although phenolic compounds are recognized as key neuroprotective constituents, their anti-hemorrhagic mechanisms remain. This study aimed to validate 4-hydroxybenzaldehyde (4-HBd), a major phenolic component of G. elata, as a therapeutic candidate against ischemic stroke (IS)-associated HT, with a focus on its modulation of PI3K-AKT signaling. A rat model of transient middle cerebral artery occlusion with induced HT (tMCAO-HT) was established and treated with 4-HBd (20\u00a0mg/kg) for assessment of intracerebral hemorrhage and neurological function. Integrated transcriptomic and metabolomic profiling identified 214 differentially expressed genes and 38 differential metabolites. Molecular docking simulations evaluated 4-HBd binding to PI3K and AKT, and in vitro validation was performed in hypoxia-exposed PC12\u00a0cells using viability assays and western blot analysis. 4-HBd administration significantly attenuated cerebral hemorrhage (P\u00a0<\u00a00.01) and improved neurological function (P\u00a0<\u00a00.01). Multi-omics analysis revealed convergent enrichment of the PI3K-AKT pathway (KEGG: hsa04151), supported by high-affinity docking to both PI3K (\u0394G\u00a0=\u00a0-5.7\u00a0kcal/mol) and AKT (\u0394G\u00a0=\u00a0-5.3\u00a0kcal/mol). Treatment enhanced p-PI3K and p-AKT expression (P\u00a0<\u00a00.01), rescuing PC12\u00a0cells viability under hypoxic conditions (P\u00a0<\u00a00.05). 4-HBd exerts protective effects against HT by restoring PI3K-AKT signaling.",
"42163413": "ID: 42163413\nTitle: Gut microbiota-derived indole-3-propionic acid promotes lymph node metastasis in gastric cancer via the aryl-hydrocarbon receptor signaling pathway.\nAbstract: Gut microbiota (GM) regulates the tumor microenvironment through microbial metabolites. Indole 3-propionic acid (3-IPA) is one such metabolite that regulates gastrointestinal barrier function. In this study, we investigated the effects of 3-IPA on the progression of lymph node metastasis of gastric cancer (GC) and the molecular mechanisms that underlie them. The microbial metabolites were identified using a fecal metabolomic assay in GC patients. Lymphangiogenesis was evaluated using tube formation and wound healing assays in vitro. The expression of aryl hydrocarbon receptor (AHR), CYP1A1, and vascular endothelial growth factor receptor 3 (VEGFR3) were assayed using quantitative real-time PCR (qRT-PCR) and western blot (WB) analyses. Matrigel plug and popliteal lymph node metastasis model were employed to validate the influence on lymphangiogenesis and lymph node metastasis in vivo. Fecal metabolomic and microbiome profiling was drastically different between GC patients with lymph node metastasis (GC-LM) and those without metastasis. The GC-LM group showed high 3-IPA expression in the feces; 3-IPA had no significant effect on GC cells; Human lymphatic endothelial cells showed greater tube formation and promoted migration after 3-IPA administration. Also, upregulation of AHR, CYP1A1, and VEGFR3 was observed. Moreover, administration of the AHR inhibitor suppressed tube formation and lymph node metastasis both in vitro and in vivo. Our findings suggest that gut microbiota-derived 3-IPA functions as a lymph node metastasis promoter through the AHR/CYP1A1-VEGFR3 axis in GC. 3-IPA could serve as a prognostic biomarker and conceivably a therapeutic target for GC lymph node metastasis.",
"42283270": "ID: 42283270\nTitle: Identification of traumatic intracerebral hemorrhage associated metabolites using untargeted metabolomics.\nAbstract: Traumatic intracerebral hemorrhage (TICH) is a severe neurological emergency whose metabolic mechanisms remain largely unresolved. This study used serum metabolomics analysis to compare the metabolic profiles of TICH patients (n\u2009=\u200910) with non-TICH controls (n\u2009=\u200910). LC-MS/MS analysis identified a total of 3183 metabolites. The relative abundances of benzene and its derivatives, organic acids and their derivatives were significantly increased in the serum of ICH patients, while fatty acid, glycerophospholipid, and sphingomyelin metabolites were generally decreased. Multidimensional statistical methods were used to screen for significantly differentially expressed metabolites. Metabolite regulatory networks revealed the potential roles of amino acid metabolism, lipid metabolism (GP/SP/FA), and aromatic compounds (benzenes) in regulating TICH metabolism. Enrichment analysis revealed that these metabolites were highly enriched in lipid metabolism, amino acid metabolism, and neural signaling pathways, and were significantly associated with inflammatory drug pathways. The differentially expressed metabolites were further mapped to the Human Metabolite Database (HMDB) and subjected to metabolic-disease association analysis, suggesting that these metabolites may be closely related to the pathogenesis of TICH. ROC analysis demonstrated good diagnostic performance of five key metabolites in both discovery and validation cohorts (AUC > 0.70), with hypoxanthine and L-histidine showing the highest accuracy (AUC > 0.93). Correlation analysis indicated that key metabolites were associated with hematoma volume, NIHSS and GCS scores. In vitro experiments further confirmed that, under conditions of neuronal injury, the changes in these metabolites exhibit consistency. This study provides a theoretical basis for the development of potential biomarkers and precise intervention strategies.",
"42329535": "ID: 42329535\nTitle: Age-related metabolomic signatures and stroke susceptibility in a population-based cohort.\nAbstract: Aging-related metabolic dysregulation and vascular vulnerability contribute substantially to stroke susceptibility, yet subtype-specific metabolic signatures remain incompletely characterized. Employing a nested case-control design within the Taizhou Longitudinal Study, we quantified 296 lipoprotein parameters and 54 metabolites in 1208 stroke-control pairs using nuclear magnetic resonance. Logistic regression estimated subtype-specific associations, and machine learning constructed prediction models for ischemic stroke (IS) and intracerebral hemorrhage (ICH). Distinct metabolic profiles were observed across stroke subtypes. Triglyceride-enriched lipoproteins and several low-molecular-weight metabolites were positively associated with both IS and ICH, whereas apolipoprotein A-related components showed inverse associations, with generally stronger effects observed for IS than for ICH. Age-stratified and interaction analyses revealed age-dependent heterogeneity, especially among histidine and lipoprotein composition measures. To further characterize systemic metabolic vulnerability, we constructed a weighted metabolic risk score (MRS), which was associated with age and statistically accounted for part of the age-stroke association (average causal mediation effects: 0.020 for IS; 0.025 for ICH). MRSs were also positively correlated with age and inflammatory markers, particularly for IS (both P\u2009<\u20090.001). Metabolite-based models improved risk discrimination beyond traditional risk factors for both IS and ICH. These findings identify subtype-specific metabolic signatures of stroke and suggest that circulating metabolomic profiles reflect age-associated metabolic alterations relevant to stroke susceptibility beyond traditional cardiometabolic risk factors.",
"42332755": "ID: 42332755\nTitle: Gut microbiota-derived metabolites as potential therapeutic agents for intervertebral disc degeneration: insights from network pharmacology and molecular docking.\nAbstract: Increasing evidence highlights the critical role of gut microbiota diversity in maintaining systemic homeostasis; however, the mechanisms by which microbiota-derived metabolites regulate host targets remain incompletely understood. Intervertebral disc degeneration (IDD) is strongly associated with chronic inflammation and metabolic dysregulation. This study employed a network pharmacology approach to elucidate metabolite-target interactions underlying the gut-disc axis. Gut microbiota-derived metabolites were retrieved from the gutMGene database, and their potential targets were predicted using the Similarity Ensemble Approach and SwissTargetPrediction. IDD-related genes were collected from GeneCards and OMIM databases. Overlapping targets were identified to construct a protein-protein interaction (PPI) network and screen core genes. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed using R software. A gut microbiota-metabolites-targets (G-M-T) network was established, followed by molecular docking to assess metabolite-target binding affinities. Twenty-two overlapping targets were identified, among which nine key candidates were initially screened. Network analysis revealed IL6, TLR4, CXCL8, and JUN as core targets due to their high connectivity. Enrichment analyses indicated that these targets were mainly involved in inflammatory responses, oxidative stress, apoptosis, extracellular matrix metabolism, and IL-17- and lipid-related pathways. The G-M-T network highlighted butyrate, propionate, acetate, succinate, trimethylamine oxide, and 3-indolepropionic acid as core metabolites. Molecular docking suggested favorable binding affinities, with 3-indolepropionic acid exhibiting the strongest interactions. Gut microbiota-derived metabolites, particularly 3-indolepropionic acid, may modulate IDD progression by targeting IL6, TLR4, CXCL8, and JUN through inflammation- and lipid-related pathways, providing mechanistic insights into the gut-disc axis.",
"42360541": "ID: 42360541\nTitle: The gut microbial metabolite 3-indolepropionic acid as a functional neuroprotective agent against intracerebral hemorrhage: integrating epidemiological screening with in vivo validation.\nAbstract: Intracerebral hemorrhage (ICH) is a severe stroke subtype with limited therapeutic options. Emerging evidence highlights the diet-gut-brain axis in neurological outcomes, yet the specific metabolic mediators remain elusive. This study integrated epidemiological, genetic, and experimental approaches to investigate the potential neuroprotective role of gut-derived metabolites in ICH. Utilizing Global Burden of Disease data and Mendelian randomization analysis, we explored the associations between dietary habits and ICH, and investigated putative causal relationships between specific gut microbiota and disease risk. Subsequent network pharmacology analysis predicted that 3-indolepropionic acid (3-IPA) might exert neuroprotective effects primarily through anti-apoptotic pathways. To evaluate these findings in vivo, we established a mouse model of ICH. Administration of 3-IPA significantly ameliorated neurological deficits and improved cognitive memory in the Morris water maze test. Furthermore, immunofluorescence and Western blot analyses indicated that 3-IPA treatment was associated with the upregulation of the anti-apoptotic protein BCL2 and the reduction of pro-apoptotic markers in the peri-hematomal region. In conclusion, our multidisciplinary study outlines a potential biological pathway linking dietary patterns, gut microbial metabolism, and brain injury recovery. Our findings suggest that the gut microbial metabolite 3-IPA protects against ICH-induced secondary brain injury, potentially by attenuating neuronal apoptosis, highlighting it as a promising metabolic intervention target for ICH therapy.",
"42437599": "ID: 42437599\nTitle: Blood Biochemistry Age Clock - An interpretable estimate of biological age and predictor of all-cause-mortality derived from routinely ordered blood biomarkers.\nAbstract: \"Omic\" aging clocks(ACs) represent an established predictor of biological-age(BA)/all-cause mortality(ACM); however, they are expensive and lack interpretability/explainability. We developed a Blood-Biochemistry Age Clock (BBAC) composed of 11 routine blood biomarkers. The AC functions by transforming the individual's levels of blood biomarkers to years added/subtracted according to \"biomarker-ACM risk-profile\". The BBAC and PhenoAge were calculated for individuals of the UKB cohort and the results were associated with ACM and disease incidence (eight common chronic diseases) using univariant/multivariate Cox mortality analysis. The BBAC calculation procedure was further optimised. Mortality analysis was likewise performed on NHANES dataset with additional ACs (PCAge/LinAge) serving as predictors. Comparisons between ACs were done using Akaike Information Criterion (AIC). In univariate ACM prediction on UKB cohort BBAC outperformed PhenoAge (AIC - 910749.6 vs. 912914.9). Similarly, BBAC was a better univariate disease incidence predictor(lower AIC). In multivariate ACM prediction PhenoAge exceeded BBAC (AIC - 890855.6 vs. 893294.4). Nevertheless, the optimised version of BBAC was better in predicting ACM in uni (BBAC/PhenoAge AIC - 154165.7/155217.6) as well as in multivariant setting (BBAC/PhenoAge AIC - 151006.9/151031.9). For multivariant disease incidence prediction the results were mixed. On the NHANES cohort BBAC and PhenoAge performed similarly, while PCAge and LinAge achieved the best mortality prediction power. BBAC is an explainable/interpretable AC with good ACM prediction ability.",
"42439654": "ID: 42439654\nTitle: Emerging New Pathways in Malignant Neoplasms and Neurodegenerative Disorders: Perspectives for Therapeutics.\nAbstract: Neurodegenerative disorders such as Alzheimer's disease (AD) and malignant neoplasms are among the most prevalent age-associated diseases worldwide. Although cancer is characterized by uncontrolled proliferation, resistance to apoptosis, and metabolic reprogramming, AD and other neurodegenerative disorders such as Lewy body disease (LBD) including Parkinson's Disease (PD) and fronto-temporal lobar degeneration (FTLD) are defined by synaptic dysfunction, neuronal loss, neuroinflammation, and impaired proteostasis with misfolded protein aggregates. Despite these contrasting phenotypes, converging epidemiological and molecular data support an inverse relationship between cancer and neurodegenerative disorders, whereby a history of cancer is associated with reduced AD risk, whereas AD is linked to a lower incidence of multiple malignancies. These observations suggest that oncogenesis and neurodegeneration may represent divergent outcomes of shared biological processes dysregulated during aging. This conundrum likely reflects differential regulation of core cellular pathways governing cell survival, stress responses, metabolism, and genomic integrity but could also reflect the differential influence of aging pathways and secreted growth factors. Pro-survival and proliferative signaling pathways commonly activated in cancer, including PI3K-AKT-mTOR signaling, altered p53 function, enhanced DNA damage tolerance, and anabolic metabolism, are often impaired in AD, LBD and FTLD, where neurons exhibit heightened vulnerability to stress, mitochondrial dysfunction, defective autophagy, and activation of pro-apoptotic cascades. Conversely, tumor-suppressive mechanisms that restrain proliferation may protect against malignancy but increase susceptibility to degeneration in post-mitotic neurons. Aging-related processes such as cellular senescence, immune dysregulation, and loss of proteostasis may further exert divergent effects in oncogenesis and neurodegeneration. This review aims to clarify associations between specific cancer types and neurodegenerative disorders, examine shared and opposing selected molecular mechanisms linking specific cancers and neurodegeneration, and contextualize these relationships within broader aging pathways (e.g., cell senescence, proteostasis). By integrating epidemiological, mechanistic, and therapeutic perspectives, we highlight unifying biological principles and translational opportunities at the intersection of cancer, neurodegeneration, and aging.",
"42443803": "ID: 42443803\nTitle: Metabolomic profiling reveals key metabolic pathway alterations in monochorionic diamniotic twins with selective intrauterine growth restriction.\nAbstract: Selective intrauterine growth restricted (sIUGR) is a major cause of stillbirth and adverse pregnancy outcomes in monochorionic diamniotic (MCDA) twins. However, the underlying pathophysiologic mechanism of sIUGR remains poorly understood. The study aims to investigate the metabolite perturbations and metabolic mechanisms of sIUGR fetuses through a metabolomics study. Umbilical cord blood was collected from 30 pairs of MCDA sIUGR twin fetuses and 11 pairs of MCDA preterm (PT) twins, followed by non-targeted metabolomics using gas chromatography-mass spectrometry. Data were further analyzed using partial least squares discriminant analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, and Spearman correlation analysis. Our results revealed significant metabolic differences in the umbilical cord blood among small for gestational age, appropriate for gestational age and PT fetuses, potentially linked to abnormalities in carbohydrate, amino acid, and lipid metabolism. A total of 156 metabolites were identified, of which 53 showed significant differences between the groups. Specifically, tryptophan levels were higher in the sIUGR group, while glutamic acid and palmitic acid levels were lower. Based on the KEGG enrichment analysis and the correlation analysis, we hypothesize that the tryptophan-indole metabolism pathway, which may impact immune regulation and neurodevelopment, requires further attention. Other key metabolic pathways, such as arginine metabolism and the citrate cycle were also altered. Our findings offer valuable insights into the biochemical disruptions associated with sIUGR. These results enhance our understanding of the metabolic mechanisms underlying sIUGR and pave the way for future research on potential diagnostic and therapeutic strategies.",
"42451089": "ID: 42451089\nTitle: Effects of Probiotic-Phytonutrient Blends on Defecation, Intestinal Barrier Function, and Gut Microbiota: A Randomized, Placebo-Controlled Trial.\nAbstract: Background/Objectives: Probiotic interventions are widely used to improve intestinal health; however, comparative evidence on multi-strain formulations with different potencies, particularly when combined with plant-based complexes, remains limited. This study evaluated the effects of two probiotic blends containing phytonutrients: PBP1, comprising Lacticaseibacillus strains, and PBP2, comprising Lacticaseibacillus, Lactobacillus, and Bifidobacterium strains. The effects on bowel function, microbial metabolites, and gut barrier-related markers were investigated. Methods: In this randomized, double-blind, placebo-controlled trial, participants received PBP1, PBP2, or placebo for 8 weeks. Stool patterns (7-day Bristol Stool Form Scale (BSFS) diary), fecal short-chain fatty acids (SCFAs), tryptophan metabolites, zonulin, and gut microbiota were assessed at baseline and Week 8. Efficacy was evaluated by comparing each intervention group with the placebo group. Results: Both PBP1 and PBP2 significantly increased the proportion of normal stool types (BSFS types 3-5) compared with placebo (p < 0.05). Fecal SCFA levels, including acetate, propionate, and butyrate, were significantly increased in both intervention groups. Notably, butyrate levels were significantly elevated compared with placebo. Fecal tryptophan levels decreased, while indole metabolites showed increasing trends, with an inverse correlation observed between tryptophan and indole, particularly in the PBP2 group. Fecal zonulin showed a decreasing trend, with significant reductions in participants with 25.0 \u2264 BMI < 30.0 kg/m2. Microbiome analysis revealed preserved alpha diversity with selective compositional shifts, including enrichment of Lactobacillus-related taxa. Conclusions: Supplementation with PBP1 and PBP2 improved bowel function and was associated with changes in microbiome-derived metabolites, including SCFAs and tryptophan-indole metabolism, with BMI-dependent changes in barrier markers. These findings suggest a potential role of microbiome-mediated metabolic modulation in intestinal health.",
"42456112": "ID: 42456112\nTitle: Hydraulic architecture traits influence the co-optimization of efficiency and safety in cycads.\nAbstract: As a present-day relict lineage, cycads possess key anatomical traits for understanding the evolution of plant hydraulics; however, how their hydraulic architecture influences the co-optimization of hydraulic safety and efficiency under drought remains unclear. We examined rachis cross-sectional anatomy traits in 20 cycad species and analyzed correlations between hydraulic construction design, tissue fractions, tissue connectivity, and hydraulic function. Additionally, we quantified the distance of cycads from the global hydraulic safety-efficiency trade-off boundary line (LBD) and assessed anatomical contributions to this distance. We found that cycad rachises resembled fern rhizomes, in that most histological and architectural traits did not correlate with embolism vulnerability, except that greater architectural dissection increased vulnerability at the water potential corresponding to 88% embolism. Cycads with higher conduit lumen fractions (Flx) and conduit-phloem connectivity (Ccphl), and lower conduit-parenchyma connectivity (Ccpar), exhibited greater embolism resistance. Notably, cycads showed a longer LBD compared with ferns, noncycad gymnosperms, and angiosperms, and this distance was shortened by larger pit membrane area and fraction and by higher phloem fraction and Flx. Species in Cycadaceae and Zamiaceae exhibited distinct hydraulic architectures. Cycadaceae species, which typically occupy wetter habitats, showed higher Flx and Ccphl, whereas Zamiaceae species from more arid habitats exhibited greater architectural dissection, higher conduit wall fractions (Fwx) and higher Ccpar. These differences reflect contrasting ecological strategies underlying cycad adaptation to divergent environments. Our findings demonstrate that xylem tissue fraction and connectivity play a central role in maintaining hydraulic function under drought, providing insight into water-stress regulation in ancient plant lineages.",
"42460153": "ID: 42460153\nTitle: Disease-predominant loci across Alzheimer's disease, Parkinson's disease and Lewy body dementia: evidence from the UK Biobank prospective cohort, conditional GWAS and colocalization.\nAbstract: Alzheimer's disease (AD), Parkinson's disease (PD) and Lewy body dementia (LBD) overlap clinically, pathologically and genetically, complicating interpretation of cross-disorder genome-wide association study (GWAS) signals. We analysed 322,963 UK Biobank participants with bidirectional time-varying Cox models, one-year and two-year lag analyses, and competing-risk sensitivity models to quantify AD-PD clinical co-occurrence. We then analysed European-ancestry AD, PD and LBD GWAS summary statistics using linkage disequilibrium score regression (LDSC), GCTA-mtCOJO/GSMR, MAGMA, stratified LDSC, brain eQTL/mQTL SMR with HEIDI filtering, and Bayesian colocalization for selected methylation probes. Conditional loci were compared with original GWAS loci to separate shared liability from retained disorder-predominant associations. PD was associated with subsequent AD (fully adjusted HR 2.27, 95% CI 1.94-2.65; P = 6.40E-25), and AD was associated with subsequent PD (HR 3.14, 95% CI 2.56-3.85; P = 2.10E-28). Lag and competing-risk sensitivity analyses remained concordant. LDSC estimated positive genetic correlations for AD-PD (rg = 0.20; P = 0.0086) and PD-LBD (rg = 0.61; P = 0.0005). Conditioning reduced genome-wide significant loci from 14 to 9 for AD, from 24 to 21 for PD and from 5 to 2 for LBD. Retained loci included AD signals near CR1, BIN1, CLU, SPI1, MS4A, PICALM, ABCA7 and APOE; PD signals near GBA, NUCKS1, TMEM163, STK39, GAK/TMEM175, BST1, SNCA, LRRK2, MAPT and RIT2; and LBD signals near SNCA/MMRN1 and APOE. MAGMA and S-LDSC highlighted amyloid, lipid, immune, synaptic-vesicle and brain-tissue enrichment patterns. Brain QTL analyses prioritized retained eQTL and mQTL signals, and colocalization supported shared PD-GWAS/mQTL signals at HLA-DRB5, ARHGAP27, CRHR1, MAPT and KANSL1. AD and PD show bidirectional clinical co-occurrence, whereas conditional genetic analyses retain a smaller set of disease-predominant loci and regulatory signals across AD, PD and LBD. These findings refine cross-disorder interpretation and nominate loci for independent genetic and functional validation.",
"42464166": "ID: 42464166\nTitle: Integrated transcriptomic and metabolomic analyses reveal phytohormone signaling mechanisms underlying differential regeneration potential in microspore-derived calli from hulled and hulless barley.\nAbstract: Isolated microspore culture (IMC) is an effective model for investigating plant cell totipotency and is widely used in plant breeding programs to rapidly produce doubled haploid lines. However, the limited regeneration capacity of hulless barely restricts the broader application of IMC in breeding improvement and research. In this study, two hulled barley genotypes (Hua30 and L07) exhibiting high regeneration capability and two hulless barley genotypes (Zangqing2000 and Ximala22) with poor regeneration capability were selected to comparatively evaluate the regeneration potential of microspore-derived calli generated via IMC through integrated metabolomic and transcriptomic analyses. The regeneration capability of the two hulled genotypes exceeded 200 green plantlets per 100\u00a0mg microspore-derived callus, whereas that of the hulless genotypes was nearly absent. A total of 2,647 differentially expressed genes (DEGs) and 128 differentially accumulated metabolites (DAMs) were identified in microspore-derived callus from hulled genotypes relative to hulless genotypes. Integrative analysis of transcriptomic and metabolomic datasets indicated that phytohormone signaling pathways play a central role in regulating regeneration competence acquisition. Hulled barley exhibited enhanced hormonal homeostasis and comparatively lower levels of jasmonic acid (JA) and brassinosteroids (BR), which are critical determinants of regeneration capacity in microspore calli. The exogenous application of JA and BR to the induction media markedly inhibited the subsequent regeneration of plantlets in hulled barley. Several transcription factors (TFs) associated with plant regeneration, including WOX7, BBM2, and LBD, showed differential expression patterns between hulled and hulless barley, suggesting their potential functions in regulating regeneration capacity. In addition, the hulled/hulless caryopsis phenotype may be closely associated with the regeneration potential of the microspore-derived callus. These findings provide mechanistic insights into the molecular mechanisms underlying plant regeneration in barley.",
"42465542": "ID: 42465542\nTitle: LC-MS-based serum metabolomics reveals distinct metabolic signatures in patients with intracerebral Hemorrhage.\nAbstract: Intracerebral hemorrhage (ICH) is a severe neurological disease with high mortality and disability, profoundly affecting patients' neurological function, daily activities, and quality of life. This study aimed to characterize the serum metabolic profile of patients with ICH and identify potential metabolic biomarkers associated with disease pathogenesis. Liquid chromatography-mass spectrometry (LC-MS) was employed to systematically analyze serum metabolite profiles and class distributions in 20 patients with and without ICH. Data quality was evaluated using quality control samples, while orthogonal partial least squares-discriminant analysis (OPLS-DA), differential metabolite analysis, KEGG pathway enrichment, Human Metabolome Database (HMDB), Metabolite Set Enrichment Analysis (MSEA), and receiver operating characteristic (ROC) analyses were performed. A total of 3,178 metabolites were identified. In patients with ICH, benzene and substituted derivatives were the most abundant metabolite class (15.63%), followed by organic acids (12.47%), amino acids and their metabolites (12.41%), and heterocyclic compounds (12.07%). Quality assessment demonstrated low variability in control samples (CV < 0.3), and OPLS-DA showed significant separation between the ICH and control groups (p < 0.01). Differential expression analysis revealed increased levels of benzene and substituted derivatives and organic acids, accompanied by decreased amino acids and lipid metabolites. KEGG pathway enrichment indicated significant involvement of linoleic acid, \u03b1-linolenic acid, arachidonic acid, retrograde endocannabinoid, choline metabolism in cancer, and glycerophospholipid metabolism. HMDB and MSEA analyses further demonstrated associations between differential metabolites and multiple metabolic diseases and physiological or pathological states. ROC analysis showed excellent diagnostic performance for several metabolites, with Dibutyl phthalate (AUC = 0.980), Octadecanamide (AUC = 0.960), Hypoxanthine (AUC = 0.840), and Lenticin (AUC = 0.810). These findings demonstrate distinct alterations in the serum metabolomic profile of patients with ICH and provide new insights into the metabolic mechanisms underlying ICH. The identified differential metabolites may serve as promising biomarkers for the diagnosis and investigation of ICH.",
"42465922": "ID: 42465922\nTitle: Data-driven trajectories of atrophy explain clinical heterogeneity across Lewy body diseases.\nAbstract: Lewy body diseases (LBD) collectively share \u03b1-synuclein Lewy pathology, yet present wide clinical heterogeneity, with overlapping motor and non-motor features and progression patterns that challenge traditional diagnostic boundaries. To resolve this spatiotemporal heterogeneity at the biological level, we applied a data-driven atrophy progression framework to MRI data from 833 individuals across Parkinson's disease (PD), dementia with Lewy bodies (DLB), and prodromal idiopathic REM sleep behaviour disorder (iRBD) using the Subtype and Stage Inference (SuStaIn) algorithm. Four transdiagnostic subtypes (A: Early cortico-limbic/late basal ganglia, B: Early basal ganglia/late limbic, C: Early temporo-limbic/late basal ganglia, and D: Early basal ganglia-cingulate/late cortex) emerged, each defined by a distinct spatiotemporal progression of atrophy that explained cognitive, motor, and psychiatric variability. An early cortico-limbic/late basal ganglia subtype represented a dementia-prone subtype across clinical diagnoses, with limbic involvement associating with the emergence of visual hallucinations. These biologically relevant spatiotemporal atrophy subtypes provide an interpretable stratification of patients with LBD, with potential to refine prognosis, improve clinical trial stratification, and guide precision therapeutic approaches. This work was made possible by an Ignition grant from the University of Sydney and University College London (Global Engagement Fund). Evidence before this study: Parkinson's disease (PD), dementia with Lewy bodies (DLB), and isolated REM sleep behaviour disorder (iRBD), sit on a Lewy body disease spectrum with overlapping clinical features but marked heterogeneity in symptom profile, timing, and progression. Neuroimaging and neuropathological studies report diverse patterns of neurodegeneration within each syndrome, with partial overlap across the broader spectrum. Recent, large-scale subtyping work suggests at least two spatiotemporal neurodegeneration trajectories. However, in vivo imaging subtyping which has particularly strong translational relevance, has largely focused on a single syndrome or has included limited representation of the full Lewy body disease continuum. Added value of this study: This study includes a large, balanced cohort spanning PD, DLB and prodromal iRBD with detailed clinical and neuropsychological phenotyping. Using MRI-derived atrophy, we identified four transdiagnostic subtypes that capture clinically meaningful variability beyond syndromic diagnosis. We found that stage, an indicator of accumulated atrophy better addresses the between-syndromic differences in disease duration. We also show that certain subtypes with early limbic degeneration are associated with visual hallucinations, and are linked to amygdalar atrophy, and that subtype plus stage improves prediction of hallucinations beyond amygdalar volume alone. Longitudinal analysis further identified a subset of patients with PD with earlier cortico-limbic degeneration as being at higher risk of cognitive impairment.Implications of all the available evidence: The current field of LBD is moving towards a biologically grounded stratification and staging criteria that better reflects clinical heterogeneity. These transdiagnostic subtypes alongside stage, provide complementary information that can inform emerging LBD staging frameworks and enable more targeted clinical trial design through improved stratification and risk enrichment.",
"42475381": "ID: 42475381\nTitle: Neuropsychiatric Diagnostic and Treatment Conundrums: Case Study of an Inpatient With a Complex Illness Presenting With Overlapping Features of Frontotemporal and Lewy Body Dementia.\nAbstract: Frontotemporal dementia (FTD) and Lewy body dementia (LBD) are distinct neurodegenerative disorders that rarely co-occur. However, their overlapping features can obscure diagnosis and complicate management. We present the case of a 65-year-old man with a history of alcohol use disorder, diabetes, and blindness who developed acute behavioral changes, catatonia, and fluctuating mental status. He exhibited signs consistent with a behavioral variant FTD, including disinhibition, executive dysfunction, and hypersexuality, as well as features associated with LBD, including visual hallucinations, autonomic instability, and waxing-and-waning impairment in cognition. His hospital course was marked by episodic disorientation, variable language use, and persecutory delusions. Neuroimaging, cerebrospinal fluid analysis, and serial neuropsychological testing yielded mixed and inconclusive results, contributing to the diagnostic ambiguity. Treatment included lorazepam, which improved catatonic symptoms but was discontinued due to risk of delirium, and aripiprazole, which was tapered due to suspected neuroleptic sensitivity. The patient was ultimately discharged to memory care with a diagnosis of an unspecified dementia. This case underscores the challenges of diagnosing and managing patients with overlapping features of multiple neurodegenerative disorders. Recognizing points of overlap between syndromes like FTD and LBD is key to tailoring interventions and avoiding harm. Serial cognitive assessments, functional neuroimaging, and biomarker analysis may improve diagnostic accuracy, although these tools have limitations. A deeper understanding of the pathophysiology of overlapping dementia syndromes is crucial for improving diagnostic clarity and guiding treatment strategies.",
"42475839": "ID: 42475839\nTitle: Genomic identification and functional characterization of the nuclear receptor gene family in relation to sex determination and gonad development in the Pacific oyster (Crassostrea gigas).\nAbstract: Nuclear receptors (NRs) are a large superfamily of transcription factors that control a wide range of physiological processes by modulating the expression of downstream target genes. Numerous studies have confirmed that NR family members play critical and conserved roles in sex determination and gonadal development across metazoans. However, in mollusks, systematic characterization of NRs and their potential functions in gonadal regulation remain largely unexplored. In this study, 46 NR gene family members in the Pacific oyster (Crassostrea gigas) were identified and assigned to eight subfamilies. All NR family members contain at least one of the two core domains (DNA-binding domain, DBD; ligand-binding domain, LBD), and conserved exon-intron structures were observed within the same subgroup, indicating their evolutionary conservation. Furthermore, expression profiling revealed high expression of CgNR2F, CgNR5A1-1, and CgNR0B1 in undifferentiated gonads, suggesting their potential involvement in sex determination. CgNR1A and CgNR2E5 were specifically expressed in female gonads and exhibited female-biased expression patterns, indicating a putative role in ovarian development. Moreover, CgNR3A and CgNR3B showed high expression levels during the undifferentiated stage and early male development stage, implying their possible participation in male gonadal development and gametogenesis. These results expand the understanding of the NR gene family in C. gigas and help elucidate the potential functions of NR genes in sex determination and gonadal development.",
"42477717": "ID: 42477717\nTitle: Amygdalar nuclei vulnerability to protein aggregates in Lewy body diseases.\nAbstract: The amygdala is highly vulnerable to protein aggregation and heavily affected in Lewy body diseases (LBDs). However, vulnerability might vary per amygdalar nucleus and it is unclear if the pattern of vulnerability across the nuclei differs between types of protein aggregation and between LBDs. In this study, we aimed to assess the vulnerability of amygdalar nuclei to multiple types of protein aggregation across LBDs. Post-mortem amygdala tissue of donors with incidental LBD (iLBD, n\u2009=\u20096), Parkinson's disease (PD; n\u2009=\u200918), dementia with Lewy bodies (DLB; n\u2009=\u20099) and Alzheimer's disease with Lewy bodies (AD\u2009+\u2009LB; n\u2009=\u200915) was immunostained with antibodies against alpha-synuclein (aSyn; EP1536Y and 5G4), amyloid beta (A\u03b2; 4G8), phosphorylated tau (p-tau; AT8) and phosphorylated TDP-43 (p-TDP-43; 11-9), and quantitatively analyzed using QuPath. Neuronal and astrocytic aSyn pathology were most pronounced in the parahippocampal-amygdaloid transition area (PHA) and the basal nucleus, a pattern shared by all disease groups. Vulnerability to A\u03b2 pathology varied per group but was highest in the PHA in AD\u2009+\u2009LB, whereas diffuse plaques were most common in the accessory basal nucleus. The PHA of DLB and both the basal and accessory basal nucleus of AD\u2009+\u2009LB cases were most susceptible to p-tau pathology, with fine granular cytoplasmic neuronal tau inclusions being mostly observed in the basal nucleus and neurofibrillary tangles in the accessory basal nucleus. The nuclei in the ventromedial part of the amygdala (PHA, ventral part of the basal nucleus, and cortical nucleus) were found to be hotspots for protein aggregation across LBDs. aSyn pathology in these nuclei predominantly correlated with dementia, hallucinations and anxiety. Our results show that amygdalar nuclei vulnerability differs per protein aggregate and disease entity, although the PHA, basal nucleus and cortical nucleus are generally more vulnerable. Together, our study provides a deeper insight into the selective vulnerability of amygdalar nuclei to protein aggregates and their relation to clinical characteristics in LBDs.",
"42483926": "ID: 42483926\nTitle: Phytochemical-based Neuroprotection and In-silico Docking-driven Identification of Active Natural Compounds to Combat Neuropathy.\nAbstract: Neuropathic pain, a devastating neurological disorder attributed to impairment or malfunctioning of the somatosensory system, affecting 10% of the world population. Current therapy emphasizes symptomatic management, featuring high-order side effects. Phytocompounds as neuroprotective agents are of growing interest, and can be screened using structure-based docking, and can act upon a variety of pathways with fewer adverse effects. A comprehensive literature survey was conducted covering studies published between 2000 and 2022 using scientific databases including PubMed, Scopus, Web of Science, ScienceDirect, and Google Scholar. The neuroprotective potential of medicinal plants and their bioactive phytochemicals was screened using in silico experiments targeting neuropathy-related molecular targets, followed by the evaluation of in vitro and in vivo activities. The studies showed that phytochemicals have multitarget neuroprotective activities, including antioxidant activity, modulation of neurotransmitter signaling, inhibition of inflammatory mediators, and modulation of neuropathic signaling ion channels. Several phytochemicals demonstrated notable binding affinities in docking studies, including icariin with NMDA receptors (-12.646 kcal/mol), aegeline with MAO-A (-10.06 kcal/mol) and MAO-B (-10.09 kcal/mol), and zerumbone with cannabinoid receptors CB1 (-7.80 kcal/mol) and CB2 (-9.40 kcal/mol). Other compounds, such as chlorogenic acid, myricetin, rutin, and piperine, also exhibited significant interactions with key neuropathic targets involved in neuroinflammation and pain signaling pathways. Docking studies identified that icariin, aegeline, and zerumbone are predicted lead molecules because they can interact with targets of interest, including NMDA, MAO, and CB receptors. Phytochemical neuroprotective drugs offer a promising approach to managing neuropathy. Integration of molecular docking approaches with experimental pharmacological studies provides a powerful strategy for identifying bioactive natural compounds with therapeutic potential. These findings support advancing phytochemicals as lead candidates for the development of safer, more effective treatments for neuropathy and neuropathic pain.",
"42486521": "ID: 42486521\nTitle: Cross-sectional analysis of variation in diagnosis of Lewy body dementia in three English regions: data from the DETERMIND programme.\nAbstract: We aimed to examine regional differences in the relationship between core clinical features assessed using the Improving the DIAgnosis and Management Of Neurodegenerative Dementias of Lewy body type in the NHS (DIAMOND-Lewy) dementia with Lewy bodies (DLB) Assessment Toolkit and memory service diagnoses of Lewy body dementia (LBD). Secondary analysis of a multicentre observational study. Memory clinics in three sites across England (North East, London and South East) from July 2019 to March 2023. 935 individuals with a new memory service diagnosis of dementia enrolled in the DETERMinants of quality of life, care and costs, and consequences of INequalities in people with Dementia and their carers (DETERMIND) programme. Core clinical features of DLB were assessed using the DLB Assessment Toolkit. The relationship between core clinical features and memory service diagnosis of LBD was examined using Bayesian probit models. There were higher rates of LBD diagnosis from memory services in the cohort in North East England compared with the London and South East centres (11% vs 4%; risk ratio (RR)=1.72 (1.35-2.08)) and evidence of a regional moderating effect on the relationship between clinical features and LBD diagnosis (RR=1.73 (1.26-2.40)).All core clinical features of DLB were associated with LBD diagnosis in North East England, whereas visual hallucinations were the most influential diagnostic feature in London and the South East (RR=3.18 (2.29-4.02)). Regional differences in LBD diagnosis in UK memory services appear to reflect different rates of recognition of specific LBD clinical features. Routinely using a standardised DLB Assessment Toolkit and improving awareness of non-hallucination features in LBD could help to address this disparity.",
"42491938": "ID: 42491938\nTitle: Dynamic, state-dependent characteristics of cognitive fluctuations in Lewy body dementia: a magnetoencephalography study.\nAbstract: Cognitive fluctuations are a hallmark clinical feature of Lewy body dementia (LBD), yet their underlying neural mechanisms remain poorly understood. This study aimed to identify dynamic, state-dependent neural signatures of cognitive fluctuations in LBD using magnetoencephalography and dynamic functional connectivity based on hidden Markov modelling. Resting-state magnetoencephalography data were acquired from individuals with LBD, Parkinson's disease without dementia and cognitively normal controls. Hidden Markov modelling was used to identify transient brain states followed by spectral analyses across regions and states. Additionally, associations between regional spectral power and cognitive fluctuations severity, measured by the Clinician Assessment of Fluctuation, were assessed. Patients with LBD exhibited a distinct pattern of brain dynamics, particularly in two states (States 2 and 6), characterized by increased fractional occupancy of State 2 and markedly reduced occupancy of State 6, contrasting with the more distributed state engagement observed in Parkinson's disease and normal controls. Spectral analyses revealed widespread slowing in LBD, with elevated theta/beta power ratios in frontal, parietal and visual cortices-most pronounced in States 2 and 6. Region-specific theta/beta power ratio elevations were identified in the anterior cingulate, medial prefrontal cortex, posterior cingulate, dorsal visual stream and auditory cortex. Critically, Clinician Assessment of Fluctuation scores correlated positively with spectral power in low frequency (\u03b4 and \u03b8) and negatively with power in the high frequency (\u03b1 and \u03b2), particularly in the ventral visual stream, default mode network hubs and sensorimotor regions. These findings reveal dynamic and spatially specific electrophysiological abnormalities in LBD closely linked to cognitive fluctuations severity, suggesting that magnetoencephalography-hidden-Markov-model characteristics hold promise as biomarkers for diagnosis, monitoring and therapeutic targeting in LBD.",
"42495784": "ID: 42495784\nTitle: Genetically encoded tools for tracking metabolites in live cells.\nAbstract: Biosensors enable the in situ measurement of metabolites in living systems over time and space. Fully genetically encoded metabolite biosensors (fGEMBs) use fluorescent proteins (FPs) linked to ligand binding domains (LBDs) to transduce the ligand binding event to a measurable change in the fluorescence behavior of the FP. Because these sensors are genetically encoded, they can be expressed in cells using standard protein expression approaches, and the fluorescence changes are quantified using fluorimetry, fluorescence microscopy, and/or flow cytometry. While there are general sensor design principles to follow, an fGEMB must be engineered for each metabolite based on a particular LBD. This development process can be slow, but there are strategies emerging to increase testing throughput and improve structure-guided design. While genetically-encoded FPs remain popular, there are now numerous chemigenetic and nucleic acid-based metabolite sensors (cGEMBs) that incorporate small molecule fluorophores. De novo design of LBDs is rapidly advancing as well, and the field may soon exhibit a shift away from relying on nature's catalog of LBDs. Despite the engineering challenges, the metabolite biosensor field has expanded significantly in recent years to meet the demand for new and better-performing sensors that visualize metabolites within their cellular environments.",
"42502242": "ID: 42502242\nTitle: Comparative Screening of Alzheimer's Disease, Lewy Body Dementia, and Frontotemporal Dementia Using miRNA and Machine Learning.\nAbstract: Current dementia diagnostic methods can be costly, invasive, or limited in their ability to distinguish between disorders with overlapping clinical symptoms. Dysregulated microRNAs (miRNAs) have emerged as promising noninvasive biomarkers for neurodegenerative disease, but individual miRNA changes alone may not capture the complex molecular patterns needed for accurate disease classification. Machine learning provides a way to integrate multiple layers of miRNA-derived information and identify disease-specific biomarker signatures. In this study, we developed machine learning models to classify dysregulated miRNAs associated with Alzheimer's disease dementia (AD), Lewy body dementia (LBD), and frontotemporal dementia (FTD). Each miRNA was represented using sequence-derived descriptors, predicted gene targets, and KEGG pathway features. The highest-performing models trained on AD, LBD, and FTD achieved 10-fold cross-validation accuracies of 90.6%, 92.9%, and 100%, respectively. When evaluated on independent datasets, the AD, LBD, and FTD models achieved accuracies of 88.9%, 77.8%, and 90.9%, respectively. Cross-disease testing showed reduced performance when models were applied across dementia types, suggesting partially disease-specific miRNA patterns while also indicating overlap among the molecular signatures of AD, LBD, and FTD. These results suggest that machine learning-based integration of miRNA sequence, target-gene, and pathway information can improve the identification of dementia-associated biomarker signatures and may support the future development of noninvasive diagnostic tools for dementia.",
"42518955": "ID: 42518955\nTitle: Neuropsychiatric symptom profile in neurocognitive disorders and their relationship with functional decline.\nAbstract: Neuropsychiatric symptoms (NPS) are common in neurocognitive disorders (NCD) and are known to negatively impact patient's functional abilities. However, our understanding of the relationship between individual NPS and functional decline in patients with NCD across the spectrum of cognitive impairment is limited. Here we examine the relationship between specific NPS to characterize their effects on patient's function within and across different etiologies. Longitudinal observational study using the National Alzheimer's Coordinating Center Uniform Data Set (NACCUDS). We examined NPS as characterized by expert clinicians and report its impact on the outcome of functional decline, measured by the Functional Assessment Questionnaire (FAQ), a standardized assessment of activities of daily living, by dementia etiology (Alzheimer's disease (AD, N\u202f=\u202f11,044), Lewy Body Disease (LBD, N\u202f=\u202f921), and behavioral variant frontal temporal lobe dementia (bvFTD, N\u202f=\u202f933)). We find apathy was the most commonly endorsed and the most persistent symptom across dementia types in all groups and was associated with more rapid functional decline in AD and bvFTD. On the contrary, depression, occurring in 40% or more of all groups, was not associated with worsening functional impairment in any group. We identified patterns that indicated higher rates of disinhibition and persistent disinhibition in bvFTD compared to AD and LBD. Psychosis had unique impact on functional decline in AD and LBD as did agitation in AD. Differential impact of individual NPS across dementia etiologies and their impact on functional decline may have important consequences for clinical trial designs for the treatment of these symptoms.",
"42529077": "ID: 42529077\nTitle: Shotgun metagenomic analysis reveals taxonomic and functional alterations in the gut microbiome across prodromal and symptomatic Lewy body disease.\nAbstract: Lewy body disease (LBD) is a progressive neurodegenerative a-synucleinopathy, whereas isolated REM sleep behavior disorder (iRBD) is recognized as a prodromal stage of LBD. Although growing evidence implicates the gut-brain axis in neurodegeneration, the taxonomic and functional roles of the gut microbiome across the prodromal-to-symptomatic LBD continuum remain poorly defined. Here, we performed shotgun metagenomic sequencing on stool samples from 25 patients with LBD (10 mild cognitive impairment due to LBD [MCI-LB] and 15 dementia with Lewy bodies [DLB]), 10 individuals with iRBD, and their household matched cohabitant controls to characterize disease-associated microbial alterations while minimizing environmental confounding. Despite no significant differences in global microbial diversity, we identified convergent shifts in microbial taxa, metabolic pathways, and gene families across disease stages. Both LBD and iRBD showed increased abundance of microbial taxa potentially associated with gut barrier disruption, as well as higher abundance of functional pathways related to lipopolysaccharide biosynthesis. LBD showed lower abundance of pathways related to complex carbohydrate fermentation, and both groups showed lower abundance of pathways associated with neurotransmitter-related metabolism. In particular, pathways and gene families associated with starch degradation were reduced in LBD, and those associated with histidine-to-glutamate/ GABA metabolism were reduced in both groups. These exploratory findings represent the first high-resolution, shotgun metagenomic characterization of gut microbiome alterations across the LBD continuum, highlighting functional patterns that may serve as candidate markers of disease progression in future longitudinal and mechanistic studies.",
"42530713": "ID: 42530713\nTitle: Integrative Analysis Reveals Interactions Between Gut Microbiota-Derived Metabolites and the Brain in Parkinson's Disease.\nAbstract: Parkinson's disease (PD) is a neurodegenerative disorder increasingly associated with gut microbiota alterations, yet the mechanisms by which microbial metabolites influence PD remain unclear. Here, we applied an integrative computational and experimental strategy to identify key gut microbial metabolites and host genes potentially involved in PD. Differentially abundant gut microbes were obtained from the gutMDisorder database and their corresponding metabolites from gutMGene, with predicted protein targets generated using the Similarity Ensemble Approach. Transcriptomic data from PD brain tissues were analyzed to identify differentially expressed genes, which were intersected with metabolite targets, followed by enrichment and protein-protein interaction analyses. Three machine learning algorithms were applied for gene prioritization, while molecular docking evaluated metabolite-gene binding affinities and ProTox3.0 predicted toxicity and blood-brain barrier permeability. In vitro assays further assessed the functional effects of 3-indolepropionic acid in a rotenone-induced SH-SY5Y cell model. Our analyses identified 44 PD-associated microbial taxa linked to 77 metabolites and 905 predicted target genes, with 29 overlapping differentially expressed genes enriched in synaptic signaling and dopaminergic pathways. Dopamine receptor D2 (DRD2) emerged as a central hub gene, with strong docking interactions predicted for two indole metabolites, 3-(1H-indol-3-yl)propanoate and 3-indolepropionic acid. Functional validation showed that 3-indolepropionic acid improved cell viability, reduced apoptosis, and preserved DRD2 expression under neurotoxic stress. Together, these findings suggest that specific gut microbial metabolites may modulate host dopaminergic signaling via DRD2, offering new insights into the microbiota-brain axis and potential targets for further PD research.",
"42534654": "ID: 42534654\nTitle: Tryptophan metabolism in liver transplantation immune tolerance.\nAbstract: Liver transplantation is a life-saving treatment for end-stage liver disease, but long-term outcomes are limited by complications of lifelong immunosuppression. Inducing immune tolerance has become a major research priority. Tryptophan (Trp) metabolism, particularly the kynurenine pathway, is a key endogenous regulator of peripheral tolerance. This review moves beyond a simple description of metabolic routes and provides a critical, integrated analysis. We systematically compare the non-redundant immunosuppressive roles of indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO2) in liver transplant immunity, dissect the Trp/kynurenine/AhR pathways that reprograms immune cell function, and incorporate gut-microbiota-dependent indole metabolism as an upstream gut-liver axis node. Clinical evidence is stratified by level, and major translational barriers, including safety risks, delivery challenges, and lack of validated biomarkers are discussed. Current data suggest that combined metabolite panels may outperform single markers, but therapeutic targeting of Trp metabolism remains a preclinical research direction rather than an established therapy.",
"42539784": "ID: 42539784\nTitle: Pharmacologic targeting of midasin (MDN1) reveals a potential therapeutic vulnerability in ESR1-mutant breast cancer.\nAbstract: Although most cases of estrogen receptor-positive (ER+) breast cancer initially respond to endocrine therapy, many patients ultimately develop resistance. A major contributor to endocrine resistance in metastatic disease is the acquisition of constitutively active somatic mutations in the estrogen receptor ligand-binding domain (LBD). We previously identified midasin (MDN1), a ribosome biogenesis protein, as significantly overexpressed in letrozole-resistant MCF-7 cells. Because these cells are ERlow/- and represent only a subset of endocrine-resistant tumors, we hypothesized that ESR1 mutations cooperate with MDN1 dysregulation to confer a survival advantage. To address this, the cBioPortal database was queried to assess correlations between breast cancer subtypes and MDN1 expression levels. MCF-7 cell lines harboring ER point mutations were evaluated by RNA sequencing and immunoblot analysis to measure ER and MDN1 expression. To identify pharmacologic inhibitors of midasin, computational docking analyses were performed using a panel of ribozinoindole (Rbin) analogs, followed by biological evaluation studies. Initial analyses demonstrated that MDN1 expression is elevated in human breast cancer tumors, including luminal, HER2+, and triple-negative breast cancer. RNA sequencing of parental MCF-7 cells and ESR1-mutant derivatives, MCF-7 Y537S and MCF-7 D538G, revealed comparable MDN1 transcript levels across all cell lines. In contrast, immunoblot analysis showed mutation-dependent differences in MDN1 protein expression, with the highest levels observed in MCF-7 D538G cells, followed by MCF-7 Y537S cells and then parental MCF-7 cells. Computational docking analyses of Rbin analogs led to the selection of Rbin-1 and Rbin-2 for biological evaluation. Viability assays revealed minimal activity for Rbin-1, whereas Rbin-2 reduced proliferation by 30%-55% across all three cell lines, with the most pronounced effects observed in MCF-7 D538G cells at 24 and 48 h. Consistent with these findings, Rbin-2 treatment decreased MDN1 protein expression by approximately 50% in all cell lines, while ER levels remained largely unchanged. Collectively, these results establish the feasibility of pharmacologically targeting midasin in mammalian cell lines and support a functional link between MDN1 expression and ESR1 mutation-driven endocrine resistance. This work provides a foundation for future mechanistic studies of midasin as a potential therapeutic vulnerability in ER-mutant breast cancer.",
"42543729": "ID: 42543729\nTitle: PagCOBL5 Integrates Transcriptional and Spatial Cues to Confer G-Layer Deposition in Poplar.\nAbstract: Angiosperm trees reorient their stems by producing tension wood (TW), a specialised xylem that generates contractile force. TW fibres develop a gelatinous (G) layer rich in cellulose, yet the molecular mechanisms governing G-layer formation remain poorly understood. COBRA-like genes encode glycosylphosphatidylinositol (GPI)-anchored proteins known to regulate cellulose deposition. Here, we functionally characterised PagCOBL5 in hybrid poplar (Populus alba \u00d7 P. glandulosa) by identifying its upstream regulator and interaction partner. PagCOBL5 was preferentially expressed in mature xylem fibres, with high abundance in TW. Under mechanical stress, cobl5 knockout mutants exhibited impaired negative gravitropism and significantly thinner G-layer-phenotypes that were reversed in PagCOBL5-overexpressing lines. Furthermore, we found that the transcription factors PagLBD21 and PagLBD25 participate in the upstream negative regulation of PagCOBL5 expression, with the lbd21 lbd25/+ mutant exhibiting an enhanced gravitropic response and altered xylem cell differentiation. At the protein level, PagCOBL5 directly interacted with the cellulose synthase subunits PagCESA8b. This interaction positions PagCOBL5 as a key component recruited and spatially organised by the directionally moving cellulose synthase complex (CSC). Together, these results reveal a sophisticated regulatory and protein-interaction framework centred on PagCOBL5, providing pivotal molecular insights into how transcriptional modulation and cellulose synthase complexes coordinate G-layer formation and mechanical force generation during the gravitropic response.",
"42556137": "ID: 42556137\nTitle: Data-driven trajectories of atrophy explain clinical heterogeneity across Lewy body diseases.\nAbstract: Lewy body diseases (LBD) collectively share \u03b1-synuclein Lewy pathology, yet present wide clinical heterogeneity, with overlapping motor and non-motor features and progression patterns that challenge traditional diagnostic boundaries. To resolve this spatiotemporal heterogeneity at the biological level, we applied a data-driven atrophy progression framework to MRI data from 833 individuals across Parkinson's disease, dementia with Lewy bodies, and prodromal isolated REM sleep behaviour disorder using the Subtype and Stage Inference algorithm. Four transdiagnostic subtypes (A: Early cortico-limbic/late basal ganglia, B: Early basal ganglia/late limbic, C: Early temporo-limbic/late basal ganglia, and D: Early basal ganglia-cingulate/late cortex) emerged, each defined by a distinct spatiotemporal progression of atrophy that explained cognitive, motor, and psychiatric variability. An early cortico-limbic/late basal ganglia subtype represented a dementia-prone subtype across clinical diagnoses, with limbic involvement associating with the emergence of visual hallucinations. These biologically relevant spatiotemporal atrophy subtypes provide an interpretable stratification of patients with LBD, with the potential to refine prognosis, improve clinical trial stratification, and guide precision therapeutic approaches. This work was made possible by an Ignition grant from the University of Sydney and University College London (Global Engagement Fund).",
"42556722": "ID: 42556722\nTitle: Distinct competitive and allosteric binding modes of nanobodies targeting EphA4.\nAbstract: EphA4 signaling is a key negative regulator of axonal regeneration and a genetic modifier of amyotrophic lateral sclerosis (ALS), making EphA4 an attractive but mechanistically underexplored therapeutic target. Although EphA4-targeting nanobodies have shown inhibitory potential, the structural principles governing their binding and inhibitory mechanisms remain largely unknown. Here, we report high-resolution crystal structures of the EphA4 ligand-binding domain (LBD) in complex with four nanobodies (Nb50, Nb53, Nb57, and Nb60), resolved at 1.34-2.21 \u00c5. Nb50, Nb53, and Nb57 competitively engage the canonical ephrin-binding pocket through deep CDR3 insertion, directly mimicking ephrin recognition. In contrast, Nb60 adopts a previously unrecognized binding mode, contacting two EphA4 molecules at noncanonical sites in the crystal structure through framework-dominated interactions and supporting a structural model for steric and allosteric restriction of ephrin access. Integrated biophysical analyses reveal distinct thermodynamic and kinetic signatures underlying these binding mechanisms. Together, our findings uncover unexpected structural diversity in nanobody-mediated EphA4 recognition and provide a framework for rational development of EphA4-targeted modulators for ALS and related neurodegenerative conditions.",
"42562944": "ID: 42562944\nTitle: Which chemical features are captured by ChemBERTa's attention?\nAbstract: Transformer-based models such as ChemBERTa have demonstrated strong performance across a wide range of molecular prediction tasks by learning contextual representations from SMILES strings. Despite this success, the internal organization of the chemical and structural information learned by these models remains poorly understood. In this work, we investigate which chemical concepts, functional groups, and structural features are captured by ChemBERTa's attention mechanisms across layers and heads. To address this question, we formulate the Attention Matrix Pattern Capture (AMPC) problem and introduce two complementary algorithms: AMPC-Chem-FG, which assesses whether attention patterns reflect predefined chemical concepts and functional groups, and AMPC-Struct, which evaluates the alignment between attention patterns and three-dimensional molecular structure represented by Coulomb matrices. Using a curated dataset derived from the ZINC database, our framework identifies specialized layer-head pairs that consistently emerge as statistical outliers and exhibit strong associations with chemically meaningful features. The results reveal specialized attention patterns related to ring structures, bond types, chirality, and functional groups. Furthermore, a layer-head pair achieves approximately 65% similarity to Coulomb-matrix representations, suggesting that ChemBERTa can capture information related to three-dimensional molecular organization despite being trained solely on SMILES strings. Finally, we demonstrate that embeddings constructed from AMPC-identified attention heads can improve downstream prediction performance compared with randomly selected heads and conventional ChemBERTa representations, highlighting the practical utility of the discovered specialization. Together, these findings provide new insights into how molecular transformers organize chemical information and offer a pathway toward more interpretable and task-informed molecular representations.",
"42568211": "ID: 42568211\nTitle: Artificial intelligence-based 3D segmentation of tangle-associated TDP-43 in neurodegeneration.\nAbstract: TAR DNA-binding protein 43 (TDP-43) inclusions are often associated with hyperphosphorylated tau, thus neurofibrillary tangles as the hallmark of Alzheimer's disease (AD) and primary age-related tauopathy (PART). TDP-43 in AD is associated with cognitive impairment, and while staging is known, the localization, cellular and inclusion characteristics of TDP-43 are yet to be elucidated. We investigate relationships between TDP-43 inclusions and the tangle maturation continuum in AD, PART, and co-pathologies by multiplex immunostaining combined with artificial intelligence (AI)-based segmentation via object recognition, reconstruction, and quantification. We performed anti-phosphorylated TDP-43 immunofluorescence with phosphorylated tau labeling different stages and modifications of tangles (AT8, pS396, TauC3, MN423, GT38) in three controls, three cases with PART and TDP-43 (PART-TDP), five cases with high likelihood AD and TDP-43 (AD-TDP), and four cases of high likelihood AD with TDP-43 and Lewy Body disease (AD-TDP-LBD). Confocal imaging was taken from eight regions: amygdala (amygdala-BL and amygdala-CM) and hippocampus (Cornu Ammonis (CA)-1, CA2/3, CA4, dentate gyrus (DG), subiculum (SUB)), and entorhinal cortex (ERC) and quantified with AI segmentation to identify 3D spatial relations, thus the maturity of neurofibrillary tangle associated TDP-43 (TAT) inclusions. TATs, which were either identified by pTDP-43 and AT8 or pTDP-43 and pS396 double positivity, were also investigated by Thioflavin S (ThioS) histochemistry. We found pS396 labeled mature TATs predominated in PART and AD in every region. Basolateral and centromedial amygdala displayed overall greatest number of pre-TATs and mature TATs. Mature TATs were homogenously distributed among hippocampal subfields whereas CA4 and DG had the greatest mature TAT composition. ERC revealed closer numbers of pre-TATs and mature TATs yet mature TATs predominated all groups. Unbiased AI-based object identification, reconstruction, and TAT maturation analysis pipeline in conjunction with TDP-43, tau, and ThioS multiplex immunostaining demonstrated unique aggregation and maturation patterns, highlighting region-specific dynamics in the neurodegenerative processes of PART and AD.",
"42569517": "ID: 42569517\nTitle: Fine-scale individualized gyral folding-based cortical similarity networks reveal distinct organizational patterns in Alzheimer's disease and Lewy body dementia.\nAbstract: Alzheimer's disease (AD) and Lewy body dementia (LBD) are common neurodegenerative dementias with overlapping clinical presentations, making differential diagnosis challenging. While structural magnetic resonance imaging (MRI) has revealed characteristic regional atrophy patterns, regional morphometric measures alone may not fully capture distributed cortical alterations. Morphometric similarity networks (MSNs) offer a systems-level framework to characterize coordinated structural organization, but existing approaches typically rely on atlas-based parcellations that may obscure individual-specific cortical folding geometry. Here, we propose a fine-scale, folding-informed cortical similarity network framework based on automatically detected three-hinge gyral (3HG) landmarks. Using a thickness-constrained arealization strategy in native surface space, we define individualized cortical regions and construct subject-specific MSNs without cross-subject registration. We then investigate how network topology relates to landmark-defined node count and how these properties differ between AD and LBD. We find that several graph theoretical metrics, particularly global efficiency and characteristic path length, exhibit clear associations with the number of detected landmarks, indicating that topology in individualized networks is partly shaped by node availability. When accounting for landmark count, several apparent group differences in global topology are attenuated, whereas multiple heterogeneity-related metrics remain significant, indicating that node-count scaling substantially influences the interpretation of individualized network topology. Nevertheless, multivariate topological patterns remain informative for AD/LBD classification after residualizing for node count, and landmark count itself provides modest diagnostic information. These findings highlight node-count scaling as a key methodological consideration in individualized structural networks and suggest that folding-based MSNs capture disease-related variation in cortical network organization between AD and LBD.",
"42570991": "ID: 42570991\nTitle: Activated microglial phenotypes in the hippocampal CA2 subfield are implicated in Lewy body disease progression.\nAbstract: Histopathologic staging models of neuronal \u03b1-synuclein pathology (n-asyn) in Lewy body disease (LBD) seldom evaluate brain regions with direct synaptic connectivity to model the role of microglial processes. We address this gap by testing the hypothesis that, within the well-defined synaptic connectivity of the intrahippocampal circuit, n-asyn is associated with activated microglial phenotypes. We selected a cohort of autopsy-confirmed LBD patients and minimal age-related copathologies (n\u2009=\u200962) and a control cohort of cognitively healthy patients with isolated hippocampal tau accumulation (i.e., primary age-related tauopathy, PART; n\u2009=\u200912), to control for neurodegenerative pathology without amyloid plaques. We immunostained consecutive hippocampal sections for n-asyn and established markers of activated microglial phenotypes, Iba1, HLA-DR, and CD68. With validated digital histology methods, we measured percent area occupied (%AO) of each marker in 6 hippocampal subfields to compare and correlate microglial morphologic and proteomic activation phenotypes between cohorts and used linear mixed effects models to compare the %AO between subfields while covariying for demographics. We also constructed groups of n-asyn restricted to the cornu ammonis (CA) 2-3 subfields (Focal Subtype) or widespread n-asyn within additional subfields (Widespread Subtype) to model hypothesized n-asyn spread within the intrahippocampal circuit. LBD patients exhibited increased HLA-DR and CD68%AO in most hippocampal subfields compared with PART. In LBD patients, all microglial markers were the highest in the CA2. CA2 n-asyn correlated with HLA-DR and CD68 but not Iba1%AO. Patients classified as Widespread Subtype had worse cognitive impairment and increased CA2 HLA-DR and CD68%AO. CA2 HLA-DR and CD68%AO correlated with distal n-asyn in retrograde, but not anterograde connected subfields. Our data show that activated microglial phenotypes in the CA2 of LBD patients are associated with worse clinical outcomes and retrograde n-asyn transmission. These data suggest that measures of microglial states can refine LBD histopathological progression models.",
"42575875": "ID: 42575875\nTitle: Progression to Dementia in Very Late-Onset Schizophrenia-Like Psychosis Stratified by Alzheimer's Disease and Lewy Body Disease Biomarkers: A Retrospective Cohort Study.\nAbstract: Very late-onset schizophrenia-like psychosis (VLOSLP) is clinically heterogeneous, and its relationship with dementia-related neurodegenerative disease remains unresolved. We examined whether Alzheimer's disease (AD) and Lewy body disease (LBD) biomarker status were associated with dementia progression in VLOSLP. We retrospectively identified patients who visited the University of Osaka Hospital between January 2018 and December 2023 and met criteria for VLOSLP. Twenty-two participants with AD and/or LBD biomarker data and at least one follow-up assessment within 775\u2009days were classified as biomarker-negative (BMs-neg; n\u2009=\u20097) or biomarker-positive (BMs-pos; n\u2009=\u200915). Group comparisons were performed using Mann-Whitney U tests and Fisher's exact tests. The BMs-pos group showed older onset age and lower memory scores than the BMs-neg group. Dementia progression was more frequent in the BMs-pos group than in the BMs-neg group, although the difference was not statistically significant (8/15 [53.3%] vs. 1/7 [14.3%]; p\u2009=\u20090.165; odds ratio 6.31; 95% CI 0.55-353.18). Five of eight participants with AD biomarker positivity progressed to AD dementia. Three of seven participants with LBD biomarker positivity progressed to dementia, including two diagnosed with dementia with Lewy bodies. Follow-up MMSE, CDR, and CDR-SB scores differed significantly between groups. AD and/or LBD biomarker-positive VLOSLP may be associated with greater dementia progression and cognitive decline, although findings should be interpreted cautiously given the small sample size and retrospective design. These results support the clinical value of considering neurodegenerative biomarkers when evaluating the prognosis and underlying pathology of VLOSLP.",
"42578001": "ID: 42578001\nTitle: Associations of Different Inflammatory Markers with Neurological Deficit Severity and Short-Term Prognosis in Young Patients with Ischemic Stroke.\nAbstract: To investigate the correlation between inflammatory markers and neurological deficit severity in young ischemic stroke (YIS) patients, and to evaluate their predictive value for short\u2011term prognosis. We retrospectively collected clinical data from 196 YIS patients at Nanjing Brain Hospital between January 2022 and December 2025. Patients were divided into mild stroke (MIS) and moderate\u2011to\u2011severe stroke (MSS) groups based on the National Institutes of Health Stroke Scale (NIHSS) scores assessed within 24\u00a0hours of admission. Short-term prognosis at 3 months was evaluated using the modified Rankin Scale (mRS), and patients were classified into good and poor outcome groups. Correlation analysis was used to evaluate the relationships between inflammatory markers and NIHSS scores. LASSO regression was conducted to screen variables, followed by Firth's penalized logistic regression to correct for small-sample bias. Receiver operating characteristic curves were generated to evaluate predictive performance. The systemic inflammatory response index (SIRI), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and monocyte-to-lymphocyte ratio (MLR) were markedly elevated in the MSS group and positively correlated with NIHSS scores. SIRI, PLR, and MLR were significantly higher in the poor outcome group. LASSO identified D\u2011dimer (D-D), low-density lipoprotein cholesterol (LDL\u2011C), and NLR as independent predictors of poor outcomes. The area under the curve (AUC) for NLR was 0.592, whereas the combined model (D-D + LDL-C + NLR) yielded an AUC of 0.734. PLR exhibited the strongest correlation with neurological deficit severity. The combined model may provide a more accurate laboratory\u2011based tool for risk stratification in YIS patients.",
"42578227": "ID: 42578227\nTitle: Application of Acute Physical Therapy in Respiratory Failure Secondary to Bilateral Medial Medullary Infarction and Long-Term Follow-Up: A Case Report.\nAbstract: Bilateral medial bulbar infarction (BMMI) represents a rare yet critical form of posterior circulation ischemic stroke encountered in clinical practice. The condition progresses rapidly and is associated with a heightened risk of secondary central respiratory failure, severe pulmonary infection, and multiple systemic functional impairments, including dysphagia, limb paralysis, and sensory abnormalities. Consequently, both the disability and mortality rates remain elevated. Currently, systematic clinical studies focusing on early physical intervention, phased rehabilitation programs, and long-term prognosis follow-up for patients with BMMI during the acute phase are relatively limited. This report reviews the clinical diagnosis and treatment, early acute physical therapy, and two-year long-term rehabilitation follow-up data of a 53-year-old male patient with BMMI, who presented with acute central respiratory failure, severe pulmonary infection, and pronounced bulbar palsy. It summarizes the clinical progression characteristics, stepwise rehabilitation intervention strategies, and prognostic patterns associated with this condition. The objective is to provide a clinical reference for early rehabilitation interventions, the formulation of individualized treatment plans, and the assessment of long-term prognosis for patients with BMMI complicated by severe multi-system dysfunction.",
"42578421": "ID: 42578421\nTitle: Cholesterol Drives IFITM3+ Microglia Activation and Induces STING Mediated Neuroinflammation After Ischemic Stroke.\nAbstract: Cerebral ischemic stroke triggers extensive neuronal membrane breakdown, releasing a massive load of cholesterol that overwhelms resident microglia. Dysregulated microglial cholesterol metabolism has been implicated in post-stroke neuroinflammation, yet the specific pathogenic microglial subpopulations, their molecular signatures, and the downstream inflammatory cascades remain poorly defined. We employed a permanent distal middle cerebral artery occlusion (dMCAO) model combined with single-cell RNA sequencing (scRNA-seq) to profile immune cell transcriptomes and identify cholesterol-associated microglial markers. Cholesterol dynamics, lipid droplet accumulation, and inflammatory marker expression were quantified via immunofluorescence and transmission electron microscopy. Therapeutic interventions included pharmacological cholesterol mobilization with 2-hydroxypropyl-\u03b2-cyclodextrin (H\u03b2CD), pharmacological STING inhibition with C-176, and microglia-targeted STING knockdown using AAV9 vectors. Cerebral injury and neurological function were assessed through infarct volume measurement, white matter integrity analysis, and behavioral assays (rotarod and grip strength) in dMCAO, tMCAO, and perioperative stroke (PIS) models. Using scRNA-seq, we identified interferon-induced transmembrane protein 3 (IFITM3) as a specific marker for a microglial subpopulation that was characterized by upregulated ACAT1, enhanced cholesterol esterification, and accumulation of cholesterol crystals and lipid droplets. This IFITM3+ microglia population peaked at 7\u2009days post-stroke and correlated with NLRP3 inflammasome activation and STING signaling. Pharmacological reduction of cholesterol burden with H\u03b2CD attenuated lipid droplet formation, suppressed mitochondrial DNA leakage, and inhibited STING pathway activation. Correspondingly, H\u03b2CD and C-176 administration significantly reduced cerebral infarct size, mitigated white matter demyelination, and improved motor function in dMCAO and tMCAO models. We further found that AAV-mediated STING knockdown recapitulated the above protective effects in H\u03b2CD and C-176 treated stroke mice. Furthermore, H\u03b2CD treatment ameliorated microglial inflammation and improved functional outcomes in a PIS model. IFITM3+ microglia is a pro-inflammatory and cholesterol-laden subpopulation that exacerbates post-stroke cerebral ischemic brain injury. Targeting the microglial cholesterol axis by H\u03b2CD or inhibiting the STING pathway represents a promising therapeutic strategy to mitigate ischemic brain injury and improve neurological function.",
"42578435": "ID: 42578435\nTitle: Diagnostic Performance of Mobile Low-Field MRI and CT for Acute Headache as the Isolated Clinical Manifestation in the Neurology Emergency Department.\nAbstract: Headache may manifest as the sole or predominant presenting symptom of various types of acute stroke. While mobile low-field magnetic resonance imaging (mLF-MRI) shows promise for rapid and accurate diagnosis in the emergency department (ED), its diagnostic concordance using computed tomography (CT) as the reference standard requires clarification. This prospective study included 199 patients who presented to the ED of Beijing Tiantan Hospital with headache within 72\u2009h of onset, without Face-Arm-Speech Test (FAST) symptoms, and who underwent 0.23-T mLF-MRI between January and July 2024. This study evaluated the diagnostic utility of 0.23-T mLF-MRI in emergency patients presenting with an isolated acute headache. We specifically compared the consistency of mLF-MRI and CT in detecting subarachnoid hemorrhage (SAH) and other causes. Of the 199 patients with headache who did not have FAST symptoms, 71 (35.68%) were diagnosed with stroke, including 60 cases of SAH and 2 patients with intracerebral hemorrhage (ICH). Notably, 9 patients presenting with headaches but without FAST symptoms were diagnosed with acute ischemic stroke. The diagnostic concordance between the fluid-attenuated inversion recovery (FLAIR) sequence of mLF-MRI and CT for SAH was excellent (\u03ba\u2009=\u20090.99). The mLF-MRI provided short scanning times and offered a portable, low-power diagnostic tool. For emergency patients with headaches as the initial and isolated clinical manifestation, mLF-MRI may serve as a supplementary diagnostic imaging modality that provides additional diagnostic information in selected ED settings. mLF-MRI, especially FLAIR sequences, demonstrated high CT-referenced diagnostic concordance for SAH and may also detect early ischemic lesions.",
"42579199": "ID: 42579199\nTitle: Astrocyte-Microglia Crosstalk in Post-Hemorrhagic Neurovascular Microenvironment: Mechanistic Nodes, Cross-Stroke Comparisons, and Therapeutic Reprogramming.\nAbstract: Intracerebral hemorrhage (ICH) produces a rapidly evolving and spatially heterogeneous neurovascular microenvironment in which secondary injury is shaped not only by hematoma volume and location, but also by the interaction of blood-derived toxins, blood-brain barrier disruption, edema, oxidative stress, protease activity, and glial responses. Increasing evidence suggests that these processes are better understood as dynamic network events rather than isolated inflammatory pathways. This review applies a network-centered framework to astrocyte-microglia coupling, viewing it as a critical control layer that may either support injury containment and hematoma resolution or drive persistent neurotoxicity and failed repair. Comparisons with ischemic stroke are used to distinguish shared inflammatory modules from hemorrhage-specific drivers, including heme, hemoglobin, iron overload, thrombin, fibrinogen, and clot-associated protease signaling. Integrating findings from single-cell and spatially resolved studies, the review summarizes the temporal and spatial organization of post-hemorrhagic microenvironment remodeling and discusses astrocyte-dependent regulation of barrier function, edema dynamics, immunometabolism, redox buffering, and synaptic homeostasis. It also examines how astrocyte-derived cues influence microglial state transitions through danger sensing, inflammasome signaling, cyclic GMP-AMP synthase-stimulator of interferon (IFN) genes signaling, phagocytic containment, iron-handling programs, complement-mediated synaptic vulnerability, and interaction with infiltrating myeloid cells. Recurring astrocyte-microglia network motifs are further evaluated as therapeutic control points, with emphasis on how lesion stage and spatial compartmentalization shape intervention windows for purinergic, chemokine, cytokine, IFN, complement-coagulation, and lipid/iron signaling pathways. Translational priorities, limitations, and therapeutic opportunities are discussed across hematoma-toxicity reduction, barrier and edema repair, network reprogramming, and regenerative microenvironment shaping. Meaningful improvement in ICH outcome will likely depend on biomarker-guided and stage-specific reprogramming of astrocyte-microglia network dynamics to restore microenvironmental balance, rather than on nonspecific suppression of neuroinflammation.",
"42579302": "ID: 42579302\nTitle: Reply to the Letter to the Editor: 'Stress Hyperglycemia Ratio Is Associated with Intracardiac Thrombus in Acute Ischemic Stroke'.\nAbstract: ",
"42579394": "ID: 42579394\nTitle: Engineered Brain-Targeted Exosomes Delivering FGF1 for Sustained Glycemic Regulation and Multitarget Neurovascular Protection in Diabetic Stroke.\nAbstract: Diabetic stroke is characterized by a hyperglycemic and pro-inflammatory microenvironment that exacerbates neurovascular dysfunction. However, the blood-brain barrier (BBB) remains a formidable obstacle, restricting the delivery of most therapeutic molecules. To address this, we developed a non-invasive treatment strategy using engineered exosomes. Specifically, we fabricated FGF1-loaded exosomes functionalized with the rabies virus glycoprotein (RVG) peptide (FGF1-RVG Exo). This platform facilitates selective, neuron-targeted delivery of FGF1 to the ischemic penumbra via RVG-mediated transcytosis. In a diabetic stroke mouse model, FGF1-RVG Exo exhibited superior pharmacological efficacy compared to free FGF1, achieving robust therapeutic outcomes with only once-weekly administration. Notably, a single dose during the acute phase elicited a sustained hypoglycemic effect lasting up to two weeks and effectively ameliorated systemic insulin resistance. Locally, the accumulation of exosomes within the lesion led to a significant reduction in infarct volume and cell apoptosis, while promoting neovascularization and the recovery of motor and cognitive functions. This brain-targeted strategy achieves a peripheral-central synergistic modulation, addressing the multi-target requirements of diabetic stroke management. Collectively, our findings provide a novel paradigm for treating diabetic ischemic stroke and a potent strategy for the targeted delivery of growth factors to the central nervous system.",
"42579790": "ID: 42579790\nTitle: Ultrastructural neuroprotection by intrathecal interleukin-6 antagonism in a rat model of permanent focal cerebral ischemia.\nAbstract: This study aimed to determine whether intrathecal administration of an interleukin-6 (IL-6) neutralizing antibody could reduce ultrastructural neuronal and vascular damage in a rat model of permanent middle cerebral artery occlusion (MCAO). Forty male Wistar rats were randomly assigned to four groups: Control, Sham-operated, Occlusion (MCAO\u2009+\u2009saline), and Treatment (MCAO\u2009+\u2009anti-rat IL-6 antibody). One week later, ischemic core brain tissue was processed for transmission electron microscopy to evaluate neuronal, axonal, and microvascular integrity. The Occlusion group showed severe ischemic injury, including mitochondrial swelling with cristolysis, cytoplasmic vacuolization, axonal edema, endothelial swelling, and perivascular astrocyte edema. By contrast, the Treatment group demonstrated marked ultrastructural preservation. Endothelial swelling and perivascular edema were reduced, neuronal nuclei were more preserved, and myelin sheath separation in white matter fibers was less pronounced than in the Occlusion group. Direct intrathecal IL-6 blockade was associated with qualitative cellular-level neuroprotection after permanent focal cerebral ischemia. The treatment attenuated inflammatory vascular injury and white matter damage, supporting IL-6 as a potential therapeutic target for limiting secondary stroke injury.",
"42579823": "ID: 42579823\nTitle: Clinical Significance of the Hyperintense Reperfusion Marker and Ocular Gadolinium Leakage After Thrombectomy: A Retrospective ETIS Study.\nAbstract: Despite successful recanalization after mechanical thrombectomy for acute ischemic stroke, a substantial proportion of patients experience early neurologic deterioration or infarct progression. Early blood-brain barrier disruption, visualized on post-contrast fluid-attenuated inversion recovery (pcFLAIR) imaging as hyperintense acute reperfusion marker (HARM) or gadolinium leakage in ocular structures (GLOS), has been proposed as a marker of reperfusion injury, but its determinants and prognostic significance in thrombectomy cohorts remain uncertain. We aimed to evaluate whether HARM and GLOS are associated with poor clinical outcomes after mechanical thrombectomy. Secondary objectives included their association with poor radiologic outcomes and the identification of baseline and procedural predictors. We retrospectively analyzed data from the French Endovascular Treatment in Ischemic Stroke (ETIS) registry (2010-2021), including consecutive patients admitted to Versailles and Foch Hospital. All patients underwent mechanical thrombectomy at Foch Hospital and pcFLAIR imaging within 4-48 hours postgadolinium administration. Independent predictors of HARM and GLOS were identified through multivariable logistic regression, and their associations with early neurologic deterioration, poor 3-month functional outcome, infarct growth, and hemorrhagic transformation (HT) outcomes were evaluated. Among 229 patients (mean age 69.7 \u00b1 14.9 years, 52.0% female), HARM was observed in 48.9% and GLOS in 41.9%. Overall, 60.3% of patients had either HARM or GLOS, including 29.3% with both markers, 19.7% with isolated HARM, and 11.4% with isolated GLOS. HARM was independently associated with early neurologic deterioration (adjusted odds ratio [aOR] 3.45; 95% CI 1.33-8.95) and infarct growth (aOR 2.46; 95% CI 1.22-4.95), but not with HT or 3-month functional outcome. GLOS was not independently associated with clinical or radiologic outcomes. Older age, higher creatinine, and a shorter interval between the first and second FLAIR were common predictors of both HARM and GLOS, whereas single-pass recanalization was an independent predictor of HARM only. In this large thrombectomy cohort, HARM was independently associated with early neurologic deterioration and infarct progression after thrombectomy, supporting its role as an imaging marker of early blood-brain barrier disruption. GLOS, although frequent, was not independently associated with clinical or radiologic outcomes. Prospective studies with early and serial imaging are required to clarify the prognostic relevance of HARM. NCT03776877 (ETIS registry).",
"42579828": "ID: 42579828\nTitle: Distal Vessel Occlusions in Acute Ischemic Stroke: Reframing Patient Selection and Reperfusion Strategies.\nAbstract: Mechanical thrombectomy (MT) has revolutionized the treatment of acute ischemic stroke because of large vessel occlusion (LVO), but distal and medium vessel occlusions (DMVOs) remain a gray zone. DMVOs account for a substantial proportion of ischemic strokes and can cause long-term disability or death despite often presenting with only mild to moderate symptoms. Their biologic and anatomic diversity-including small vessel caliber, variable perfusion territories, collateral dependence, and complex access pathways-creates distinct patterns of natural history, treatment responsiveness, and procedural risk compared with proximal LVO. Recent randomized trials and meta-analyses, conducted in broadly defined DMVO populations, did not demonstrate functional benefit of endovascular therapy (EVT) over best medical therapy (BMT) and observed numerically higher rates of intracranial hemorrhage with MT. These neutral results have fueled skepticism and guideline recommendations against routine EVT for DMVO stroke; however, they coexist with emerging trial data suggesting that treatment effects may depend on refined patient selection and optimized, distal-specific techniques, as well as with registry findings indicating that many patients with DMVO remain disabled despite BMT. In this narrative, we provide an interpretative synthesis of the available evidence to argue that the apparent discrepancy between biologic plausibility and neutral trial results reflects, at least in part, heterogeneity of DMVO definitions and phenotypes, limitations of severity and outcome scales, anatomy- and device-related safety constraints, and the unique mechanics and biology of small vessel thrombus retrieval rather than an absence of biologic efficacy. We highlight clinical, imaging, anatomic, and thrombus-related features which may help identify subgroups more likely to benefit from distal reperfusion and discuss emerging technical and pharmacologic strategies-including DMVO-specific device adaptations, intraarterial thrombolysis, and hybrid reperfusion approaches-which aim to reduce mechanical trauma while preserving the advantages of timely recanalization. Together, these considerations support a shift from viewing distal MT as a failed extension of proximal EVT to recognizing DMVO stroke as a distinct syndrome that requires tailored selection, techniques, and outcome assessment."
},
"globalTags": {
"brain": 5,
"humans": 31,
"parkinson disease": 1,
"gastrointestinal microbiome": 11,
"molecular docking simulation": 5,
"cell line, tumor": 3,
"gut microbiota": 6,
"gut\u2013brain axis": 1,
"indole compounds": 1,
"microbial metabolites": 2,
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},
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