PathMap Literature Based Discovery Engine

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Experiment #00000139

Foundational Dietary Theory: The dietary synergy between Hi-Maize and 6x Spermidine Yeast creates a potential cellular supply-and-clearance loop within the brain's astrocytes. Circulating spermidine metabolites utilize documented astrocytic polyamine uptake systems to access the central nervous system. Once inside, this exogenous spermidine drives FAM134B-mediated ER-phagy, clearing the endoplasmic reticulum matrix. This clearance removes the ER-stress bottleneck, allowing newly transcribed astrocytic EAAT2—upregulated by gut-derived butyrate from Hi-Maize fermentation—to successfully traffic to the plasma membrane and mitigate synaptic glutamate excitotoxicity.

Starch, Resistant _gates_from_starch__resistant Butyric Acid _gates_to_butyric_acid _gates_from_butyric_acid Glutamate Plasma Membrane Transport Proteins _gates_to_glutamate_plasma_membrane_transport_proteins Spermidine _gates_from_spermidine Autophagy
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Experiment #00000138

Dietary butyrate from resistant starch may synergize with sulforaphane-driven Nrf2 activation and spermidine-mediated FAM134B ER-phagy in order to restore astrocytic EAAT2 membrane trafficking and potentially clear synaptic glutamate excitotoxicity in neurodegeneration. (Literature Based Discovery)

Starch, Resistant _gates_from_starch__resistant Butyrate _gates_to_butyrate _gates_from_butyrate NF-E2-Related Factor 2 _gates_to_nf_e2_related_factor_2 Sulforaphane _gates_from_sulforaphane Spermidine
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Experiment #00000136

Borneol-mediated membrane permeability can enhance the therapeutic delivery of plant-derived extracellular vesicles to deep-seated endometriotic lesions, bridging the gap between existing delivery enhancements for CNS ischemia and local anti-fibrotic treatments.

Borneol _gates_from_borneol Drug Delivery Systems _gates_to_drug_delivery_systems _gates_from_drug_delivery_systems Extracellular Vesicles _gates_to_extracellular_vesicles _gates_from_extracellular_vesicles Fibrosis _gates_to_fibrosis
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Experiment #00000132

Discovery: Considering PubMed #41177462, intranasal S-GEVs co-functionalized with ApoE peptides may bypass the cribriform plate and target astrocytic LRP1 receptors in order to suppress NF-κB and may resolve some neuroinflammation in Alzheimer's and ALS.

Administration, Intranasal _gates_from_administration__intranasal Blood-Brain Barrier _gates_to_blood_brain_barrier Apolipoproteins E _gates_from_apolipoproteins_e Low Density Lipoprotein Receptor-Related Protein-1 _gates_to_low_density_lipoprotein_receptor_related_protein_1 Signal Transduction _gates_from_signal_transduction
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Experiment #00000130

Targeted alteration of the oral microbiome via a single polyphenol- and fiber-dense meal plan creates an immediate shift in the microbial composition of involuntary nocturnal microaspiration droplets. Upon entry into the lower respiratory tract, this eubiotic bacterial influx acts as an acute molecular signal that rapidly modulates microglia reactivity and neuroinflammation via the lung-brain axis, bypassing systemic colonic metabolite transport.

Dietary modification _gates_from_dietary_modification Dysbiosis _gates_to_dysbiosis _gates_from_dysbiosis Respiratory Aspiration _gates_to_respiratory_aspiration _gates_from_respiratory_aspiration Microglia _gates_to_microglia
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Experiment #00000127

Neuroinflammatory astrocyte subtypes in the mouse brain

Pathologic Processes _gates_from_pathologic_processes Gene Expression Regulation _gates_to_gene_expression_regulation _gates_from_gene_expression_regulation Biological Phenomena _gates_to_biological_phenomena _gates_from_biological_phenomena Neuroinflammatory Diseases _gates_to_neuroinflammatory_diseases
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Experiment #00000126

Hypothesis: Intranasal delivery of Spermidine-modified Ginseng Extracellular Vesicles (S-GEVs) loaded with multi-targeted mRNA suppresses MARK2-eIF2α-driven RAN translation to prevent dipeptide repeat clogging of FG-nucleoporins, synergizing with progranulin-mediated lysosomal clearance to arrest TMEM106B amyloid accumulation and block the execution of p38-Lamin B1-dependent Karyoptosis in motor neurons.

Spermidine _gates_from_spermidine Lysosomal Degradation _gates_to_lysosomal_degradation _gates_from_lysosomal_degradation Protein Aggregates _gates_to_protein_aggregates _gates_from_protein_aggregates Cell Death _gates_to_cell_death
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Experiment #00000115

Ebola Virus Outbreak Solution Hypothesis: Oral ginger-derived extracellular vesicles may serve as an acid-stable, inexpensive, and supply-chain ready clinical solution to deliver 6-shogaol to macrophages, triggering CASA autophagy to degrade EBOV VP40 and halt viral egress.

Ginger extract _gates_from_ginger_extract Autophagy _gates_to_autophagy Autophagy (CASA) _gates_from_autophagy__casa_ Viral Matrix Proteins _gates_to_viral_matrix_proteins Proteolysis _gates_from_proteolysis
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Experiment #00000113

COPD Related Alveoli and Lung Microbiome Axis Restoration Hypothesis: The use of 'pre-digested' (fermented) plant-based nutritional additives as a means to circumvent the bioavailability paradox in patients with gut dysbiosis, effectively using botanical matrices as drug-delivery vehicles. Nucleotide supplementation may enhance the ability of A. muciniphila to modulate gut mucosal barrier integrity in hyperuricemia patients. *Akkermansia* possesses unique enzymes (β-N-acetylhexosaminidases) that allow it to colonize the mucosal layer and participate in mucin degradation.

Fermentation _gates_from_fermentation Bioavailability _gates_to_bioavailability _gates_from_bioavailability Homeostasis _gates_to_homeostasis Plant Preparations _gates_from_plant_preparations Probiotics
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Experiment #00000105

Gap Analysis: There is no PubMed data showing wet lab data or analysis of TPD-43 proteinopathy found (or not found) in the Cochlear, Spiral, or Scarpa's Ganglion of Amyotrophic Lateral Sclerosis patient data post mortem.

Amyotrophic Lateral Sclerosis _gates_from_amyotrophic_lateral_sclerosis TDP-43 proteinopathy _gates_to_tdp_43_proteinopathy _gates_from_tdp_43_proteinopathy Spiral Ganglion _gates_to_spiral_ganglion Peripheral Nerves _gates_from_peripheral_nerves _gates_to_amyotrophic_lateral_sclerosis
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Experiment #00000101

Hypothesis: If Botox were injected into the nerve ending on the third toe on the left foot, the toxin can "climb" retrograde from toe through motor neurons eventually to the brain and temporarily inhibit vesicular docking "from toe to head", potentially allowing a timed pharmacological therapeutic window for toxic EV clearance through the lymph system instead of docking and seeding.

Botulinum Toxins, Type A _gates_from_botulinum_toxins__type_a Axonal Transport _gates_to_axonal_transport _gates_from_axonal_transport SNARE Proteins _gates_to_snare_proteins _gates_from_snare_proteins Lymphatic Vessel Endothelial Hyaluronan Receptor-1 _gates_to_lymphatic_vessel_endothelial_hyaluronan_receptor_1
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Experiment #00000097

Evaluation of Known Roles of ARHGAP32, RGNEF (ARHGEF28), and TDP-43 in Neurodegenerative Disease found in PubMed Literature as of August 5, 2026

DNA-Binding Proteins _gates_from_dna_binding_proteins RNA Splicing _gates_to_rna_splicing _gates_from_rna_splicing Neuronal Plasticity _gates_to_neuronal_plasticity Synaptic Transmission _gates_to_synaptic_transmission Neuronal Dysfunction
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Experiment #00000092

A Top-Down Mechanism for Sporadic ALS Initiated by Ocular Metal Dyshomeostasis and Retrograde Exosomal Transport along the Subcortical Visual Axis

Eye Diseases _gates_from_eye_diseases Retinal Diseases _gates_to_retinal_diseases _gates_from_retinal_diseases Extracellular Vesicles _gates_to_extracellular_vesicles _gates_from_extracellular_vesicles Motor Neurons _gates_to_motor_neurons
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Experiment #00000090

Ferroptosis

Ferroptosis _gates_from_ferroptosis _gates_to_ferroptosis Spinal Cord Injuries _gates_from_spinal_cord_injuries Cell Death _gates_to_cell_death _gates_from_cell_death CD14 Antigen _gates_to_cd14_antigen
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Experiment #00000089

Use of MBTPS1 inhibitors is a plausible strategy to prevent the terminal phase of nuclear death in specific cellular contexts.

Membrane-Bound Transcription Factor Peptidase, Site 1 _gates_from_membrane_bound_transcription_factor_peptidase__site_1 SREBP Activation _gates_to_srebp_activation _gates_from_srebp_activation Cellular Lipid Homeostasis _gates_to_cellular_lipid_homeostasis _gates_from_cellular_lipid_homeostasis Terminal Cell Death _gates_to_terminal_cell_death
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Experiment #00000086

Parkinson's Disease versus Alzheimer's Disease: Shared and Exclusive Pathways

Pathologic Processes _gates_from_pathologic_processes Mitochondrial Diseases _gates_to_mitochondrial_diseases Lipid Metabolism Disorders _gates_from_lipid_metabolism_disorders Lipid Droplet Accumulation _gates_to_lipid_droplet_accumulation _gates_from_lipid_droplet_accumulation Lysosomal Storage Diseases
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Experiment #00000077

The use of lysosome-acidifying nanoparticles (AcNPs) could potentially be adapted to treat nanoplastic-induced lysosomal alkalization or membrane rigidification, as these nanoparticles act to restore the degradative capacity lost during environmental contaminant stress.

Nanoplastic exposure _gates_from_nanoplastic_exposure Lysosomes _gates_to_lysosomes _gates_from_lysosomes Autophagy _gates_to_autophagy Nanoparticles _gates_from_nanoparticles Hydrogen-Ion Concentration
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Experiment #00000076

Nanoplastic-induced lysosomal membrane remodeling may sequester WDR44, creating a 'hotspot' for α-synuclein aggregation initiation.

Nanoplastics internalization _gates_from_nanoplastics_internalization Lysosomal accumulation _gates_to_lysosomal_accumulation _gates_from_lysosomal_accumulation Lysosomal Membranes _gates_to_lysosomal_membranes WDR44 _gates_from_wdr44 WDR44 protein
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Experiment #00000075

Polystyrene nanoplastics (PS-NPs) may act as a scaffold for the recruitment and accumulation of WDR44 at the lysosomal membrane, thereby accelerating the de novo aggregation of alpha-synuclein in the early stages of PD.

Nanoplastic exposure _gates_from_nanoplastic_exposure Lysosomal Storage Diseases _gates_to_lysosomal_storage_diseases _gates_from_lysosomal_storage_diseases alpha-Synuclein _gates_to_alpha_synuclein WDR44 _gates_from_wdr44 Protein Aggregates
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Experiment #00000074

OGT (O-GlcNAc transferase) modulation via pharmacological agonists can prevent degeneration of cranial nerves following traumatic or surgical stress.

Trauma/Stress _gates_from_trauma_stress Ferritinophagy/Oxidative Stress _gates_to_ferritinophagy_oxidative_stress Autophagy _gates_from_autophagy N-Acetylglucosaminyltransferases _gates_to_n_acetylglucosaminyltransferases _gates_from_n_acetylglucosaminyltransferases Neuronal Survival
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Experiment #00000068

ALS; FUS; STMN2; TDP-43; protein translation; stress granule

Cell Nucleus _gates_from_cell_nucleus RNA Splicing _gates_to_rna_splicing _gates_from_rna_splicing Protein Biosynthesis _gates_to_protein_biosynthesis _gates_from_protein_biosynthesis Motor Neuron Disease _gates_to_motor_neuron_disease
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Experiment #00000065

Does pathologically seeded TDP-43 exit the retina via anterograde axonal transport along the optic tract to midbrain hubs, enter the systemic circulation inside extracellular vesicles, and subsequently traffic into pancreatic beta-cells to accelerate type 2 diabetes phenotypes?

TAR DNA-Binding Protein 43 _gates_from_tar_dna_binding_protein_43 Extracellular Vesicles _gates_to_extracellular_vesicles Systemic circulating EVs _gates_from_systemic_circulating_evs Insulin-Secreting Cells _gates_to_insulin_secreting_cells Axonal Transport _gates_to_axonal_transport
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Experiment #00000064

Lon Protease, Alternaria; IL-33; TSLP; alarmins; asthma; chronic rhinosinusitis; fungal allergen; innate lymphoid cells

Alternaria _gates_from_alternaria Alarmins _gates_to_alarmins _gates_from_alarmins Immunity, Innate _gates_to_immunity__innate _gates_from_immunity__innate Lon-Peptidase _gates_to_lon_peptidase
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Experiment #00000054

What dietary habits are beneficial towards reducing excess/harmful tyramine in order to improve liver and gut health?

Dietary Proteins _gates_from_dietary_proteins Aromatic-L-Amino-Acid Decarboxylases _gates_to_aromatic_l_amino_acid_decarboxylases _gates_from_aromatic_l_amino_acid_decarboxylases Tyramine _gates_to_tyramine _gates_from_tyramine Gastrointestinal Diseases _gates_to_gastrointestinal_diseases
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Experiment #00000051

Is TDP-43 proteinopathy associated with toxoplasmosis?

Datasets as Topic _gates_from_datasets_as_topic Toxoplasmosis or Toxoplasma gondii _gates_to_toxoplasmosis_or_toxoplasma_gondii TAR DNA-Binding Protein 43 _gates_from_tar_dna_binding_protein_43 _gates_to_datasets_as_topic Toxoplasmosis _gates_from_toxoplasmosis Not Found
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Experiment #00000048

The ALS-T2D comorbidity is driven by a bidirectional, exosome-mediated proteostatic collapse. Peripheral tissues (muscle, pancreas) dictate CNS TDP-43 stability via exosomal miRNAs (miR-126a-5p) and glucose-dependent modifications (O-GlcNAcylation). Conversely, pharmacological activation of ubiquitin-peptidases (e.g., Acarbose targeting USP46) or restitution of glycolytic cofactors (F2,6BP) represent novel, cross-disciplinary therapeutic targets capable of halting systemic proteinopathy.

Diabetes Mellitus, Type 2 _gates_from_diabetes_mellitus__type_2 Extracellular Vesicles _gates_to_extracellular_vesicles _gates_from_extracellular_vesicles DNA-Binding Proteins _gates_to_dna_binding_proteins _gates_from_dna_binding_proteins Amyotrophic Lateral Sclerosis _gates_to_amyotrophic_lateral_sclerosis
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Experiment #00000040

Can inhaled COVID-19 vaccinations be used to help treat COPD?

Pulmonary Disease, Chronic Obstructive _gates_from_pulmonary_disease__chronic_obstructive Administration, Inhalation _gates_to_administration__inhalation _gates_from_administration__inhalation Immunity, Mucosal _gates_to_immunity__mucosal Mucous Membrane _gates_to_mucous_membrane _gates_from_mucous_membrane
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Experiment #00000039

What is the current evidence for RGNEF (ARHGEF28) functioning as a primary upstream regulator of axonal transport and TDP-43 homeostasis in ALS, and how does the failure of this 'terminal tether' initiate the pathological continuum compared to downstream protein aggregation?

Metabolic Stress _gates_from_metabolic_stress Protein Aggregation _gates_to_protein_aggregation _gates_from_protein_aggregation RNA Metabolism _gates_to_rna_metabolism _gates_from_rna_metabolism Axonal Transport _gates_to_axonal_transport
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Experiment #00000038

Map the direct mechanical and axonal transport pathways connecting intranasal administration or trigeminal nerve delivery to the clearance of TDP-43 aggregates in sporadic ALS, and the delivery of CRISPR-Cas/ASO gene therapies targeting C9orf72 hexanucleotide repeat expansions in the cerebellum and brainstem.

Intranasal Route _gates_from_intranasal_route Blood-Brain Barrier _gates_to_blood_brain_barrier C9orf72 Protein _gates_to_c9orf72_protein _gates_from_c9orf72_protein Brain _gates_to_brain Intranasal Administration
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Experiment #00000037

How does karyoptosis occur compared to apoptosis? SOD1 seems to be associated with apoptosis in some ALS phenotypes, but is SOD1 associated with ALS pathological karyoptosis as well?

Proteotoxic stress _gates_from_proteotoxic_stress p38 kinase signaling _gates_to_p38_kinase_signaling _gates_from_p38_kinase_signaling Apoptosis _gates_to_apoptosis Superoxide Dismutase-1 _gates_from_superoxide_dismutase_1 Karyoptosis (LaminB1 phosphorylation)
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Experiment #00000030

Can AI and single-cell RNA sequencing help map cryptic TDP-43 splicing errors in sporadic ALS to design BBB-penetrant CRISPR gene therapies before neurotoxicity begins?

Single-Cell Analysis _gates_from_single_cell_analysis RNA Splicing _gates_to_rna_splicing _gates_from_rna_splicing Blood-Brain Barrier _gates_to_blood_brain_barrier _gates_from_blood_brain_barrier Neurotoxicity Syndromes _gates_to_neurotoxicity_syndromes
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Experiment #00000024

If RGNEF fails agitate and regulate TDP-43 at the RGNEF NF242 Terminal, does this cause TDP-43 propteinopathy?

Protein Interaction Mapping _gates_from_protein_interaction_mapping RNA Stability _gates_to_rna_stability Peptide Fragments _gates_from_peptide_fragments RNA Recognition Motif _gates_to_rna_recognition_motif Metabolic stress _gates_from_metabolic_stress
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Experiment #00000016

Analyze the potential for zinc-binding competition between synaptic transporters (e.g., SLC39A8, ZnT3) and ALS-associated proteins (RGNEF, TDP-43) in the RGC-thalamic axis. Can this competition explain the coexistence of RGC excitotoxicity and STMN2 depletion in clinical samples?

TAR DNA-Binding Protein 43 _gates_from_tar_dna_binding_protein_43 Stathmin 2 _gates_to_stathmin_2 SLC39A8 protein, human _gates_from_slc39a8_protein__human Zinc _gates_to_zinc Excitotoxicity _gates_from_excitotoxicity
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Experiment #00000015

Given that schizophrenia is characterized by a deficit in the attenuation of sensory input via corollary discharge, how might pathologically elevated RGC signaling—potentially caused by synaptic glutamate overflow without zinc modulation—interfere with the thalamic integration of extra-retinal CD signals to effectively reverse the predictive timing of visual stability?

SLC39A8 Protein _gates_from_slc39a8_protein Zinc Deficiency _gates_to_zinc_deficiency _gates_from_zinc_deficiency Glutamic Acid _gates_to_glutamic_acid _gates_from_glutamic_acid Thalamus _gates_to_thalamus
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Experiment #00000013

Can BMAA, a known glutamate mimic, cause hyperexcited retinal ganglion cells and cause them to "misfire" corollary discharge?

Amino Acids, Diamino _gates_from_amino_acids__diamino Retina _gates_to_retina _gates_from_retina Corollary Discharge _gates_to_corollary_discharge NMDA receptors _gates_to_nmda_receptors NMDA receptor activation
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Experiment #00000012

If a toxin with a thermodynamic affinity for Zinc GREATER THAN that of Glutamate AND LESS THAN that of RGNEF, under certain conditions a pathway exists wherein the toxin could shuttle synaptic retinal zinc to RGNEF, thus potentially ultimately resulting in the retinal TDP-43 proteinopathy seen in the retina post mortem in Sporadic Amyotrophic Lateral Sclerosis

Synaptic Zinc _gates_from_synaptic_zinc Receptors, Glutamate _gates_to_receptors__glutamate _gates_from_receptors__glutamate Zinc Dyshomeostasis in RGCs _gates_to_zinc_dyshomeostasis_in_rgcs _gates_from_zinc_dyshomeostasis_in_rgcs TDP-43 Proteinopathy _gates_to_tdp_43_proteinopathy
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Experiment #00000009

How does autophagy work?

Cellular Stress _gates_from_cellular_stress Autophagy _gates_to_autophagy _gates_from_autophagy Phagosomes _gates_to_phagosomes _gates_from_phagosomes Apoptosis _gates_to_apoptosis
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Experiment #00000007

Simply put, we still don’t know why neurons are dying in ALS, and why motor neurons die while other types of neurons don’t. Even for genetic forms c9orf72 familial ALS, why is it that the mutation is in every cell but the motor neurons are dying ie have increased susceptibility?

Axonal Transport _gates_from_axonal_transport Motor Neuron Disease _gates_to_motor_neuron_disease C9orf72 Repeat Expansion _gates_from_c9orf72_repeat_expansion Dipeptide Repeats _gates_to_dipeptide_repeats _gates_from_dipeptide_repeats VAPB protein, human
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Experiment #00000006

Does existing in vitro data show that Quercetin-induced autophagy can successfully degrade DUX4 or its downstream misfolded proteins?

Quercetin _gates_from_quercetin Autophagy _gates_to_autophagy _gates_from_autophagy Misfolded Proteins _gates_to_misfolded_proteins _gates_from_misfolded_proteins DUX4 _gates_to_dux4
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Experiment #00000003

Does long-term microplastic or bisphenol exposure act as a catalyst for alpha-synucleitin aggregation in Parkinson's disease by disrupting lysosomal membrane permeabilization?

Environmental Exposure _gates_from_environmental_exposure Endolysosomes _gates_to_endolysosomes _gates_from_endolysosomes Lysosomal Membranes _gates_to_lysosomal_membranes _gates_from_lysosomal_membranes Autophagy _gates_to_autophagy
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