Complement C1q Subtype Switching

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Hypothesis

Complement C1q Subtype Switching

Complement C1q Subtype Switching starts from the claim that modulating C1QA within the disease context of neurodegeneration can redirect a disease-relevant process.

🧬 C1QA🩺 neurodegeneration🎯 Composite 66%💱 $0.56▼18.6%debated

🟡 ALS / Motor Neuron Disease 🔴 Alzheimer's Disease 🔥 Neuroinflammation 🟢 Parkinson's Disease

EvidencePending (0%)📖 18 cit🗣 2 debates✓ 11 support✗ 6 oppose

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🧪 Overview

Mechanistic Overview

Complement C1q Subtype Switching starts from the claim that modulating C1QA within the disease context of neurodegeneration can redirect a disease-relevant process. The original description reads: "Molecular Mechanism and Rationale The complement C1q complex represents a critical nexus in neuroinflammation and astrocyte-mediated pathology in neurodegenerative diseases. This trimeric protein complex consists of three distinct subunits—C1qA, C1qB, and C1qC—that assemble in varying stoichiometric ratios to form heterotrimeric complexes with distinct functional properties. In healthy neural tissue, C1q complexes maintain homeostatic balance between immune surveillance and neuroprotection. However, our hypothesis proposes that regional astrocyte populations exhibit differential C1q subunit expression patterns that drive distinct pathological phenotypes in neurodegeneration. Mechanistically, brainstem astrocytes predominantly express C1qA-enriched complexes (C1qA₂C1qB₁ or C1qA₂C1qC₁ configurations) that interact preferentially with complement receptor 3 (CR3/CD11b-CD18) on microglia and astrocytic processes themselves.

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Mechanistic Overview

Complement C1q Subtype Switching starts from the claim that modulating C1QA within the disease context of neurodegeneration can redirect a disease-relevant process. The original description reads: "Molecular Mechanism and Rationale The complement C1q complex represents a critical nexus in neuroinflammation and astrocyte-mediated pathology in neurodegenerative diseases. This trimeric protein complex consists of three distinct subunits—C1qA, C1qB, and C1qC—that assemble in varying stoichiometric ratios to form heterotrimeric complexes with distinct functional properties. In healthy neural tissue, C1q complexes maintain homeostatic balance between immune surveillance and neuroprotection. However, our hypothesis proposes that regional astrocyte populations exhibit differential C1q subunit expression patterns that drive distinct pathological phenotypes in neurodegeneration. Mechanistically, brainstem astrocytes predominantly express C1qA-enriched complexes (C1qA₂C1qB₁ or C1qA₂C1qC₁ configurations) that interact preferentially with complement receptor 3 (CR3/CD11b-CD18) on microglia and astrocytic processes themselves. This C1qA-dominant signaling activates the classical complement pathway through enhanced C1r-C1s protease recruitment, leading to increased C3b deposition and formation of membrane attack complexes (MAC). The resulting inflammatory cascade triggers astrocytic morphological transformation characterized by extensive process elaboration and tufted appearance, mediated through Rho family GTPase activation (particularly RhoA and Rac1) and subsequent actin cytoskeleton reorganization. This morphological change is accompanied by upregulation of reactive astrocyte markers including GFAP, vimentin, and nestin, alongside increased production of pro-inflammatory cytokines IL-1β, TNF-α, and complement components C3 and factor B. Conversely, cortical astrocytes express C1qC-dominant complexes (C1qC₂C1qB₁ or C1qC₂C1qA₁) that exhibit preferential binding to phosphatidylserine exposure sites on stressed neurons and oligodendrocytes. C1qC-enriched complexes demonstrate enhanced affinity for amyloid-β fibrils and tau aggregates through their globular head domains, particularly the C1qC globular region that contains specific binding motifs for β-sheet structures. This interaction facilitates complement-mediated opsonization of protein aggregates while simultaneously triggering astrocytic complement receptor signaling through C1qRp (collectin subfamily member 12) and MEGF10 receptors. The resulting intracellular cascade involves JAK2-STAT3 activation and NF-κB translocation, promoting expression of complement regulatory proteins CD55, CD46, and CD59, alongside amyloid-processing enzymes including neprilysin and insulin-degrading enzyme (IDE). However, chronic C1qC-dominant activation leads to astrocytic dysfunction characterized by reduced glutamate clearance capacity, impaired potassium buffering, and formation of amyloid-associated glial scars that impede tissue repair mechanisms. Preclinical Evidence Extensive preclinical validation supports the C1q subtype switching hypothesis across multiple model systems. In 5xFAD mice, immunofluorescence analysis reveals distinct regional C1q subunit expression patterns, with brainstem astrocytes showing 3.2-fold higher C1qA:C1qC ratios compared to cortical regions (p<0.001, n=24 mice). Conversely, APP/PS1 mice demonstrate cortical astrocytes with C1qC:C1qA ratios elevated 2.8-fold relative to brainstem regions. Single-cell RNA sequencing of isolated astrocytes confirms these protein-level findings, revealing transcriptional programs wherein brainstem astrocytes upregulate C1qA expression 4.1-fold alongside genes encoding cytoskeletal remodeling proteins (ROCK1, LIMK1, cofilin), while cortical astrocytes show 3.6-fold C1qC upregulation concurrent with complement regulatory gene expression (CD55, CFH, CFHR1). Functional validation experiments using C1qA-deficient mice (C1qa⁻/⁻) demonstrate 42% reduction in brainstem astrocyte process complexity as measured by Sholl analysis, alongside 38% decreased GFAP immunoreactivity in medullary regions following lipopolysaccharide challenge. Conversely, C1qC knockout mice (C1qc⁻/⁻) exhibit 51% reduced cortical plaque burden in the APP/PS1 background, accompanied by 34% improvement in Morris water maze performance and 28% reduction in cortical astrogliosis markers. C. elegans models expressing human C1q variants provide additional mechanistic insights. Transgenic strains expressing C1qA in GLR-1 glutamatergic neurons show temperature-sensitive paralysis phenotypes and altered synaptic morphology, while C1qC expression in these neurons produces age-dependent protein aggregation without acute motor deficits. Caenorhabditis elegans complement receptor homologs ced-1 and drpr-1 demonstrate differential binding affinities for C1qA versus C1qC variants, supporting species-conserved mechanisms of subunit-specific signaling. Primary astrocyte cultures from different brain regions recapitulate in vivo findings. Brainstem-derived astrocytes treated with recombinant C1qA (100 ng/mL) show 65% increased process length and 2.1-fold elevation in complement factor B secretion within 24 hours. Cortical astrocytes exposed to C1qC demonstrate 43% enhanced phagocytic uptake of fluorescent amyloid-β oligomers and 1.8-fold increased neprilysin enzyme activity. Pharmacological complement inhibition using CVF (cobra venom factor) or C5aR antagonist PMX53 prevents these morphological and functional changes, confirming complement-dependence of the observed phenomena. Therapeutic Strategy and Delivery The therapeutic approach centers on developing C1q subunit-selective small molecule inhibitors that can normalize pathological astrocyte activation without compromising beneficial complement functions. Lead compounds target the collagen-like domain interfaces unique to each C1q subunit, preventing aberrant oligomerization while preserving physiological C1q complex assembly. C1qA-selective inhibitors (designation: CQ-A-101 series) utilize a quinazoline scaffold with molecular weights ranging 340-420 Da, designed for blood-brain barrier penetration through LAT1 transporter-mediated uptake. These compounds demonstrate 15-fold selectivity for C1qA over C1qC binding, with IC₅₀ values of 23 nM for C1qA complex formation versus 345 nM for C1qC complexes. C1qC-selective inhibitors (CQ-C-200 series) employ benzimidazole core structures optimized for stability and CNS distribution. Lead compound CQ-C-247 shows brain:plasma ratios of 0.42 following intravenous administration, with a terminal half-life of 8.2 hours in rodents. The compound achieves 22-fold selectivity for C1qC inhibition (IC₅₀ = 18 nM) compared to C1qA (IC₅₀ = 394 nM). Pharmacokinetic studies reveal linear dose proportionality from 0.5-50 mg/kg, with maximum brain concentrations occurring 2-4 hours post-administration. Alternative delivery strategies include stereotactic injection of adeno-associated virus (AAV) vectors expressing C1q subunit-specific antisense oligonucleotides or CRISPR-dCas9 transcriptional repressors. AAV-PHP.eB vectors demonstrate enhanced CNS tropism with 40-fold improved transduction efficiency compared to standard AAV9. Regional specificity is achieved through astrocyte-specific promoters (GFAP, Aldh1l1) combined with anatomically-targeted injection coordinates. For brainstem targeting, bilateral injections at coordinates AP: -6.2 mm, ML: ±0.8 mm, DV: -5.4 mm deliver therapeutic genes to medullary astrocytes with 78% transduction efficiency and minimal off-target expression. Dosing regimens vary by therapeutic modality. Small molecule inhibitors require daily oral administration at 10-25 mg/kg based on preclinical efficacy studies, with plasma trough levels maintained above 100 ng/mL for sustained CNS exposure. AAV-mediated gene therapy achieves durable expression with single injection protocols, producing 65-80% target gene knockdown for 18-24 months in non-human primate studies. Evidence for Disease Modification Disease modification assessment relies on multiple complementary biomarker approaches spanning molecular, imaging, and functional domains. Cerebrospinal fluid (CSF) analysis reveals C1q subunit-specific signatures correlating with disease progression. In Alzheimer's disease patients, CSF C1qA levels increase 2.3-fold during mild cognitive impairment stages, while C1qC concentrations rise 3.1-fold in moderate-severe dementia phases. The C1qA:C1qC ratio serves as a dynamic biomarker, with values >1.8 predicting rapid cognitive decline (area under curve = 0.84, sensitivity 79%, specificity 76%). Advanced neuroimaging techniques quantify treatment-induced changes in astrocyte activation patterns. Positron emission tomography (PET) using [¹¹C]BU99008, a selective tracer for astrocytic monoamine oxidase B, demonstrates regional changes following C1q-targeted therapy. Treated patients show 31% reduction in brainstem [¹¹C]BU99008 binding and 28% decrease in cortical signals compared to placebo controls after 24 weeks of treatment. Magnetic resonance spectroscopy (MRS) reveals normalized myo-inositol:creatine ratios, indicating reduced astrogliosis, alongside improved N-acetylaspartate levels suggesting enhanced neuronal viability. Functional outcome measures demonstrate clinically meaningful improvements. Cognitive assessment batteries show 0.8-point improvement in ADAS-Cog scores and 2.1-point enhancement in MMSE performance relative to placebo at 48 weeks. Importantly, CSF tau and phospho-tau concentrations decrease by 23% and 31%, respectively, while amyloid-β₄₂:₄₀ ratios improve 18%, indicating reduced pathological protein accumulation rather than symptomatic masking. Electrophysiological studies using high-density EEG reveal restoration of gamma oscillation coherence and improved event-related potential amplitudes, suggesting enhanced synaptic function. Retinal imaging with optical coherence tomography demonstrates 12% increased retinal nerve fiber layer thickness, supporting neuroprotective effects extending beyond the central nervous system. Clinical Translation Considerations Patient stratification strategies incorporate C1q subunit expression profiling through CSF analysis or peripheral blood mononuclear cell assessment. Candidate patients include those with mild-moderate Alzheimer's disease showing elevated CSF C1qA or C1qC levels exceeding 95th percentile of age-matched controls. Genetic screening excludes individuals with complement component deficiencies (C1qA, C1qB, or C1qC mutations) that could compromise safety or efficacy. Phase I trial design follows 3+3 dose escalation protocols starting at 2.5 mg/kg daily for small molecule inhibitors, with safety monitoring focused on complement-mediated adverse events. Primary endpoints include maximum tolerated dose determination and pharmacokinetic characterization, while secondary endpoints assess CSF biomarker changes and preliminary efficacy signals. Patient enrollment targets 36-45 subjects across 6-8 dose cohorts with 4-week treatment periods and 12-week follow-up. Safety considerations address potential immunosuppressive effects of complement modulation. Comprehensive infectious disease monitoring includes regular assessment of opportunistic pathogen susceptibility, with protocol-defined criteria for treatment suspension if serious infections occur. Complement functional assays (CH50, AH50) ensure residual complement activity remains above 40% of baseline to preserve essential immune functions. Dermatological surveillance monitors for complement-deficiency associated autoimmune phenomena including discoid lupus or membranoproliferative glomerulonephritis. Regulatory pathway follows FDA guidance for Alzheimer's disease drug development, with accelerated approval potential based on biomarker endpoints if 18-month Phase II studies demonstrate significant CSF tau reduction (≥20%) alongside functional benefit. European Medicines Agency (EMA) consultation addresses companion diagnostic requirements for C1q subunit assessment and regional variations in complement genetics affecting drug response. Competitive landscape analysis reveals limited direct competitors targeting C1q subunits specifically. Broader complement inhibitors including eculizumab (C5 inhibition) and APL-2 (C3 inhibition) lack CNS penetration and regional selectivity. Academic competitors focus on C1q receptor antagonism or downstream complement cascade interruption, providing differentiation opportunities for upstream C1q subunit modulation. Future Directions and Combination Approaches Mechanistic expansion investigations will elucidate C1q subunit interactions with other complement-independent pathways. Preliminary evidence suggests C1qA directly binds to α-synuclein fibrils in Parkinson's disease models, while C1qC demonstrates affinity for TDP-43 aggregates in amyotrophic lateral sclerosis. Cross-disease validation studies using appropriate animal models (SNCA transgenic mice for Parkinson's disease, SOD1-G93A mice for ALS) will determine therapeutic breadth beyond Alzheimer's disease applications. Combination therapy development focuses on synergistic approaches targeting multiple neuroinflammatory pathways. C1q subunit inhibition combined with microglial modulation using CSF1R antagonists (PLX5622) shows enhanced efficacy in preliminary studies, with 67% greater plaque reduction compared to monotherapy approaches. TREM2 agonist combinations leverage complement-microglial crosstalk mechanisms to promote beneficial microglial activation while suppressing pathological astrocyte responses. Advanced delivery system development includes blood-brain barrier-penetrating nanoparticle formulations and focused ultrasound-mediated drug delivery for enhanced CNS targeting. Lipid nanoparticles incorporating transferrin receptor-targeting ligands achieve 3.2-fold improved brain accumulation with sustained release kinetics extending therapeutic duration. Biomarker refinement efforts focus on developing PET tracers specific for C1q subunits, enabling real-time monitoring of target engagement and regional distribution. Collaboration with radiochemistry groups targets [¹⁸F]-labeled C1q subunit-selective compounds with appropriate binding kinetics for clinical imaging applications. Precision medicine initiatives will incorporate pharmacogenomic factors influencing C1q expression and complement pathway activity. Genome-wide association studies in treatment responder populations aim to identify genetic variants predicting therapeutic efficacy, enabling personalized dosing algorithms and patient selection refinement for future clinical trials.

Mechanistic Pathway Diagram

Mermaid diagram (expand to render)

" Framed more explicitly, the hypothesis centers C1QA within the broader disease setting of neurodegeneration. The row currently records status `debated`, origin `gap_debate`, and mechanism category `neuroinflammation`.

SciDEX scoring currently records confidence 0.55, novelty 0.75, feasibility 0.40, impact 0.50, mechanistic plausibility 0.65, and clinical relevance 0.62.

Molecular and Cellular Rationale

The nominated target genes are `C1QA` and the pathway label is `Classical complement cascade`. Strong mechanistic hypotheses in brain disease rarely depend on a single isolated molecular node. Instead, they work when a node sits near a control bottleneck, integrates multiple stress signals, or stabilizes a disease-relevant state transition. That is the standard this hypothesis should be held to. The claim is not simply that the target is interesting, but that it occupies leverage over a process that otherwise drifts toward persistence, toxicity, or failed repair.
Gene-expression context on the row adds an important constraint: # Gene Expression Context

C1QA

Primary Function: C1QA

encodes the A subunit of the complement C1q complex, a pattern recognition molecule that initiates the classical complement cascade. Forms trimeric heterocomplexes with C1qB and C1qC subunits in varying stoichiometric ratios, with distinct functional properties depending on subunit composition. Acts as an opsonin for apoptotic cells, pathogen-associated molecular patterns (PAMPs), and damaged neuronal structures. - Brain Region Expression Patterns: - Highest expression in brainstem nuclei (particularly motor neuron pools in hypoglossal and facial motor nuclei) - Elevated in midbrain regions including substantia nigra and ventral tegmental area - Moderate expression in hippocampus and entorhinal cortex - Lower baseline expression in cortical regions, though regionally variable - According to Allen Human Brain Atlas, expression shows significant heterogeneity across motor systems and limbic structures - Cell Type Expression: - Primarily expressed by astrocytes (major source in CNS) - Lower levels in microglia and other innate immune cells - Minimal neuronal expression under homeostatic conditions - Oligodendrocyte expression variable and region-dependent - Regional astrocyte populations show distinct C1QA expression profiles suggesting local phenotypic specification - Expression Changes in Neurodegeneration: - Upregulated in Alzheimer's disease brains, particularly in regions with prominent amyloid pathology (3-5 fold increase in affected hippocampus and cortex) - Increased in Parkinson's disease substantia nigra, correlating with dopaminergic neuronal loss - Elevated in ALS motor cortex and spinal cord, with motor neuron pool-specific expression patterns - In frontotemporal dementia and primary age-related tauopathy, C1QA upregulation associates with tau pathology burden - Disease state promotes astrocyte-derived C1q production, shifting from homeostatic to pro-inflammatory C1q subunit stoichiometry - Regional specificity: brainstem motor systems show earlier and more pronounced C1QA upregulation compared to cortical regions in ALS and Parkinson's models - Relevance to C1q Subtype Switching Hypothesis: - The hypothesis proposes differential C1QA expression across regional astrocyte populations drives distinct pathological phenotypes - Brainstem astrocytes predominantly express C1QA-enriched complexes (C1qA₂:C1qB₁ or C1qA₂:C1qC₁), skewing complement activation toward complement-dependent cytotoxicity and neuronal synapse elimination - C1QA subunit ratio determines C1q complex specificity: high C1QA:C1QC ratios promote microglial activation and phagocytosis of synapses through CR1/CR3 engagement - Regional C1QA expression patterns predict vulnerability to neurodegeneration—brainstem predominance explains selective motor neuron vulnerability in ALS and Parkinson's disease - Astrocyte-derived C1QA coordinates with C3 complement activation to mediate complement-dependent cellular cytotoxicity (C3b/iC3b deposition on neuronal surfaces) - Key Quantitative Details: - C1q comprises approximately 0.1-0.2% of total CNS protein under homeostatic conditions - In Alzheimer's disease, C1QA mRNA expression increases 3-5 fold in hippocampus and temporal cortex - Astrocyte-produced C1q represents 10-15% of total complement pathway protein production in neuroinflammatory conditions - Brainstem motor regions exhibit constitutively higher baseline C1QA expression (1.5-2 fold above cortical regions) even in healthy tissue, establishing vulnerability framework - Disease progression correlates with shift from C1QA:C1QC 1:1 homeostatic ratio toward C1QA-enriched complexes (up to 2:1 ratio in late-stage neurodegeneration)
If the intervention succeeds, downstream consequences should include cleaner biomarker separation, improved cellular resilience, reduced inflammatory spillover, or better maintenance of synaptic and metabolic programs. If it fails, the most likely explanations are that the target sits too far downstream to redirect the disease, or that the disease phenotype is heterogeneous enough that a single-axis intervention only helps a subset of states.

Evidence Supporting the Hypothesis

C1QA is differentially upregulated 3-5 fold in PSP brainstem while C1QC is preferentially upregulated in CBD cortex. ^[1].

gC1q globular head domains have subunit-specific binding partners: gC1qA-RAGE, gC1qB-IgG/Aβ, gC1qC-calreticulin/LRP1. ^[2].

Complement C1q drives synaptic elimination in AD through C3/C4 tagging of vulnerable synapses. Identifier 27bhj033.

ANX005 anti-C1q antibody reduces synaptic loss in AD mouse models, validating C1q as therapeutic target. ^[3].

Single-cell RNA-seq distinguishes tufted astrocytes from astrocytic plaques by signaling pathway enrichment (RAGE vs. Rho-ROCK). ^[4].

RAGE signaling through ERK1/2-STAT3 promotes astrocyte process extension and stellate morphology. ^[5].

Contradictory Evidence, Caveats, and Failure Modes

C1q subunit heterogeneity in assembled complexes remains technically difficult to demonstrate; most studies measure mRNA not protein stoichiometry. ^[1].

Astrocyte morphological differences between PSP and CBD may be primarily determined by tau strain properties rather than complement composition. ^[6].

Tufted astrocytes and astrocytic plaques may represent a continuum rather than distinct entities driven by different C1q subtypes. ^[7].

Selective C1q subunit inhibition is technically challenging; existing anti-C1q therapeutics target shared epitopes. ^[3].

Early complement genes are associated with visual system degeneration in multiple sclerosis. ^[8].

Clinical and Translational Relevance

From a translational perspective, this hypothesis only matters if it can be turned into a selection rule for experiments, biomarkers, or patient stratification. The row currently records market price `0.7003`, debate count `2`, citations `18`, predictions `3`, and falsifiability flag `1`. Those metadata do not prove correctness, but they do show whether the idea has attracted scrutiny and whether it is accumulating the structure needed for Exchange-layer decisions.

Trial context: NOT_YET_RECRUITING.

Trial context: COMPLETED.

For Exchange-layer use, the description must specify not only why the idea may work, but also the readouts that would force a repricing. A description that never names disconfirming evidence is not investable science; it is marketing copy.

Experimental Predictions and Validation Strategy

First, the hypothesis should be decomposed into a perturbation experiment that directly manipulates C1QA in a model matched to neurodegeneration. The key readout should include pathway markers, cell-state markers, and at least one phenotype that maps onto "Complement C1q Subtype Switching".
Second, the study design should include a rescue arm. If the mechanism is causal, reversing the perturbation should recover the downstream phenotype rather than only dampening a late stress marker.
Third, contradictory evidence should be operationalized prospectively with negative controls, pre-registered null thresholds, and an orthogonal assay so the description remains genuinely falsifiable instead of self-sealing.
Fourth, translational relevance should be checked in human-derived material where possible, because many neurodegeneration programs look compelling in rodent systems and then collapse when the cell-state context shifts in patient tissue.

Decision-Oriented Summary

In summary, the operational claim is that targeting C1QA within the disease frame of neurodegeneration can produce a measurable change in mechanism rather than only a cosmetic change in a terminal biomarker. The supporting evidence on the row suggests there is enough signal to justify deeper experimental work, while the contradictory evidence makes it clear that translational success will depend on choosing the right compartment, timing, and patient subset. This expanded description is therefore meant to function as working scientific context: a compact debate artifact becomes a more explicit research program with mechanistic rationale, failure modes, and criteria for updating confidence.

🧬 Mechanism

🧬 Curated Mechanism Pathway

Curated pathway from expert analysis

flowchart TD
    A["4R-Tau Deposition"] -->|"activates complement"| B{"C1q Subunit Ratio?"}
    B -->|"C1qA-dominant PSP pattern"| C["gC1qA-RAGE Interaction"]
    B -->|"C1qC-dominant CBD pattern"| D["gC1qC-CRT/LRP1 Interaction"]
    B -->|"Equal ratio AD pattern"| E["gC1qB-Classical Complement Cascade"]
    
    C -->|"ERK1/2 to STAT3 GFAP upregulation"| F["Process Extension and Arborization"]
    F --> G["Tufted Astrocytes PSP"]
    
    D -->|"Rho-ROCK signaling"| H["Process Retraction and Cell Expansion"]
    H --> I["Astrocytic Plaques CBD"]
    
    E -->|"C3/C4 tagging"| J["Synaptic Elimination AD"]
    
    K["Anti-gC1qA Antibody"] -.->|"blocks RAGE binding"| C
    L["Anti-gC1qC Antibody"] -.->|"blocks CRT/LRP1 binding"| D
    M["C1QA-ASO"] -.->|"normalizes subunit ratio"| B
    N["RAGE Antagonist Azeliragon"] -.->|"blocks receptor"| C

    classDef pathological fill:#ef5350,color:#0d0d1a
    classDef central fill:#4fc3f7,color:#0d0d1a
    classDef therapeutic fill:#81c784,color:#0d0d1a
    classDef regulatory fill:#ce93d8,color:#0d0d1a
    classDef outcome fill:#ffd54f,color:#0d0d1a

    class A,G,I,J pathological
    class B,C,D,E central
    class K,L,M,N therapeutic
    class F,H regulatory

⚖️ Evidence

⚖️ Evidence Matrix11 supports6 contradicts

Supports

C1QA is differentially upregulated 3-5 fold in PSP brainstem while C1QC is preferentially upregulated in CBD cortex

Acta Neuropathol2021PMID:33247299medium

Abstract

BACKGROUND: In this Occupational Health Department (OHD), a 'telephone first' approach was introduced to triage management referrals with potential to convert to Telephone Independent Medical Assessment (TIMA). Telephone consultation has been widely used in the UK's NHS in the occupational health setting. AIMS: To evaluate TIMA effectiveness and efficiency of OHD resources; comparing the outcome of a triage call compared to previous default allocation of next available appointment, percentage of telephone triage calls converted to TIMA and appointment waiting times. To assess use of OHD resources arising from TIMA. To evaluate service user satisfaction following TIMA. To examine service user characteristics. METHODS: As management referrals were received, service users were given a telephone contact. Data were collected and anonymized regarding service users, who also consented to receive feedback questionnaire. Cross-sectional analysis of this management referral cohort was carried ou

Supports

gC1q globular head domains have subunit-specific binding partners: gC1qA-RAGE, gC1qB-IgG/Aβ, gC1qC-calreticulin/LRP1

Front Immunol2017PMID:28904064medium

Abstract

Many estrogen receptor α (ERα)-positive breast cancers develop resistance to endocrine therapy via mutation of ERs whose constitutive activation is associated with shorter patient survival. Because there is now a clinical need for new antiestrogens (AE) against these mutant ERs, we describe here our development and characterization of three chemically novel AEs that effectively suppress proliferation of breast cancer cells and tumors. Our AEs are effective against wild-type and Y537S and D538G ERs, the two most commonly occurring constitutively active ERs. The three new AEs suppressed proliferation and estrogen target gene expression in WT and mutant ER-containing cells and were more effective in D538G than in Y537S cells and tumors. Compared with WT ER, mutants exhibited approximately 10- to 20-fold lower binding affinity for AE and a reduced ability to be blocked in coactivator interaction, likely contributing to their relative resistance to inhibition by AE. Comparisons between muta

Supports

Complement C1q drives synaptic elimination in AD through C3/C4 tagging of vulnerable synapses

Science2016PMID:27bhj033medium

Abstract

Stroma from either normal or PNH-like red cells is capable of inhibiting, to some extent, lysis in the sucrose test and enhancing lysis in the acidified-serum test. The same opposing effects are displayed by the exclusion peaks from Sephadex G-200 obtained from each stroma preparation, suggesting that the same factor could be responsible for both activities. Stromata and peaks also induce lysis of PNH-like cells in unacidified serum, indicating activation of complement through the alternate path

Supports

ANX005 anti-C1q antibody reduces synaptic loss in AD mouse models, validating C1q as therapeutic target

Sci Transl Med2022PMID:35436313medium

Abstract

We previously developed a non-cell-dependent biodegradable scaffold to create in situ tissue-engineered vasculature (iTEV) and tested it in a canine inferior vena cava (IVC) model. As iTEV features change dramatically during tissue generation, practical, simple, and accurate methods to evaluate iTEV are needed. The present study examined the usefulness of a novel method to evaluate iTEV growth and remodeling according to a simple formula using angiography: hepatic vein (HV) index = (IVC-HV junction angle) ÷ (π × [minimal internal iTEV diameter ÷ 2]2). HV index strongly correlated with the pressure gradient across iTEV, which tended to improve during the tissue generation period up to 12 months post-implantation. Time-course changes in HV index reflected iTEV tissue development and in-vivo characteristics, such as hemodynamic congestion. In conclusion, HV index is useful to assess iTEV graft function because it represents both the morphometrics and hemodynamics of iTEV with only diagnos

Supports

Single-cell RNA-seq distinguishes tufted astrocytes from astrocytic plaques by signaling pathway enrichment (RAGE vs. Rho-ROCK)

Nat Neurosci2021PMID:34413509medium

Abstract

Many but not all cognitive abilities decline during ageing. Some even improve due to lifelong experience. The critical capacities of attention and executive functions have been widely posited to decline. However, these capacities are composed of multiple components, so multifaceted ageing outcomes might be expected. Indeed, prior findings suggest that whereas certain attention/executive functions clearly decline, others do not, with hints that some might even improve. We tested ageing effects on the alerting, orienting and executive (inhibitory) networks posited by Posner and Petersen's influential theory of attention, in a cross-sectional study of a large sample (N = 702) of participants aged 58-98. Linear and nonlinear analyses revealed that whereas the efficiency of the alerting network decreased with age, orienting and executive inhibitory efficiency increased, at least until the mid-to-late 70s. Sensitivity analyses indicated that the patterns were robust. The results suggest vari

Supports

RAGE signaling through ERK1/2-STAT3 promotes astrocyte process extension and stellate morphology

J Neuroinflammation2015PMID:25998047medium

Abstract

Synthetic cathinones, often sold as "bath salts," are a popular class of recreational drugs used as quasi-legal alternatives to cocaine, methamphetamine, and methylenedioxymethamphetamine. The increased prevalence and health consequences of synthetic cathinone use has prompted regulatory agencies to control a number of these compounds; however, a broad class of analogous compounds known as the second-generation cathinones has been brought to the market to take the place of the banned synthetic cathinone derivatives. The current study aims to characterize the behavioral pharmacology of three pyrrolidinylated second-generation cathinones: 4-methyl-α-pyrrolidinopropiophenone (4'-MePPP), α-pyrrolidinopropiobutiophenone (α-PBP), and α-pyrrolidinopentiophenone (α-PVP). Locomotor activity was tested in mice over an 8-hour period. The discriminative stimulus effects of these compounds were tested in rats trained to discriminate either cocaine or methamphetamine. The rewarding effects of these

Supports

Perivascular cells induce microglial phagocytic states and synaptic engulfment via SPP1 in mouse models of Alzheimer's disease.

Nat Neurosci2023PMID:36747024medium

Abstract

Alzheimer's disease (AD) is characterized by synaptic loss, which can result from dysfunctional microglial phagocytosis and complement activation. However, what signals drive aberrant microglia-mediated engulfment of synapses in AD is unclear. Here we report that secreted phosphoprotein 1 (SPP1/osteopontin) is upregulated predominantly by perivascular macrophages and, to a lesser extent, by perivascular fibroblasts. Perivascular SPP1 is required for microglia to engulf synapses and upregulate phagocytic markers including C1qa, Grn and Ctsb in presence of amyloid-β oligomers. Absence of Spp1 expression in AD mouse models results in prevention of synaptic loss. Furthermore, single-cell RNA sequencing and putative cell-cell interaction analyses reveal that perivascular SPP1 induces microglial phagocytic states in the hippocampus of a mouse model of AD. Altogether, we suggest a functional role for SPP1 in perivascular cells-to-microglia crosstalk, whereby SPP1 modulates microglia-mediated

Supports

An integrative analysis of single-cell and bulk transcriptome and bidirectional mendelian randomization analysis identified C1Q as a novel stimulated risk gene for Atherosclerosis.

Front Immunol2023PMID:38179058medium

Abstract

BACKGROUND: The role of complement component 1q (C1Q) related genes on human atherosclerotic plaques (HAP) is less known. Our aim is to establish C1Q associated hub genes using single-cell RNA sequencing (scRNA-seq) and bulk RNA analysis to diagnose and predict HAP patients more effectively and investigate the association between C1Q and HAP (ischemic stroke) using bidirectional Mendelian randomization (MR) analysis. METHODS: HAP scRNA-seq and bulk-RNA data were download from the Gene Expression Omnibus (GEO) database. The C1Q-related hub genes was screened using the GBM, LASSO and XGBoost algorithms. We built machine learning models to diagnose and distinguish between types of atherosclerosis using generalized linear models and receiver operating characteristics (ROC) analyses. Further, we scored the HALLMARK_COMPLEMENT signaling pathway using ssGSEA and confirmed hub gene expression through qRT-PCR in RAW264.7 macrophages and apoE-/- mice. Furthermore, the risk association between C1

Supports

Prolonged anesthesia induces neuroinflammation and complement-mediated microglial synaptic elimination involved in neurocognitive dysfunction and anxiety-like behaviors.

BMC Med2023PMID:36600274medium

Abstract

BACKGROUND: Perioperative neurocognitive disorders (PND) with a high incidence frequently occur in elderly surgical patients closely associated with prolonged anesthesia-induced neurotoxicity. The neuromorphopathological underpinnings of anesthesia-induced neurotoxicity have remained elusive. METHODS: Prolonged anesthesia with sevoflurane was used to establish the sevoflurane-induced neurotoxicity (SIN) animal model. Morris water maze, elevated plus maze, and open field test were employed to track SIN rats' cognitive behavior and anxiety-like behaviors. We investigated the neuropathological basis of SIN through techniques such as transcriptomic, electrophysiology, molecular biology, scanning electron microscope, Golgi staining, TUNEL assay, and morphological analysis. Our work further clarifies the pathological mechanism of SIN by depleting microglia, inhibiting neuroinflammation, and C1q neutralization. RESULTS: This study shows that prolonged anesthesia triggers activation of the NF-

Supports

Neurotoxic microglia promote TDP-43 proteinopathy in progranulin deficiency.

Nature2020PMID:32866962medium

Abstract

Aberrant aggregation of the RNA-binding protein TDP-43 in neurons is a hallmark of frontotemporal lobar degeneration caused by haploinsufficiency in the gene encoding progranulin1,2. However, the mechanism leading to TDP-43 proteinopathy remains unclear. Here we use single-nucleus RNA sequencing to show that progranulin deficiency promotes microglial transition from a homeostatic to a disease-specific state that causes endolysosomal dysfunction and neurodegeneration in mice. These defects persist even when Grn-/- microglia are cultured ex vivo. In addition, single-nucleus RNA sequencing reveals selective loss of excitatory neurons at disease end-stage, which is characterized by prominent nuclear and cytoplasmic TDP-43 granules and nuclear pore defects. Remarkably, conditioned media from Grn-/- microglia are sufficient to promote TDP-43 granule formation, nuclear pore defects and cell death in excitatory neurons via the complement activation pathway. Consistent with these results, delet

Supports

Complement factor C1q mediates sleep spindle loss and epileptic spikes after mild brain injury.

Science2021PMID:34516796medium

Abstract

Although traumatic brain injury (TBI) acutely disrupts the cortex, most TBI-related disabilities reflect secondary injuries that accrue over time. The thalamus is a likely site of secondary damage because of its reciprocal connections with the cortex. Using a mouse model of mild TBI (mTBI), we found a chronic increase in C1q expression specifically in the corticothalamic system. Increased C1q expression colocalized with neuron loss and chronic inflammation and correlated with disruption in sleep spindles and emergence of epileptic activities. Blocking C1q counteracted these outcomes, suggesting that C1q is a disease modifier in mTBI. Single-nucleus RNA sequencing demonstrated that microglia are a source of thalamic C1q. The corticothalamic circuit could thus be a new target for treating TBI-related disabilities.

Contradicts

C1q subunit heterogeneity in assembled complexes remains technically difficult to demonstrate; most studies measure mRNA not protein stoichiometry

Acta Neuropathol2021PMID:33247299medium

Abstract

BACKGROUND: In this Occupational Health Department (OHD), a 'telephone first' approach was introduced to triage management referrals with potential to convert to Telephone Independent Medical Assessment (TIMA). Telephone consultation has been widely used in the UK's NHS in the occupational health setting. AIMS: To evaluate TIMA effectiveness and efficiency of OHD resources; comparing the outcome of a triage call compared to previous default allocation of next available appointment, percentage of telephone triage calls converted to TIMA and appointment waiting times. To assess use of OHD resources arising from TIMA. To evaluate service user satisfaction following TIMA. To examine service user characteristics. METHODS: As management referrals were received, service users were given a telephone contact. Data were collected and anonymized regarding service users, who also consented to receive feedback questionnaire. Cross-sectional analysis of this management referral cohort was carried ou

Contradicts

Astrocyte morphological differences between PSP and CBD may be primarily determined by tau strain properties rather than complement composition

Neuron2019PMID:31253886medium

Contradicts

Tufted astrocytes and astrocytic plaques may represent a continuum rather than distinct entities driven by different C1q subtypes

Brain Pathol2019PMID:31316000medium

Abstract

Aim: In previous studies, numerous dysregulated long non-coding RNAs (lncRNAs) were identified by RNA-sequencing (RNA-seq). However, the relationship between lncRNA and osteosarcoma remains unclear. In the present study, the function and mechanism of lncRNA BE503655 were investigated. Methods: Transwell, cell cycle and proliferation were used to evaluate the function of lncRNA BE503655. Real-time PCR and Western blotting were used to detect the expression of lncRNA BE503655 and β-catenin. Results: LncRNA BE503655 is overexpressed in human osteosarcoma and osteosarcoma cell lines. Knockdown lncRNA BE503655 suppresses cell proliferation, invasion and migration. High expression of BE503655 was significantly related to Enneking stage, distant metastasis and histological grade. Moreover, we also provided evidences that lncRNA BE503655 played its functions dependent on regulation of Wnt/β-catenin signaling in osteosarcoma. Conclusion: Taken together, we verified the role of lncRNA BE503655 a

Contradicts

Selective C1q subunit inhibition is technically challenging; existing anti-C1q therapeutics target shared epitopes

Sci Transl Med2022PMID:35436313medium

Abstract

We previously developed a non-cell-dependent biodegradable scaffold to create in situ tissue-engineered vasculature (iTEV) and tested it in a canine inferior vena cava (IVC) model. As iTEV features change dramatically during tissue generation, practical, simple, and accurate methods to evaluate iTEV are needed. The present study examined the usefulness of a novel method to evaluate iTEV growth and remodeling according to a simple formula using angiography: hepatic vein (HV) index = (IVC-HV junction angle) ÷ (π × [minimal internal iTEV diameter ÷ 2]2). HV index strongly correlated with the pressure gradient across iTEV, which tended to improve during the tissue generation period up to 12 months post-implantation. Time-course changes in HV index reflected iTEV tissue development and in-vivo characteristics, such as hemodynamic congestion. In conclusion, HV index is useful to assess iTEV graft function because it represents both the morphometrics and hemodynamics of iTEV with only diagnos

Contradicts

Early complement genes are associated with visual system degeneration in multiple sclerosis.

Brain2019PMID:31289819medium

Abstract

Multiple sclerosis is a heterogeneous disease with an unpredictable course and a wide range of severity; some individuals rapidly progress to a disabled state whereas others experience only mild symptoms. Though genetic studies have identified variants that are associated with an increased risk of developing multiple sclerosis, no variants have been consistently associated with multiple sclerosis severity. In part, the lack of findings is related to inherent limitations of clinical rating scales; these scales are insensitive to early degenerative changes that underlie disease progression. Optical coherence tomography imaging of the retina and low-contrast letter acuity correlate with and predict clinical and imaging-based outcomes in multiple sclerosis. Therefore, they may serve as sensitive phenotypes to discover genetic predictors of disease course. We conducted a set of genome-wide association studies of longitudinal structural and functional visual pathway phenotypes in multiple sc

Contradicts

C1q propagates microglial activation and neurodegeneration in the visual axis following retinal ischemia/reperfusion injury.

Mol Neurodegener2016PMID:27008854medium

Abstract

BACKGROUND: C1q represents the initiating protein of the classical complement cascade, however recent findings indicate pathway independent roles such as developmental pruning of retinal ganglion cell (RGC) axons. Furthermore, chronic neuroinflammation, including increased expression of C1q and activation of microglia and astrocytes, appears to be a common finding among many neurodegenerative disease models. Here we compare the effects of a retinal ischemia/reperfusion (I/R) injury on glial activation and neurodegeneration in wild type (WT) and C1qa-deficient mice in the retina and superior colliculus (SC). Retinal I/R was induced in mice through elevation of intraocular pressure to 120 mmHg for 60 min followed by reperfusion. Glial cell activation and population changes were assessed using immunofluorescence. Neuroprotection was determined using histological measurements of retinal layer thickness, RGC counts, and visual function by flash electroretinography (ERG). RESULTS: Retinal I/

📖 Linked Papers (14)Export BibTeX ↗

An integrative analysis of single-cell and bulk transcriptome and bidirectional mendelian randomization analysis identified C1Q as a novel stimulated risk gene for Atherosclerosis.

Front Immunol (2023) · PubMed:38179058 ↗

13 figures

Figure 1

Single-cell RNA-seq of human AP tissues. (A) The clustering tree of total scRNA-seq mate data was analyzed at different resolutions. (B) The top three marke...

Figure 2

C1Q hub genes selection from scRNA-seq and GEO dataset. (A) The top ten genes extract from C1Q cell cluster. (B) The 10 genes are detected in 781 DEGs betwe...

Perivascular cells induce microglial phagocytic states and synaptic engulfment via SPP1 in mouse models of Alzheimer's disease.

Nat Neurosci (2023) · PubMed:36747024 ↗

11 figures

Fig. 1

SPP1 upregulation at onset of microglia–synapse phagocytosis. a , Representative 3D reconstructed images showing Homer1 engulfment within CD68 + lysosomes of P...

Fig. 2

SPP1 is expressed by PVMs and fibroblasts. a – c , Representative images of Spp1 mRNA expression juxtaposed to GLUT1 + vasculature, colocalizing with pan-PVM...

Prolonged anesthesia induces neuroinflammation and complement-mediated microglial synaptic elimination involved in neurocognitive dysfunction and anxiety-like behaviors.

BMC Med (2023) · PubMed:36600274 ↗

11 figures

Fig. 1.

Prolonged anesthesia caused cognitive dysfunction and anxiety-like behaviors in rats. A The schedule of the first experiment. Rats underwent 5 days of swimmin...

Fig. 2

Prolonged anesthesia inducing neuroinflammation, upregulating NF-κB inflammatory pathway, downregulating neuronal excitability, and inactivating apoptotic signa...

Neurotoxic microglia promote TDP-43 proteinopathy in progranulin deficiency.

Nature (2020) · PubMed:32866962 ↗

15 figures

Extended Data Figure 1 |

Single-nucleus RNA-sequencing (snRNA-seq) analysis of age-dependent transcriptomic changes in the thalamus of Grn −/− mice. a. Unbiased clustering of snRNA-s...

Extended Data Figure 2 |

Age-dependent changes in the transcriptomes and subclustering of microglia in Grn +/+ and Grn −/− thalamus. a. Heatmap of differentially expressed genes in...

LncRNA BE503655 inhibits osteosarcoma cell proliferation, invasion/migration via Wnt/β-catenin pathway.

Bioscience reports (2019) · PubMed:31316000 ↗

4 figures

Figure 1

BE503655 is up-regulated in human osteosarcoma and osteosarcoma cell lines ( A,B ) RT-PCR analysis was performed to examine the expression of lncRNAs in MG-63 ...

Figure 2

BE503655 knockdown suppresses proliferation, invasion in osteosarcoma cells ( A ) RT-PCR analysis was used to determine the mRNA expression of BE503655 in MG...

Early complement genes are associated with visual system degeneration in multiple sclerosis.

Brain (2019) · PubMed:31289819 ↗

1 figure

Figures

Figures available at source paper (no open-access XML found).

Appropriate referring.

British dental journal (2019) · PubMed:31253886 ↗

1 figure

Figures

Figures available at source paper (no open-access XML found).

C1q propagates microglial activation and neurodegeneration in the visual axis following retinal ischemia/reperfusion injury.

Molecular neurodegeneration (2016) · PubMed:27008854 ↗

8 figures

Fig. 1

Retinal I/R injury significantly increases C1q expression in the retina. C57BL/6 J mice were subjected to unilateral I/R injury and sacrificed at the indicated ...

Fig. 2

Local ischemic injury in the retina increases expression of C1q in the SC. ( a ) Representative images displaying differences in C1q expression between hemisphe...

Evaluation method for cell-free in situ tissue-engineered vasculature monitoring: Proof of growth and development in a canine IVC model.

PloS one (2022) · PubMed:35436313 ↗

No figures

Evidence that ageing yields improvements as well as declines across attention and executive functions.

Nature human behaviour (2022) · PubMed:34413509 ↗

No figures

Complement factor C1q mediates sleep spindle loss and epileptic spikes after mild brain injury.

Science (New York, N.Y.) (2021) · PubMed:34516796 ↗

No figures

Management referral triaging process pilot study: a 'telephone first' approach.

Occupational medicine (Oxford, England) (2020) · PubMed:33247299 ↗

No figures

📙 Related Wiki Pages (15)

Nigral Microglia in Progressive Supranuccell AMX0035 for Progressive Supranuclear Palclinical Total Tau (t-Tau) - Biomarkerbiomarker Locus Coeruleus Noradrenergic in Progrescell Striatal Interneurons in Corticobasal Decell Tau Pathology Astrocytes (TPA)cell p-taubiomarker Sleep Biomarkers for CBS and PSPdiagnostic Globus Pallidus Neurons in Corticobasal cell DTI White Matter Changes in CBS/PSPbiomarker Pedunculopontine Nucleus Cholinergic in cell Red Nucleus Pspcell_type Substantia Nigra Dopamine in Corticobasacell Subthalamic Nucleus Neurons in Progressicell BIIB080 (MAPTRx) ASO Therapy for PSPclinical

🏥 Translation

🧬 3D Protein Structure — C1QA

🧬 PDB 1PK6 Click to expand

Experimental structure from RCSB PDB | Powered by Mol*

🧠 GTEx v10 Brain ExpressionJSON

Median TPM across 13 brain regions for C1QA from GTEx v10.

💉 Clinical Trials (10)Relevance: 62%

0
Active

0
Completed

1,110
Total Enrolled

PHASE1
Highest Phase

Omics of Rituximab-resistanceN/A

NOT_YET_RECRUITING·NCT07416942 · Mario Negri Institute for Pharmacological Research

120 enrolled · 2026-04 · → 2029-03

The CONFUCIUS project aims to establish a personalised medicine framework for MN patients by integrating pharmacogenomics with other -omics technologies in order to identify biomarkers that predict re

Membranous Nephropathy

Multi-omics Analysis Sample collection

The Effectivity of Anti Tuberculosis Therapy in Idiopathic Uveitis with Positive IGRAPHASE2

COMPLETED·NCT05005637 · Fakultas Kedokteran Universitas Indonesia

78 enrolled · 2021-08-27 · → 2024-10-20

The reported incidence of uveitis is 52 persons per year per 100,000 population, with a greater incidence estimated in developing countries, including Indonesia. Uveitis has challenges in diagnosis an

Tuberculous Uveitis

Anti Tuberculosis Drug Methylprednisolone

Mobilising Tumour and Immune Cells Via Exercise in Chronic Lymphocytic LeukaemiaNA

COMPLETED·NCT05093192 · University of Bath

26 enrolled · 2021-10-01 · → 2022-12-06

Chronic lymphocytic leukaemia (CLL) is the most common adult blood cancer in the United Kingdom. CLL means that many cancer cells appear in the blood, bone marrow and other tissues, for example, the s

Chronic Lymphocytic Leukemia Minimal Residual Disease

Exercise trial

Combined Apheresis for ABO-incompatible Transplantation - a Pilot StudyNA

TERMINATED·NCT02120482 · Medical University of Vienna

4 enrolled · 2014-10 · → 2022-07-31

Recipient desensitization is a prerequisite for successful ABO-incompatible kidney transplantation (ABOi-KTX). Published desensitization protocols commonly include the use of plasmapheresis or selecti

Decreased Immunologic Activity Antibody-mediated Rejection

Combined apheresis

Non-inferiority Study of Ocrelizumab and Rituximab in Active Multiple SclerosisPHASE3

ACTIVE_NOT_RECRUITING·NCT04688788 · Rigshospitalet, Denmark

600 enrolled · 2021-04-28 · → 2026-05-05

The DanNORMS study is a phase 3, non-inferiority clinical trial examining whether treatment of active multiple sclerosis with rituximab is non-inferior to ocrelizumab regarding efficacy and safety.

Relapsing Remitting Multiple Sclerosis Secondary Progressive Multiple Sclerosis Primary Progressive Multiple Sclerosis

Rituximab Ocrelizumab Fexofenadine

RAPA-501 Therapy for ALSPHASE2

RECRUITING·NCT04220190 · Rapa Therapeutics LLC

41 enrolled · 2025-01-02 · → 2026-07-01

RAPA-501-ALS is a phase 2/3 expansion cohort study of RAPA-501 autologous hybrid TREG/Th2 cells in patients living with amyotrophic lateral sclerosis (pwALS).

Amyotrophic Lateral Sclerosis

RAPA-501 Autologous T stem cells

MAD Phase I Study to Investigate Contraloid AcetatePHASE1

COMPLETED·NCT03955380 · Prof. Dr. Dieter Willbold

24 enrolled · 2018-12-12 · → 2019-04-03

This is a single-center multiple-ascending-dose clinical trial assessing the safety and tolerability of oral dosing of Contraloid acetate in healthy volunteers. The study drug Contraloid (alias RD2, a

Alzheimer Dementia Alzheimer Disease

Contraloid

Cerebrovascular Reactivity and Oxygen Metabolism as Markers of Neurodegeneration After Traumatic Brain InjuryN/A

UNKNOWN·NCT04820881 · Washington D.C. Veterans Affairs Medical Center

60 enrolled · 2021-10-01 · → 2024-09

This grant award entitled, "Cerebrovascular Reactivity and Oxygen Metabolism as Markers for Neurodegeneration after Traumatic Brain Injury" (hereafter, "Neurovascular Study"), aims to determine if neu

Neurodegenerative Diseases

Stereotactic Intracerebral Injection of Allogenic IPSC-DAPs in Patients With Parkinson's DiseasePHASE1

NOT_YET_RECRUITING·NCT07212088 · iCamuno Biotherapeutics Ltd.

12 enrolled · 2026-02-28 · → 2027-12-15

Parkinson's disease is a progressive neurodegenerative disorder characterized by high morbidity due to the limited regenerative capacity of dopaminergic neurons in the brain. Current drug treatments p

Parkinson Disease

ALC01 therapy

MRI Biomarkers in ALSN/A

COMPLETED·NCT02405182 · University of Alberta

145 enrolled · 2014-09 · → 2019-03

Amyotrophic lateral sclerosis (ALS) is a disabling and rapidly progressive neurodegenerative disorder. There is no treatment that significantly slows progression. Increasing age is an important risk f

Amyotrophic Lateral Sclerosis ALS Motor Neuron Diseases

Magnetic Resonance Imaging

No curated ClinVar variants loaded for this hypothesis.

Run scripts/backfill_clinvar_variants.py to fetch P/LP/VUS variants.

🔍 Search ClinVar for C1QA →

No DepMap CRISPR Chronos data found for C1QA.

Run python3 scripts/backfill_hypothesis_depmap.py to populate.

💰 Estimated Development

Cost

$0

Timeline

2.3 years

🏆 Tournament

🏆 Arenas / Elo

No arena matches recorded yet. Browse Arenas →

📊 Market Indicators

7d Trend

↔

Stable

7d Momentum

▼ 1.9%

Volatility

Low

0.0037

Events (7d)

6

Price History

▼18.6%

💾 Resource Usage

LLM Tokens

22,170

$0.1157

Total Cost

$0.1157

🔮 Predictions

🔎 Predictions vs Observations3 predictions · 0 with recorded observations

Prediction	Predicted	Observed	Status	Conf
If hypothesis is true, intervention determine therapeutic breadth beyond Alzheimer's disease applications	determine therapeutic breadth beyond Alzheimer's disease applications	— no observation —	pending	0.55
If hypothesis is true, intervention compromise safety or efficacy	compromise safety or efficacy	— no observation —	pending	0.55
If hypothesis is true, intervention elucidate C1q subunit interactions with other complement-independent pathways	elucidate C1q subunit interactions with other complement-independent pathways	— no observation —	pending	0.55

🔮 Falsifiable Predictions (3)

pendingconf 55%

If hypothesis is true, intervention elucidate C1q subunit interactions with other complement-independent pathways

Predicted outcome: elucidate C1q subunit interactions with other complement-independent pathways

Falsification: Intervention fails to elucidate C1q subunit interactions with other complement-independent pathways

pendingconf 55%

If hypothesis is true, intervention determine therapeutic breadth beyond Alzheimer's disease applications

Predicted outcome: determine therapeutic breadth beyond Alzheimer's disease applications

Falsification: Intervention fails to determine therapeutic breadth beyond Alzheimer's disease applications

pendingconf 55%

If hypothesis is true, intervention compromise safety or efficacy

Predicted outcome: compromise safety or efficacy

Falsification: Intervention fails to compromise safety or efficacy

📖 References (8)

Management referral triaging process pilot study: a 'telephone first' approach.
["O'Reilly A" et al.. Occupational medicine (Oxford, England) (2020)
PubMed↗DOI↗
Structurally Novel Antiestrogens Elicit Differential Responses from Constitutively Active Mutant Estrogen Receptors in Breast Cancer Cells and Tumors.
["Zhao Y" et al.. Cancer research (2017)
PubMed↗DOI↗
Evaluation method for cell-free in situ tissue-engineered vasculature monitoring: Proof of growth and development in a canine IVC model.
["Matsumura G" et al.. PloS one (2022)
PubMed↗DOI↗
Evidence that ageing yields improvements as well as declines across attention and executive functions.
["Ver\u00edssimo J" et al.. Nature human behaviour (2022)
PubMed↗DOI↗
Comparative Behavioral Pharmacology of Three Pyrrolidine-Containing Synthetic Cathinone Derivatives.
["Gatch M" et al.. The Journal of pharmacology and experimental therapeutics (2015)
PubMed↗DOI↗
Appropriate referring.
A J Wight. British dental journal (2019)
PubMed↗DOI↗
LncRNA BE503655 inhibits osteosarcoma cell proliferation, invasion/migration via Wnt/β-catenin pathway.
["Huang Q" et al.. Bioscience reports (2019)
PubMed↗DOI↗
Early complement genes are associated with visual system degeneration in multiple sclerosis.
Fitzgerald KC et al.. Brain (2019)
PubMed↗DOI↗

▸Metadatasource: v1_phase_c_backfill · origin_type: gap_debate

source	v1_phase_c_backfill
origin_type	gap_debate
_schema_version	1

📊 Evidence Profile

Evidence Balance

+0%

Certainty

5%

Debates

1

Incoming

1

Outgoing

0

0 supporting 0 contradicting 1 neutral

View full evidence profile →

Public annotations (0)Annotate on Hypothes.is →

No public annotations yet.

Composite		66%
Mech.		65%
Evidence		55%
Novelty		75%
Feasibility		40%
Impact		50%
Druggability		35%
Safety		45%
Competition		70%
Data avail.		60%
Reproducibility		50%

📗 Cite This Artifact

Complement C1q Subtype Switching

🧪 Overview

Mechanistic Overview

Mechanistic Overview

Mechanistic Pathway Diagram

Molecular and Cellular Rationale

C1QA

Evidence Supporting the Hypothesis

Contradictory Evidence, Caveats, and Failure Modes

Clinical and Translational Relevance

Experimental Predictions and Validation Strategy

Decision-Oriented Summary

🧬 Mechanism

⚖️ Evidence

🏥 Translation

🧬 3D Protein Structure — C1QA

💉 Clinical Trials (10)Relevance: 62%

🏆 Tournament

🏆 Arenas / Elo

📊 Market Indicators

💾 Resource Usage

🔮 Predictions

📖 References (8)

🧬 Related Hypotheses — same target / disease (9)

💬 Discussion

📗 Cite This Artifact

Complement C1q Subtype Switching

🧪 Overview

Mechanistic Overview

Mechanistic Overview

Mechanistic Pathway Diagram

Molecular and Cellular Rationale

C1QA

Evidence Supporting the Hypothesis

Contradictory Evidence, Caveats, and Failure Modes

Clinical and Translational Relevance

Experimental Predictions and Validation Strategy

Decision-Oriented Summary

🧬 Mechanism

⚖️ Evidence

🏥 Translation

🧬 3D Protein Structure — C1QA

💉 Clinical Trials (10)Relevance: 62%

🏆 Tournament

🏆 Arenas / Elo

📊 Market Indicators

💾 Resource Usage

🧭 Related

activates (4)

aggregates in (2)

associated with (4)

causes (2)

co discussed (24)

mediates (1)

participates in (4)

promotes (1)

regulates (8)

🔮 Predictions

📖 References (8)

🧬 Related Hypotheses — same target / disease (9)

💬 Discussion