Biology subjects

Li, A. W.

Publications and source records attributed to Li, A. W..

5 recordsLinked to original sources

bioRxiv2026

Disentangling Context-Specific Alzheimer's Disease Progression Signatures through an Explainable AI Framework

Alzheimer's disease (AD) progression involves stage-dependent transcriptional changes that are often masked by dominant cellular and biological variation. Here, we present ADVISE (Alzheimer's Disease Variational Isolation of Signal Embeddings), an interpretable deep generative framework designed to disentangle Braak stage-associated transcriptional signals from background biological variation through separate latent representations. Using explainable AI, ADVISE prioritizes genes and pathways contributing to the disease-specific representation. Applying ADVISE to large-scale single-nucleus RNA sequencing data from the human prefrontal cortex, we identify shared and context-specific signatures of AD progression across global, sex-specific, and cell-type-specific analyses, revealing convergent molecular programs involving synaptic transmission, HSF1-associated proteostatic stress responses, and SLIT/ROBO axon guidance. Notably, ADVISE prioritizes ROBO2 as a progression-associated candidate in excitatory neurons. Experimental validation using CRISPR activation in hiPSC-derived excitatory neurons demonstrates that ROBO2 activation reduces the phosphorylated Tau-to-total Tau ratio. ADVISE thus reveals context-dependent molecular signatures of AD progression and bridges human single-cell discoveries with experimental validation of candidate regulators of AD pathology.

bioinformatics↗

bioRxiv2026

Nextstrain automates real-time phylodynamic analysis of open data for endemic and emerging pathogens

MotivationGenome sequencing provides an exceptional window into the evolutionary and epidemiological dynamics of endemic and emerging pathogens, and thus allows for better, more targeted, public health interventions. Online genomic surveillance platforms can provide near real-time insight into these dynamics. ResultsNextstrain provides continually updated real-time genomic surveillance for 21 viruses and the bacterial pathogen Mycobacterium tuberculosis, with most analyses relying solely on open sequence data. Each pathogen includes steps to fetch and curate open data, classify sequences using established nomenclature systems, perform phylogenetic analyses, and share the results publicly. These analyses are automated, with most running daily to provide continually updated snapshots of pathogen evolution. Availability and ImplementationAll source code is available at https://github.com/nextstrain. Phylogenetic results can be visualized and downloaded at https://nextstrain.org/pathogens, and open sequence data and curated metadata are available at https://nextstrain.org/pathogens/files.

bioinformatics↗

bioRxiv2021

A novel antibody against the furin cleavage site of SARS-CoV-2 spike protein: effects on proteolytic cleavage and ACE2 binding

SARS-CoV-2 harbors a unique S1/S2 furin cleavage site within its spike protein, which can be cleaved by furin and other proprotein convertases. Proteolytic activation of SARS-CoV-2 spike protein at the S1/S2 boundary facilitates interaction with host ACE2 receptor for cell entry. To address this, high titer antibody was generated against the SARS-CoV-2-specific furin motif. Using a series of innovative ELISA-based assays, this furin site blocking antibody displayed high sensitivity and specificity for the S1/S2 furin cleavage site, and demonstrated effective blockage of both enzyme-mediated cleavage and spike-ACE2 interaction. The results suggest that immunological blocking of the furin cleavage site may afford a suitable approach to stem proteolytic activation of SARS-CoV-2 spike protein and curtail viral infectivity.

immunology↗

bioRxiv2021

Multi-antigen recognition circuits overcome challenges of specificity, heterogeneity, and durability in T cell therapy for glioblastoma

Treatment of solid cancers with chimeric antigen receptor (CAR) T cells is plagued by the lack of target antigens that are both tumor-specific and homogeneously expressed. We show that multiantigen prime-and-kill recognition circuits have the flexibility and precision to overcome these challenges in attacking glioblastoma. A synNotch receptor that recognizes a specific priming antigen - the heterogeneous glioblastoma neoantigen EGFRvIII or a brain tissue-specific antigen - is used to locally induce expression of a CAR, enabling thorough but controlled tumor killing by targeting of homogeneous antigens that are not absolutely tumor specific. Moreover, regulated CAR expression maintains a higher fraction of the T cells in the naive-like state which is associated with higher durability in vivo. In summary, using circuits that integrate recognition of multiple imperfect but complementary antigens, we improve the specificity and persistence of T cells directed against glioblastoma, providing a general recognition strategy applicable to other solid tumors.

immunology↗

bioRxiv2020

Modular biomaterials vaccine technology protects against multiple pathogens and septic shock

Broad spectrum vaccines could provide a solution to the emergence of antibiotic resistant microbes, pandemics and engineered biothreat agents. Here, we describe a modular vaccine (composite infection vaccine technology (ciVAX)) which can be rapidly assembled and in which 4 of the 5 components are already approved for human use. ciVAX consists of an injectable biomaterial scaffold with factors to recruit and activate dendritic cells (DC) in vivo and microbeads conjugated with the broad-spectrum opsonin Fc-Mannose-binding Lectin (FcMBL) that is pre-bound to polysaccharide-rich cell wall antigens, such as the pathogen-associated molecular patterns (PAMPs) fractions, captured from whole inactivated bacteria. Vaccination of mice and rabbits with ciVAX generates potent humoral and T cell responses to PAMPs isolated from native antibiotic-resistant E. coli and S. aureus, and ciVAX protects mice and pigs against lethal E coli challenge in sepsis and septic shock models. In addition to the efficacy of ciVAX against homologous challenge, PAMPS isolated from an infected animal protects other animals against infection by heterologous challenge using different E. coli serotypes - demonstrating the potential for use of ciVAX in controlling pandemics. The advantage of the ciVAX technology is the strong immunogenicity with limited reactogenicity, the use of inactivated pathogens, and the modular manufacture using cGMP approved products which can be stockpiled ready for the next pandemic. One Sentence SummaryBiomaterial vaccine induces strong immunogenicity, weak reactogenicity, and protects from E. coli sepsis in rodents and pigs, and MRSA skin abscess.

immunology↗