Biology subjects

Chen, J. W.

Publications and source records attributed to Chen, J. W..

7 recordsLinked to original sources

bioRxiv2026

Biological foundation models illuminate annotation blind spots in evolutionarily divergent genomes

Chromosome-scale assemblies are increasingly available for non-model organisms, but functional annotation remains limited when deep evolutionary divergence erodes primary amino-acid sequence identity even though protein structural similarity can remain conserved. We present a hybrid annotation framework that decouples gene-model discovery from cross-species similarity assignment by combining Evo2-based ab initio prediction of exon-intron structures with ESM-2 protein-embedding-based structural similarity mapping. Applied to the sea lamprey, the framework derives high- or medium-confidence cross-species similarity assignments for 73,485 Evo2-derived translated protein models, including 35,395 high-confidence calls, and expands the deduplicated structural catalog to 31,286 loci, including 20,871 additions absent from the Ensembl baseline. A joint alignment-structure classification identifies 21,391 structurally supported catalog loci that a fixed human DIAMOND protein search does not confidently assign on its own, including 21,184 loci with no detectable human protein-sequence match and 207 loci with only low-confidence matches in the classical 20-30% amino-acid-identity twilight zone. These rescue-space totals describe catalog loci rather than validated one-to-one human-absent genes. In a single-cell RNA sequencing application, a stricter UTR-aware Ensembl+Evo2 reference improves gene recovery and expands the interpretable feature space of the lamprey immune compartment relative to the Ensembl baseline. This enables more resolved annotation of four transcriptionally defined immune cell states, including VLRA+-associated T-like and VLRB+-associated B-like programs together with oxidative iron-handling and iron-associated VLR-linked states. Together, these results show that structural protein signal often persists beyond the limits of pairwise sequence alignment and that an embedding-based annotation layer can extend that signal to improve downstream comparative and single-cell analyses in evolutionarily divergent genomes.

bioinformatics↗

bioRxiv2025

Affinity Maturation and Light-Chain-Mediated Paratope Diversification Anticipate Viral Evolution

A key goal of vaccinology is to train the immune system to combat current pathogens while simultaneously preparing it for future evolved variants. Understanding factors contributing to anticipatory breadth, wherein affinity maturation against an ancestral strain yields neutralization capacity against evolved variants, is therefore of great importance. Here, we investigated the mechanism of anticipatory breadth development in a public antibody family targeting the functionally restricted ACE2 binding site on SARS-CoV-2. IGHV3-53/66 antibodies isolated from memory B cells of infection-naive individuals vaccinated with the ancestral Wuhan-strain mRNA vaccine frequently neutralized evolved Omicron variants and contained several hallmark mutations previously shown to enhance neutralization breadth. Comparative analyses with antibodies from Omicron breakthrough infections revealed that breadth-associated patterns of somatic hypermutation emerged independently of variant exposure. However, Omicron infection had a marked impact on light chain pairing frequencies, suggestive of variant-imposed selection of favorable light chains. Analysis of available IGHV3-53/66 antibody structures complexed with SARS-CoV-2 receptor binding domain (RBD) clarified these findings; convergent somatic mutations on the heavy chain largely refined contacts with invariant RBD residues, while light chain pairings shifted epitopes to avoid steric challenges posed by Omicron mutations. These findings support a model of anticipatory breadth with three key elements: (1) targeting of a functionally restricted epitope, (2) affinity maturation to establish an affinity buffer, and (3) variable chain pairing to generate paratope diversity. These elements each serve to compensate for a distinct consequence of viral mutagenesis, offering a mechanistic framework for anticipating viral evolution. Graphical Summary O_FIG O_LINKSMALLFIG WIDTH=157 HEIGHT=200 SRC="FIGDIR/small/672735v1_ufig1.gif" ALT="Figure 1"> View larger version (51K): org.highwire.dtl.DTLVardef@1e4e893org.highwire.dtl.DTLVardef@1610bddorg.highwire.dtl.DTLVardef@520909org.highwire.dtl.DTLVardef@1cf4edc_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2024

Chemoresistance to additive PARP/PI3K dual inhibition in triple-negative breast cancer cell lines is associated with adaptive stem cell-like prevalence

Cancer stem-like cells (CSCs) are posited to exhibit specialized oncogenic capacity to drive malignancies. CSCs are distinguished by enhanced hallmarks of cancer, including apoptosis avoidance, phenotypic plasticity and aberrant growth pathway signaling. Standard-of-care chemotherapies targeted to rapidly cycling cells routinely fail to eliminate this resistant subpopulation, leading to disease recurrence and metastasis. Triple-negative breast cancer (TNBC), a highly aggressive subtype of breast cancer, is enriched for tumor-propagating CD44+/CD24-/low CSCs, which are poorly ablated by chemotherapeutics and are associated with poor prognosis. CD44 governs sustained PI3K signaling in breast cancer, which is essential for CSC maintenance. PI3K inhibition can elicit DNA damage and down-regulate BRCA1 expression, which in turn enhance the synthetic lethality of PARP inhibitors. Here, we examined a dual chemotherapeutic approach targeting these pathways by combining a pan-PI3K inhibitor (Buparlisib) and a PARP1 inhibitor (Olaparib) on a panel of TNBC cell lines with distinct mutational profiles and proportions of CSCs. We observed differential sensitivity to this dual inhibition strategy and varying cellular stress and resistance responses across eight TNBC lines. The dual chemotherapeutic effect is associated with a reduction in S-phase cells, an increased in apoptotic cells and elevated expression of cleaved PARP, indicating a provoked replicative stress response. We observed that PARP/PI3K inhibition efficacy was potentiated by repeated administration in some TNBC lines and identified critical treatment schedules, which further potentiated the dual chemotherapeutic effect. Dual inhibition induced small but significant increases in CSC relative abundance as marked by CD44+/CD24-/low or ALDH1+ cells and increased stress and survival signaling in multiple TNBC cell lines, suggesting this sub-population contributes to TNBC chemoresistance. These results suggest the additive effects of PARP and PI3K inhibition against CSC phenotypes may be enhanced by temporally-staged administration in TNBC cells.

cancer biology↗

bioRxiv2023

ReTrace: Topological evaluation of white matter tractography algorithms using Reeb graphs

We present ReTrace, a novel graph matching-based topological evaluation and validation method for tractography algorithms. ReTrace uses a Reeb graph whose nodes and edges capture the topology of white matter fiber bundles. We evaluate the performance of 96 algorithms from the ISMRM Tractography Challenge and the the standard algorithms implemented in DSI Studio for the population-averaged Human Connectome Project (HCP) dataset. The existing evaluation metrics such as the f-score, bundle overlap, and bundle overreach fail to account for fiber continuity resulting in high scores even for broken fibers, branching artifacts, and mis-tracked fiber crossing. In contrast, we show that ReTrace effectively penalizes the incorrect tracking of fibers within bundles while concurrently pinpointing positions with significant deviation from the ground truth. Based on our analysis of ISMRM challenge data, we find that no single algorithm consistently outperforms others across all known white matter fiber bundles, highlighting the limitations of the current tractography methods. We also observe that deterministic tractography algorithms perform better in tracking the fundamental properties of fiber bundles, specifically merging and splitting, compared to probabilistic tractography. We compare different algorithmic approaches for a given bundle to highlight the specific characteristics that contribute to successful tracking, thus providing topological insights into the development of advanced tractography algorithms.

neuroscience↗

bioRxiv2023

Co-Targeting IL-6 and EGFR signaling for the treatment of schwannomatosis and associated pain

Patients with Schwannomatosis (SWN) overwhelmingly present with intractable, debilitating chronic pain. There are no effective therapies to treat SWN. The drivers of pain response and tumor progression in SWN are not clear. The pain is not proportionally linked to tumor size and is not always relieved by tumor resection, suggesting that mechanisms other than mechanical nerve compression exist to cause pain. SWN research is limited by the lack of clinically-relevant models. Here, we established novel patient-derived xenograft (PDX) models, dorsal root ganglia (DRG) imaging model, and combined with single-cell resolution intravital imaging and RNASeq, we discovered: i) schwannomas on the peripheral nerve cause macrophage influx into the DRG, via secreting HMGB1 to directly stimulate DRG neurons to express CCL2, the key macrophage chemokine, ii) once recruited, macrophages cause pain response via overproduction of IL-6, iii) IL-6 blockade in a therapeutic setting significantly reduces pain but has modest efficacy on tumor growth, iv) EGF signaling is a potential driver of schwannoma growth and escape mechanism from anti-IL6 treatment, and v) combined IL-6 and EGFR blockade simultaneously controlled pain and tumor growth in SWN models. Our findings prompted the initiation of phase II clinical trial (NCT05684692) for pain relief in patients with SWN.

neuroscience↗

bioRxiv2020

STAMPede: A Precision Oncology Catalogue of Solid Tumors

Molecular profiling of tumor specimens is a key contributor in the application of precision medicine toward patient care in oncology. The presence of genetic mutational data may provide insight into the etiology of the cancer and inform about the available therapeutic options for patients diagnosed with various cancer types. However, the ability to centrally organize, structure, and visualize this genetic data can be hindered by the lack of necessary computational infrastructure. Here we present a somatic tumor data visualization portal titled STAMPede that utilizes tumor sequencing data from an in-house solid tumor oncology sequencing panel at Stanford Health Care. STAMPede is intended to provide Stanford healthcare providers and clinical researchers an easy to navigate web-based portal to query and display gene-, variant-, and cancer-level summary statistics.

genomics↗

bioRxiv2020

Obtusaquinone is a cysteine modifying compound that targets Keap1 for degradation

We have previously identified the natural product Obtusaquinone (OBT) as a potent antineoplastic agent with promising in vivo activity in glioblastoma and breast cancer through the activation of oxidative stress; however, the molecular properties of this compound remained elusive. We used a multidisciplinary approach comprising medicinal chemistry, quantitative mass spectrometry-based proteomics, functional studies in cancer cells, pharmacokinetic analysis, as well as mouse xenograft models to develop and validate novel OBT analogs and charaterize the molecular mechanism of action of OBT. We here show that OBT and analogs, which have improved pharmacological properties, bind to cysteine residues with particular affinity to cysteine-rich Keap1, a member of the CUL3 ubiquitin ligase complex. This binding promotes an overall stress response and results in ubiquitination and proteasomal degradation of Keap1 and downstream activation of the Nrf2 pathway.

cancer biology↗