Biology subjects

Yan, J.

Publications and source records attributed to Yan, J..

At least 19 recordsLinked to original sources

bioRxiv2026

Localized Chromatin Rewiring Shapes Rhythmic Transcription within a Stable 3D Genome in Rice

How spatial genome architecture coordinates rhythmic gene transcription across scales in plants remains poorly understood. Here, we integrated bridge linker Hi-C (BL-Hi-C), H3K9ac ChIP-seq and RNA-seq at six time points across a 24-h circadian cycle in rice. While global higher-order structure was largely invariant, with 84.5% of A/B compartments and over 95% of topologically associating domains (TADs) conserved across all time points, we identified 557 dynamic compartment transitions coupled to changes in active chromatin marks. Within this stable structural scaffold, 35.8% of TADs containing clustered loci of multiple rhythmic genes with synchronized expression phases. In contrast, fine-scale intradomain contacts and chromatin loops exhibited pronounced temporal plasticity. Chromatin interactions connected rhythmic genes with diverse expression phases. Myb-binding motifs were enriched at chromatin interaction anchors at dawn and early day (ZT0 and ZT4). Together, our findings demonstrate that localized chromatin rewiring occurs within relatively stable architectural frameworks, providing a spatiotemporal context for circadian gene regulation in rice.

genomics↗

bioRxiv2026

ScienceRSI: Recursive Scientific Self-Improvement

Scientific AI can improve cumulatively when capabilities developed in one model become useful learning signals for the next. We introduce ScienceRSI, a framework for recursive scientific self-improvement organized around specialize, verify, transfer, and reuse. Compact experts develop complementary scientific capabilities; shared evaluation identifies their useful contributions; a target model integrates those contributions and can serve as the starting point for further specialization. This organization connects reasoning, model scaling, and iteration through reusable scientific capabilities. We evaluate its transfer step in 4B[->]4B, 4B[->]8B, and 8B[->]27B configurations. ScienceRSI ranks first among the compared methods on all five science benchmarks for the 4B and 8B students. Relative to rubric-based reinforcement learning, scientific-reasoning averages improve by 2.0 and 1.9 percentage points, and domain-science averages by 3.3 and 2.1 points, respectively. In a separate cross-generation 27B extension, reported scores improve over Vanilla on all seven benchmarks, with the unweighted mean rising from 87.3% to 94.0%. These results support verified capability transfer across model scales as a practical foundation for ScienceRSI. Accumulating these gains over repeated rounds is the next step toward sustained recursive scientific improvement.

bioinformatics↗

bioRxiv2026

ANO6 Scaffolds ER Mitochondria Contacts to Govern Spatial Lipid Compartmentalization and Ferroptosis Evasion in Chemoresistant Breast Cancer

Background: Metabolic glycerophospholipid remodeling promotes tumor persistence under neoadjuvant chemotherapy in breast cancer; however, how resistant cells evade lipotoxicity from accumulating peroxidizable lipids presents an intriguing metabolic conundrum. The underlying organelle-level spatial mechanisms remain poorly defined. Methods: Integrated multi-omic profiling of paired pre- and post-NAC clinical specimens was performed. Engineered ANO6 models (wild-type, knockout, and conformational mutants) were characterized using subcellular lipidomics of purified mitochondria-associated ER membranes (MAMs), electron microscopy, in situ proximity ligation assays, and preclinical xenograft models. Results: Chemoresistant lesions exhibited marked ANO6 upregulation and polyunsaturated phospholipid (PUFA-PL) accumulation without enhanced apoptosis. Beyond its canonical role as a plasma membrane scramblase, ANO6 operates as an organelle contact scaffold at MAMs, leveraging its conformational activation to coordinate inter-organellar tethering. ANO6 directly recruits vimentin (VIM) and VAPB to assemble a VIM-ANO6-VAPB-PTPIP51 tethering platform, structurally bridging intermediate filaments to organelle contact sites. This complex tightens ER-mitochondria coupling, establishing a specialized structural platform that routes and sequesters peroxidizable lipids into protective cytoplasmic lipid droplets, thereby shielding functional membrane bilayers from ferroptotic peroxidation. Functional dissection revealed that the active scaffolding conformation (I612A) sustains MAMs integrity and lipid packaging, whereas scaffold deficiency (D703R) compromises contact architecture. Pharmacologically perturbing this platform with niclosamide destabilized lipid sequestration, selectively resensitizing chemoresistant cells to synthetic lethal ferroptosis in vitro and in vivo. Conclusions: ANO6-mediated contact scaffolding governs spatial lipid compartmentalization, establishing the ANO6-MAMs structural axis as a potential target to exploit lipid metabolic vulnerabilities in refractory breast cancer.

cancer biology↗

bioRxiv2026

Plantaricin JK from Lactiplantibacillus plantarum ZJ316 inhibits enterohemorrhagic Escherichia coli O104:H4 and alters fecal microbial communities in vitro

Enterohemorrhagic Escherichia coli (EHEC) O104:H4 is a highly virulent foodborne pathogen for which antibiotic therapy is contraindicated, severely restricting conventional treatment options; therefore, the development of novel antimicrobial strategies is essential. This study investigated the antibacterial activity and gut microbiota-modulating effects of plantaricin JK (PlnJK), a two-peptide bacteriocin from Lactiplantibacillus plantarum. Chemically synthesized PlnJK exhibited a minimum inhibitory concentration (MIC) of 32 M against E. coli O104:H4, disrupting membrane integrity as evidenced by increased extracellular conductivity, ATP depletion, and ultrastructural damage. In an in vitro fecal fermentation model, PlnJK reduced Escherichia-Shigella abundance from 36.70% to 30.60% which contains E. coli O104:H4-related taxa, enriched Clostridium (5.70% vs 2.40% in infection group), Rikenellaceae, and Lactobacillaceae, and significantly elevated short-chain fatty acid (SCFA) levels including butyrate (p < 0.01) and isovalerate (p < 0.05). To translate this into a deliverable format, CRISPR-Cas9-engineered L. plantarum strains with plnJK knockout, complementation, and overexpression were constructed. Compared with the chemically synthesized peptide, LAB-derived PlnJK--especially from the overexpression strain--showed superior efficacy in restoring microbial diversity and enhancing SCFA production, significantly increased Shannon index and reduced dominance (p < 0.01), while promoting butyrate (p < 0.01) and isovalerate (p < 0.01) production compared to the knockout control. The engineered strains further revealed a clear dose-dependent effect, as overexpression potentiated while knockout abolished the beneficial modulation. These findings demonstrate that PlnJK acts through membrane disruption and beneficially modulates gut microecology, with LAB-mediated in situ delivery offering a promising strategy for anti-EHEC live biotherapeutic development.

microbiology↗

bioRxiv2026

Neuro-Metabolic and Vascular Dysregulation are Functional Biomarkers of Acquired Brain Injury

Emerging clinical and neuropathological evidence suggests a direct link between traumatic brain injury (TBI) and neurodegenerative diseases (ND), but the mechanisms by which TBI contributes to ND onset and progression remain unclear. To bridge this gap, the NINDS TBI-ADRD consortium developed a diagnostic framework to guide the design and evaluation of TBI-ADRD experiments using translational neuroimaging (DCE-MRI, 18F-FDG-PET) and advanced image-processing pipelines. Neuro-metabolic and vascular dysregulation (MVD) and metabolic functional connectomics (MFC) were evaluated in 8-month C57BL/6J mice at 30- and 60-days post-injury (DPI). Both MVD and MFC revealed significant changes at 30- and 60-DPI that were sex- and injury side-dependent. Female mice showed greater regional MVD alterations, while MFC identified sex-dependent changes at 30-DPI that diminished by 60-DPI. These findings suggest that a single mid-life closed-head injury induces sexually dimorphic MVD and brain network remodeling, supporting the potential of MVD as a sensitive biomarker for improved clinical monitoring post-TBI.

neuroscience↗

bioRxiv2026

Development and design rules for a modular human peptide-tag adaptor CAR T cell system

CAR T cells are highly effective in haematological malignancies, but limited post-infusion control and tumour antigen heterogeneity remain major challenges. Modular CAR systems address these limitations using interchangeable adaptor molecules (AM) to control CAR T cell engagement and redirect targeting toward different antigens, yet the design principles underlying effective modular function remain undefined. We present our modular platform, BRiDGE CAR, and systematically examine how CAR and adaptor configuration influence activity. BRiDGE CAR activity was influenced by CAR hinge length and adaptor format and valency; a medium-length hinge combined with a full-length, bivalent adaptor supported potent activity across multiple tumour antigens and consistently controlled tumour growth across the tested xenograft models. During repeated antigen challenge, CD33-directed BRiDGE CAR T cells retained less-differentiated phenotypes than direct CD33-targeting CAR T cells. In vivo, BRiDGE CAR T cells persisted during adaptor withdrawal and regained antitumour activity upon adaptor re-administration, while IL-18 armouring enhanced tumour control at a reduced CAR T-cell dose. We identified key design parameters governing rules for adaptor-mediated CAR activity, with antigen targeting and CAR T cell function remaining independently modifiable, establishing BRiDGE CAR as a flexible and controllable modular platform.

cancer biology↗

bioRxiv2026

Valine Engages a Prefrontal mGluR5 Allosteric Site to Preserve Social Behavior

Branched-chain amino acid metabolism is linked to neurodevelopmental disorders, but whether a defined amino acid directly modulates cortical receptor signaling to control behavior is unknown. Here, we show that valine is uniquely required for sociability through medial prefrontal cortex (mPFC) circuitry. Partial dietary valine restriction, but not comparable leucine or isoleucine restriction, or mPFC-restricted acceleration of BCAA catabolism through Bckdk loss, disrupts social interaction, and local valine supplementation rescues behavior. LiP-SMap, surface plasmon resonance, cryo-EM, and mutagenesis identify metabotropic glutamate receptor 5 (mGluR5) as a direct valine target and reveal a valine-selective allosteric pocket distinct from the glutamate site. Valine is signaling-biased: it drives {beta}-arrestin-linked output yet has little standalone Gq efficacy, instead potentiating glutamate-evoked mGluR5 signaling to recruit endocannabinoid/CB1 feedback, gate inhibitory transmission, and preserve mPFC-dependent social behavior. Together, these findings identify valine as a diet-derived allosteric ligand that links amino acid availability to cortical circuit control of social behavior.

neuroscience↗

bioRxiv2026

Dual-Antigen CCHFV Vaccine Induces Neutralizing Immunity and Protection Against Lethal Challenge

Crimean-Congo hemorrhagic fever virus (CCHFV) is a WHO-priority pathogen with high mortality and wide global distribution. A major challenge in CCHFV vaccine development is identifying antigens that induce functional cellular and humoral immunity. We previously showed that the CCHF nucleoprotein (NP) elicits protective responses in mice and non-human primates but does not induce neutralizing antibodies. We therefore systematically screened six chimeric DNA vaccines expressing different CCHF glycoproteins combined with NP. A construct comprising the ectodomain of the glycoprotein Gc and NP elicited robust antibody and T-cell responses to both antigens. The Gc-NP gene was subsequently developed as a lipid nanoparticle-formulated mRNA vaccine using a scalable manufacturing pipeline. Gc-NP mRNA-LNP induced robust antigen-specific humoral and cellular responses comparable to those elicited by the corresponding DNA vaccine, despite the substantially lower dose. Both vaccine approaches generated Gc-directed neutralizing antibody responses against CCHFV pseudovirus and protected mice against homologous Hoti and heterologous IbAr10200 strain challenge. These findings demonstrate that systematic antigen screening combined with genetic vaccine platforms can identify a potent multi-antigen CCHF vaccine candidate.

immunology↗

bioRxiv2026

Cause-excluded Effect Evaluation: a framework for the faithful assessment of genetic perturbation target identification

Identifying which gene drives a desired cell-state transition is a foundational inverse problem in target discovery and cell-state engineering, yet far less developed than forward prediction. We show that prevailing benchmarks inflate performance through two artefacts: training leakage, where test-perturbation cells are seen during fitting, and evaluation leakage, where the perturbed gene's own expression change exposes the answer. Here, we introduce Cause-excluded Effect Evaluation (CEE), a framework that separates train and test perturbation targets, removes target-gene self-effects from expression profiles and scores candidates in downstream response space. With CEE, we find that simple structure-based methods consistently outperform complex deep learning models across 16 single-cell perturbation datasets, revealing that the recoverable signal is governed by low-rank and additive structure in perturbation responses rather than by model complexity. Our work disentangles evaluation artefacts from genuine predictive capacity and offers a design principle for developing perturbation target identification methods.

bioinformatics↗

bioRxiv2026

Continuous amyloid staging complements global amyloid burden in early Alzheimer's disease

Introduction: Early Alzheimer's disease (AD) staging remains challenging because clinical categories and global amyloid PET measures provide only coarse characterization of disease progression. We developed a continuous amyloid staging score from regional amyloid PET to complement global amyloid burden. Methods: Using longitudinal florbetapir PET from the Alzheimer's Disease Neuroimaging Initiative (ADNI), we trained an end-to-end deep learning model to directly estimate a continuous amyloid staging score. We evaluated longitudinal consistency, its relationship with global amyloid burden, regional contributors to early-stage variation, and whether the staging score stratified subsequent memory decline among participants matched for baseline global amyloid burden. Cognitive analyses were replicated in A4+LEARN. Results: The staging score better preserved longitudinal visit order than existing amyloid staging approaches. During early disease stages, it captured regional amyloid variation despite relatively stable global amyloid burden. Among participants with similar baseline global amyloid burden, higher staging scores were associated with faster subsequent memory decline in both ADNI and A4+LEARN. Discussion: A continuous amyloid staging score complements global amyloid burden for early AD staging and cognitive risk stratification. Keywords: Alzheimer's disease; amyloid PET; disease staging; cognitive decline

neuroscience↗

bioRxiv2026

Chain of Structures: Connecting Reasoning and Generation for Protein Design

Scientific design requires reasoning in scientific spaces that represent the objects being designed. Building on Scinetics' Chain of Science Tokens, we present chain-of-structures (COS) as a concrete protein-design case study that connects reasoning and generation through explicit structural states. In this technical report, we apply COS to enzyme design, where catalytic function requires precise local geometry within a compatible global fold, making it a demanding test of reasoning from chemical requirements to protein structure. Starting from a reaction specification and target length, COS couples a language reasoning expert with an all-atom generation expert across four rounds: catalytic core, active site, global backbone, and complete sequence and structure. Each reasoning state directly conditions generation, and the resulting structure becomes context for the next decision. Discrete residue constraints and continuous latents connect the two experts, enabling structural supervision of the reasoning interface. On the evaluated benchmark, COS leads the compared baselines on five of six metrics, achieving 57.0% EC3 agreement and a TM-score of 0.729.

bioinformatics↗

bioRxiv2026

The cleaved C-terminal domain of GmERS1-1 modulates cell cycle via GmACR1

Ethylene signaling orchestrates plant development and stress adaptation, yet how post-translational modifications of its receptors coordinate growth regulation remains unresolved. Here, we uncover a proteolytic processing mechanism of the soybean ethylene receptor GmERS1-1 that directly gates cell cycle progression. The GmERS1-1 mutants exhibit elevated yield under field conditions, whereas overexpression suppresses growth and hypersensitizes plants to ethylene. Ethylene triggers nuclear translocation of C-terminal domain (GmERS1-1-CEND), which is indispensable for receptor function. Mechanistically, GmERS1-1-CEND scaffolds a trimeric complex with GmACR1 and GmCDK7, enforcing G2/M phase arrest, thereby decoupling cell division from canonical ethylene transcriptional responses. Strikingly, ethylene-induced cell cycle blockade during apple fruit maturation mirrors this pathway, suggesting deep conservation across angiosperms. Our work defines a receptor processing-dependent signaling axis that directly interlinks phytohormone perception with cell cycle control, proposing tunable targets (e.g., GmERS1-1 cleavage efficiency) for engineering crop architecture and productivity.

plant biology↗

bioRxiv2026

Integrative genetic and transcriptomic analysis identifies candidate genes and compounds for Fragile X syndrome and autism spectrum disorder

Fragile X syndrome (FXS) is the most commonly known monogenic cause of autism spectrum disorder (ASD), yet how FXS biology relates to polygenic architecture of idiopathic ASD remains poorly defined. We integrated publicly available genetic data relevant to ASD and FXS, including population case-control risk, symptom discordance within monozygotic twin pairs, contrasts between ASD and other psychiatric disorders, and genetic variation associated with circulating plasma fragile X messenger ribonucleoprotein (FMRP) abundance. These data were used to identify associated genes and pathways across tissues and prioritize small molecules predicted to reverse genetically associated transcriptional signatures. Cross-tissue analysis identified XRN2 as the strongest association for population ASD risk and PPP3CA as the strongest association with FMRP abundance, providing distinct candidate links to ASD and FXS biology. We found no evidence that population ASD risk and symptom discordance within monozygotic twin pairs share common-variant architecture after accounting for linkage disequilibrium, suggesting that these phenotypes capture at least partially distinct sources of genetic signal. Connectivity mapping identified candidate compounds across eight genetic signatures, including several with biologically plausible mechanisms. Together, these findings provide a genetics-anchored framework for connecting FXS and ASD biology and for prioritizing candidate therapeutic mechanisms and compounds, while highlighting methodological safeguards needed for reliable integrative genomic drug repurposing.

bioinformatics↗

bioRxiv2026

Prime editing enables high-throughput identification and characterization of selective MutSβ inhibitors

DNA mismatch repair (MMR) maintains genome stability but paradoxically drives expansion of pathogenic repeats responsible for trinucleotide repeat disorders. Attenuating repeat instability through targeted inhibition of MMR is therefore a therapeutic strategy of interest; however, progress is constrained by a lack of robust methods for defining and isolating MMR subpathways. We exploited features of prime editing to profile the effects of core MMR genes on thousands of programmed DNA mispairs in cells and resolved distinct MMR processes, including a noncanonical, loop-directed mechanism. Guided by these results, we built a set of scalable reporters that detect loss of separable MMR processes and screened ~72,000 small molecules for activity against MutS{beta}-directed MMR. This effort identified a novel series of MutS{beta} inhibitors that reduced (CAG)n expansion in a cell model. Altogether, this study establishes several methods for systematically interrogating MMR, with demonstrated capacity to identify inhibitors of therapeutic value.

bioengineering↗

bioRxiv2026

Discovery and Characterization of Four Novel Vibrio coralliilyticus Phages Support the Proposal of Two New Genera

Vibrio coralliilyticus (V. coralliilyticus) is an emerging coral pathogen associated with tissue-loss diseases in reef-building corals and diseases in other marine organisms, such as oyster larvae. Despite the great ecological and economic significance of this pathogenic bacterium, characterization of bacteriophages infecting V. coralliilyticus remains limited, particularly of temperate phages. In this study, we describe the isolation and characterization of four novel phages - Vibrio phages Satoshi, Kolob, Ushijima, and Kane - obtained from coastal waters near L[a]ie, Hawaii, using the indigenous Hawaiian V. coralliilyticus strain OCN008 as the host. All four phages produced small, turbid plaques and encoded integrases, consistent with temperate lifestyles. The genome organization and taxonomic relationships of the viruses were examined using whole-genome sequencing and comparative genomics, while representative virion morphologies were examined by transmission electron microscopy. To the best of the authors' knowledge, these are the first V. coralliilyticus phages reported from Oahu, Hawaii. Comparative genomic analyses support the placement of all four phages within the class Caudoviricetes, but outside of any previously described orders, families, or genera within the class. Satoshi, Kolob, and Ushijima, along with previously described V. coralliilyticus phage CKB-S2, cluster within one genus-level lineage, while Kane, which has no close relatives in available databases, represents a distinct, previously undescribed lineage. All four phages were also found to contain homologs to experimentally established virulence factors, which may contribute to the pathogenicity of the host bacterium during lysogeny. Together, these isolates expand the diversity of phages infecting V. coralliilyticus and support the proposal of two new genera of Caudoviricetes: the genus Mokushimavirus, containing Satoshi, Kolob, Ushijima, and CKB-S2, and the genus Laievirus, containing Kane.

microbiology↗

bioRxiv2026

Divergent amyloid trajectories distinguish normal aging from Alzheimer's disease progression

Aging is the greatest risk factor for Alzheimer's disease (AD), yet how and when AD-related pathological progression diverges from aging remains poorly understood. This distinction is particularly difficult at early stages, when clinically and biomarker-defined populations contain individuals following fundamentally different trajectories. Here, we model AD progression as a deviation from aging using longitudinal amyloid PET and a self-supervised trajectory-learning framework. In ADNI, the learned trajectory revealed a shared early path that bifurcated into an aging branch and an AD-related branch. The two branches showed distinct profiles in amyloid burden, cognitive decline, risk of progression to AD dementia, and genetic risk. Unseen participants from the independent NACC cohort were projected onto the trajectory without retraining, further reproducing key branch-specific biological and genetic patterns. Together, the bifurcating trajectory provides a biologically grounded framework for resolving early-stage heterogeneity and enabling risk stratification beyond binary amyloid status.

neuroscience↗

bioRxiv2026

Altered stimulus-specific adaptation at the auditory cortex of a mouse model of Fragile X Syndrome

Auditory hypersensitivity or decreased sound tolerance is a common phenotype of Fragile X Syndrome (FXS). Impairments in adaptation, defined as the reduction in the neuronal responsiveness to repeating sounds, can contribute to this prevalent phenotype. Previous studies on event-related potential observed impairments in mismatch negativity (MMN) in both FXS individuals and in the FMR1-knockout (KO) mouse model of FXS. Therefore, in the present study we characterized stimulus-specific adaptation (SSA), a neural correlate of MMN, at the auditory cortex (AC) of anesthetized (with ketamine/xylazine) female and male postnatal day 20 (P20) wild-type (WT) and FMR1-KO mice, using the oddball paradigm with either 4 Hz or 1 Hz repetition rate. We observed robust SSA at the 4 Hz repetition rate of the oddball paradigm in the AC neurons of all four groups of animals. We also noted that the strength of SSA diminished between 4 to 1 Hz repetition rate. In addition, at both the 4 Hz and 1 Hz repetition rate, reduced SSA was observed particularly in the male FMR1-KO mice compared to their WT counterparts, while female WT and FMR1-KO mice displayed similar SSA. In terms of sex differences, male FMR1-KO mice had lower SSA than female FMR1-KO mice, while SSA was similar in male and female WT mice. Overall, our observation of reduced SSA in the male FMR1-KO mice suggests that impairments in neuronal adaptation potentially contribute to the auditory hypersensitivity phenotype particularly within the male population.

neuroscience↗

bioRxiv2026

Adeno-Associated Virus Mediated Expression of Bcl-xL Attenuates Apoptosis in Fuchs Endothelial Corneal Dystrophy

Fuchs Endothelial Corneal Dystrophy (FECD) is characterized by progressive corneal endothelial cell loss and the formation of corneal guttae. Currently, there is a global shortage of donor corneas and new strategies are needed to reduce the need for corneal transplantation. While adeno-associated viruses (AAVs) have the capacity to deliver anti-apoptotic genes to human corneal endothelial cells (CECs), this has not been fully explored as a therapeutic strategy for FECD. In this study, we evaluated the transduction efficiency of self-complementary (sc-) and single-stranded (ss-) AAV2 serotypes in human CECs and ex vivo tissues and assessed whether AAV-mediated expression of Bcl-xL could attenuate apoptosis in FECD. Seventeen scAAV2 serotypes were screened for transduction efficiency in normal human CECs via green fluorescent protein (GFP) expression. The top 4 AAV2 serotypes were further evaluated in FECD cell lines, healthy cadaveric donor specimens, and FECD patient specimens. FECD cell lines were transduced with anti-apoptotic ssAAV2/5-Bcl-xL (AAV2/5-CAG-eGFP-P2A-BCLXL) and treated with etoposide to induce apoptosis. We found that scAAV2/5 demonstrated high transduction efficiency across all normal and FECD cell lines and tissues. We observed that ssAAV2/5-mediated expression of Bcl-xL provided significant protection against etoposide-induced apoptosis in FECD CECs (71.68%{+/-}0.69 vs 23.96%{+/-}8.88%, p=0.018). Our findings show that AAVs have the potential for therapeutic gene delivery to the human corneal endothelium, and that targeting the Bcl-xL mediated apoptotic pathway can be further explored as a therapeutic for FECD.

cell biology↗