Biology subjects

Huang, Y.

Publications and source records attributed to Huang, Y..

At least 55 records · Page 3Linked to original sources

bioRxiv2026

Computational simulation reveals the critical role of spike-timing-dependent plasticity in synchrony

Emerging research on desynchronization reveals strong relations to memory formation and recollection with much of the evidence originating from studies of the hippocampus, a brain region central to memory processing. However, growing evidence emphasizing the role of desynchronization is accompanied by challenges, most notably the synchronization/desynchronization conundrum. The conundrum arises from an apparent contradiction between learning and Shannon's information theory: spike-timing-dependent plasticity (STDP) acquires information via synchronized populational activity whereas information theory suggests that information channel is encoded through higher variability. Both frameworks are well-founded. Learning is widely accepted as the mathematical abstraction of STDP while Shannon's information theory showcases its power ubiquitously across fields from communication systems to neuroscience. Here, we propose that learning and Shannon's information theory are not necessarily opposing principles. Rather, learning plays a critical role in the process of synchronization and desynchronization. To justify our claim, we conduct computational simulations based on a Hodgkin-Huxley neuronal model coupled with NMDA, AMPA, and GABA synapses with inputs of biologically realistic spiking data. Our results show that enabling STDP significantly influences synchronization and desynchronization dynamics. Specifically, we find that STDP and desynchronization form a regulatory loop, in which STDP regulates the level of synchrony, and synchrony regulates subsequent learning strength. Further study reveals STDP is capable of switching neurons from synchronization to desynchronization. This framework mitigates the synchronization/desynchronization conundrum by clarifying the relationship between desynchronization and learning, and offers a new perspective on how synchrony contributes to memory formation and recollection.

neuroscience↗

bioRxiv2026

Variation in enhancer activity across brain regions defines neurological disease risk and shapes cellular pathology

Genetic variants associated with neurological traits are enriched in enhancers active in neurons. However, there are many types of neurons with varying functions across the brain, making it difficult to pinpoint insights into disease pathology. We set out to investigate whether cell type and brain region specificity of transcriptional enhancers could reveal new insights into the cellular pathology of neurological traits. We performed H3K27ac ChIP-seq on neurons and glia sorted from post-mortem tissue for six brain regions in triplicate and integrated these datasets with existing single-cell ATAC-seq data. While 87% of neuronal enhancers had similar activity across brain regions, we identified 40,049 neuronal regulatory elements that vary in activity across brain regions, which we termed Brain Region Variable Elements (BRVEs). Some BRVEs reflect differences in cell composition, such as a high proportion of medium spiny neurons (MSNs) in the nucleus accumbens, whereas others capture developmental trajectories, including enhancers with robust activity across telencephalic regions that are inactive in the diencephalic hypothalamus. Genetic variants within BRVEs are disproportionately enriched for the heritability of neurological traits, capturing far more heritability than neuronal enhancers with uniform activity across the brain. Additionally, genes linked to BRVEs are also more likely to be implicated in neuropsychiatric disorders by differential expression studies. Finally, we present a new method, GWAS-LOCATE, that leverages variation in enhancer activity across the brain to assign 23,494 GWAS loci to specific cell types and brain regions, including 9.8% linked to MSNs. This includes a BMI risk locus linked to the transcription factor ISL1. ISL1 knockdown in iPSC-derived MSNs revealed differentially expressed genes enriched for BMI heritability, supporting a role for ISL1-mediated MSN pathways with BMI. Collectively, these findings demonstrate that the enhancer specificity across the brain provides a powerful framework for dissecting complex trait biology and revealing cellular pathology.

genetics↗

bioRxiv2026

ACAN regulates VSMC mitochondrial homeostasis through the YAP1/TAZ pathway and contributes to the onset and progression of aortic dissection

Objective: Aortic dissection (AD) is a serious, life-threatening cardiovascular crisis. While vascular proteoglycans normally buffer hemodynamic stress, their aberrant accumulation in the AD aorta predisposes to rupture. Aggrecan (ACAN) is among the most frequently elevated proteoglycans in this setting, yet its pathogenic relationship to AD remains undefined. This study aimed to investigate the role of ACAN in AD and identify potential therapeutic targets. Approach and Results: We employed human tissues, animal models, and cell cultures. Western blotting and immunohistochemistry (IHC) were performed on aortic samples from AD patients and controls to assess contractile markers, MMPs, ACAN, and SOX9. In vivo, AD was induced in mice using {beta}-aminoisobutyric acid (BAPN) and Ang II, with AAV-mediated ACAN knockdown in VSMCs. Histological staining confirmed model validity and enabled assessment of AD incidence, mortality, and protein expression changes. In vitro, human aortic vascular smooth muscle cells (HAVSMCs) were stimulated with Ang II, and SOX9 and ACAN were silenced via siRNA to evaluate the functional impact of ACAN downregulation. In human AD aortas, elevated ACAN and its upstream transcription factor SOX9 drove VSMC phenotypic switching and ECM degradation. In mice, ACAN knockdown corrected AD-induced medial structural disruption, elastin fragmentation, and collagen deposition, markedly reducing incidence and mortality while curbing excessive mitochondrial fission and rescuing functional integrity. ACAN silencing attenuated Ang II-induced mitochondrial damage in HAVSMCs via the RNA-seq-identified YAP1/TAZ pathway, and Verteporfin restored homeostasis. Conclusion: ACAN is aberrantly expressed in AD and murine aortas. ACAN downregulation delays disease progression by preserving mitochondrial homeostasis and function via the YAP1/TAZ pathway.

pharmacology and toxicology↗

bioRxiv2026

Loss of TDP-43 function drives cryptic circular RNAs in neurodegenerative diseases

TAR DNA-binding protein 43 (TDP-43) is a key pathological hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) and a critical regulator of RNA splicing. While loss of TDP-43 induces aberrant splicing in linear transcripts, its impact on circular RNA (circRNA) biogenesis remains unexplored. Here, we show that TDP-43 depletion in human neurons induces widespread circRNA changes, especially upregulation of a distinct class of cryptic circRNAs that arise specifically upon loss of TDP-43. Some of these cryptic circRNAs incorporate cryptic exons derived from intronic sequences. Notably, these cryptic circRNAs exhibit greater stability than their corresponding linear RNA isoforms and accumulate progressively in neurons. Moreover, cryptic circRNAs are elevated in postmortem brain tissues from ALS, FTD and Alzheimer's disease (AD) patients. These findings reveal a previously unrecognized role for TDP-43 in repressing cryptic circRNA formation and establish these circRNAs as stable molecular signatures of TDP-43 dysfunction.

neuroscience↗

bioRxiv2026

Rac1 and CHK1 Converge on Abi-1 to Regulate DNA Repair Dependency and Treatment Response in Human Cancers

Radiation therapy (RT) resistance remains a major clinical challenge, yet biomarkers guiding precision radiosensitization are lacking. We previously demonstrated that Rac1 promotes RT resistance in glioblastoma (GBM) by inducing Abi-1-S323 dephosphorylation and enhancing non-homologous end joining (NHEJ). Here, we identify Abi-1-S323 as a key regulator of DNA repair states and a determinant of therapeutic efficacy in human cancers. Clinically, loss of Abi-1-S323 phosphorylation was associated with poor outcomes in patients with RT-treated GBM. Bioinformatic analyses revealed that non-small cell lung cancer (NSCLC) and head and neck cancer (HNC) are among the cancers with frequent RAC1 amplification, suggesting that these tumor types may have increased Rac1-Abi-1 signaling activity. Loss of Abi-1-S323 phosphorylation also predicted poor outcomes in patients with RT-treated HNC. Consistent with these clinical observations, high Rac1 activity and low Abi-1-S323 phosphorylation were associated with enhanced DNA double-strand break repair and radioresistance in NSCLC and HNC models, whereas genetic or pharmacological inhibition of this signaling impaired DNA repair and radiosensitized tumors in vitro and in vivo. Mechanistically, we identified CHK1 as a kinase that phosphorylates Abi-1 at S323 and defines an alternative homologous recombination (HR)-dependent repair state. Tumors with high Rac1-Abi-1 signaling exhibited elevated NHEJ capacity and were selectively radiosensitized by Rac1 inhibition, whereas tumors with low Rac1-Abi-1 signaling displayed high CHK1 activity, preferentially relied on HR, and were selectively radiosensitized by CHK1 inhibition. These findings establish Abi-1-S323 as a biomarker defining therapeutically distinct DNA repair states and provide a framework for precision radiosensitization.

cancer biology↗

bioRxiv2026

Multispecies translational evaluation of an NMDA receptor modulator reveals analgesic, autonomic-stabilizing, and stress mitigating effects without evidence of abuse liability

CNS4 is an agonist concentration-biased NMDAR modulator exhibiting GluN2 subtype-dependent activity. Here we evaluated the translational pharmacology of CNS4 across mice, rats, and client-owned surgical oncology dogs. In mice, CNS4 did not produce conditioned place preference, indicating lack of reward liability. CNS4 produced dose-dependent reductions in locomotor activity without motor impairment on accelerating rotarod testing. CNS4 also maintained body temperature 0.5 to 1 degree Celsius above the vehicle group in mice and dogs, consistent with NMDAR-dependent thermoregulatory activity and contrasting with hypothermic effects reported for NMDAR channel blockers such as ketamine. In fear-conditioning paradigms, CNS4 did not impair fear learning, memory consolidation, or fear expression. CNS4 reduced acute stress-induced sucrose preference, suggesting modulation of stress-responsive neural circuits. In a rat spinal nerve ligation model of neuropathic pain, both single-dose and three-day repeated CNS4 administration significantly reversed mechanical, pressure, and thermal hypersensitivity, supporting analgesic efficacy with no apparent evidence of rapid tolerance development. In client-owned surgical oncology dogs undergoing standard veterinary procedures, preliminary findings from 14 dogs (8 CNS4-treated, 6 vehicle-treated) demonstrated stable intraoperative mean arterial pressure and heart rate. Postoperatively, CNS4-treated dogs exhibited normal physiological recovery, with respiratory rate, heart rate, and body temperature returning toward the normal canine range, and required approximately 8% less propofol for anesthetic induction. Collectively, these findings support CNS4 as a novel NMDAR modulator with thermoregulatory, anti-agitative, analgesic, and autonomic-stabilizing properties without evidence of abuse liability, supporting continued translational development for neuropathic pain and possibly neuropsychiatric disorders.

pharmacology and toxicology↗

bioRxiv2026

A J-protein-licensed CHD3 chromatin remodeling complex promotes H3K27me3 spreading to maintain cell identity in plants

Stable inheritance of epigenetic states is essential for cellular identity and developmental robustness and requires ATP-dependent chromatin remodeling, yet the molecular composition and regulatory mechanisms of plant CHD3 chromatin remodelers have remained unknown. Here we show that the Arabidopsis CHD3 remodeler PICKLE (PKL) assembles with a defined set of J-domain proteins (JDPs) to form stable CHD3 chromatin remodeling complexes in plants that are compositionally distinct from their animal counterparts. Loss of JDPs phenocopies pkl mutants, and JDPs are required for nucleosome densification and H3K27me3 spreading at thousands of Polycomb target genes. Mechanistically, JDPs perform dual functions by promoting PKL protein stability while directly stimulating PKL chromatin remodeling activity through their plant-specific DUF3444 domain that binds the N-terminal tail of histone H3. Deletion of the DUF3444 domain severely impairs PKL remodeling activity without disrupting complex assembly, leading to defective H3K27me3 spreading, impaired facultative heterochromatin maintenance, and loss of cell identity. Together, our findings define plant CHD3 chromatin remodeling complexes and reveal a mechanism that regulates CHD3-mediated chromatin remodeling to support the propagation of repressive chromatin states in plants.

plant biology↗

bioRxiv2026

Intranasal Fritillaria taipaiensis nanovesicles alleviate acute lung injury via the lung-brain axis

Acute lung injury (ALI) is a severe inflammatory syndrome frequently complicated by brain injury, which worsens outcomes. Here, we explored whether regulation of the lung-brain axis represents a therapeutic strategy for the management of ALI. We show that intranasal administration of Fritillaria taipaiensis-derived exosome-like nanovesicles (Ft-ELNs) ameliorates LPS-induced ALI and ALI-associated hypothalamic inflammation in mice. Ft-ELNs preferentially accumulate in the lungs, inhibiting TRPV1 in both the lungs and the hypothalamus to establish the lung-brain axis. In parallel, Ft-ELNs primarily regulate systemic humoral immunity by inhibiting the VEGFR1/PI3K/AKT/NF?B signaling pathway. In vitro experiments further confirmed that Ft-ELNs are efficiently internalized by alveolar epithelial MLE-12 cells, exerting protective effects by suppressing VEGFR1 expression. Mechanistically, we identified Ft-miR1 of Ft-ELNs as the key functional effector that directly targets the Flt1 3'UTR to inhibit VEGFR1 expression. These data suggest that Ft-ELNs attenuate lung-brain axis inflammation by targeting VEGFR1 and may hold potential as novel therapeutic agents for the treatment of severe ALI.

immunology↗

bioRxiv2026

A single cooperative experience increases corticolimbic synaptic density and prosocial behavior

Cooperation is typically studied as an output of the social brain, as opposed to an experience that shapes it. Here, we developed a task in rats that permits interaction while requiring joint action for reward. Cooperation depended on dyad familiarity and visual access. Anterior cingulate cortex (ACC) to basolateral amygdala (BLA) projections were activated during cooperation with a familiar partner, whereas ACC to anterior insula (AI) projections were simultaneously suppressed regardless of familiarity. A single 90 min cooperative experience increased presynaptic marker SV2A, detected by positron emission tomography (PET), in the amygdala and insula one day later. Concurrently, rodents demonstrated heightened attention toward a distressed conspecific. Cooperation is thus an experience that recruits dissociable corticolimbic pathways and changes brain and behavior beyond the encounter itself.

neuroscience↗

bioRxiv2026

Attenuated Salmonella-Mediated Delivery of GSDMD Potentiates PD-1 Blockade Therapy against Melanoma

Immunotherapy has emerged as a core therapeutic strategy for melanoma. Programmed death protein 1 (PD-1) is a critical immune checkpoint molecule that restrains host anti-tumor immunity, and therapeutic agents blocking the PD-1 signaling pathway have been widely deployed in clinical practice. Nevertheless, single-agent PD-1 blockade fails to elicit robust clinical responses in the majority of patients. Therefore, there is an urgent unmet need to develop combinatorial regimens capable of augmenting the anti-tumor efficacy of PD-1 inhibition. Gasdermin D (GSDMD), a pore-forming effector protein that orchestrates pyroptosis, exerts inherent anti-tumor activities upon overexpression. However, whether GSDMD can synergize with PD-1 blockade to enhance therapeutic outcomes against melanoma remains poorly defined. To address this question, we established an attenuated Salmonella engineered strain for targeted delivery of GSDMD, and further investigated the anti-melanoma therapeutic efficacy of combining this engineered bacterium with anti-PD-1 antibody via immunofluorescence staining, flow cytometry and other analytical approaches. Our in vivo results demonstrated that combinatorial treatment markedly suppressed melanoma progression in tumor-bearing mice relative to monotherapy with either GSDMD-expressing bacteria or anti-PD-1 antibody alone. Mechanistically, co-treatment upregulated intratumoral expression of GSDMD and the pro-apoptotic protein BAX, while simultaneously downregulating PD-1 expression. In addition, the GSDMD/anti-PD-1 combination significantly elevated the proportions of CD4 and CD8 T lymphocytes in both peripheral blood and splenic tissues, and facilitated robust tumor infiltration by these two T cell subsets. Compared with phosphate-buffered saline (PBS) and scramble control groups, combinatorial therapy promoted tumor infiltration of M1-type tumor-associated macrophages (TAMs) and repolarized TAMs away from the immunosuppressive M2 phenotype. Consistently, serum levels of the pro-inflammatory cytokines TNF- and IFN-{gamma} were markedly elevated following combined intervention. Collectively, this study verifies that attenuated Salmonella carrying GSDMD synergizes with anti-PD-1 antibody to elicit potent anti-tumor effects in melanoma-bearing mice by amplifying systemic and intratumoral anti-tumor immune responses, which provides a preclinical rationale for novel combinatorial therapeutic strategies against melanoma.

cancer biology↗

bioRxiv2026

Single-Cell Analytics for Dose Response (SCADR) discriminates PTEN missense variants by lipid and protein phosphatase dysfunction

The proliferation of sequencing efforts has revealed a vast and expanding catalog of single nucleotide gene variants, many associated to, but with unclear roles in disease. Fully charactering variant impacts and linking specific protein dysfunctions to disease are challenging due to the multi-functional nature of many proteins and varying degree of variant effects on these functions. Lagging are sensitive approaches to empirically assess the impact of missense variant-induced single amino acid changes on a wide range of protein functions. To address these issues, we have developed an open-source computational analysis tool called SCADR (Single-Cell Analytics for Dose Response) for simultaneously measuring and comparing impacts of exogenously-expressed variants on multiple signaling pathways using multiplex phospho-antibody spectral flow cytometry in human cell lines. SCADR retains and correlates single-cell measures of signal protein activity states along with expression levels of exogenously-expressed variants, providing rich characterization of multiple protein functions, signaling protein interactions, and enhanced discrimination of variant impacts on different signaling pathways, highlighting each variants unique dysfunction profile. Here, we apply SCADR for analyses of the impact of 6 variants of the tumor-suppressor protein PTEN (P38H, C124S, G129E, Y138L, D268E, 4A) expressed in HEK293 cells on the phosphorylation states of the canonical and noncanonical downstream signaling proteins Akt, S6, CREB, ERK, and p38 detected with fluorophore-conjugated phospho-antibodies, along with an antibody detecting an N-terminal HA tag on PTEN variants allowing measures of dose-response effects of each variants expression on signaling cascades. Results identify variant-specific impacts on downstream signaling cascades.

genomics↗

bioRxiv2026

Rate of meristem initiation driven by the MADS-WUS axis contributes to floral survival and inflorescence evolution in grasses

Crop domestication has repeatedly shaped inflorescence architecture to improve floral production, but mechanisms coordinating the rate of floral initiation, maturation and survival remain unclear. Combining morphometry, modelling and molecular genetic analyses, we show that floral production in the indeterminate barley (Hordeum vulgare L.) inflorescence follows an "initiate fast-die young" strategy orchestrated by a main MADS-box gene, SPIKELET INITIATION AND FERTILITY (SIF). SIF accomplishes this duality by coordinately terminating the inflorescence meristem via WUSCHEL and activating the floral meristem via APETALA1 (Vrn-H1). Hereby, the ancestral SIF "slow" allele promotes a timely commitment to floral maturation, whereas the derived "fast" allele permits more floral initiations. Postdomestication selection of SIF alleles thus enables diversified reproductive strategies in barley populations to maintain yield traits in the field. Finally, we show that a lineage-specific SIF duplication contributed to meristem fate transition and inflorescence evolution during Triticeae cold adaptation. Our results establish developmental rate as a key driver of architectural innovation and reproductive success.

plant biology↗

bioRxiv2026

Corpusome, a cross-body-site human microbiome corpus for representation learning

Machine-learning models of the human microbiome are trained mostly on stool samples from single cohorts, limiting cross-body-site representation and cross-study generalization. Progress is constrained less by algorithms than by the absence of a harmonized multi-body-site corpus carrying the technical metadata needed to model, rather than ignore, batch structure. Here we release Corpusome, a harmonized two-tier cross-body-site human microbiome corpus for representation learning: a harmonized corpus of 187,546 human microbiome samples integrating standardized profiles from curatedMetagenomicData, the American Gut Project, and the EBI MGnify platform. Corpusome follows a two-tier design preserving both functional depth and cross-body-site breadth: a shotgun tier (22,588 samples, 93 studies) with species- and pathway-level profiles, and a 16S tier (164,958 samples, from a full pull of 708 MGnify studies) with genus-level profiles extending coverage to oral, skin, respiratory, and urogenital sites. It spans six body sites and two modalities, with harmonized metadata for batch-aware modelling. Body-site signal exceeds technical/source variance in the 16S tier by approximately 2.4-fold.

microbiology↗

bioRxiv2026

SenSASP: A Unified, Multi-Layer Database of Senescence and SASP Genes

Research on cellular senescence and the senescence-associated secretory phenotype (SASP) draws on independently curated gene resources that differ in scope, identifiers, and update cycles, making cross-resource integration error-prone. We unified four widely used resources, CellAge, GenAge, the SenMayo signature, and the Reactome Cellular Senescence pathway, onto a single canonical identifier (the Ensembl gene ID) and enriched every gene with three annotation layers absent from all four inputs: cross-species conservation, tissue and cell-type expression, and high-confidence protein-protein interactions. Unification collapsed 1,460 summed source entries into 1,250 unique genes (210 redundant entries removed, 14.4%) while preserving full source provenance: 173 genes are corroborated by two or more resources and two (IL6, JUN) by all four. The three annotation layers reach 95.8%, 97.9%, and 93.0% of genes, with 89.4% annotated across all three. A 500-gene random sample of identifier mappings was validated against HGNC and Ensembl (98.0% exact match). The result, SenSASP, is a single, machine-readable, provenance-tracked database of harmonized identifiers and net-new functional context, illustrated here with a gene-prioritization score and a tissue-expression atlas. SenSASP is freely available at https://xuan13hao.github.io/sensasp/

cell biology↗

bioRxiv2026

Proximity-induced protein deglycosylation by endogenous O-GlcNAcase

O-GlcNAcylation is an important post translational modification that regulates numerous cellular processes, yet tools enabling selective removal of O GlcNAc from individual proteins via endogenous O-GlcNAcase (OGA) in living cells remain limited. Here, we report De-O GlcNAcylation-targeting chimeras (DOGTACs), a chemically induced proximity strategy that selectively reduces O GlcNAc from target proteins by recruiting endogenous OGA. Initial designs incorporating potent competitive OGA inhibitors efficiently engaged OGA but failed to induce de-O-GlcNAcylation, revealing that catalytic competence is essential for productive proximity-driven editing. By attenuating inhibitor potency while retaining sufficient OGA engagement, we developed optimized DOGTACs that promote concentration- and time-dependent, target-specific de-O-GlcNAcylation in living cells without perturbing global O-GlcNAc levels. Furthermore, we successfully applied DOGTAC to additional target proteins across multiple cell lines. Collectively, this work established attenuated competitive inhibitors as effective recruitment modules for catalytic enzyme engagement and a novel framework, DOGTAC, for targeted de-O-GlcNAcylation via endogenous OGA recruitment in living cells.

cell biology↗

bioRxiv2026

Model-based assessment of race, sex, and electrode montage in ECT

Objective: This computational modeling study quantified the influence of sex and race-related cranial anatomy on predicted brain-wide current flow during electroconvulsive therapy (ECT) across conventional (bifrontal (BF), bitemporal/bilateral (BL), right unilateral (RUL)) and experimental (focal electrically administered seizure therapy (FEAST) and frontomedial (FM)) electrode montages. The objective was to determine whether race-associated variability meaningfully contributes to differences in ECT stimulation metrics across montages. Methods: Finite element head models of Chinese, Black, and Caucasian subjects were developed using high-resolution magnetic resonance imaging and analyzed using the Realistic vOlumetric- Approach-based Stimulator for Transcranial electric stimulation (ROAST) pipeline (N = 150 total; n = 50 per cohort, comprising 25 M and 25 F, age range: 20-30 years). Five ECT montages were simulated under a constant-current condition (900mA). Stimulation strength (Ebrain/Eth) was quantified as 90th percentile of brain-wide E-field magnitude (Ebrain) relative to neuronal activation threshold (Eth = 0.25 V/cm) quantified stimulation strength. Overall focality was evaluated as a percentage of brain volume stimulated above the neural activation threshold (Ebrain [≥] Eth), while laterality was quantified as the median right-to-left hemispheric E-field magnitude ratio. The effects of race, sex, and montage on stimulation strength, focality, and hemispheric laterality were statistically analyzed. Results: Substantial race- and sex-related differences observed in cranial anatomy resulted in systematic variation in predicted ECT-induced E-field intensity. Brain-wide E-field magnitude varied by both race and montage, with the largest fields generally observed in Caucasian head models and during BL stimulation. Montage exerted the strongest effect on stimulation strength (Ebrain/Eth) with BL and FEAST producing the highest stimulation strengths, followed by RUL and FM, while BF produced the lowest. Caucasian subjects generally predicted higher stimulation strengths than Black and Chinese subjects, whereas females predicted modestly higher stimulation strengths than males. Laterality was primarily determined by montage, with FEAST producing the greatest hemispheric asymmetry, followed by RUL. Chinese subjects demonstrated higher laterality ratios than both Black and Caucasian subjects. BL, RUL, and FEAST stimulated substantially larger brain volumes above neural activation threshold (less focal stimulation) than BF. Lower focality was observed in Caucasian subjects relative to Black and Chinese subjects, and in females relative to males. Conclusions: Electrode montage was the primary determinant of predicted ECT stimulation strength, focality, and laterality. Race-related anatomical differences and, to a lesser extent, sex-related differences systematically altered stimulation patterns, supporting consideration of individualized anatomy in ECT dosing and treatment optimization.

neuroscience↗

bioRxiv2026

Multiplexed Quantification of Variant Abundance in the Globin Gene Family: Integrating Saturation Mutagenesis with Cross-Paralog Prediction

Widespread genetic testing has expanded variant identification, yet functional characterization remains a bottleneck in genome guided medicine. Here, we present a modified Variant Abundance by Massively Parallel Sequencing (VAMP-seq) platform integrating experimental and computational approaches for high-resolution abundance profiling of protein variants. Utilizing a lentiviral integration system, we systematically assessed the stability effects of 2,696 amino acid substitutions in {zeta}-globin (HBZ) via saturation mutagenesis in human cells, achieving complete variant coverage with high reproducibility. Representative variants showed strong concordance with orthogonal low-throughput validation assays. We further developed a deep learning framework leveraging VAMP-seq derived HBZ data to predict variant abundance across thalassemia-associated globin paralogs (HBA, HBB, and HBG1) not experimentally tractable. Our hybrid framework demonstrates how targeted experimental profiling combined with AI-driven extrapolation can accelerate variant interpretation across protein family members.

genetics↗

bioRxiv2026

Virtual-cell models compress unseen intervention geometry through a target-specific generalization bottleneck

Predictive models of cellular perturbation are often judged by how closely they reconstruct molecular states after unseen interventions. We show that high state-level similarity can coexist with loss of the relationships that distinguish perturbations, a failure we term Intervention Geometry Compression (IGC). Across established models and perturbation settings, unseen interventions show weakened global and local geometry, reduced between-intervention variance and spectral collapse. The failure is not primarily explained by response-space capacity. Instead, diagnostic projections localize much of the missing geometry to a small number of residual response directions learned from seen interventions; these directions outperform complexity-matched random subspaces and replicate in an independent Jiang perturbation resource. Polarity captures part, but not all, of this continuous orientation signal. Time-resolved analyses further show that correct trajectory entry markedly improves downstream propagation, while a held target's own early empirical response rapidly reveals endpoint orientation. Finally, same-target empirical anchoring transfers intervention identity across contexts far more effectively than increasing exposure to other interventions. These results identify intervention-coordinate assignment as an information bottleneck in virtual-cell generalization and support a design principle: empirically anchor intervention identity, then use models to generalize anchored effects across cellular contexts.

bioinformatics↗