Biology subjects

Yu, B.

Publications and source records attributed to Yu, B..

At least 37 records · Page 2Linked to original sources

bioRxiv2026

Distinct senescent β-cell senotypes differentially drive islet aging and dysfunction

Biological aging greatly impacts the bodys ability to handle glucose, and represents a major risk factor the development and progression of type 2 diabetes (T2D). Nonetheless, despite advances in cellular senescence research and the development of new senolytic therapies, the heterogeneity of cellular senescence in the human endocrine pancreas, as well as its roles in normal aging, remains to be elucidated at the single-cell level. Here, we performed single-cell-resolved spatial proteomics and transcriptomics on intact pancreas from 26 donors (ages 20-80) and multiplexed single-cell RNA sequencing and functional assays on dispersed islets from 14 donors (ages 34-69). We identify two discrete SnC subpopulations distinguished by relative expression of CDKN1A and CDKN2A. CDKN1A senescent cells (SnCs) exhibit loss of {beta}-cell identity, impaired insulin secretion, and a proinflammatory SASP associated with increased islet immune infiltration. In contrast, CDKN2A SnCs retain transcriptional identity and functional competence, with lower inflammatory signaling. Together, these findings identify heterogeneous and functionally divergent senotypes in the human pancreas, distinguishing an adaptive (CDKN2A) from a maladaptive (CDKN1A) senescence program, thus providing a mechanism-guided framework for senescence-targeted therapies in T2D.

cell biology↗

bioRxiv2026

miR-6818-5p Drives Ovarian Granulosa Cell Dysfunction in PCOS via Targeting HSD17B2 and Modulating PI3K/Caspase-9 Axis

Polycystic ovary syndrome (PCOS) is a prevalent endocrine disorder characterized by hyperandrogenism, ovulatory dysfunction, and polycystic ovaries, with granulosa cell dysfunction being a key pathological feature. This study aimed to investigate the role of microRNA-6818-5p in PCOS pathogenesis. Quantitative PCR revealed a significant upregulation of circulating miR-6818-5p in PCOS patients compared to healthy controls. In vitro, functional assays in the human granulosa cell line KGN demonstrated that miR-6818-5p overexpression markedly inhibited cell proliferation (assessed by CCK-8 assay) and promoted apoptosis (measured by Annexin V/PI flow cytometry). Mechanistically, dual-luciferase reporter assay and Western blotting identified HSD17B2 as a direct target of miR-6818-5p, with miR-6818-5p mimics significantly suppressing HSD17B2 protein expression. In conclusion, our findings reveal that elevated miR-6818-5p in PCOS may contribute to follicular development dysfunction by targeting HSD17B2 to disrupt granulosa cell proliferation and apoptosis balance, offering novel insights into PCOS pathology and highlighting miR-6818-5p as a potential diagnostic biomarker and therapeutic target.

molecular biology↗

bioRxiv2026

Reduction of Weight Gain by Modulating Mitochondrial Energy Coupling Efficiency Using a Bromo-Coenzyme Q10 analog (6-Br-Q0C10)

Synthetic 6-Br-Q0C10 has been shown to have a partial electron transfer activity of native coenzyme Q in the isolated mitochondria. It reduces energy coupling efficiency by 30 %, suggesting that it may be useful in the management of obesity. The effect of 6-Br-Q0C10 on cell growth has been confirmed by several cell lines. Whether or not it behaves in the same way in the animal, however, has not yet been tested. Recently, we investigated the effect of 6-Br-Q0C10 on growth of rats. When 6-Br-Q0C10 was dissolved in different media, such as carboxymethyl cellulose, ethanol, and mixture of oil and butter and then feed to rats It shows no toxicity and little negative effects on growth as measured body weight gains over a period of time. When higher concentration (0.5 mg) of 6-Br-Q0C10 was given to each rat in 0.3 mL of oil/butter (70%/30%) mixture via intragastric injection daily for a period, a significant reduction in body weight gains was observed. These results validate the earlier observation that 6-Br-Q0C10 reduces the growth (30-60%) of all cell lines tested, in a time- and concentration dependent manner. These results strengthen the idea of using 6-Br-Q0C10 to manage obesity. It is also implying that 6-BrQ0C10 may slow the growth rate of cancer cells and thus prolong life. (This study was partially funded by NIH grants AA030221 and DA046258 to S.L.Chang.)

biochemistry↗

bioRxiv2026

Nuclear Receptor Liver Receptor Homolog-1 drives Intestinal Stem Cell regeneration and UPR/ER stress response after gut injury

Stem cell renewal and crypt survival are tightly controlled processes critical for gut repair. Defining key regulators of intestinal healing is critical for the development of new epithelial-targeted therapies. We previously showed that the nuclear receptor LRH-1 (NR5A2) maintains intestinal epithelial health and protects against inflammatory damage. Here, using lineage tracing and selective LRH-1 knockout in the Atoh1+ secretory lineage we show LRH-1 is vital for intestinal stem cell (ISC) regeneration in complementary in vivo and ex vivo injury-recovery models. Transcriptomic profiling and pathway analysis reveal downregulation of ER stress and unfolded protein response (UPR) programs. Using a new in vivo model to ascertain how LRH-1 directly impacts intestinal cell responses, we identify key ER stress response genes Ire1 and Xbp1 as potential LRH-1 targets. Together our results uncover a novel mechanism whereby LRH-1 sustains the IRE1-XBP1 arm of the UPR to support injury-induced dedifferentiation and ISC regeneration. Our findings highlight LRH-1 as a promising therapeutic target for restoring epithelial integrity in inflammatory intestinal disorders.

cell biology↗

bioRxiv2026

Covalent tumor anchoring spatially orchestrates antitumor immunity

Protein immunotherapies can elicit potent tumor rejection, but reversible target engagement, incomplete tumor retention, and systemic leakage often erode spatial control. Here, we develop covalently anchored tumor immunotherapeutic proteins (CATIPs), a modular platform that uses proximity-enabled covalent chemistry to immobilize immune cues on tumor-cell surfaces after intratumoral administration. CATIPs combine tumor-targeting nanobodies with payloads for T cell engagement, co-stimulation, and cytokine support. In human PBMC-reconstituted NSG mice, CATIPs completely eradicated treated EGFR-positive tumors, outperforming matched non-covalent proteins while limiting redistribution, systemic T cell activation, cytokine release, xGVHD-associated morbidity, and on-target, off tumor toxicity. In immunocompetent melanoma models, CATIPs remodeled the tumor microenvironment, expanded antigen-specific CD8+ T cells, induced antigen-restricted abscopal control, and generated durable protection against local and metastatic rechallenge. CATIP-engineered tumor cells further functioned as whole-cell vaccines. Thus, covalent tumor anchoring converts local protein delivery into tumor-surface immune programming, enabling systemic, tumor-specific, durable antitumor immunity while limiting systemic immunopathology.

synthetic biology↗

bioRxiv2026

Machine learning cross-platform proteomic imputation enables protein quality scoring and replication of epidemiological associations

High-throughput affinity-based proteomics has advanced biomedical research, yet fundamental, persistent discordance between mainstream platforms (SomaScan and Olink) routinely undermines the replication of findings. This platform-driven non-replication complicates downstream biological validation and biomarker prioritization. Here, we develop a machine learning-based framework for cross-platform protein value imputation to resolve this translational bottleneck. Using paired proteomic data measured by both SomaScan and Olink from 5,325 participants of the Multi-Ethnic Study of Atherosclerosis, we developed models to impute cross-platform measurements and applied them to two independent and demographically distinct cohorts (Cardiovascular Health Study [N=3,171] and UK Biobank [UKB; N=41,405]) for external validation. Our bi-directional model 1) established an imputation performance-based protein fidelity index, validated against gold-standard measurements from Atherosclerosis Risk in Communities study (N=101) and Nurses Health Study (N=54), 2) enabled imputation of platform-exclusive protein measurements, and 3) facilitated calibration of overlapping proteins. We demonstrate the utility of this framework through three applications: 1) fidelity-informed analyses enhanced the replication of biomarker discovery, 2) recovery of SomaScan signals that were previously inaccessible in UKBs original Olink measurements, and 3) improved replication performance for overlapping proteins. Our study offers a translational roadmap that allows researchers to achieve reliable epidemiological replication, target specific assays for future optimization, and prioritize biological signal over platform noise.

bioinformatics↗

bioRxiv2026

Neuromodulation of Foxp2+ hypothalamic neurons induces therapeutic hypothermia

The inability to selectively trigger therapeutic hypothermia independent of environmental cooling has hindered causal analysis of its broader physiological benefits. Here, we employed P57, a natural product that pharmacologically induces therapeutic hypothermia circumventing external cold stress, to identify the neuronal substrates underlying hypothermia-induced antitumor effects. Integrating functional ultrasound imaging, activity-dependent neuronal labeling, and single-nucleus RNA sequencing, we identify a previously unrecognized population of Foxp2 neurons in the medial preoptic area (MPA) that are selectively activated by P57. Inhibition of MPA Foxp2+ neurons abolishes P57-induced hypothermia, whereas the paraventricular hypothalamus (PVH) serves as a critical downstream node. Importantly, targeted activation of MPA Foxp2 neurons is sufficient to induce sustained hypothermia, suppress systemic metabolism, and inhibit tumor growth, providing causal evidence that neuronally driven reductions in core body temperature can exert antitumor effects. Together, these findings establish MPA Foxp2 neurons as a controllable node for therapeutic hypothermia induction and demonstrate that neuromodulation of defined neuronal populations can achieve therapeutic benefit by directly controlling physiological states.

neuroscience↗

bioRxiv2026

Landscape-scale navigation unlocks antibody CDR structural logic for AI-guided rescue and therapeutic optimization

While AI offers transformative potential for therapeutic antibody design, the lack of ground-truth data fundamentally constrains our ability to model the epistatic topology of fitness landscapes. Here, we establish a high-throughput workflow to characterize tens of thousands of antibody variants per week with gold-standard biophysical precision. By combinatorially assembling functional variants from deep mutational scanning, we charted antibody fitness landscapes comprising over 17,000 data points, which revealed an extremely rugged, non-navigable epistatic topology. Yet, navigating at this unprecedented scale enabled the discovery of rare peak clusters exhibiting simultaneous enhancements in affinity and productivity. Strikingly, ProteinMPNN predicted the CDR-dependent productivity landscape with remarkable accuracy, suggesting that sequence-structure compatibility within CDRs gates cellular productivity. This insight enabled a structure-guided rescue strategy combining AlphaFold3 and ProteinMPNN, which successfully restored the cellular productivity of high-affinity, low-productivity clones via single amino acid substitutions. Two elite variants drawn directly from peak clusters further demonstrated 20- to 100-fold in vivo efficacy gains in a murine psoriasis model. Our findings establish CDR structural fitness as a fundamental determinant of antibody cellular productivity and validate landscape-scale navigation as a powerful framework for therapeutic antibody optimization.

bioengineering↗

bioRxiv2026

Development of a Humanized Anti-Fibrotic Antibody Targeting Extracellular Collagen Assembly to Reduce Post-Traumatic Scarring

BackgroundExcessive accumulation of fibrillar collagen causes pathological scarring and fibrosis. A promising anti-fibrotic strategy targets the extracellular assembly of collagen fibrils rather than intracellular synthesis pathways. We previously developed a chimeric monoclonal antibody targeting the C-terminal telopeptide of the 2(I) chain of human collagen I that effectively disrupts fibrillogenesis. This study details the engineering of a humanized antibody variant optimized for therapeutic application, augmented with a collagen-binding peptide (CBP) to enhance targeted retention in fibrotic tissues. MethodsA humanized ACA was engineered by in silico homology modeling, complementarity-determining region grafting, and sequence optimization to eliminate chemical liabilities. Variants were expressed in mammalian cells and evaluated for binding kinetics and specificity. To improve spatial localization, the CBP was fused to the antibody. The lead variant was assessed for in vitro cytotoxicity, matrix retention, and in vivo efficacy using a rabbit model of post-traumatic knee arthrofibrosis. ResultsThe humanized ACA variants maintained high specificity and affinity for the 2Ct target domain. Fusing the CBP to the C-terminus of the light chain (C-cbpACA) successfully enhanced matrix retention without compromising target engagement or causing cellular toxicity. In the rabbit arthrofibrosis model, intra-articular C-cbpACA delivery significantly reduced flexion contracture and decreased total collagen deposition in the joint capsule compared to untreated controls. ConclusionWe successfully engineered a clinically viable, humanized, and matrix-targeted anti-fibrotic antibody that specifically inhibited extracellular collagen assembly and exhibited enhanced localization within fibrotic tissues. This construct represents a promising therapeutic strategy for mitigating pathological scarring and improving post-traumatic functional outcomes.

pathology↗

bioRxiv2026

Neurodegeneration risk variants promote lysosomal TMEM106B fibrilaccumulation

Variants in TMEM106B and GRN, which encode lysosomal proteins, interact through unknown mechanisms to increase the risk of age-related cognitive decline and neurodegeneration. Here, we show that these variants converge on a single molecular intermediate: the cleaved intra-lysosomal fibril core of TMEM106B, a precursor to amyloid fibrils that accumulate in the aging brain. A protein-coding TMEM106B risk variant (p.T185) drives fibril core accumulation by impairing its degradation and GRN risk variants amplify this effect. Mice over-expressing the fibril core develop hallmarks of neurodegeneration, and cryo-electron tomography reveals intra-lysosomal fibrils in cultured neurons, mice, and diseased human brain. In GRN-mutation carriers, in whom fibril burden is greatest, fibrils extrude through ruptured lysosomal membranes. These findings identify intra-lysosomal TMEM106B fibrillization as a convergent neurodegeneration mechanism and potential therapeutic target.

cell biology↗

bioRxiv2026

Effects of the Coenzyme Q10 Analog 6-Bromo-ubiquinone (6-Br-Q0C10) on Mammalian Cell Growth

Synthetic 6-Br-Q0C10 has been shown to exhibit a partial electron transfer activity of native coenzyme Q in the isolated mitochondria. It reduces energy coupling efficiency by approximately 30%, suggesting that it may be useful in modulating cell growth in tissue culture. Whether or not it behaves in the same way in the whole cells, or animal, however, has not yet been fully examined. Recently we have investigated the effect of 6-Br-Q0C10 across multiple cell lines using three detection methods. Treatment with 6-Br-Q0C10 reduces cell proliferation in all cell lines tested, with different effectiveness. Obesity-related cell lines were the most susceptible, and a pronounced inhibitory effect was also observed in cancer cell lines. These results strengthen the idea of using 6-Br-Q0C10 to manage obesity or to retard the growth of rate cancer cells and thus prolonging life.

biochemistry↗

bioRxiv2026

Real-Time Cell Analysis Reveals Distinct Roles of S100A4 in Regulating Proliferation, Migration, and Invasion of JAR Choriocarcinoma Cells

S100A4, a metastasis promoting calcium binding protein, drives tumor progression through pleiotropic mechanisms, yet its context dependent functions in gestational malignancies remain elusive. To dynamically decode its role in choriocarcinoma pathogenesis, we leveraged label free real time cell analysis (RTCA) to profile malignant phenotypes in JAR cells following siRNA mediated S100A4 silencing, complemented by apoptosis assessment and targeted signaling profiling. Efficient knockdown (verified by qPCR/Western blotting) significantly attenuated cellular proliferation (96 hr cell index slope decreased vs. scramble control; p<0.01) and suppressed migration capacity (p<0.01). Critically, S100A4 depletion did not induce apoptosis (flow cytometry and cleaved caspase 3/9 blotting confirmed no significant change), and invasion through Matrigel coated membranes remained statistically unaltered despite comparable experimental rigor. Mechanistically, S100A4 silencing triggered adaptive signaling rewiring: IRS1 and PI3K expression were elevated, Akt1 was suppressed, while MEK1/2 remained unchanged suggesting compensatory pathway activation.

cell biology↗

bioRxiv2026

Explaining the unexplained admixture mapping signals via rare variants: the HCHS/SOL

In admixed populations, formed by a mixing of two or more previously isolated populations, genomic segments can be traced to their ancestral populations ("ancestries"). Admixture mapping (AM) associates local ancestry with outcomes in admixed populations, detecting signals when causal variants differ in frequency or effect across ancestral populations. Prior work showed that adjusting for nearby GWAS-identified common variants does not fully explain some AM signals. Here, we assessed two approaches to explain the previously unexplained AM signal: (1) including sets of rare variants; (2) increasing the genomic region considered when searching for common variants. We studied these hypotheses comprehensively using a whole-genome sequencing dataset coupled with metabolomics from the Hispanic Community Health Study/Study of Latinos. We detected multiple sets of rare variants with replicated association with metabolite levels. Yet these rare variants appear to explain only a small fraction of the AM signal, while inclusion of common variants from a larger genomic region appears to explain the majority of the AM signals.

genetics↗

bioRxiv2026

How the olfactory bulb maintains stable odor manifolds amid adaptation and representational drift

Adaptive coding in sensory circuits enables stable perception while accommodating experience-dependent changes. In the olfactory bulb (OB), repeated odor exposure reshapes population activity even without explicit behavioral feedback, but the underlying circuit mechanisms remain unclear. By analyzing longitudinal two-photon calcium imaging datasets from the mouse OB, we identified three concurrent forms of representational change: gain adaptation, similarity-dependent pattern separation or convergence, and a rotation of encoding subspace resulting in the representational drift. Using a computational model of the mitral cell-granule cell circuit, we showed that Hebbian plasticity and structural connectivity constraints are sufficient to reproduce these transformations. Despite global representational drift, the relative geometry of odor response vectors remained stable, preserving a low-dimensional odor manifold. Together, our results reveal how local plasticity and network structure jointly enable both stability and flexibility in early sensory coding.

neuroscience↗

bioRxiv2026

Urine Recirculation During Normothermic Kidney Preservation Improves Energy Balance Involving the Urea and TCA Cycles

BackgroundDeceased donor kidneys experience cellular stress before undergoing transplantation. To alleviate this, preservation techniques were developed including normothermic machine perfusion (NMP). MethodsHere, we performed kidney NMP on discarded human kidneys for up to 24 hours. Volume management was regulated either by urine recirculation (UR) or urine replacement (NUR) with Ringers lactate. Notably, UR led to longer perfusion times compared to NUR. To investigate kidney NMP metabolic traits with or without UR over time, we performed longitudinal metabolomics analyses of perfusates of eight NMP kidneys by 2D-gas chromatography mass spectrometry (GCxGC-MS). ResultsOver 600 metabolic features were profiled, from which 74 were identified and 54 consistently quantified across 26 perfusate samples. Most notably, elevated levels of disaccharides (different isomers), hydroxy-purines, urea, glutamate and amino acids associated with the perfusion factor UR. Moreover, donor estimated glomerular filtration rate (eGFR) correlated significantly with the accumulation of lactate and gluconate. Most strikingly, lactate levels seemed to be more balanced in UR NMP perfusate, which otherwise accumulated rapidly within the first six hours. ConclusionsKidney preservation by NMP was previously limited to hours. UR-NMP affected kidney energy homeostasis, carbohydrate & purine metabolism and the Urea and TCA cycles. These insights add value to explain how urine-driven adaptations contribute to prolonged kidney function under NMP. Research in contextO_ST_ABSEvidence before this studyC_ST_ABSDeceased donors provide kidneys that experience cellular stress during retrieval and during transplantation. To attenuate tissue damage, preservation techniques were optimised to offer the most optimal environment for kidney organs retrieved from donation after circulatory death and brain death patients. Normothermic machine perfusion (NMP) of donor kidneys has been considered feasible, safe, offers viability assessment and contributes to favourable outcomes. However, there has been a limit in the length of time that this preservation method could be applied to kidney organs, thereby potentially restricting functional recovery of the kidney before organ transplantation. Added value of this studyBefore urine recirculation (UR) was introduced, NMP time was limited to a few hours. Remarkably, NMP with UR led to longer perfusion times and more stable kidney organ function as compared to no urine recirculation (NUR). In order to find out why, we compared urine recirculation with Ringers lactate solution for volume management during NMP on discarded human kidneys for up to 24 hours. Kidney NMP metabolic traits with or without UR over time were measured. More than 600 metabolic features were profiled, Most strikingly, lactate levels seemed to be more balanced in UR NMP perfusate of the course of 24 hours, which otherwise accumulated rapidly within the first six hours. Taken together, UR-NMP affected kidney energy metabolic pathways and rendering these more balanced. Ultimately, these urine-driven adaptations contribute to prolonged kidney function under NMP. Implications of all the available evidenceNMP as a procedure to preserve kidney organs including urine recirculation is now becoming standard in many transplantation units around the world. Our study provided a molecular snapshot of why kidney organs preserved in this way are maintained longer with a functionally active metabolism. This provides the basis for additional improvements leading to better kidney organ preservation, ultimately resulting in benefits for kidney transplant recipients.

pathology↗

bioRxiv2025

CausalGRN: deciphering causal gene regulatory networks from single-cell CRISPR screens

Large-scale single-cell CRISPR screens with single-cell RNA-seq (scRNA-seq) readouts provide critical data to map causal gene regulatory networks (GRNs). However, translating the complex scRNA-seq outputs into reliable causal insights remains a major analytical challenge. Here we present CausalGRN, a scalable computational framework that infers causal GRNs and predicts cellular responses to unseen perturbations. CausalGRN first mitigates pervasive spurious partial correlations in sparse scRNA-seq data through a novel adaptive thresholding correction, enabling robust inference of an undirected graph. It then orients this graph using observed perturbation outcomes. The resulting directed GRN can be used to predict the downstream effects of novel perturbations via network propagation. Across both simulations and diverse experimental datasets, CausalGRN substantially outperforms existing approaches in network reconstruction accuracy and in predicting the effects of unseen perturbations, providing a principled bridge from perturbation data to causal gene regulation.

bioinformatics↗

bioRxiv2025

Cysteine protease cathepsin B promotes high population density-induced mutagenesis, driving genome evolution and competitive growth in response to the crowding stress

In a wide variety of species from invertebrates to mammals, overpopulation has been shown to induce low fertility and high mortality. Although density-dependent population regulation is widespread in the animal kingdom, the underlying molecular mechanisms remain poorly understood. We show here that C. elegans animals respond to the crowding stress by secreting CPR-4, a homologue of human cathepsin B cysteine protease, to promote chromosomal DNA damage in germ cells, leading to high density-induced deficiencies that include increased embryonic lethality and larval arrest and decreased brood size. CPR-4 mediates these crowding responses through the insulin-like growth factor receptor DAF-2, multiple components in the insulin signaling pathway, and the SKN-1/Nrf transcription factor. Whole genome sequencing analyses of animals from 10 generations of continual growth in the crowded condition reveal that CPR-4-induced DNA damage produces an average of 2.9 more de novo genome mutations per animal per generation and a 75% increase in mutation rate compared with animals grown in the uncrowded condition. CPR-4-induced mutagenesis also facilitates evolution of the genomes through multi-generational crowding selection, leading to biased mutation distributions towards the intergenic regions over the gene bodies and crowd-inducible growth advantage. Our findings suggest that CPR-4 acts as a crucial crowd-responding factor to induce chromosomal DNA damage, leading to density-dependent deficiencies, increased genome mutation rates, and genome evolution and competitive growth of animals in response to the crowding stress.

developmental biology↗

bioRxiv2025

Fast scanning small angle X-ray scattering of hydrated biological cells

Due to their high penetration depth, X-rays enable us to obtain information from the interior of whole, unsliced cells. Scanning small angle X-ray scattering (SAXS), in particular, reveals real-space images in dark field representation as well as structural information in reciprocal space. However, obtaining information on anisotropy and orientation from cells in an aqueous, close-to-physiological environment remains challenging. Here, we extend the recently introduced fast scanning SAXS mode with short exposure times of few milliseconds to such hydrated samples by combining a newly developed, X-ray compatible microfluidic sample chamber and innovative data analysis that includes an effective noise-filtering method. This strategy enables the systematic analysis of radiation damage by quantifying the SAXS signal. Our results demonstrate that scanning SAXS can be used to obtain intracellular information of fixed-hydrated cells and the approach may in the future be applicable to living cells as well. SynopsisFast scanning SAXS on biological cells in aqueous environment reveals intracellular anisotropy and orientation and allows for systematic assessment of radiation damage caused by the measurements.

biophysics↗