Biology subjects

Wen, P.

Publications and source records attributed to Wen, P..

11 recordsLinked to original sources

bioRxiv2026

A High-Fidelity 3D Fluid-Structure Interaction Framework for Predictive Microfluidic Design

The commercial maturation of microfluidics remains bottlenecked by empirical prototyping and an absence of predictive digital design capabilities. Because optimizing advanced technologies such as passive particle separation fundamentally hinges on the precise coupling of fluid dynamics and particle mechanics, conventional two-dimensional or decoupled fluid simulations inherently fail to capture authentic multiscale behaviors. To bridge this gap, we establish a high-fidelity three-dimensional fluid-structure interaction framework combining a high-order Arbitrary Lagrangian-Eulerian mapping-based finite element method with a localized hierarchical dynamic mesh strategy. Engineered to accurately resolve complex multiscale hydrodynamics, this architecture utilizes deterministic lateral displacement structures as a stringent test case. Validated against experimental data for rigid microspheres and tumor cells, the framework predicts transport trajectories and critical separation diameters with sub-micron precision. Crucially, the simulation explicitly resolves the M-shaped spatial fluctuation of local size thresholds alongside the dynamic vertical migration of particles. Unveiling these hidden physical mechanisms provides a deterministic explanation for highly debated phenomena such as mixed-mode transport. By enabling the rigorous in silico evaluation of complex non-periodic architectures, this framework serves as a powerful instrument for predictive structural optimization. Such capabilities establish the essential infrastructure for microfluidic digital design, accelerating the transition from empirical trial-and-error to precision simulation-driven engineering.

bioengineering↗

bioRxiv2025

Multi-omics reveals lipid metabolism, mitochondrial and extracellular matrix dysregulation of diabetic cardiomyopathy in the human heart

Diabetic cardiomyopathy (DbCM) is a condition characterized by myocardial dysfunction in diabetes. Although the clinical recognition of DbCM is increasing, its underlying molecular mechanisms remain poorly understood. We aimed to conduct a comprehensive multi-omics analysis of heart tissue from cardiomyopathy patients (both with and without diabetes),alongside tissue from healthy donors, by integrating transcriptomic, 4D-DIA proteomic, and full-spectrum widely targeted metabolomic data. Differential analyses revealed a significant metabolic pattern in patients with DbCM, characterized by increasing utilization of triglyceride-derived fatty acids. Correlation analyses highlighted impaired BNIP3L-mediated mitophagy as a potential contributor to the disruption of fatty acid metabolism and mitochondrial dysfunction in DbCM. Protein interaction and fibrotic trichrome analyses showed that patients with DbCM had impaired cardiac matrix repair compared to patients with cardiomyopathy without diabetes. These findings provide a system-level understanding of DbCM and reveal molecular signatures driving its progression, offering insights for targeted therapeutic strategies against diabetic heart disease.

bioinformatics↗

bioRxiv2025

High-speed mapping of whole-mouse peripheral nerves at subcellular resolution

In contrast to the rapid advancements in mesoscale connectomic mapping of the mammalian brain, similar mapping the peripheral nervous system has remained challenging due to the bodys size and complexity. Here, we present a high-speed blockface volumetric imaging system with an optimized workflow of whole-body clearing, capable of imaging the entire adult mouse at micrometer resolution within 40 hours. Three-dimensional reconstruction of individual spinal fibers in Thy1-EGFP mice reveals distinct morphological features of sensory and motor projections along the ventral and dorsal rami. Immunostaining facilitates body-wide mapping of sympathetic nerves and their branches, highlighting their perivascular patterns in limb muscles, bones, and most visceral organs. Viral tracing elucidates the fine architecture of vagus nerves and individual vagal fibers, revealing unexpected projection routes to various organs. Our approach offers an effective means to achieve a holistic understanding of cellular-level interactions among different systems that underlie body physiology and disease. HighlightsO_LIImaging of whole adult mouse at uniform subcellular resolution within 40 hours C_LIO_LIReconstruction of 191 thoracic spinal neuron projections for Thy1-EGFP mice C_LIO_LIMapping of immunolabeled sympathetic projections and their perivascular patterns C_LIO_LIResolving virus-labeled architecture of vagus nerves and complex single-fiber routes C_LI

neuroscience↗

bioRxiv2024

Functional localization of visual motion area FST in humans

The fundus of the superior temporal sulcus (FST) in macaques is implicated in the processing of complex motion signals, yet a human homolog remains elusive. Here we considered potential localizers and evaluated their effectiveness in delineating putative FST (pFST), from hMT and MST, two nearby motion-sensitive areas in humans. Nine healthy participants underwent scanning sessions with 2D and 3D motion localizers, as well as population receptive field (pRF) mapping. We observed consistent anterior and inferior activation relative to hMT and MST in response to stimuli that contained coherent 3D, but not 2D, motion. Motion opponency and myelination measures further validated the functional and structural distinction between pFST and hMT/MST. At the same time, standard pRF mapping techniques that reveal the visual field organization of hMT/MST proved suboptimal for delineating pFST. Our findings provide a robust framework for localizing pFST in humans, and underscore its distinct functional role in motion processing.

neuroscience↗

bioRxiv2024

Acetylcholine modulates prefrontal outcome coding during threat learning under uncertainty

Outcomes can vary even when choices are repeated. Such ambiguity necessitates adjusting how much to learn from each outcome by tracking its variability. The medial prefrontal cortex (mPFC) has been reported to signal the expected outcome and its discrepancy from the actual outcome (prediction error), two variables essential for controlling the learning rate. However, the source of signals that shape these coding properties remains unknown. Here, we investigated the contribution of cholinergic projections from the basal forebrain because they carry precisely timed signals about outcomes. One-photon calcium imaging revealed that as mice learned different probabilities of threat occurrence on two paths, some mPFC cells responded to threats on one of the paths, while other cells gained responses to threat omission. These threat- and omission-evoked responses were scaled to the unexpectedness of outcomes, some exhibiting a reversal in response direction when encountering surprising threats as opposed to surprising omissions. This selectivity for signed prediction errors was enhanced by optogenetic stimulation of local cholinergic terminals during threats. The enhanced threat-evoked cholinergic signals also made mice erroneously abandon the correct choice after a single threat that violated expectations, thereby decoupling their path choice from the history of threat occurrence on each path. Thus, acetylcholine modulates the encoding of surprising outcomes in the mPFC to control how much they dictate future decisions.

neuroscience↗

bioRxiv2024

A Drosophila model to screen Alport syndrome COL4A5 variants for their functional pathogenicity

Alport syndrome is a hereditary chronic kidney disease, attributed to rare pathogenic variants in either of three collagen genes (COL4A3/4/5) with most localized in COL4A5. Trimeric type IV Collagen 345 is essential for the glomerular basement membrane that forms the kidney filtration barrier. A means to functionally assess the many candidate variants and determine pathogenicity is urgently needed. We used Drosophila, an established model for kidney disease, and identify Col4a1 as the functional homolog of human COL4A5 in the fly nephrocyte (equivalent of human podocyte). Fly nephrocytes deficient for Col4a1 showed an irregular and thickened basement membrane and significantly reduced nephrocyte filtration function. This phenotype was restored by expressing human reference (wildtype) COL4A5, but not by COL4A5 carrying any of three established pathogenic patient-derived variants. We then screened seven additional patient COL4A5 variants; their ClinVar classification was either likely pathogenic or of uncertain significance. The findings support pathogenicity for four of these variants; the three others were found benign. Thus, demonstrating the effectiveness of this Drosophila in vivo kidney platform in providing the urgently needed variant-level functional validation. SUMMARY STATEMENTDrosophila, an established model of kidney disease, was used to develop an in vivo functional screen to determine causation for COL4A5 genetic variants linked to Alport syndrome, a progressive nephropathy.

genetics↗

bioRxiv2022

Structural basis for BIRC6 to balance apoptosis and autophagy

Caspase-9 is the initiator caspase for the intrinsic apoptotic cell death pathway, and is critical to the activation of effector caspases during apoptosis, but how its levels and activities are maintained remains unclear. The gigantic Inhibitor of Apoptosis Protein (IAP) BIRC6/BRUCE/Apollon not only inhibits apoptosis, but also promotes ubiquitination of the key autophagic protein LC3 and inhibits autophagy. Here we show that BIRC6 forms an anti-parallel U-shaped dimer in a 3.6-[A] cryo-EM structure with multiple previously unannotated domains, including a ubiquitin-like domain, and discover that the mitochondria-derived pro-apoptotic factor Smac/DIABLO binds BIRC6 by interacting with one BIR domain, two carbohydrate-binding modules and two helices in the central cavity. Notably, Smac outcompetes the effector caspase 3 and the pro-apoptotic protease HtrA2, but not caspase 9, for binding BIRC6. BIRC6 strongly inhibits cellular activity of caspase 9, but weakly suppresses that of caspase 3. Meanwhile, BIRC6 binds LC3 through an LC3-interacting region, probably following dimer disruption of this BIRC6 region. Deficiency in LC3 ubiquitination promotes autophagy and autophagic degradation of BIRC6, and inhibits apoptosis. Moreover, induction of autophagy promotes autophagic degradation of both procaspase-9 and active caspase-9, but not of effector caspases. These results are important to understand how the balance between apoptosis and autophagy is regulated under pathophysiological conditions.

cell biology↗

bioRxiv2022

Identifying cortical areas that underlie the transformation from retinal to world motion signals

Accurate motion perception requires that the visual system integrate the retinal motion signals received by the two eyes into a single representation of 3D (i.e., world) motion. However, most experimental paradigms limit the motion stimuli to the fronto-parallel plane (i.e., 2D motion) and are thus unable to dissociate retinal and world motion signals. Here, we used stereoscopic displays to present separate motion signals to the two eyes and examined their representation in visual cortex using fMRI. Specifically, we presented random-dot motion stimuli that produced percepts of various 3D motion trajectories. We also presented control stimuli that contained the same retinal motion energy in the two eyes but were inconsistent with any 3D motion trajectory. We decoded the stimuli from BOLD activity using a probabilistic decoding algorithm. We found that 3D motion direction can be reliably decoded in three major clusters in the human visual system. In early visual cortex (V1-V3), we found no significant difference in decoding performance between the 3D motion and control stimuli, suggesting that these areas represent retinal motion rather than world motion signals. In voxels in and surrounding hMT and IPS0 however, decoding performance was consistently superior for 3D motion compared to control stimuli. Our results reveal the parts of the visual processing hierarchy that are critical for the transformation of retinal into world motion signals and suggest a role for IPS0 in the representation of 3D motion signals, in addition to its sensitivity to 3D object structure and static depth.

neuroscience↗

bioRxiv2022

Mapping genomic regulation of kidney disease and traits through high-resolution and interpretable eQTLs

Expression quantitative trait locus (eQTL) studies illuminate genomic variants that regulate specific genes and contribute to fine-mapped loci discovered via genome-wide association studies (GWAS). Efforts to maximize their accuracy are ongoing. Using 240 glomerular (GLOM) and 311 tubulointerstitial (TUBE) micro-dissected samples from human kidney biopsies, we discovered 5,371 GLOM and 9,787 TUBE eQTLs by incorporating kidney single-nucleus open chromatin data and transcription start site distance as an "integrative prior" for Bayesian statistical fine mapping. The use of an integrative prior resulted in higher resolution eQTLs illustrated by (1) smaller numbers of variants in credible sets with greater confidence, (2) increased enrichment of partitioned heritability for GWAS of two kidney traits, (3) an increased number of variants colocalized with the GWAS loci, and (4) enrichment of computationally predicted functional regulatory variants. A subset of variants and genes were validated experimentally in vitro and using a Drosophila nephrocyte model. More broadly, this study demonstrates that tissue-specific eQTL maps informed by single-nucleus open chromatin data have enhanced utility for diverse downstream analyses.

genomics↗

bioRxiv2020

HGF-induced activation of NEPHRIN and NEPH1 serves as a novel mechanism for recovery of podocytes from injury

When activated, slit diaphragm proteins NEPHRIN and NEPH1 enable signaling pathways leading to podocyte actin cytoskeleton reorganization, which is critical for podocyte recovery from injury. However, the mechanisms through which these proteins are activated remain unknown. This study presents a novel concept showing ligand-induced activation of NEPHRIN and NEPH1. We first identified phosphatase SHP-2, which directly dephosphorylated these proteins. We next identified HGF, a known SHP-2 modulator, as a rapid inducer of NEPHRIN and NEPH1 phosphorylation. Using baculovirus expressed recombinant purified proteins, SPR (surface plasma resonance), molecular modeling and peptide binding approaches, we show that HGF directly binds NEPHRIN and NEPH1 extracellular domains. Further, using cultured podocytes and Drosophila nephrocytes, we demonstrate that while HGF treatment repaired injured podocytes, the addition of inhibitory NEPH1 or NEPHRIN peptides blocked HGF-induced recovery. Overall, this study shows novel activation and deactivation mechanisms for NEPHRIN and NEPH1 that are required for their function.

cell biology↗

bioRxiv2020

Death recognition by undertaker bees

Dead conspecifics removal is important of being social to avoid pathogen transmission, which resulted in the evolution of a specific caste of undertaking workers in all hives bee species. However, it is mysterious that how the undertakers distinguish death and life instantly. Through integrative studies of behavioural tests and chemical analyses, a novel mechanism for dead conspecifics recognition is found in the Asian bee Apis cerana cerana Fabricius. The bees detect quickly the death of conspecifics based on decreased cuticular hydrocarbon (CHC) emissions, caused by the cooling of the dead bee. Specifically, with the decline of body temperature in death, the CHC emission was reduced. Undertakers perceived the major CHCs. Addition of synthetic CHCs, followed by heating, inhibited undertaking behaviour. Among these CHCs, heptacosane and nonacosane are the major compounds in a natural bee hive, providing a continuous signal associated with life. Via changing the vapour pressure then the ratio of emitted compounds encoding the physiological status of signal sender, insect chemical communication can be finely tuned by body temperature. This straightforward death recognition mechanism requiring little cost can be universal in animal living in social groups, especially in the social insects. Body temperature affected behaviour can response to increasing frequency of extreme weathers in global climate change, which help explain the recent worldwide bee health problem.

animal behavior and cognition↗