Biology subjects

Yang, H.

Publications and source records attributed to Yang, H..

At least 199 records · Page 11Linked to original sources

bioRxiv2025

Multiple interactions mediate the localization of BLTP2 at ER-PM contacts to control plasma membrane dynamics

BLTP2/KIAA0100, a bridge-like lipid transfer protein, was reported to localize at contacts of the endoplasmic reticulum (ER) with either the plasma membrane (PM) or recycling tubular endosomes depending on the cell type. Our findings suggest that mediating bulk lipid transport between the ER and the PM is a key function of this protein as BLTP2 tethers the ER to tubular endosomes only after they become continuous with the PM and that it also tethers the ER to macropinosomes in the process of fusing with the PM. We further identify interactions underlying binding of BLTP2 to the PM, including phosphoinositides, the adaptor proteins FAM102A and FAM102B, and also N-BAR domain proteins at membrane-connected tubules. The absence of BLTP2 results in the accumulation of intracellular vacuoles, many of which are connected to the plasma membrane, pointing to a role of the lipid transport function of BLTP2 in the control of PM dynamics.

cell biology↗

bioRxiv2025

ATP-sensitive isoforms of P2X5: A reevaluation of its function across species

The P2X receptor family comprises ATP-gated non-selective cation channels central to physiological processes across the nervous, immune, cardiovascular, respiratory, and reproductive systems. While P2X1, P2X2, P2X3, P2X4, and P2X7 are well-established as ATP-sensitive, P2X5 isoforms and transcript variants (TVs) have traditionally been considered ATP-insensitive, limiting their functional exploration. This study identifies previously overlooked ATP-sensitive P2X5 isoforms across diverse species. Through gene profiling and next-generation sequencing (NGS), we found that the zfP2X5TV2 isoform dominates ATP-sensitive forms in zebrafish. In mice, ATP-sensitive mP2X5G317 (mP2X5.1) comprises [~]90% of transcripts, while in rats, exon 3-containing rP2X5F191 accounts for over 70%. In human cell lines, ATP-sensitive isoforms retaining exons 3, 7, and 10 represent [~]15-30% of P2X5 transcripts. RNA-seq from human tissues confirms frequent retention of exons 3 and 7 and polymorphic exon 10 expression. ATP-sensitive P2X5 variants were also identified in chickens, bullfrogs, dogs, cows, and naked mole-rats. These findings challenge the prevailing assumption of ATP-insensitivity, highlighting the need to reassess P2X5s roles in physiological and pathological contexts.

physiology↗

bioRxiv2025

SAMHD1 enhances HIV-1-induced apoptosis in monocytic cells via the mitochondrial pathway

Sterile alpha motif (SAM) and histidine-aspartate (HD) domain-containing protein 1 (SAMHD1) inhibits HIV-1 replication in non-dividing cells by reducing the intracellular dNTP pool. SAMHD1 enhances spontaneous apoptosis in cells, but its effects on HIV-1-induced apoptosis and the underlying mechanisms remain unknown. Here we uncover a new mechanism by which SAMHD1 enhances HIV-1-induced apoptosis in monocytic cells through the mitochondrial pathway. We found that endogenous SAMHD1 enhances apoptosis levels induced by HIV-1 infection in dividing THP-1 cells. Mechanistically, SAMHD1 expression decreases the mitochondrial membrane potential and promotes cytochrome c release induced by HIV-1 infection in THP-1 cells, thereby enhancing mitochondrial apoptotic pathway. SAMHD1-enhanced apoptosis is associated with increased expression of the pro-apoptotic protein BCL-2-interacting killer (BIK) in cells. We further demonstrated that BIK contributes to SAMHD1-enhanced apoptosis during HIV-1 infection. Overall, our results reveal an unappreciated regulatory mechanism of SAMHD1 in enhancing HIV-1-induced apoptosis via the mitochondrial pathway in monocytic cells.

microbiology↗

bioRxiv2025

ORP2 regulates free cholesterol accumulation in hepatocytes during MASH

BackgroundCholesterol crystals in hepatocytes are known to strongly associate with human Metabolic Dysfunction-Associated Steatohepatitis (MASH). However, it remains unclear which molecular pathway(s) regulates free cholesterol accumulation, and therefore the formation of cholesterol crystals in hepatocytes. In cultured cell lines, oxysterol-binding protein-related protein 2 (ORP2) functions to deliver cholesterol to the plasma membrane from internal organelles. MethodsHere, we generated liver-specific ORP2 knockout (ORP2-LKO) mice and characterized their metabolic phenotypes on chow and high fat diet. ResultsThe ORP2-LKO mice developed much more severe hepatic steatosis than wild type mice after high-fat diet feeding. They also demonstrated more severe liver inflammation and damage. Notably, free but not esterified cholesterol, as well as cholesterol crystals accumulated in ORP2-LKO liver. The expression of Cyp7a1 was significantly upregulated in ORP2-LKO liver, accompanied with accumulation of taurocholic acid. Our results thus unveil an important in vivo function of ORP2 in preventing free cholesterol from accumulating in mouse liver. Conclusionsour results suggest that impaired cholesterol trafficking may enhance the deposition of cholesterol crystals in hepatocytes, promoting the development of MASH.

cell biology↗

bioRxiv2025

Boosting the detection of enhancer-promoter loops via novel normalization methods for chromatin interaction data

Accurately detecting enhancer-promoter loops from genome-wide interaction data, such as Hi-C, is crucial for understanding gene regulation. Current normalization methods, such as Iterative Correction and Eigenvector decomposition (ICE), are commonly used to remove biases in Hi-C data prior to chromatin loop detection. However, while structural or CTCF-associated loop signals are retained, enhancer-promoter interaction signals are often greatly diminished after ICE normalization and similar methods, making these regulatory loops harder to detect. To address this limitation, we developed Raichu, a novel method for normalizing chromatin contact data. Raichu identifies nearly twice as many chromatin loops as ICE, recovering almost all loops detected by ICE and revealing thousands of additional enhancer-promoter loops missed by ICE. With its enhanced sensitivity for regulatory loops, Raichu detects more biologically meaningful differential loops between conditions in the same cell type. Furthermore, Raichu performs consistently across different sequencing depths and platforms, including Hi-C, HiChIP, and single-cell Hi-C, making it a versatile tool for uncovering new insights into three- dimensional (3D) genomic organization and transcriptional regulation.

bioinformatics↗

bioRxiv2024

Structural basis of phosphate export by human XPR1

Phosphate is essential for all life forms because of its indispensable roles in energy metabolism, nucleic acid and phospholipid synthesis, cellular signaling, and the formation of bones and teeth. Its homeostasis is maintained through balanced import and export processes. In humans, XPR1 has been proposed as the sole phosphate exporter, although some controversy remains. Here, we report the closed and open structures of human XPR1, purified in the absence and presence of exogenous InsP6, respectively. The exporter forms a symmetric homodimer, with transmembrane helix (TM) 1 serving as the dimeric interface. The transmembrane domain of each protomer contains a transport module (TM5-10) and a supporting module (TM1-4). Compared to the closed XPR1, the open structure demonstrates a significant displacement of the extracellular portion of TM9 towards the periphery of the phosphate transport pathway, creating an open portal to the extracellular milieu. Additionally, a potential phosphate ion coordination site is strategically located in the middle of the transport pathway. On the intracellular side, the pathway entrance is obstructed by a cluster of residues, the C-plug, positioned on the carboxyl side of TM10. Consistently, the removal of the C-terminus significantly increases the transport activity of XPR1 in reconstituted liposomes. Our findings provide a comprehensive understanding of the export mechanism of human XPR1 and hold promise for the development of potential therapeutics for primary familial brain calcification and ovarian cancer.

biochemistry↗

bioRxiv2024

Engineering tissue-mimetic hydrogels with continuous viscoelastic gradient for programmed cell migration

The dynamic, viscoelastic nature of the extracellular matrix (ECM), with variations in stiffness and viscosity, plays a key role in cellular behaviors like mechano-sensing, migration, and force generation. Viscoelastic hydrogels are important for mimicking the ECM to study cell migration and tissue engineering. However, creating hydrogels with continuous viscoelastic gradients is challenging due to issues with spatial resolution, reproducibility, and accurately replicating native tissue properties. Here we present a novel approach to generate hydrogels with precisely controllable viscoelastic gradients using drop-by-drop condensation. This approach allows fine-tuned replication of the tissue-specific local mechanical properties, resulting in hydrogels of heterogeneous viscoelasticity. Directed migration and separation of multiple cell lines are thus driven by local viscosity and elasticity rather than solely stiffness. By incorporating non-linear mechanical gradients, this technique provides insights into ECM viscoelasticitys role in cellular behavior and offers a versatile platform for advanced tissue engineering and regenerative medicine applications.

biophysics↗

bioRxiv2024

Chicken shank color determined by Inhibition of dermal melanin (ID) is mediated by a structural variation regulating CDKN2A expression

It is well established that the color of a chickens shank is primarily determined by four genetic loci. Among these, the Inhibition of dermal melanin (ID) locus, which suppresses black pigmentation in the dermal layer of the shank, is the sole sex-linked mutation and its molecular mechanisms remained elusive. In this study, a resource family with segregating shank colors was constructed. A genome-wide association study utilizing FarmCPU software identified a top-associated SNP located on the Z chromosome. Subsequent linkage mapping further refined the candidate region, enabling the screening of the candidate structural variation. The candidate structural variation is associated with the yellow shank and characterized by a 143 bp deletion accompanied by a 2 bp insertion. Within the same Topologically Associating Domain, only the CDKN2A gene showed differential expression. Functional studies, including CRISPR/Cas9-edited cells, provided evidence that this mutation regulates CDKN2A transcription and is responsible for the ID shank color in chickens. The absence of melanocytes is likely due to their apoptosis. This study completes the puzzle of chicken shank color genetics and paves the way for the application of the ID mutation in the auto-sexing of chicks which is intensively needed in layer and broiler industries.

genetics↗

bioRxiv2024

Electron-density informed effective and reliable de novo molecular design and lead optimization with ED2Mol

Generative drug design opens new avenues for discovering novel compounds within the vast chemical space rather than conventional screening against limited compound libraries. However, the practical utility of the generated molecules is frequently constrained, as many designs prioritize a narrow range of pharmacological properties while neglecting physical reliability, which hinders the success rate of subsequent wet-lab evaluations. To address this, we propose ED2Mol, a deep learning-based approach that leverages fundamental electron density information to improve de novo molecular generation and lead optimization. The extensive evaluations across multiple benchmarks demonstrate that ED2Mol surpasses existing methods in terms of generation success rate and >97% physical reliability. It also facilitates automated lead optimization that is not fully implemented by other methods using fragment-based strategies. Furthermore, ED2Mol exhibits generalizability to more challenging, unseen allosteric pocket benchmarks, attaining consistent performance in both de novo molecule generation and lead optimization. More importantly, ED2Mol has been applied to various real-world essential targets, successfully identifying wet-lab validated bioactive compounds, ranging from FGFR3 orthosteric inhibitors to CDC42 allosteric inhibitors and GCK allosteric activators. The directly generated binding modes of these compounds with target proteins are close to predictions through molecular docking and further validated via the X-ray co-crystal structure. All these results highlight ED2Mols potential as a useful tool in realistic drug design with enhanced effectiveness, physical reliability, and practical applicability.

bioinformatics↗

bioRxiv2024

Remote-Controlled Wireless Bioelectronics for Fluoxetine Therapy to Promote Wound Healing in a Porcine Model

Wound healing presents a significant challenge in biomedical science, requiring precise therapeutic delivery and real-time monitoring. Bioelectronic systems offer a promising solution but remain largely unexplored for wound care, particularly in large animal models that reflect human healing dynamics. This study introduces a remote controlled wireless bioelectronic platform equipped with an iontophoretic pump to deliver fluoxetine, a selective serotonin reuptake inhibitor that promotes wound repair. In vitro and ex-vivo testing validated efficient on demand fluoxetine delivery. In vivo experiments in a porcine wound model demonstrated clear therapeutic efficacy over 3-day and 7-day periods. The system enhanced healing outcomes, increasing re-epithelialization by 37% (H&E staining), reducing the M1/M2 macrophage ratio by 33%, and stimulating neuronal growth at the wound site. This bioelectronic platform delivers fluoxetine in a controlled, remotely-controlled manner while allowing for wound direct wound imaging that can be used to monitor wound healing progress. Additionally, it allows precise dose and temporal delivery of treatment to enhance the outcome of future large animal wound healing studies.

bioengineering↗

bioRxiv2024

DeepMapper: Attention-Based AutoEncoder for System Identification in Wound Healing and Stage Prediction

Advancements in bioelectronic sensors and actuators have paved the way for real-time monitoring and control of wound healing progression. Real-time monitoring allows for precise adjustment in treatment strategies that align with an individuals unique biological response. However, due to the complexities of human-drug interactions and a lack of predictive models it is challenging to determine just how one should adjust drug dosage to achieve the desired biological response. This work proposes an adaptive closed-loop control framework that integrates deep learning, optimal control, and reinforcement learning to update treatment strategies in real-time with the goal of accelerating wound closure. The proposed approach eliminates the need for mathematical modeling of complex nonlinear wound healing dynamics. We demonstrate the convergence of the controller via an in silico experimental setup, where the proposed approach successfully accelerates the wound healing process by 17.71%. Finally, we share the experimental setup and results of an in vivo implementation to highlight the translational potential of our work. Our data-driven model estimates a 40% acceleration in wound closure.

systems biology↗

bioRxiv2024

Radiation damage behavior of soft matter in ultrafast cryo-electron microscopy (cryo-UEM)

Whether time-modulated pulsed-electron imaging in ultrafast electron microscopy (UEM) can mitigate the electron radiation damage that occurs to samples, is still controversial. The effectiveness of such mitigation effect and relevant potential application in cryo-EM remain to be explored. Herein, we built an ultrafast cryo-EM (cryo-UEM) device based on an ultrafast laser system. Using such equipment and the saturated aliphatic hydrocarbon compounds (C44H90), the fading curves of diffraction intensity and corresponding critical electron doses (Ne) of the samples were carefully measured under different imaging modes, temperatures, imaging dose rates and pulsed repetition rates. Our experimental results show that, the fading curves and Ne values of the C44H90 crystals are uncorrelated with the imaging electron dose rates and do not show dependence on the dose-rate effect. As the temperature decreased, the Ne values of the sample increased, indicating the cryoprotective effect on radiation damage to the samples. Surprisingly, at a constant temperature, the fading curves and Ne values of the sample in multi-electrons-packet and near-single-electron-packet pulsed modes are all approximately the same as those in conventional continuous electron-beam mode, even when the results are obtained at different pulsed repetition rates. These results show that the time-modulated pulsed electron beam does not seem to mitigate the electron radiation damage that occurs on samples. Our findings offer new insights and experimental basis for the radiation damage behavior of samples under electron beams, and provide guidance and inspiration for elucidating the fundamental principles of radiation damage.

biophysics↗

bioRxiv2024

Effect of OASL on OXA-induced immunogenic cell death in gastric cancer via cGAS-STING pathway

This study investigates the role of 2-5 oligoadenylate synthetase-like (OASL) in Oxaliplatin (OXA)-induced immunogenic cell death (ICD) in Gastric cancer (GC) cells through the cGAS-STING signaling pathway. Knockdown of OASL enhanced ICD expression, while overexpression had the opposite effect. RNA sequencing of OASL-knockdown and control GC cells treated with OXA revealed significant enrichment of the second messenger signaling pathway (cGAMP). cGAMP could directly activate STING as a second messenger, and cGAS was a key synthetic enzyme upstream of cGAMP. Next, the role of OASL in OXA-induced ICD in GC cells was validated through the cGAS-STING signaling pathway. The Co-IP and immunofluorescence results confirmed that the OASL and cGAS proteins can bind directly. Further research validated these findings in vivo. Results show that OASL regulates OXA-induced ICD in GC cells via the cGAS-STING pathway, impacting chemosensitivity. The findings suggest new targets and strategies for improving GC therapy by modulating OASL expression to enhance OXA sensitivity through immunogenic mechanisms.

cancer biology↗

bioRxiv2024

Cells Prioritize the Regulation of Cell Mass Density

A cells global physical state is characterized by its volume and dry mass. The ratio of cell mass to volume is the cell mass density (CMD), which is also a measure of macromolecular crowding and concentrations of all proteins. Using the Fluorescence eXclusion method (FXm) and Quantitative Phase Microscopy (QPM), we investigate CMD dynamics after exposure to sudden media osmolarity change. We find that while the cell volume and mass exhibit complex behavior after osmotic shock, CMD follows a straightforward monotonic recovery in 48 hours. The recovery is cell-cycle independent and relies on a coordinated adjustment of protein synthesis and volume growth rates. Surprisingly, we find that the protein synthesis rate decreases when CMD increases. This result is explained by CMD-dependent nucleoplasm-cytoplasm transport, which serves as negative regulatory feedback on CMD. The Na+/H+ exchanger NHE plays a role in regulating CMD by affecting both protein synthesis and volume change. Taken together, we reveal that cells possess a robust control system that actively regulates CMD during environmental change.

biophysics↗

bioRxiv2024

An optical brain-machine interface reveals a causal role of posterior parietal cortex in goal-directed navigation

Cortical circuits contain diverse sensory, motor, and cognitive signals, and form densely recurrent networks. This creates challenges for identifying causal relationships between neural populations and behavior. We developed a calcium imaging-based brain-machine interface (BMI) to study the role of posterior parietal cortex (PPC) in controlling navigation in virtual reality. By training a decoder to estimate navigational heading and velocity from PPC activity during virtual navigation, we discovered that mice could immediately navigate toward goal locations when control was switched to BMI. No learning or adaptation was observed during BMI, indicating that naturally occurring PPC activity patterns are sufficient to drive navigational trajectories in real time. During successful BMI trials, decoded trajectories decoupled from the mouses physical movements, suggesting that PPC activity relates to intended trajectories. Our work demonstrates a role for PPC in navigation and offers a BMI approach for investigating causal links between neural activity and behavior.

neuroscience↗

bioRxiv2024

Himalayan whole-genome sequences provide insight into population formation and adaptation

High-altitude environments pose substantial challenges for human survival and reproduction, attracting considerable attention to the demographic and adaptive histories of high-altitude populations. Previous work focused mainly on Tibetans, establishing their genetic relatedness to East Asians and their genetic adaptation to high altitude, especially at EPAS1. Here, we present 87 new whole-genome sequences from 16 Himalayan populations and the insight they provide into the genomic history of the region. We show that population structure in the Himalayas began to emerge as early as 10,000 years ago, predating archaeological evidence of permanent habitation above 2,500 meters by approximately 6,000 years. The high prevalence of the introgressed adaptive EPAS1 haplotype in all high-altitude populations today supports a shared genetic origin and its importance for survival in this region. We also identify additional selection signals in genes associated with hypoxia, physical activity, immunity and metabolism which could have facilitated adaptation to the harsh environment. Over time, increasing genetic structure led to the diverse and strongly differentiated ethnic groups observed today, most of which maintained small population sizes throughout their history or experienced severe bottlenecks. Between 6,000 and 3,000 years ago, a few uniparental lineages became predominant, likely coinciding with the advent of agriculture, although significant population growth was not observed in the Himalayas except in the Tibetans. In more recent times, we detect bidirectional gene flow between high-altitude and lowland groups, occurring on both sides of the Himalayan range. The timing of this admixture aligns with the rise and expansion of historical regional powers, particularly during the Tibetan Empire and the northern Indian Gupta Empire. In the past few centuries, migrations to the Himalayas seem to have occurred alongside conflicts and population displacements in nearby regions and show some sex bias.

genomics↗

bioRxiv2024

Physiological, transcriptomic and metabolomic responses of the marine diatom Phaeodactylum tricornutum to auxin

Auxin, an essential phytohormone, is widely used to promote plant growth and development. However, the effect of auxin on diatoms and its mechanism remain underexplored. Here, we studied the impact of auxin 3-indoleacetic acid (IAA) on the marine diatom Phaeodactylum tricornutum and the underlying molecular mechanisms. We found that 5 g L-1 of IAA promotes the growth of P. tricornutum in a time- dependent manner. Treatment with IAA resulted in significant changes in photosynthetic pigments and malondialdehyde, chlorophyll fluorescence, and antioxidant enzyme activities. In addition, transcriptomics showed that IAA exposure leads to upregulation of a large number of differential genes (DEGs) in carbon fixation and porphyrin metabolism, several of which were verified by qPCR. Furthermore, corresponding metabolites of these pathways were also validated by metabolomic analysis. Thus, IAA exhibits growth-promotion effect on the diatom mainly through increasing photosynthetic carbon sequestration and the expression of genes in porphyrin synthesis. Our results provide key data on the action mechanism of IAA in promoting the growth of a diatom.

plant biology↗

bioRxiv2024

Neuromorphic Imaging Cytometry on Human Blood Cells

AO_SCPLOWBSTRACTC_SCPLOWImage-enhanced cytometry and sorting are powerful technologies that provide single-cell resolution and, where possible, cell actuation based on spatial and fluorescence characterisation. With the emergence of deep learning (DL), numerous cytometry-related works incorporate DL to assist their research in handling data-intensive and repetitive workloads. The rich spatial information provided by single-cell images has exceptional use with DL models to classify cells, detect rare cell events, disclose irregularity and achieve higher sample purity than a conventional feature-gating strategy. One of the significant challenges in these image-enable technologies is the constrained throughput owing to the data-expensive image acquisition and balancing between speed and resolution. This work introduces a novel paradigm by adopting a bio-inspired neuromorphic photosensor to capture fast-moving cell events. It facilitates a data-efficient, fluorescence-sensitive, fast inference approach to establish a foundation for neuromorphic-enabled cytometry/sorting applications. We have also curated the first neuromorphic-encoded cell dataset, including human blood cells (red blood cells, neutrophils, lymphocytes, thrombocytes), endothelial cells and polystyrene-based microparticles. To evaluate the data quality and potential of DL-based gating, we have directly trained a hybrid classification model based on this dataset, accomplishing a promising performance of 97% accuracy and F1 score with a significant reduction in memory usage and power consumption. Combining neuromorphic imaging and DL holds substantial potential to develop into a next-generation AI-assisted cytometry and sorting application.

cell biology↗