Biology subjects

Chen, Z.

Publications and source records attributed to Chen, Z..

At least 289 records · Page 16Linked to original sources

bioRxiv2025

A comprehensive benchmarking study of protein structure alignment tools based on downstream task performance

In this study, we investigate the performance of nine protein structure alignment tools by analyzing the influence of alignment results in accomplishing three downstream biological tasks: homology detection, phylogeny reconstruction, and function inference. These tools include (1) traditional sequential methods using both 3D and 2D structure representations, (2) non-sequential methods, (3) flexible methods, and (4) deep-learning methods. Canonical sequence alignment methods Needleman-Wunsch algorithm and BLASTp are used as baseline methods. We show that accuracies in downstream tasks can be uncorrelated with alignment quality metrics such as TM-score and RMSD, highlighting the discrepancy between the alignment results and the purposes of using them. We identify scenarios where structure alignment results outperform sequence alignment results. In homology detection, structure-based methods are much better than sequence alignment. In phylogeny reconstruction, structure-based methods generally outperform sequence-based methods on the filtered dataset with proteins sharing low sequence similarity. Moreover, we show that structure information improves the overall performance of these tools when used together with sequence information in phylogeny reconstruction and function inference. We also test the running time and CPU/GPU memory consumption of these tools for a large number of queries. Our study suggests that biological problems that were previously addressed with sequence-based methods using only sequence information could be further improved by using structure information alone or using both sequence and structure information. The trade-off between task accuracy and speed is the major consideration in developing new alignment tools for downstream tasks. We recommend both TMalign and KPAX for these tasks because of their good balance between running time and memory consumption, and relatively good and stable accuracy performance in downstream tasks. In tasks that require a large number of pairwise comparisons, such as homology detection and function inference, traditional methods outperform DL methods at the cost of long running time, and Foldseek is the best choice to achieve relatively high accuracy in a reasonable time. 1 Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=179 HEIGHT=200 SRC="FIGDIR/small/642719v1_fig1.gif" ALT="Figure 1"> View larger version (69K): org.highwire.dtl.DTLVardef@9ba569org.highwire.dtl.DTLVardef@88cc4eorg.highwire.dtl.DTLVardef@11d2070org.highwire.dtl.DTLVardef@13cd20d_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOFig. 1:C_FLOATNO Graphical abstract. C_FIG

bioinformatics↗

bioRxiv2025

Sky islands of Southwest China. II: Unraveling hidden species diversity of talpid moles using phylogenomics and skull-based deep learning

The sky islands of Southwest China, characterized by dramatic topographical and climatic variations, are prominent hotspots of biodiversity and endemism. Organisms inhabiting middle-to-high elevation habitats in this region are geographically isolated within distinct mountain chains, which over geological time have been subjected to isolation-by-distance and isolation-by-environment. These processes have led to profound allopatric diversification and strong phylogeographic structuring, resulting in a plethora of genetically distinct cryptic species, as is becoming increasingly evident for many small mammal families. However, morphological conservatism can pose significant challenges in delineating these clades within species complexes. In this study, we leverage artificial intelligence technologies to unravel the hidden species diversity of moles (family Talpidae) in Southwest Chinas sky islands. We first employed ultraconserved elements (UCEs) to investigate the evolutionary history of talpid moles, conducted molecular species delimitation using mitochondrial and multi-locus genes, and utilized both traditional and geometric morphometrics to examine their morphological disparity. To address the challenges of morphology based cryptic species identification, we developed a deep learning Hierarchical Identification of Species NETwork (HIS-NET) to create an image-based model that analyzes four different views of the skull/mandible to distinguish genera and species hierarchically. HIS-NET not only achieved expert-level accuracy in species identification but also effectively distinguished between cryptic and known species, aiding in the identification of key morphological variation intervals. Our results support the recognition of allopatrically distributed taxa in Euroscaptor and Parascaptor as full species, thereby confirming that species diversity in this region remains underestimated. Beyond advancing our understanding of speciation in this unique and fragile ecosystem, our study serves as a proof-of-concept, demonstrating the power of deep learning in unraveling hidden biodiversity within this and other species complexes.

zoology↗

bioRxiv2025

Ultrasound Directly Activates Sparse Neurons and Modulates Visual Circuits in Deafened Mice

Focused ultrasound neuromodulation (FUN) is widely regarded as a next-generation technology for neural modulation, with applications spanning rodents, non-human primates, and humans. While mechanistic studies are advancing, a persistent confound--auditory interference--casts doubt on whether ultrasound exerts direct mechanical effects or merely indirect auditory responses. To resolve this, we engineered a circular ultrasound transducer compatible with two-photon calcium imaging and examined its effects on the primary visual cortex (V1) of surgically deafened mice, eliminating auditory contributions. Our results reveal that ultrasound directly activates a sparse subset of ultrasound-sensitive neurons (USSN) (response rate >30%) in V1, comprising only a small fraction of the total population and exhibiting a spatially sparse distribution. The proportion of USSN scale with ultrasound pressure, confirming a direct neuromodulatory effect independent of audition. Intriguingly, despite this sparse activation, ultrasound significantly modulates V1 circuitry: it alters the dynamics of light-sensitive neurons (LSN), with subsets showing excitation, inhibition, or no change in response to visual stimuli. These findings provide the first rigorous in-vivo evidence that FUN induces direct mechanical effects on neural activity, disentangling them from auditory confounds. By demonstrating both the specificity and broader circuit-level impact of ultrasound in deafened mice, this study reframes our understanding of FUNs mechanisms and strengthens its potential as a precise neuromodulatory tool. HighlightsO_LIUltrasound directly activates sparse neurons in deafened mice, demonstrating auditory-independent effects. C_LIO_LISparse ultrasound-sensitive neurons in V1 show pressure-dependent responses. C_LIO_LIUltrasound modulates visual circuitry, with diverse excitatory and inhibitory effects. C_LI

neuroscience↗

bioRxiv2025

Deciphering the molecular mechanisms of FET fusion oncoprotein-DNA hollow co-condensates

Biomolecules such as nucleic acids and proteins can undergo liquid-liquid phase separation to form biomolecular condensates with diverse architectures. However, fundamental questions surrounding the biophysical principles that govern condensate architecture and their potential biotechnological applications remain unresolved. Here, we report that the FUS/EWS/TAF15 family fusion oncoprotein FUS-ERG forms hollow co-condensates with double-stranded DNA containing GGAA microsatellites. Through a combination of biochemical assays, super-resolution imaging, and mathematical modeling, we reveal that the interior surface of hollow co-condensates exhibits properties distinct from those of the external surface, a phenomenon we term nested asymmetric phase separation. Furthermore, we demonstrate that the self-organization and morphology control of FUS-ERG hollow co-condensates can be harnessed for DNA-based information manipulation, enabling targeted DNA deletion within dsDNA libraries and facilitating dynamic, hierarchical data selection. These findings provide critical insights into the biophysical mechanisms underlying multicomponent phase-separated cellular bodies and establish a foundation for leveraging condensate morphology in biotechnology.

biophysics↗

bioRxiv2025

Hierarchical Lineage Tracing Reveals Diverse Pathways of AML Treatment Resistance

Cancer cells adapt to treatment, leading to the emergence of clones that are more aggressive and resistant to anti-cancer therapies. We have a limited understanding of the development of treatment resistance as we lack technologies to map the evolution of cancer under the selective pressure of treatment. To address this, we developed a hierarchical, dynamic lineage tracing method called FLARE (Following Lineage Adaptation and Resistance Evolution). We use this technique to track the progression of acute myeloid leukemia (AML) cell lines through exposure to Cytarabine (AraC), a front-line treatment in AML, in vitro and in vivo. We map distinct cellular lineages in murine and human AML cell lines predisposed to AraC persistence and/or resistance via the upregulation of cell adhesion and motility pathways. Additionally, we highlight the heritable expression of immunoproteasome 11S regulatory cap subunits as a potential mechanism aiding AML cell survival, proliferation, and immune escape in vivo. Finally, we validate the clinical relevance of these signatures in the TARGET-AML cohort, with a bisected response in blood and bone marrow. Our findings reveal a broad spectrum of resistance signatures attributed to significant cell transcriptional changes. To our knowledge, this is the first application of dynamic lineage tracing to unravel treatment response and resistance in cancer, and we expect FLARE to be a valuable tool in dissecting the evolution of resistance in a wide range of tumor types.

cancer biology↗

bioRxiv2025

A monophyletic origin of domesticated barley

The origin of domesticated barley has been debated extensively over the past century. Early botanical and comparative morphological research and recent genetic research supported a polyphyletic origin. A monophyletic origin was proposed after the discovery that a single genetic locus controls the presence of hull-less grains in all domesticated barley. Interpreting the origin of domesticated barley is further complicated by the archaeological record showing that the first domesticates had two rows of grain on the inflorescence, as does its wild progenitor. However, these two-rowed types effectively disappeared from the record for thousands of years, and they were replaced by derived six-rowed types that dominated barleys cultivation history and only reappeared in the record around one thousand years ago. Here, we used two independent datasets with large sample sizes and genome-wide genetic markers to re-evaluate barley cultivation history. We unequivocally demonstrate that modern domesticated barley has a monophyletic origin. Phylogenetic reconstruction and examination of current archaeological records suggests that the west Fertile Crescent was most likely where barley was first domesticated. Modern two-rowed types were likely derived from six-rowed domesticated types not earlier than 3,500 years ago in modern Turkiye and Iran. We conclude that the two distinct non-brittle rachis haplotypes, coinciding with distinct row types in cultivated barley, are likely the results of two chronological events along the same evolutionary line. Our results provide a reconcilable framework for explaining genetic and phytogeographic patterns and pave the way for a consensus on the origin of barley domestication.

evolutionary biology↗

bioRxiv2025

NtLLG4-mediated unconventional polar exocytosis of NtPPME1 coordinates cell wall rigidity and membrane dynamics to control pollen tube integrity

Plant fertilization relies on controlled pollen tube growth that integrates membrane dynamics and cell wall expansion. We previously identified an unconventional exocytic pathway wherein Golgi-derived secretory vesicles (GDSVs) bypass the trans-Golgi network to deliver Nicotiana tabacum pectin methylesterase 1 (NtPPME1), thereby modulating cell wall rigidity. However, the mechanisms linking this patwhay with membrane dynamics and signaling remain elusive. Here, we used cryo-FIB-SEM and 3D tomography to identified GDSVs as a distinct vesicle population at the pollen tube tip. We further demonstrated that tobacco LORELEI-like-GPI-anchored protein 4 (NtLLG4), a key signaling molecule controlling membrane dynamics and integrity, functions as a receptor for NtPPME1, regulating its polar exocytosis via GDSVs to control cell wall stiffness. Furthermore, we identified trafficking signals which direct the unconventional exocytosis of NtPPME1 across intracellular organelles. Our findings reveal a crucial mechanism coupling cell wall rigidity with membrane signaling to control pollen tube growth and integrity during fertilization. TeaserWe reveal a mechanism coupling cell wall rigidity with member signaling to control pollen tube growth and integrity during plant fertilization.

plant biology↗

bioRxiv2025

Unraveling the Neurocognitive Mechanisms of Delayed Punishment in Second- and Third-Party Contexts

Second-party punishment (SPP) and third-party punishment (TPP) are essential in regulating social behavior and maintaining social norms, yet the effectiveness may wane when punishment is delayed. Currently, the decision-making and neural mechanisms underlying SPP and TPP under temporal delays remain largely unexplored. This study investigated both SPP and TPP punishment decisions with time-delay (immediate vs. delayed) using a hypothetical criminal scenario assessment task with fMRI. Results showed increased activity in the bilateral precuneus and left temporoparietal junction (TPJ) and stronger left TPJ-dorsolateral prefrontal cortex (dlPFC) connectivity in SPP compared to TPP. Interestingly, third-parties imposed more severe punishment in delayed conditions than in immediate ones, accompanied by enhanced neural activity in dorsomedial prefrontal cortex (dmPFC), left TPJ, ventrolateral prefrontal cortex (vlPFC), ventromedial prefrontal cortex (vmPFC), and caudate nucleus. This delay effect was evident only in misdemeanor and felony cases, with no differences in capital offenses, suggesting a moderating effect of criminal severity. In contrast, SPP showed no significant changes in punishment or neural response across immediate and delayed conditions. Multivariate pattern analysis further indicated that dmPFC, TPJ, vlPFC, vmPFC and caudate function together to encode punishment severity in TPP contexts, a pattern not observed in SPP. These findings underscore distinct decision-making mechanisms between SPP and TPP under temporal delays, with implications for understanding justice-related processing in the human brain under time constraints. Significance statementWithin the justice system, punishing norm violators is often hindered when they flee, resulting in delayed punishments. However, little is known about how second-party (SPP) and third-party (TPP) implement punishment with time delays. The current study investigated this using real criminal scenarios with time delays under fMRI scanning. We found that third parties imposed more severe punishment on defendants in delayed conditions than in immediate ones, reflected by enhanced neural activity in the dorsomedial prefrontal cortex, left temporoparietal junction, ventrolateral prefrontal cortex, ventromedial prefrontal cortex, and caudate nucleus. In contrast, no significant differences were observed in second-party punishment. We also found a moderating effect of criminal severity: the difference between immediate and delayed sanctions by third-parties was present in misdemeanor and felony cases but not in capital offenses. These results shed light on the decision-making mechanisms of SPP and TPP in contexts involving temporal delay, which may have deep impact in different disciplines, e.g., social science, cognitive neuroscience and legal system.

neuroscience↗

bioRxiv2025

Cell type-specific epigenetic regulatory circuitry of coronary artery disease loci

Coronary artery disease (CAD) is the leading cause of death worldwide. Recently, hundreds of genomic loci have been shown to increase CAD risk, however, the molecular mechanisms underlying signals from CAD risk loci remain largely unclear. We sought to pinpoint the candidate causal coding and non-coding genes of CAD risk loci in a cell type-specific fashion. We integrated the latest statistics of CAD genetics from over one million individuals with epigenetic data from 45 relevant cell types to identify genes whose regulation is affected by CAD-associated single nucleotide variants (SNVs) via epigenetic mechanisms. Applying two statistical approaches, we identified 1,580 genes likely involved in CAD, about half of which have not been associated with the disease so far. Enrichment analysis and phenome-wide association studies linked the novel candidate genes to disease-specific pathways and CAD risk factors, corroborating their disease relevance. We showed that CAD-SNVs are enriched to regulate gene expression by affecting the binding of transcription factors (TFs) with cellular specificity. Of all the candidate genes, 23.5% represented non-coding RNAs (ncRNA), which likewise showed strong cell type specificity. We conducted a proof-of-concept biological validation for the novel CAD ncRNA gene IQCH-AS1. CRISPR/Cas9-based gene knockout of IQCH-AS1, in a human preadipocyte strain, resulted in reduced preadipocyte proliferation, less adipocyte lipid accumulation, and atherogenic cytokine profile. The cellular data are in line with the reduction of IQCH-AS1 in adipose tissues of CAD patients and the negative impact of risk alleles on its expression, suggesting IQCH-AS1 to be protective for CAD. Our study not only pinpoints CAD candidate genes in a cell type-specific fashion but also spotlights the roles of the understudied ncRNA genes in CAD genetics.

bioinformatics↗

bioRxiv2025

A novel method for detection of Cas9 gRNAs using a fluorophore-labeled DNA oligo

Clustered regularly interspaced short palindromic repeats (CRISPR) associated protein 9 (Cas9) has become one of the most important gene editing tools. CRISPR guide RNA (gRNA) serves as an important component in guiding Cas proteins to a target site in gene editing processes. For effective gene editing or site specific gene integration, levels of gRNA present in a target cell are critical. Especially, for prime editing, even the ratio of different gRNAs present in target cells has a major effect on gene editing efficiency. Therefore, having a convenient, highly sensitive method for direct detection of gRNAs can improve editing design and optimize targeting efficiency. Here, we have developed a convenient, highly sensitive method for direct detection of gRNAs, which may be used to improve editing design and optimize targeting efficiency.

molecular biology↗

bioRxiv2025

Dynamic early recruitment of GAK-Hsc70 regulates coated pit maturation

Clathrin-mediated endocytosis (CME) is the process by which clathrin assembles on the plasma membrane to form clathrin-coated pits (CCPs), which then invaginate, accumulate cargo and are released by fission from the membrane to form clathrin-coated vesicles (CCVs). A transition of nascent CCPs from flat-to-curved has been observed by various methods. However, what drives this transition remains unknown and controversial. GAK and its chaperone protein, Hsc70, are well-known to mediate clathrin release from CCVs and several studies have observed a late burst of GAK recruitment as CCVs form. Other studies have proposed that early recruitment of GAK-Hsc70 could function to provide the necessary energy source to remodel nascent flat clathrin lattices, replacing hexagons with pentagons and enabling a gain of curvature and invagination of the growing CCP; however, direct functional evidence is lacking. Here we show that GAK knockdown inhibits CCP formation and invagination. Furthermore, mutations in the J domain of GAK that abolish Hsc70 recruitment to and activation at CCPs, lead to the accumulation of GAK at CCPs, hinder CCP stabilization and invagination and result in a striking increase in the proportion of short-lived, abortive CCPs. These findings support the hypothesis that GAK-Hsc70 promotes the turnover and remodeling of nascent clathrin assemblies required for curvature development during CME. Significance StatementGAK and its chaperone protein, Hsc70, are known to be recruited to clathrin-coated vesicles (CCVs) to mediate clathrin uncoating. Previous studies have proposed that early recruitment of GAK-Hsc70 to CCPs could function to remodel nascent flat clathrin lattices, replacing hexagons with pentagons and enabling a gain of curvature of the assembling polymeric coat. However, there are conflicting views, and direct functional evidence is lacking. Here we show that GAK knockdown inhibits CCP formation and invagination. A detailed domain-specific mutational analysis of GAK pinpointed the importance of J domain-Hsc70 interactions in regulating crucial early steps of CME including CCP stabilization and invagination. These findings support a hypothesis that GAK-Hsc70 promotes turnover of clathrin at nascent CCPs required for curvature development.

cell biology↗

bioRxiv2025

Blood Vessels Bioengineered from Induced Pluripotent Stem Cell Derived Mesenchymal Stem Cells and Functional Scaffolds

The development of small-diameter vascular grafts remains a major challenge in tissue engineering due to limited remodelling and regenerative capabilities. While strides have been made on the biofabrication of vessel mimics, little clinical translation success had been achieved to treat coronary artery disease (CAD). This study aimed to fabricate patient-specific bioengineered vessels using induced pluripotent stem cells (iPSCs) and functionalised biodegradable scaffolds. Human iPSCs were differentiated into mesenchymal stem cells (iMSCs) using SB431542, then further into vascular smooth muscle cells (VSMCs) with PDGF-BB and TGF-{beta}1. Human bone marrow-derived MSCs (hBM-MSCs) were used to optimize differentiation protocols. Electrospun poly-L-lactide (PLLA) scaffolds coated with silk fibroin improved cell adhesion and proliferation. Both hBM-MSCs and iMSCs were seeded on these scaffolds for in-scaffold VSMC differentiation. The resulting cell-laden scaffolds were rolled into tubular structures ([~]3 mm inner diameter, [~]20 mm length). Over 34-36 days, iPSCs differentiated into iMSCs expressing MSC markers (CD73, CD90, CD105), followed by successful VSMC differentiation within 9 days, confirmed by -SMA, CNN1, SM22, and MYH-11 expression. Silk fibroin-coated PLLA scaffolds enhanced MSC adhesion and proliferation compared to uncoated scaffolds. The engineered tubular grafts displayed VSMC markers and mechanical properties akin to autologous coronary artery bypass grafting (CABG) grafts. This study developed a versatile method to fabricate tissue-engineered blood vessels using stem cells and silk fibroin-coated scaffolds. The resulting grafts exhibited tunica media-like structures and mechanical properties comparable to autografts used in CABG, showing strong potential for clinical application.

bioengineering↗

bioRxiv2025

Enhancing Immune Cell Activation through Cold Atmospheric Plasma: Disruption of PD-1/PD-L1/PD-L2 Immune Checkpoints via Molecular Dynamics

The PD-1/PD-L1/PD-L2 immune checkpoint plays a critical role in regulating immune responses, and its dysfunction is implicated in immune evasion by cancer cells. Cold atmospheric plasma (CAP) has emerged as a promising cancer therapeutic modality with the potential to modulate immune checkpoints. This study employs molecular dynamics (MD) simulations to investigate the impact of CAP-induced oxidation on the interactions between PD-1 and its ligands, PD-L1 and PD-L2. We simulated the PD-1/PD-L1 and PD-1/PD-L2 complexes under different oxidation levels. Key residues within the interaction site of the ligands are modified using Vienna PTM 2.0 online server. Umbrella sampling and other MD analyses revealed that increasing oxidation levels leads to weaken the binding affinity between PD-1 and both PD-L1 and PD-L2. These findings suggest that CAP may offer a novel strategy for enhancing anti-tumor immunity. This computational study provides valuable insights into the molecular mechanisms underlying CAPs effects on immune regulation and highlights its potential for cancer immunotherapy.

immunology↗

bioRxiv2025

Theta oscillations dictate the evolution of memories across periods of sleep or wakefulness

How does the brain select which experiences to consolidate into long-term memory? Numerous neurobiological frameworks suggest that certain memories are "tagged" at learning for consolidation during later sleep. However, experimental evidence of such a tagging mechanism in the human brain is lacking. Using electroencephalography in humans, we reliably differentiate brain states for memories that are tagged at learning for consolidation across sleep or wakefulness. The tagging of memories for consolidation across sleep (but not wakefulness) was linked to 3-8Hz theta rhythms during learning. The magnitude of this tagging-related theta response predicted the coupling of slow oscillations to sleep spindles during post-learning sleep (an established neural correlate of sleep-dependent memory processing). In turn, slow oscillation-spindle coupling was associated with better memory performance at the post-sleep test. These findings provide new insights into the neural mechanisms through which our brains determine which information is retained for the future.

neuroscience↗

bioRxiv2025

Biophysical modeling reveals the transcriptional regulatory mechanism of Spo0A, the master regulator in starving Bacillus subtilis

In starving Bacillus subtilis bacteria, the initiation of two survival programs - biofilm formation and sporulation - is both controlled by the same phosphorylated master regulator Spo0A[~]P. Its gene, spo0A, is transcribed from two promoters, Pv and Ps, that are respectively regulated by RNAP holoenzymes bearing {sigma}A and {sigma}H. Notably, transcription is directly autoregulated by Spo0A[~]P binding sites known as 0A1, 0A2, and 0A3 box, located in between the two promoters. It remains unclear whether, at the onset of starvation, these boxes activate or repress spo0A expression, and whether the Spo0A[~]P transcriptional feedback plays a role in the increase in spo0A expression. Based on the experimental data of the promoter activities under systematic perturbation of the promoter architecture, we developed a biophysical model of transcription regulation of spo0A by Spo0A[~]P binding to each of the 0A boxes. The model predicts that Spo0A[~]P binding to its boxes does not affect the RNA polymerase recruitment to the promoters but instead affects the transcriptional initiation rate. Moreover, the effects of Spo0A[~]P binding to 0A boxes are mainly repressive and saturated early at the onset of starvation. Therefore, the increase in spo0A expression is mainly driven by the increase in RNAP holoenzyme levels. Additionally, we reveal that Spo0A[~]P affinity to 0A boxes is strongest at 0A3 and weakest at 0A2 and that there are attractive forces between the occupied 0A boxes. Our findings, in addition to clarifying how the sporulation master regulator is controlled, offer a framework to predict regulatory outcomes of complex gene-regulatory mechanisms. ImportanceCell differentiation is often critical for survival. In bacteria, differentiation decisions are controlled by transcriptional master regulators under transcriptional feedback control. Therefore, understanding how master regulators are transcriptionally regulated is required to understand differentiation. However, in many cases, underlying regulation is complex with multiple transcription factor binding sites and multiple promoters, making it challenging to dissect the exact mechanisms. Here, we address this problem for the B. subtilis master regulator Spo0A. Using a biophysical model, we quantitatively characterize the effect of individual transcription factor binding sites on each spo0A promoter. Further, the model allows to identify the specific transcription step that is affected by transcription factor binding. Such model is promising for the quantitative study of a wide range of master regulators involved in transcriptional feedback.

biophysics↗

bioRxiv2025

Regulation of fatty acid oxidation involved in high altitude hypoxia induced cardiomyocyte ferroptosis via the SIRT1-PPARα-GPX4 signaling pathway

The heart experiences damage and undergoes changes in energy metabolism under condition of hypoxia. Ferroptosis is a novel form of cell death characterized by the accumulation of reactive oxygen species (ROS) and excessive lipid oxidation. However, the relationship between cardiac energy metabolism and ferroptosis at high altitudes remains unexplored. This study investigates the effects of high-altitude hypoxia on cardiac function and explores underlying mechanisms. The results demonstrate that exposure to high-altitude hypoxia induces structural and functional damage to the heart, leading to myocardial cell injury and oxidative stress, which are accompanied by ferroptosis. Inhibition of ferroptosis with Fer-1 significantly enhances hypoxia-induced expression of GPX4 and SLC7A11, reduces ROS levels, restores the GSH/GSSG ratio, and improves viability of hypoxia-damaged myocardial cells. Further investigation revealed that hypoxia induces mitochondrial damage and disrupts fatty acid {beta}-oxidation (FAO), accompanied by downregulation of PPAR. Activation of PPAR with WY14643 enhances FAO, suppresses ferroptosis, and boosts cell viability and ATP levels under hypoxic conditions. Overexpression of SIRT1 upregulates PPAR, enhances FAO, and mitigates ferroptosis, these effects are reversed by the PPAR inhibitor GW6471. Resveratrol, a natural SIRT1 activator, improves cardiac function and mitochondrial structure, enhances FAO, and reduces ferroptosis in high-altitude hypoxia-induced cardiac injury through the SIRT1-PPAR-GPX4 pathway. These findings identify the SIRT1-PPAR-GPX4 pathway as a potential therapeutic target for high-altitude-induced cardiac injury.

cell biology↗

bioRxiv2025

Automatic detection of fluorescently labeled synapses in volumetric in vivo imaging data

Synapses are submicron structures that connect and enable communication between neurons. Many forms of learning are thought to be encoded by synaptic plasticity, wherein the strength of specific synapses is regulated by modulating expression of neurotransmitter receptors. For instance, regulation of AMPA-type glutamate receptors is a central mechanism controlling the formation and recollection of long-term memories. A critical step in understanding how synaptic plasticity drives behavior is thus to directly observe, i.e., image, fluorescently labeled synapses in living tissue. However, due to their small size and incredible density -- with one [~]0.5 {micro}m diameter synapse every cubic micron -- accurately detecting individual synapses and segmenting each from its closely abutting neighbors is challenging. To overcome this, we trained a convolutional neural network to simultaneously detect and separate densely labeled synapses. These tools significantly increased the accuracy and scale of synapse detection, enabling segmentation of hundreds of thousands of individual synapses imaged in living mice.

neuroscience↗

bioRxiv2025

Evidence for evolution of a new sex chromosome within the Marchantiales haploid plant lineage

Sex chromosomes have evolved independently in numerous lineages across the tree of life, in both diploid-dominant species, including many animals and plants, and the less studied haploid-dominant plants and algae. Strict genetic sex determination ensures that individuals reproduce by outcrossing. However, species with separate sexes (termed dioecy in diploid plants, and dioicy in haploid plants) may sometimes evolve different sex systems, and become monoicous, with the ability to self-fertilize. Here, we study dioicy-monoicy transitions in the ancient liverwort haploid plant lineage, using three telomere-to-telomere gapless chromosome-scale reference genome assemblies from the Ricciaceae group of Marchantiales. Ancestral liverworts are believed to have been dioicous, with U and V chromosomes (chromosome 9) determining femaleness and maleness, respectively. We confirm the finding that monoicy in Ricciocarpos natans evolved from a dioicous ancestor, and most ancestrally U chromosomal genes have been retained on autosomes in this species. We also describe evidence suggesting the possible re-evolution of dioicy in the genus Riccia, with probable de novo establishment of a sex chromosome from an autosome (chromosome 5), and further translocations of genes from the new sex chromosome to autosomes. Our results also indicated that m-chromosomes are consistent genomic features, and may have evolved independently from sex chromosomes in Ricciocarpos and Riccia lineages.

evolutionary biology↗