Biology subjects

Zhang, Y.-H.

Publications and source records attributed to Zhang, Y.-H..

12 recordsLinked to original sources

bioRxiv2026

A direct, MFRN-independent Fe(II) transfer pathway at mitochondria-lysosome contacts

Mitochondrial iron homeostasis is fundamental to respiration and redox balance, and its dysregulation is implicated in neurodegeneration, cardiomyopathy, and metabolic diseases. Although lysosomes harbor the major cellular iron reservoir, the prevailing model holds that mitochondria acquire Fe(II) directly from the cytosolic labile iron pool (LIP) via MFRN transporters. Here, we challenge the canonical view by identifying a direct, MFRN-independent Fe(II) transfer pathway at mitochondria-lysosome contacts (MLCs). This VPS39/TOMM22/SFXN1-coordinated pathway enables lysosome-to-mitochondria Fe(II) flux bypassing the cytosolic LIP. Using live-cell structured illumination microscopy (SIM), we visualize direct Fe(II) transfer specifically occurring at MLCs. Multiple lines of evidence confirm that VPS39 and TOMM22 stabilize MLCs, while SFXN1 serves as the core effector protein for this MLC-dependent Fe(II) transport. Notably, SFXN1 knockdown markedly reduces mitochondrial Fe(II) levels independent of its established serine transport function. This pathway reveals a major route for mitochondrial Fe(II) acquisition to support redox homeostasis.

cell biology↗

bioRxiv2026

ISPpu10 is a structure-gated bridge RNA recombinase that drives safe, large-scale genomic plasticity

IS110 elements employ bridge RNA to direct target site recognition, yet whether additional layers of specificity exist beyond RNA-DNA base pairing is unknown. Here we identified ISPpu10, an IS110 element in Pseudomonas putida that is associated with >100-kb segmental amplifications during adaptive laboratory evolution. All insertions mapped to multiple identical copies of a single conserved intergenic sequence harboring a GC-rich 5' extension that forms a stem-loop. Systematic mismatch and compensatory substitution scanning revealed a sequence-structure dual-match logic: base pairing between the bridge RNA and target DNA serves as an RNA-guided match, whereas the target-encoded stem-loop provides an additional specificity determinant. Transplanting this stem-loop into Escherichia coli targets improved on-target integration and reduced genome-wide off-target insertion, establishing the stem-loop as a portable structural gate. These findings reveal a structural recognition layer beyond base-pairing, suggesting how bacteria reconcile transposition with genome integrity and offering a strategy for precise genome editing.

microbiology↗

bioRxiv2025

Targeted intervention of senescence induced by a 5' half fragment of tRNASec(NCA) with antisense oligonucleotide extends healthspan and lifespan in mice

In light of increasing attention being paid to aging research globally, the accumulation of aging hallmarks and their corresponding targeting therapeutics have been substantially revealed. However, uncovering the genuine drivers within epigenetic alterations that lead to aging remains a formidable challenge. In this study, we identified tRNASec(NCA) as the most severely damaged tRNA species in the kidneys of naturally aged mice. This damage not only dysregulated selenoproteins with anti-aging effects, but also generates a 5'-tRNA fragment cleaved at the 34th position, which accumulates in an age-dependent manner. Mechanistically, the 5'-tRNASec(NCA) half interacts and activates Toll-like receptor 7, thereby triggering innate immune responses and promoting cellular senescence in both mice and human cells. Moreover, in a naturally aged mice model, administration of an antisense oligonucleotide (ASO) targeting the 5'-tRNASec(NCA) half remarkably ameliorates aging markers, enhances telomere length, and extends healthspan and lifespan. In addition, ASO-5'-tRNASec(NCA) half plays another role in directly targeting and downregulating BCAT1 via the RNAi pathway to intervene in the senescence process. Our findings underscore tRNA damage as a novel aging hallmark, and targeting the damage-induced products presents a novel strategy for aging intervention, thus expanding our knowledge of the aging process.

genetics↗

bioRxiv2024

Main compounds in sweat, such as squalene and fatty acids, should be promising pheromone components for humans

Pheromones are chemicals released outside the body by organisms to transmit information between individuals of the same species, thereby regulating behavior and physiology. Many biological and psychological studies have shown that human sweat does indeed contain chemical information related to gender, sex, emotion, etc., but there is no convincing answer to its chemical components. We conducted a GC-MS analysis of the chemical composition of adult and child sweat of Han Chinese, and found that the main components were squalene and fatty acids, and there were sex differences in adults, but not in children. Based on our long-term research on the coding rules of pheromones in a variety of animals, especially rodents, as well as men having more sweat glands and sebaceous glands, we speculate that squalene and many common fatty acids are likely to encode olfactory information such as sex and emotion in one component or a mix of components or in a dose-dependent manner. We also discussed that the main olfactory system and olfactory learning in social interactions should play an important role in human pheromone perception.

physiology↗

bioRxiv2024

Telomere-to-telomere sheep genome assembly reveals new variants associated with wool fineness trait

Ongoing efforts to improve sheep reference genome assemblies still leave many gaps and incomplete regions, resulting in a few common failures and errors in sheep genomic studies. Here, we report a complete, gap-free telomere-to-telomere (T2T) genome of a ram (T2T-sheep1.0) with a size of 2.85 Gb, including all autosomes and chromosomes X and Y. It adds 220.05 Mb of previously unresolved regions (PURs) and 754 new genes to the most updated reference assembly, ARS-UI_Ramb_v3.0, and contains four types of repeat units (SatI, SatII, SatIII, and CenY) in the centromeric regions. T2T-sheep1.0 exhibits a base accuracy of >99.999%, corrects several structural errors in previous reference assemblies, and improves structural variant (SV) detection in repetitive sequences. We identified 192,265 SVs, including 16,885 new SVs in the PURs, from the PacBio long-read sequences of 18 global representative sheep. With the whole-genome short-read sequences of 810 wild and domestic sheep representing 158 global populations and seven wild species, the use of T2T-sheep1.0 as the reference genome has improved population genetic analysis based on [~]133.31 million SNPs and 1,265,266 SVs, including 2,664,979 novel SNPs and 196,471 novel SVs. T2T-sheep1.0 improves selective tests by detecting several novel genes and variants, including those associated with domestication (e.g., ABCC4) and selection for the wool fineness trait (e.g., FOXQ1) in tandemly duplicated regions.

genomics↗

bioRxiv2024

Telomere-to-telomere genome assembly of a male goat reveals novel variants associated with cashmere traits

A complete goat (Capra hircus) reference genome enhances analyses of genetic variation, thus providing novel insights into domestication and selection in goats and related species. Here, we assembled a telomere-to-telomere (T2T) gap-free genome (2.86 Gb) from a cashmere goat (T2T-goat1.0), which included a Y chromosome of 20.9 Mb. With a base accuracy of >99.999%, T2T-goat1.0 corrected numerous genome-wide structural and base errors in previous assemblies and added 288.5 Mb of previously unresolved regions (PURs) and 446 newly assembled genes to the reference genome. We sequenced the genomes of five representative goat breeds for PacBio reads, and used T2T-goat1.0 as a reference to identify a total of 63,417 structural variations (SVs) with up to 4711 SVs (7.41%) in the PURs and 507 overlapping genes significantly enriched (Padj. < 0.05) in the keratin filament pathway. T2T-goat1.0 was applied in population analyses of global wild and domestic goats, which revealed 32,419 SVs and 25,397,794 SNPs, including 870 SVs and 545,026 SNPs in the PURs. Also, our analyses revealed a set of novel selective variants and genes associated with domestication (e.g., NKG2D and ABCC4) and cashmere traits (e.g., ABCC4 and ASIP).

genomics↗

bioRxiv2022

Hydroxycitric acid inhibits oxalate nephropathies formation through crystallization regulation and activation of the PPARα pathway

Oxalate-induced nephropathies comprise a range of kidney disorders, for which there are no efficient pharmacological treatments. Hydroxycitric acid (HCA) is a derivative of citric acid with a variety of pharmacological activities including reducing body weight and calcium salt deposition. However, the specific mechanism of inhibition of oxalate nephropathies by this compound is not well understood. In this study, we successfully applied bioinformatics-based and simulated drug molecular docking approaches to predict potential targets of HCA. Subsequently, we explored the molecular mechanisms of HCA inhibition of renal calcium oxalate (CaOx) deposition and nephrotoxicity in an oxalate-induced NRK-52E cell model and an oxalate nephropathy rat model. HCA could effectively inhibit CaOx crystal deposition and reduce crystal adhesion and oxidative damage, effectively inhibit lipid deposition caused by high oxalate, and reduce lipid nephrotoxicity. HCA is more effective than traditional stone medications in inhibiting CaOx deposition and kidney damage. Further cellular transcriptomic analysis and in vitro results showed that HCA could stably bind peroxisome proliferator-activated receptor (PPAR) and promote PPAR-RXR heterodimer formation, thus promoting the expression of downstream oxidative stress molecules (Nrf2, HO-1, SOD) and inhibiting calcium ion release and mitochondrial dysfunction, thus reducing oxalate-induced renal lipid peroxidation damage. Therefore, HCA, a novel drug with the ability to modulate lipid metabolism and inhibit CaOx formation, may be a therapeutic option for the treatment of oxalate nephropathies.

biochemistry↗

bioRxiv2022

Knowledge Mapping of Alternative Splicing of Cancer From 2012 to 2021: A Bibliometric Analysis

BackgroundAs a processing method of RNA precursors, alternative splicing plays a critical role in normal cell physiological activities. Aberrant alternative splicing events are associated with cancer development and are promising targets for cancer treatment. However, no detailed and unbiased study describes the current state of alternative splicing of cancer research. This study aims to conduct a bibliometric analysis of alternative splicing of cancer research in the last decade to measure and recognize the current state and trends. MethodsWeb of Science Core Collection was used to acquire the articles. Utilizing three bibliometric tools (CiteSpace, VOSviewer, R-bibliometrix), we were able to measure and recognize the influence and collaboration data of individual articles, journals, and co-citations. Analysis of co-occurrence and bursts information helped us identify the trending research areas related to alternative splicing of cancer. ResultsFrom 2012 to 2021, the total number of papers on alternative splicing of cancer published in 766 academic journals was 3,507, authored by 20,406 researchers in 405 institutions from 80 countries/regions. Research involving alternative splicing of cancer genes was primarily conducted in the United States and China, with the United States retaining the prime status; simultaneously, the Chinese Academy of Sciences, Fudan University and National Cancer Institute were the institutions with strong research capabilities. Scorilas Andreas is the scholar with the most publications, while the most co-citations were generated by Wang, Eric T. Plos One published the most papers on alternative splicing of cancer, while J biol chem was the most co-cited academic journal in this field. Furthermore, these publications covered a wide range of areas, but were still primarily focused on the fields of molecular, biology, and immunology. The results of keyword co-occurrence analysis can be divided into three types: molecular (P53, CD44, Androgen receptor, SRSF3, ESRP1), pathological process (apoptosis, EMT, metastasis, angiogenesis, proliferation), and disease (breast cancer, colorectal cancer, prostate cancer, hepatocellular carcinoma, gastric cancer). ConclusionResearch on alternative splicing of cancer has been a hot topic over the past decade, increasing in intensity each year. Current alternative splicing of cancer studies focused on hallmarks of alternative splicing in cancer, and alternative splicing signatures including diagnostic and therapeutic targets. Among them, the current trends are splicing factors regulating epithelial-mesenchymal transition and other hallmarks, aberrant splicing events in tumors, and further mechanisms. These might give researchers interested in this field a forward-looking perspective and inform further research.

cancer biology↗

bioRxiv2022

Single-cell RNA Sequencing of Pediatric Ependymoma Unravels Subclonal Heterogeneity Associated with Patient Survival

Ependymoma (EPN) is a malignant glial tumor occurring throughout central nervous system which commonly presents in children. Although recent studies have characterized EPN samples at both the bulk and single-cell level, intra-tumoral heterogeneity across subclones remains a confounding factor which impedes understanding of EPN biology. In this study, we generated a high-resolution single-cell dataset of pediatric ependymoma with a particular focus on the comparison of subclone differences within tumors, and show upregulation of cilium-associated genes in more highly differentiated subclone populations. As a proxy to traditional pseudotime analysis, we applied a novel trajectory scoring method to reveal cellular compositions associated with poor survival outcomes across primary and relapsed patients. Furthermore, we identified putative cell-cell communication features between relapsed and primary samples and show upregulation of pathways associated with immune cell crosstalk. Our results reveal both inter- and intratumoral gene expression profiles and tumor differentiation and provide a framework for studying transcriptomic signatures of individual subclones in ependymoma at single-cell resolution.

bioinformatics↗

bioRxiv2021

Hyperspectral sensing of photosynthesis, stomatal conductance, and transpiration for citrus tree under drought condition

Obtaining variation in water use and photosynthetic capacity is a promising route toward yield increases, but it is still too laborious for large-scale rapid monitoring and prediction. We tested the application of hyperspectral reflectance as a high-throughput phenotyping approach for early identification of water stress and rapid assessment of leaf photosynthetic traits in citrus trees. To this end, photosynthetic CO2 assimilation rate (Pn), stomatal conductance (Cond) and transpiration rate (Trmmol) were measured with gas-exchange approaches alongside measurements of leaf hyperspectral reflectance from citrus grown across a gradient of soil drought levels. Water stress caused Pn, Cond and Trmmol rapid and continuous decreases in whole drought period. Upper layer was more sensitive to drought than middle and lower layers. Original reflectance spectra of three drought treatments were surprisingly of low diversity and could not track drought responses, whereas specific hyperspectral spectral vegetation indices (SVIs) and absorption features or wavelength position variables presented great potential. Performance of four machine learning algorithms were assessed and random forest (RF) algorithm yielded the highest predictive power for predicting photosynthetic parameters. Our results indicated that leaf hyperspectral reflectance was a reliable and stable method for monitoring water stress and yield increasing in large-scale orchards. HighlightAn efficient and stable methods using hyperspectral features for early and pre-visual identification of drought and machine learning techniques for predicting photosynthetic capacity.

physiology↗

bioRxiv2020

Cascade Diversification Directs the Generation of Neuronal Diversity in Hypothalamus

The hypothalamus contains an astounding heterogeneity of neurons to achieve its role in regulating endocrine, autonomic and behavioral functions. Despite previous progress in deciphering the gene regulatory programs linked to hypothalamus development, its molecular developmental trajectory and origin of neuronal diversity remain largely unknown. Here we combine transcriptomic profiling of 43,261 cells derived from Rax+ hypothalamic neuroepithelium with lineage tracing to map a developmental landscape of mouse hypothalamus and delineate the developmental trajectory of radial glial cells (RGCs), intermediate progenitor cells (IPCs), nascent neurons and peptidergic neurons in the lineage hierarchy. We show that RGCs adopt a conserved strategy for multipotential differentiation but generate both Ascl1+ and Neurog2+ IPCs, which display regionally differential origins in telencephalon. As transit-amplifying cells, Ascl1+ IPCs differ from their telencephalic counterpart by displaying fate bifurcation to produce both glutamatergic and GABAergic neurons. After classifying the developing neurons into 29 subtypes coded by diverse transcription factors, neurotransmitters and neuropeptides, we identified their molecular determinants via regulon analysis and further found that postmitotic neurons at nascent state possess the potential to resolve into more diverse subtypes of peptidergic neurons. Together, our study offers a single-cell framework for hypothalamus development and reveals that multiple cell types along the order of lineage hierarchy contribute to the fate diversification of hypothalamic neurons in a stepwise fashion, suggesting that a cascade diversifying model can deconstruct the origin of neuronal diversity.

developmental biology↗

bioRxiv2019

Recombinase system-dependent copackaging strategy for highly efficient neurocircuit tracing

Mapping the detailed cell-type-specific input networks and neuronal projectomes are essential to understand brain function in normal and pathological states. However, several properties of current tracing systems, including labeling sensitivity, trans-synaptic efficiencies, reproducibility among different individuals and different Cre-driver animals, still remained unsatisfactory. Here, we developed MAP-ENVIVIDERS, a recombinase system-dependent vector mixing-based strategy for highly efficient neurocircuit tracing. MAP-ENVIVIDERS enhanced tracing efficiency of input networks across the whole brain, with over 10-fold improvement in diverse previously poor-labeled input brain regions and particularly, up to 70-fold enhancement in brainstem compared with the current standard rabies-virus-mediated systems. MAP-ENVIVIDERS was over 10-fold more sensitive for cell-type-specific labeling than previous strategies, enabling us to capture individual cell-type-specific neurons with extremely complex axonal branches and presynaptic axonal boutons, both about one order of magnitude than previously reported and considered. MAP-ENVIVIDERS provides powerful tools for deconstructing novel input/output circuitry towards functional studies and disorders-related mechanisms.

neuroscience↗