Biology subjects

Yang, H.

Publications and source records attributed to Yang, H..

At least 379 records · Page 21Linked to original sources

bioRxiv2023

Conservation and Expansion of Transcriptional Factor Repertoire in the Fusarium oxysporum Species Complex

The Fusarium oxysporum species complex (FOSC) includes both plant and human pathogens that cause devastating plant vascular wilt diseases and threaten public health. Each F. oxysporum genome comprises core chromosomes (CCs) for housekeeping functions and accessory chromosomes (ACs) that contribute to host-specific adaptation. This study inspected global transcription factor profiles (TFomes) and their potential roles in coordinating CCs and ACs functions to accomplish host-specific pathogenicity. Remarkably, we found a clear positive correlation between the sizes of TFome and proteome of an organism, and FOSC TFomes are larger due to the acquisition of ACs. Among a total of 48 classified TF families, 14 families involved in transcription/translation regulations and cell cycle controls are highly conserved. Among 30 FOSC expanded families, Zn2-C6 and Znf_C2H2 are most significantly expanded to 671 and 167 genes per family, including well-characterized homologs of Ftf1 (Zn2-C6) and PacC (Znf_C2H2) involved in host-specific interactions. Manual curation of characterized TFs increased the TFome repertoires by 3%, including a disordered protein Ren1. Expression profiles revealed a steady expression of conserved TF families and specific activation of AC TFs. Functional characterization of these TFs could enhance our understanding of transcriptional regulation involved in FOSC cross-kingdom interactions, disentangle species-specific adaptation, and identify targets to combat diverse diseases caused by this group of fungal pathogens.

genomics↗

bioRxiv2023

Rigosertib promotes anti-tumor immunity via autophagic degradation of PD-L1 in colorectal cancer cells

Rigosertib (RGS) is a benzyl styryl sulfone which exhibits impressive cytotoxicity in cancer cells. However, its modulating effect on tumor immune microenvironment remains elusive. In our experiments, compared with immunodeficient mouse model, increased tumor growth arrest and robust anti-tumor immunity were observed in RGS-treated colorectal cancer (CRC) xenograft tumors in immunocompetent mice. Intriguingly, RGS markedly down-regulated programmed cell death ligand 1 (PD-L1) expression in both vivo and in vitro. Meanwhile, RGS increased autophagic vacuole number in CRC cells as seen by transmission electron microscopy and immunofluorescence. Moreover, increased LC3-II level and tandem- mRFP- GFP- LC3 labeled vacuole accumulation demonstrated RGS-induced autophagic flux. Mechanistically, it is the activation of AMP-activated protein kinase-UNC-51-like kinase 1 (AMPK-ULK1) axis, rather than the canonical mTOR signaling pathway, that plays a pivotal role in RGS-induced autophagy. AMPK-ULK1 dependent autophagy inhibition, by either short interfering RNA or chemical inhibitors, blocked RGS-induced PD-L1 degradation. Finally, RGS exhibited synergistic anti-tumor activity with cytotoxic T-lymphocyte-associated protein 4 monoclonal antibody in the CRC xenograft model. Furthermore, apart from the immunomodulatory effect, we also confirmed the direct cytotoxicity of RGS in inducing mitochondria-related apoptosis. Altogether, considering its PD-L1 inhibitory and cytotoxic effects, RGS could be a promising drug for CRC therapy.

cancer biology↗

bioRxiv2023

GLI1 facilitates rheumatoid arthritis by collaborative regulation of DNA methyltransferases

Rheumatoid arthritis (RA) is characterized by joint synovitis and bone destruction, the etiology of which remains to be explored. Overactivation of M1 macrophages and osteoclasts has been thought a direct cause of joint inflammation and bone destruction. Glioma-associated oncogene homolog 1 (GLI1) has been revealed to be closely linked to bone metabolism. In this study, GLI1-expression in synovial tissue of RA patients showed to be positively correlated with RA-related scores and was highly expressed in collagen-induced arthritis (CIA) mouse articular macrophage-like cells. The decreased expression and inhibition of nuclear transfer of GLI1 downregulated macrophage M1 polarization and osteoclast activation, the effect of which was achieved by modulation of DNA methyltransferases (DNMTs) via transcriptional regulation and protein interaction ways. By pharmacological inhibition of GLI1, the proportion of proinflammatory macrophages and the number of osteoclasts were significantly reduced, and the joint inflammatory response and bone destruction in CIA mice were alleviated. This study clarified the mechanism of GLI1 in macrophage phenotypic changes and activation of osteoclasts, suggesting potential applications of GLI1 inhibitor in the clinical treatment of RA.

cell biology↗

bioRxiv2023

Unraveling the causal genes and transcriptomic determinants of human telomere length

Telomere length (TL) shortening is a pivotal indicator of biological aging and is associated with many human diseases. The genetic determinates of human TL have been widely investigated, however, most existing studies were conducted based on adult tissues which are heavily influenced by lifetime exposure. Based on the analyses of terminal restriction fragment (TRF) length of telomere, individual genotypes, and gene expressions on 166 healthy placental tissues, we systematically interrogated TL-modulated genes and their potential functions. We found that placental TL is relatively longer across human tissues and which maintenance is mostly connected to genes responsible for alternative lengthening of telomeres. Trans-ancestral TL genome-wide association studies (GWASs) on 644,553 individuals identified 20 novel genetic associations and provided increased polygenic determination of human TL. Next, we integrated the powerful TL GWAS with placental expression quantitative trait locus (eQTL) mapping to prioritize 31 likely causal genes, among which 4 were functionally validated, including MMUT, RRM1, KIAA1429, and YWHAZ. Finally, modeling transcriptomic signatures and TRF-based TL improved the prediction performance of human TL. This study deepened our understanding of causal genes and transcriptomic determinants of human TL, promoting the mechanistic research on fine-grained TL regulation.

genetics↗

bioRxiv2023

EMBER multi-dimensional spectral microscopy enables quantitative determination of disease- and cell-specific amyloid strains

In neurodegenerative diseases proteins fold into amyloid structures with distinct conformations (strains) that are characteristic of different diseases. However, there is a need to rapidly identify amyloid conformations in situ. Here we use machine learning on the full information available in fluorescent excitation/emission spectra of amyloid binding dyes to identify six distinct different conformational strains in vitro, as well as A{beta} deposits in different transgenic mouse models. Our EMBER (excitation multiplexed bright emission recording) imaging method rapidly identifies conformational differences in A{beta} and tau deposits from Down syndrome, sporadic and familial Alzheimers disease human brain slices. EMBER has in situ identified distinct conformational strains of tau inclusions in astrocytes, oligodendrocytes, and neurons from Picks disease. In future studies, EMBER should enable high-throughput measurements of the fidelity of strain transmission in cellular and animal neurodegenerative diseases models, time course of amyloid strain propagation, and identification of pathogenic versus benign strains. SignificanceIn neurodegenerative diseases proteins fold into amyloid structures with distinct conformations (strains) that are characteristic of different diseases. There is a need to rapidly identify these amyloid conformations in situ. Here we use machine learning on the full information available in fluorescent excitation/emission spectra of amyloid binding dyes to identify six distinct different conformational strains in vitro, as well as A{beta} deposits in different transgenic mouse models. Our imaging method rapidly identifies conformational differences in A{beta} and tau deposits from Down syndrome, sporadic and familial Alzheimers disease human brain slices. We also identified distinct conformational strains of tau inclusions in astrocytes, oligodendrocytes, and neurons from Picks disease. These findings will facilitate the identification of pathogenic protein aggregates to guide research and treatment of protein misfolding diseases.

neuroscience↗

bioRxiv2023

Artificial channel separation of monochrome multi-structure microscopy image

Fluorescence microscopy is a powerful tool for life sciences, which employs fluorescent tags to label and observe cellular structures and their dynamics. However, due to the spectral overlap between different dyes, a limited number of structures can be separately labeled and imaged for live cell applications. Here we propose a novel double-structure network (DBSN) that consists of multiple connected models, which can extract six subcellular structures from three images with only two separate fluorescent labels. DBSN combines the intensity-balance models to compensate for uneven fluorescent labels for different structures and the structure-separation models to extract multiple different structures with the same fluorescent labels. Therefore, DBSN permits the imaging of multiple structures with only one fluorescent label. It significantly reduces photobleaching, breaks the bottleneck of the existing technologies, and would have vast applications in cell biology.

biophysics↗

bioRxiv2023

RAB7 deficiency impairs pulmonary artery endothelial function and promotes pulmonary hypertension

Pulmonary arterial hypertension (PAH) is a devastating and progressive disease with limited treatment options. Endothelial dysfunction plays a central role in development and progression of PAH, yet the underlying mechanisms are incompletely understood. The endosome-lysosome system is important to maintain cellular health and the small GTPase RAB7 regulates many functions of this system. Here, we explored the role of RAB7 in endothelial cell (EC) function and lung vascular homeostasis. We found reduced expression of RAB7 in ECs from PAH patients. Endothelial haploinsufficiency of RAB7 caused spontaneous PH in mice. Silencing of RAB7 in ECs induced broad changes in gene expression revealed via RNA sequencing and RAB7 silenced ECs showed impaired angiogenesis, expansion of a senescent cell fraction, combined with impaired endolysosomal trafficking and degradation, which suggests inhibition of autophagy at the pre-degradation level. Further, mitochondrial membrane potential and oxidative phosphorylation were decreased, and glycolysis was enhanced. Treatment with the RAB7 activator ML-098 reduced established PH in chronic hypoxia/SU5416 rats. In conclusion, we demonstrate here for the first time the fundamental impairment of EC function by loss of RAB7 that leads to PH and show RAB7 activation as a potential therapeutic strategy in a preclinical model of PH.

physiology↗

bioRxiv2023

USP39 promotes hepatocellular carcinogenesis through regulating alternative splicing in cooperation with SRSF6/HNRNPC

Abnormal alternative splicing (AS) caused by alterations in spliceosomal factors is implicated in cancers. Standard models posit that splice site selection is mainly determined by early spliceosomal U1, U2 snRNPs. Whether and how other mid/late-acting spliceosome components such as USP39 modulate tumorigenic splice site choice remain largely elusive. We observed that hepatocyte-specific knock-in of USP39 promoted hepatocarcinogenesis and potently regulated splice site selection. In human liver cancer cells, USP39 promoted tumor proliferation in a spliceosome-dependent manner. USP39 depletion deregulated hundreds of AS events, including the oncogenic splice-switching of KANK2. Mechanistically, we developed a novel RBP-motif enrichment analysis and found that USP39 modulated exon inclusion/exclusion by interacting with SRSF6/HNRNPC in both humans and mice. Our data represent a paradigm for the control of splice site selection by mid/late-acting spliceosome proteins and their interacting RBPs. USP39 and possibly other mid/late-acting spliceosome proteins may represent potential prognostic biomarkers and targets for cancer therapy. Graphic Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=97 SRC="FIGDIR/small/525324v1_ufig1.gif" ALT="Figure 1"> View larger version (32K): org.highwire.dtl.DTLVardef@34cbc1org.highwire.dtl.DTLVardef@2d0ee2org.highwire.dtl.DTLVardef@2c4bd6org.highwire.dtl.DTLVardef@26db00_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2023

Does the territorial behaviour of the Amur tiger affect the accuracy of occupancy estimation?

1. Accurate estimates of wildlife distributions and population persistence are essential for conservation programs. Occupancy models that account for detection probability have been used to characterize the occupancy and habitat selection of imperilled species. However, failure to distinguish between true-presence and pseudo-presence associated with territorial behaviour can result in the overestimation of the occupancy probability of target species in unsuitable habitats, and this can have major implications for the development of conservation strategies. 2. For highly territorial wildlife species requiring high-quality habitat for survival, occasional Presence in unsuitable areas might be related to dispersal or migration, but this does not reflect actual occupancy and habitat use. True-Presence and Pseudo-Presence should be distinguished for target species to better reflect their actual occupancy and habitat use. 3. To investigate the effect of True-Presence and Pseudo-Presence on wildlife occupancy estimation, we developed a modified model (Mm) that considers the territorial behaviour of the Amur tiger in northeast China, which distinguished between True-Presence and Pseudo-Presence. We compared two models, Mm and M0 (conventional occupancy model), and assessed model performance using goodness-of-fit evaluation, detection and occupancy probability, and favourable variable selection. 4. We found that Mm, which has fewer favourable variables, is more powerful than M0 for estimating detection and occupancy probability, as well as characterizing the effect of various factors on the habitat use of Amur tigers. Furthermore, Mm significantly reduced the overestimation of occupancy probability outside the home range compared with M0, and detection probability estimates did not significantly differ between M0 and Mm. Finally, Mm provided more empirical habitat selection variables for the Amur tiger. 5. Our results revealed how True-Presence and Pseudo-Presence affect the occupancy probability and habitat selection of Amur tigers. Our method improves the accuracy of occupancy models; it can also be used to characterize the habitat selection and distribution of wildlife species and be applied to other territorial species.

ecology↗

bioRxiv2023

Trophoblast organoids with physiological polarity model placental structure and function

Human trophoblast organoids (TOs) are a three-dimensional ex vivo culture model that can be used to study various aspects of placental development, physiology, and pathology. Previously, we showed that TOs derived from full-term human placental tissue could be used as models of trophoblast innate immune signaling and teratogenic virus infections. Here, we developed a method to culture TOs under conditions that recapitulate the cellular orientation of chorionic villi in vivo, with the multi-nucleated syncytiotrophoblast (STB) localized to the outer surface of organoids and the proliferative cytotrophoblasts (CTBs) located on the inner surface. We show that standard TOs containing the STB layer inside the organoid (STBin) develop into organoids containing the STB on the outer surface (STBout) when cultured in suspension with gentle agitation. STBout organoids secrete higher levels of select STB-associated hormones and cytokines, including human chorionic gonadotropin (hCG) and interferon (IFN)-{lambda}2. Using membrane capacitance measurements, we also show that the outermost surface of STBout organoids contain large syncytia comprised of >50 nuclei compared to STBin organoids that contain small syncytia (<10 nuclei) and mononuclear cells. The growth of TOs under conditions that mimic the cellular orientation of chorionic villi in vivo thus allows for the study of a variety of aspects of placental biology under physiological conditions.

cell biology↗

bioRxiv2023

A pilot study of stable isotope fractionation in Bombyx mori rearing

Hydrogen, oxygen, carbon, and nitrogen isotopes derived from three different strains of silkworms at different life stages involved in silkworm rearing, were measured to understand the fractionation characteristics of stable isotopes at different stages of silkworm development, and to trace the movement of these isotopes from food to larva to excrement and finally to silk. We found that silkworm strain had little effect on {delta}2H, {delta}18O and {delta}13C values. However, a large difference was found in the {delta}15N levels of newly-hatched silkworms between Jingsong Haoyue and Hua Kang No.3 orthogonal strains, suggesting that the mating and egg laying differences may result in an inconsistent kinetic nitrogen isotope fractionation. The {delta}13C values of silkworm pupae and silkworm cocoon also displayed significant differences, suggesting that heavy carbon isotopes are greatly fractionated from the larva to the silk during cocoon formation. Overall, these results may be used to clarify the relationship between isotope fractionation and the ecological process of the Bombyx mori and expand our ability to resolve stable isotope anomalies at a small regional-scale level.

biochemistry↗

bioRxiv2022

PanCanSurvPlot: A Large-scale Pan-cancer Survival Analysis Web Application

The identification of reliable tumor prognostic markers can help clinicians and researchers predict tumor development and patient survival outcomes more accurately, which plays a vital role in clinical diagnosis, treatment effectiveness assessment, and prognostic evaluation. Existing web tools supporting online survival analysis are gradually failing to meet the increasing demands of researchers in terms of the dataset size, richness of survival analysis methods, and diversity of customization features. Therefore, there is an urgent need for a large-scale, one-stop pan-cancer survival analysis web server. We developed PanCanSurvPlot (https://smuonco.shinyapps.io/PanCanSurvPlot/), a Shiny web tool that has incorporated a total of 215 cancer-related datasets from the GEO and TCGA databases, covering nearly 100,000 genes (mRNAs, miRNAs, and lncRNAs), approximately 45,000 samples, 51 different cancer types, and 13 different survival outcomes. The website also provides two cutoff methods based on median and optimal cutpoints. All survival analysis results from the log-rank test and univariate Cox regression are presented in a clear and straightforward summary table. Finally, users can customize color schemes and cutpoint levels to quickly obtain high-quality Kaplan-Meier survival plots that meet publication requirements.

cancer biology↗

bioRxiv2022

Comparative analysis of chloroplast genome between wild and cultivated Rehmannia glutinosa Libosch.

Rehmanniae radix, as a tonic Chinese medicine, has a good therapeutic effect on cardiovascular and cerebrovascular diseases and central nervous system diseases, and has a good development prospect in the international market. R.glutinosa Libosch has a large number of source varieties, and the wild and cultivated varieties are different types of R.glutinosa Libosch. There has been a lot of controversy in the formulation of scientific names for wild and cultivated types of R.glutinosa Libosch. In order to learn more about the genetic information of wild R.glutinosa Libosch and explore the phylogenetic relationship between wild R.glutinosa Libosch and cultivated R.glutinosa Libosch. In the current study, we constructed and annotated a complete circular chloroplast genome of wild R.glutinosa Libosch. The chloroplast genome of wild R.glutinosa Libosch. is 153,678 bp in length, including two inverted repeat (IR) regions of 25,759 bp, separated by a large single copy (LSC) region of 84,544 bp and a small single copy (SSC) region of 17,616 bp. The GC content of whole chloroplast genome is 37.9%. The genome contains 133 different genes, including 88 protein-coding genes, 37 tRNA genes, and 8 rRNA genes. Among them, 23 genes contained introns, 50 SSR loci and 49 long repeats were found by Microsatellite scan, and codon use showed obvious A, T base preference. Nine variation regions were screened by mVISTA analysis and combined with DnaSP analysis, and psaJ-rpl33 was finally identified as a region with high variation, which could be used as a candidate DNA barcode for later interspecific identification of R.glutinosa Libosch.. Neighbor-joining method phylogenomic analysis showed that wild R.glutinosa Libosch. formed a monophyletic group, and was sister to other groups of R.glutinosa Libosch.The results of this study revealed the chloroplast genome information of wild R.glutinosa Libosch in detail, and found the genetic information difference between wild and cultivated R.glutinosa Libosch. which laid the foundation for the variety identification, genetic engineering, biosynthesis and other studies.

molecular biology↗

bioRxiv2022

The structural basis of itch receptor MRGPRX1 activation

Mas-related G-protein-coupled receptors X1-X4 (MRGPRX1-X4) are four primate-specific receptors that are recently reported to be responsible for many biological processes, including itch sensation, pain transmission, and inflammatory reactions. MRGPRX1 is the first identified human MRGPR, and its expression is restricted to primary sensory neurons. Due to its dual roles in itch and pain signaling pathways, MRGPRX1 has been regarded as a promising target for itch remission and pain inhibition. Here, we reported a cryo-electron microscopy (cryo-EM) structure of Gq-coupled MRGPRX1 in complex with a synthetic agonist compound 16 in an active conformation at an overall resolution of 3.0 angstrom via a NanoBiT tethering strategy. Compound 16 is a new pain-relieving compound with high potency and selectivity to MRGPRX1 over opioid receptor. According to the structure analysis, we revealed that MRGPRX1 shares common features of the Gq-mediated receptor activation mechanism of MRGPRX family members. However, the variable residues in orthosteric pocket of MRGPRX1 exhibits the unique agonist recognition pattern, which may facilitate to design MRGPRX1-specific modulators. Together with receptor activation and itch behavior evaluation assays, our study provides a structural snapshot to modify therapeutic molecules for itch relieving and analgesia targeting MRGPRX1.

biochemistry↗

bioRxiv2022

Proteomic Landscape of Human Spermatozoa: Optimized Extraction Method and Application

Human spermatozoa proteomics exposed to some physical, biological or chemical stressors is being explored. However, there is a lack of optimized sample preparation methods to achieve in-depth protein coverage for sperm cells. Meanwhile, it is not clear whether antibiotics can regulate proteins to affect sperm quality. Here, we systematically compared a total of six different protein extraction methods based the combination of three commonly used lysis buffers and physical lysis strategies. The urea buffer combined with ultrasonication (UA_ultrasonication) produced the highest protein extraction rate, leading to the deepest coverage of human sperm proteome (5685 protein groups) from healthy human sperm samples. Since the antibiotics, amoxicillin and clarithromycin, have been widely used against H. pylori infection, we conduct a longitudinal study of sperm proteome via data-independent acquisition tandem mass spectrometry (DIA-MS/MS) on an infected patient during on and off therapy with these two drugs. The semen examination and morphological analysis were performed combined with proteomics analysis. Our results indicated that antibiotics may cause an increase in the sperm concentration and the rate of malformed sperm and disrupt proteome expression in sperm. This work provides an optimized extraction method to characterize the in-depth human sperm proteome and to extend its clinical applications.

biochemistry↗

bioRxiv2022

ACNN-6mA: Prediction of N6-Methyladenine Loci in Multiple Species Based on Rice Dataset Pre-training Model

N6-methyladenine is an epigenetic modification that plays a significant role in various cellular processes. Genome-wide monitoring of methylation sites is conducive to understanding the biological function of methylation. Due to the limitations of traditional dry and wet experiments, a series of machine learning and deep learning methods have been developed to detect methylation sites, but their detection species are single or performance is poor. First of all, we conducted sufficient experiments on the widely studied rice datasets, and compared with the previous research, we have greatly improved in various indicators on the two rice datasets. Then we used the models trained on the rice dataset to fine-tune training in half of the other 11 datasets and predict the other half of the independent datasets. Then we used 11 trained models to test 11 species respectively. It was found that ACNN-6mA could obtain higher AUC, ACC and MCC whether cross-species prediction or independent verification set prediction. ACNN-6mA model and code for follow-up researchers is provided as an open-source tool available at https://github.com/jrebai/ACNN-6mA.

bioinformatics↗

bioRxiv2022

Upgrading Voxel-wise Encoding Model via Integrated Integration over Features and Brain Networks

A central goal of cognitive neuroscience is to build computational models that predict and explain neural responses to sensory inputs in the cortex. Recent studies attempt to borrow the representation power of deep neural networks (DNN) to predict the brain response and suggest a correspondence between artificial and biological neural networks in their feature representations. However, each DNN instance is often specified for certain computer vision tasks which may not lead to optimal brain correspondence. On the other hand, these voxel-wise encoding models focus on predicting single voxels independently, while brain activity often demonstrates rich and dynamic structures at the population and network levels during cognitive tasks. These two important properties suggest that we can improve the prevalent voxel-wise encoding models by integrating features from DNN models and by integrating cortical network information into the models. In this work, we propose a new unified framework that addresses these two aspects through DNN feature-level ensemble learning and brain atlas-level model integration. Our proposed approach leads to superior performance over previous DNN-based encoding models in predicting whole-brain neural activity during naturalistic video perception. Furthermore, our unified framework also facilitates the investigation of the brains neural representation mechanism by accurately predicting the neural response corresponding to complex visual concepts.

neuroscience↗

bioRxiv2022

The nanopore sequencing of a Chinese rhesus macaque revealed patterns of methylation, recombination, and selection for structural variations

Rhesus macaques (Macaca mulatta) are the most extensively studied nonhuman primate species for human biomedical modeling. However, little is known about the biological pattern of genome-wide structural variations (SVs) and the evolutionary forces underlying SVs. Here, we conducted genomic sequencing and analyses based on Nanopore long reads and Illumina short reads technology. We called SVs between the two subspecies (China vs. India), using three methods of assembly-based and long-reads-based algorithms. Interestingly, we found significantly more SVs in X-chromosome than in autosomes, consistent with the expectation of the faster-X divergence at the subspecies level. With the fine-scale methylation frequencies and recombination rates, we found duplications with significantly lower methylation frequencies while higher recombination rates than other types of SVs, suggesting a higher level of transcriptional and evolutionary potential for duplications than for other SVs types. A genome-wide scan of selective sweep revealed that over 3% of SVs are under positive selection. Moreover, X chromosome showed significantly higher number of positively selected SVs than do autosomes, suggesting the "faster-X effect" of SVs. Our study revealed a different evolutionary importance for duplications compared with other SVs forms. We also revealed the "faster-X effect" of SVs, which could provide raw material upon which positive selection can further play.

genomics↗