Biology subjects

Cao, Z.

Publications and source records attributed to Cao, Z..

At least 73 records · Page 4Linked to original sources

bioRxiv2024

Endogenous retroviruses activate MARCO-mediated inflammatory response to block retroviral infection

Endogenous retroviruses (ERVs) are remnants of ancient retroviral infections and can profoundly affect the host antiviral innate immune response, although the mechanisms by which these changes occur are largely unknown. Here we report that chicken-specific ERVs exert genetic resistance to exogenous retrovirus infection. Mechanistically, chicken-specific ERVs activated the scavenger receptor MARCO (macrophage receptor with collagenous structure)-mediated TLR3-IL-1{beta} inflammatory response in macrophages. Under the presence of MARCO, macrophages response to viral infection through inducing TLR3-IL-1{beta} inflammatory response. Conversely, lack of MARCO increased the viral replication levels and attenuated the antiviral inflammatory response. MARCO-mediated ligand delivery enhances TLR3-IL-1{beta} antiviral response, and IL-1{beta} expression is responsible for viral inhibition. Restoring MARCO or IL-1{beta} expression overcomes viral infection in macrophages. Our study provides new insights into the molecular mechanisms underlying the host defense against exogenous retroviruses infection and may have important implications for the development of novel therapeutic strategies against retroviruses infection.

immunology↗

bioRxiv2024

Survival of hepatocytes from executioner caspase activation promotes liver regeneration by enhancing JAK/STAT3 activity

Activation of executioner caspases, which is a key step in the apoptotic process, has been reported to promote tissue regeneration by sending pro-proliferation signals to the surrounding cells. However, whether executioner caspase activation (ECA) has cell-autonomous effect on tissue regeneration is not clear. Here, by generating transgenic mice carrying a lineage tracing system for cells that have experienced ECA, we demonstrate that transient ECA occurs in hepatocytes during liver regeneration after partial hepatectomy (PHx) or carbon tetrachloride (CCl4) treatment. Instead of committing apoptotic cell death, the majority of hepatocytes with ECA survive and proliferate to contribute to liver regeneration. Interestingly, inhibition of ECA in livers results in reduced hepatocyte proliferation and impaired regeneration, whereas increasing ECA to a level sufficient to kill hepatocytes also impedes regeneration, suggesting that ECA needs to be precisely controlled during liver regeneration. Mechanistic studies show that ECA promotes hepatocyte proliferation during regeneration through enhancing JAK/STAT3 activity. Our work reveals an essential role of survival of hepatocytes from ECA in liver regeneration.

developmental biology↗

bioRxiv2024

Repeated activation of preoptic area-recipient neurons in posterior paraventricular nucleus mediates chronic heat-induced negative emotional and hyperarousal states

Mental and behavioral disorders are associated with extended period of hot weather as found in heatwaves, but the underlying neural circuit mechanism is poorly known. The posterior paraventricular thalamus (pPVT) is a hub for emotional processing and receives inputs from the hypothalamic preoptic area (POA), the well-recognized thermoregulation center. The present study was designed to explore whether chronic heat exposure leads to aberrant activities in POA recipient pPVT neurons and subsequent changes in emotional states. By devising an air heating paradigm mimicking the condition of heatwaves and utilizing emotion-related behavioral tests, viral track tracing, in vivo calcium recordings, optogenetic manipulations and electrophysiological recordings, we found that chronic heat exposure for 3 weeks led to negative emotional valence and hyperarousal states in mice. The pPVT neurons receive monosynaptic excitatory and inhibitory innervations from the POA. These neurons exhibited a persistent increase in neural activity following chronic heat exposure, which was essential for chronic heat-induced emotional changes. Notably, these neurons were also prone to display stronger neuronal activities associated with anxiety responses to stressful situations. Furthermore, we observed saturated neuroplasticity in the POA-pPVT excitatory pathway after chronic heat exposure that occluded further potentiation. Taken together, long-term aberration in the POA to pPVT pathway offers a neurobiological mechanism of emotional and behavioral changes seen in extended periods of hot weather like heatwaves.

neuroscience↗

bioRxiv2024

PLINDER: The protein-ligand interactions dataset and evaluation resource

Protein-ligand interactions (PLI) are foundational to small molecule drug design. With computational methods striving towards experimental accuracy, there is a critical demand for a well-curated and diverse PLI dataset. Existing datasets are often limited in size and diversity, and commonly used evaluation sets suffer from training information leakage, hindering the realistic assessment of method generalization capabilities. To address these shortcomings, we present PLIN-DER, the largest and most annotated dataset to date, comprising 449,383 PLI systems, each with over 500 annotations, similarity metrics at protein, pocket, interaction and ligand levels, and paired unbound (apo) and predicted structures. We propose an approach to generate training and evaluation splits that minimizes task-specific leakage and maximizes test set quality, and compare the resulting performance of DiffDock when retrained with different kinds of splits.

biochemistry↗

bioRxiv2024

The effects of L-carnitine and fructose in improved Ham's F10 on sperm culture in idiopathic severe asthenospermia within 24h

Trial designTo study the effects of L-carnitine and fructose on semen parameters of severe asthenospermia patients by sperm culturing in vitro within 24h. We optimized the energy composition and antioxidant substances of sperm culture medium in vitro (based on Hams F10 culture medium) by orthogonal test for preparing high quality culture medium. Sperms of 60 patients with idiopathic severe asthenospermia were collected, and cultured in vitro within 24h, by Hams F10 culture medium added to different concentrations of L-carnitine and fructose and culture temperature, whose effects on sperm motility were observed to determine which is the most appropriate concentration and temperature. MethodsFor determining the appropriate concentration of L-carnitine and fructose and the suitable culture temperature in Hams F10 culture medium, the orthogonal experiments were carried out to optimize above three factors, which had great influence on sperm viability, survival rate, deformity rate and DNA fragmentation index (DFI). ResultsThe final concentration of L-carnitine and fructose was determined in terms of initial tests to assess the effects of different concentrations (4, 8, 12, and 16 mg/ml L-carnitine and 0.125, 0.250, 0.375, and 0.50 mg/ml fructose) on sperm viability and motility in culture. During the operation of processing and culturing sperms in vitro within 24h, orthogonal test showed that sperm viability was better at the final concentration of 8 mg/ml L-carnitine and 0.375 mg/mL fructose in improved Hams F10 culture medium at 36.5 . ConclusionIdiopathic severe asthenospermia sperm can be effectively improved by the modified Hams F10 culture medium of the final concentration of 8 mg/ml L- carnitine and 0.375 mg/mL fructose in at 36.5 within 24h, which has shown better culture effect and is superior to Hams F10 basic medium.

biochemistry↗

bioRxiv2024

CosGeneGate Selects Multi-functional and Credible Biomarkers for Single-cell Analysis

Selecting representative genes or marker genes to distinguish cell types is an important task in single-cell sequencing analysis. Although many methods have been proposed to select marker genes, the genes selected may have redundancy and/or do not show cell-type-specific expression patterns to distinguish cell types. Here we present a novel model, named CosGeneGate, to select marker genes for more effective marker selections. CosGeneGate is inspired by combining the advantages of selecting marker genes based on both cell-type classification accuracy and marker gene specific expression patterns. We demonstrate the better performance of the marker genes selected by CosGeneGate for various downstream analyses than the existing methods with both public datasets and newly sequenced datasets. The non-redundant marker genes identified by CosGeneGate for major cell types and tissues in human can be found at the website as follows: https://github.com/VivLon/CosGeneGate/blob/main/marker gene list.xlsx.

bioinformatics↗

bioRxiv2024

Adipocyte microRNA-802 promotes adipose tissue inflammation and insulin resistance by modulating macrophages in obesity

Adipose tissue inflammation is now considered to be a key process underlying metabolic diseases in obese individuals. However, it remains unclear how adipose inflammation is initiated and maintained or the mechanism by which inflammation develops. We found that microRNA-802 (miR-802) expression in adipose tissue is progressively increased with the development of dietary obesity in obese mice and humans. The increasing trend of miR-802 preceded the accumulation of macrophages. Adipose tissue-specific knockout of miR-802 lowered macrophage infiltration and ameliorated systemic insulin resistance. Conversely, the specific overexpression of miR-802 in adipose tissue aggravated adipose inflammation in mice fed a high-fat diet. Mechanistically, miR-802 activates noncanonical and canonical NF-{kappa}B pathways by targeting its negative regulator, TRAF3. Next, NF-{kappa}B orchestrated the expression of chemokine and SREBP1, which translated into strong recruitment and M1-like polarization of macrophages. Our findings indicate that miR-802 endows adipose tissue with the ability to recruit and polarize macrophages, which underscores miR-802 as an innovative and attractive candidate for miRNA-based immune therapy for adipose inflammation.

immunology↗

bioRxiv2024

Clostridium ablates tumors by degrading collagen mesh andinducing ferroptosis

The supportive role of extracellular matrix in tumor growth and the drug resistance of tumor cells stand the major challenges in treating cancer. Here, we report the discovery of an oncolytic Clostridium strain, named RJ-1, which simultaneously expresses collagenases and produces iron-containing particles through intrabacterial mineralization. The secreted collagenases degrade pre-existing collagen mesh and show a collagen concentration-dependent degradation feature. Iron-containing particles released from RJ-1 by autolysis generate ferrous ions in the lysosomal acid environment following cell uptake and subsequently induce ferroptosis via the Fenton reaction. Due to selective germination in tumor sites, systemic administration of RJ-1 spores synchronously destructs dense tumor extracellular matrix and causes non-apoptotic tumor cell death. In collagen-dense tumor-bearing mice, a single intravenous injection achieves a favorable tolerance and rapid oncolysis of giant tumors with a size of [~]1000 mm3. This work finds a dual collagenase-expressing and iron-concentrating bacterium, proposing an alternative strategy to combat tumors.

microbiology↗

bioRxiv2024

Joint distribution of nuclear and cytoplasmic mRNA levels in stochastic models of gene expression: analytical results and parameter inference

Common stochastic models of gene expression predict the analytical distribution of the total mRNA level per cell but not at subcellular resolution. Here, for a wide class of models of transcription initiation, we obtain an exact steady-state solution for the joint distribution of nuclear and cytoplasmic mRNA levels per cell. Correcting the solution for extrinsic noise and fitting to single human cell data, we precisely quantify the extent of bursty expression in thousands of genes and associate it with their biological functions.

biophysics↗

bioRxiv2024

Feather degradation in Stenotrophomonas maltophilia relies on conversion and internalization of keratin monomer

Feather keratin is the most abundant nitrogen source waste in nature. This insoluble material cannot be directly utilized as nutrition by most organisms, especially animals and plants. While feathers are naturally decomposed by some microorganisms through keratinase-based degradation which remains mechanistically not fully understood. In this study, we find that when feathers serve as the only nutrient source for Stenotrophomonas maltophilia culture, keratin monomer of about 10 kDa is present in the medium as a predominant hydrolyzed product. We further show that keratin monomers bind to cells and in turn enter cells via an undetermined pathway. The cell entry of keratin monomer elicits keratinase activity to promote the forward reaction in keratin hydrolysis. This study highlights the importance of keratin monomer production as the first step in feather biodegradation, in which the insoluble feather is converted into soluble intermediate to facilitate its internalization and complete hydrolysis. ImportanceA large amount of feathers have been produced in poultry breeding, which could cause environmental pollution if not processed in time. On the other hand, amino acids degraded from feathers can be used in many fields, such as feed, fertilizer, daily chemicals and other fields. Biodegradable feathers have the advantages of low energy consumption, mild conditions and no destruction of the amino acids obtained from degradation. We previously isolated and identified a highly efficient feather-degrading bacterium, Stenotrophomonas maltophilia DHHJ, which can grow well on the medium with feathers as the only nutrient and completely degrade feathers. We know, feather particles are much larger than bacterial cells. In what form and how they are absorbed into cells by bacteria are interesting and critical questions for feather degradation. In our research, feathers had been first degraded extracellularly by basically expressed keratinase into keratin monomers. The keratin monomers bound to cells and enter across the membrane and can induce further expression of keratinase. The understanding of keratin monomers provides new clues for the study of feather degradation mechanisms.

microbiology↗

bioRxiv2024

Screening of functional maternal-specific chromatin regulators in early embryonic development

The early stages of embryonic development rely on maternal products for proper regulation. However, systematic screening for functional maternal-specific factors has been challenging due to the time- and labor-intensive nature of traditional approaches. Here, we combined a computational pipeline and F0 homozygous mutation technology to screen for functional maternal-specific chromatin regulators in zebrafish embryogenesis and identified Mcm3l, Mcm6l, and Npm2a as playing essential roles in DNA replication and cell division. Our results contribute to understanding the molecular mechanisms underlying early embryo development and highlight the importance of maternal-specific chromatin regulators in this critical stage.

developmental biology↗

bioRxiv2024

Mathematical Modelling Indicates Th-cell Targeted Antibody-Dependent Cellular Cytotoxic Is a Crucial Obstacle Hurdling HIV Vaccine Development

HIV poses a significant threat to human health. Although some progress has been made in the development of an HIV vaccine, there is currently no reported success in achieving an effective and fully functional vaccine for HIV. This highlights the challenges involved in HIV vaccine development. Through mathematical modeling, we have conducted a systematic study on the impact of antibody-dependent cellular cytotoxicity (ADCC) on HIV-specific immune responses. Unlike other viral infections, the ADCC effect following HIV infection may cause significant damage to the follicular center Th cells, leading to apoptosis of follicular center cells and rapid death of effector Th cells. This impedes the generation of neutralizing antibodies and creates barriers to viral clearance, thereby contributing to long-term infection. Another challenge posed by this effect is the substantial reduction in vaccine effectiveness, as effective antigenic substances such as gp120 bind to Th cell surfaces, resulting in the apoptosis of follicular center Th cells due to ADCC, hindering antibody regeneration. To address this issue, we propose the concept of using bispecific antibodies. By genetically editing B cells to insert the bispecific antibody gene, which consists of two parts-one targeting the CD4 binding site of HIV, such as the broadly neutralizing antibody 3BNC117, and the other targeting antibodies against other viruses, such as the spike protein of SARS-CoV-2-we can simultaneously enhance the levels of two pathogen-specific antibodies through stimulation with non-HIV-antigens corresponding to the other part of the chimeric antibody, such as the spike protein. This study contributes to the elucidation of the pathophysiology of HIV, while also providing a theoretical framework for the successful development of an HIV vaccine.

immunology↗

bioRxiv2024

PRMT5 deficiency disturbs Nur77 methylation to inhibit endometrial stromal cell differentiation in recurrent implantation failure

Various posttranslational modifications (PTMs) have been implicated in endometrial stromal cell (EnSC) differentiation, but the potential role of PTM crosstalk has not been identified. Here, we report that protein arginine methyltransferase 5 (PRMT5) is indispensable for human endometrial decidualization, functioning as a key regulator of decidualization defect in recurrent implantation failure (RIF) patients. Uterine-selective deletion of Prmt5 led to defective embryo implantation in mice due to impaired EnSC decidualization. Mechanistically, we find that PRMT5 catalyzes symmetric dimethylation of orphan nuclear receptor Nur77 at arginine 346, which in turn promotes Nur77 nuclear localization and increases its transcriptional activity in EnSC. Moreover, we demonstrate that PRMT5-mediated Nur77 methylation antagonizes AKT-induced phosphorylation of Nur77 at serine 351 in the transition from proliferation to differentiation of EnSC and disruption of the balance between methylation and phosphorylation of Nur77 is essentially involved in the endometrium of RIF patients. Furthermore, by modulating the methylation-phosphorylation of Nur77 and its transcriptional activity, we rescued impaired decidualization in RIF, further highlighting the critical role of the PRMT5/AKT/Nur77 complex in uterine receptivity to embryo implantation.

cell biology↗

bioRxiv2023

Understanding Genome Structure Facilitates the Use of Wild Lentil Germplasm for Breeding: A Case Study with Shattering Loci

Plant breeders are generally reluctant to cross elite crop cultivars with their wild relatives to introgress novel desirable traits due to associated negative traits such as pod shattering. This results in a genetic bottleneck that could be reduced through better understanding of the genomic locations of the gene(s) controlling this trait. We integrated information on parental genomes, pod shattering data from multiple environments, and high-density genetic linkage maps to identify pod shattering QTLs in three lentil interspecific recombinant inbred line (RIL) populations. The broad-sense heritability on a multi-environment basis varied from 0.46 (in LR-70, Lens culinaris x L. odemensis) to 0.77 (in LR-68, L. orientalis x L. culinaris). Genetic linkage maps of the interspecific populations revealed reciprocal translocations of chromosomal segments that differed among the populations, and which were associated with reduced recombination. Segregation distortion was also observed for clusters of SNPs on multiple chromosomes per population, further affecting introgression. Two major QTL, on chromosomes 4 and 7, were repeatedly detected in the three populations and contain several candidate genes. These findings will be of significant value for lentil breeders to strategically access novel superior alleles while minimizing the genetic impact of pod shattering from wild parents.

plant biology↗

bioRxiv2023

Revisiting the Kuleshov effect with authentic films: A behavioral and fMRI study

As a fundamental film theory, montage theory posits that film editing significantly influences the viewers perception. The Kuleshov effect, a central concept in montage theory, proposes that the emotional interpretation of neutral facial expressions is influenced by the accompanying emotional scene in a face-scene-face sequence. However, concerns persist regarding the validity of previous studies, often employing inauthentic film materials like static images, leaving the question of its existence in authentic films unanswered. This study addresses these concerns by utilizing authentic films in two experiments. In Experiment 1, multiple film clips were captured under the guidance of a professional film director and seamlessly integrated into authentic film sequences. A total of 59 participants viewed these face-scene-face film sequences and were tasked with rating the valence of neutral faces. The findings revealed that the interpretation of emotion in neutral faces is significantly influenced by the accompanying fearful or happy scene, eliciting perceptions of negative or positive emotion from the neutral face. These results affirm the existence of the Kuleshov effect within authentic film sequences. In Experiment 2, 31 participants engaged in a similar task under functional magnetic resonance imaging (fMRI). The results revealed neural correlates supporting the existence of the Kuleshov effect at a neural level. These correlates include the cuneus, precuneus, hippocampus, parahippocampal gyrus, post cingulate gyrus, orbitofrontal cortex, fusiform gyrus, and insula. These findings also underscore the contextual framing inherent in the Kuleshov effect. By seamlessly integrating film theory and cognitive neuroscience experiments, this comprehensive study provides robust evidence supporting the existence of the Kuleshov effect. It significantly enhances our understanding of film editing and its profound impact on viewers perception.

neuroscience↗

bioRxiv2023

The receptor VLDLR binds East Equine Encephalitis virus through multiple distinct modes

Eastern Equine Encephalitis virus (EEEV) is an alphavirus that can cause severe diseases in infected humans. The very low-density lipoprotein receptor (VLDLR) was recently identified as a receptor of EEEV. Herein, we performed cryo-electron microscopy structural and biochemistry studies on the specific interactions between EEEV and VLDLR. Our results show that VLDLR binds EEEV at three different sites A, B and C through its membrane-distal 8 LDLR class A (LA) repeats (LA1-8). Site A is located in the cleft in between the E1-E2 heterodimers of the surface trimeric spikes. Site B is located near the connecting {beta} ribbon in between the B and A-C domains of E2 and is in proximity to site A, while site C is on the domain B of E2. LA1 and LA5 specifically recognize site A, whereas LA2, LA3 and LA6 can bind both sites A and C. The binding of VLDLR LAs to EEEV is in complex modes. The LA1-2 mediated binding plays a critical role in mediating virus entry. The mutation W132G of VLDLR impairs the binding of LA3, drives the switch of the binding modes, and significantly enhances the attachment of EEEV to the cell. The W132G variant of VLDLR could be identified in human genome and SNP sequences, implying that people with similar mutations in VLDLR may be highly susceptible to EEEV infection.

microbiology↗

bioRxiv2023

ProTokens: A Machine-Learned Language for Compact and Informative Encoding of Protein 3D Structures

Understanding functions of proteins and designing proteins committed to specific functions in silico are highly valuable for science, industry and therapeutics. However, there is a long-standing divergence in how to present function-related protein structures to the machine learning models: Although the 1-dimensional (1D) representation of proteins via Anfinsens tokens (i.e., amino acids) is sufficient in principle and more machine-friendly, it is less successful in structure-oriented protein design compared to symmetry-constrained 3D representation (i.e., atom coordinates). Aiming to bridge the gap between 1D and 3D protein representations and harvest the advantages of the two, we develop probabilistic tokenization theory for metastable protein structures. We present an unsupervised learning strategy, which conjugates inverse folding with structure prediction, to encode protein structures into artificial amino-acid tokens (ProTokens) and decode them back to atom coordinates. We show that tokenizing protein structures variationally can lead to compact and informative representations. Compared to amino acids -- the Anfinsens tokens -- ProTokens are easier to detokenize and more descriptive of finer conformational ensembles. Therefore, protein structures can be efficiently compressed, stored, aligned and compared in the form of ProTokens. By unifying the discrete and continuous representations of protein structures, ProTokens also enable all-atom protein structure design via various generative models without the concern of symmetry or modality mismatch, and allows scalable foundation models to perceive, process and explore the microscopic structures of biomolecules effectively.

bioinformatics↗

bioRxiv2023

Ubiquitin Ligase MARCH5 Regulates the Formation of Mitochondria Derived Pre-peroxisomes

Peroxisome biogenesis involves two pathways: growth and division from pre-existing mature peroxisomes and de novo biogenesis from the endoplasmic reticulum, with a contribution from mitochondria, particularly in peroxisome deficient cells. However, the key components that regulate peroxisome de novo biogenesis are largely unknown. Dual organelle localized ubiquitin ligase MARCH5 functions on peroxisomes to regulate pexophagy. Here, we show that mitochondria localized MARCH5 is essential for the formation of vesicles in the de novo biogenesis of peroxisomes from mitochondria. Loss of MARCH5 specifically impedes the budding of PEX3-containing vesicles from mitochondria, thereby blocking the formation of pre-peroxisomes. Overall, our study highlights a novel function of MARCH5 for mitochondria derived pre-peroxisomes, emphasizing MARCH5 as one key regulator to maintain peroxisome homeostasis.

cell biology↗