Biology subjects

Zhang, L.

Publications and source records attributed to Zhang, L..

At least 1,189 records · Page 66Linked to original sources

bioRxiv2021

AutoGGN: A Gene Graph Network AutoML tool for Multi-Omics Research

Omics data identifies biological characteristics from genetic to phenotypic levels during the life span. Molecular interaction networks have a fundamental impact on life activities. Integrating omics data and molecular interaction networks will help researchers delve into comprehensive information underlying the data. Here, we proposed a new multimodal method called AutoGGN to aggregate multi-omics data and molecular interaction networks based on graph convolutional neural networks. We evaluated AutoGGN using two different tasks: cancer type classification and single-cell stage classification. On both tasks, AutoGGN showed better performance compared to other methods, the trend is relevant to the ability of utilizing much more information from biological data. The phenomenon indicated AutoGGN has the potential to incorporate valuable information from molecular interaction networks and multi-omics data effectively. Furthermore, in order to provide a better understanding of the mechanism of prediction results, we assessed the explanation using SHAP module and identified the key genes contributing to the prediction of classification, which will provide insights for the downstream design of biological experiments.

bioinformatics↗

bioRxiv2021

Effects of non-invasive brain stimulation on visual perspective taking: A meta-analytic study

Visual perspective taking (VPT) is a critical ability required by complex social interaction. Non-invasive brain stimulation (NIBS) has been increasingly used to examine the causal relationship between brain activity and VPT, yet with heterogeneous results. In the current study, we conducted two meta-analyses to examine the effects of NIBS of the right temporoparietal junction (rTPJ) or dorsomedial prefrontal cortex (dmPFC) on VPT, respectively. We performed a comprehensive literature search to identify qualified studies, and computed the standardized effect size (ES) for each combination of VPT level (Level-1: visibility judgment; Level-2: mental rotation) and perspective (self and other). Thirteen studies (rTPJ: 12 studies, 23 ESs; dmPFC: 4 studies, 14 ESs) were included in the meta-analyses. Random-effects models were used to generate the overall effects. Subgroup analyses for distinct VPT conditions were also performed. We found that rTPJ stimulation significantly improved participants visibility judgment from the allocentric perspective, whereas its effects on other VPT conditions are negligible. Stimulation of dmPFC appeared to influence Level-1 performance from the egocentric perspective, although it was only based on a small number of studies. Notably, contrary to some theoretical models, we did not find strong evidence that these regions are involved in Level-2 VPT with a higher requirement of mental rotation. These findings not only advanced our understanding of the causal roles of the rTPJ and dmPFC in VPT, but also revealed the efficacy of NIBS on VPT is relatively small. Researchers should also be cautious about the potential publication bias and selective reporting.

neuroscience↗

bioRxiv2021

Geraniol Enhances Inhibitory Inputs to Paraventricular Thalamic Nucleus and Induces Sedation in Mice

Geraniol (GE), a plant-derived acyclic monoterpene, shows a wide variety of beneficial effects. Notably, recent studies have reported the potential sedative effects of GE in fish and rats. However, the mechanisms of GE in sedation remain elusive. Here, we found that GE reduced locomotion, relieved pentylenetetrazol (PTZ)-induced seizures, altered the electroencephalogram (EEG), and facilitated general anesthesia in mice. Meanwhile, GE decreased c-Fos expression and suppressed the calcium activity in the paraventricular thalamic nucleus (PVT). Microinjection of GE into the PVT reduced locomotion and facilitated propofol-induced anesthesia. Furthermore, the electrophysiology results showed that GE-induced dramatic membrane hyperpolarization and suppressed the neuronal activity of PVT neurons, mainly by prolonging spontaneous inhibitory postsynaptic currents and inducing tonic inhibitory currents via GABAA receptors. Our study revealed that GE enhances inhibitory inputs to PVT neurons and induces sedation in mice. These findings provide a potential candidate for further development of sedatives and anesthetics. Graphic Summary O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=156 SRC="FIGDIR/small/441289v1_ufig1.gif" ALT="Figure 1"> View larger version (37K): org.highwire.dtl.DTLVardef@fd8424org.highwire.dtl.DTLVardef@1ee77caorg.highwire.dtl.DTLVardef@faab42org.highwire.dtl.DTLVardef@101b921_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2021

Variations in soil nutrient dynamics and bacterial communities in long-term tea monoculture production systems

Long-term monoculture agriculture systems could lead to soil degradation and yield decline. The ways in which soil microbiotas interact with one another, particularly in response to long-term tea monoculture systems are currently unclear. In this study, through the comparison of three independent tea plantations across eastern China composed of varying stand ages (from 3 years to 90 years after conversion from forest), we found that long-term tea monoculture led to significant increases in soil total organic carbon (TOC) and microbial nitrogen (MBN). Additionally, the structure, function and co-occurrence network of soil microbial communities were investigated by pyrosequencing 16S rRNA genes. The pyrosequencing analysis revealed that structures and functions of soil bacterial communities were significantly affected by different stand ages of tea plantations, but sampling sites and land-use conversion (from forest to tea plantation) still outcompeted stand age to control the diversity and structure of soil bacterial communities. Further RDA analysis revealed that the C and N availability improvement in tea plantation soils led to variation of structure and function in soil microbial communities. Moreover, co-occurrence network analysis of soil bacterial communities also demonstrated that interactions among soil bacteria taxa were strengthened with the increasing stand age of respective tea stands. Overall, this study provides a comprehensive understanding of the impact of long-term monoculture stand age on soil nutrient dynamics and bacterial communities in tea production.

ecology↗

bioRxiv2021

Spatial transcriptome sequencing revealed spatial trajectory in the Non-Small Cell Lung Carcinoma

Deepening understanding in the heterogeneity of tumors is critical for clinical treatment. Here we investigate tissue-wide gene expression heterogeneity throughout a multifocal lung cancer using the spatial transcriptomics (ST) technology. We identified gene expression gradients in stroma adjacent to tumor regions that allow for re-understanding of the tumor micro-environment. The establishment of these profiles was the first step towards an unbiased view of lung cancer and can serve as a dictionary for future studies. Tumor subclones were detected by ST technology in our research, while we contrast the EMT ability among in subclones which inferred the possible trajectory of tumor metastasis and invasion, which was confirmed by constructing the pseudo-time model of spatial transition within subclones. Together, these results uncovered lung cancer spatial heterogeneity, highlight potential tumor micro-environment differences and spatial evolution trajectory, and served as a resource for further investigation of tumor microenvironment.

cancer biology↗

bioRxiv2021

The receptor kinase SRF3 coordinates iron-level and flagellin dependent defense and growth responses in plants

Iron is critical for host-pathogen interactions. While pathogens seek to scavenge iron to spread, the host aims at decreasing iron availability to reduce pathogen virulence. Thus, iron sensing and homeostasis are of particular importance to prevent host infection and part of nutritional immunity. While the link between iron homeostasis and immunity pathways is well established in plants, how iron levels are sensed and integrated with immune response pathways remain unknown. We identified a receptor kinase, SRF3 coordinating root growth, iron homeostasis and immunity pathways via regulation of callose synthase activity. These processes are modulated by iron levels and rely on SRF3 extracellular and kinase domain which tune its accumulation and partitioning at the cell surface. Mimicking bacterial elicitation with the flagellin peptide flg22 phenocopies SRF3 regulation upon low iron levels and subsequent SRF3-dependent responses. We propose that SRF3 is part of nutritional immunity responses involved in sensing external iron levels.

plant biology↗

bioRxiv2021

METTL9 regulates N1-histidine methylation of zinc transporters to promote tumor growth

Methyltransferase like 9 (Mettl9) is a member of the methyltransferase like protein family which is characterized by the presence of binding domains for S-adenosyl methionine, (SAM), a co-substrate for methylation reactions. Despite METTL9 is predicted to be a methyltransferase, its enzymatic activity, substrate specificities and biological functions are still poorly characterized. In this study, we revealed a tumor-promoting role for METTL9. We found that deletion of Mettl9 in tumor cells suppresses tumor growth and elicits potent anti-tumor immunity. Mechanistically, METTL9 is a N1-histidine methyltransferase which methylates the histidine residues of a x-His-x-His (xHxH) motif on the substrates. This motif is found extensively in zinc transporter families SLC39s and SLC30s, particularly in SLC39A7. Deletion of Mettl9 impairs cytoplasmic zinc homeostasis, resulting in an altered gene expression program with increased endoplasmic reticulum (ER) stress and reduced cell cycle. Mutation of key METTL9 catalyzed methylhistidine residues of SLC39A7 impairs cytoplasmic zinc homeostasis and affects cell growth as well. Notably, METTL9 expression is increased in some cancer types and its higher expression is associated with worse clinical outcomes, particularly in liver and pancreatic cancer. In summary, our work identified METTL9 as a potential new oncogene and its mediated methylation is of regulatory importance. Identifying selective and potent small-molecule inhibitors of METTL9 could thus represent novel therapeutic strategy for anti-proliferative cancer drugs.

cancer biology↗

bioRxiv2021

A Two-Component System FleS/FleR Regulates Multiple Virulence-Related Traits in Pseudomonas aeruginosa

Microorganisms commonly use two-component systems (TCSs) to detect specific environmental changes and respond accordingly for their own benefit. However, the regulatory mechanisms and physiological roles of a majority of TCSs are still elusive. In this study, we focused on a previously predicted TCS FleS/FleR in Pseudomonas aeruginosa to systematically investigate its regulation and physiological roles. Loss of fleS or fleR or both genes led to decreased biofilm formation and attenuated motility in PAO1, which could be restored by heterologously complementation of FleR but not FleS, confirming that the sensor kinase FleS and the response regulator FleR constitute a TCS pair. To determine the regulatory spectrum of this TCS, we conducted transcriptome sequencing and comparison between the wild-type strain and the fleR deletion mutant. The result showed that the TCS regulates about 440 genes including most of them are involved in the virulence-related pathways, e.g. siderophore biosynthesis, pyocyanin biosynthesis, type III/VI secretion systems, c-di-GMP metabolism, flagellar assembly etc. In addition to its roles in controlling biofilm formation and motility we have already shown, FleR was demonstrated to regulate the production of virulence factors such as pyocyanin and elastase, mediate stress response to SDS, and autoregulate its own expression. Moreover, EMSA assays revealed that FleR regulates flagellum biosynthesis genes flgBCDE, flgFGHIJKL, filC, which are essential for the bacterial motility, by directly interacting with their promoters. Taken together, these results expanded our understanding on the biological roles of FleS/FleR and provided new insights on its regulatory mechanisms.

molecular biology↗

bioRxiv2021

Single-cell analysis reveals MHCII expressing keratinocytes in pressure ulcers with worse healing outcomes

Pressure ulcer (PU) is a chronic wound often seen in spinal cord injury patients and other bed-bound individuals, particularly in the elderly population. Despite its association with high mortality, the pathophysiology of PU remains poorly understood. Here, we compared single-cell transcriptomic profiles of human epidermal cells from PU wound edges with those from uninjured skin and acute wounds (AWs) in healthy donors. We identified significant shifts in the cell composition and gene expression patterns in PU. In particular, we found that major histocompatibility complex class II (MHCII) expressing keratinocytes were enriched in patients with worse healing outcomes. Furthermore, we showed that the IFN{gamma} in PU-derived wound fluid could induce MHCII expression in keratinocytes and that these wound fluid-treated keratinocytes inhibited autologous T cell activation. In line with this observation, we found that T cells from PUs enriched with MHCII+ keratinocytes produced fewer inflammatory cytokines. Overall, our study provides a high-resolution molecular map of human PU compared to AW and intact skin, providing new insights into PU pathology and the future development of tailored wound therapy.

genomics↗

bioRxiv2021

A suite of activity-based probes to dissect the KLK activome in drug-resistant prostate cancer

Kallikrein-related peptidases (KLKs) are a family of secreted serine proteases, which form a network - the KLK activome - with an important role in proteolysis and signaling. In prostate cancer (PCa), increased KLK activity promotes tumor growth and metastasis through multiple biochemical pathways, and specific quantification and tracking of changes in the KLK activome could contribute to validation of KLKs as potential drug targets. Herein we report a technology platform based on novel activity-based probes (ABPs) and inhibitors with unprecedented potency and selectivity enabling simultaneous orthogonal analysis of KLK2, KLK3 and KLK14 activity in hormone-responsive PCa cell lines and tumor homogenates. Using selective inhibitors and multiplexed fluorescent activity-based protein profiling (ABPP) we dissect the KLK activome in PCa cells and show that increased KLK14 activity leads to a migratory phenotype. Furthermore, using biotinylated ABPs we show that active KLK molecules are secreted into the bone microenvironment by PCa cells following stimulation by osteoblasts suggesting KLK-mediated signaling mechanisms could contribute to PCa metastasis to bone. Together our findings show that ABPP is a powerful approach to dissect dysregulation of the KLK activome as a promising and previously underappreciated therapeutic target in advanced PCa.

biochemistry↗

bioRxiv2021

DAnIEL: A User-Friendly Web Server for Fungal ITS Amplicon Sequencing Data

Trillions of microbes representing all kingdoms of life are resident in, and on, humans holding essential roles for host development and physiology. The last decade over a dozen online tools and servers, accessible via public domain, have been developed for the analysis of bacterial sequences, however, the analysis of fungi is still in its infancy. Here we present a web server dedicated to the comprehensive analysis of the human mycobiome for (i) translating raw sequencing reads to data tables and high-standard figures; (ii) integrating statistical analysis and machine learning with a manually curated relational database; (iii) comparing the users uploaded datasets with publicly available from the Sequence Read Archive. Using 2,048 publicly available ITS samples, we demonstrated the utility of DAnIEL web server on large scale datasets and show the differences in fungal communities between human gut, skin, nasopharynx, and oral body sites.

bioinformatics↗

bioRxiv2021

CoVac501, a self-adjuvanting peptide vaccine conjugated with TLR7 agonists, against SARS-CoV-2 induces protective immunity

Safe, economical and effective vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are needed to achieve adequate herd immunity and halt the pandemic. We have constructed a novel SARS-CoV-2 vaccine, CoVac501, which is a self-adjuvanting peptide vaccine conjugated with Toll-like receptor 7 (TLR7) agonists. The vaccine contains two immunodominant peptides screened from receptor-binding domain (RBD) and is fully chemically synthesized. And the vaccine has optimized nanoemulsion formulation, outstanding stability and safety. In non-human primates (NHPs), CoVac501 elicited high and persistent titers of RBD-specific and protective neutralizing antibodies (NAbs), which were also effective to RBD mutations. CoVac501 was found to elicit the increase of memory T cells, antigen-specific CD8+ T cell responses and Th1-biased CD4+ T cell immune responses in NHPs. More importantly, the sera from the immunized NHPs can prevent infection of live SARS-CoV-2 in vitro. One-Sentence SummaryA novel SARS-CoV-2 vaccine we developed, CoVac501, which is a fully chemically synthesized and self-adjuvanting peptides conjugated with TLR7 agonists, can induce high-efficient humoral and cellular immune responses against SARS-CoV-2.

immunology↗

bioRxiv2021

Differential variation of NSCs in root branch orders of Fraxinus mandshurica Rupr. seedlings across different drought intensities and soil substrates

Non-structural carbohydrates (NSCs) facilitate plants adapt to drought stress, could characterize trees growth and survival ability and buffer against external disturbances. Previous studies have focused on the distribution and dynamics of NSCs among different plant organs under drought conditions. However, discussion about the NSC levels of fine roots in different root branch order were little, especially the relationship between fine root trait variation and NSCs content. The aim of the study is to shed light into the synergistic variation of fine root traits and NSC content in different root branch order under different drought and soil substrate conditions. 2-year-old Fraxinus mandshurica Rupr. potted seedlings were planted in three different soil substrates (humus, loam and sandy-loam soil) and conducted to four drought intensities (CK, mild drought, moderate drought and severe drought) for two months. With the increase of drought intensity, the biomass of fine roots decreased significantly. Under the same drought intensity, seedlings in sandy-loam soil have higher root biomass, and the coefficient of variation of fifth-order roots (37.4%, 44.5% and 53.0% in humus, loam and sandy loam, respectively) is higher than that of lower-order roots. With the increase of drought intensity, the specific root length (SRL) and average diameter (AD) of all five orders increased and decreased, respectively. The fine roots in humus soil had higher soluble sugar content and lower starch content. Also, the soluble sugar and starch content of fine roots showed decreasing and increasing tendency respectively. Soluble sugar and starch explain the highest degree of total variation of fine root traits, that is 32.0% and 32.1% respectively. With ascending root order, the explanation of the variation of root traits by starch decreased (only 6.8% for fifth-order roots). The response of different root branch order fine root morphological traits of F. mandshurica seedlings to resource fluctuations ensures that plants maintain and constructure the root development by an economical way to obtain more resources.

ecology↗

bioRxiv2021

Performance Determinants of Unsupervised Clustering Methods for Microbiome Data

BackgroundIn microbiome data analysis, unsupervised clustering is often used to identify naturally occurring clusters, which can then be assessed for associations with characteristics of interest. In this work, we systematically compared beta diversity and clustering methods commonly used in microbiome analyses. We applied these to four published datasets where highly distinct microbiome profiles could be seen between sample groups. ResultsAlthough no single method outperformed the others consistently, we did identify key scenarios where certain methods can underperform. Specifically, the Bray Curtis metric resulted in poor clustering in a dataset where high-abundance OTUs were relatively rare. In contrast, the unweighted UniFrac metric clustered poorly when used on a dataset with a high prevalence of low-abundance OTUs. To test our proposition, we systematically modified properties of the poorly performing datasets and found that this approach resulted in improved Bray Curtis and unweighted UniFrac performance. Based on these observations, we rationally combined the Bray Curtis metric and the unweighted UniFrac metrics and found that this new beta diversity metric showed high performance across all datasets. We also evaluated our findings by examining a clinical dataset where clusters are less separated. ConclusionsOur systematic evaluation of clustering performance in these five datasets demonstrates that there is no existing clustering method that universally performs best across all datasets. We propose a combined metric of Bray Curtis and unweighted UniFrac that capitalizes on the complementary strengths of the two metrics.

microbiology↗

bioRxiv2021

The first report and biological characteristics of Helcococcus ovis isolated from clinical bovine mastitis in a Chinese dairy herd

Helcococcus ovis (H. ovis) was first reported in ovine subclinical mastitis milk and post-mortem examinated organs in Spain and the United Kingdom in 1999, subsequently, it appeared in cattle, horse, goat, and human. However, isolation and characterization of the strain in clinical bovine mastitis is unknown. Therefore, our objective was to identify the pathogen in clinical bovine mastitis. A total of 4 strains from 34 bovine mastitis milk samples were identified, there are tiny and transparent colonies from clinical bovine mastitis milk samples in a Chinese dairy farm, however, these colonies could not be identified using on-farm biochemical tests. The isolates were transported to Mastitis Diagnostic Laboratory of China Agricultural University in Beijing. The colonies were identified as a mixture of H. ovis and Arcanobacterium pyogenes according to microscopic examination and 16S rRNA gene sequencing and the phylogenetic tree was constructed using 16S rRNA gene sequence of H. ovis isolates. In addition, the growth curve and biochemistry test were performed, we also examined the antimicrobial resistance profiles and constructed murine mammary infection model. Our results showed that the H. ovis were closely related to the strains isolated from China and Japan, growth speed of H. ovis was relatively slower than Strep.agalactiae, the phenotypic characteristics were similar to CCUG37441 and CCUG39041 except to lactose, isolates were sensitive to most of antimicrobials except daptomycin, H. ovis could lead to murine mastitis. In this report, we firstly described the characteristics of H. ovis that are associated with clinical bovine mastitis in China.

microbiology↗

bioRxiv2021

Unbalanced dietary patterns contribute to the pathogenesis of precocious puberty by affecting gut microbiota and host metabolites

Precocious puberty (PP) mostly stems from endocrine disorders. However, its triggering factors, especially for the early onset of partial PP, and the associated pathogenic mechanisms remain ambiguous. In this study, a systematic analysis in the form of a questionnaire of lifestyles, gut microbiome, and serum metabolome data was carried out to examine the pathogenesis of PP in a cohort comprised of 200 girls, with or without PP. The analysis revealed substantial alterations in gut microbiota, serum metabolites, as well as lifestyle patterns in the PP group, which were characterized by an elevated abundance of {beta}-glucuronidase-producing and butyrate-producing bacteria, and excessive lipid concentration with decreased levels of organic nitrogen compounds in the serum of the participants. These differential microbes and metabolites tend to be reliable non-invasive diagnostic biomarkers aiding the early diagnosis of PP and exhibit a strong discriminative power (AUC = 0.93 and AUC = 0.97, respectively). Furthermore, the microbial biomarkers were confirmed in an independent validation cohort (n = 83, AUC = 0.85). Moreover, structural equation modeling revealed that unhealthy dietary habits were the primary contributors for the alteration of gut microbiota and serum metabolites, triggering the imbalance in the host hormones that leads to premature physical development. Our study determines a causal relationship among the gut microbiota, host metabolites, diet, and clinical characteristics of preadolescent girls who experienced early onset of PP, and formulates non-invasive diagnostic tools demonstrating excellent performance for the early detection of PP.

microbiology↗

bioRxiv2021

Identification of decondensed large-scale chromatin regions by TSA-seq and their localization to a subset of chromatin domain boundaries

Large-scale chromatin compaction is nonuniform across the human genome and correlates with gene expression and genome organization. Current methodologies for assessing large-scale chromatin compaction are indirect and largely based on assays that probe lower levels of chromatin organization, primarily at the level of the nucleosome and/or the local compaction of nearby nucleosomes. These assays assume a one-to-one correlation between local nucleosomal compaction and large-scale compaction of chromosomes that may not exist. Here we describe a method to identify interphase chromosome regions with relatively high levels of large-scale chromatin decondensation using TSA-seq, which produces a signal proportional to microscopic-scale distances relative to a defined nuclear compartment. TSA-seq scores that change rapidly as a function of genomic distance, detected by their higher slope values, identify decondensed large-scale chromatin domains (DLCDs), as then validated by 3D DNA-FISH. DLCDs map near a subset of chromatin domain boundaries, defined by Hi-C, which separate active and repressed chromatin domains and correspond to compartment, subcompartment, and some TAD boundaries. Most DLCDs can also be detected by high slopes of their Hi-C compartment score. In addition to local enrichment in cohesin (RAD21, SMC3) and CTCF, DLCDs show the highest local enrichment to super-enhancers, but are also locally enriched in transcription factors, histone-modifying complexes, chromatin mark readers, and chromatin remodeling complexes. The localization of these DLCDs to a subset of Hi-C chromatin domain boundaries that separate active versus inactive chromatin regions, as measured by two orthogonal genomic methods, suggests a distinct role for DLCDs in genome organization.

genomics↗

bioRxiv2021

Emerging SARS-CoV-2 mutation hotspots associated with clinical outcomes

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of the ongoing coronavirus disease 2019 (COVID-19) pandemic. Understanding the influence of mutations in the SARS-CoV-2 gene on clinical outcomes and related factors is critical for treatment and prevention. Here, we analyzed 209,551 high-coverage complete virus sequences and 321 RNA-seq samples to mine the mutations associated with clinical outcome in the SARS-CoV-2 genome. Several important hotspot variants were found to be associated with severe clinical outcomes. Q57H variant in ORF3a protein were found to be associated with higher mortality rate, and was high proportion in severe cases (39.36%) and 501Y.V2 strains (100%) but poorly proportional to asymptomatic cases (10.04%). T265I could change nsp2 structure and mitochondrial permeability, and evidently higher in severe cases (20.12%) and 501Y.V2 strains (100%) but lower in asymptomatic cases (1.43%). Additionally, R203K and G204R could decrease the flexibility and immunogenic property of N protein with high frequency among severe cases, VUI 202012/01 and 484K.V2 strains. Interestingly, the SARS-CoV-2 genome was more susceptible to mutation because of the high frequency of nt14408 mutation (which located in RNA polymerase) and the high expression levels of ADAR and APOBEC in severe clinical outcomes. In conclusion, several important mutation hotspots in the SARS-CoV-2 genome associated with clinical outcomes was found in our study, and that might correlate with different SARS-CoV-2 mortality rates.

bioinformatics↗