Biology subjects

Ren, Z.

Publications and source records attributed to Ren, Z..

120 records · Page 7Linked to original sources

bioRxiv2019

Systematic search for schizophrenia pathways sensitive to perturbation by immune activation

Immune activation has been recently found to play a large part in the development of schizophrenia, but the underlying mechanism remains largely unknown. Here, we report the construction of a high-quality protein interaction network for schizophrenia (SCZ Network) using a \"neighborhood walking\" approach to searching across human interactome network for disease-related neighborhoods. The spatiotemporal expression pattern of the immune genes in the SCZ Network demonstrates that this disease network is sensitive to the perturbation of immune activation during mid- to late fetal development and adolescence. The immune genes in the network are involved in pathways regulating the formation, structure and function of synapses and neural connections. Using single-cell transcriptome sequencing on the brains of immune-activated mice, we found that immune activation disturbed the SCZ network in the major brain cell types and the dysregulated pathways were also involved in synapse regulation, demonstrating that our \"neighborhood walking\" approach enables biological discovery in complex disorders.

systems biology↗

bioRxiv2019

The Aging Microenvironment Shapes Alveolar Macrophage Identity in Aging

A dysfunctional response to inhaled pathogens and toxins drives a substantial portion of the susceptibility to acute and chronic lung disease in the elderly. We used transcriptomic profiling combined with genetic lineage tracing, heterochronic adoptive transfer, parabiosis and treatment with metformin to show that the lung microenvironment defines the phenotype of long-lived alveolar macrophages during aging. While tissue-resident alveolar macrophages persist in the lung without input from monocytes over the lifespan, severe lung injury results in their replacement with monocyte-derived alveolar macrophages. These monocyte-derived alveolar macrophages are also shaped by the microenvironment both during aging and in response to a subsequent environmental challenge to become transcriptionally and functionally similar to tissue-resident alveolar macrophages. These findings show that changes in alveolar macrophage phenotypes during injury and aging are not cell autonomous but instead are shaped by changes in the aging lung microenvironment.

immunology↗

bioRxiv2019

Controlling Strawberry Mites: Comparison of New Bio-Pesticides and Conventional Chemical Pesticides

BACKGROUNDTetranychus cinnabarinus is one of the pest insects most severely influencing strawberry production. It has a high attack rate and causes severe economic losses. Laboratory toxicity tests and greenhouse experiments were carried out using 13 acaricides to determine their efficacy and potential mechanisms of action.\n\nRESULTSAbamectin showed the highest efficacy against T. cinnabarinus female mites; its LC50 value was 0.18mg L-1. Pyridaben, cyhalothrin, veratrine, and carbosulfan showed reasonably high efficacy; their LC50 values were 2.69 mg L-1, 3.94 mg L-1, 5.98 mg L-1, and 6.75 mg L-1, respectively. Less effective were hexythiazox and bifenthrin, their LC50 values were 9.82 mg L-1 and 19.09 mg L-1, respectively. Other acaricides such as spirodiclofen, chlorantraniliprole, chlorfenapyr, spinosad, and bifenazate did not show good efficacy. The status of female mites treated with avermectin, pyridaben, kanghebio and cyhalothrin changed significantly under a fluorescence microscope. There were no significant differences among female mites treated with spirotetramat, chlorantraniliprole, spinosad and bifenazate. Enzyme activity tests showed that Kanghebio and cyhalothrin obviously inhibited Ca2+-adenosine triphosphatase (Ca2+-ATPase), while veratrine and kanghebi obviously inhibited acetylcholinesterase (TChE) and monoamine oxidase (MAO). Cyhalothrinexerted an auxo-action on MAO. Greenhouse experiment indicated that abamectin showed the best efficacy, as well as the longest duration of efficacy, pyridaben, cyhalothrin, veratrine, and kanghebio followed, while carbosulfan, hexythiazox, and bifenthrin performed the worst.\n\nCONCLUSIONSOur study provided a scientific basis for chemical pesticides to be replaced by these and potentially other new bio-pesticides.

biochemistry↗

bioRxiv2019

A Clostridia-rich microbiota contributes to increased excretion of bile acids in diarrhea-predominant irritable bowel syndrome

ObjectiveAn excess of fecal bile acids (BAs) is thought to be one of the mechanisms for diarrhea-predominant irritable bowel syndrome (IBS-D). However, the factors causing excessive BA excretion remains unclear. Given the importance of gut microbiota in BA metabolism, we hypothesized that gut dysbiosis might contribute to excessive BA excretion in IBS-D.\n\nDesignMetabolomic and metagenomic analyses were performed of specimens from 290 IBS-D patients and 89 healthy volunteers. By transplanting human microbiota and manipulating specific microbiome species in mice, the effects of microbiota on host BA metabolism were assessed at metabolic, genetic and protein levels. Effects of individual and mixed BAs on enterohepatic feedback pathways were also tested in vitro and in vivo.\n\nResultsTotal fecal BAs were excessively excreted in 24.5% of IBS-D patients. Their fecal metagenomes showed increased abundances of Clostridia and BA-transforming genes (hdhA and bais). The increases of Clostridia bacteria (e.g. C. scindens) were positively associated with the levels of fecal BAs and serum 7-hydroxy-4-cholesten-3-one (C4), while being negatively correlated with serum fibroblast growth factor 19 (FGF19). Both Clostridia-rich human microbiota and C. scindens enhanced levels of serum C4 and hepatic conjugated BAs in mice recipients and reduced ileal FGF19 expression. Inhibition of Clostridium species by vancomycin yielded opposite findings. Clostridia-derived BAs (e.g. conjugated and free ursodeoxycholic acid) significantly suppressed intestinal FGF19 expression.\n\nConclusionThe Clostridia-rich microbiota contributes to excessive BA excretion in IBS-D patients. This study provided the basis for more precise clinical diagnosis and management for IBS-D.

microbiology↗

bioRxiv2019

Ultrafast Structural Changes Decomposed from Serial Crystallographic Data

Direct visualization of electronic and molecular events during chemical and biochemical reactions will offer unprecedented mechanistic insights. Ultrashort pulses produced by X-ray free electron lasers (XFELs) offer an unprecedented opportunity for direct observations of transient events as short-lived as tens of femtoseconds. This paper presents an in-depth analysis of the serial crystallographic datasets collected by Barends & Schlichting et al. (Science 350, 445, 2015) that probe the ligand photodissociation in carbonmonoxy myoglobin (MbCO), a long-serving hallmark for observing ultrafast dynamics in a biological system. This analysis reveals electron density changes that are caused directly by the formation of high-spin 3d atomic orbitals of the heme iron upon the CO departure and the dynamic behaviors of these newly formed orbitals in a time series within the first few picoseconds. The heme iron is found vibrating at a high frequency and developing a positional modulation that causes the iron to pop out of and recoil back into the heme plane in succession. These findings here provide long-awaited visual validations for previous works using ultrafast spectroscopy and molecular dynamics simulations. This analysis also extracts electron density variations largely in the solvent during the first period of a low frequency oscillation previously detected by coherence spectroscopy. This work demonstrates the power and importance of the analytical methods in detecting and isolating transient, often very weak signals of electronic changes arising from chemical reactions in proteins.\n\nSummaryDirect imaging of ultrafast and subtle structural events during a biochemical reaction, such as a single electronic transition from one atomic or molecular orbital to another, is highly desirable but has been beyond the reach of protein crystallography. It entails the capability of observing changes in electronic distributions at both an ultrafast time scale and an ultrahigh spatial resolution (Itatani et al., Nature 432, 867, 2004). The recent developments in femtosecond serial crystallography at X-ray free electron lasers (XFELs) have brought the achievable temporal resolution within a striking distance. This paper presents the electron density map decomposed from the XFEL data that shows the remanence of several 3d atomic orbitals of the heme iron at an available spatial resolution although the map component is not an accurate image of the atomic orbitals. A key strategy that has enabled the findings here is a numerical deconvolution to resolve concurrent variations in a series of time-resolved electron density maps so that the electron densities influenced by an electron transfer event can be isolated as a partial change from the overwhelming presence of the bulk electrons that are not directly involved in bonding. Even at the limited spatial resolution, the subtle changes in electron distribution due to a spin crossover can be decoupled from far greater changes due to atomic displacements. Direct observations of electronic orbitals could offer unprecedented mechanistic insights into a myriad of chemical and biochemical reactions such as electron transfer in redox reactions, and formation, rupture, and isomerization of chemical bonds.\n\nLigand photodissociation in carbonmonoxy myoglobin (MbCO) has been a benchmark for studying ultrafast protein dynamics in a biological system. A number of studies in time-resolved crystallography have progressively improved the time resolution (from [S]rajer et al., Science 274, 1726, 1996 to Barends et al., Science 350, 445, 2015). This paper presents an in-depth analysis of the serial crystallographic datasets of MbCO that Barends & Schlichting et al. (2015) contributed to the Protein Data Bank. First, a component of electron density distributions clearly shows the characteristic shape of the high-spin 3d orbitals reappeared at the heme iron upon the photodissociation of the CO ligand despite the limited accuracy of the orbital image due to the available spatial resolution. Second, the dynamic behaviors of these newly regained 3d orbitals within picoseconds after the photolysis provide long-awaited structural validation for previous spectroscopic observations and computational simulations. Specifically, the newly formed densities are oscillating with the heme iron at a high frequency of a thousand wavenumbers and developing a positional modulation during the first few picoseconds (Champion, Science 310, 980, 2005). The iron pops out of the heme plane at a few picoseconds and recoils back and pops out again afterwards. The dominant oscillation at a low frequency of several tens wavenumbers previously detected by coherence spectroscopy can be clearly resolved from the time series of electron density maps. The associated changes in electron density during the first cycle of the oscillation are largely located in the solvent rather than on the protein or heme, which suggests that the low frequency oscillations in a number of heme proteins, including MbCO, likely originate from a photolysis triggered pressure wave propagating in the solvated protein. Finally, these findings of chemical signals are isolated from coexisting thermal artifacts also by the numerical deconvolution. It is modeled in this study that the ultrashort XFEL pulses cause a transient spike of the local temperature at the heme site of hundreds of K.

biophysics↗

bioRxiv2019

EPIC: MHC-I epitope prediction integrating mass spectrometry derived motifs and tissue-specific expression profiles

BackgroundAccurate prediction of epitopes presented by human leukocyte antigen (HLA) is crucial for personalized cancer immunotherapies targeting T cell epitopes. Mass spectrometry (MS) profiling of eluted HLA ligands, which provides high-throughput measurements of HLA associated peptides in vivo, can be used to faithfully model the presentation of epitopes on the cell surface. In addition, gene expression profiles measured by RNA-seq data in a specific cell/tissue type can significantly improve the performance of epitope presentation prediction. However, although large amount of high-quality MS data of HLA-bound peptides is being generated in recent years, few provide matching RNA-seq data, which makes incorporating gene expression into epitope prediction difficult. MethodsWe collected publicly available HLA peptidome and matching RNA-seq data of 34 cell lines derived from various sources. We built position score specific matrixes (PSSMs) for 21 HLA-I alleles based on these MS data, then used logistic regression (LR) to model the relationship among PSSM score, gene expression and peptide length to predict whether a peptide could be presented in each of the cell line. We further built a universal LR model, termed Epitope Presentation Integrated Prediction (EPIP), based on more than 180,000 unique HLA ligands collected from public sources and ~3,000 HLA ligands generated by ourselves, to predict epitope presentation for 66 common HLA-I alleles. ResultsWhen evaluating EPIP on large, independent HLA eluted ligand datasets, it performed substantially better than other popular methods, including MixMHCpred (v2.0), NetMHCpan (v4.0), and MHCflurry (v1.2.2), with an average 0.1% positive predictive value (PPV) of 52.01%, compared to 37.24%, 36.96%, 24.90% and 23.76% achieved by MixMHCpred, NetMHCpan-4.0 (EL), NetMHCpan-4.0 (BA) and MHCflurry, respectively. It is also comparable to EDGE, a recent deep learning-based model that is not publicly available, on predicting epitope presentation and selecting immunogenic cancer neoantigens. However, the simplicity and flexibility of EPIP makes it easier to be applied in diverse situations, and we demonstrated this by generating MS data for the HCC4006 cell line and adding the support of HLA-A*33:03 to EPIP. EPIP is publicly available as a web tool < http://epip.genomics.cn/>. Conclusionswe have developed an easy to use, publicly available epitope prediction tool, EPIP, that incorporates information from both MS and RNA-seq data, and demonstrated its superior performance over existing public methods.

bioinformatics↗

bioRxiv2018

A family of transcription factors that limit lifespan: ETS factors have conserved roles in longevity

Increasing average population age, and the accompanying burden of ill health, is one of the public health crises of our time. Understanding the basic biology of the ageing process may help ameliorate the pathologies that characterise old age. Ageing can be modulated, often through changes in gene expression where regulation of transcription plays a pivotal role. Activities of Forkhead transcription factors (TFs) are known to extend lifespan, but detailed knowledge of the broader transcriptional networks that promote longevity is lacking. This study focuses on the E twenty-six (ETS) family of TFs. This family of TFs is large, conserved across metazoa, and known to play roles in development and cancer, but the role of its members in ageing has not been studied extensively. In Drosophila, an ETS transcriptional repressor, Aop, and an ETS transcriptional activator, Pnt, are known to genetically interact with Foxo and activating Aop is sufficient to extend lifespan. Here, it is shown that Aop and Foxo effect a related gene-expression programme. Additionally, Aop can modulate Foxos transcriptional output to moderate or synergise with Foxo activity depending on promoter context, both in vitro and in vivo. In vivo genome-wide mRNA expression analysis in response to Aop, Pnt or Foxo indicated, and further experiments confirmed, that combinatorial activities of the three TFs dictate metabolic status, and that direct reduction of Pnt activity is sufficient to promote longevity. The role of ETS factors in longevity was not limited to Pnt and Aop. Knockdown of Ets21c or Eip74EF in distinct cell types also extended lifespan, revealing that lifespan is limited by transcription from the ETS binding site in multiple cellular contexts. Reducing the activity of the C. elegans ETS TF Lin-1 also extended lifespan, a finding that corroborates established evidence of roles of this TF family in ageing. Altogether, these results reveal the ETS family of TFs as pervasive and evolutionarily conserved brokers of longevity.

genetics↗

bioRxiv2018

Identification, Genotyping, and Pathogenicity of Trichosporon spp. Isolated from Giant Pandas

Trichosporon is the dominant genus of epidermal fungi in giant pandas and causes local and deep infections. To provide the information needed for the diagnosis and treatment of trichosporosis in giant pandas, the sequence of ITS, D1/D2, and IGS1 loci in 29 isolates of Trichosporon spp. which isolated from the body surface of giant pandas were combination to investigate interspecies identification and genotype. Morphological development was examined via slide culture. Additionally, mice were infected by skin inunction, intraperitoneal injection, and subcutaneous injection for evaluation of pathogenicity. The twenty-nine isolates of Trichosporon spp. were identified as belonging to 11 species, and Trichosporon jirovecii and T. asteroides were the commonest species. Four strains of T. laibachii and one strain of T. moniliiforme were found to be of novel genotypes, and T. jirovecii was identified to be genotype 1. T. asteroides had the same genotype which involved in disseminated trichosporosis. The morphological development processes of the Trichosporon spp. were clearly different, especially in the processes of single-spore development. Pathogenicity studies showed that 7 species damaged the liver and skin in mice, and their pathogenicity was stronger than other 4 species. T. asteroides had the strongest pathogenicity and might provoke invasive infection. The pathological characteristics of liver and skin infections caused by different Trichosporon spp. were similar. So it is necessary to identify the species of Trichosporon on the surface of giant panda. Combination of ITS, D1/D2, and IGS1 loci analysis, and morphological development process can effectively identify the genotype of Trichosporon spp.

microbiology↗

bioRxiv2018

Regional collapsing of rare variation implicates specific genic regions in ALS

Large-scale sequencing efforts in amyotrophic lateral sclerosis (ALS) have implicated novel genes using gene-based collapsing methods. However, pathogenic mutations may be concentrated in specific genic regions. To address this, we developed two collapsing strategies, one focuses rare variation collapsing on homology-based protein domains as the unit for collapsing and another gene-level approach that, unlike standard methods, leverages existing evidence of purifying selection against missense variation on said domains. The application of these two collapsing methods to 3,093 ALS cases and 8,186 controls of European ancestry, and also 3,239 cases and 11,808 controls of diversified populations, pinpoints risk regions of ALS genes including SOD1, NEK1, TARDBP and FUS. While not clearly implicating novel ALS genes, the new analyses not only pinpoint risk regions in known genes but also highlight candidate genes as well.

genetics↗

bioRxiv2018

Improvements to the rice genome annotation through large-scale analysis of RNA-Seq and proteomics datasets

Rice (Oryza sativa) is one of the most important worldwide crops. The genome has been available for over 10 years and has undergone several rounds of annotation. We created a comprehensive database of transcripts from 29 public RNA sequencing datasets, officially predicted genes from Ensembl plants, and common contaminants in which to search for protein-level evidence. We re-analysed nine publicly accessible rice proteomics datasets. In total, we identified 420K peptide spectrum matches from 47K peptides and 8,187 protein groups. 4168 peptides were initially classed as putative novel peptides (not matching official genes). Following a strict filtration scheme to rule out other possible explanations, we discovered 1,584 high confidence novel peptides. The novel peptides were clustered into 692 genomic loci where our results suggest annotation improvements. 80% of the novel peptides had an ortholog match in the curated protein sequence set from at least one other plant species. For the peptides clustering in intergenic regions (and thus potentially new genes), 101 loci were identified, for which 43 had a high-confidence hit for a protein domain. Our results can be displayed as tracks on the Ensembl genome or other browsers supporting Track Hubs, to support re-annotation of the rice genome.

plant biology↗

bioRxiv2018

Single-Cell Transcriptomic Analysis of Human Lung Reveals Complex Multicellular Changes During Pulmonary Fibrosis

Pulmonary fibrosis is a devastating disorder that results in the progressive replacement of normal lung tissue with fibrotic scar. Available therapies slow disease progression, but most patients go on to die or require lung transplantation. Single-cell RNA-seq is a powerful tool that can reveal cellular identity via analysis of the transcriptome, but its ability to provide biologically or clinically meaningful insights in a disease context is largely unexplored. Accordingly, we performed single-cell RNA-seq on lung tissue obtained from eight transplant donors and eight recipients with pulmonary fibrosis and one bronchoscopic cryobiospy sample. Integrated single-cell transcriptomic analysis of donors and patients with pulmonary fibrosis identified the emergence of distinct populations of epithelial cells and macrophages that were common to all patients with lung fibrosis. Analysis of transcripts in the Wnt pathway suggested that within the same cell type, Wnt secretion and response are restricted to distinct non-overlapping cells, which was confirmed using in situ RNA hybridization. Single-cell RNA-seq revealed heterogeneity within alveolar macrophages from individual patients, which was confirmed by immunohistochemistry. These results support the feasibility of discovery-based approaches applying next generation sequencing technologies to clinically obtained samples with a goal of developing personalized therapies.\n\nOne Sentence SummarySingle-cell RNA-seq applied to tissue from diseased and donor lungs and a living patient with pulmonary fibrosis identifies cell type-specific disease-associated molecular pathways.

systems biology↗

bioRxiv2017

Comparative Qualitative Phosphoproteomics Analysis Identifies Shared Phosphorylation Motifs and Associated Biological Processes in Flowering Plants

Phosphorylation is regarded as one of the most prevalent post-translational modifications and plays a key role in regulating cellular processes. In this work we carried out a comparative bioinformatics analysis of phosphoproteomics data, to profile two model species representing the largest subclasses in flowering plants the dicot Arabidopsis thaliana and the monocot Oryza sativa, to understand the extent to which phosphorylation signaling and function is conserved across evolutionary divergent plants. Using pre-existing mass spectrometry phosphoproteomics datasets and bioinformatic tools and resources, we identified 6,537 phosphopeptides from 3,189 phosphoproteins in Arabidopsis and 2,307 phosphopeptides from 1,613 phosphoproteins in rice. The relative abundance ratio of serine, threonine, and tyrosine phosphorylation sites in rice and Arabidopsis were highly similar: 88.3: 11.4: 0.4 and 86.7: 12.8: 0.5, respectively. Tyrosine phosphorylation shows features different from serine and threonine phosphorylation and was found to be more frequent in doubly-phosphorylated peptides in Arabidopsis. We identified phosphorylation sequence motifs in the two species to explore the similarities, finding nineteen pS motifs and two pT motifs that are shared in rice and Arabidopsis; among them are five novel motifs that have not previously been described in both species. The majority of shared motif-containing proteins were mapped to the same biological processes with similar patterns of fold enrichment, indicating high functional conservation. We also identified shared patterns of crosstalk between phosphoserines with motifs pSXpS, pSXXpS and pSXXXpS, where X is any amino acid, in both species indicating this is an evolutionary conserved signaling mechanism in flowering plants. However, our results are suggestive that there is greater co-occurrence of crosstalk between phosphorylation sites in Arabidopsis, and we were able to identify several pairs of motifs that are statistically significantly enriched to co-occur in Arabidopsis proteins, but not in rice.

bioinformatics↗