Biology subjects

Zhu, S.

Publications and source records attributed to Zhu, S..

At least 181 records · Page 10Linked to original sources

bioRxiv2021

RNA pull-down-Confocal Nanoscanning (RP-CONA) detects quercetin as pri-miR-7/HuR interaction inhibitor that decreases α-Synuclein levels

RNA-protein interactions are central to all gene expression processes and contribute to variety of human diseases. Therapeutic approaches targeting RNA-protein interactions have shown promising effects on some diseases that are previously regarded as incurable. Here we developed a fluorescent on-bead screening platform: RNA pull-down-Confocal Nanoscanning (RP-CONA), to identify RNA-protein interaction modulators in eukaryotic cell extracts. Using RP-CONA, we identified small molecules that disrupt the interaction between HuR, an inhibitor of brain-enriched miR-7 biogenesis, and the conserved terminal loop of pri-miR-7-1. Importantly, miR-7s primary target is an mRNA of -Synuclein, which contributes to aetiology of Parkinsons disease. Our method identified a natural product quercetin as a molecule able to upregulate cellular miR-7 levels and downregulate the expression of -Synuclein. This opens up new therapeutic avenues towards treatment of Parkinsons disease as well as provides novel methodology to search for RNA-protein interaction modulators.

molecular biology↗

bioRxiv2020

Heterogeneity of Neuronal Populations Within Columns of Primate V1 Revealed by High-Density Recordings

Primary visual cortex (V1) has been the focus of extensive neurophysiological investigation, and its laminar organization provides a key exemplar of the functional logic of neocortical microcircuits. Using newly developed high-density, linear array probes, we measured visual responses from large populations of simultaneously recorded neurons distributed across layers of macaque V1. In single recordings, myriad differences in the functional properties of neuronal subpopulations could be observed. In particular, we found that although standard measurements of orientation selectivity yielded only minor differences between laminar compartments, decoding of stimulus orientation from layer 4C responses was superior to that of both superficial and deep layers within the same cortical column. The superior orientation discrimination within layer 4C was associated with greater response reliability of individual neurons rather than lower correlated activity with neuronal populations. The results demonstrate the utility of high-density electrophysiology in revealing the functional organization and network properties of neocortical microcircuits in single experiments.

neuroscience↗

bioRxiv2020

First Glimpse of Gut Microbiota of Quarantine Insects in China

Quarantine insects are economically important pests that frequently invade new habitats. A rapid and accurate monitoring method to trace the geographical source of invaders is therefore needed for prevention, detection, and eradication. Current methods based on insect genetics are often too slow. We developed a novel tracing method based on insect gut microbiota. The source location of microbiota of insects can be used to rapidly determine the insects geographic origin. We analyzed 179 gut microbiota samples belonging to 591 individuals of 22 quarantine insect species collected from 36 regions in China and abroad. The gut microbiotas of these insects mainly included Actinobacteria, Bacteroidetes, Cyanobacteria, Firmicutes, Proteobacteria, and Tenericutes. The diversity of the insect gut microbiota was closely related to geographic and environmental factors. Different insect species could be distinguished at the phylum level of microbiota. Populations of individual insect species from different regions could be distinguished at the genus level of microbiota. A method for determining the geographical origin of invasive insect species was tentatively established, but its practical applicability requires further study.

microbiology↗

bioRxiv2020

Massively parallel sequencing of 165 ancestry-informative SNPs and forensic biogeographical ancestry inference in three southern Chinese Sinitic/Tai-Kadai populations

Ancestry informative markers (AIMs), which are distributed throughout the human genome, harbor significant allele frequency differences among diverse ethnic groups. The use of sets of AIMs to reconstruct population history and genetic relationships is attracting interest in the forensic community, because biogeographic ancestry information for a casework sample can potentially be predicted and used to guide the investigative process. However, subpopulation ancestry inference within East Asia remains in its infancy due to a lack of population reference data collection and incomplete validation work on newly developed or commercial AIM sets. In the present study, 316 Chinese persons, including 85 Sinitic-speaking Haikou Han, 120 Qiongzhong Hlai and 111 Daozhen Gelao individuals belonging to Tai-Kadai-speaking populations, were analyzed using the Precision ID Ancestry Panel (165 AISNPs). Combined with our previous 165-AISNP data (375 individuals from 6 populations), the 1000 Genomes Project and forensic literature, comprehensive population genetic comparisons and ancestry inference were further performed via ADMIXTURE, TreeMix, PCA, f-statistics and N-J tree. Although several nonpolymorphic loci were identified in the three southern Chinese populations, the forensic parameters of this ancestry inference panel were better than those for the 23 STR-based Huaxia Platinum System, which is suitable for use as a robust tool in forensic individual identification and parentage testing. The results based on the ancestry assignment and admixture proportion evaluation revealed that this panel could be used successfully to assign individuals at a continental scale but also possessed obvious limitations in discriminatory power in intercontinental individuals, especially for European-Asian admixed Uyghurs or in populations lacking reference databases. Population genetic analyses further revealed five continental population clusters and three East Asian-focused population subgroups, which is consistent with linguistic affiliations. Ancestry composition and multiple phylogenetic analysis further demonstrated that the geographically isolated Qiongzhong Hlai harbored a close phylogenetic relationship with Austronesian speakers and possessed a homogenous Tai-Kadai-dominant ancestry, which could be used as the ancestral source proxy in population history reconstruction of Tai-Kadai-speaking populations and as one of the representatives for forensic database establishment. In summary, more population-specific AIM sets focused on East Asian subpopulations, comprehensive algorithms and high-coverage population reference data should be developed and validated in the next step.

genetics↗

bioRxiv2020

Sirt5 deficiency causes post-translational protein malonylation and dysregulated cellular metabolism in chondrocytes under obesity conditions

ObjectiveObesity accelerates the development of osteoarthritis (OA) during aging and is associated with altered chondrocyte cellular metabolism. The objective of this study was to investigate the role of sirtuin 5 (SIRT5) in regulating chondrocyte protein lysine malonylation (MaK) and cellular metabolism under obesity-related conditions. MethodsMaK and SIRT5 were immunostained in knee articular cartilage of obese db/db mice and different aged C57BL6 mice with or without destabilization of the medial meniscus (DMM) surgery to induce OA. Primary chondrocytes were isolated from 7-day-old WT and Sirt5-/- mice and treated with varying concentrations of glucose and insulin to mimic obesity. Sirt5-dependent effects on MaK and metabolism were evaluated by Western blot, Seahorse Respirometry, and gas/chromatography-mass/spectrometry (GC-MS) metabolic profiling. ResultsMaK was significantly increased in cartilage of db/db mice and in chondrocytes treated with high concentrations of glucose and insulin (GluhiInshi). Sirt5 protein was increased in an age-dependent manner following joint injury, and Sirt5 deficient primary chondrocytes had increased MaK, decreased glycolysis rate, and reduced basal mitochondrial respiration. GC-MS identified 41 metabolites. Sirt5 deficiency altered 13 distinct metabolites under basal conditions and 18 metabolites under GluhiInshi treatment. Pathway analysis identified a wide range of Sirt5-dependent altered metabolic pathways that include amino acid metabolism, TCA cycle, and glycolysis. ConclusionThis study provides the first evidence that Sirt5 broadly regulates chondrocyte metabolism. We observed changes in Sirt5 and MaK levels in cartilage with obesity and joint injury, suggesting that the Sirt5-MaK pathway may contribute to altered chondrocyte metabolism that occurs during OA development.

cell biology↗

bioRxiv2020

TRPM2 promotes pancreatic cancer by PKC/MAPK pathway

BackgroundThe mechanism of pancreatic cancer(PA) is not fully understanded. In our last report, TRPM2 plays a promising role in pancreatic cancer. However, the mechanism of TRPM2 is still unknown in this dismal disease. This study was designed to investigate the role and mechanism of TRPM2 in pancreatic cancer. MethodsTRPM2 overexpressed and siRNA plasmid were created and transfected with pancreatic cancer cell line(BxPC-3) to construct the cell model. We employed CCK-8, Transwell, scratch wound, and nude mice tumor bearing model to investigate the role of TRPM2 in pancreatic cancer. Besides, we collected the clinical data, tumor tissue sample(TT) and para-tumor sample(TP) from the pancreatic cancer patients treated in our hospital. We analyzed the mechanism of TRPM2 in pancreatic cancer by transcriptome analysis, Westernblot, and PCR. ResultsOverexpressed TRPM2 could promote pancreatic cancer in proliferation, migration, and invasion ability in no matter the cell model or nude mice tumor bearing model. TRPM2 level is highly negative correlated to the overall survival and progression-free survival time in PA patients, however, it is significantly increased in PA tissue as the tumor stage increases. The transcriptome analysis, GSEA analysis, Westernblot, and PCR results indicates TRPM2 is highly correlated with PKC/MAPK pathways. ConclusionTRPM2 could directly activate PKC by calcium or indirectly activate PKC{varepsilon} and PKC{delta} by increased DAG in PC, which promote PC by downstream MAPK/MEK pathway activation.

cancer biology↗

bioRxiv2020

Sex-specific classification of drug-induced Torsade de Pointes susceptibility using cardiac simulations and machine learning

Torsade de Pointes (TdP), a rare but lethal ventricular arrhythmia, is a toxic side effect of many drugs. To assess TdP risk, safety regulatory guidelines require quantification of hERG channel block in vitro and QT interval prolongation in vivo for all new therapeutic compounds. Unfortunately, these have proven to be poor predictors of torsadogenic risk, and are likely to have prevented safe compounds from reaching clinical phases. While this has stimulated numerous efforts to define new paradigms for cardiac safety, none of the recently developed strategies accounts for patient conditions. In particular, despite being a well-established independent risk factor for TdP, female sex is vastly underrepresented in both basic research and clinical studies, and thus current TdP metrics are likely biased toward the male sex. Here, we apply statistical learning to synthetic data, generated by simulating drug effects on cardiac myocyte models capturing male and female electrophysiology, to develop new sex-specific classification frameworks for TdP risk. We show that (1) TdP classifiers require different features in females vs. males; (2) malebased classifiers perform more poorly when applied to female data; (3) female-based classifier performance is largely unaffected by acute effects of hormones (i.e., during various phases of the menstrual cycle). Notably, when predicting TdP risk of intermediate drugs on female simulated data, male-biased predictive models consistently underestimate TdP risk in women. Therefore, we conclude that pipelines for preclinical cardiotoxicity risk assessment should consider sex as a key variable to avoid potentially lifethreatening consequences for the female population.

pharmacology and toxicology↗

bioRxiv2020

Mitohormesis reprograms macrophage metabolism to enforce tolerance

Macrophages generate mitochondrial reactive oxygen and electrophilic species (mtROS, mtRES) as antimicrobials during Toll-like receptor (TLR)-dependent inflammatory responses. Whether mitochondrial stress caused by these molecules impacts macrophage function is unknown. Here we demonstrate that both pharmacologically- and lipopolysaccharide (LPS)-driven mitochondrial stress in macrophages triggers a stress response called mitohormesis. LPS-driven mitohormetic stress adaptations occur as macrophages transition from an LPS-responsive to LPS-tolerant state where stimulus-induced proinflammatory gene transcription is impaired, suggesting tolerance is a product of mitohormesis. Indeed, like LPS, pharmacologically-triggered mitohormesis suppresses mitochondrial oxidative metabolism and acetyl-CoA production needed for histone acetylation and proinflammatory gene transcription, and is sufficient to enforce an LPS-tolerant state. Thus, mtROS and mtRES are TLR-dependent signaling molecules that trigger mitohormesis as a negative feedback mechanism to restrain inflammation via tolerance. Moreover, bypassing TLR signaling and pharmacologically triggering mitohormesis represents a novel anti-inflammatory strategy that co-opts this stress response to impair epigenetic support of proinflammatory gene transcription by mitochondria. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=141 SRC="FIGDIR/small/347443v1_ufig1.gif" ALT="Figure 1"> View larger version (49K): org.highwire.dtl.DTLVardef@c5c03org.highwire.dtl.DTLVardef@16cd130org.highwire.dtl.DTLVardef@119b461org.highwire.dtl.DTLVardef@914ee4_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2020

Comparative analysis of temporal transcriptome reveals the relationship between pectin degradation and pathogenicity of defoliating Verticillium dahliae to Upland cotton (Gossypium hirsutum)

Verticillium wilt (VW), caused by Verticillium dahliae Kleb., is a major plant disease that causes heavy annual losses around the world, especially in Upland cotton (Gossypium hirsutum). The disease-causing pathogen can be classified into defoliating (D) and non-defoliating (ND) pathotypes based on the induced symptoms. At present, little is known about the complex mechanisms of fungal pathogenicity and cotton resistance to it. Comparative analysis of temporal transcriptome was performed on two V. dahliae strains, Vd_086 (D) and Vd_BP2 (ND), at key development stages (hyphal growth, microsclerotia production, and spore germination) to reveal the functional process on plant defoliation and death. Differentially expressed gene (DEG) analysis revealed a strong correlation between cell wall protein kinase activities and the early pathogenicity of defoliating Vd_086. With weighted gene co-expression network analysis (WGCNA), six specific gene modules were correlated with the biological traits of the fungal samples. Functional enrichment with Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways together with DEG analysis revealed six pectin degrading enzymes including Polygalacturonase gene 1 (PG1), Pectate lyase gene (PEL) and Pectinesterase gene 1 (PME1) expressed in the early development of Vd_086 that may be related to the robust pathogenicity of this strain during the early invasion. The expression of four of these genes was verified by real-time quantitative reverse transcription PCR (qRT-PCR). In addition, we identified Mitogen-Activated Protein Kinase (MAPK) signaling "hub" genes that may regulate these pectinases. In a word, enhanced expression of pectin degradation enzymes is associated with the stronger pathogenicity of Vd_086 than Vd_BP2, especially at early infection stages. The disease-causing capability is likely regulated by MAPK signaling genes. This study provides new insight into molecular mechanisms of the plant-pathogen interaction on the VW disease, facilitating more effective control measures against this pathogen, including molecular breeding for the VW-resistant cotton cultivars. Author summaryVerticillium wilt (VW), caused by fungal pathogen Verticillium dahliae (Vd), is arguably the most devastating disease in cotton production for decades. Molecular biologists and plant breeders have been working hard to identify host plant resistant genes for many years but have met with little success due to the large complex genome of cotton. The V. dahliae strains are grouped in two pathotypes, of which defoliating (D) strains cause total leaf loss of infected cotton plants and non-defoliating (ND) strains do not. Comparative transcriptome analysis of D strain Vd_086 and ND strain Vd_BP2 identified the candidate genes and molecular mechanisms related to the Vd pathogenicity. Besides the difference in pathogenicity, these strains are distinguishable by the rate of hyphal elongation, microsclerotia production, and spore germination. With these phenotypes, transcriptome sequencing of both strains was performed at the three growth phases. By the combination of comparative transcriptomic differentially expressed gene (DEG) analysis and weighted gene correlation network analysis (WGCNA), cell wall-associated pectinase genes were found to be active at hyphal elongation stage of the V. dahliae pathogen and ribosome-related processes were activated for microsclerotia production. Gene modification processes were activated with many protein kinases at spore germination stage that for the next infection cycle. Furthermore, four pectinases in the pentose and glucuronate interconversion (PGI) pathway were identified and verified as highly expressed in the D strain with strong pathogenicity to Upland cotton (Gossypium hirsutum). Our results provided evidence in support of the hypothesis that stronger early pathogenicity of the D strain is resulted from greater plant cell wall pectin degradability. Transcription factors (TFs) and "hub" module genes were identified in searching of protein interaction for possible regulators of the recognized pectinases. TFs involved in mitogen-activated protein kinase (MAPK) signaling pathway were shown to regulate not only hyphal processes but also the entire growth period of V. dahliae. This is the first study known to use module extraction techniques of WGCNA to identify differentially co-expressed genes between two fungal pathotypes of V. dahliae strains. The study provides new insights into molecular mechanisms of the plant-pathogen interaction and may lead to molecular breeding for resistant cotton cultivars to effectively control this devastating disease.

microbiology↗

bioRxiv2020

Monoclonal Antibodies Capable of Binding SARS-CoV-2 Spike Protein Receptor Binding Motif Specifically Prevent GM-CSF Induction.

A severe acute respiratory syndrome (SARS)-like coronavirus (SARS-CoV-2) has recently caused a pandemic COVID-19 disease that infected more than 25.6 million and killed 852,000 people worldwide. Like the SARS-CoV, SARS-CoV-2 also employs a receptor-binding motif (RBM) of its envelope spike protein for binding the host angiotensin-converting enzyme 2 (ACE2) to gain viral entry. Currently, extensive efforts are being made to produce vaccines against a surface fragment of a SARS-CoV-2, such as the spike protein, in order to boost protective antibody responses. It was previously unknown how spike protein-targeting antibodies would affect innate inflammatory responses to SARS-CoV-2 infections. Here we generated a highly purified recombinant protein corresponding to the RBM of SARS-CoV-2, and used it to screen for cross-reactive monoclonal antibodies (mAbs). We found two RBM-binding mAbs that competitively inhibited its interaction with human ACE2, and specifically blocked the RBM-induced GM-CSF secretion in both human monocyte and murine macrophage cultures. Our findings have suggested a possible strategy to prevent SARS-CoV-2-elicited "cytokine storm", and provided a potentially useful criteria for future assessment of innate immune-modulating properties of various SARS-CoV-2 vaccines. One Sentence SummaryRBM-binding Antibodies Inhibit GM-CSF Induction.

immunology↗

bioRxiv2020

Genetic signatures for lineage/sublineage classification of HPV16, 18, 52 and 58 variants

Increasing evidences indicate that high-risk HPV variants are heterogeneous in carcinogenicity and ethnic dispersion. In this work, we identified genetic signatures for convenient determination of lineage/sublineage of HPV16, 18, 52 and 58 variants. Using publicly available genomes, we found that E2 of HPV16, L2 of HPV18, L1 and LCR of HPV52, and L2, LCR and E1 of HPV58 contain the proper genetic signature for lineage/sublineage classification. Sets of hierarchical signature nucleotide positions (SNPs) were further confirmed for high accuracy (>98%) by classifying HPV genomes obtained from Chinese females, which included 117 HPV16 variants, 48 HPV18 variants 117 HPV52 variants and 89 HPV58 variants. The circulation of HPV variants posing higher cancer risk in Eastern China, such as HPV16 A4 and HPV58 A3, calls for continuous surveillance in this region. The marker genes and signature nucleotide positions may facilitate cost-effective diagnostic detections of HPV variants in clinical settings.

evolutionary biology↗

bioRxiv2020

Metformin chlorination byproducts in drinking water exhibit marked toxicity to nematode worms, human cells, and mice

Metformin (MET), a worldwide used drug for type 2 diabetes, has been found with the largest amount by weight among all drugs in aquatic environment, including the drinking water sources where chlorination inevitably transforms MET into chlorination byproducts. Although MET has health-promoting properties, whether or how its chlorination byproducts affect health remains largely unknown. Here we reveal that MET chlorination byproducts Y (C4H6ClN5) and C (C4H6ClN3) exhibit marked toxicity, even higher than that of the well-known poisonous arsenic, to live worms and human cells. Moreover, both byproducts are harmful to mice and Y at 250 ng/L destroys the mouse small intestine integrity. Strikingly, we detected MET and byproduct C in worldwide drinking water. Both byproducts are increasingly produced with more MET present during chlorination process. Unprecedentedly, we unveil boiling and activated carbon adsorption as effective solutions that are in urgent demand globally for removing these byproducts from water.

pharmacology and toxicology↗

bioRxiv2020

Piezo1 potentially mediates inflammation in balloon-inflated rat brain and its bidirectional mechanosensitivity

Brain injury after intracerebral hemorrhage is extremely complicated, and the exact mechanism remains puzzling. Piezo1, a novel mammalian mechanosensitive ion channel, has been identified to play important roles in several pathologic and physiologic procedures that involve cellular mechanotransduction. However, the role of Piezo1 in hematoma compression after intracerebral hemorrhage is still unclear. In the present study, we established a balloon-inflated rat brain model mimicking the pure mechanical compression of a hematoma and detected balloon compression in the basal ganglia region of the brain, resulting in abnormal behaviors and a significant increase in the expression of Piezo1 and proinflammatory cytokines. These effects were reversed by GsMTx4, an antagonist of Piezo1. Additionally, the balloon deflation time affected behavioral function and the levels of Piezo1 and proinflammatory cytokines. These results establish the first in vivo evidence for the role of Piezo1 in blood-brain neuroinflammation after hematoma compression. Piezo1 may therefore be a potential therapeutic target for the treatment of intracerebral hemorrhage.

neuroscience↗

bioRxiv2020

BERTMeSH: Deep Contextual Representation Learning for Large-scale High-performance MeSH Indexing with Full Text

Motivation With the rapid increase of biomedical articles, large-scale automatic Medical Subject Headings (MeSH) indexing has become increasingly important. FullMeSH, the only method for large-scale MeSH indexing with full text, suffers from three major drawbacks: FullMeSH 1) uses Learning To Rank (LTR), which is time-consuming, 2) can capture some pre-defined sections only in full text, and 3) ignores the whole MEDLINE database.Results We propose a computationally lighter, full-text and deep learning based MeSH indexing method, BERTMeSH, which is flexible for section organization in full text. BERTMeSH has two technologies: 1) the state-of-the-art pre-trained deep contextual representation, BERT (Bidirectional Encoder Representations from Transformers), which makes BERTMeSH capture deep semantics of full text. 2) a transfer learning strategy for using both full text in PubMed Central (PMC) and title and abstract (only and no full text) in MEDLINE, to take advantages of both. In our experiments, BERTMeSH was pre-trained with 3 million MEDLINE citations and trained on approximately 1.5 million full text in PMC. BERTMeSH outperformed various cutting edge baselines. For example, for 20K test articles of PMC, BERTMeSH achieved a Micro F-measure of 69.2%, which was 6.3% higher than FullMeSH with the difference being statistically significant. Also prediction of 20K test articles needed 5 minutes by BERTMeSH, while it took more than 10 hours by FullMeSH, proving the computational efficiency of BERTMeSH.Contact zhusf{at}fudan.edu.cnCompeting Interest StatementThe authors have declared no competing interest.View Full Text

bioinformatics↗

bioRxiv2020

Comparative analysis of clonal evolution among patients with right-sided colon cancer, left-sided colon cancer and rectal cancer

Background Tumor multi-region sequencing reveals intratumor heterogeneity (ITH) and clonal evolution which play a key role in progression and metastases of the tumor. However, large-scale high depths multiregional sequencing of colorectal cancer (CRC) has not been well studied. In addition, the comparative analysis among right-sided colon cancer (RCC), left-sided colon cancer (LCC) and rectal cancer (RC) patients as well as the study of lymph node metastasis (LN) with extranodal tumor deposits (ENTD) from evolutionary perspective remain unknown.Results In this prospective study, we recruited different stages of 68 CRC patients with RCC (18), LCC (20) and RC (30). We performed high-depth whole exome sequencing (WES) of 206 tumor regions including 176 primary tumors, 19 LN and 11 ENTD samples. Our results showed ITH with a Darwinian pattern of evolution. We identified that the evolution pattern of LCC and RC was more complex and divergent than RCC, suggesting the evolutionary diversity in the initiation and progression of LCC and RC. Genetic and evolutionary evidences found that both LN and ENTD were of polyclonal in origin. Moreover, ENTD was a distinct entity from LN and evolved later.Conclusions In conclusion, our study showed the Darwinian pattern of evolution with differences in clonal evolution between RCC with LCC and RC.Competing Interest StatementThe authors have declared no competing interest.View Full Text

cancer biology↗

bioRxiv2020

Network-based cancer gene relationship prediction method reveals perturbations in the cancer gene network

The perturbations of protein-protein interactions (PPIs) were found to be the main cause of cancer. Previous gene relationship prediction methods which were trained with non-disease gene interaction data were not compatible to map the PPI network in cancer. Therefore, we established a novel cancer specific PPI prediction method dubbed NECARE, which was based on relational graph convolutional network (R-GCN) with knowledge-based features. It achieved the best performance with a Matthews correlation coefficient (MCC) = 0.84{+/-}0.03 and an F1 = 91{+/-}2% comparing with other methods. With NECARE, we mapped the cancer interactome atlas and revealed that the perturbations of PPIs were enriched on 1362 genes, which were named cancer hub genes. Those genes were found to over-represent with mutations occurring at protein-macromolecules binding interfaces. Furthermore, over 42% of cancer treatment-related genes belonged to hub genes, which were significantly related to the prognosis of 32 types of cancers. Finally, by coimmunoprecipitation, we confirmed that the NECARE prediction method was highly reliable with a 90% accuracy. Overall, we provided the novel network-based protein-protein interaction prediction method and mapped the perturbation of cancer interactome. NECARE is available at: https://github.com/JiajunQiu/NECARE.

bioinformatics↗

bioRxiv2020

Inter-determination of blood metabolite levels and gut microbiome supported by Mendelian randomization

The gut microbiome has been implicated in a variety of physiological states, but controversy over causality remains unresolved. Here, we performed bidirectional Mendelian randomization (MR) analyses on 3,432 Chinese individuals with whole genome, whole metagenome, anthropometric, and blood metabolic trait data. We identified 58 causal relationships between the gut microbiome and blood metabolites, and replicated 43 of them. Increased relative abundances of fecal Oscillibacter and Alistipes were causally linked to decreased triglyceride concentration. Conversely, blood metabolites such as glutamic acid appeared to decrease fecal Oxalobacter, and members of Proteobacteria were influenced by metabolites such as 5-methyltetrahydrofolic acid, alanine, glutamate, and selenium. Two-sample MR with data from Biobank Japan partly corroborated results with triglyceride and with uric acid, and also provided causal support for published fecal bacterial markers for cancer and cardiovascular diseases. This study illustrates the value of human genetic information to help prioritize gut microbial features for mechanistic and clinical studies.

genetics↗

bioRxiv2020

Population Bottlenecks and Intra-host Evolution during Human-to-Human Transmission of SARS-CoV-2Population Bottlenecks and Intra-host Evolution during Human-to-Human Transmission of SARS-CoV-2

The emergence of the novel human coronavirus, SARS-CoV-2, causes a global COVID-19 (coronavirus disease 2019) pandemic. Here, we have characterized and compared viral populations of SARS-CoV-2 among COVID-19 patients within and across households. Our work showed an active viral replication activity in the human respiratory tract and the co-existence of genetically distinct viruses within the same host. The inter-host comparison among viral populations further revealed a narrow transmission bottleneck between patients from the same households, suggesting a dominated role of stochastic dynamics in both inter-host and intra-host evolutions. Author summaryIn this study, we compared SARS-CoV-2 populations of 13 Chinese COVID-19 patients. Those viral populations contained a considerable proportion of viral sub-genomic messenger RNAs (sgmRNA), reflecting an active viral replication activity in the respiratory tract tissues. The comparison of 66 identified intra-host variants further showed a low viral genetic distance between intra-household patients and a narrow transmission bottleneck size. Despite the co-existence of genetically distinct viruses within the same host, most intra-host minor variants were not shared between transmission pairs, suggesting a dominated role of stochastic dynamics in both inter-host and intra-host evolutions. Furthermore, the narrow bottleneck and active viral activity in the respiratory tract show that the passage of a small number of virions can cause infection. Our data have therefore delivered a key genomic resource for the SARS-CoV-2 transmission research and enhanced our understanding of the evolutionary dynamics of SARS-CoV-2.

genetics↗