Biology subjects

Zhu, R.

Publications and source records attributed to Zhu, R..

At least 91 records · Page 5Linked to original sources

bioRxiv2021

Efficient gradient boosting for prognostic biomarker discovery

MotivationGradient boosting decision tree (GBDT) is a powerful ensemble machine learning method that has the potential to accelerate biomarker discovery from high-dimensional molecular data. Recent algorithmic advances, such as Extreme Gradient Boosting (XGB) and Light Gradient Boosting (LGB), have rendered the GBDT training more efficient, scalable and accurate. These modern techniques, however, have not yet been widely adopted in biomarkers discovery based on patient survival data, which are key clinical outcomes or endpoints in cancer studies. ResultsIn this paper, we present a new R package Xsurv as an integrated solution which applies two modern GBDT training framework namely, XGB and LGB, for the modeling of censored survival outcomes. Based on a comprehensive set of simulations, we benchmark the new approaches against traditional methods including the stepwise Cox regression model and the original gradient boosting function implemented in the package gbm. We also demonstrate the application of Xsurv in analyzing a melanoma methylation dataset. Together, these results suggest that Xsurv is a useful and computationally viable tool for screening a large number of prognostic candidate biomarkers, which may facilitate cancer translational and clinical research. AvailabilityXsurv is freely available as an R package at: https://github.com/topycyao/Xsurv Contactxuefeng.wang@moffitt.org Supplementary informationSupplementary data are available at Bioinformatics online.

bioinformatics↗

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 lectin receptors for conserved SARS-CoV-2 glycosylation sites

New SARS-CoV-2 variants are continuously emerging with critical implications for therapies or vaccinations. All 22 N-glycan sites of SARS-CoV-2 Spike remain highly conserved among the variants B.1.1.7, 501Y.V2 and P.1, opening an avenue for robust therapeutic intervention. Here we used a comprehensive library of mammalian carbohydrate-binding proteins (lectins) to probe critical sugar residues on the full-length trimeric Spike and the receptor binding domain (RBD) of SARS-CoV-2. Two lectins, Clec4g and CD209c, were identified to strongly bind to Spike. Clec4g and CD209c binding to Spike was dissected and visualized in real time and at single molecule resolution using atomic force microscopy. 3D modelling showed that both lectins can bind to a glycan within the RBD-ACE2 interface and thus interferes with Spike binding to cell surfaces. Importantly, Clec4g and CD209c significantly reduced SARS-CoV-2 infections. These data report the first extensive map and 3D structural modelling of lectin-Spike interactions and uncovers candidate receptors involved in Spike binding and SARS-CoV-2 infections. The capacity of CLEC4G and mCD209c lectins to block SARS-CoV-2 viral entry holds promise for pan-variant therapeutic interventions.

molecular biology↗

bioRxiv2021

Synthetic multistability in mammalian cells

In multicellular organisms, gene regulatory circuits generate thousands of molecularly distinct, mitotically heritable states, through the property of multistability. Designing synthetic multistable circuits would provide insight into natural cell fate control circuit architectures and allow engineering of multicellular programs that require interactions among cells in distinct states. Here we introduce MultiFate, a naturally-inspired, synthetic circuit that supports long-term, controllable, and expandable multistability in mammalian cells. MultiFate uses engineered zinc finger transcription factors that transcriptionally self-activate as homodimers and mutually inhibit one another through heterodimerization. Using model-based design, we engineered MultiFate circuits that generate up to seven states, each stable for at least 18 days. MultiFate permits controlled state-switching and modulation of state stability through external inputs, and can be easily expanded with additional transcription factors. Together, these results provide a foundation for engineering multicellular behaviors in mammalian cells.

synthetic biology↗

bioRxiv2021

Machine Learning to Summarize and Provide Context for Sleep and Eating Schedules.

The relative timing of sleep and of eating within the circadian day is important for human health. Despite much data on sleep, and a growing data set for eating, there remains a need for an interpretative framework for the understanding of this data for health decisions. This study provides a new statistical and machine learning analysis of more than 500 participants in the Daily24 project. From their data, and the analysis, we propose a framework for determining the classification of participants into different chronotypes and with that the ability to realize the potential impact of daily circadian habits on health. We propose that our resulting distribution curves could be used, similar to NHANES (National Health and Nutrition Examination Survey) data for pediatric growth, as a measure for circadian misalignment and used to help guide re-entrainment schedules. Author summaryDaily habits can be positive, negative or neutral for human health. Generally sleep and eating schedules are assumed without thought for their potential to help or interfere with health. In this study we propose a framework, based on data from more than 500 participants, for evaluating the relative timing of meals and sleep schedules. This evaluation, similar to pediatric growth charts, can guide clinical suggestions for those at the extremes, while helping others to realize that they are unusual relative to the population average

bioinformatics↗

bioRxiv2020

The size of helical pitch is important for microtubule plus end dynamic instability

Microtubule (MT) dynamic instability is a conserved phenomenon underlying essential cellular functions such as cell division, cell migration and intracellular transport, and is a key target of many chemotherapeutic agents. However, it remains unclear how the organization of tubulin dimers at the nanometer scale translates into dynamic instability as an emergent property at the micrometer scale. Tubulin dimers are organized into left-handed helical MT lattice, and most present-day MTs converge at a 1.5 dimer helical pitch that causes a seam in an otherwise symmetric helix. Because presently there are no experimental methods that can precisely manipulate tubulin subunit with sub-dimer resolution, the impact of helical pitch on dynamic instability remains unknown. Here by using stochastic simulations of microtubule assembly dynamics we demonstrate that helical pitch plays essential roles in MT plus end dynamic instability. By systematically altering helical pitch size, one half-dimer at a time, we found that a helical pitch as small as one half-dimer is sufficient to inhibit short-term MT length plateaus associated with diminishing GTP-tubulin cap. Notably, MT plus end dynamics quantitatively scale with the size of helical pitch, rather than being clustered by the presence or absence of helical symmetry. Microtubules with a 1.5 dimer helical pitch exhibit growth and shrinkage phases and undergo catastrophe and rescue similar to experimentally observed microtubules. Reducing helical pitch to 0 promotes rapid disassembly, while increasing it causes microtubules to undergo persistent growth, and it is the 1.5 dimer helical pitch that yields the highest percentage of MTs that undergo alternating growth and shrinkage without being totally disassembled. Finally, although the 1.5 dimer helical pitch is conserved among most present-day MTs, we find that other parameters, such as GTP hydrolysis rate, can partially compensate for changes in helical pitch. Together our results indicate that helical pitch is a determinant of MT plus end dynamic instability and that the evolutionarily conserved 1.5 dimer helical pitch promotes dynamic instability required for microtubule-dependent cellular functions.

cell biology↗

bioRxiv2020

Identification of microbial markers across populations in early detection of colorectal cancer

Several studies have investigated the association between microbial and colorectal cancer (CRC). However, the replicable markers for early stage adenoma diagnosis across multiple populations remain elusive. Here, a meta-analysis of six studies, comprising a total of 1057 fecal samples, was performed to identify candidate markers. By adjusting the potential confounders, 11 and 26 markers (P<0.05) were identified and separately applied into constructing Random Forest classifier models to discriminate adenoma from control, and adenoma from CRC, achieving robust diagnostic accuracy with AUC = 0.80 and 0.89, respectively. Moreover, these markers demonstrated high diagnostic accuracy in independent validation cohorts. Pooled functional analysis and targeted qRT-PCR based genetic profiles reveal that the altered microbiome triggers different pathways of ADP-heptose and menaquinone biosynthesis (P<0.05) in adenoma vs. control and adenoma vs. CRC sequences respectively. The combined analysis of heterogeneous studies confirm adenoma-specific but universal markers across multi-populations, which improves early diagnosis and prompt treatment of CRC.

pathology↗

bioRxiv2020

Alterations in bile acid metabolizing gut microbiota and specific bile acid genes as a precision medicine to subclassify NAFLD

Background & AimsMultiple mechanisms for the gut microbiome contributing to the pathogenesis of non-alcoholic fatty liver disease (NAFLD) have been implicated. Here, we aim to investigate the contribution and potential application for altered bile acid (BA) metabolizing microbe in NAFLD using whole metagenome sequencing (WMS) data. Methods86 well-characterized biopsy-proven NAFLD patients and 38 healthy controls were included in the discovery cohort. Assembly-based analysis was performed to identify BA-metabolizing microbes. Statistical tests, feature selection and microbial interaction analysis were integrated to identify microbial alterations and markers in NAFLD. An independent validation cohort was subjected to similar analyses. ResultsNAFLD microbiota exhibited decreased diversity and microbial interactions. We established a classifier model with 53 differential species exhibiting a robust diagnostic accuracy (AUC=0.97) for dectecting NAFLD. Next, 8 important differential pathway markers including secondary BA biosynthesis were identified. Specifically, increased abundance of 7-HSDH, baiA and baiB were detected in NAFLD. Further, 10 of 50 BA-metabolizing metagenome-assembled genomes (MAG)s, from Bacteroides ovatus and Eubacterium biforme, were dominant in NAFLD and interplayed as a synergetic ecological guild. Importantly, two subtypes of NAFLD patients were observed according to secondary BA metabolism potentials. Elevated capability for secondary BA biosynthesis was also observed in the validation cohort. ConclusionsWe identified novel bacterial BA-metabolizing genes and microbes that may contribute to NAFLD pathogenesis and serve as disease markers. Microbial differences in BA-metabolism and strain-specific differences among patients highlight the potential for precision medicine in NAFLD treatment.

pathology↗

bioRxiv2020

Diversity and biogeography of Woesearchaeota: A comprehensive analysis of multi-environment data

Woesearchaeota is a newly proposed archaeal phylum frequently detected in various environments. Due to the limited systematical study, little is known about their distribution, taxonomy, and metabolism. Here, we conducted a comprehensive study for Woesearchaeota with 16S ribosomal RNA (rRNA) gene sequencing data of 27,709 samples and metagenomic whole genome sequencing (WGS) data of 1,266 samples. We find that apart from free-living environments, Woesearchaeota also widely distribute in host-associated environments. And host-associated environmental parameters greatly affect their distribution. 81 Woesearchaeota genomes, including 33 genomes firstly reconstructed in this project, were assigned to 59 Woesearchaeota species, suggesting their high taxonomic diversity. Comparative analysis indicated that Woesearchaeota have an open pan-genome with small core genome. Metabolic reconstruction showed that particular metabolic pathway absence in specific environments, demonstrated the metabolic diversity of Woesearchaeota varies in differences environments. These results have placed host-associated environments into the global biogeography of Woesearchaeota and have demonstrated their genomic diversity for future investigation of adaptive evolution.

ecology↗

bioRxiv2020

Identification of the keystone species in non-alcoholic fatty liver disease by causal inference and dynamic intervention modeling

ObjectiveKeystone species are required for the integrity and stability of an ecological community, and therefore, are potential intervention targets for microbiome related diseases. DesignHere we describe an algorithm for the identification of keystone species from cross-sectional microbiome data of non-alcoholic fatty liver disease (NAFLD) based on causal inference theories and dynamic intervention modeling (DIM). ResultsEight keystone species in the gut of NAFLD, represented by P. loveana, A. indistinctus and D. pneumosintes, were identified by our algorithm, which could efficiently restore the microbial composition of the NAFLD toward a normal gut microbiome with 92.3% recovery. These keystone species regulate intestinal amino acids metabolism and acid-base environment to promote the growth of the butyrate-producing Lachnospiraceae and Ruminococcaceae species. ConclusionOur method may benefit microbiome studies in the broad fields of medicine, environmental science and microbiology. SUMMARYWhat is already known about this subject? O_LINon-alcoholic fatty liver disease (NAFLD) is a complex multifactorial disease whose pathogenesis remains unclear. C_LIO_LIDysbiosis in the gut microbiota affects the initiation and development of NAFLD, but the mechanisms is yet to be established. C_LIO_LIKeystone species represent excellent candidate targets for gut microbiome-based interventions, as they are defined as the species required for the integrity and stability of the ecological system. C_LI What are the new findings? O_LINAFLD showed significant dysbiosis in butyrate-producing Lachnospiraceae and Ruminococcaceae species. C_LIO_LIMicrobial interaction networks were constructed by the novel algorithm with causal inference. C_LIO_LIKeystone species were identified form microbial interaction networks through dynamic intervention modeling based on generalized Lotka-Volterra model. C_LIO_LIEight keystone species of NAFLD with the highest potential for restoring the microbial composition were identified. C_LI How might it impact on clinical practice in the foreseeable future? O_LIAn algorithm for the identification of keystone species from cross-sectional microbiome data based on causal inference theories and dynamic intervention modeling. C_LIO_LIEight keystone species in the gut of NAFLD, represented by P. loveana, A. indistinctus and D. pneumosintes, which could efficiently restore the microbial composition of the NAFLD toward a normal gut microbiome. C_LIO_LIOur method may benefit microbiome studies in the broad fields of medicine, environmental science and microbiology. C_LI

bioinformatics↗

bioRxiv2020

Background white noise and speech facilitate visual working memory

In contrast to background white noise, the detrimental effects of background speech on verbal working memory (WM) were often explained by speech interference in the same verbal modality. Yet, those results were confounded with potential differences between arousal levels induced by speech and white noise. To address the role of arousal, in the present study, we minimized the verbal interference and used a visual WM task to test the influence of background speech or white noise. Electrodermal activity (EDA) and Electromyography (EMG) were recorded simultaneously to indicate the arousal levels of participants. Results showed that both background speech and white noise significantly improved visual WM performance. The change of performance further correlated with the change of physiological signals linked with arousal. Taken together, our results suggest that both background speech and white noise facilitate visual WM through raising the arousal level.

physiology↗

bioRxiv2020

Dr AFC: Drug Repositioning Through Anti-Fibrosis Characteristic

Fibrosis is a key component in the pathogenic mechanism of many diseases. These diseases involving fibrosis may share common mechanisms, therapeutic targets and therefore, common intervention strategies and medicines may be applicable for these diseases. For this reason, deliberately introducing anti-fibrosis characteristics into modelling may lead to more success in drug repositioning. In this study, anti-fibrosis knowledge base was first built by collecting data from multiple resources. Both structural and biological profiles were derived from the knowledge base and used for constructing machine learning models including Structural Profile Prediction Model (SPPM) and Biological Profile Prediction Model (BPPM). Three external public data sets were employed for validation purpose and further exploration of potential repositioning drugs in wider chemical space. The resulting SPPM and BPPM models achieve area under the receiver operating characteristic curve (AUC) of 0.879 and 0.972 in the training set, and 0.814 and 0.874 in the testing set. Additionally, our results also demonstrate that substantial amount of multi-targeting natural products possess notable anti-fibrosis characteristics and might serve as encouraging candidates in fibrosis treatment and drug repositioning. To leverage our methodology and findings, we developed repositioning prediction platform, Drug Repositioning based on Anti-Fibrosis Characteristic (Dr AFC) that is freely accessible via https://www.biosino.org/drafc.

bioinformatics↗

bioRxiv2020

Structural basis underlying strong interactions between ankyrins and spectrins

Ankyrins (encoded by ANK1/2/3 corresponding to Ankyrin-R/B/G or AnkR/B/G), via binding to spectrins, connect plasma membranes with actin cytoskeleton to maintain mechanical strengths and to modulate excitabilities of diverse cells such as neurons, muscle cells, and erythrocytes. Cellular and genetic evidences suggest that each isoform of ankyrins pairs with a specific {beta}-spectrin in discrete subcellular membrane microdomains for distinct functions, though the molecular mechanisms underlying such ankyrin/{beta}-spectrin pairings are unknown. In this study, we discover that a conserved and short extension N-terminal to the ZU5N-ZU5C-UPA tandem (exZZU) is critical for each ankyrin to bind to {beta}-spectrins with high affinities. Structures of AnkB/G exZZU in complex with spectrin repeats13-15 of {beta}2/{beta}4-spectrins solved here reveal that the extension sequence of exZZU forms an additional {beta}-strand contributing to the structural stability and enhanced affinity of each ZU5N/spectrin repeat interaction. The junction site between the extension and ZU5N is exactly the position of a splicing-mediated miniexon insertion site of AnkB/G. The complex structures further reveal that the UPA domain of exZZU directly participates in spectrin binding. Formation of the exZZU supramodule juxtaposes the ZU5N and UPA domains for simultaneous interacting with spectrin repeats 14 and 15. However, our biochemical and structural investigations indicate that the direct and strong interactions between ankyrins and {beta}-spectrins do not appear to determine their pairing specificities. Therefore, there likely exists additional mechanism(s) for modulating functional pairings between ankyrins and {beta}-spectrins in cells.

biochemistry↗

bioRxiv2020

The transmembrane serine protease inhibitors are potential antiviral drugs for 2019-nCoV targeting the insertion sequence-induced viral infectivity enhancement

At the end of 2019, the SARS-CoV-2 induces an ongoing outbreak of pneumonia in China1, even more spread than SARS-CoV infection2. The entry of SARS-CoV into host cells mainly depends on the cell receptor (ACE2) recognition and spike protein cleavage-induced cell membrane fusion3,4. The spike protein of SARS-CoV-2 also binds to ACE2 with a similar affinity, whereas its spike protein cleavage remains unclear5,6. Here we show that an insertion sequence in the spike protein of SARS-CoV-2 enhances the cleavage efficiency, and besides pulmonary alveoli, intestinal and esophagus epithelium were also the target tissues of SARS-CoV-2. Compared with SARS-CoV, we found a SPRR insertion in the S1/S2 protease cleavage sites of SARS-CoV-2 spike protein increasing the cleavage efficiency by the protein sequence aligment and furin score calculation. Additionally, the insertion sequence facilitates the formation of an extended loop which was more suitable for protease recognition by the homology modeling and molicular docking. Furthermore, the single-cell transcriptomes identified that ACE2 and TMPRSSs are highly coexpressed in AT2 cells of lung, along with esophageal upper epithelial cells and absorptive enterocytes. Our results provide the bioinformatics evidence for the increased spike protein cleavage of SARS-CoV-2 and indicate its potential target cells.

microbiology↗

bioRxiv2020

PGC1/PPAR Drive Cardiomyocyte Maturation through Regulation of Yap1 and SF3B2

Cardiomyocytes undergo significant levels of structural and functional changes after birth--fundamental processes essential for the heart to produce the volume and contractility to pump blood to the growing body. However, due to the challenges in isolating single postnatal/adult myocytes, how individual newborn cardiomyocytes acquire multiple aspects of mature phenotypes remains poorly understood. Here we implemented large-particle sorting and analyzed single myocytes from neonatal to adult hearts. Early myocytes exhibited a wide-ranging transcriptomic and size heterogeneity, maintained until adulthood with a continuous transcriptomic shift. Gene regulatory network analysis followed by mosaic gene deletion revealed that peroxisome proliferator-activated receptor coactivator-1 signaling--activated in vivo but inactive in pluripotent stem cell-derived cardiomyocytes--mediates the shift. The signaling regulated key aspects of cardiomyocyte maturation simultaneously through previously unrecognized regulators, including Yap1 and SF3B2. Our study provides a single-cell roadmap of heterogeneous transitions coupled to cellular features and unveils a multifaceted regulator controlling cardiomyocyte maturation. Significance StatementHow the individual single myocytes achieve full maturity remains a black box, largely due to the challenges with the isolation of single mature myocytes. Understanding this process is particularly important as the immaturity and early developmental arrest of pluripotent stem cell-derived myocytes has emerged a major concern in the field. Here we present the first study of high-quality single-cell transcriptomic analysis of cardiac muscle cells from neonatal to adult hearts. We identify a central transcription factor and its novel targets that control key aspects of myocyte maturation, including cellular hypertrophy, contractility, and mitochondrial activity.

developmental biology↗

bioRxiv2019

Large-scale transgenic Drosophila resource collections for loss- and gain-of-function studies

The Transgenic RNAi Project (TRiP), a Drosophila functional genomics platform at Harvard Medical School, was initiated in 2008 to generate and distribute a genome-scale collection of RNAi fly stocks. To date, the TRiP has generated >15,000 RNAi fly stocks. As this covers most Drosophila genes, we have largely transitioned to development of new resources based on CRISPR technology. Here, we present an update on our libraries of publicly available RNAi and CRISPR fly stocks, and focus on the TRiP-CRISPR overexpression (TRiP-OE) and TRiP-CRISPR knockout (TRiP-KO) collections. TRiP-OE stocks express sgRNAs targeting upstream of a gene transcription start site. Gene activation is triggered by co-expression of catalytically dead Cas9 (dCas9) fused to an activator domain, either VP64-p65-Rta (VPR) or Synergistic Activation Mediator (SAM). TRiP-KO stocks express one or two sgRNAs targeting the coding sequence of a gene or genes, allowing for generation of indels in both germline and somatic tissue. To date, we have generated more than 5,000 CRISPR-OE or -KO stocks for the community. These resources provide versatile, transformative tools for gene activation, gene repression, and genome engineering.

genetics↗

bioRxiv2019

Reconstructing species evolutionary trees using the numerical features of microRNA

Research has revealed that some microRNAs show obvious lineage or species specificity, but others show highly conserved properties among species. Based on these properties, we aimed to reconstruct a species evolution tree using a new technique that refers to the numerical features of microRNA. First, we selected 132 microRNA numerical features that included base content, secondary structure matching state frequency, free energy features and information entropy features, and 32 species that included 22 animals, 9 plants and a representative virus group. Second, we found several significantly different numerical features among lineages or species by statistical analysis and confirmed that differences in each numerical feature were not identical. Third, we designed a comprehensive feature and confirmed that it showed obvious lineage and species specificity. Last, species trees were built using the comprehensive feature. The results showed that the reconstructed species tree was almost in keeping with the actual chronological order of species evolution. This indicated that our analysis was effective. Our research strategy offers a new route for investigating species evolution.

bioinformatics↗

bioRxiv2019

Discovery Function Labels Based On Numerical Features Of MicroRNA Found In Plant

MicroRNAs(miRNAs),are a class of small endogenous non-coding RNAs that play Important post-transcriptional regulation role by degrading targeted mRNAs or repressing mRNA translation. We screened 84 miRNAs belonging to 21 conserved family from 4014 miRNAs in miRBase database which distributed in 47 plant species. Of the predicted 274 target genes,42 GO terms were found in the Gene Ontology. With the 135 numerical features which extracted by perl program, the difference significantly result of ANOVA (P<0.001) and multiple comparison show that the function labels G...,GC content and Helix in biological process, cellular component and biological function, respectively. Our result have suggested a potential connection between numerical features of miRNAs and the function of target genes of miRNAs.

bioinformatics↗