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Biology subjects

Leng, J.

Publications and source records attributed to Leng, J..

15 recordsLinked to original sources

Flippable Siamese Differential Neural Network for Differential Graph Inference

Differential graph inference is a critical analytical technique that enables researchers to accurately identify the variables and their interactions that change under different conditions. By comparing two conditions, researchers can gain a deeper understanding of the differences between them. Currently, the mainstream methods in differential graph inference are mathematical optimization algorithms, including sparse optimization based on Gaussian graphical models or sparse Bayesian regression. These methods can eliminate many false positives in graphs, but at the cost of heavy reliance on the prior distributions of data or parameters, and they suffer from the curse of dimensionality. To address these challenges, we introduce a new architecture called the Flippable Siamese Differential Neural Network (FSDiffNet). We originally established the concept of flippability and the theoretical foundation of flippable neural networks, laying the groundwork for building a flippable neural network. This theoretical framework guided the design of architecture and components, including the SoftSparse activation function and high-dilation circular padding diagonal convolution. FSDiffNet uses large-scale pre-training techniques to acquire differential features and perform differential graph inference. Through experiments with simulated and real datasets, FSDiffNet outperforms existing state-of-the-art methods on multiple metrics, effectively inferring key differential factors related to conditions such as autism and breast cancer. This proves the effectiveness of FSDiffNet as a solution for differential graph inference challenges.

bioinformatics↗

Collagen-Based Gut-on-Chip for in vitro modeling of intestinal barrier function and host-pathogen interactions

The human intestine, characterized by its villi and crypt structures, plays a critical role in nutrient absorption, barrier function, and host defense. However, traditional in-vitro models employing synthetic membranes like polydimethylsiloxane (PDMS) and polycarbonate (PC) often fail to accurately replicate the complex physiological environment of the intestine. To address this limitation, we developed a gut-on-chip, incorporating a porous collagen type I membrane, to better mimic the natural extracellular matrix (ECM) and create a more physiologically relevant in vitro system. Thin, porous collagen type I membranes were fabricated and characterized by linear close contact profilometry to determine their thickness, which closely approximated the in vivo intestinal basement membrane. Caco-2 cells cultured within the device exhibited the formation of villi-like structures, tight junction formation, and mucin production, demonstrating successful differentiation and functional barrier formation on the collagen membrane. We investigated the devices capacity to model host-pathogen interactions by infecting the cell layer with Candida albicans. Confocal microscopy revealed hyphal invasion of the epithelial cells, and permeability assays demonstrated increased layer permeability following infection, highlighting the devices ability to replicate infection processes and their impact on barrier integrity. This gut-on-chip, by integrating physiological membrane and replicating key structural and functional aspects of the intestine, offers a promising platform for studying intestinal physiology and host-pathogen dynamics.

bioengineering↗

Investigation of 3D Printed Bioresorbable Vascular Scaffold Crimping Behavior

The rise in additive manufacturing (AM) offers myriad opportunities for 3D-printed polymeric vascular scaffolds, such as customization and on-the-spot manufacturing, in vivo biodegradation, incorporation of drugs to prevent restenosis, and visibility under X-ray. To maximize these benefits, informed scaffold design is critical. Polymeric bioresorbable vascular scaffolds (BVS) must undergo significant deformation prior to implantation in a diameter-reduction process known as crimping which enables minimally invasive surgery. Understanding the behavior of vascular scaffolds in this step provides twofold benefits: first, it ensures the BVS is able to accommodate stresses occurring during this process to prevent failure, and further, it provides information on the radial strength of the BVS, a key metric to understanding its post-implant performance in the artery. To capitalize on the fast manufacturing speed AM provides, a low time cost solution for understanding scaffold performance during this step is necessary. Through simulation of the BVS crimping process in ABAQUS using experimentally obtained bulk material properties, we have developed a qualitative analysis tool which is capable of accurately comparing relative performance trends of varying BVS designs during crimping in a fraction of the time of experimental testing, thereby assisting in the integration of informed design into the additive manufacturing process.

bioengineering↗

Alteration of the chicken upper respiratory microbiota following H9N2 avian influenza virus infection

Several studies have highlighted the importance of the gut microbiota in developing immunity against viral infections in chickens. We have previously shown that H9N2 avian influenza A virus (AIV) infection retards the diversity of the natural colon associated microbiota, which may further influence chicken health following recovery from infection. The effects of influenza infection on the upper respiratory tract (URT) microbiota are largely unknown. Here we showed that H9N2 AIV infection lowers alpha diversity indices in the acute phase of infection in URT, largely due to the family Lactobacillaceae being highly enriched during this time in the respiratory microbiota. Interestingly, microbiota diversity did not return to levels similar to control chickens in the recovery phase after viral shedding has ceased. Beta diversity followed similar trend following challenge. Lactobacillus associate statistically with the disturbed microbiota of infected chickens at acute and recovery phase of infection. Additionally, we study age-related changes in the respiratory microbiota during maturation in chickens. From 7 to 28 days of age, species richness and evenness were observed to advance over time as the microbial composition evolved. Maintaining microbiota homeostasis might be considered as a potential therapeutic target to prevent or aid recovery from H9N2 AIV infection.

microbiology↗

Mechanically stimulated osteocytes maintain tumor dormancy in bone metastasis of non-small cell lung cancer by releasing small extracellular vesicles

Although preclinical and clinical studies have shown that exercise can inhibit bone metastasis progression, the mechanism remains poorly understood. Here, we found that non-small cell lung cancer (NSCLC) cells adjacent to bone tissue had a much lower proliferative capacity than the surrounding tumor cells. Subsequently, it was demonstrated that osteocytes, sensing mechanical stimulation generated by exercise, inhibit NSCLC cell proliferation and sustain the dormancy thereof by releasing small extracellular vesicles with tumor suppressor microRNAs, such as miR-99b-3p. Furthermore, mechanical loading of the tibia inhibited the bone metastasis progression of NSCLC. Notably, bone metastasis progression of NSCLC was inhibited by moderate exercise, and combinations with zoledronic acid had additive effects. Moreover, exercise preconditioning effectively suppressed bone metastasis progression. This study significantly advances the understanding of the mechanism underlying exercise-afforded protection against bone metastasis progression.

cancer biology↗

Tissue- and sex-specific DNA damage tracks aging in rodents and humans

DNA damage causes genomic instability underlying many human diseases. Traditional approaches to DNA damage analysis provide minimal insights into the spectrum of disease-driving DNA lesions and the mechanisms causing imbalances in damage formation and repair. Here we used untargeted mass spectrometry-based adductomics1 to discover 114 putative DNA lesions and modifications consistently detected in humans and two independent analyses in rats, showing species-, tissue-, age-, and sex-biases. As evidence of methodologic rigor, 10 selected adductomic signals were structurally validated as epigenetic marks: 5-MdC, 5-HMdC, 5-FdC; DNA damage products: N2-CMdG, 1,N6 {varepsilon}-dA, 3,N4-{varepsilon}dC, M1dG, O6/N2-MdG, and 8-Oxo-dG; and established analytical artifacts: cyclobutane dimers of 2-deoxycytosine. With steady-state levels of putative DNA adducts integrating multiple cell types in each tissue, there was strong age-dependent variation for many putative adducts, including N2-CMdG, 5-HMdC, and 8-Oxo-dG in rats and 1,N6 {varepsilon}-dA in human heart, as well as sex biases for 67 putative adducts in rat tissues. These results demonstrate the potential of untargeted adductomic analysis for defining DNA adducts as disease determinants, assigning substrates to DNA repair pathways, discovering new metabolically-driven DNA lesions, and quantifying inter-individual variation in DNA damage and repair across populations.

biochemistry↗

PathExpSurv: Pathway Expansion for Explainable Survival Analysis and Disease Gene Discovery

MotivationIn the field of biology and medicine, the interpretability and accuracy are both important when designing predictive models. The interpretability of many machine learning models such as neural networks is still a challenge. Recently, many researchers utilized prior information such as biological pathways to develop bioinformatics methods based on neural networks, so that the prior information can provide some insights and interpretability for the models. However, the prior biological knowledge may be incomplete and there still exists some unknown information to be explored. ResultsWe proposed a novel method, named PathExpSurv, to gain an insight into the black-box model of neural network for cancer survival analysis. We demonstrated that PathExpSurv could not only incorporate the known prior information into the model, but also explore the unknown possible expansion to the existing pathways. We performed downstream analyses based on the expanded pathways and successfully identified some key genes associated with the diseases and original pathways. AvailabilityPython source code of PathExpSurv is freely available at https://github.com/Wu-Lab/PathExpSurv. Contactlywu@amss.ac.cn Supplementary informationSupplementary data are available at Bioinformatics online.

bioinformatics↗

An RNA binding protein, RNP1A, works with Contractility Kit proteins to facilitate macropinocytosis

Cell shape regulation is important for many biological processes. Some cell shape regulating proteins harbor mechanoresponsive properties that enable them to sense and respond to mechanical cues, allowing for cell adaptation. In Dictyostelium discoideum, mechanoresponsive network proteins include Cortexillin I and IQGAP1, which assemble in the cytoplasm into macromolecular complexes, which we term Contractility Kits. In vivo fluorescence cross-correlation spectroscopy revealed that Cortexillin I also interacts with an RNA-binding protein, RNP1A. The rnp1A knockdown cells have reduced cell growth rate, reduced adhesion, defective cytokinesis, and a gene expression profile that indicates rnp1A knockdown cells shift away from the vegetative growth state. RNP1A binds to transcripts encoding proteins involved in macropinocytosis. One of these, DlpA, facilitates macropinosome maturation, similar to RNP1A. Loss of different CK proteins leads to macropinocytotic defects characterized by reduced macropinocytotic crown size. RNP1A interacts with IQGAP1 in vivo and has cross-talk with IQGAP1 during macropinocytosis. Overall, RNP1A contributes to macropinocytosis, in part through interacting with transcripts encoding macropinocytotic proteins like dlpA, and does so in coordination with the Contractility Kit proteins.

cell biology↗

Genome-wide association reveals host-specific genomic traits in Escherichia coli

Escherichia coli is an opportunistic pathogen that can colonize or infect various host species. There is a significant gap in our understanding to what extent genetic lineages of E. coli are adapted or restricted to specific hosts. In addition, genomic determinants underlying such host specificity are unknown.By analyzing a randomly sampled collection of 1198 whole-genome sequenced E. coli isolates from four countries (Germany, UK, Spain, and Vietnam), obtained from five host species (human, pig, cattle, chicken, and wild boar) over 16 years, from both healthy and diseased hosts, we demonstrate that certain lineages of E. coli are frequently detected in specific hosts. We report a novel nan gene cluster, designated nan-9, putatively encoding acetylesterases and determinants of uptake and metabolism of sialic acid, to be associated with the human host as identified through genome wide association studies. In silico characterization predicts nan-9 to be involved in sialic acid (Sia) metabolism. In vitro growth experiments with a representative {Delta}nan E. coli mutant strain, using sialic acids 5-N-acetyl neuraminic acid (Neu5Ac) and N-glycolyl neuraminic acid (Neu5Gc) as the sole carbon source, indicate an impaired growth behaviour compared to the wild-type. In addition, we identified several additional E. coli genes that are potentially associated with adaptation to human, cattle and chicken hosts, but not for the pig host. Collectively, this study provides an extensive overview of genetic determinants which may mediate host specificity in E. coli. Our findings should inform risk analysis and epidemiological monitoring of (antimicrobial resistant) E. coli.

genomics↗

Metagenomic investigation of the equine faecal microbiome reveals extensive taxonomic and functional diversity

BackgroundThe horse plays crucial roles across the globe, including in horseracing, as a working and companion animal and as a food animal. The horse hindgut microbiome makes a key contribution in turning a high fiber diet into body mass and horsepower. However, despite its importance, the horse hindgut microbiome remains largely undefined. Here, we applied culture-independent shotgun metagenomics to thoroughbred equine faecal samples to deliver novel insights into this complex microbial community. ResultsWe performed metagenomic sequencing on five equine faecal samples to construct 123 high- or medium-quality metagenome-assembled genomes from Bacteria and Archaea. In addition, we recovered nearly 200 bacteriophage genomes. We document surprising taxonomic and functional diversity, encompassing dozens of novel or unnamed bacterial genera and species, to which we have assigned new Candidatus names. Many of these genera are conserved across a range of mammalian gut microbiomes. ConclusionsOur metagenomic analyses provide new insights into the bacterial, archaeal and bacteriophage components of the horse gut microbiome. The resulting datasets provide a key resource for future high-resolution taxonomic and functional studies on the equine gut microbiome.

genomics↗

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↗

Low pathogenic avian influenza virus infection retards colon microbiome diversification in two different chicken lines

A commensal microbiome regulates and is in turn regulated by viruses during host infection which can influence virus infectivity. In this study, analysis of colon microbiome population changes following a low pathogenicity avian influenza virus (AIV) of the H9N2 subtype infection of two different chicken breeds was conducted. Using 16S rRNA sequencing and subsequent data analysis we found reduced microbiome alpha diversity in the acute period of AIV infection (day 2-3) in both Rhode Island Red and VALO chicken lines. From day 4 post infection a gradual increase in diversity of the colon microbiome was observed, but the diversity did not reach the same level as in uninfected chickens by day 10 post infection, suggesting that AIV infection retards the natural accumulation of colon microbiome diversity, which may further influence chicken health following recovery from infection. Beta diversity analysis indicated differences in diversity between the chicken lines during and following acute influenza infection suggesting the impact of host gut microflora dysbiosis following H9N2 influenza virus infection could differ for different breeds.

microbiology↗

Nanoscale pattern extraction from relative positions of sparse 3D localisations

We present a method for extracting high-resolution ordered features from localisation microscopy data by analysis of relative molecular positions in 2D or 3D. This approach allows pattern recognition at sub-1% protein detection efficiencies, in large and heterogeneous samples, and in 2D and 3D datasets. We used this method to infer ultrastructure of the nuclear pore, the cardiomyocyte Z-disk, DNA origami structures and the centriole.

cell biology↗

LESSeq: Local event-based analysis of alternative splicing using RNA-Seq data

Alternative splicing, which can be observed genome-wide by RNA-Seq, is important in cellular development and evolution. Comparative RNA-Seq experiments between different cellular conditions allow alternative splicing signatures to be detected. However, inferring alternative splicing signatures from short-read technology is unreliable and still presents many challenges before biologically significant signatures may be identified. To enable the robust discovery of differential alternative splicing, we developed the Local Event-based analysis of alternative Splicing using RNA-Seq (LESSeq) pipeline. LESSeq utilizes information of local splicing events (i.e., the partial structures in genes where transcript-splicing patterns diverge) to identify unambiguous alternative splicing. In addition, LESSeq quantifies the abundance of these alternative events using Maximum Likelihood Estimation (MLE) and provides their significance between different cellular conditions. The utility of LESSeq is demonstrated through two case studies relevant to human variation and evolution. Using an RNA-Seq data set of lymphoblastoid cell lines in two human populations, we examined within-species variation and discovered population-differential alternative splicing events. With an RNA-Seq data set of several tissues in human and rhesus macaque, we studied cross-species variation and identified lineage-differential alternative splicing events. LESSeq is implemented in C++ and R, and made publicly available on GitHub at: https://github.com/gersteinlab/LESSeq

bioinformatics↗

Nationwide population genetic screening improves outcomes of newborn screening for hearing loss in China

PurposeConcurrent newborn hearing and genetic screening has been reported, but its benefits have not been statistically proven due to limited sample sizes and outcome data. To fill this gap, we analyzed outcomes of a large number of newborns with genetic screening results.\n\nMethodsNewborns in China were screened for 20 hearing-loss-related genetic variants from 2012-2017. Genetic results were categorized as positive, at-risk, inconclusive, or negative. Hearing screening results, risk factors, and up-to-date hearing status were followed-up via phone interviews.\n\nResultsWe completed genetic screening on one million newborns and followed up 12,778. We found that a positive genetic result significantly indicated a higher positive predictive value of the initial hearing screening (60% vs. 5.0%, P<0.001) and a lower rate of loss-to-follow-up (5% vs. 22%, P<0.001) than an inconclusive one. Importantly, 42% of subjects in the positive group with reported or presymptomatic hearing loss were \"missed\" by conventional hearing screening. Furthermore, genetic screening identified 0.23% of subjects predisposed to preventable ototoxicity.\n\nConclusionOur results demonstrate that limited genetic screening identified additional cases, reduced loss-to-follow-up, and informed families of ototoxicity risks, providing convincing evidence to support integrating genetic screening into universal newborn hearing screening programs.

genetics↗