Biology subjects

Lin, Y.

Publications and source records attributed to Lin, Y..

At least 325 records · Page 18Linked to original sources

bioRxiv2021

Adaptation and phenotypic diversification of Bacillus thuringiensis 407 biofilm are accompanied by a fuzzy spreader morphotype

Bacillus cereus group (Bacillus cereus sensu lato) has a diverse ecology, including various species that produce biofilms on abiotic and biotic surfaces. While genetic and morphological diversification enable the adaptation of multicellular communities, this area remains largely unknown in the Bacillus cereus group. In this work, we dissected the experimental evolution of Bacillus thuringiensis 407 Cry-during continuous recolonization of plastic beads. We observed the evolution of a distinct colony morphotype that we named fuzzy spreader (FS) variant. Most multicellular traits of the FS variant displayed higher competitive ability versus the ancestral strain, suggesting an important role for diversification in the adaptation of B. thuringiensis to the biofilm lifestyle. Further genetic characterization of FS variant revealed the disruption of a guanylyltransferase gene by an insertion sequence (IS) element, which could be similarly observed in the genome of a natural isolate. The evolved FS and the deletion mutant in the guanylyltransferase gene (Bt407{Delta}rfbM) displayed similarly altered aggregation and hydrophobicity compared to the ancestor strain, suggesting that adaptation process highly depends on the physical adhesive forces.

microbiology↗

bioRxiv2021

Exploring ensemble structures of Alzheimer's amyloid β (1-42) monomer using linear regression for the MD simulation and NMR chemical shift

Aggregation of intrinsically disordered amyloid {beta} (A{beta}) is a hallmark of Alzheimers disease. Although complex aggregation mechanisms have been increasingly revealed, structural ensembles of A{beta} monomers with heterogeneous and transient properties still hamper detailed experimental accesses to early events of amyloidogenesis. We herein developed a new mathematical tool based on multiple linear regression to obtain the reasonable ensemble structures of A{beta} monomer by using the solution nuclear magnetic resonance (NMR) and molecular dynamics simulation data. Our approach provided the best-fit ensemble to two-dimensional NMR chemical shifts, also consistent with circular dichroism and dynamic light scattering analyses. The major monomeric structures of A{beta} including {beta}-sheets in both terminal and central hydrophobic core regions and the minor partially-helical structures suggested initial structure-based explanation on possible mechanisms of early molecular association and nucleation for amyloid generation. A wide-spectrum application of the current approach was also indicated by showing a successful utilization for ensemble structures of folded proteins. We propose that multiple linear regression in combination to experimental results will be highly promising for studies on protein misfolding diseases and functions by providing a convincing template structure. Graphic abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=90 SRC="FIGDIR/small/457317v1_ufig1.gif" ALT="Figure 1"> View larger version (32K): org.highwire.dtl.DTLVardef@1b4e6eeorg.highwire.dtl.DTLVardef@1a533eeorg.highwire.dtl.DTLVardef@f48eb3org.highwire.dtl.DTLVardef@1c4bf9a_HPS_FORMAT_FIGEXP M_FIG C_FIG

biophysics↗

bioRxiv2021

Light-sheet photonic force optical coherence elastography for high-throughput quantitative 3D micromechanical imaging

Microscale mechanical properties of the extracellular matrix (ECM) and dynamic cell-ECM interactions play an important role in physiological processes and disease. However, it remains a challenge for current mechanical characterization methods to combine quantitative 3D imaging of ECM mechanics with cellular-scale resolution and dynamic monitoring of cell-mediated changes to pericellular viscoelasticity. Here, we present light-sheet photonic force optical coherence elastography (LS-pfOCE) to address these challenges by leveraging a light-sheet for parallelized, non-invasive, and localized mechanical loading. We demonstrate the capabilities of LS-pfOCE by imaging the micromechanical heterogeneity of fibrous 3D collagen matrices and perform a live-cell study to image micromechanical heterogeneity induced by NIH-3T3 cells seeded in 3D fibrin constructs. We also show that LS-pfOCE is able to quantify temporal variations in pericellular viscoelasticity in response to altered cellular activity. By providing access to the spatiotemporal variations in the micromechanical properties of 3D complex biopolymer constructs and engineered cellular systems, LS-pfOCE has the potential to drive new discoveries in the rapidly growing field of mechanobiology.

biophysics↗

bioRxiv2021

Broad neutralizing nanobody against SARS-CoV-2 engineered from pre-designed synthetic library

SARS-CoV-2 infection is initiated with Spike glycoprotein binding to the receptor of human angiotensin converting enzyme 2 via its receptor binding domain. Blocking this interaction is considered as an effective approach to inhibit virus infection. Here we report the discovery of a neutralizing nanobody, VHH60, directly produced from a humanized synthetic nanobody library. VHH60 competes with human ACE2 to bind the receptor binding domain of the Spike protein with a KD of 2.56 nM, inhibits infections of both live SARS-CoV-2 and pseudotyped viruses harboring wildtype, escape mutations and prevailing variants at nanomolar level. VHH60 also suppresses SARS-CoV-2 infection and propagation 50-fold better and protects mice from death two times longer than that of control group after live virus inoculation on mice. VHH60 therefore is a powerful synthetic nanobody with a promising profile for disease control against COVID19.

microbiology↗

bioRxiv2021

Regeneration of humoral immunity from pluripotent stem cells by defined transcription factors

Regeneration of humoral immunity from pluripotent stem cells (PSCs) is a crucial aim in translational medicine. However, reconstitution of complete, sustained, and functional B lymphopoiesis from PSCs has not yet been developed. Here, we successfully achieved regenerative B lymphopoiesis in B-cell deficient animals transplanted with PSC-derived hematopoietic progenitors (iHPCs) guided by synergistic expression of Runx1, Hoxa9, and Lhx2. Upon transplantation, the iHPCs immediately gave rise to pro/pre-B cells in recipients bone marrow, which were able to further differentiate into the entire B cell lineages, including innate B-1a, B-1b, MZ B cells, as well as adaptive FO B cells. In responding to antigen stimuli, the regenerative B cells produced adaptive humoral immune responses, sustained a prolonged antigen-specific antibody production, and formed immune-memory. Particularly, the regenerative B cells in spleen showed developing patterns of immunoglobulin chain-switch and hyper-mutation via a cross-talk with the host T follicular helper cells, which eventually formed T cell-dependent humoral responses. This study provides de novo evidence that B lymphopoiesis can be regenerated from PSCs via a HSC-independent approach, which provides insights into treating B-cell related humoral deficiencies using PSCs as unlimited cell resource.

immunology↗

bioRxiv2021

Dual effects of presynaptic membrane mimetics on α-synuclein amyloid aggregation

Aggregation of intrinsically disordered -synuclein (SN) under various conditions is closely related to synucleinopathies. Although various biological membranes have shown to alter the structure and aggregation propensity of SN, a thorough understanding of the molecular and mechanical mechanism of amyloidogenesis in membranes remains unanswered. Herein, we examined the structural changes, binding properties, and amyloidogenicity of three variations of SN mutants under two types of liposomes, 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) and presynaptic vesicle mimetic (Mimic) membranes. While neutrally charged DOPC membranes elicited marginal changes in the structure and amyloid fibrillation of SNs, negatively charged Mimic membranes induced dramatic helical folding and biphasic amyloid generation. At low concentration of Mimic membranes, the amyloid fibrillation of SNs was promoted in a dose-dependent manner. However, further increases in the concentration constrained the fibrillation process. These results suggest the dual effect of Mimic membranes on regulating the amyloidogenesis of SN, which is rationalized by the amyloidogenic structure of SN and condensation-dilution of local SN concentration. Finally, we propose physicochemical properties of SN and membrane surfaces, and their propensity to drive electrostatic interactions as decisive factors of amyloidogenesis.

biophysics↗

bioRxiv2021

Multiple shifts in gene network interactions shape phenotypes of Drosophila melanogaster selected for long and short night sleep duration

All but the simplest phenotypes are believed to result from interactions between two or more genes forming complex networks of gene regulation. Sleep is a complex trait known to depend on the system of feedback loops of the circadian clock, and on many other genes; however, the main components regulating the phenotype and how they interact remain an unsolved puzzle. Genomic and transcriptomic data may well provide part of the answer, but a full account requires a suitable quantitative framework. Here we conducted an artificial selection experiment for sleep duration with RNA-seq data acquired each generation. The phenotypic results are robust across replicates and previous experiments, and the transcription data provides a high-resolution, time-course data set for the evolution of sleep-related gene expression. In addition to a Hierarchical Generalized Linear Model analysis of differential expression that accounts for experimental replicates we develop a flexible Gaussian Process model that estimates interactions between genes. 145 gene pairs are found to have interactions that are different from controls. Our method appears to be not only more specific than standard correlation metrics but also more sensitive, finding correlations not significant by other methods. Statistical predictions were compared to experimental data from public databases on gene interactions. Mutations of candidate genes implicated by our results affected night sleep, and gene expression profiles largely met predicted gene-gene interactions.

genomics↗

bioRxiv2021

RESEPT: tissue architecture inference and visualization from spatially resolved transcriptomics

Spatially resolved transcriptomics provides a new way to define spatial contexts and understand biological functions in complex diseases. Although some computational frameworks can characterize spatial context via various clustering methods, the detailed spatial architectures and functional zonation often cannot be revealed and localized due to the limited capacities of associating spatial information. We present RESEPT, a deep-learning framework for characterizing and visualizing tissue architecture from spatially resolved transcriptomics. Given inputs as gene expression or RNA velocity, RESEPT learns a three-dimensional embedding with a spatial retained graph neural network from the spatial transcriptomics. The embedding is then visualized by mapping as color channels in an RGB image and segmented with a supervised convolutional neural network model. Based on a benchmark of sixteen 10x Genomics Visium spatial transcriptomics datasets on the human cortex, RESEPT infers and visualizes the tissue architecture accurately. It is noteworthy that, for the in-house AD samples, RESEPT can localize cortex layers and cell types based on a pre-defined region-or cell-type-specific genes and furthermore provide critical insights into the identification of amyloid-beta plaques in Alzheimers disease. Interestingly, in a glioblastoma sample analysis, RESEPT distinguishes tumor-enriched, non-tumor, and regions of neuropil with infiltrating tumor cells in support of clinical and prognostic cancer applications.

bioinformatics↗

bioRxiv2021

AFEchidna is a R package for genetic evaluation of plant and animal breeding datasets

Progeny tests play important roles in plant and animal breeding programs, and mixed linear models are usually performed to estimate variance components of random effects, estimate the fixed effects (Best Linear Unbiased Estimates, BLUEs) and predict the random effects (Best Linear Unbiased Predictions, BLUPs) via restricted maximum likehood (REML) methods in progeny test datasets. The current pioneer software for genetic assessment is ASReml, but it is commercial and expensive. Although there is free software such as Echidna or the R package sommer, the Echidna syntax is complex and the R package functionality is limited. Therefore, this study aims to develop an R package named AFEchidna based on Echidna software. The mixed linear models are conveniently implemented for users through the AFEchidna package to solve variance components, genetic parameters and the BLUP values of random effects, and the batch analysis of multiple traits, multiple variance structures and multiple genetic parameters can be also performed, as well as comparison between different models and genomic BLUP analysis. The AFEchidna package is free, please email us (yzhlinscau@163.com) to get a copy if reader is interested for it. The AFEchidna package is developed to expand free genetic assessment software with the expectation that its efficiency could be close to the commercial software.

plant biology↗

bioRxiv2021

PlasLR Enables Adaptation of Plasmid Prediction for Error-Prone Long Reads

Plasmids are extra-chromosomal genetic elements commonly found in bacterial cells that support many functional aspects including environmental adaptations. The identification of these genetic elements is vital for the further study of function and behaviour of the organisms. However it is challenging to separate these small sequences from longer chromosomes within a given species. Machine learning approaches have been successfully developed to classify assembled contigs into two classes (plasmids and chromosomes). However, such tools are not designed to directly perform classification on long and error-prone reads which have been gaining popularity in genomics studies. Assembling complete plasmids is still challenging for many long-read assemblers with a mixed input of long and error-prone reads from plasmids and chromosomes. In this paper, we present PlasLR, a tool that adapts existing plasmid detection approaches to directly classify long and error-prone reads. PlasLR makes use of both the composition and coverage information of long and error-prone reads. We evaluate PlasLR on multiple simulated and real long-read datasets with varying compositions of plasmids and chromosomes. Our experiments demonstrate that PlasLR substantially improves the accuracy of plasmid detection on top of the state-of-the-art plasmid detection tools. Moreover, we show that using PlasLR before long-read assembly helps to enhance the assembly quality in terms of plasmid recovery and near complete chromosome assembly from metagenomic datasets.

bioinformatics↗

bioRxiv2021

Anatomical Structures, Cell Types, and Biomarkers Tables Plus 3D Reference Organs in Support of a Human Reference Atlas

1.This paper reviews efforts across 16 international consortia to construct human anatomical structures, cell types, and biomarkers (ASCT+B) tables and three-dimensional reference organs in support of a Human Reference Atlas. We detail the ontological descriptions and spatial three-dimensional anatomical representations together with user interfaces that support the registration and exploration of human tissue data. Four use cases are presented to demonstrate the utility of ASCT+B tables for advancing biomedical research and improving health.

cell biology↗

bioRxiv2021

Gene Expression Associated with Individual Variability in Intrinsic Functional Connectivity

It has been revealed that intersubject variability (ISV) in intrinsic functional connectivity (FC) is associated with a wide variety of cognitive and behavioral performances. However, the underlying organizational principle of ISV in FC and its related gene transcriptional profiles remain unclear. Using resting-state fMRI data from the Human Connectome Project (299 participants) and microarray gene expression data from the Allen Human Brain Atlas, we conducted a transcription-neuroimaging association study to investigate the spatial configurations of ISV in intrinsic FC and their associations with gene transcriptional profiles. We found that the multimodal association cortices showed the greatest ISV in FC, while the unimodal cortices and subcortical areas showed the least ISV. Importantly, partial least squares regression analysis revealed that the transcriptional profiles of genes associated with human accelerated regions (HARs) could explain 31.29% of the variation in the spatial distribution of ISV in FC. The top-related genes in the transcriptional profiles were enriched for the development of the central nervous system, neurogenesis and the cellular components of synapse. Moreover, we observed that the effect of gene expression profile on the heterogeneous distribution of ISV in FC was significantly mediated by the cerebral blood flow configuration. These findings highlighted the spatial arrangement of ISV in FC and their coupling with variations in transcriptional profiles and cerebral blood flow supply.

neuroscience↗

bioRxiv2021

The Dual Mechanisms of Cognitive Control dataset: A theoretically-guided within-subject task fMRI battery

Cognitive control is a critical higher mental function, which is subject to considerable individual variation, and is impaired in a range of mental health disorders. We describe here the initial release of Dual Mechanisms of Cognitive Control (DMCC) project data, the DMCC55B dataset, with 55 healthy unrelated young adult participants. Each participant performed four well-established cognitive control tasks (AX-CPT, Cued Task-Switching, Sternberg Working Memory, and Stroop) while undergoing functional MRI scanning. The dataset includes a range of state and trait self-report questionnaires, as well as behavioural tasks assessing individual differences in cognitive ability. The DMCC project is on-going and features additional components (e.g., related participants, manipulations of cognitive control mode, resting state fMRI, longitudinal testing) that will be publicly released following study completion. This DMCC55B subset is released early with the aim of encouraging wider use and greater benefit to the scientific community. The DMCC55B dataset is suitable for benchmarking and methods exploration, as well as analyses of task performance and individual differences.

neuroscience↗

bioRxiv2021

Long-term repair of porcine articular cartilage using cryopreservable, clinically compatible human embryonic stem cell-derived chondrocytes

Osteoarthritis (OA) impacts hundreds of millions of people worldwide, with those affected incurring significant physical and financial burdens. Injuries such as focal defects to the articular surface are a major contributing risk factor for the development of OA. Current cartilage repair strategies are moderately effective at reducing pain but often replace damaged tissue with biomechanically inferior fibrocartilage. Here we describe the development, transcriptomic ontogenetic characterization and quality assessment at the single cell level, as well as the scaled manufacturing of an allogeneic human pluripotent stem cell-derived articular chondrocyte formulation that exhibits long-term functional repair of porcine articular cartilage. These results define a new potential clinical paradigm for articular cartilage repair and mitigation of the associated risk of OA.

bioengineering↗

bioRxiv2021

Golden pompano genome resource enables discovery of valuable gene determining growth traits

One important goal of fish genetic breeding is to identify valuable loci and genes that can facilitate growth and thereby productivity. Few such loci or genes have been identified in golden pompano (Trachinotus ovatus), a species of significant economic value. In this study, we produced a high-quality chromosome-level genome assembly of the golden pompano by de novo sequencing and assemblies for 2 parents and 200 F1 offspring by genome re-sequencing. We exploited these assemblies to identify loci and genes by QTL mapping, Kompetitive Allele Specific PCR (KASP) genotyping, and haplotype-based regional association analysis based on growth records of a 64 biparental and 147 individuals from a naturally occurring population. At a locus 291kb from BSNP21031, we identified a somatostatin receptor type 1-like (designated as gpsstr1) gene in which the BSNP1369 of the promoter region was highly associated with growth. Loss of sstr1a, the homolog of gpsstr1 in zebrafish, caused growth retardation. Sstr1a mediated growth via sstr2 and Wnt-gsk-3{beta} signaling pathways. Our findings provide new insights into the underlying mechanisms controlling growth. Our strategy can serve as an effective way to uncover novel genomic information and facilitate improvement of fish growth.

genomics↗

bioRxiv2021

Sex differences in microRNA expression in first and third trimester human placenta

Maternal and fetal pregnancy outcomes related to placental function vary based on fetal sex, which may be the result of sexually dimorphic epigenetic regulation of RNA expression. We identified sexually dimorphic miRNA expression throughout gestation in human placentae. Next-generation sequencing was used to identify miRNA expression profiles in first and third trimester uncomplicated pregnancies using tissue obtained at chorionic villous sampling (n=113) and parturition (n=47). Sequencing and differential expression (DE) analysis identified 432 mature miRNAs expressed in the first trimester female, 425 in the first trimester male, 400 in the third trimester female, and 508 in the third trimester male placenta (baseMean >10). Of these, 11 sexually dimorphic (FDR<0.05, baseMean >10) miRNAs were identified in the first and 4 miRNAs were identified in the third trimester, including miR-361-5p, significant in both trimesters, all upregulated in females. Across gestation, 207 miRNAs were DE across gestation, common to both females and males, miR-4483, the most DE across gestation. There were twice as many female-specific differences across gestation as male-specific (44 miRNAs vs 21 miRNAs), indicating that miRNA abundance across human gestation is sexually dimorphic. Pathway enrichment analysis identified significant pathways that were differentially regulated in first and third trimester as well as across gestation. This work provides the normative sex dimorphic miRNA atlas in first and third trimester, as well as the sex independent and sex specific placenta miRNA atlas across gestation which may be used to identify biomarkers of placental function and direct functional studies investigating placental sex differences. Summary SentenceSex dimorphism in miRNA expression is more pronounced in first compared to third trimester placenta, and there are twice as many female-specific gestational differences, indicating miRNA abundance across human gestation is also sexually dimorphic.

developmental biology↗

bioRxiv2021

Interferon-armed RBD dimer enhances the immunogenicity of RBD for sterilizing immunity against SARS-CoV-2

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a global crisis, urgently necessitating the development of safe, efficacious, convenient-to-store, and low-cost vaccine options. A major challenge is that the receptor-binding domain (RBD)-only vaccine fails to trigger long-lasting protective immunity if used solely for vaccination. To enhance antigen processing and cross-presentation in draining lymph nodes (DLNs), we developed an interferon (IFN)-armed RBD dimerized by immunoglobulin fragment (I-R-F). I-R-F efficiently directs immunity against RBD to DLN. A low dose of I-R-F induces not only high titer long-lasting neutralizing antibodies but also comprehensive T cell responses than RBD, and even provides comprehensive protection in one dose without adjuvant. This study shows that the I-R-F vaccine provides rapid and complete protection throughout upper and lower respiratory tracts against high dose SARS-CoV-2 challenge in rhesus macaques. Due to its potency and safety, this engineered vaccine may become one of the next-generation vaccine candidates in the global race to defeat COVID-19.

immunology↗

bioRxiv2021

A quantile integral linear model to quantify genetic effects on phenotypic variability

Detecting genetic variants associated with the variance of complex traits, i.e. variance quantitative trait loci (vQTL), can provide crucial insights into the interplay between genes and environments and how they jointly shape human phenotypes in the population. We propose a quantile integral linear model (QUAIL) to estimate genetic effects on trait variability. Through extensive simulations and analyses of real data, we demonstrate that QUAIL provides computationally efficient and statistically powerful vQTL mapping that is robust to non-Gaussian phenotypes and confounding effects on phenotypic variability. Applied to UK Biobank (N=375,791), QUAIL identified 11 novel vQTL for body mass index (BMI). Top vQTL findings showed substantial enrichment for interactions with physical activities and sedentary behavior. Further, variance polygenic scores (vPGS) based on QUAIL effect estimates showed superior predictive performance on both population-level and within-individual BMI variability compared to existing approaches. Overall, QUAIL is a unified framework to quantify genetic effects on the phenotypic variability at both single-variant and vPGS levels. It addresses critical limitations in existing approaches and may have broad applications in future gene-environment interaction studies.

genetics↗