Biology subjects

Lin, A.

Publications and source records attributed to Lin, A..

At least 91 records · Page 5Linked to original sources

bioRxiv2022

PanCanSurvPlot: A Large-scale Pan-cancer Survival Analysis Web Application

The identification of reliable tumor prognostic markers can help clinicians and researchers predict tumor development and patient survival outcomes more accurately, which plays a vital role in clinical diagnosis, treatment effectiveness assessment, and prognostic evaluation. Existing web tools supporting online survival analysis are gradually failing to meet the increasing demands of researchers in terms of the dataset size, richness of survival analysis methods, and diversity of customization features. Therefore, there is an urgent need for a large-scale, one-stop pan-cancer survival analysis web server. We developed PanCanSurvPlot (https://smuonco.shinyapps.io/PanCanSurvPlot/), a Shiny web tool that has incorporated a total of 215 cancer-related datasets from the GEO and TCGA databases, covering nearly 100,000 genes (mRNAs, miRNAs, and lncRNAs), approximately 45,000 samples, 51 different cancer types, and 13 different survival outcomes. The website also provides two cutoff methods based on median and optimal cutpoints. All survival analysis results from the log-rank test and univariate Cox regression are presented in a clear and straightforward summary table. Finally, users can customize color schemes and cutpoint levels to quickly obtain high-quality Kaplan-Meier survival plots that meet publication requirements.

cancer biology↗

bioRxiv2022

Light-Activated Assembly of Connexon Nanopores in Synthetic Cells

During developmental processes and wound healing, activation of living cells occurs with spatiotemporal precision and leads to rapid release of soluble molecular signals, allowing communication and coordination between neighbors. Non-living systems capable of similar responsive release hold great promise for information transfer in materials and site-specific drug delivery. One non-living system that offers a tunable platform for programming release is synthetic cells. Encased in a lipid bilayer structure, synthetic cells can be outfitted with molecular conduits that span the bilayer and lead to material exchange. While previous work expressing membrane pore proteins in synthetic cells demonstrated content exchange, user-defined control over release has remained elusive. In mammalian cells, connexon nanopore structures drive content release and have garnered significant interest since they can direct material exchange through intercellular contacts. Here, we focus on connexon nanopores and present activated release of material from synthetic cells in a light-sensitive fashion. To do this, we re-engineer connexon nanopores to assemble after post-translational processing by a protease. By encapsulating proteases in light-sensitive liposomes, we show that assembly of nanopores can be triggered by illumination, resulting in rapid release of molecules encapsulated within synthetic cells. Controlling connexin nanopore activity provides an opportunity for initiating communication with extracellular signals and for transferring molecular agents to the cytoplasm of living cells in a rapid, light-guided manner.

synthetic biology↗

bioRxiv2022

An HBV mRNA vaccine with favorable virological suppression and superior immunity

BRIEF ABSTRACTHere we report on the development and comprehensive evaluations of an mRNA vaccine for chronic hepatitis B (CHB) treatment. In two different HBV carrier mouse models generated by viral vector-mediated HBV transfection (pAAV-HBV1.2 and rAAV8-HBV1.3), this vaccine demonstrates sufficient and persistent virological suppression, and robust immunogenicity in terms of induction of strong innate immune activation, high-level virus-specific antibodies, memory B cells and T cells. mRNA platform therefore holds prospects for therapeutic vaccine development to combat CHB.

immunology↗

bioRxiv2022

Incorporating Knowledge of Plates in Batch Normalization Improves Generalization of Deep Learning for Microscopy Images

Data collected by high-throughput microscopy experiments are affected by batch effects, stemming from slight technical differences between experimental batches. Batch effects significantly impede machine learning efforts, as models learn spurious technical variation that do not generalize. We introduce batch effects normalization (BEN), a simple method for correcting batch effects that can be applied to any neural network with batch normalization (BN) layers. BEN aligns the concept of a "batch" in biological experiments with that of a "batch" in deep learning. During each training step, data points forming the deep learning batch are always sampled from the same experimental batch. This small tweak turns the batch normalization layers into an estimate of the shared batch effects between images, allowing for these technical effects to be standardized out during training and inference. We demonstrate that BEN results in dramatic performance boosts in both supervised and unsupervised learning, leading to state-of-the-art performance on the RxRx1-Wilds benchmark.1

bioinformatics↗

bioRxiv2022

Ancestral reconstruction of the MotA stator subunit reveals that conserved residues far from the pore are required to drive flagellar motility

The bacterial flagellar motor (BFM) is a rotary nanomachine powered by the translocation of ions across the inner membrane through the stator complex. The stator complex consists of two membrane proteins: MotA and MotB (in H+ powered motors), or PomA and PomB (in Na+ powered motors). In this study we used ancestral sequence reconstruction (ASR) to probe which residues of MotA correlate with function and may have been conserved to preserve motor function. We reconstructed ten ancestral sequences of MotA and found four of them were motile in combination with contemporary E. coli MotB and in combination with our previously published functional ancestral MotBs. Sequence comparison between wild-type (WT) E. coli MotA and MotA-ASRs revealed 30 critical residues across multiple domains of MotA that were conserved among all motile stator units. These conserved residues included pore-facing, cytoplasm-facing and MotA-MotA intermolecular facing sites. Overall, this work demonstrates the role of ASR in assessing conserved variable residues in a subunit of a molecular complex.

microbiology↗

bioRxiv2022

The Crux toolkit for analysis of bottom-up tandem mass spectrometry proteomics data

The Crux tandem mass spectrometry data analysis toolkit provides a collection of algorithms for analyzing bottom-up proteomics tandem mass spectrometry data. Many publications have described various individual components of Crux, but a comprehensive summary has not been published since 2014. The goal of this work is to summarize the functionality of Crux, focusing on developments since 2014. We begin with empirical results demonstrating our recently implemented speedups to the Tide search engine. Other new features include a new score function in Tide, two new confidence estimation procedures, as well as three new tools: Param-medic for estimating search parameters directly from mass spectrometry data, Kojak for searching cross-linked mass spectra, and DIAmeter for searching data independent acquisition data against a sequence database.

bioinformatics↗

bioRxiv2022

Kinetic and Structural Analysis of Ribonucleotide Extension by DNA Polymerase η

DNA polymerases catalyze DNA synthesis with high fidelity, which is essential for all life. Extensive kinetic and structural efforts have been executed in exploring mechanisms of DNA polymerases, surrounding their kinetic pathway, catalytic mechanisms, and factors that dictate polymerase fidelity. Recent time-resolved crystallography studies on DNA polymerase {eta} (Pol {eta}) and {beta} have revealed essential transient events during DNA synthesis reaction, such as mechanisms of primer deprotonation, separated roles of the three metal ions, and conformational changes that disfavor incorporation of the incorrect substrate. DNA-embedded ribonucleotides (rN) are the most common lesion on DNA and a major threat to genome integrity. While kinetics of rN incorporation has been explored and structural studies have revealed that DNA polymerases have a steric gate that destabilizes rNTP binding, mechanism of extension upon rN addition remains poorly characterized. Using steady-state kinetics, static and time-resolved X-ray crystallography with Pol {eta} as a model system, we showed that the extra hydroxyl group on the primer terminus does not reduce the catalytic efficiency of Pol {eta}. However, rN ended primers alter the dynamics of the polymerase active site as well as the catalysis and fidelity of DNA synthesis. During rN extension, Pol {eta} fidelity drops significantly across different sequence context. Systematic structural studies suggest that the rN at the primer end improved primer alignment and reduced barriers in C2-endo to C3-endo sugar conformation change. Our work provides important insights for rN extension and implicates a possible mechanism for rN removal.

biochemistry↗

bioRxiv2022

MOAHIT: A Web Tool for visualizing tumormulti-omics data with human anatomy heatmaps

Multi-omics data plays an important role in cancer research, helping clinicians to better explore drug targets and biomarkers. At present, there exist several databases including TCGA (the Cancer Genome Atlas) and GDSC (Genomics of Drug Sensitivity in Cancer), which contain multi omics data on multiple cancer species, as well as various web tools for analyzing the multi-omics data, which are widely used in oncology research. Tumor heterogeneity is a widespread phenomenon, reflected by differences in multi-omics data of cancers originating from different tissues and organs. However, there is a lack of convenient analysis and visualization tools to explore tumor heterogeneity. As a result, we developed a web tool called Multi-Omics Anatomy Heatmap in Tumors (MOAHIT) based on shiny programming. This tool enables users to analyze and visualize the heterogeneity of human tissues. In addition, MOAHIT enables users to produce a beautiful human anatomy heatmap to visualize the heterogeneity between distinct cancers in the multi-omics data.

bioinformatics↗

bioRxiv2022

The CD103-XCR1 axis mediates the recruitment of immunoregulatory dendritic cells after traumatic injury

During wounding and material implantation there is a disturbance in tissue homeostasis and release of self-antigen, and regulation between tolerance and auto-inflammation in injury is not well understood. Here, we analyzed antigen-presenting cells in biomaterial-treated muscle injury and found that pro-regenerative materials enrich Batf3-dependent CD103+XCR1+CD301b+ dendritic cells associated with cross-presentation and self-tolerance. Muscle trauma was accompanied by CD8+ iTregs and expansion of CD103+XCR1+CD62L- adaptive immune cells. Up-regulation of E-Cadherin (the ligand for CD103) and XCL-1 in injured tissue suggests a mechanism for cell recruitment to trauma. Without cross-presenting cells T cell activation increases, pro-regenerative macrophage polarization decreases, and muscle healing is impaired. These data describe a regulatory communication network through CD103+XCR1+ immune cells resulting in downstream effects on tissue regeneration.

bioengineering↗

bioRxiv2022

Efficient meta-analysis of multivariate genome-wide association studies with Meta-MOSTest

MotivationGenome-wide association studies (GWAS) have been successful in identifying genetic variants associated with a particular phenotype. However, many complex phenotypes are influenced by multiple genetic variants with small effects. Detecting the genetic pleiotropy can provide insights into biological mechanisms influencing complex human phenotypes. The recently developed Multivariate Omnibus Statistical Test (MOSTest) has proven to be efficient and powerful, suited for complex large-scale data. The method substantially increased discovery of genetic variants associated with brain MRI phenotypes in the UK Biobank compared to conventionally use multivariate approach. Here we extend the MOSTest to meta-analysis (Meta-MOSTest), facilitating data analysis of multiple phenotypes across multiple cohorts. We evaluated our updated approach in the UK Biobank using brain MRI phenotypes, by comparing the discovery yield of the single-cohort MOSTest versus Meta-MOSTest through simulating sub-cohorts of different sample sizes from 265 to 26501 subjects. ResultsOur method works efficiently on large-scale cohorts with a large number of MRI phenotypes. We found that lower per-cohort sample sizes resulted in a reduced discovery yield indicating a loss of statistical power. However, with a minimum sample size of 250 subjects across cohorts, Meta-MOSTest was equivalent to MOSTest on discovery yield while maintaining a well-calibrated type I error and equivalent statistical power. We conclude that Meta-MOSTest is a useful tool for multivariate analysis across separate brain imaging genetics cohorts. Availability and implementationAll codes are freely available on GitHub: MOSTest and Meta-MOSTest.

bioinformatics↗

bioRxiv2022

The Norwegian Mother, Father, and Child cohort study (MoBa) genotyping data resource: MoBaPsychGen pipeline v.1

BackgroundThe Norwegian Mother, Father, and Child Cohort Study (MoBa) is a population-based pregnancy cohort, which includes approximately 114,500 children, 95,200 mothers, and 75,200 fathers. Genotyping of MoBa has been conducted through multiple research projects, spanning several years; using varying selection criteria, genotyping arrays, and genotyping centres. MoBa contains numerous interrelated families, which necessitated the implementation of a family-based quality control (QC) pipeline that verifies and accounts for diverse types of relatedness. MethodsThe MoBaPsychGen pipeline, comprising pre-imputation QC, phasing, imputation, and post-imputation QC, was developed based on current best-practice protocols and implemented to account for the complex structure of the MoBa genotype data. The pipeline includes QC on both single nucleotide polymorphism (SNP) and individual level. Phasing and imputation were performed using the publicly available Haplotype Reference Consortium release 1.1 panel as a reference. Information from the Medical Birth Registry of Norway and MoBa questionnaires were used to identify biological sex, year of birth, reported parent-offspring (PO) relationships, and multiple births (only available in the offspring generation). ResultsIn total, 207,569 unique individuals (90% of the unique individuals included in the study) and 6,981,748 autosomal SNPs passed the MoBaPsychGen pipeline. A further 174,462 chromosome X and 3,200 PAR SNPs are available in a subset of these individuals (N = 204,913 and 135,593, respectively). The relatedness checks performed throughout the pipeline allowed identification of within-generation and across-generation first-degree, second-degree, and third-degree relatives. The individuals passing post-imputation QC comprised 64,471 families ranging in size from singletons to 84 unique individuals (singletons are included as families as other family members may not have been genotyped, imputed, or passed post-imputation QC). The relationships identified include 287 monozygotic twin pairs, 22,884 full siblings, 117,004 PO pairs, 23,299 second-degree relative pairs, and 10,828 third-degree relative pairs. DiscussionMoBa contains a highly complex relatedness structure, with a variety of family structures including singletons, PO duos, full (mother, father, child) PO trios, nuclear families, blended families, and extended families. The availability of robustly quality-controlled genetic data for such a large cohort with a unique extended family structure will allow many novel research questions to be addressed. Furthermore, the MoBaPsychGen pipeline has potential utility in similar cohorts.

genetics↗

bioRxiv2022

Functional imaging and quantification of multi-neuronal olfactory responses in C. elegans

Many animals perceive odorant molecules by collecting information from ensembles of olfactory neurons. Each neuron employs receptors that are tuned to recognize certain odorant molecules by chemical binding affinity. Olfactory systems are able, in principle, to detect and discriminate diverse odorants by using combinatorial coding strategies. Multineuronal imaging with high-throughput stimulus delivery allows comprehensive measurement of ensemble-level sensory representations. We have used microfluidics and multineuronal imaging to study ensemble-level olfactory representations at the sensory periphery of the nematode C. elegans. The collective activity of nematode chemosensory neurons reveals high-dimensional representations of olfactory information across a broad space of odorant molecules. We reveal diverse tuning properties and dose-response curves across chemosensory neurons and across odorants. We describe the unique contribution of each sensory neuron to an ensemble-level code for volatile odorants. We also show how natural stimuli, a set of nematode pheromones, are encoded by the sensory periphery. The integrated activity of the C. elegans chemosensory neurons contains sufficient information to robustly encode the intensity and identity of diverse chemical stimuli.

neuroscience↗

bioRxiv2022

Improvement of sensory deficits in Fragile X mice by increasing cortical interneuron activity after the critical period

Changes in the function of inhibitory interneurons (INs) during cortical development could contribute to the pathophysiology of neurodevelopmental disorders. Using all-optical in vivo approaches in postnatal mouse somatosensory cortex (S1), we find that parvalbumin (PV) IN precursors are hypoactive and decoupled from excitatory neurons in Fmr1-/- mice, a model of Fragile X Syndrome (FXS). This leads to a loss of PV-INs in both mice and humans with FXS. Increasing the activity of future PV-INs in neonatal Fmr1-/- mice restores PV density and ameliorates transcriptional dysregulation in S1, but not circuit dysfunction. Critically, administering a novel allosteric modulator of Kv3.1 channels after the S1 critical period does rescue circuit dynamics and tactile defensiveness. Symptoms in FXS and related disorders could be mitigated by targeting PV-INs.

neuroscience↗

bioRxiv2022

Detecting more peptides from bottom-up mass spectrometry data via peptide-level target-decoy competition

The analysis of shotgun proteomics data often involves generating lists of inferred peptide-spectrum matches (PSMs) and/or of peptides. The canonical approach for generating these discovery lists is by controlling the false discovery rate (FDR), most commonly through target-decoy competition (TDC). At the PSM level, TDC is implemented by competing each spectrums best-scoring target (real) peptide match with its best match against a decoy database. This PSM-level procedure can be adapted to the peptide level by selecting the top-scoring PSM per peptide prior to FDR estimation. Here we first highlight and empirically augment a little-known previous work by He et al., which showed that TDC-based PSM-level FDR estimates can be liberally biased. We thus propose that researchers instead focus on peptide-level analysis. We then investigate three ways to carry out peptide-level TDC and show that the most common method ("PSM-only") offers the lowest statistical power in practice. An alternative approach that carries out a double competition, first at the PSM and then at the peptide level ("PSM-and-peptide"), is the most powerful method, yielding an average increase of 17% more discovered peptides at a 1% FDR threshold relative to the PSM-only method.

bioinformatics↗

bioRxiv2022

Onlinemeta: A Web Serve For Meta-Analysis Based On R-shiny

Meta-analysis is a common statistical method used to summarize multiple studies that cover the same topic. It can provide less biased results and explain heterogeneity between studies. Although there exists a variety of meta-analysis softwares, they are rarely both convenient to use and capable of comprehensive analytical functions. As a result, we are motivated to establish a meta-analysis web tool called Meta-Analysis Online (Onlinemeta). Onlinemeta includes three major modules: risk bias analysis, meta-analysis and network meta-analysis. The risk bias analysis module can produce heatmaps and histograms, whereas the meta-analysis module accepts many types of data as input, including dichotomous variables, single-armed dichotomous variables, continuous variables, single-armed continuous variables, survival data, deft method and diagnostic experiments, and outputs well-tuned forest plots, sensitivity analysis forest plots, funnel plots, comparison table of effects, SROC curve, and crosshair plots. For network meta-analysis module, the tool can process dichotomous variables or continuous variables, and generate network plots, forest plots, SUCRA (Surface Under the Cumulative Ranking) plots, rank plots and heatmaps. Onlinemeta is available at https://smuonco.Shinyapps.io/Onlinemeta/.

bioinformatics↗

bioRxiv2022

Multivariate genetic analysis of personality and cognitive traits reveals abundant pleiotropy and improves prediction

Personality and cognition are heritable mental traits, and their genetic determinants may be distributed across interconnected brain functions. However, previous studies have employed univariate approaches which reduce complex traits to summary measures. We applied the "pleiotropy-informed" multivariate omnibus statistical test (MOSTest) to genome-wide association studies (GWAS) of 35 item and task-level measures of neuroticism and cognition from the UK Biobank (n=336,993). We identified 431 significant genetic loci and found evidence of abundant pleiotropy across personality and cognitive domains. Functional characterisation implicated genes with significant tissue-specific expression in all tested brain tissues and enriched in brain-specific gene-sets. We conditioned independent GWAS of the Big 5 personality traits and cognition on our multivariate findings, which boosted genetic discovery in other personality traits and improved polygenic prediction. These findings advance our understanding of the polygenic architecture of complex mental traits, indicating a prominence of pleiotropic genetic effects across higher-order domains of mental function. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/481967v2_ufig1.gif" ALT="Figure 1"> View larger version (89K): org.highwire.dtl.DTLVardef@1641108org.highwire.dtl.DTLVardef@9a24eeorg.highwire.dtl.DTLVardef@1eeae99org.highwire.dtl.DTLVardef@108db7f_HPS_FORMAT_FIGEXP M_FIG C_FIG

genetics↗

bioRxiv2022

MS1Connect: a mass spectrometry run similarity measure

Interpretation of newly acquired mass spectrometry data can be improved by identifying, from an online repository, previous mass spectrometry runs that resemble the new data. However, this retrieval task requires computing the similarity between an arbitrary pair of mass spectrometry runs. This is particularly challenging for runs acquired using different experimental protocols. We propose a method, MS1Connect, that calculates the similarity between a pair of runs by examining only the intact peptide (MS1) scans, and we show evidence that the MS1Connect score is accurate. Specifically, we show that MS1Connect outperforms several baseline methods on the task of predicting the species from which a given proteomics sample originated. In addition, we show that MS1Connect scores are highly correlated with similarities computed from fragment (MS2) scans, even though this data is not used by MS1Connect. The MS1Connect software will be made available upon acceptance at https://github.com/bmx8177/MS1Connect.

bioinformatics↗

bioRxiv2022

Proteomic Dissection of a Giant Cell

Many individual proteins have been identified as having defined positions relative to cell polarity axes, raising the question of what fraction of all proteins may have polarized localizations. We took advantage of the giant ciliate Stentor coeruleus to quantify the extent of polarized localization proteome-wide. This trumpet-shaped unicellular organism shows a clear morphological anterior-posterior axis defined by a circular array of cilia known as a membranellar band at one end, and a holdfast at the other end. Because individual Stentor cells are over a millimeter in length, we were able to cut the cells into three pieces along the anterior-posterior axis, followed by proteomic analysis of proteins enriched in each piece. We find that approximately 30% of all detected proteins show a polarized location relative to the anterior-posterior cell axis. Proteins with polarized enrichment include centrin-like proteins, calcium-regulated kinases, orthologs of SFI1 and GAS2, and proteases. At the organelle level, nuclear and mitochondrial proteins are enriched in the anterior half of the cell body, but not in the membranellar band itself, while ribosome related proteins are apparently uniformly distributed. RNAi of signaling proteins enriched in the membranellar band, which is the anterior-most structure in the cell, revealed a protein phosphatase 2 subunit b ortholog required for closure of the membranellar band into the ring shape characteristic of Stentor. These results suggest that a large fraction of the Stentor proteome has a polarized localization, and provide a protein-level framework for future analysis of pattern formation and regeneration in Stentor as well as defining a general strategy for subcellular spatial proteomics based on physical dissection of cells.

cell biology↗