Biology subjects

Meng, Q.

Publications and source records attributed to Meng, Q..

At least 37 records · Page 2Linked to original sources

bioRxiv2024

Time-lapse Image Super-resolution Neural Network with Reliable Confidence Evaluation for Optical Microscopy

Single image super-resolution (SISR) neural networks for optical microscopy have shown great capability to directly transform a low-resolution (LR) image into its super-resolution (SR) counterpart, enabling low-cost long-term live-cell SR imaging. However, when processing time-lapse data, current SISR models failed to exploit the important temporal dependencies between neighbor frames, often resulting in temporally inconsistent outputs. Besides, SISR models are subject to inference uncertainty that is hard to accurately quantify, therefore it is difficult to determine to what extend can we trust the inferred SR images. Here, we first build a large-scale, high-quality fluorescence microscopy dataset for the time-lapse image super-resolution (TISR) task, and conducted a comprehensive evaluation on two essential components of TISR neural networks, i.e., propagation and alignment. Second, we devised a deformable phase-space alignment (DPA) based TISR neural network (DPA-TISR), which adaptively enhances the cross-frame alignment in the phase domain and outperforms existing state-of-the-art SISR and TISR models. Third, we combined the Bayesian training scheme and Monte Carlo dropout with DPA-TISR, developing Bayesian DPA-TISR, and designed an expected calibration error (ECE)minimization framework to obtain a well-calibrated confidence map along with each output SR image, which reliably implicates potential inference errors. We demonstrate the unique characteristics of Bayesian DPA-TISR underlie the ultralong-term live-cell SR imaging capability with high spatial fidelity, superb temporal consistency, and accurate confidence quantification on a wide variety of bioprocesses.

biophysics↗

bioRxiv2024

Targeting CD19 for the treatment of B-cell related autoimmune diseases with a novel T cell engager

Autoimmune disorder, affecting more than twenty million in United States and billions of people worldwide, occurs when human immune system mistakenly attacks its own body. Autoreactive B cells, particularly the autoantibodies they produce, play a critical role in the etiology, progress, prognosis, and pathogenesis of multiple autoimmune diseases. While targeting B cells medicines, such as anti-CD19 or anti-CD20 monoclonal antibodies have produced promise in both pre-clinic models and some clinic practices, many patients failed to respond, ended less satisfactory outcome, or relapsed to monoclonal antibody therapies. Novel therapies are desperately needed to fight this challenge. In this study, based upon a symmetrical format, namely fusion of IgG and scFv technology (FIST), an anti-CD19xCD3 T cell engager (TCE) YK012, developed to treat B-cell malignancies such as precursor pre-B acute lymphatic leukemia (ALL) and non-Hodgkins lymphoma (NHL), was expanded to explore the treatment of autoimmune diseases by bringing T cells to CD19 positive B cells, including autoreactive B cell populations. Even as bivalent binding to CD3, YK012 has so significantly reduced binding affinity to TCR compared to other TCEs that, free YK012 alone does activate T cells at all. In contrast, in the presence of CD19-expressing Raji target cells and mediated by YK012, T cells can be activated in a dose-dependent manner, measured by upregulation of NFAT-reporter, CD25, IFN-{gamma} and granzyme B expression. Crosslinking of B cell with T cell by YK012, the conjugation elicited T cell-mediated potent but mild cytotoxicity only to CD19-positive Raji cells. Additionally, YK012 elicited much reduced cytokines release in vitro compared to that of Blincyto(R) biosimilar, implying a potentially me-better therapeutics replacement in clinics for B-cell related diseases. In two in vivo pharmacological studies, YK012 alleviated the pathology symptoms of a collagen-induced arthritis model and almost completely depleted the peripheral B cell in human stem cell-transplanted murine model. In summary, this study demonstrated that YK012, a FIST platform designed TCE, has the potential to treat B cell-mediated diseases including autoimmune indications with possible better efficacy and less side effects in clinical practices.

immunology↗

bioRxiv2023

CCT3 drives Sorafenib resistance by inhibiting TFRC-mediated iron uptake in HCC

Sorafenib is commonly utilized in the management of advanced hepatocellular carcinoma (HCC). However, its efficacy in extending patients survival is hindered by the development of drug resistance. By employing protein posttranslational modification (PTM) omics, including acetylome, phosphoproteome, and ubiquitinome, in conjunction with genome-wide CRISPR/Cas9 knockout library screening, we have successfully identified chaperonin containing TCP1 subunit 3 (CCT3) as a key factor contributing to Sorafenib resistance. Furthermore, we observed a reduction in the ubiquitination of CCT3 at lysine 21 (K21) subsequent to Sorafenib treatment. This study provides evidence that CCT3 hinders the recycling of transferrin receptor protein 1 (TFRC) by interacting with alpha-actinin-4 (ACTN4), which is influenced by K6-linked ubiquitination on K21. Depleting CCT3 increased the susceptibility of cells to Sorafenib-induced ferroptosis, while reintroducing CCT3 through transfection restored resistance to ferroptosis. Additionally, impairing ACTN4 or TFRC depletion compromised CCT3s ability to inhibit Sorafenib-induced ferroptosis. In summary, targeting CCT3 presents a potential strategy for overcoming Sorafenib resistance in HCC.

cancer biology↗

bioRxiv2023

KmerSV: a visualization and annotation tool for structural variants using Human Pangenome derived k-mers

SummaryKmerSV is a visualization and annotation tool for structural variants (SVs). It can be applied to assembly contigs or long-read sequences. Using k-mers it rapidly generates images and provides genome features of SVs. As an important feature, it utilizes the new Human Pangenome reference which provide haploid specific assemblies, addresses limitations in prior references and improves the discovery of SVs. Availability and implementationKmerSV is implemented in Python and available at github.com/sgtc-stanford/kmerSV

bioinformatics↗

bioRxiv2023

Consensus peaks of chromatin accessibility in the human genome

The rapid advancement of transposase-accessible chromatin using sequencing (ATAC-seq) technology, particularly with the emergence of single-cell ATAC-seq (scATAC-seq), has accelerated the studies of gene regulation. However, the absence of a generic feature reference for ATAC-seq data limits single-cell analyses and hinders the development of comprehensive cell atlases. To address this, we constructed a generic chromatin accessibility reference by aggregating peaks from 624 high-quality bulk ATAC-seq datasets, defining more than 1 million consensus peaks (cPeaks). Leveraging a deep neural network model, we expanded cPeaks to include previously unobserved regions, enhancing their coverage across diverse tissues and cell types. cPeaks exhibit consistent shapes across tissue types, sequencing technologies, and peak-calling methods, indicating that they represent inherent genomic features. Compared to existing feature defining methods and references, cPeaks show superior performance in scATAC-seq analyses, improving cell annotation and rare cell type identification. Additionally, cPeaks provide insights into chromatin dynamics during cellular differentiation and tumor progression. cPeaks can serve as a robust reference for chromatin accessibility studies to promote cross-dataset consistency and accelerate biological discoveries.

bioinformatics↗

bioRxiv2023

Functional Genomics of Gastrointestinal Escherichia coli Isolated from Patients with Cancer and Diarrhea

We describe the epidemiology and clinical characteristics of 29 patients with cancer and diarrhea in whom Enteroaggregative Escherichia coli (EAEC) was initially identified by GI BioFire panel multiplex. E. coli strains were successfully isolated from fecal cultures in 14 of 29 patients. Six of the 14 strains were identified as EAEC and 8 belonged to other diverse E. coli groups of unknown pathogenesis. We investigated these strains by their adherence to human intestinal organoids, cytotoxic responses, antibiotic resistance profile, full sequencing of their genomes, and annotation of their functional virulome. Interestingly, we discovered novel and enhanced adherence and aggregative patterns for several diarrheagenic pathotypes that were not previously seen when co-cultured with immortalized cell lines. EAEC isolates displayed exceptional adherence and aggregation to human colonoids compared not only to diverse GI E. coli, but also compared to prototype strains of other diarrheagenic E. coli. Some of the diverse E. coli strains that could not be classified as a conventional pathotype also showed an enhanced aggregative and cytotoxic response. Notably, we found a high carriage rate of antibiotic resistance genes in both EAEC strains and diverse GI E. coli isolates and observed a positive correlation between adherence to colonoids and the number of metal acquisition genes carried in both EAEC and the diverse E. coli strains. This work indicates that E. coli from cancer patients constitute strains of remarkable pathotypic and genomic divergence, including strains of unknown disease etiology with unique virulomes. Future studies will allow for the opportunity to re-define E. coli pathotypes with greater diagnostic accuracy and into more clinically relevant groupings.

microbiology↗

bioRxiv2023

A novel bacterial signal transduction system specifically senses and responds to peptidoglycan damage

The peptidoglycan (PG) layer is a mesh-like structure within the cell envelope essential for maintenance of cell shape and resistance to osmotic stress, and therefore is a primary target of many important and widely used antibiotics, such as {beta}-lactams. In Gram-negative bacteria, while signal transduction systems that monitor the state of the inner- and outer-membranes have been extensively studied and well understood, much less is known about how cells sense and respond to PG-targeting stresses. Here we show that a novel bacterial two-component system (PghKR) from Shewanella oneidensis is capable of sensing and responding to PG damage. This system is specifically activated in cells exposed to various PG-targeting antibiotics or carrying a defect in PG synthesis, resulting in induced expression of blaA and relV, which encode a {beta}-lactamase conferring resistance to {beta}-lactams and a small ppGpp synthetase responsible for antibiotic tolerance, respectively. Intriguingly, the PghKR homologs are widespread among several classes of Proteobacteria and the periplasmic domain of sensor kinase PghK contains a family 9 carbohydrate-binding module that is required for signal perception, implying that the signals could be the glycan fragments of PG. Overall, our results provide critical insights into the regulation of PG homeostasis in Gram-negative bacteria.

microbiology↗

bioRxiv2023

Self-supervised denoising for structured illumination microscopy enables long-term super-resolution live-cell imaging

Detection noise significantly degrades the quality of structured illumination microscopy (SIM) images, especially under low-light conditions. Although supervised learning based denoising methods have shown prominent advances in eliminating the noise-induced artifacts, the requirement of a large amount of high-quality training data severely limits their applications. Here we developed a pixel-realignment-based self-supervised denoising framework for SIM (PRS-SIM) that trains an SIM image denoiser with only noisy data and substantially removes the reconstruction artifacts. We demonstrated that PRS-SIM generates artifact-free images with 10-fold less fluorescence than ordinary imaging conditions while achieving comparable super-resolution capability to the ground truth (GT). Moreover, the proposed method is compatible with multiple SIM modalities such as total internal reflective fluorescence SIM (TIRF-SIM), three-dimensional SIM (3D-SIM), lattice light-sheet SIM (LLS-SIM), and non-linear SIM (NL-SIM). With PRS-SIM, we achieved long-term super-resolution live-cell imaging of various bioprocesses, revealing the clustered distribution of clathrin coated pits and detailed interaction dynamics of multiple organelles and the cytoskeleton.

cell biology↗

bioRxiv2023

Zero-shot learning enables instant denoising and super-resolution in optical fluorescence microscopy

Computational super-resolution (SR) methods, including conventional analytical algorithms and deep learning models, have substantially improved optical microscopy. Among them, supervised deep neural networks have demonstrated outstanding SR performance, however, demanding abundant high-quality training data, which are laborious and even impractical to acquire due to the high dynamics of living cells. Here, we develop zero-shot deconvolution networks (ZS-DeconvNet) that instantly enhance the resolution of microscope images by more than 1.5-fold over the diffraction limit with 10-fold lower fluorescence than ordinary SR imaging conditions in an unsupervised manner without the need for either ground truths or additional data acquisition. We demonstrate the versatile applicability of ZS-DeconvNet on multiple imaging modalities, including total internal reflection fluorescence microscopy, three-dimensional (3D) wide-field microscopy, confocal microscopy, lattice light-sheet microscopy, and multimodal structured illumination microscopy (SIM), which enables multi-color, long-term, super-resolution 2D/3D imaging of subcellular bioprocesses from mitotic single cells to multicellular embryos of mouse and C. elegans.

bioengineering↗

bioRxiv2023

scDecouple: Decoupling cellular response and infection bias in scCRISPR-seq

MotivationscCRISPR-seq is an emerging high-throughput CRISPR screening technology that combines CRISPR screening with single-cell sequencing technologies. It provides rich information on the mechanism of gene regulation. However, when scCRISPR-seq is applied in a population of heterogeneous cells, the true cellular response to perturbation is coupled with infected proportion bias of guide RNAs (gRNAs) across different cell clusters. The mixing of these effects introduces noise into scCRISPR-seq data analysis and thus obstacles to relevant studies. ResultsWe developed scDecouple to decouple true cellular response of perturbation from the influence of infected proportion bias. scDecouple first models the distribution of gene expression profiles in perturbed cells and then iteratively finds the maximum likelihood of cell cluster proportions as well as the cellular response for each gRNA. We demonstrated its performance in a series of simulation experiments. By applying scDecouple to real scCRISPR-seq data, we found that scDecouple enhances the identification of biologically perturbation-related genes. scDecouple can benefit scCRISPR-seq data analysis, especially in the case of heterogeneous samples or complex gRNA libraries. AvailabilityscDecouple is freely available at https://github.com/MengQiuchen/scDecouple. Contactweilei92@tsinghua.edu.cn, yinqingl@tsinghua.edu.cn

bioinformatics↗

bioRxiv2023

Structural variation across 138,134 samples in the TOPMed consortium

Ever larger Structural Variant (SV) catalogs highlighting the diversity within and between populations help researchers better understand the links between SVs and disease. The identification of SVs from DNA sequence data is non-trivial and requires a balance between comprehensiveness and precision. Here we present a catalog of 355,667 SVs (59.34% novel) across autosomes and the X chromosome (50bp+) from 138,134 individuals in the diverse TOPMed consortium. We describe our methodologies for SV inference resulting in high variant quality and >90% allele concordance compared to long-read de-novo assemblies of well-characterized control samples. We demonstrate utility through significant associations between SVs and important various cardio-metabolic and hemotologic traits. We have identified 690 SV hotspots and deserts and those that potentially impact the regulation of medically relevant genes. This catalog characterizes SVs across multiple populations and will serve as a valuable tool to understand the impact of SV on disease development and progression.

genomics↗

bioRxiv2022

Single molecule methylation profiles of cell-free DNA in cancer with nanopore sequencing

Epigenetic characterization of cell-free DNA (cfDNA) is an emerging approach for characterizing diseases. We developed a strategy using nanopore-based single-molecule sequencing to measure cfDNA methylomes. This approach generated up to hundreds of millions of reads per cfDNA sample from cancer patients, an order of magnitude improvement over existing nanopore methods. Leveraging methylomes of matched tumors and immune cells, we characterized cfDNA methylomes of cancer patients for longitudinal monitoring during treatment.

genomics↗

bioRxiv2022

The magnocellular division of the human medial geniculate nucleus preferentially responds to auditory transients

The medial geniculate nucleus (MGN), the auditory relay in the thalamus, is composed of three anatomical subdivisions: the ventral, dorsal and medial or magnocellular division. The functional differences among these nuclei have not been studied in humans, and in particular, the function of the magnocellular division is poorly understood in mammals in general. We anatomically segmented the MGN using proton-density-weighted magnetic resonance images (MRI) and measured the functional responses of the MGN to sustained and transient sounds, using functional MRI (fMRI). We observed that voxels in the ventromedial portion of the MGN, corresponding to the magnocellular division, exhibited a strong preference to transient sounds, whereas the remainder of the MGN showed no preference between sustained and transient sounds. We concluded that the magnocellular neurons in the MGN parallel the magnocellular neurons in its visual counterpart, the lateral geniculate nucleus (LGN), and constitute an information stream specialized for encoding stimuli dynamics. Significance statementThe medial geniculate nucleus is the auditory relay in the thalamus. It is composed of three anatomical divisions, of which the function of the magnocellular division is poorly understood. We show, using functional magnetic resonance imaging (fMRI) in humans, that the magnocellular neurons are strongly activated by transient auditory stimuli, similar to the magnocellular neurons in the lateral geniculate nucleus, the visual thalamic relay, which are rapidly adapting and specialized to encode visual transients. These results confirm that the auditory system represents stimuli using parallel information streams, employing similar encoding strategies as in other sensory modalities.

neuroscience↗

bioRxiv2022

Cardiac fibroblasts regulate cardiomyocyte hypertrophy through dynamic regulation of type I collagen

RationaleCardiomyocytes and fibroblasts in the heart communicate through both secreted growth factors as well as through sensing the structural properties of the extracellular matrix that each helps generate. Previous studies have shown that defects in fibroblast activity during disease stimulation result in altered cardiomyocyte hypertrophy, although the role that collagen might play in this communication is unknown. ObjectiveHere we investigated how type I collagen maturation and disease-responsive matrix expansion in the heart by cardiac fibroblasts impacts cardiac fibrosis and cardiomyocyte hypertrophy. Methods and ResultsWe generated and characterized Col1a2-/- mice using standard gene-targeting. Col1a2-/- mice were viable, although by young adulthood their hearts showed alterations in extracellular matrix mechanical properties, as well as an unanticipated activation of cardiac fibroblasts and induction of a progressive fibrotic response. This included increases in fibroblast number and a progressive cardiac hypertrophy, with reduced functional performance by 9 months. Col1a2-loxP targeted mice were also generated and crossed with the tamoxifen-inducible Postn-MerCreMer knock-in mice to delete the Col1a2 gene in myofibroblasts post-pressure overload injury, to more specifically implicate fibroblasts as effectors of cardiomyocyte hypertrophy in vivo. Opposite to the gradual induction of cardiac hypertrophy observed in germline Col1a2-/- mice as they matured developmentally, adult fibroblast-specific deletion of Col1a2 during pressure overload protected these mice from cardiac hypertrophy in the first week with a delayed fibrotic response. However, this reduction in hypertrophy due to myofibroblast-specific Col1a2 deletion was gradually lost over 2 and 6 weeks of pressure overload as augmented fibrosis returned. ConclusionsDefective type I collagen in the developing heart alters the structural integrity of the extracellular matrix that leads to fibroblast expansion, activation, fibrosis and hypertrophy with progressive cardiomyopathy in adulthood. However, acute deletion of type I collagen production for the first time in the adult heart during pressure overload prevents ECM expansion and inhibits cardiomyocyte hypertrophy, while gradual restoration of fibrosis again permitted hypertrophy comparable to controls.

cell biology↗

bioRxiv2022

Specific Pupylation as IDEntity Reporter (SPIDER) for the identification of Protein-Biomolecule interactions

Protein-biomolecule interactions play pivotal roles in almost all biological processes, the identification of the interacting protein is essential. By combining a substrate-based proximity labelling activity from the pupylation pathway of Mycobacterium tuberculosis, and the streptavidin (SA)-biotin system, we developed Specific Pupylation as IDEntity Reporter (SPIDER) for identifying protein-biomolecular interactions. As a proof of principle, SPIDER was successfully applied for global identification of interacting proteins, including substrates for enzyme (CobB), the readers of m6A, the protein interactome of mRNA, and the target proteins of drug (lenalidomide). In addition, by SPIDER, we identified SARS-CoV-2 Omicron variant specific receptors on cell membrane and performed in-depth analysis for one candidate, Protein-g. These potential receptors could explain the differences between the Omicron variant and the Prototype strain, and further serve as target for combating the Omicron variant. Overall, we provide a robust technology which is applicable for a wide-range of protein-biomolecular interaction studies.

systems biology↗

bioRxiv2022

Dyslexia linked to profound impairment in the magnocellular medial geniculate nucleus

The neurological basis of dyslexia, a common reading disorder, remains unclear but is hypothesized to be caused by either dysfunction of the magnocellular system in the brain, abnormal temporal processing, and/or deficient phonological skills. Using functional magnetic resonance imaging, we measured activity in the magnocellular portion of the medial geniculate nucleus, the auditory relay in the thalamus, and observed profoundly attenuated responses to non-linguistic transient but not sustained sounds in every subject with dyslexia we tested, compared to normal readers. Our finding unifies these three hypotheses and identifies a core deficit causing dyslexia.

neuroscience↗

bioRxiv2022

Prior exposure to speech rapidly modulates cortical processing of high-level linguistic structure

Neural activity has been shown to track hierarchical linguistic units in connected speech and these responses can be directly modulated by changes in speech intelligibility caused by spectral degradation. In the current study, we manipulate prior knowledge to increase the intelligibility of physically identical speech sentences and test the hypothesis that the tracking responses can be enhanced by this intelligibility improvement. Cortical magnetoencephalography (MEG) responses to intelligible speech followed by either the same (matched) or different (unmatched) unintelligible speech were measured in twenty-three normal hearing participants. Driven by prior knowledge, cortical coherence to "abstract" linguistic units with no accompanying acoustic cues (phrases and sentences) was enhanced relative to the unmatched condition, and was lateralized to the left hemisphere. In contrast, cortical responses coherent to word units, aligned with acoustic onsets, were bilateral and insensitive to contextual information changes. No such coherence changes were observed when prior experience was not available (unintelligible speech before intelligible speech). This dissociation suggests that cerebral responses to linguistic information are directly affected by intelligibility, which in turn are powerfully shaped by physical cues in speech. These results provide an objective and sensitive neural index of speech intelligibility, and explain why previous studies have reported no effect of prior knowledge on cortical entrainment.

neuroscience↗

bioRxiv2021

A human ensemble cell atlas (hECA) enables in data cell sorting

Single-cell omics data can characterize multifaceted features of massive cells and bring significant insights to biomedical researches. The accumulation of single-cell data provides growing resources for constructing atlases for all cells of a human organ or the whole body. The true assembly of a cell atlas should be cell-centric rather than file-centric. We proposed a unified information framework enabling seamless cell-centric data assembly and developed a human Ensemble Cell Atlas (hECA) as an instance. hECA version 1.0 assembled scRNA-seq data across multiple studies into one orchestrated data repository. It contains 1,093,299 labeled cells and metadata from 116 published human single-cell studies, covering 38 human organs and 11 systems. We invented three methods of applications based on the cell-centric assembly: "In data" cell sorting enables targeted data retrieval in the full atlas with customizable logic expressions; The "quantitative portraiture" system provides a multi-view presentation of biological entities (organs, cell types, and genes) of multiple granularities; The customizable reference creation allows users to use the cell-centric assembly to generate references for their own cell type annotations. Case studies on agile construction of user-defined sub-atlases and "in data" investigation of CAR-T off-targets in multiple organs showed the great potential of cell-centric atlas assembly.

bioinformatics↗