Biology subjects

Jiang, B.

Publications and source records attributed to Jiang, B..

At least 55 records · Page 3Linked to original sources

bioRxiv2023

A semi-quantitative, rapid, point of care SARS-CoV-2 serologic assay predicts neutralizing antibody levels

The ongoing COVID-19 pandemic has caused millions of deaths and the continued emergence of new variants suggests continued circulation in the human population. In the current time of vaccine availability and new therapeutic development, including antibody-based therapies, many questions about long-term immunity and protection remain uncertain. Identification of protective antibodies in individuals is often done using highly specialized and challenging assays such as functional neutralizing assays, which are not available in the clinical setting. Therefore, there is a great need for the development of rapid, clinically available assays that correlate with neutralizing antibody assays to identify individuals who may benefit from additional vaccination or specific COVID-19 therapies. In this report, we apply a novel semi-quantitative method to an established lateral flow assay (sqLFA) and analyze its ability to detect the presence functional neutralizing antibodies from the serum of COVID-19 recovered individuals. We found that the sqLFA has a strong positive correlation with neutralizing antibody levels. At lower assay cutoffs, the sqLFA is a highly sensitive assay to identify the presence of a range of neutralizing antibody levels. At higher cutoffs, it can detect higher levels of neutralizing antibody with high specificity. This sqLFA can be used both as a screening tool to identify individuals with any level of neutralizing antibody to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), or as a more specific tool to identify those with high neutralizing antibody levels who may not benefit from antibody-based therapies or further vaccination.

immunology↗

bioRxiv2023

Spatiotemporal transcriptome atlas of human embryos after gastrulation

The spatial and temporal atlas of gene expression in the human embryo at early gestation is critical in understanding embryo development, organogenesis, and disease origins. We obtained the spatiotemporal transcriptome from 90 sagittal sections of 16 whole human embryos from 3 to 8 post-conception weeks by Stereo-seq with high resolution and ultra-large field, establishing the development trajectory/regulatory profiling of 49 organs. We uncovered the organ-specific regulons as potential lineage-determining factors and identified the new regulatory networks during heart and brain development. The atlas refines the key organs/cell types vulnerable to virus infection and genetic disorders, and, reveals the dynamics of allelic gene expression in specific organs at different stages. These results present the first comprehensive delineation of the spatiotemporal transcriptomic dynamics of human organogenesis. One Sentence SummaryThe spatiotemporal transcriptome atlas presents a comprehensive delineation of human embryogenesis after gastrulation.

developmental biology↗

bioRxiv2023

Hepatic conversion of acetyl-CoA to acetate plays crucial roles in energy stresses

Accumulating evidences indicate that acetate is increased in energy stresses such as diabetes mellitus and prolonged starvation. However, it is largely unknown how and where acetate is produced and what is its biological significance. We observed overproduction of acetate in an amount comparable to ketone bodies in patients and mice with diabetes or starvation. Mechanistically, ACOT 12&8 are dramatically upregulated in liver to convert FFA-derived acetyl-CoA to acetate and CoA. This conversion not only provides large amount of acetate which fuels brain preferentially rather than muscle, but also recycles CoA which is required for sustained fatty acid oxidation and ketogenesis. Taken together, we suggest that acetate is an emerging novel "ketone body" and may be used as a parameter to evaluate the progression of energy stress in the future.

biochemistry↗

bioRxiv2023

Spatially aware deep learning reveals tumor heterogeneity patterns that encode distinct kidney cancer states

Background Abstract Background Results Discussion Methods Data Availability Code Availability Author Contributions Competing Interests Extended Data References Renal cell carcinoma (RCC) is among the 10 most common cancers worldwide and is comprised of several histological subtypes1. The clear cell histological subtype (ccRCC) is the most common form of RCC and accounts for the vast majority (75-80%) of metastatic cases1. In addition to highly recurrent mutations in hypoxia (VHL) and chromatin regulator genes (e.g. PBRM1, BAP1, SETD2), ccRCC exhibits extensive genomic intratumoral heterogeneity (ITH)2, which wa ...

cancer biology↗

bioRxiv2022

tFold-Ab: Fast and Accurate Antibody Structure Prediction without Sequence Homologs

Accurate prediction of antibody structures is critical in analyzing the function of antibodies, thus enabling the rational design of antibodies. However, existing antibody structure prediction methods often only formulate backbone atoms and rely on additional tools for side-chain conformation prediction. In this work, we propose a fully end-to-end architecture for simultaneous prediction of backbone and side-chain conformations, namely tFold-Ab. Pre-trained language models are adopted for fast structure prediction by avoiding the time-consuming search for sequence homologs. The model firstly predicts monomer structures of each chain, and then refines them into heavy-light chain complex structure prediction, which enables multi-level supervision for model training. Evaluation results verify the effectiveness of tFold-Ab for both antibody and nanobody structure prediction. In addition, we provide a public web service for antibody structure prediction at https://drug.ai.tencent.com/en.

bioinformatics↗

bioRxiv2022

Pharmacological modulators of epithelial immunity uncovered by synthetic genetic tracing of SARS-CoV-2 infection responses

Epithelial immune responses govern tissue homeostasis and offer drug targets against maladaptation. Here, we report a framework to generate drug discovery-ready reporters of cellular responses to viral infection. We reverse engineered epithelial cell responses to SARS-CoV-2, the viral agent fueling the ongoing COVID-19 pandemic and designed synthetic transcriptional reporters whose molecular logic comprises interferon-/{beta}/{gamma}-, and NF-{kappa}B pathways. Such regulatory potential reflected single-cell data from experimental models to severe COVID-19 patient epithelial cells infected by SARS-CoV-2. SARS-CoV-2, type-I interferons, and RIG-I drive reporter activation. Live-cell-image-based phenotypic drug screens identified JAK inhibitors and DNA damage inducers as antagonistic modulators of epithelial cell response to interferons, RIG-I stimulation, and SARS-CoV-2. Synergistic or antagonistic modulation of the reporter by drugs underscored their similar mechanism of action. Thus, this study describes a tool for dissecting antiviral responses to infection and sterile cues, and a rapid approach to other emerging viruses of public health concern in order to discover rational drug combinations.

bioengineering↗

bioRxiv2022

Logical design of synthetic cis-regulatory DNA for genetic tracing of cell identities and state changes

Descriptive data are rapidly expanding in biomedical research. Instead, functional validation methods with sufficient complexity remain underdeveloped. Transcriptional reporters allow experimental characterization and manipulation of developmental and disease cell states, but their design lacks flexibility. Here, we report logical design of synthetic cis-regulatory DNA(LSD), a computational framework leveraging phenotypic biomarkers and trans-regulatory networks as input to design reporters marking the activity of selected cellular states and pathways. LSD uses bulk or single-cell biomarkers and a reference genome or custom cis-regulatory DNA datasets with user-defined boundary regions. By benchmarking validated reporters, we integrated LSD with a computational classifier to rank phenotypic specificity of putative cis-regulatory DNA. Experimentally, LSD-designed reporters targeting a wide range of cell states are functional without minimal promoters. In silico, an LSD-unsupervised mesenchymal glioblastoma reporter outperformed previously validated ones. In genome-scale CRISPRa screens, it discovered known and novel bona fide cell-state-drivers. Thus, LSD captures core principles of cis-regulation and is broadly applicable to studying complex cell states and mechanisms of transcriptional regulation.

bioengineering↗

bioRxiv2022

"Double-Effect" strategy against Triple-Negative Breast Cancer via a synergistic therapy of Magneto-mechanical Force enhancing NIR-II Hypothermal Ablation

Triple-negative breast cancer (TNBC) is a form of breast cancer that is more aggressive and harder to treat than others, with a higher probability of relapse. Its highly efficient capabilities for migrating and invading other parts of the body together with the current lack of clinically established effective therapies account for a low survival rate. Thus, we propose the in-tandem use of two complementary therapeutic routes to effectively combat TNBC. Herein, a versatile magnetic-photothermal converter (MPC) is elaborately designed via integrating zinc-doped ferrite nanoparticles and polyethene glycol, synergistically enhanced through magneto-mechanical force (MMF) and near-infrared-II (NIR-II) hypothermal ablation, thereby displaying excellent therapeutic efficiency. Their combined use, which is less aggressive to the human body compared to conventional chemotherapeutic approaches, results in the splendid suppression of TNBC migration and invasion. Remotely controlling the MPCs by an external magnetic stimulus, results in cellular MMF effects that cause direct mechanical destruction to the cancer cell membrane, leading to its necrosis. Furthermore, the MMF disrupts intracellular lysosomes, thereby triggering the release of large amounts of protein hydrolases, which induce intracellular oxidative stress, and accelerate the induction of apoptosis. Complementing the therapeutic approach based on MMF, the excellent photothermal performance of the MPC in the NIR-II region (1064nm) is exploited to enable effective hypothermal ablation of the tumours, which can be achieved in deep tissue layers. The proposed multifunctional nanocomposites, together with the demonstrated "double effect" therapeutic approach, hold significant potential to pave the way for future cutting-edge weapons against the dreadful TNBC.

cancer biology↗

bioRxiv2022

Intratumoral heterogeneity and clonal evolution induced by HPV integration

The human papillomavirus (HPV) genome is integrated into host DNA in most HPV-positive cancers, but the consequences for chromosomal integrity are unknown. Continuous long-read sequencing of oropharyngeal cancers and cancer cell lines revealed a unique form of structural variation, i.e., heterocateny, characterized by diverse, interrelated, and repetitive patterns of concatemerized virus and host DNA segments within a cancer. Unique breakpoint sequences shared across structural variants facilitated stepwise reconstruction of their evolution from a common molecular ancestor. This analysis revealed that virus and virus-host concatemers are unstable and, upon insertion into and excision from chromosomes, facilitate capture, amplification, and recombination of host DNA and chromosomal rearrangements. Evidence of heterocateny was detected in extrachromosomal and intrachromosomal DNA. The data indicate that heterocateny is driven by the dynamic, aberrant replication and recombination of an oncogenic DNA virus, thereby extending known consequences of HPV integration to include promotion of intratumoral heterogeneity and clonal evolution.

cancer biology↗

bioRxiv2022

3D bioprinting of an implantable xeno-free vascularized human skin graft

Bioengineered tissues or organs produced using matrix proteins or components derived from xenogeneic sources pose risks of allergic responses, immune rejection, or even autoimmunity. Here, we report successful xeno-free isolation, expansion, and cryopreservation of human endothelial cells, fibroblasts, pericytes and keratinocytes from a single donor. We further demonstrate the bioprinting of a human skin substitute with a dermal layer containing xeno-free cultured human endothelial cells (EC), fibroblasts, and pericytes in a xeno-free bioink containing human collagen type I and fibronectin layered in a biocompatible polyglycolic acid (PGA) mesh and subsequently seeded with xeno-free human keratinocytes to form an epidermal layer. Following implantation of such bilayered skin grafts on the dorsum of immunodeficient mice, keratinocytes form a mature stratified epidermis with rete ridge-like structures. The ECs and pericytes form human EC-lined perfused microvessels within 2 weeks after implantation, preventing graft necrosis, and eliciting further perfusion of the graft by angiogenic host microvessels. In summary, we describe the fabrication of a bioprinted vascularized bilayered skin substitute under completely xeno-free culture conditions demonstrating feasibility of a xeno-free approach to complex tissue engineering.

bioengineering↗

bioRxiv2021

Horizontal Transfer and Evolution of the Biosynthetic Gene Cluster for Benzoxazinoid

Benzoxazinoids are a class of protective and allelopathic plant secondary metabolites, first identified in maize (Zea mays) and subsequently shown to be encoded by a biosynthetic gene cluster (BGC), the Bx cluster. Data mining of mining 40 high-quality grass genomes identified complete Bx clusters (containing genes Bx1 to Bx5 and Bx8) in three genera (Zea, Echinochloa and Dichanthelium) in the Panicoideae and partial clusters in the Triticeae. The Bx cluster originated from gene duplication of native analogues of Bx genes and chromosomal translocation. An ancient Bx cluster including additional Bx genes (e.g., Bx6) is found in ancestral Panicoideae. The ancient Bx cluster was gained by the Triticeae ancestor via a horizontal transfer (HT) event from the ancestral Panicoideae and later separated into three parts on different chromosomes. Bx6 appears to have been under less constrained selection during evolution of the Panicoideae as evidenced by the fact that was translocated [~]1.31-Mb away from the Bx cluster in Z. mays, moved to other chromosomes in Echinochloa, and even lost in Dichanthelium. Further investigation indicated that intense selection and polyploidization shaped the evolutionary trajectory of the Bx cluster in the grass family. This study provides the first case of HT of BGCs among plants and sheds new insights on the evolution of BGCs. SignificanceBiosynthetic gene clustering and horizontal gene transfer are two evolutionary inventions for rapid adaption by organisms. Horizontal transfer of a gene cluster has been reported in fungi and bacteria, but not in plants up to now. By mining the genomes of 40 monocot species, we deciphered the organization of Bx gene cluster, a biosynthetic gene cluster for benzoxazinoids in grasses. We found that the Bx cluster was formed by gene duplication of native analogues of individual Bx genes and directional translocation. More importantly, the Bx cluster in Triticeae was inherited from the Panicoideae via horizontal transfer. Compared with the native analogues, Bx clusters in grasses show constrained purifying selection underscoring their significance in environmental adaption.

evolutionary biology↗

bioRxiv2021

Proteomic Characterization of Serum Small Extracellular Vesicles in Human Breast Cancer

There is a lack of comprehensive understanding of breast cancer (BC) specific sEVs characteristics and composition on BC unique proteomic information from human samples. Here, we interrogated the proteomic landscape of sEVs in 167 serum samples from patients with BC, benign mammary disease (BD) and from healthy donors (HD). The analysis provides a comprehensive landscape of serum sEVs with totally 9,589 proteins identified, considerably expanding the panel of sEVs markers. Of note, serum BC-sEVs protein signatures were distinct from those of BD and HD, representing stage- and molecular subtype-specific patterns. We constructed specific sEVs protein identifiers that could serve as a liquid biopsy tool for diagnosis and classification of BC from benign mammary disease, molecular subtypes, as well as assessment of lymph node metastasis. We also identified 11 potential survival biomarkers for distant metastasis. This work may provide reference value for the accurate diagnosis and monitoring of BC progression using serum sEVs.

bioinformatics↗

bioRxiv2021

pGlycoQuant with a deep residual network for precise and minuscule-missing-value quantitative glycoproteomics enabling the functional exploration of site-specific glycosylation

Interpreting large-scale glycoproteomic data for intact glycopeptide identification has been tremendously advanced by software tools. However, software tools for quantitative analysis of intact glycopeptides remain lagging behind, which greatly hinders exploring the differential expression and functions of site-specific glycosylation in organisms. Here, we report pGlycoQuant, a generic software tool for accurate and convenient quantitative intact glycopeptide analysis, supporting both primary and tandem mass spectrometry quantitation for multiple quantitative strategies. pGlycoQuant enables intact glycopeptide quantitation with very low missing values via a deep residual network, thus greatly expanding the quantitative function of several powerful search engines, currently including pGlyco 2.0, pGlyco3, Byonic and MSFragger-Glyco. The pGlycoQuant-based site-specific N-glycoproteomic study conducted here quantifies 6435 intact N-glycopeptides in three hepatocellular carcinoma cell lines with different metastatic potentials and, together with in vitro molecular biology experiments, illustrates core fucosylation at site 979 of the L1 cell adhesion molecule (L1CAM) as a potential regulator of HCC metastasis. pGlycoQuant is freely available at https://github.com/expellir-arma/pGlycoQuant/releases/. We have demonstrated pGlycoQuant to be a powerful tool for the quantitative analysis of site-specific glycosylation and the exploration of potential glycosylation-related biomarker candidates, and we expect further applications in glycoproteomic studies.

systems biology↗

bioRxiv2021

Examining Batch Effect in Histopathology as a Distributionally Robust Optimization Problem

Computer vision (CV) approaches applied to digital pathology have informed biological discovery and development of tools to help inform clinical decision-making. However, batch effects in the images have the potential to introduce spurious confounders and represent a major challenge to effective analysis and interpretation of these data. Standard methods to circumvent learning such confounders include (i) application of image augmentation techniques and (ii) examination of the learning process by evaluating through external validation (e.g., unseen data coming from a comparable dataset collected at another hospital). Here, we show that the source site of a histopathology slide can be learned from the image using CV algorithms in spite of image augmentation, and we explore these source site predictions using interpretability tools. A CV model trained using Empirical Risk Minimization (ERM) risks learning this source-site signal as a spurious correlate in the weak-label regime, which we abate by using a training method with abstention. We find that a patch based classifier trained using abstention outperformed a model trained using ERM by 9.9, 10 and 19.4% F1 in the binary classification tasks of identifying tumor versus normal tissue in lung adenocarcinoma, Gleason score in prostate adenocarcinoma, and tumor tissue grade in clear cell renal cell carcinoma, respectively, at the expense of up to 80% coverage (defined as the percent of tiles not abstained on by the model). Further, by examining the areas abstained by the model, we find that the model trained using abstention is more robust to heterogeneity, artifacts and spurious correlates in the tissue. Thus, a method trained with abstention may offer novel insights into relevant areas of the tissue contributing to a particular phenotype. Together, we suggest using data augmentation methods that help mitigate a digital pathology models reliance on potentially spurious visual features, as well as selecting models that can identify features truly relevant for translational discovery and clinical decision support.

cancer biology↗

bioRxiv2021

Addressing Enzymatic-Independent Tumor-Promoting Function of NAMPT via PROTAC-Mediated Degradation

The rate-limiting enzyme of salvage pathway for NAD+ synthesis, NAMPT, is aberrantly overexpressed in a variety of tumor cells and is a poor prognosis factor for patient survival. NAMPT plays a major role in tumor cell proliferation, acting concurrently as an NAD+ synthase and unexpectedly, an extracellular ligand for several tumor-promoting signaling pathways. While previous efforts to modulate NAMPT activity were limited to enzymatic inhibitors with low success in clinical studies, protein degradation offers a possibility to simultaneously disrupt NAMPTs enzyme activity and ligand capabilities. Here, we report the development of two highly selective NAMPT-targeted proteolysis-targeting chimeras (PROTACs), which promoted rapid and potent NAMPT degradation in a cereblon-dependent manner in multiple tumor cell lines. Notably, both PROTAC degraders outperform a clinical candidate, FK866, in killing effect on hematological tumor cells. These results emphasize the importance and feasibility of applying PROTACs as a better strategy for targeting proteins like NAMPT with dual tumor-promoting functions, which are not easily achieved by conventional enzymatic inhibitors.

biochemistry↗

bioRxiv2021

MicroRNA-202 prevents precocious spermatogonial differentiation and meiotic initiation during mouse spermatogenesis

Spermatogonial differentiation and meiotic initiation during spermatogenesis are tightly regulated by a number of genes including those coding enzymes for miRNA biogenesis. However, whether and how single miRNAs regulate these processes remain unclear. Here, we report that miR-202, a member of the let-7 family, prevents precocious spermatogonial differentiation and meiotic initiation in spermatogenesis by regulating the timely expression of many genes including those for other key regulators. In miR-202 knockout (KO) mice, the undifferentiated spermatogonial pool is reduced, ultimately causing agametic seminiferous tubules. SYCP3, STRA8 and DMRT6 are expressed earlier in KO mice than in wild-type (WT) littermates, and Dmrt6 mRNA is a direct target of miR-202-5p. Moreover, the precocious spermatogonial differentiation and meiotic initiation were also observed in KO spermatogonial stem cells when cultured and induced in vitro, and could be rescued by the knockdown of Dmrt6. Therefore, we have not only shown that miR-202 is a novel regulator of meiotic initiation but also added a new module to the underlying regulatory network. Summary statementA single miRNA, miR-202, prevents precocious differentiation and meiotic initiation during spermatogenesis. miR-202, DMRT6 and STRA8 act together as a novel module in the regulatory network of meiotic initiation.

developmental biology↗

bioRxiv2021

Diverse tumorigenic consequences of human papillomavirus integration in primary oropharyngeal cancers

Human papillomavirus (HPV) causes 5% of all cancers and frequently integrates into host chromosomes, but the impacts of integration in tumorigenesis remain unclear. Analysis of 105 HPV-positive oropharyngeal cancers by whole genome sequencing detects viral integration in 77%, revealing five statistically significant integration hotspots near genes that regulate epithelial stem cell maintenance (i.e. SOX2, TP63, FGFR, MYC) and immune evasion (i.e. CD274). Somatic hyperamplification is enriched 16-fold near HPV integrants, and the extent of focal host genomic instability increases with local density of HPV integrants. Genes expressed at extreme outlier levels are increased 86-fold within +/- 150 kb of integrants. Across 95% of tumors with integration, host gene transcription is disrupted via intragenic integrants, chimeric transcription, outlier expression, gene breaking and/or de novo expression of noncoding or imprinted genes. We conclude that HPV integration contributes substantively to cancer development by causing extensive disruption of host genome structure and gene expression.

genomics↗

bioRxiv2021

Precision Genome and Base Editing by Regulating mRNA Nuclear Export Using Selective Inhibitors of Nuclear Export

CRISPR-based genome engineering tools are associated with off-target effects that constitutively active Cas9 protein may instigate. In the present study, we screened for irreversible small molecule off-switches of CRISPR-Cas9 and discovered that selective inhibitors of nuclear export (SINEs) could inhibit the cellular activity of CRISPR-Cas9 by interfering with the nuclear export of Cas9 mRNA. We subsequently found that SINEs, including an FDA-approved anticancer drug KPT330, could improve the specificities of CRISPR-Cas9-based genome and base editing tools in human cells.

biochemistry↗