Biology subjects

Ren, Z.

Publications and source records attributed to Ren, Z..

At least 109 records · Page 6Linked to original sources

bioRxiv2021

A chloride efflux transporter OsBIRG1 regulates grain size and salt tolerance in rice

Grain size is determined by the number of cells and cell size of the grain. Regulation of grain size is crucial for improving crop yield. However, the genes and underlying molecular mechanisms controlling grain size remain elusive. Here we report a member of Detoxification efflux carrier (DTX)/Multidrug and Toxic Compound Extrusion (MATE) family transporter, BIG RICE GRAIN 1 (BIRG1), negatively regulates the grain size in rice. BIRG1 is highly expressed in reproductive organs and roots. In birg1 grain, the size of the outer parenchyma layer cells of spikelet hulls is noticeably larger but the cell number is not altered compared with that in the wild-type (WT) grain. When expressed in Xenopus oocytes, BIRG1 exhibits chloride efflux activity. In line with the role of BIRG1 in mediating chloride efflux, the birg1 mutant shows reduced tolerance to salt stress under which the chloride level is toxic. Moreover, the birg1 grains contain higher level of chloride compared to WT grains when grown under normal paddy field. The birg1 roots accumulate more chloride than those of WT under saline condition. Collectively, our findings suggest that BIRG1 functions as a chloride efflux transporter regulating grain size and salt tolerance via controlling chloride homeostasis in rice.

plant biology↗

bioRxiv2021

A positive role of task-deactivated default mode network in narrative speech comprehension

During speech comprehension, as listeners need to keep tracking the external audio streams, the default mode network (DMN) is often de-activated and anticorrelated with task-positive networks. Such a pattern has been interpreted as the suppression of the DMN to support externally-oriented cognitive processes. Taking a "two-brain" approach, the current study demonstrated that, despite exhibiting deactivation and anticorrelated with the language network and executive control network, the DMN was not suppressed but played an active role in spoken narrative comprehension. This was evidenced by significant listener-speaker neural couplings in both the posterior and anterior DMN and the positive correlation between the coupling strength and listeners speech comprehension. Moreover, we demonstrated that the functionality of posterior DMN depended on its interaction with the executive control network, rather than its level of activation. Finally, Dynamic Causal Modeling together with the two-brain results indicates the language and executive control networks, the anterior DMN, and the posterior DMN occupied the bottom, intermediate and top layers of a hierarchical system, respectively. These results suggest that the DMN may primarily serve as an internally-oriented system that cooperates with the externally-oriented networks, which may allow the transformation of external acoustic signals into internal mental representations during language comprehension.

neuroscience↗

bioRxiv2020

Information-theory-based benchmarking and feature selection algorithm improve cell type annotation and reproducibility of single cell RNA-seq data analysis pipelines

Single cell RNA sequencing (scRNA-seq) data are now routinely generated in experimental practice because of their promise to enable the quantitative study of biological processes at the single cell level. However, cell type and cell state annotations remain an important computational challenge in analyzing scRNA-seq data. Here, we report on the development of a benchmark dataset where reference annotations are generated independently from transcriptomic measurements. We used this benchmark to systematically investigate the impact on labelling accuracy of different approaches to feature selection, of different clustering algorithms, and of different sets of parameter values. We show that an approach grounded on information theory can provide a general, reliable, and accurate process for discarding uninformative features and to optimize cluster resolution in single cell RNA-seq data analysis.

bioinformatics↗

bioRxiv2020

DNA-loop extruding SMC complexes can traverse one another in vivo

The spatial organization of chromosomes by structural maintenance of chromosomes (SMC) complexes is vital to organisms from bacteria to humans 1,2. SMC complexes were recently found to be motors that extrude DNA loops 3-11. It remains unclear, however, what happens when multiple SMC complexes encounter one another in vivo on the same DNA, how encounters are resolved, or how interactions help organize an active genome 12. Here, we set up a "crash-course track" system to study what happens when SMC complexes encounter one another. Using the parS/ParB system, which loads SMC complexes in a targeted manner13-17, we engineered the Bacillus subtilis chromosome to have multiple SMC loading sites. Chromosome conformation capture (Hi-C) analyses of over 20 engineered strains show an amazing variety of never-before-seen chromosome folding patterns. Polymer simulations indicate these patterns require SMC complexes to traverse past each other in vivo, contrary to the common assumption that SMC complexes mutually block each others extrusion activity 18. Our quantitative model of bypassing predicted that increasing the numbers of SMCs on the chromosome could overwhelm the bypassing mechanism, create SMC traffic jams, and lead to major chromosome reorganization. We validated these predictions experimentally. We posit that SMC complexes traversing one another is part of a larger phenomenon of bypassing large steric barriers which enables these loop extruders to spatially organize a functional and busy genome.

biophysics↗

bioRxiv2020

CancerVar: a web server for improved evidence-based clinical interpretation of cancer somatic mutations and copy number abnormalities

Several knowledgebases, such as CIViC and OncoKB, have been manually curated to support clinical interpretations of a limited number of "hotspot" somatic mutations in cancer, yet discrepancies or even conflicting interpretations have been observed among these knowledgebases. Additionally, while these knowledgebases have been extremely useful, they typically cannot interpret novel mutations, which may also have functional and clinical impacts in cancer. To address these challenges, we developed an automated interpretation tool called CancerVar (Cancer Variants interpretation) to score more than 12.9 million somatic mutations and classify them into four tiers: strong clinical significance, potential clinical significance, uncertain clinical significance, and benign/likely benign, based on the AMP/ASCO/CAP 2017 guideline. Considering that the AMP/ASCO/CAP rule-based scoring system may have inherent limitations, such as lack of a clear guidance on weighing different pieces of functional evidence or unclear definition for certain clinical evidence, it may cause misinterpretation for certain variants that have functional impacts but no proven clinical significance. To address this issue, we further introduced a deep learning-based scoring system to predict oncogenicity of mutations by semi-supervised generative adversarial network (SGAN) method using both functional and clinical evidence. We trained and validated the SGAN model on 5,234 somatic mutations from an in-house database of clinical reports on cancer patients, and achieved a good performance when testing on 6,226 variants that were curated by us through literature search. We also compared the prediction with several independent datasets and showed great utility in classifying variants with previously unknown interpretations. CancerVar is also incorporated into a web server that can generate automated texts with summarized descriptive interpretations, such as diagnostic, prognostic, targeted drug responses and clinical trial information for many hotspot mutations. In summary, CancerVar can facilitate clinical interpretation and hypothesis generation for somatic mutations, and greatly reduce manual workload for retrieving relevant evidence and implementing existing guidelines.

cancer biology↗

bioRxiv2020

New evidence concerning the genome designations of the AC(DC) tetraploid Avena species

The tetraploid Avena species in the section Pachycarpa Baum, including A. insularis, A. maroccana, and A. murphyi, are thought to be involved in the evolution of hexaploid oats; however, their genome designations are still being debated. Repetitive DNA sequences play an important role in genome structuring and evolution, so understanding the chromosomal organization and distribution of these sequences in Avena species could provide valuable information concerning genome evolution in this genus. In this study, the chromosomal organizations and distributions of six repetitive DNA sequences (including three SSR motifs (TTC, AAC, CAG), one 5S rRNA gene fragment, and two oat A and C genome specific repeats) were investigated using non-denaturing fluorescence in situ hybridization (ND-FISH) in the three tetraploid species mentioned above and in two hexaploid oat species. Preferential distribution of the SSRs in centromeric regions was seen in the A and D genomes, whereas few signals were detected in the C genomes. Some intergenomic translocations were observed in the tetraploids; such translocations were also detected between the C and D genomes in the hexaploids. These results provide robust evidence for the presence of the D genome in all three tetraploids, strongly suggesting that the genomic constitution of these species is DC and not AC, as had been thought previously.

genetics↗

bioRxiv2020

The CXCL12gamma chemokine immobilized by heparan sulfate on stromal niche cells controls adhesion and mediates drug resistance in multiple myeloma

The homing/retention, survival and proliferation of multiple myeloma (MM) cells critically depends on interaction with CXCL12 expressing stromal cells in the bone marrow (BM) niche. Here, we report a unique role in this interaction for the recently characterized CXCL12gamma isoform, which contains an extended C-terminal domain that binds heparan-sulfate proteoglycans (HSPGs) with an extraordinary high affinity. We observed that CXCL12{gamma} is expressed in situ by reticular stromal cells in both normal and MM BM, as well as by primary BM stromal-cell (BMSC) isolates and BMSC lines. Importantly, upon secretion, CXCL12{gamma}, unlike the CXCL12 isoform, was retained on the surface of these BMSCs. This membrane retention of CXCL12{gamma} is HSPG-mediated, since it was completely annulated by CRISPR-Cas9 mediated deletion of the heparan-sulfate (HS) co-polymerase EXT1. Recombinant CXCL12{gamma} was found to induce strong adhesion of MM cells to vascular cell-adhesion molecule 1 (VCAM-1) coated plates. Furthermore, CXCL12{gamma} expressed by BMSCs and membrane-retained by HSPGs, supported robust adhesion of MM cells to the BMSCs. Specific genetic deletion of either CXCL12{gamma} or of EXT1 significantly attenuated the ability of BMSCs to support MM cell adhesion and, in addition, impaired their capacity to protect MM cells from bortezomib-induced cell death. Our data indicate that CXCL12{gamma} functions as a membrane-bound niche chemokine, which plays a unique role in the interaction of MM cells with the stromal niche by controlling adhesion/retention as well as cell adhesion-mediated drug resistance (CAM-DR). These findings designate CXCL12{gamma} and associated HSPGs as potential therapeutic targets in MM.

cancer biology↗

bioRxiv2020

Discovery of A New Class of Integrin Antibodies for Fibrosis

Lung fibrosis, or the scarring of the lung, is a devastating disease with huge unmet medical need. There are limited treatment options and its prognosis is worse than most types of cancer. We previously discovered that MK-0429 is an equipotent pan-inhibitor of all v integrins that reduces proteinuria and kidney fibrosis in a preclinical model. In the present study, we further demonstrated that MK-0429 significantly inhibits fibrosis progression in a bleomycin-induced lung injury model. In search of newer integrin inhibitors for fibrosis, we characterized monoclonal antibodies discovered using Adimabs yeast display platform. We identified several potent neutralizing integrin antibodies with unique human and mouse cross-reactivity. Among these, Ab-31 blocked the binding of multiple v integrins to their ligands with IC50s comparable to those of MK-0429. Furthermore, both MK-0429 and Ab-31 suppressed integrin-mediated cell adhesion and latent TGF{beta} activation. In IPF patient lung fibroblasts, TGF{beta} treatment induced profound SMA expression in phenotypic imaging assays and Ab-31 demonstrated superior in vitro activity at inhibiting SMA expression, suggesting that the integrin antibody is able to modulate TGF{beta} action though mechanisms beyond the inhibition of latent TGF{beta} activation. Together, our results highlight the potential to develop newer integrin therapeutics for the treatment of fibrotic lung diseases. One Sentence Summarytargeting integrin in lung fibrosis

pharmacology and toxicology↗

bioRxiv2020

Catch and kill airborne SARS-CoV-2 to control spread of COVID-19 by a heated air disinfection system

Airborne transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) via air-conditioning systems poses a significant threat for the continued escalation of the current coronavirus disease (COVID-19) pandemic. Considering that SARS-CoV-2 cannot tolerate temperatures above 70 {degrees}C, here we designed and fabricated efficient air disinfection systems based on heated nickel (Ni) foam to catch and kill SARS-CoV-2. Virus test results revealed that 99.8% of the aerosolized SARS-CoV-2 was caught and killed by a single pass through a Ni-foam-based filter when heated up to 200 {degrees}C. Additionally, the same filter was also used to catch and kill 99.9% of Bacillus anthracis, an airborne spore. This study paves the way for preventing transmission of SARS-CoV-2 and other highly infectious airborne agents in closed environments. One Sentence SummaryHeated Ni-foam filters are capable of effectively catching and killing airborne SARS-CoV-2 and Bacillus anthracis spores.

microbiology↗

bioRxiv2020

ATAV - a comprehensive platform for population-scale genomic analyses

BackgroundA common approach for sequencing studies is to do joint-calling and store variants of all samples in a single file. If new samples keep being added or controls are re-used for several studies, the cost and time required to perform joint-calling for each analysis can become prohibitive. ResultsWe present ATAV, an analysis platform for large-scale whole-exome and whole-genome sequencing projects. ATAV stores variant and per site coverage data for all samples in a centralized database, which is efficiently queried by ATAV to support diagnostic analyses for trios and singletons, as well as rare-variant collapsing analyses for finding disease associations in complex diseases. Runtime logs ensure full reproducibility and the modularized ATAV framework makes it extensible to continuous development. Besides helping with the identification of disease-causing variants for a range of diseases, ATAV has also enabled the discovery of disease-genes by rare-variant collapsing on datasets containing more than 20,000 samples. Analyses to date have been performed on data of more than 110,000 individuals demonstrating the scalability of the framework. The ATAV data browser (http://atavdb.org/) is a web-based interface that allows users to easily access variant-level data directly from the database. Summary-level data for more than 40,000 samples can be queried by the general public representing a mix of cases and controls of diverse ancestries. Users have access to phenotype categories of variant carriers, as well as predicted ancestry, gender, and quality metrics. In contrast to many other platforms, the data browser is able to show data of newly-added samples in real-time and is therefore evolving rapidly as more and more samples are sequenced. ConclusionsSince all code is freely available on GitHub, ATAV can easily be used by other groups to build up their own platform, database, and user interface. In addition to that users can query one of the largest variant databases for patients sequenced at a tertiary care center and look up their own genes or variants of interest.

bioinformatics↗

bioRxiv2020

Molecular Basis of Far-red Sensing in Cyanobacteriochrome

Cyanobacteriochromes are small, panchromatic photoreceptors in the phytochrome superfamily that regulate diverse light-mediated adaptive processes in cyanobacteria. The molecular basis of far-red (FR) light perception by cyanobacteriochromes is currently unknown. Here we report the crystal structure of a far-red-sensing cyanobacteriochrome from Anabaena cylindrica PCC 7122, which exhibits a reversible far-red/orange photocycle. The 2.7 [A] structure of its FR-absorbing dark state, determined by room temperature serial crystallography and cryo-crystallography, reveals an all-Z,syn configuration of its bound linear tetrapyrrole (bilin) chromophore that is less extended than the bilin chromophores of all known phytochromes. Based on structural comparisons with other bilin-binding proteins and extensive spectral analyses on mutants, we identify key protein-chromophore interactions that enable far-red sensing in bilin-binding proteins. We propose that FR-CBCRs employ two distinct tuning mechanisms, which work together to produce a large batho-chromatic shift. Findings of this work have important implications for development and improvement of photoproteins with far-red absorption and fluorescence. Significance StatementPhytochromes are well known far-red-light sensors found in plants that trigger adaptive responses to facilitate competition for light capture with neighboring plants. Red- and far-red-sensing are critical to cyanobacteria living in the far-red-enriched shade of plants. Here we report the crystal structure of a far-red-sensing cyanobacteriochrome, a distant cyanobacterial relative of phytochrome. These studies shed insight into the poorly understood molecular basis of far-red-sensing by phytobilin-based photoreceptors. Owing to the deep tissue penetration of far-red light, far-red-sensing photoreceptors offer promising protein scaffolds for developing gene-based photoswitches, optoacoustic contrast agents and fluorescent probes for in situ imaging and optogenetic applications.

biochemistry↗

bioRxiv2020

Cellbow: a robust customizable cell segmentation program

Time-lapse live cell imaging of a growing cell population is routine in many biological investigations. A major challenge in imaging analysis is accurate segmentation, a process to define the boundaries of cells based on raw image data. Current segmentation methods relying on single boundary features have problems in robustness when dealing with inhomogeneous foci which invariably happens in cell population imaging. Here, we demonstrated that combined with multi-layer training set strategy, a neural-network-based algorithm Cellbow can achieve accurate and robust segmentation of cells in broad and general settings. It can also facilitate long-term tracking of cell growth and division. Furthermore, Cellbow is customizable and generalizable. It is broadly applicable to segmenting fluorescent images of diverse cell types with no further training needed. For bright-field images, only a small set of sample images of the specific cell type from the user may be needed for training. To facilitate the application of Cellbow, we provide a website on which one can online test the software, as well as an ImageJ plugin for the user to visualize the performance before software installation.

systems biology↗

bioRxiv2020

Structure and mechanism of a primate ferroportin

Ferroportin is the only cellular iron exporter in human and essential for iron homoeostasis. Mutations in ferroportin are associated with hemochromatosis or ferroportin diseases characterized by a paradoxical combination of anemia and abnormal accumulation of iron in cells. Ferroportin is also the target of hepcidin, which is a hormone that downregulates ferroportin activity. However, due to a lack of three-dimensional structures, the mechanism of iron transport by ferroportin and its regulation by hepcidin remains unclear. Here we present the structure of a ferroportin from the primate Philippine tarsier (TsFpn) at 3.0 [A] resolution determined by cryo-electron microscopy. TsFpn has a structural fold common to major facilitator superfamily of transporters and the current structure is in an outward-open conformation. The structure identifies two potential ion binding sites with each site coordinated by two residues. Functional studies demonstrate that TsFpn is a H+/Fe2+ antiporter and that transport of one Fe2+ is coupled to the transport of two H+ in the opposite direction such that the transport cycle is electroneutral. Further studies show that the two ion binding sites affect transport of H+ and Fe2+ differently. The structure also provides mechanistic interpretation for mutations that cause ferroportin diseases.

biochemistry↗

bioRxiv2020

Resetting proteostasis with ISRIB prevents pulmonary fibrosis

Aging is among the most important risk factors for the development of pulmonary fibrosis. We found that a small molecule that specifically inhibits translational inhibition induced by activation of the integrated stress response (ISRIB) attenuated the severity of pulmonary fibrosis in young and old mice. The more severe fibrosis in old compared to young mice was associated with increased recruitment of pathogenic monocyte-derived alveolar macrophages. Using genetic lineage tracing and transcriptomic profiling we found that ISRIB modulates stress response signaling in alveolar epithelial cells resulting in decreased apoptosis and decreased recruitment of pathogenic monocyte-derived alveolar macrophages. These data support multicellular model of fibrosis involving epithelial cells, pathogenic monocyte-derived alveolar macrophages and fibroblasts. Inhibition of the integrated stress response in the aging lung epithelium ameliorates pulmonary fibrosis by preventing the prolonged recruitment of monocyte-derived alveolar macrophages.

immunology↗

bioRxiv2020

Structure and mechanism of human diacylglycerol acyltransferase 1

Human diacylglycerol O-acyltransferase-1 (hDGAT1) synthesizes triacylglycerides and is required for dietary fat absorption and fat storage. The lack of 3-dimensional structure has limited our understanding of substrate recognition and mechanism of catalysis, and hampers rational targeting of hDGAT1 for therapeutic purposes. Here we present the structure of hDGAT1 in complex with a substrate oleoyl Coenzyme A at 3.1 [A] resolution. hDGAT1 forms a homodimer and each protomer has nine transmembrane helices that carve out a hollow chamber in the lipid bilayer. The chamber encloses highly conserved catalytic residues and has separate entrances for the two substrates fatty acyl Coenzyme A and diacylglycerol. The N-terminus of hDGAT1 makes extensive interactions with the neighboring protomer, and is required for enzymatic activity.

biochemistry↗

bioRxiv2019

Explaining the genetic causality for complex diseases via deep association kernel learning

The genetic effect explains the causality from genetic mutation to the development of complex diseases. Existing genome-wide association study (GWAS) approaches are always built under a linear assumption, restricting their generalization in dissecting complicated causality such as the recessive genetic effect. Therefore, a sophisticated and general GWAS model that can work with different types of genetic effects is highly desired. Here, we introduce a Deep Association Kernel learning (DAK) model to enable automatic causal genotype encoding for GWAS at pathway level. DAK can detect both common and rare variants with complicated genetic effects that existing approaches fail. When applied to real-world GWAS data, our approach discovered potential casual pathways that could be explained by alternative biological studies.

bioinformatics↗

bioRxiv2019

Placental Editome Profiling Reveals Widespread RNA-Editing Dysregulation in Preeclampsia

Dysregulated RNA editing is well documented in several diseases such as cancer. The extent to which RNA editing might be involved in diseases originated in the placenta remains unknown, because RNA editing has rarely been studied in the placenta. Here, we have systematically profiled RNA editome on the placentae from 9 patients with early-onset severe preeclampsia (EOSPE) and 32 normal subjects, and a widespread RNA editing dysregulation in EOSPE has been identified. The mis-edited gene set is enriched with known preeclampsia-associated genes and differentially expressed genes in EOSPE. The \"RNA editing events\" at two microRNA binding sites in 3-UTR of the LEP mRNA were generated, which could lead to increased expression level of LEP in trophoblast cells. Upregulation of LEP were also observed in the placentae of PE patients. These results suggest that widespread placental RNA editing may be involved in placental development and dysregulation of RNA editing in the placenta may contribute to the pathogenesis of preeclampsia.

genomics↗

bioRxiv2019

Distinct molecular processes in placentae involved in two major subtypes of preeclampsia

Patients with preeclampsia display a spectrum of onset time and severity of clinical presentation, yet the underlying molecular bases for the early-onset and late-onset clinical subtypes are not known. Since the root cause of PE is thought to be located in the placentae, we carried out RNA-seq on 65 high-quality placenta samples, including 33 from 30 patients and 32 from 30 control subjects, to search for molecular features. We identified two functionally distinct sets of dysregulated genes in two major subtypes: metabolism-related genes, notably transporter genes, in early-onset severe preeclampsia and immune-related genes in late-onset severe preeclampsia, while the late-onset mild preeclampsia could not be distinguished from normal controls. A small number of dysregulated transcription factors may drive the widespread gene dysregulation in both early-onset and late-onset patients. These results suggest that early-onset and late-onset severe preeclampsia have different molecular mechanisms, whereas the late-onset mild preeclampsia may have no placenta-specific causal factors.

genomics↗