Biology subjects

Wang, G.

Publications and source records attributed to Wang, G..

At least 433 records · Page 24Linked to original sources

bioRxiv2020

Large-scale Phenotypic Drug Screen Identifies Neuroprotectants in Zebrafish and Mouse Models of Retinitis Pigmentosa

Retinitis pigmentosa (RP) and associated inherited retinal diseases (IRDs) are caused by rod photoreceptor degeneration, necessitating therapeutics promoting rod photoreceptor survival. To address this, we tested compounds for neuroprotective effects in zebrafish and mouse RP models, reasoning drugs effective across species may translate better clinically. We first performed a large-scale phenotypic drug screen using a larval zebrafish model of inducible RP. 2,934 compounds, mostly human-approved drugs, were tested across six concentrations. Statistically, 113 compounds achieved "hit" status. Secondary tests of 42 high-priority hits confirmed eleven lead compounds. Nine leads were then evaluated in mouse RP models, with six exhibiting neuroprotective effects. An analysis of potential mechanisms of action suggested complementary activities. Paired lead compound assays in zebrafish showed additive neuroprotective effects for the majority. These results highlight the value of cross-species phenotypic drug discovery and suggest combinatorial drug therapies may provide enhanced therapeutic benefits for patients with RP and IRDs.

neuroscience↗

bioRxiv2020

Conversion of marginal land into switchgrass conditionally accrues soil carbon and reduces methane consumption

Switchgrass (Panicum virgatum L.) is a perennial C4 grass native to tallgrass prairies of the Central US, and a promising bioenergy feedstock. Switchgrass can be cultivated on soils with low nutrient contents and its rooting depth, of up to 2 m, has brought attention to the crop as a potential mechanism to sequester and build soil carbon (C). Switchgrass, therefore, offers multifaceted benefits on degraded soils by enhancing soil organic matter content. However, to evaluate the sustainability of switchgrass-based biofuel production, it is crucial to understand the impacts of land conversion and switchgrass establishment on biotic/abiotic characteristics of various soils. In this study, we characterized the ecosystem-scale consequences of switchgrass growing at two highly-eroded, Dust Bowl remnant field sites from Oklahoma US, with silt-loam (SL) or clay-loam (CL) soil textures having low nitrogen (N), phosphorus (P), and C contents. Paired plots at each site, including fallow control and switchgrass-cultivated, were assessed. Our results indicated that switchgrass significantly increased soil C at the SL site and reduced microbial diversity at the CL site. The CL site exhibited significantly higher CO2 flux and higher respiration from switchgrass plots. Strikingly, switchgrass significantly reduced the CH4 consumption by an estimated 39% for the SL site and 47% for the CL site. Structural equation modeling identified soil temperature, P content, and soil moisture levels as the most influential factors regulating both CO2 and CH4 fluxes. CO2 flux was also influenced by microbial biomass while CH4 flux was influenced by microbial diversity. Together, our results suggest that site selection by soil type is a crucial factor in improving soil C stocks and mitigating greenhouse gas (GHG) fluxes, especially considering our finding that switchgrass reduced methane consumption, implying that carbon balance considerations should be accounted for to fully evaluate the sustainability of switchgrass cultivation.

molecular biology↗

bioRxiv2020

Fine-mapping and QTL tissue-sharing information improve causal gene identification and transcriptome prediction performance

The integration of transcriptomic studies and GWAS (genome-wide association studies) via imputed expression has seen extensive application in recent years, enabling the functional characterization and causal gene prioritization of GWAS loci. However, the techniques for imputing transcriptomic traits from DNA variation remain underdeveloped. Furthermore, associations found when linking eQTL studies to complex traits through methods like PrediXcan can lead to false positives due to linkage disequilibrium between distinct causal variants. Therefore, the best prediction performance models may not necessarily lead to more reliable causal gene discovery. With the goal of improving discoveries without increasing false positives, we develop and compare multiple transcriptomic imputation approaches using the most recent GTEx release of expression and splicing data on 17,382 RNA-sequencing samples from 948 post-mortem donors in 54 tissues. We find that informing prediction models with posterior causal probability from fine-mapping (dap-g) and borrowing information across tissues (mashr) lead to better performance in terms of number and proportion of significant associations that are colocalized and the proportion of silver standard genes identified as indicated by precision-recall and ROC (Receiver Operating Characteristic) curves. All prediction models are made publicly available at predictdb.org. Author summaryIntegrating molecular biology information with genome-wide association studies (GWAS) sheds light on the mechanisms tying genetic variation to complex traits. However, associations found when linking eQTL studies to complex traits through methods like PrediXcan can lead to false positives due to linkage disequilibrium of distinct causal variants. By integrating fine-mapping information into the models, and leveraging the widespread tissue-sharing of eQTLs, we improve the proportion of likely causal genes among significant gene-trait associations, as well as the prediction of "ground truth" genes.

genomics↗

bioRxiv2020

Population sequencing enhances understanding of tea plant evolution

Tea is an economically important plant characterized by a large genome size and high heterozygosity and species diversity. In this study, we assembled a 3.26 Gb high-quality chromosome-scale genome for tea using the Longjing 43 cultivar of Camellia sinensis var. sinensis. Population resequencing of 139 tea accessions from around the world was used to investigate the evolution of tea and to reveal the phylogenetic relationships among tea accessions. With the spread of tea cultivation, hybridization has increased the heterozygosity and wide-ranging gene flow among tea populations. Population genetics and transcriptomics analyses revealed that during domestication, the selection for disease resistance and flavor in C. sinensis var. sinensis populations has been stronger than that in C. sinensis var. assamica populations. The data compiled in this study provide new resources for the marker assisted breeding of tea and are a basis for further research on the genetics and evolution of tea.

genomics↗

bioRxiv2020

Rhesus macaques can be effectively infected with SARS-CoV-2 via ocular conjunctival route

The outbreak of Corona Virus Disease 2019 caused by the severe acute respiratory syndrome coronavirus (SARS-CoV-2) is highly transmitted. The potential extra-respiratory transmission routes remain uncertain. Five rhesus macaques were inoculated with 1x106 TCID50 of SARS-CoV-2 via conjunctival (CJ), intratracheal (IT), and intragastric (IG) routes, respectively. Remarkably, the CJ inoculated-macaques developed mild interstitial pneumonia and viral load was detectable in the conjunctival swabs at 1 days post-inoculation (dpi). Only via IT inoculation, viral load was detected in the anal swab at 1-7 dpi and macaque showed weight loss. However, viral load was undetectable after IG inoculation. Comparatively, viral load was higher in the nasolacrimal system but lesions of lung were relatively mild and local via CJ inoculation compared with that via IT inoculation, demonstrating distinct characteristics of virus dispersion. Both the two routes affected the alimentary tract. Therefore the clinicians need to protect eye while working with patients.

microbiology↗

bioRxiv2020

Reinfection could not occur in SARS-CoV-2 infected rhesus macaques

A global pandemic of Corona Virus Disease 2019 (COVID-19) caused by severe acute respiratory syndrome CoV-2 (SARS-CoV-2) is ongoing spread. It remains unclear whether the convalescing patients have a risk of reinfection. Rhesus macaques were rechallenged with SARS-CoV-2 during an early recovery phase from initial infection characterized by weight loss, interstitial pneumonia and systemic viral dissemination mainly in respiratory and gastrointestinal tracts. The monkeys rechallenged with the identical SARS-CoV-2 strain have failed to produce detectable viral dissemination, clinical manifestations and histopathological changes. A notably enhanced neutralizing antibody response might contribute the protection of rhesus macaques from the reinfection by SARS-CoV-2. Our results indicated that primary SARS-CoV-2 infection protects from subsequent reinfection. One Sentence SummaryNeutralizing antibodies against SARS-CoV-2 might protect rhesus macaques which have undergone an initial infection from reinfection during early recovery days.

microbiology↗

bioRxiv2020

Phenotype Prediction using a Tensor Representation and Deep Learning from Data Independent Acquisition Mass Spectrometry

A novel approach for phenotype prediction is developed for mass spectrometric data. First, the data-independent acquisition (DIA) mass spectrometric data is converted into a novel file format called "DIA tensor" (DIAT) which contains all the peptide precursors and fragments information and can be used for convenient DIA visualization. The DIAT format is fed directly into a deep neural network to predict phenotypes without the need to identify peptides or proteins. We applied this strategy to a collection of 102 hepatocellular carcinoma samples and achieved an accuracy of 96.8% in classifying malignant from benign samples. We further applied refined model to 492 samples of thyroid nodules to predict thyroid cancer; and achieved a predictive accuracy of 91.7% in an independent cohort of 216 test samples. In conclusion, DIA tensor enables facile 2D visualization of DIA proteomics data as well as being a new approach for phenotype prediction directly from DIA-MS data.

bioinformatics↗

bioRxiv2020

A dataset of speed-resolved blood perfusion and oxygen saturation in human skin response to thermal stimulation

The functional status of vessels can be determined by assessing blood perfusion. By integrating diffuse reflectance spectroscopy (DRS) and laser Doppler Flowmetry (LDF), the speed-resolved blood perfusion and blood oxygen saturation can be measured simultaneously by Enhanced Perfusion and Oxygen Saturation (EPOS). The dataset presented in this descriptor contains EPOS data recorded from a forearm point exposed to different levels of thermal stimulation, the classical LDF at control points, the R-R time series and data regarding characteristics of subjects. All data were recorded from 60 recruited healthy subjects. Half of the subjects received different levels of thermal stimulation, and half of them were blank controls. We believe that this dataset will lead to the development of local blood perfusion methods that can be used to index vessel function assessments. This publicly available dataset will be beneficial to the microcirculation evaluation.

bioengineering↗

bioRxiv2020

A single-cell analysis of the molecular lineage of chordate embryogenesis

In multicellular organisms, a single zygote develops along divergent lineages to produce distinct cell types. What governs these processes is central to the understanding of cell fate specification and stem cell engineering. Here we used the protochordate model Ciona savignyi to determine gene expression profiles of every cell of single embryos from fertilization through the onset of gastrulation and provided a comprehensive map of chordate early embryonic lineage specification. We identified 47 cell types across 8 developmental stages up to the 110-cell stage in wild type embryos and 8 fate transformations at the 64-cell stage upon FGF-MAPK inhibition. The identities of all cell types were evidenced by in situ expression pattern of marker genes and expected number of cells based on the invariant lineage. We found that, for the majority of asymmetrical cell divisions, the bipotent mother cell shows predominantly the gene signature of one of the daughter fates, with the other daughter being induced by subsequent signaling. Our data further indicated that the asymmetric segregation of mitochondria in some of these divisions does not depend on the concurrent fate inducing FGF-MAPK signaling. In the notochord, which is an evolutionary novelty of chordates, the convergence of cell fate from two disparate lineages revealed modular structure in the gene regulatory network beyond the known master regulator T/Brachyury. Comparison to single cell transcriptomes of the early mouse embryo showed a clear match of cell types at the tissue level and supported the hypothesis of developmental-genetic toolkit. This study provides a high-resolution single cell dataset to understand chordate embryogenesis and the relationship between fate trajectories and the cell lineage. HighlightsO_LITranscriptome profiles of 47 cell types across 8 stages in early chordate embryo C_LIO_LIBipotent mother in asymmetric division shows the default daughter fate C_LIO_LIModular structure of the notochord GRN beyond the known function of T C_LIO_LIInvariant lineage and manual cell isolation provide truth to trajectory analysis C_LI

developmental biology↗

bioRxiv2020

Transferrin-dependent crosstalk between the intestinal tract and commensal microbes contributes for immune tolerance

Crosstalks between gastrointestinal tract and commensal microbes regulate immune tolerance and maintain host intestinal homeostasis. However, molecular events that regulate the crosstalks remain poorly understood. Here, we show that microbial products (lipopolysaccharide, lipoteichoic acid and DNA) up-regulate host transferrin, an iron supplier of commensal bacteria, to induce hosts immune tolerance by negatively regulating toll-like receptor (TLR) signaling. Transferrin level in germ-free and broad-spectrum antibiotics-treated mice is much less than that in normal mice. Transferrin is found to silence TLR signaling complex by directly interacting with CD14, a co-receptor of many TLRs. Transferrin knock-down impaired host tolerogenic responses as well as broad-spectrum antibiotics treatment. Our findings reveal that commensal bacteria up-regulate and beneficially use host transferrin as a negative regulator of TLR signaling to shape host immunity and contribute for intestinal tolerance.

immunology↗

bioRxiv2020

Robust differentiation of human pluripotent stem cells into endothelial cells via temporal modulation of ETV2 with modified mRNA

Human induced pluripotent stem cell (h-iPSC)-derived endothelial cells (h-iECs) have become a valuable tool in regenerative medicine. However, current differentiation protocols remain inefficient and lack reliability. Here, we describe a method for rapid, consistent, and highly efficient generation of h-iECs. The protocol entails the delivery of modified mRNA encoding the transcription factor ETV2 at the intermediate mesodermal stage of differentiation. This approach reproducibly differentiated thirteen diverse h-iPSC lines into h-iECs with exceedingly high efficiency. In contrast, standard differentiation methods that relied on endogenous ETV2 were inefficient and notably inconsistent. Our h-iECs were functionally competent in many respects, including the ability to form perfused vascular networks in vivo. Importantly, timely activation of ETV2 was critical, and bypassing the mesodermal stage produced putative h-iECs with reduced expansion potential and inability to form functional vessels. Our protocol has broad applications and could reliably provide an unlimited number of h-iECs for vascular therapies.

cell biology↗

bioRxiv2020

Lower Soil Carbon Loss Due to Persistent Microbial Adaptation to Climate Warming

Soil microbial respiration is an important source of uncertainty in projecting future climate and carbon (C) cycle feedbacks. Despite intensive studies for two decades, the magnitude, direction, and duration of such feedbacks are uncertain, and their underlying microbial mechanisms are still poorly understood. Here we examined the responses of soil respiration and microbial community structure to long-term experimental warming in a temperate grassland ecosystem. Our results indicated that the temperature sensitivity of soil microbial respiration (i.e., Q10) persistently decreased by 12.0{+/-}3.7% across 7 years of warming. Integrated metagenomic and functional analyses showed that microbial community adaptation played critical roles in regulating respiratory acclimation. Incorporating microbial functional gene abundance data into a microbially-enabled ecosystem model significantly improved the modeling performance of soil microbial respiration by 5-19%, compared to the traditional non-microbial model. Model parametric uncertainty was also reduced by 55-71% when gene abundances were used. In addition, our modeling analyses suggested that decreased temperature sensitivity could lead to considerably less heterotrophic respiration (11.6{+/-}7.5%), and hence less soil C loss. If such microbially mediated dampening effects occur generally across different spatial and temporal scales, the potential positive feedback of soil microbial respiration in response to climate warming may be less than previously predicted.

ecology↗

bioRxiv2020

High-quality de novo genome assembly of Kappaphycus alvarezii based on both PacBio and HiSeq sequencing

The red algae Kappaphycus alvarezii is the most important aquaculture species in Kappaphycus, widely distributed in tropical waters, and it has become the main crop of carrageenan production at present. The mechanisms of adaptation for high temperature, high salinity environments and carbohydrate metabolism may provide an important inspiration for marine algae study. Scientific background knowledge such as genomic data will be also essential to improve disease resistance and production traits of K. alvarezii. 43.28 Gb short paired-end reads and 18.52 Gb single-molecule long reads of K. alvarezii were generated by Illumina HiSeq platform and Pacbio RSII platform respectively. The de novo genome assembly was performed using Falcon_unzip and Canu software, and then improved with Pilon. The final assembled genome (336 Mb) consists of 888 scaffolds with a contig N50 of 849 Kb. Further annotation analyses predicted 21,422 protein-coding genes, with 61.28% functionally annotated. Here we report the draft genome and annotations of K. alvarezii, which are valuable resources for future genomic and genetic studies in Kappaphycus and other algae.

genomics↗

bioRxiv2020

Selective Germline Genome Edited Pig Meninges Grafts for the Abdominal Wall Closure in Damage Control Surgery

Reconstruction of abdominal wall defects is still a big challenge in surgery, especially where there is insufficient fascia muscular or excessive tension of the defects in emergency and life-threatening scenarios. Indeed, the concept of damage control surgery has been advanced in the management of both traumatic and nontraumatic surgical settings. The strategy requires abridged surgery and quick back to intensive care units (ICU) for aggressive resuscitation. In the damage control laparotomy, patients are left with open abdomen or provisional closure of the abdomen with a planned return to the operating room for definitive surgery. So far, various techniques have been utilized to achieve early temporary abdominal closure, but there is no clear consensus on the ideal method or material for abdominal wall reconstruction. We recently successfully created the selective germline genome-edited pig (SGGEP) and here we aimed to explore the feasibility of in vivo reconstruction of the abdominal wall in a rabbit model with SGGEP meninges grafts (SGGEP-MGs). Our result showed that the SGGEP-MGs could restore the integrity of the defect very well. After 7 weeks of engraftment, there was no sign of herniation observed, the grafts were re-vascularized, and the defects were well repaired. Histologically, the boundary between the graft and the host was very well integrated and there was no strong inflammatory response. Therefore, this kind of closure could help restore the fluid and electrolyte balance and to dampen systemic inflammatory response in damge control surgery while ADM graft failed to establish re-vascularization as the same as the SGGEP-MG. It is concluded that the meninges of SGGEP could serve as a high-quality alternative for restoring the integrity of the abdominal wall, especially for damage control surgery.

synthetic biology↗

bioRxiv2020

A Generalized Discrete Dynamic Model for Human Epidemics

A discrete dynamic model for human epidemics was developed in present study. The model included major parameters as transmission strength and its decline parameters, mean incubation period, hospitalization time, non-hospitalization daily mortality, non-hospitalization daily recovery rate, and hospitalization proportion, etc. Sensitivity analysis of the model indicated the total cumulative cases significantly increased with initial transmission strength, hospitalization time. The total cumulative cases significantly decreased with transmission strengths decline and hospitalization proportion, and linearly decreased with non-hospitalization daily mortality and non-hospitalization daily recovery rate. In a certain range, the total cumulative cases significantly increased with mean incubation period. Sensitivity analysis demonstrated that dynamic change of transmission strength is one of the most important and controllable factors. In addition, reducing the delay for hospitalization is much effective in weakening disease epidemic. Non-hospitalization recovery rate is of importance for enhancing immunity to recover from the disease.

microbiology↗

bioRxiv2020

The Pathogenicity of 2019 Novel Coronavirus in hACE2 Transgenic Mice

Severe acute respiratory syndrome CoV-2 (SARS-CoV-2) caused the Corona Virus Disease 2019 (COVID-19) cases in China has become a public health emergency of international concern (PHEIC). Based on angiotensin converting enzyme 2 (ACE2) as cell entry receptor of SARS-CoV, we used the hACE2 transgenic mice infected with SARS-CoV-2 to study the pathogenicity of the virus. Weight loss and virus replication in lung were observed in hACE2 mice infected with SARS-CoV-2. The typical histopathology was interstitial pneumonia with infiltration of significant lymphocytes and monocytes in alveolar interstitium, and accumulation of macrophages in alveolar cavities. Viral antigens were observed in the bronchial epithelial cells, alveolar macrophages and alveolar epithelia. The phenomenon was not found in wild type mice with SARS-CoV-2 infection. The pathogenicity of SARS-CoV-2 in hACE2 mice was clarified and the Kochs postulates were fulfilled as well, and the mouse model may facilitate the development of therapeutics and vaccines against SARS-CoV-2.

microbiology↗

bioRxiv2020

Structural insights into secretory immunoglobulin A and its interaction with a pneumococcal adhesin

Secretory Immunoglobulin A (SIgA) is the most abundant antibody at the mucosal surface. SIgA possesses two additional subunits besides IgA: the joining chain (J-chain) and secretory component (SC). SC is the ectodomain of the polymeric immunoglobulin receptor (pIgR), which functions to transport IgA to the mucosa. The underlying mechanism of how the J-chain and pIgR/SC facilitates the assembly and secretion of SIgA remains to be understood. During the infection of Streptococcus pneumoniae, a pneumococcal adhesin SpsA hijacks SIgA and unliganded pIgR/SC to evade host defense and gain entry to human cells. How SpsA specifically targets SIgA and pIgR/SC also remains unclear. Here we report a cryo-electron microscopy structure of the Fc region of human IgA1 (Fc) in complex with J-chain and SC (Fc-J-SC), which reveals the organization principle of SIgA. We also present the structure of Fc-J-SC in complex with SpsA, which uncovers the specific interaction between SpsA and human pIgR/SC. These results advance the molecular understanding of SIgA and shed light on the pathogenesis of S. pneumoniae.

immunology↗

bioRxiv2020

A fast genetically encoded fluorescent sensor for faithful in vivo acetylcholine detection in mice, fish, worms and flies

Here we design and optimize a genetically encoded fluorescent indicator, iAChSnFR, for the ubiquitous neurotransmitter acetylcholine, based on a bacterial periplasmic binding protein. iAChSnFR shows large fluorescence changes, rapid rise and decay kinetics, and insensitivity to most cholinergic drugs. iAChSnFR revealed large transients in a variety of slice and in vivo preparations in mouse, fish, fly and worm. iAChSnFR will be useful for the study of acetylcholine in all animals.

neuroscience↗