Biology subjects

Wei, S.

Publications and source records attributed to Wei, S..

At least 91 records · Page 5Linked to original sources

bioRxiv2022

Reactive Oxygen Species-induced Protein Carbonylation Promotes Deterioration of Physiological Activity of Wheat Seeds

During the seed aging process, reactive oxygen species (ROS) can induce the carbonylation of proteins, which changes their functional properties and affects seed vigor. However, the impact and regulatory mechanisms of protein carbonylation on wheat seed vigor are still unclear. In this study, we investigated the changes in wheat seed vigor, carbonyl protein content, ROS content and embryo cell structure during an artificial aging process, and we analyzed the correlation between protein carbonylation and seed vigor. During the artificial wheat-seed aging process, the activity levels of antioxidant enzymes and the contents of non-enzyme antioxidants decreased, leading to the accumulation of ROS and an increase in the carbonyl protein content, which ultimately led to a decrease in seed vigor, and there was a significant negative correlation between seed vigor and carbonyl protein content. Moreover, transmission electron microscopy showed that the contents of protein bodies in the embryo cells decreased remarkably. We postulate that during the wheat seed aging process, an imbalance in ROS production and elimination in embryo cells leads to the carbonylation of proteins, which plays a negative role in wheat seed vigor.

physiology↗

bioRxiv2021

A model-guided pipeline for drug cardiotoxicity screening with human stem-cell derived cardiomyocytes

New therapeutic compounds go through a preclinical drug cardiotoxicity screening process that is overly conservative and provides limited mechanistic insight, leading to the misclassification of potentially beneficial drugs as proarrhythmic. There is a need to develop a screening paradigm that maintains this high sensitivity, while ensuring non-cardiotoxic compounds pass this phase of the drug approval process. In this study, we develop an in vitro-in silico pipeline using human induced stem-cell derived cardiomyocytes (iPSC-CMs) to address this problem. The pipeline includes a model-guided optimization that produces a voltage-clamp (VC) protocol to determine drug block of seven cardiac ion channels. Such VC data, along with action potential (AP) recordings, were acquired from iPSC-CMs before and after treatment with a control solution or a low-, intermediate-, or high-risk drug. We identified significant AP prolongation (a proarrhythmia indicator) in two high-risk drugs and, from the VC data, determined strong ion channel blocks that led to the AP changes. The VC data also uncovered an undocumented funny current (If) block by quinine, which we confirmed with experiments using a HEK-293 expression line. We present a new approach to cardiotoxicity screening that simultaneously evaluates proarrhythmia risk (e.g. AP prolongation) and mechanism (e.g. channel block) from iPSC-CMs.

bioengineering↗

bioRxiv2021

Identifying Upper Airway and Evaluating Adenoid in Lateral Cephalometric Radiographs of Pediatric Patients Using Image-based Deep Learning Technique

PurposeAdenotonsillar hypertrophy is considered as one of the primary causes of pediatric obstructive sleep apnea. In clinical practice, pediatric patients with potential obstructive apnea should undergo assessment of upper airway obstruction and adenotonsillar size. As lack of well-trained physicians in China, large numbers of such patients could not be accurately evaluated in time. We attempted to find a better way to assess upper airway obstruction. MethodsWe developed a computational method which may allow clinicians to trace upper airway obstruction. We utilized a Detectron2 Mask R-CNN architecture that was pretrained on ImageNet-1k dataset. We then trained it on our COCO dataset using transfer learning for segmentations of upper airway and related key structures. With the instance segmentations, we utilized a tracing algorithm developed by our own to sketch the contours of key segments. At the end, our system would use the traced landmarks to calculate the targeted clinical data. ResultsWe validated the effective-ness of the algorithm in two steps. First, we used a validation set (COCO dataset) to evaluate the segmentation performance of our system. Our system achieved a mean segmentation AP of 61.30, with airway segmentation AP of 55.64 and cranial base segmentation AP of 66.96. In addition, the AP50 was 99.49 and AP75 was 73.62. Second,we analyzed the data from our system and experts using a single rater, absolute-agreement, 2-way mixed-effects model, and got ICC value of 0.73 with 95% confident interval = 0.63-0.81. ConclusionsIn this study, we created a deep-learning based system to help clinicians evaluate upper airway in lateral cephalometric radiographs which we believe could improve clinical practice. With the evolving of technology, our system would become more integrated into medical care of OSA, freeing the clinical practitioners from repetitive tasks and enabling them to concentrate on improved patient care.

bioengineering↗

bioRxiv2021

Artificial selection of stable rhizosphere microbiota leads to heritable plant phenotype changes

Research on artificial selection of microbial community has become popular due to perspectives in improving plant and animal health1-4. However, reported results still lack consistency5-8. We hypothesized that artificial selection may provide desired outcomes provided that microbial community structure has stabilized along the selection process. In a ten-generation artificial selection experiment involving 1,800 plants, we selected rhizosphere microbiota of Brachypodium distachyon that were associated with high or low levels of leaf greenness, a proxy for plant health9. Monitoring of the rhizosphere microbiota dynamics showed strong oscillations in community structure during an initial transitory phase of five generations, with no heritability in the selected property. In the last five generations, the structure of microbial communities displayed signs of stabilization, concomitantly to the appearance of heritability in leaf greenness. Selection pressure, initially ineffective, became successful in changing the greenness index in the intended direction, especially toward high greenness values. We showed a remarkable congruence between plant traits and selected microbial community structures, highlighting two phylogenetically distinct microbial sub-communities correlating with leaf greenness, whose abundance was significantly steered by directional artificial selection. Understanding microbial community structure stabilization can thus help improve the reliability of artificial microbiota selection. Short SentenceStable microbiota selection enables trait heritability

evolutionary biology↗

bioRxiv2021

Application of an integrated computational antibody engineering platform to design SARS-CoV-2 neutralizers

As the COVID-19 pandemic continues to spread, hundreds of new initiatives including studies on existing medicines are running to fight the disease. To deliver a potentially immediate and lasting treatment to current and emerging SARS-CoV-2 variants, new collaborations and ways of sharing are required to create as many paths forward as possible. Here we leverage our expertise in computational antibody engineering to rationally design/optimize three previously reported SARS-CoV neutralizing antibodies and share our proposal towards anti-SARS-CoV-2 biologics therapeutics. SARS-CoV neutralizing antibodies, m396, 80R, and CR-3022 were chosen as templates due to their diversified epitopes and confirmed neutralization potency against SARS. Structures of variable fragment (Fv) in complex with receptor binding domain (RBD) from SARS-CoV or SARS-CoV2 were subjected to our established in silico antibody engineering platform to improve their binding affinity to SARS-CoV2 and developability profiles. The selected top mutations were ensembled into a focused library for each antibody for further screening. In addition, we convert the selected binders with different epitopes into the trispecific format, aiming to increase potency and to prevent mutational escape. Lastly, to avoid antibody induced virus activation or enhancement, we applied NNAS and DQ mutations to the Fc region to eliminate effector functions and extend half-life.

bioengineering↗

bioRxiv2021

De novo assembly, annotation, and comparative analysis of 26 diverse maize genomes

We report de novo genome assemblies, transcriptomes, annotations, and methylomes for the 26 inbreds that serve as the founders for the maize nested association mapping population. The data indicate that the number of pan-genes exceeds 103,000 and that the ancient tetraploid character of maize continues to degrade by fractionation to the present day. Excellent contiguity over repeat arrays and complete annotation of centromeres further reveal the locations and internal structures of major cytological landmarks. We show that combining structural variation with SNPs can improve the power of quantitative mapping studies. Finally, we document variation at the level of DNA methylation, and demonstrate that unmethylated regions are enriched for cis-regulatory elements that overlap QTL and contribute to changes in gene expression. One sentence summaryA multi-genome analysis of maize reveals previously unknown variation in gene content, genome structure, and methylation.

genomics↗

bioRxiv2020

Female mice are more prone to develop an addictive-like phenotype for sugar consumption

BackgroundThe concept of "sugar addiction" is gaining increasing attention in both the lay media and scientific literature. However, the concept of sugar addiction is controversial and only a few studies have attempted to determine the "addictive" properties of sugar using rigorous scientific criteria. ObjectiveHere we set out to systematically test the addictive properties of sugar in male and female mice using established paradigms and models from the drug addiction field. MethodsMale and female C57BL/6N (8-10 weeks old) were evaluated in 4 experimental procedures to study the addictive properties of sugar: (i) a drinking in the dark (DID) procedure to model sugar binging; (ii) a long-term free choice home cage drinking procedure measuring the sugar deprivation effect (SDE) following an abstinence phase; (iii) a long-term operant sugar self-administration with persistence, motivation and compulsivity measures and (iv) intracranial self-administration (ICSS). ResultsFemale mice were more vulnerable to the addictive properties of sugar than male mice, showing higher binge and long-term, excessive drinking, a more pronounced relapse-like drinking following deprivation, and higher persistence and motivation for sugar. No sex differences were seen in a compulsivity test or reward sensitivity measured using ICSS following extended sugar consumption. ConclusionThis study demonstrates the occurrence of an addictive-like phenotype for sugar in male and female mice, similar to drugs of abuse, and suggests sex-dependent differences in the development of sugar addiction.

neuroscience↗

bioRxiv2020

Single-dose ethanol intoxication causes acute and lasting neuronal changes in the brain

Alcohol intoxication at early ages is a risk factor for development of addictive behavior. To uncover neuronal molecular correlates of acute ethanol intoxication, we used stable-isotope labeled mice combined with quantitative mass spectrometry to screen over 2000 hippocampal proteins of which 72 changed synaptic abundance up to two-fold after ethanol exposure. Among those were mitochondrial proteins and proteins important for neuronal morphology, including MAP6 and Ankyrin-G. Based on these candidate proteins, we found acute and lasting molecular, cellular, and behavioral changes following a single intoxication in alcohol-naive mice. Immunofluorescence analysis revealed a shortening of axon initial segments. Longitudinal two-photon in vivo imaging showed increased synaptic dynamics and mitochondrial trafficking in axons. Knockdown of mitochondrial trafficking in dopaminergic neurons abolished conditioned alcohol preference in Drosophila. This introduces mitochondrial trafficking as a process implicated in reward learning, and highlights the potential of high-resolution proteomics to identify cellular mechanisms relevant for addictive behavior.

neuroscience↗

bioRxiv2020

Two antagonistic effect genes mediate separation of sexes in a fully dioecious plant

Plant sex determining systems and sex chromosomes are often evolutionarily young. Here, we present the early stage of sex chromosome in a fully dioecious plant, P. deltoides, by determining separate sequences of the physically small X- and Y-linked regions. Intriguingly, two Y genes are absent from the X counterpart. One gene represses female structures by producing siRNAs that block expression of a gene necessary for development of female structures, via RNA-directed DNA methylation and siRNA-guided mRNA cleavage. The other gene generates long non-coding RNA transcripts that, in males, soak up miRNAs that specifically inhibit androecium development. Transformation experiments in Arabidopsis thaliana show that the two genes affect gynoecium and androecium development independently and antagonistically. Sex determination in the poplar therefore has the properties proposed for the first steps in the evolution of dioecy in flowering plants, with two genes whose joint effects favor close linkage, as is observed in poplar.

plant biology↗

bioRxiv2020

A variant in SMOC2, inhibiting BMP signaling by competitively binding to BMPR1B, causes multiple epiphyseal dysplasia

Previously study showed that SMOC, a matricellular protein, inhibits BMP signaling downstream of its receptor via activation of mitogen-activated protein kinase (MAPK) signaling. In our study, exome sequencing revealed a missense mutation (c.1076T>G, p.Leu359Arg) in EC domain of SMOC2 in a Chinese family with multiple epiphyseal disease (MED). The pathogenicity of this SMOC2 variant was verified by Smoc2L359R/L359R knock-in mice. Of note, decreasing phosphorylation of SMAD1/5/9 was detected in growth plates and primary chondrocytes from Smoc2L359R/L359R mice. Furthermore, binding affinity of mutant SMOC2 with collagen IX and HSPG in the extracellular matrix of cartilage were reduced while binding affinity with BMPRIB was intact. In addition, in contrast to previously results, that SMOC2 cannot antagonize BMP activity in the presence of a constitutively activated BMP receptor. These results support that SMOC2 with p.Leu359Arg variant act as an antagonist of canonical BMP pathway by competitively binding with BMP receptors.

genomics↗

bioRxiv2019

The RNA helicase DDX3 induces neural crest by promoting AKT activity

Mutations in the RNA helicase DDX3 have emerged as a frequent cause of intellectual disability in humans. Because many patients carrying DDX3 mutations have additional defects in craniofacial structures and other tissues containing neural crest (NC)-derived cells, we hypothesized that DDX3 is also important for NC development. Using Xenopus tropicalis as a model, we show that DDX3 is required for normal NC induction and craniofacial morphogenesis by regulating AKT kinase activity. Depletion of DDX3 decreases AKT activity and AKT-dependent inhibitory phosphorylation of GSK3{beta}, leading to reduced levels of {beta}-catenin and Snai1, two GSK3{beta} substrates that are critical for NC induction. DDX3 function in regulating these downstream signaling events during NC induction is likely mediated by RAC1, a small GTPase whose translation depends on the RNA helicase activity of DDX3. These results suggest an evolutionarily conserved role of DDX3 in NC development by promoting AKT activity, and provide a potential mechanism for the NC-related birth defects displayed by patients harboring mutations in DDX3 and its downstream effectors in this signaling cascade.

developmental biology↗

bioRxiv2019

High-Throughput Functional Annotation of Natural Products by Integrated Activity Profiling

Determining mechanism of action (MOA) is one of the biggest challenges in natural products discovery. Here, we report a comprehensive platform that uses Similarity Network Fusion (SNF) to improve MOA predictions by integrating data from the cytological profiling high-content imaging platform and the gene expression platform FUSION, and pairs these data with untargeted metabolomics analysis for de novo bioactive compound discovery. The predictive value of the integrative approach was assessed using a library of target-annotated small molecules as benchmarks. Using Kolmogorov-Smirnov (KS) tests to compare in-class to out-of-class similarity, we found that SNF retains the ability to identify significant in-class similarity across a diverse set of target classes, and could also find target classes that were not detectable in either platform alone. This confirmed that integration of expression-based and image-based phenotypes can accurately report on MOA. Furthermore, we integrated untargeted metabolomics of complex natural product fractions with the SNF network to map biological signatures to specific metabolites. Three examples are presented where SNF coupled with metabolomics was used to directly functionally characterize natural products and accelerate identification of bioactive metabolites, including the discovery of the novel azoxy-containing biaryl compounds parkamycins A and B. Our results support SNF integration of multiple phenotypic screening approaches along with untargeted metabolomics as a powerful approach for advancing natural products drug discovery. Significance statementNew data-driven methods to aid in the discovery and biological characterization of natural products are necessary to advance the field. Assigning the mechanism of action (MOA) to novel bioactive compounds is an essential step in drug discovery and a major challenge in chemical biology. Despite technological advances in isolation, synthesis and screening strategies that make many bioactive substances readily available, in most cases their biological targets remain unknown. Additionally, a major bottleneck in natural products discovery efforts is de-replication of the large number of known compounds that predominate in crude extracts and fraction libraries. Advances in metabolomics has provided a better understanding of the constituents present in these libraries, but is not sufficient in itself to drive the discovery of novel biologically active metabolites. Here we describe an unbiased, data-driven strategy which integrates phenotypic screening with metabolomics into a single platform that provides rapid identification and functional annotation of natural products. This approach can be applied to any cohort of uncharacterized chemicals and represents a strategy that could significantly accelerate the process of drug discovery.

pharmacology and toxicology↗

bioRxiv2019

Genome analysis of the steroid-degrading denitrifying Denitratisoma oestradiolicum DSM 16959 and Denitratisoma sp. strain DHT3

Steroid hormones (androgens and estrogens) are crucial for development, reproduction, and communication of multicellular eukaryotes. The ubiquitous distribution and persistence of steroid hormones in our ecosystems have become an environmental issue due to the adverse effects on wildlife and humans upon long-term exposure. Microbial degradation is critical for the removal of steroid hormones from ecosystems. The aerobic degradation pathways for androgens and estrogens and the anaerobic degradation pathway for androgen have been studied into some details; however, the mechanism for anaerobic estrogen degradation remains completely unknown. Here, we presented the circular genomes of D. oestradiolicum DSM 16959 and Denitratisoma sp. strain DHT3, two betaproteobacteria capable of anaerobic estrogen degradation. We identified the genes involved in steroid transformation and in the anaerobic 2,3-seco pathway in both genomes. Additionally, the comparative genomic analysis revealed that genes exclusively represented in estrogen-degrading anaerobes might play a role in anaerobic estrogen catabolism.

microbiology↗

bioRxiv2019

Construction of simplified microbial consortia to degrade recalcitrant materials based on enrichment and dilution-to-extinction cultures

The capacity of microbes degrading recalcitrant materials has been extensively explored from environmental remediation to industrial applications. Although significant achievements were obtained with single strains, focus is now going toward the use of microbial consortia because of advantages in terms of functional stability and efficiency. While consortia assembly attempts were made from several known single strains, another approach consists in obtaining consortia from complex environmental microbial communities in search for novel microbial species, genes and functions. However, assembling efficient microbial consortia from complex environmental communities is far from trivial due to large diversity and biotic interactions at play. Here we propose a strategy containing enrichment and dilution-to-extinction cultures to construct simplified microbial consortia (SMC) for keratinous waste management, from complex environmental communities. Gradual dilutions were performed from a keratinolytic microbial consortium, and dilution 10-9 was selected to construct a SMC library. Further compositional analysis and keratinolytic activity assays demonstrated that microbial consortia were successfully simplified, without impacting their biodegradation capabilities. These SMC possess promising potential for efficient keratinous valorization. More importantly, this reasoning and methodology could be transferred to other topics involving screening for simplified communities for biodegradation, thus considerably broadening its application scope.\n\nImportanceMicrobial consortia have got more and more attention and extensive applications due to their potential advantages. However, a high diversity of microbes is likely to hide uncontrollable risks in practice specific to novel strains and complicated interaction networks. Exploring a convenient and efficient way to construct simplified microbial consortia is able to broaden the applied scope of microbes. This study presents the approach based on enrichment and dilution-to-extinction cultures, which gain abundance microbial consortia including some without losing efficiency from the enriched functional microbial community. The microbial interactions at the strain level were evaluated by using compositional identification and correlation analysis, which contribute to revealing the roles of microbes in the degradation process of recalcitrant materials. Our findings provide a systematic scheme to achieve optimizing microbial consortia for biodegradation from an environmental sample, could be readily applied to a range of recalcitrant materials management from environmental remediation to industrial applications.

microbiology↗

bioRxiv2019

Shared and Distinct Dysfunction of Dynamic Connectivity Networks across Schizophrenia, Bipolar Disorder and Major Depression Disorder

Dynamic functional connectivity (DFC) analysis can capture time-varying properties of connectivity and may provide further information about transdiagnostic psychopathology across major psychiatric disorders. In this study, we used resting state functional MRI and a sliding-window method to study DFC in 150 schizophrenia (SZ), 100 bipolar disorder(BD), 150 major depressive disorder (MDD), and 210 healthy controls (HC). DFC were clustered into two functional connectivity states. Significant 4-group differences in DFC were found only in state 2. Post hoc analyses showed that transdiagnostic dysconnectivity among there disorders featured decreased connectivity within visual, somatomotor, salience and frontoparietal networks. Our results suggest that decreased connectivity within both lower-order (visual and somatomotor) and higher-order (salience and frontoparietal) networks may serve as transdiagnostic marker of these disorders, and that these dysconnectivity is state-dependent. Targeting these dysconnectivity may improve assessment and treatment for patients that having more than one of these disorders at the same time.

neuroscience↗

bioRxiv2019

Bimodal Regulation of the PRC2 Complex by USP7 Underlies Melanomagenesis

Although overexpression of EZH2, a catalytic subunit of the polycomb repressive complex 2 (PRC2), is an eminent feature of various cancers, the regulation of its abundance and function remains insufficiently understood. We report here that the PRC2 complex is physically associated with ubiquitin-specific protease USP7 in melanoma cells where USP7 acts to deubiquitinate and stabilize EZH2. Interestingly, we found that USP7-catalyzed H2BK120 deubiquitination is a prerequisite for chromatin loading of PRC2 thus H3K27 trimethylation. Genome-wide analysis of the transcriptional targets of the USP7/PRC2 complex identified a cohort of genes including FOXO1 that are involved in cell growth and proliferation. We demonstrated that the USP7/PRC2 complex drives melanoma cell proliferation and tumorigenesis in vitro and in vivo. We showed that the expression of both USP7 and EZH2 elevates during melanoma progression, corresponding to a diminished FOXO1 expression, and the level of the expression of USP7 and EZH2 strongly correlates with histological grades and prognosis of melanoma patients. These results reveal a dual role for USP7 in the regulation of the abundance and function of EZH2, supporting the pursuit of USP7 as a therapeutic target for melanoma.

cell biology↗

bioRxiv2019

Genome-wide developed microsatellites reveal a weak population differentiation in the hoverfly Eupeodes corollae (Diptera: Syrphidae) across China

The hoverfly, Eupeodes corollae, is a worldwide natural enemy of aphids and a plant pollinator. To provide insights into the biology of this species, we examined its population genetic structure by obtaining 1.15-GB random genomic sequences using next-generation sequencing and developing genome-wide microsatellite markers. A total of 79,138 microsatellite loci were initially isolated from the genomic sequences; after strict selection and further testing of 40 primer pairs in eight individuals, 24 polymorphic microsatellites with high amplification rates were developed. These microsatellites were used to examine the population genetic structure of 96 individuals from four field populations collected across southern to northern China. The number of alleles per locus ranged from 5 to 13 with an average of 8.75; the observed and expected heterozygosity varied from 0.235 to 0.768 and from 0.333 to 0.785, respectively. Population genetic structure analysis showed weak genetic differentiation among the four geographical populations of E. corollae, suggesting a high rate of gene flow reflecting likely widespread migration of E. corollae in China.

molecular biology↗

bioRxiv2019

A new transgenic reporter line reveals Wnt-dependent Snail2 re-expression and cranial neural crest differentiation in Xenopus

During vertebrate embryogenesis, the cranial neural crest (CNC) forms at the neural plate border and subsequently migrates and differentiates into many types of cells. The transcription factor Snail2, which is induced by canonical Wnt signaling to be expressed in the early CNC, is pivotal for CNC induction and migration in Xenopus. However, snail2 expression is silenced during CNC migration, and its roles at later developmental stages remain unclear. We generated a transgenic X. tropicalis line that expresses enhanced green fluorescent protein (eGFP) driven by the snail2 promoter/enhancer, and observed eGFP expression not only in the pre-migratory and migrating CNC, but also the differentiating CNC. This transgenic line can be used directly to detect deficiencies in CNC development at various stages, including subtle perturbation of CNC differentiation. In situ hybridization and immunohistochemistry confirm that Snail2 is reexpressed in the differentiating CNC. Using a separate transgenic Wnt reporter line, we show that canonical Wnt signaling is also active in the differentiating CNC. Blocking Wnt signaling shortly after CNC migration causes reduced snail2 expression and impaired differentiation of CNC-derived head cartilage structures. These results suggest that Wnt signaling drives the reexpression of snail2 in the post-migratory CNC and regulates CNC differentiation.

developmental biology↗