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Yang, Z.

Publications and source records attributed to Yang, Z..

At least 613 records · Page 34Linked to original sources
bioRxiv2019

The properties of 5-methyltetrahydrofolate dehydrogenase (MthfD) and its role in the tetrahydrofolate (THF)-dependent dicamba demethylation system in Rhizorhabdus dicambivorans Ndbn-20

The herbicide dicamba is initially degrade via demethylation in Rhizorhabdus dicambivorans Ndbn-20. A gene cluster scaffold 66 containing a THF-dependent dicamba methyltransferase dmt and three THF metabolic-related genes, namely, mthfD, dhc and purU, is responsible for dicamba demethylation in this strain. However, the characteristics and functions of MthfD, Dhc and PurU have not been elucidated. In this study, MthfD was synthesized in Escherichia coli BL21(DE3) and purified as a His6-tagged protein. Purified MthfD was found to be a monomer, and exhibited 5-CH3-THF dehydrogenase activity in vitro. The Kcat and Km for 5-CH3-THF were 0.23 s-1 and 16.48 M, respectively. However, 5,10-CH2-THF reductase activity was not detected for MthfD yet. Gene disruption results showed that mthfD is essential for dicamba degradation, whereas dhc is dispensable. Our studies revealed that MthfD physiologically is a 5-CH3-THF dehydrogenase that catalyzes the irreversible dehydrogenation of 5-CH3-THF to 5,10-CH2-THF in the THF regeneration pathway during dicamba demethylation in R. dicambivorans Ndbn-20.

microbiology↗
bioRxiv2019

Multiple human adipocyte subtypes and mechanisms of their development

Human adipose tissue depots perform numerous diverse physiological functions, and are differentially linked to metabolic disease risk, yet only two major human adipocyte subtypes have been described, white and "brown/brite/beige." The diversity and lineages of adipocyte classes have been studied in mice using genetic methods that cannot be applied in humans. Here we circumvent this problem by studying the fate of single mesenchymal progenitor cells obtained from human adipose tissue. We report that a minimum of four human adipocyte subtypes can be distinguished by transcriptomic analysis, specialized for functionally distinct processes such as adipokine secretion and thermogenesis. Evidence for the presence of these adipocytes subtypes in adult humans is evidenced by differential expression of key adipokines leptin and adiponectin in isolated mature adipocytes. The human adipocytes most similar to the mouse "brite/beige" adipocytes are enriched in mechanisms that promote iron accumulation and protect from oxidative stress, and are derived from progenitors that express high levels of cytokines such as IL1B, IL8, IL11 and the IL6 family cytokine LIF, and low levels of the transcriptional repressors ID1 and ID3. Our finding of this adipocyte repertoire and its developmental mechanisms provides a high-resolution framework to analyze human adipose tissue architecture and its role in systemic metabolism and metabolic disease.

physiology↗
bioRxiv2018

Identification of TTN as a novel candidate gene for atrioventricular block in a Chinese pedigree by whole-exome sequencing

PurposeCardiovascular diseases are the most common cause of death globally. In which atrioventricular block (AVB) is a common disorder with genetic causes, but the responsible genes have not been fully identified yet. To determine the underlying causative genes involved in cardiac AVB, here we report a three-generation Chinese family with severe autosomal dominant cardiac AVB that has been ruled out as being caused by known genes mutations.\n\nMethodsWhole-exome sequencing was performed in five affected family members across three generations, and co-segregation analysis was validated on other members of this family.\n\nResultsWhole-exome sequencing and subsequent co-segregation validation identified a novel germline heterozygous point missense mutation, c.49287C>A (p.N16429K), in the titin (TTN, NM_001267550.2) gene in all 5 affected family members, but not in the unaffected family members. The point mutation is predicted to be functionally deleterious by in-silico software tools. Our finding was further supported by the conservative analysis across species.\n\nConclusionBased on this study, TTN was identified as a potential novel candidate gene for autosomal dominant AVB; this study expands the mutational spectrum of TTN gene and is the first to implicate TTN mutations as AVB disease causing in a Chinese pedigree.

genetics↗
bioRxiv2018

Nanoporous Boron Nitride for High Efficient Water Desalination

Membrane filtration processes for water desalination have been greatly improved thanks to rapid development of nanoporous 2-dimentional (2D) materials. Nanoporous graphene and molybdenum disulfide have proved to show promising properties for desalination. In this study, we detailly investigated the desalination performance of a different nanoporous 2D material, nanoporous boron nitride (BN), by Molecular Dynamics simulation. Our calculations demonstrated that nanoporous BN allows for rapid water permeability with effective salt rejection. The permeability is not only two orders of magnitude higher than existing commercial techniques but also much higher than nanoporous graphene and molybdenum disulfide membranes. We further showed that the pores with B-h edges or with N-h edges present different desalination efficiency. Compared to N-h pores, B-h pores have better desalination performance in term of higher water flux. To the best of our knowledge, nanoporous BN is the 2D material having the highest water permeability thus far while maintaining high salt rejection. Overall, our results shed light on the potential

biophysics↗
bioRxiv2018

Robust Antibacterial Activity of Tungsten Oxide (WO3-X) Nanodots

Antibacterial agents are an important tool in the prevention of bacterial infections. Inorganic materials are attractive due to their high stability under a variety of conditions compared to organic antibacterial agents. Herein tungsten oxide nanodots (WO3-X), synthesized by a simple one-pot synthetic approach, was found to exhibit efficient antibacterial capabilities. The analyses with colony-forming units (CFU) showed excellent antibacterial activity of WO3-X against both gram-negative E. coli (Escherichia coli) and gram-positive S. aureus (Staphylococcus aureus) strains. The scanning electron microscopy (SEM) and transmission electron microscopy (TEM) images revealed clear damage to the bacterial cell membranes, which was further confirmed by molecular dynamics simulations. Additionally, exposure to simulated sunlight was found to further increase germicidal activity of WO3-X nanodots - a 30-minute exposure to sunlight (combining 50 g/mL WO3-X nanodots) showed a 70% decrease in E. coli viability compared to without exposure. Electron spin resonance spectroscopy (ESR) was used to elucidate the underlying mechanism of this photocatalytic activity through the generation of hydroxyl radical species. Cell counting kit-8 (CCK-8) and the live/dead assay were further employed to evaluate the cytotoxicity of WO3-X nanodots on eukaryotic cells, which demonstrated their general biocompatibility. In all, our results suggest WO3-X nanodots have considerable potential in antibacterial applications, while also being biocompatible at large.

pharmacology and toxicology↗
bioRxiv2018

Proteome Integral Stability Alteration assay dramatically increases throughput and sensitivity in profiling factor-induced proteome changes

Various factors, including drugs as well as non-molecular influences, induce alterations in the stability of proteins in cell lysates, living cells and organisms. These alterations can be probed by applying a stability-modifying agent, such as elevated temperature, to a varying degree. As a second dimension of variation, drug concentration or factor intensity can be used. However, the corresponding analysis scheme has a low throughput and high cost. Additionally, since traditional data analysis employs curve fitting, proteins with unusual behavior are frequently ignored. The novel Proteome Integral Stability Alteration (PISA) assay avoids these issues altogether, increasing the analysis throughput by one to two orders of magnitude for unlimited number of parameter variation points. The consumption of the compound and biological material decreases by the same factor. We envision widespread use of the PISA approach in chemical biology and drug development.

cancer biology↗
bioRxiv2018

The long noncoding RNA Hand2as orchestrates heart development through regulation of precise expression of HAND2

Rigorous exploration and dissection of potential actions and effects of long noncoding RNA (lncRNA) in animals remain challenging. Here using multiple knockout mouse models and single-cell RNA sequencing, we demonstrate that the divergent lncRNA Hand2as has a key, complex modulatory effect on the expression of its neighboring gene HAND2 and subsequently on heart development and function, largely independent of Hand2as transcription and transcripts. Full-length deletion of Hand2as in mouse causes moderate yet prevalent upregulation of HAND2 in hundreds of cardiac cells, resulting in profound biological consequences, including dysregulated cardiac gene programs, congenital heart defects and perinatal lethality. We propose a cis-functional role for the Hand2as locus in dampening HAND2 expression to restrain cardiomyocyte proliferation, thereby orchestrating a balanced development of cardiac cell lineages. This study highlights the need for complementary genetic and single-cell approaches to delineate the function and primary molecular effects of an lncRNA in animals.\n\nImpact statementThe long noncoding RNA Hand2as critically controls the precise expression of its neighboring gene HAND2, thereby balancing cardiac lineages and expression programs that are essential for heart development and function.

developmental biology↗
bioRxiv2018

IL-25 induces beige fat to improve metabolic homeostasis via macrophage and innervation

Beige fat dissipates energy and functions as a defense against cold and obesity, but the underlying mechanisms remain unclear. We found that the signaling of interleukin (IL)-25 including its cognate receptor, IL-17 receptor B (IL-17RB), increased in adipose tissue upon cold and {beta}3-adrenoceptor agonist stimulation. IL-25 induced the browning effect in white adipose tissue (WAT) by releasing IL-4, 13 and promoting alternative activation of macrophages to regulate innervation, which characterized as tyrosine hydroxylase (TH) up-regulation to produce more catecholamine including norepinephrine. Blockade of IL-4R and depletion of macrophages with clodronate-loaded liposomes in vivo significantly impaired the browning of WAT. Obese mice administered with IL-25 were protected from obesity on a high-fat diet and the subsequent metabolic disorders, and the process involved the uncoupling protein 1 (UCP1)-mediated thermogenesis. In conclusion, the activation of IL-25 signaling on beige fat might play a therapeutic potential for obesity and its associated metabolic disorders.

biochemistry↗
bioRxiv2018

Single particle cryo-EM reconstruction of 52 kDa streptavidin at 3.2 Angstrom resolution

The fast development of single particle cryo-EM has made it more feasible to obtain the 3D structure of well-behaved macromolecules with molecular weight higher than 300 kDa at ~3 [A] resolution. It remains a challenge to obtain high resolution structure of molecules smaller than 100 kDa using single particle cryo-EM, mainly due to the low contrast of the molecules embedded in vitreous ice. In this work, we applied the Cs-corrector-VPP coupled cryo-EM to study 52 kDa streptavidin (SA) protein supported on a thin layer of graphene film and embedded in vitreous ice. We were able to solve both the apo-SA and biotin-bound SA at near-atomic resolution using single particle cryo-EM. We demonstrated that the method is capable to determine the structure of molecule as small as 39 kDa and potentially even smaller molecules. Furthermore, we found that using the graphene film to avoid the adsorption to the air-water interface is critical to maintain the proteins high-resolution structural information.

biophysics↗
bioRxiv2018

pyMeSHSim: an integrative python package to realize biomedical named entity recognition, normalization and comparison

SummaryComputing semantic similarity between two texts, like disease descriptions, has become important for many biomedical text mining applications. Here, we present PyMeSHSim, which is an integrative, lightweight and data-rich MeSH toolkit that recognizes biomedical named entities (bio-NEs) from texts, maps the bio-NEs to the controlled vocabulary MeSH and measures the semantic similarity between the MeSH terms.\n\nAvailabilityPackages source code and test datasets are available under the GPLv3 license at https://github.com/luozhhub/pyMeSHSim\n\nContactzhen-xia.chen@mail.hzau.edu.cn or zhy630@mail.hzau.edu.cn

bioinformatics↗
bioRxiv2018

Conformational states control Lck switching between free and confined diffusion modes in T cells

T cell receptor (TCR) phosphorylation by Lck is an essential step in T cell activation. It is known the conformational states of Lck control enzymatic activity; however, the underlying principles of how Lck finds its substrate in the plasma membrane remain elusive. Here, single-particle tracking is paired with photoactivatable localization microscopy (sptPALM) to observe the diffusive modes of Lck in the plasma membrane. Individual Lck molecules switched between free and confined diffusion in resting and stimulated T cells. Conformational state, but not partitioning into membrane domains, caused Lck confinement as open conformation Lck was more confined than closed. Further confinement of kinase-dead versions of Lck suggests that Lck interacts with open active Lck to cause confinement, irrespectively of kinase activity. Our data supports a model that confined diffusion of open Lck results in high local phosphorylation rates and closed Lck diffuses freely to enable wide-range scanning of the plasma membrane.

immunology↗
bioRxiv2018

The ghr-miR164 and GhNAC100 module participates in cotton plant defence against Verticillium dahliae

Previous reports have shown that many miRNAs were identified at the early induction stage during which Verticillium dahliae localizes at the root surface. In this study, we constructed two sRNA libraries of cotton root responses to this fungus at the later induction stage when the pathogen enters the root vascular tissue. We identified 71 known miRNAs and 378 novel miRNAs from two pathogen-induced sRNAs and the control libraries. Combined with degradome and sRNA sequencing, 178 corresponding miRNA target genes were identified, in which 40 target genes from differentially expressed miRNAs were primarily associated with oxidation-reduction and stress responses. More importantly, we characterized the ghr-miR164-GhNAC100 module in the response of the plant to V dahliae infection. A GUS fusion reporter showed that ghr-miR164 directly cleaved the mRNA of GhNAC100 in the post-transcriptional process. ghr-miR164-silencing increased the resistance of the plant to this fungus, while the knockdown of GhNAC100 elevated the susceptibility of the plant, indicating that ghr-miR164-GhNAC100 modulates plant defence through the post-transcriptional regulation. Our data documented that there are numerous miRNAs at the later induction stage that participate in the plant response to V. dahliae, suggesting that miRNAs play important roles in plant resistance to vascular disease.\n\nHighlightAccording to degradome and sRNA sequencings of cotton root in responses to Verticillium dahliae at the later induction stage, many miRNAs and corresponding targets including ghr-miR164-GhNAC100 module participate plant defence.

molecular biology↗
bioRxiv2018

Bayesian Estimation of Species Divergence Times Using Correlated Quantitative Characters

Discrete morphological data have been widely used to study species evolution, but the use of quantitative (or continuous) morphological characters is less common. Here, we implement a Bayesian method to estimate species divergence times using quantitative characters. Quantitative character evolution is modelled using Brownian diffusion with character correlation and character variation within populations. Through simulations, we demonstrate that ignoring the population variation (or population "noise") and the correlation among characters leads to biased estimates of divergence times and rate, especially if the correlation and population noise are high. We apply our new method to the analysis of quantitative characters (cranium landmarks) and molecular data from carnivoran mammals. Our results show that time estimates are affected by whether the correlations and population noise are accounted for or ignored in the analysis. The estimates are also affected by the type of data analysed, with analyses of morphological characters only, molecular data only, or a combination of both; showing noticeable differences among the time estimates. Rate variation of morphological characters among the carnivoran species appears to be very high, with Bayesian model selection indicating that the independent-rates model fits the morphological data better than the autocorrelated-rates model. We suggest that using morphological continuous characters, together with molecular data, can bring a new perspective to the study of species evolution. Our new model is implemented in the MCMCtree computer program for Bayesian inference of divergence times.

evolutionary biology↗
bioRxiv2018

Gating TrkB switch by methylglyoxal enables GLO1 as a target for depression

The endogenous metabolite methylglyoxal (MGO) has recently emerged as a potential mediator of psychiatric disorders, such as anxiety and depression, but its precise mechanism of action remains poorly understood. Here, we find that MGO concentrations are decreased in the prefrontal cortex and hippocampus in rats subjected to chronic stress, and low-dose MGO treatment remarkedly enhances resilience to stress and alleviates depression-like symptoms. This effect is achieved by MGOs promotion on the synaptic plasticity in prefrontal cortex and hippocampus. Both in vitro and in vivo experiments show that MGO provokes the dimerization and autophosphorylation of TrkB and the subsequent activation of downstream Akt/CREB signaling, which leads to a rapid and sustained expression of brain-derived neurotrophic factor (BDNF). We further demonstrate that MGO directly binds to the extracellular domain of TrkB, but not its intracellular domain. In addition, we also identify a natural product luteolin and its derivative lutD as potent inhibitors of Glyoxalase 1 and validate their antidepressant effects in chronic stress rat models. The antidepressant role of endogenous MGO provides a new basis for the understanding and therapeutic intervention design for stress-associated mental disorders.

neuroscience↗
bioRxiv2018

Asparagine availability is an essential limiting factor for poxvirus protein synthesis

Virus actively interfaces with host metabolism because viral replication relies on host cells to provide nutrients and energy. For efficient viral replication in culture, vaccinia virus (VACV; the prototype poxvirus) prefers glutamine to glucose, to the extent that in glutamine-free medium, VACV replication is inefficient. Remarkably, VACV replication can be fully rescued from glutamine depletion by asparagine supplementation. By global metabolic profiling, genetic and chemical intervening of asparagine supply, we provide evidence demonstrating that the requirement of asparagine for efficient viral replication accounts for VACVs preference of glutamine to glucose, rather than because glutamine is superior to glucose in feeding the tricarboxylic acid (TCA) cycle. Further, we show that asparagine availability is a critical factor for efficient viral protein synthesis. Our study highlights that the asparagine metabolism, whose regulation has been evolutionarily tailored in mammalian cells, presents a critical barrier to poxvirus replication, suggesting new directions of anti-viral strategy development.

microbiology↗
bioRxiv2018

The N-end rule E3 ligase UBR2 activates Nlrp1b inflammasomes

Innate immunity relies on the formation of different inflammasomes to initiate immune responses. The recognition of diverse infection and other danger signals by innate immune receptors trigger caspase-1 activation that induces pyroptosis. Anthrax lethal factor (LF) is a secreted bacterial protease that known to potently activate Nlrp1b inflammasomes in mouse macrophages, but the molecular mechanism underlying LF-induced Nlrp1b activation remains unknown. We here carried out both a mouse genome-wide siRNA screen and a CRISPR/Cas9 knockout screen seeking to identify genes that participate in Nlrp1b activation triggered by LF treatment. We found that the N-end rule pathway E3 ligase UBR2 is required for Nlrp1b activation and a ubiquitin conjugating E2 enzyme E2O is also involved in this process via its physically interaction with UBR2. We show that LF triggers activation of Nlrp1b by initiating the degradation of the N-terminal fragment of Nlrp1b itself that produced via an auto-cleavage process. This study deepens our understanding of innate immunity defense against bacterial infection by elucidating the functional role of UBR2-mediated N-end rule pathway in LF-induced Nlrp1b activation.

immunology↗
bioRxiv2018

Diagnostic Whole Exome Sequencing in Patients with Short Stature

Short stature is among the most common reasons for children being referred to the pediatric endocrinology clinics. The cause of short stature is broad, in which genetic factors play a substantial role, especially in primary growth disorders. However, identifying the molecular causes for short stature remains as a challenge because of the high heterogeneity of the phenotypes. Here, whole exome sequencing (WES) was used to identify the genetic causes of short stature with unknown etiology for 20 patients aged from 1 to 16 years old. The genetic causes of short stature were identified in 9 of the 20 patients, corresponding to a molecular diagnostic rate of 45%. Notably, in 2 of the 9 patients identified with genetic causes, the diagnosed diseases based on WES are different from the original clinical diagnosis. Our results highlight the clinical utility of WES in the diagnosis of rare, high heterogeneity disorders.

genetics↗