Biology subjects

Zhou, X.

Publications and source records attributed to Zhou, X..

At least 451 records · Page 25Linked to original sources

bioRxiv2022

Structural basis of human PRPS2 filaments

PRPP synthase (PRPS) transfers the pyrophosphate groups from ATP to ribose-5-phosphate to produce 5-phosphate ribose-1-pyrophosphate (PRPP), a key intermediate in the biosynthesis of several metabolites including nucleotides, dinucleotides and some amino acids. There are three PRPS isoforms encoded in human genome. While hPRPS1 and hPRPS2 are expressed in most tissues, hPRPS3 is exclusively expressed in testis. Although hPRPS1 and hPRPS2 share 95% sequence identity, hPRPS2 has been shown to be less sensitive to allosteric inhibition and specifically upregulated in certain cancers in the translational level. Recent studies demonstrate that PRPS can form a subcellular compartment termed the cytoophidium in multiple organisms across prokaryotes and eukaryotes. Forming the cytoophidium is considered as a distinctive mechanism involving the polymerization of the protein. In order to investigate the function and molecular mechanism of hPRPS2 polymerization, we solve the polymer structure of hPRPS2 at 3.08[A] resolution using cryo-Electron Microscopy (cryo-EM). hPRPS2 hexamers stack into polymers in the conditions with the allosteric/competitive inhibitor ADP. The binding modes of ADP at the canonical allosteric site and at the catalytic active site are clearly determined. A point mutation disrupting the inter-hexamer interaction prevents hPRPS2 polymerization and results in significantly reduced catalytic activity. Our findings suggest that the regulation of hPRPS2 polymer is distinct from E. coli PRPS polymer and provide new insights to the regulation of hPRPS2 with structural basis.

biochemistry↗

bioRxiv2022

The global distribution and environmental drivers of the soil antibiotic resistome

BackgroundLittle is known about the global distribution and environmental drivers of key microbial functional traits such as antibiotic resistance genes (ARGs). Soils are one of Earths largest reservoirs of ARGs, which are integral for soil microbial competition, and have potential implications for plant and human health. Yet, their diversity and global patterns remain poorly described. Here, we analyzed 285 ARGs in soils from 1012 sites across all continents, and created the first global atlas with the distributions of topsoil ARGs. ResultsWe show that ARGs peaked in high latitude cold and boreal forests. Climatic seasonality and mobile genetic elements, associated with the transmission of antibiotic resistance, were also key drivers of their global distribution. Dominant ARGs were mainly related to multidrug resistance genes and efflux pump machineries. We further pinpointed the global hotspots of the diversity and proportions of soil ARGs. ConclusionsTogether, our work provides the foundation for a better understanding of the ecology and global distribution of the environmental soil antibiotic resistome.

ecology↗

bioRxiv2022

Chaperone-mediated Autophagy Deficiency Reprograms Cancer Metabolism Via TGFβ Signaling to drive Mesenchymal Tumor Growth

The role of chaperone-mediated autophagy (CMA) in cancer initiation and progression is not well understood due to the lack of a loss-of-function cancer models of LAMP2A, the key regulator of this process. Here, by generating an isoform-specific knockout of LAMP2A, we show that CMA deficiency promotes proliferation and tumor growth in human cancers of mesenchymal origin. Accordingly, we observed that LAMP2A diminishes in metastatic lesions compared to matched primary human tumors from the same patients. Loss of CMA enhanced TGF{beta} signaling in tumors, rewired the tumor metabolome to promote anabolic pathways and mitochondrial metabolism, meeting the metabolic requirements of rapid growth. Mechanistically, we show that TGF{beta}R2 enhances the enzymatic activity of glucose-6-phosphate dehydrogenase (G6PD), the rate-limiting enzyme of the pentose phosphate pathway (PPP), to promote the generation of nucleotides. Consequently, pharmacological inhibition of TGF{beta}-signaling in LAMP2A-KO cells suppresses G6PD activity, mitochondrial metabolism, and proliferation to WT levels. Conversely, pharmacological inhibition of mitochondrial metabolism suppressed LAMP2A-KO driven proliferation. Overall, our study provides a molecular mechanism on the CMAs tumor-suppressive function by connecting two important oncogenic pathways, the TGF{beta} signaling and PPP metabolism, to the loss-of-function LAMP2A in mesenchymal cancer types.

cancer biology↗

bioRxiv2022

The role of proton in a eukaryotic zinc transporter

Zinc transporter 8 (ZnT8) is mainly expressed in pancreatic islet {beta} cells and is responsible for H+-coupled uptake (antiport) of Zn2+ into the lumen of insulin secretory granules. Structures of human ZnT8 and its prokaryotic homolog YiiP have provided structural basis for constructing a plausible transport cycle for Zn2+. However, the mechanistic role that protons play in the transport process remains unclear. Here we present a lumen-facing cryo-EM structure of ZnT8 from Xenopus tropicalis (xtZnT8) in the presence of Zn2+ at a luminal pH (5.5). Compared to a Zn2+-bound xtZnT8 structure at a cytosolic pH (7.5), the low-pH structure displays an empty transmembrane Zn2+-binding site with a disrupted coordination geometry. Combined with a Zn2+-binding assay our data suggest that protons may disrupt Zn2+ coordination at the transmembrane Zn2+-binding site in the lumen-facing state, thus facilitating Zn2+ release from ZnT8 into the lumen.

biochemistry↗

bioRxiv2022

Rapid Regulation of Local Temperature and TRPV1 Ion Channels with Wide-Field Plasmonic Thermal Microscopy

Plasmonic absorption of light can create significant local heat and has become a promising tool for rapid temperature regulation in diverse fields, from biomedical technology to optoelectronics. Current plasmonic heating usually relies on specially designed nanomaterials randomly distributed in the space and hardly provides uniform temperature regulation in a wide field. Herein we report a rapid temperature regulation strategy on a plain gold-coated glass slip using the plasmonic scattering microscopy, which can be referred to as wide-field plasmonic thermal microscopy (W-PTM). We calibrated the W-PTM by monitoring the phase transition of the temperature-sensitive polymer solutions, showing that it can provide a temperature regulation range of 33-80 {degrees}C. Moreover, the W-PTM provides imaging capability, thus allowing the statistical analysis of the phase-transitioned polymeric nanoparticles. Finally, we demonstrated that W-PTM can be used for noninvasive and local regulation of the transient receptor potential vanilloid 1 (TRPV1) ion channels in the living cells, which can be monitored by simultaneous fluorescence imaging of calcium influx. With the nondestructive local temperature-regulating and concurrent fluorescence imaging capability, we anticipate that W-PTM can be a powerful tool to study cellular activities associated with cellular membrane temperature changes.

bioengineering↗

bioRxiv2022

Loss of growth differentiation factor 9 causes an arrest of early folliculogenesis in zebrafish - a novel insight into its action mechanism

Growth differentiation factor 9 (GDF9) is the best characterized growth factor released by the oocyte; however, most information about GDF9 functions comes from studies in the mouse model. In this study, we created a mutant for Gdf9 gene (gdf9-/-) in zebrafish using TALEN approach. The loss of Gdf9 caused a complete arrest of follicle development at primary growth (PG) stage. These follicles eventually degenerated, and all mutant females gradually changed to males through sex reversal, which could be prevented by mutation of the male-promoting gene dmrt1. Interestingly, the phenotypes of gdf9-/- could be rescued by mutation of inhibin (inha-/-) but not estradiol, suggesting a potential role for the activin-inhibin system in Gdf9 actions. In gdf9 null follicles, activin {beta}Aa (inhbaa) expression decreased dramatically; however, its expression rebounded in the double mutant (gdf9-/-;inha-/-). These results clearly indicate that although endocrine hormones such as follicle-stimulating hormone (FSH) are important for folliculogenesis, the activation of PG follicles requires intrinsic factors from the oocyte, such as Gdf9, which in turn works on the neighboring follicle cells to trigger follicle activation, probably via activins.

developmental biology↗

bioRxiv2022

Insulin signaling and extended longevity in ants

In most organisms, the cost of reproduction is a shorter lifespan. However, the reproductive caste in eusocial insect species (queen) exhibits an extraordinarily longer lifespan than non-reproductive castes (workers) despite having a similar genome, thus contradicting the aging dogma. In the absence of the queen, Harpegnathos saltator ants can undergo a caste switch from workers to reproductive pseudo-queens (gamergates). Gamergates exhibit a dramatically prolonged lifespan. When placed in the presence of a reproductive, they revert to worker status and their lifespan is then shortened accordingly. To understand this unique relationship between reproduction and longevity, we analyzed tissue-specific gene expression between castes. Insulin is upregulated in the gamergate brain that leads to oogenesis, but surprisingly correlates with extended longevity. This correlates with increased lipid synthesis and elevated production of vitellogenin in the fat body, which are both transported to the egg. We show that the production of vitellogenin in the fat body is due to the systemic activation of the MAPK branch of the insulin/IGF signaling (IIS)-pathway. In contrast, reduced expression of insulin receptors in the fat body of gamergates and the production in their developing ovary of an anti-insulin (Imp-L2) lead to the downregulation of the AKT/FOXO branch of the IIS-signaling pathway in the fat body, and to the dramatically extended longevity. This reveals a dual-pathway mechanism that reconciles increased longevity in the context of active reproduction in eusocial insects. One Sentence SummaryInsulin-dependent reproduction in ants correlates with extended longevity through insulin inhibition by anti-insulin Imp-L2.

physiology↗

bioRxiv2022

Structural basis of the M-N protein interaction in a SARS-COV-2-related Betacoronavirus

The membrane (M) protein is the most abundant structural protein of coronaviruses including SARS-COV-2 and plays a central role in virus assembly through its interaction with various partner proteins. However, mechanistic details about how M protein interacts with others remain elusive due to lack of high-resolution structures. Here, we present the first crystal structure of a coronavirus M protein from Pipistrellus bat coronavirus HKU5 (batCOV5-M), which is closely related to SARS-COV-2 M protein. Furthermore, an interaction analysis indicates that the carboxy-terminus of the batCOV5 nucleocapsid (N) protein mediates its interaction with batCOV5-M. Combined with a computational docking analysis an M-N interaction model is proposed, providing insight into the mechanism of M protein-mediated protein interactions.

biophysics↗

bioRxiv2022

Multiplexed protein detection and parallel binding kinetics analysis with label-free digital single-molecule counting

Multiplexed protein detection is critical for improving the drug and biomarkers screening efficiency. Here we show that multiplexed protein detection and parallel protein interaction analysis can be realized by evanescent scattering microscopy with label-free digital single-molecule counting. We implemented an automatic single-molecule counting strategy with high temporal resolution to precisely determine the binding time, which improves the counting efficiency and accuracy. We show that digital single-molecule counting can recognize proteins with different molecular weights, thus making it possible to monitor the protein binding processes in the solution by real time tracking the numbers of free and bound proteins landing on the sensor surface. Furthermore, we show that this strategy can simultaneously analyze the kinetics of two different protein interaction processes on the surface and in the solution. This work may pave a way to investigate complicated protein interactions, such as the competition of biomarker-antibody binding in biofluid with biomarker-protein binding on the cellular membrane.

biochemistry↗

bioRxiv2022

SARS-CoV-2 impacts the transcriptome and epigenome at the maternal-fetal interface in pregnancy

During pregnancy, the maternal-fetal interface plays vital roles in fetal development. Its disruption is frequently found in pregnancy complications. Recent works show increased incidences of adverse pregnancy outcomes in COVID-19 patients; however, the mechanism remains unclear. Here, we analyzed the molecular impacts of SARS-CoV-2 infection on the maternal-fetal interface. Generating bulk and single-nucleus transcriptomic and epigenomic profiles from COVID-19 patients and control samples, we discovered aberrant immune activation and angiogenesis patterns in patients. Surprisingly, retrotransposons were dysregulated in specific cell types. Notably, reduced enhancer activities of LTR8B elements were functionally linked to the downregulation of Pregnancy-Specific Glycoprotein genes in syncytiotrophoblasts. Our findings revealed that SARS-CoV-2 infection induced significant changes to the epigenome and transcriptome at the maternal-fetal interface, which may be associated with pregnancy complications. One-Sentence SummaryPregnant COVID-19 patients show placental epigenetic and transcriptional changes, associated with adverse pregnancy outcomes.

genomics↗

bioRxiv2022

Representing linguistic communicative goals in the premotor cortex

Linguistic communication is often regarded as an action conveying the speakers communicative goal to the addressee. With both correlational (an fMRI study) and causal (a lesion study) evidence, we demonstrated that communicative goals are represented in human premotor cortex. Participants read scripts each containing a sentence said by the speaker with a goal of either a promise, a request, or a reply. The fMRI results showed that the premotor cortex represented more information on communicative goals than the perisylvian language regions. The lesion study results showed that, relative to healthy controls, the understanding of communicative goals was impaired in patients with lesions in the premotor cortex, whereas no reliable difference between the healthy controls and lesion controls. These findings convergently suggest that the premotor cortex is crucial for representing the goals conveyed by language, supporting the theoretical view that linguistic communication can be seen as a goal-directed action.

neuroscience↗

bioRxiv2022

A comprehensive investigation of statistical and machine learning approaches for predicting complex human diseases on genomic variants

BackgroundQuantifying an individuals risk for common diseases is an important goal of precision health. The polygenic risk score (PRS), which aggregates multiple risk alleles of candidate diseases, has emerged as a standard approach for identifying high-risk individuals. A variety of tools have been developed to implement PRS. However, benchmarks for comparatively evaluating the performance of these different methods and for assessing their potential to guide future clinical applications are lacking. ResultsWe systematically validated and compared thirteen statistical methods, five machine learning models and two ensemble models using simulated data, twenty-two common diseases with internal training sets and four diseases with external summary statistics from the UK Biobank resource. The effects of disease heritability, single nucleotide polymorphism (SNP) effect size and sample size are evaluated using simulated data. We also investigated the correlations between methods and their standard deviations of different diseases. ConclusionsIn general, statistical methods outperform machine learning models, and ensemble models, such as Super Learner, generally perform the best for most situations. We observed the correlations were relatively high if the methods were from the same category and the external summary statistics from large cohort GWAS could decrease the standard deviation of method correlations. By varying three factors in the simulated data, we also identified that disease heritability had a strong effect on the predictive performance of individual methods. Both the number and effect sizes of risk SNPs are important; and while sample size strongly influences the performance of machine learning models, but not statistical methods.

bioinformatics↗

bioRxiv2022

Simultaneous and sequential multi-species coronavirus vaccination

Although successful COVID-19 vaccines have been developed, multiple pathogenic coronavirus species exist, urging for development of multi-species coronavirus vaccines. Here we developed prototype LNP-mRNA vaccine candidates against SARS-CoV-2 (Delta variant), SARS-CoV and MERS-CoV, and test how multiplexing of these LNP-mRNAs can induce effective immune responses in animal models. A triplex scheme of LNP-mRNA vaccination induced antigen-specific antibody responses against SARS-CoV-2, SARS-CoV and MERS-CoV, with a relatively weaker MERS-CoV response in this setting. Single cell RNA-seq profiled the global systemic immune repertoires and the respective transcriptome signatures of multiplexed vaccinated animals, which revealed a systemic increase in activated B cells, as well as differential gene expression signatures across major adaptive immune cells. Sequential vaccination showed potent antibody responses against all three species, significantly stronger than simultaneous vaccination in mixture. These data demonstrated the feasibility, antibody responses and single cell immune profiles of multi-species coronavirus vaccination. The direct comparison between simultaneous and sequential vaccination offers insights on optimization of vaccination schedules to provide broad and potent antibody immunity against three major pathogenic coronavirus species. One sentence summaryMultiplexed mRNA vaccination in simultaneous and sequential modes provide broad and potent immunity against pathogenic coronavirus species.

immunology↗

bioRxiv2022

The mechanism underlying redundant functions of the YTHDF proteins

The YTH N6-methyladenosine RNA binding proteins (YTHDFs) mediate the functional effects of N6-methyladenosine (m6A) on RNA. Recently, a report proposed that all YTHDFs work redundantly to facilitate RNA decay, raising questions about the exact functions of individual YTHDFs, especially YTHDF1 and YTHDF2. We show that YTHDF1 and YTHDF2 differ in their low-complexity domains (LCDs) and exhibit different behaviors in condensate formation and subsequent physiological functions. Biologically, we also find that the global stabilization of RNA after depletion of all YTHDFs is driven by increased P-body formation and is not strictly m6A dependent.

cell biology↗

bioRxiv2022

FoxP3-mediated blockage of ryanodine receptor 2 is the molecular basis for the contact-based suppression by regulatory T cells

The suppression mechanism of regulatory T cells is an intensely investigated topic. As our focus has shifted towards a model centered on indirect inhibition of dendritic cells, a universally applicable effector mechanism controlled by FoxP3 expression has not been found. Here, we report that FoxP3 blocks the transcription of ER Ca2+-release channel ryanodine receptor 2. Reduced RyR2 shuts down basal Ca2+ oscillation in Tregs, which reduces m-Calpain activities that is needed for T cells to disengage from DCs, suggesting a persistent blockage of DC antigen presentation. RyR2 deficiency renders the CD4+ T cell pool to become immune suppressive, and behave in the same manner as FoxP3+ Tregs in viral infection, asthma, hypersensitivity, colitis and tumor development. In the absence of FoxP3, RyR2-deficient CD4+ T cells rescue the systemic autoimmunity associated with Scurfy mice. Therefore, FoxP3-mediated Ca2+ signaling inhibition may be a central effector mechanism of Treg immune suppression. One Sentence SummaryCalcium channel RyR2 dictates Treg adhesion-based suppression

immunology↗

bioRxiv2022

Neurocomputational evidence that conflicting prosocial motives guide distributive justice

In the history of humanity, most conflicts within and between societies have originated from perceived inequality in resource distribution. How humans achieve and maintain distributive justice has therefore been an intensely studied issue. However, most research on the corresponding psychological processes has focused on inequality aversion and has been largely agnostic of other motives that may either align or oppose this behavioral tendency. Here we provide behavioral, computational, and neuroimaging evidence that distribution decisions are guided by three distinct motives - inequality aversion, harm aversion, and rank reversal aversion - that interact and in fact can also deter individuals from pursuing equality. At the neural level, we show that these three motives are encoded by separate neural systems, compete for representation in various brain areas processing equality and harm signals, and are integrated in the striatum, which functions as a crucial hub for translating the motives to behavior. Our findings provide a comprehensive framework for understanding the cognitive and biological processes by which multiple prosocial motives are coordinated in the brain to guide redistribution behaviors. This framework enhances our understanding of the brain mechanisms underlying equality-related behavior, suggests possible neural origins of individual differences in social preferences, and provides a new pathway to understand the cognitive and neural basis of clinical disorders with impaired social functions.

neuroscience↗

bioRxiv2022

Allosteric inhibition of PRPS is moderated by filamentous polymerization

Phosphoribosyl pyrophosphate (PRPP) is an important intermediate for the biosynthesis of purine and pyrimidine nucleotides, histidine, tryptophan, and cofactors NAD and NADP. Abnormal regulation of PRPP synthase (PRPS) has been associated with human disorders including Arts syndrome, retinal dystrophy and gouty arthritis. Recent studies have revealed that PRPS can form filamentous cytoophidia in prokaryotes and eukaryotes. Here we resolve two distinct filament structures of E. coli PRPS at near-atomic resolution under Cryo-EM. Formation of two types of filaments is controlled by the binding of different ligands. While the type A filament attenuates the allosteric inhibition of PRPS by ADP, the type B filament enhances the inhibition. In addition, a novel conformation of the regulatory flexible loop of PRPS was found occupying the ATP binding site. AMP/ADP bound at a noncanonical allosteric site interacts with the regulatory flexible loop and facilitates the binding of ATP. Our findings not only reveal molecular mechanisms of the regulation of PRPS with structural basis, but also suggest a distinctive bidirectional regulatory system for PRPP production via PRPS polymerization.

biochemistry↗

bioRxiv2022

Statistical analysis of spatially resolved transcriptomic data by incorporating multi-omics auxiliary information

Effective control of false discovery rate is key for multiplicity problems. Here, we consider incorporating informative covariates from external datasets in the multiple testing procedure to boost statistical power while maintaining false discovery rate control. In particular, we focus on the statistical analysis of innovative high-dimensional spatial transcriptomic data while incorporating external multi-omics data that provide distinct but complementary information to the detection of spatial expression patterns. We extend OrderShapeEM, an efficient covariate-assisted multiple testing procedure that incorporates one auxiliary study, to make it permissible to incorporate multiple external omics studies, to boost statistical power of spatial expression pattern detection. Specifically, we first use a recently proposed computationally efficient statistical analysis method, spatial pattern recognition via kernels, to produce the primary test statistics for spatial transcriptomic data. Afterwards, we construct the auxiliary covariate by combining information from multiple external omics studies, such as bulk or single-cell RNA-seq data and genome wise association study data, using the Cauchy combination rule. Finally, we extend and implement the integrative analysis method OrderShapeEM on the primary p-values along with auxiliary data incorporating multi-omics information for efficient covariate-assisted spatial expression analysis. We conduct a series of realistic simulations to evaluate the performance of our method with known ground truth. Four case studies in mouse olfactory bulb, mouse cerebellum, human breast cancer and human heart tissues further demonstrate the substantial power gain of our method in detecting genes with spatial expression patterns compared to existing classic approaches that do not utilize any external information.

bioinformatics↗