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Hu, Y.

Publications and source records attributed to Hu, Y..

At least 433 records · Page 24Linked to original sources

Testing microbiome associations with censored survival outcomes at both the community and individual taxon levels

BackgroundFinding microbiome associations with possibly censored survival times is an important problem, especially as specific taxa could serve as biomarkers for disease prognosis or as targets for therapeutic interventions. The two existing methods for survival outcomes, MiRKAT-S and OMiSA, are restricted to testing associations at the community level and do not provide results at the individual taxon level. An ad hoc approach testing each taxon with a survival outcome using the Cox proportional hazard model may not perform well in the microbiome setting with sparse count data and small sample sizes. MethodsWe have previously developed the linear decomposition model (LDM) that unifies community-level and taxon-level tests into one framework. Here we extend the LDM to test survival outcomes. We propose to use the Martingale residuals or the deviance residuals obtained from the Cox model as continuous covariates in the LDM. We further construct tests that combine the results of analyzing each set of residuals separately. Finally, we extend PERMANOVA, the most commonly used distance-based method for testing community-level hypotheses, to handle survival outcomes in a similar manner. ResultsUsing simulated data, we showed that the LDM-based tests preserved the false discovery rate for testing individual taxa and had good sensitivity. The LDM-based community-level tests and PERMANOVA-based tests had comparable or better power than MiRKAT-S and OMiSA. An analysis of data on the association of the gut microbiome and the time to acute graft-versus-host disease revealed several dozen associated taxa that would not have been achievable by any community-level test, as well as improved community-level tests by the LDM and PERMANOVA over those obtained using MiRKAT-S and OMiSA. Availability and ImplementationThe new methods described here have been added to our R package LDM, which is available on GitHub at https://github.com/yijuanhu/LDM.

bioinformatics↗

Chimeric mRNA based COVID-19 vaccine elicits potent neutralizing antibodies and protection against Omicron and Delta

The emerging SARS-CoV-2 variants of concern (VOCs) exhibit enhanced transmission and immune escape, reducing the efficacy and effectiveness of the two FDA-approved mRNA vaccines. Here, we explored various strategies to develop novel mRNAs vaccines to achieve safer and wider coverage of VOCs. Firstly, we constructed a cohort of mRNAs that feature a furin cleavage mutation in the spike (S) protein of predominant VOCs, including Alpha (B.1.1.7), Beta (B.1.351), Gamma (P.1) and Delta (B.1.617.2). Not present in the mRNA vaccines currently in use, the mutation abolished the cleavage between the S1 and S2 subunits, potentially enhancing the safety profile of the immunogen. Secondly, we systematically evaluated the induction of neutralizing antibodies (nAb) in vaccinated mice, and discovered that individual VOC mRNAs elicited strong neutralizing activity in a VOC-specific manner. Thirdly, the IgG produced in mice immunized with Beta-Furin and Washington (WA)-Furin mRNAs showed potent cross-reactivity with other VOCs, which was further corroborated by challenging vaccinated mice with the live virus of VOCs. However, neither WA-Furin nor Beta-Furin mRNA elicited strong neutralizing activity against the Omicron variant. Hence, we further developed an Omicron-specific mRNA vaccine that restored protection against the original and the sublineages of Omicron variant. Finally, to broaden the protection spectrum of the new Omicron mRNA vaccine, we tested the concept of bivalent immunogen. Instead of just fusing two RBDs head-to-tail, we for the first time constructed an mRNA-based chimeric immunogen by introducing the RBD of Delta variant into the entire S antigen of Omicron. The resultant chimeric mRNA was capable of inducing potent and broadly acting nAb against Omicron (both BA.1 and BA.2) and Delta, which paves the way to develop new vaccine candidate to target emerging variants in the future.

immunology↗

Transcranial photobiomodulation enhances visual working memory capacity in humans

Transcranial photobiomodulation (tPBM) is a novel and noninvasive intervention, which has shown promise for improving cognitive performances. Whether tPBM can modulate brain activity and thereby enhance working memory (WM) capacity in humans remains unclear. In this study, we delivered double-blind and sham-control tPBM with different wavelengths to the prefrontal cortex (PFC) in 90 healthy participants and conducted four electroencephalography (EEG) experiments to investigate whether individual visual working memory capacity and related neural response could be modulated. We found that 1064 nm tPBM applied to the right PFC has both a substantial impact on visual working memory capacity and occipitoparietal contralateral delay activity (CDA), no matter orientation or color feature of the memorized objects. Importantly, the CDA set-size effect during the retention mediated the effect between 1064 nm tPBM and subsequent WM performance. However, these behavioral benefits and the corresponding changes of CDA set-size effect were absent with tPBM at 852 nm wavelength or with the stimulation on the left PFC. Our findings provide converging evidence that 1064 nm tPBM applied on the right PFC can improve visual working memory capacity, as well as explain the individuals electrophysiological changes about behavioral benefits.

neuroscience↗

LabGym: A versatile computational tool for automatic quantification of user-defined animal behaviors

Quantifying animal behavior is important for many branches of biological research. Current computational tools for behavioral quantification typically rely on a few pre-defined, simplified features to identify a behavior. However, such an approach restricts the information used and the tools applicability to a limited range of behavior types or species. Here we report a new tool, LabGym, for quantifying animal behaviors without such limitations. Combining a novel approach for effective evaluation of animal motion with customizable convolutional recurrent networks for capturing spatiotemporal details, LabGym provides holistic behavioral assessment and accurately identify user-defined animal behaviors without restrictions on behavior types or animal species. It then provides quantitative measurements of each behavior, which quantify the behavior intensity and the body kinematics during the behavior. LabGym requires neither any intermediate step for processing features that causes information loss nor programming knowledge from users for post-hoc analysis. It tracks multiple animals simultaneously in various experimental settings for high-throughput and versatile analysis. It also provides users a way to generate visualizable behavioral datasets that are valuable resources for the research community. We demonstrate its efficacy in capturing subtle behavioral changes in animals ranging from soft-bodied invertebrates to mammals.

animal behavior and cognition↗

Excited-state dynamics of the all-trans protonated retinal Schiff base in CRABPII-based rhodopsin mimics

The rhodopsin mimic is a chemically synthetized complex with the retinyl Schiff base (RSB) formed between protein and the retinal chromophore, which can mimic the natural rhodopsin-like protein. The artificial rhodopsin mimic is more stable and designable than the natural protein and hence has wider uses in photon detection devices. The mimic structure RSB, like the case in the actual rhodopsin-like protein, undergoes isomerization and protonation throughout the photoreaction process. As a result, understanding the dynamics of the RSB in the photoreaction process is critical. In this study, the transient absorption spectra (TAS) of three mutants of the cellular retinoic acid-binding protein II (CRABPII)-based rhodopsin mimic at PH = 3 were recorded, from which the related excited-state dynamics of the all-trans protonated RSB (AT-PRSB) were investigated. The transient fluorescence spectra (TFS) measurements are used to validate some of the dynamic features. We find that the excited-state dynamics of AT-PRSB in three mutants share a similar pattern that differs significantly from the dynamics of 15-cis PRSB (15C-PRSB) of the rhodopsin mimic in neutral solution. By comparing the dynamics across the three mutants, we discovered that the aromatic residues near the {beta}-ionone ring structure of the retinal may help stabilize the AT-PRSB and hence slow down its isomerization rate. Furthermore, from the three mutants, we find one protein with near-infrared fluorescence emission up to 688 nm, leading to further possible applications in sensing or bioimaging.

biochemistry↗

Modeling exercise using optogenetically contractible Drosophila larvae

The pathophysiological effects of a number of metabolic and age-related disorders can be prevented to some extent by exercise and increased physical activity. However, the molecular mechanisms that contribute to the beneficial effects of muscle activity remain poorly explored. Availability of a fast, inexpensive, and genetically tractable model system for muscle activity and exercise will allow the rapid identification and characterization of molecular mechanisms that mediate the beneficial effects of exercise. Here, we report the development and characterization of an optogenetically-inducible muscle contraction (OMC) model in Drosophila larvae that we used to study acute exercise-like physiological responses. To characterize muscle-specific transcriptional responses to acute exercise, we performed bulk mRNA-sequencing, revealing striking similarities between acute exercise-induced genes in flies and those previously identified in humans. Our larval muscle contraction model opens a path for rapid identification and characterization of exercise-induced factors.

genomics↗

Lyophilized mRNA-lipid nanoparticles vaccine with long-term stability and high antigenicity against SARS-CoV-2

Advanced mRNA vaccines play vital roles against SARS-CoV-2. However, due to their poor stability, most current mRNA delivery platforms need to be stored at -20{degrees}C or -70{degrees}C, which severely limits their distribution. Herein, we present lyophilized SARS-CoV-2 mRNA-lipid nanoparticle vaccines, which can be stored at room temperature with long-term thermostability. In the in vivo Delta virus challenge experiment, lyophilized Delta variant mRNA vaccine successfully protected mice from infection and cleared the virus. Lyophilized omicron mRNA vaccine enabled to elicit both potent humoral and cellular immunity. In booster immunization experiments in mice and old monkeys, lyophilized omicron mRNA vaccine could effectively increase the titers of neutralizing antibodies against wild-type coronavirus and omicron variants. In humans, lyophilized omicron mRNA vaccine as a booster shot could also engender excellent immunity and had less severe adverse events. This lyophilization platform overcomes the instability of mRNA vaccines without affecting their bioactivity, and significantly improved their accessibility, particularly in remote regions.

immunology↗

Knockout of OsSWEET15 impaired rice embryo formation and seed-setting

we show that the knockout of a sugar transporter gene OsSWEET15 led to a significant drop in rice fertility because near half of the knockout mutant spikelets bore blighted or empty grains. The rest spikelets bore fertile grains with slightly reduced weight. Notably, the ovaries in the blighted grains of the ossweet15 mutants expanded after flowering but terminated development before the endosperm cellularization stage and aborted subsequently. GUS and GFP representing OsSWEET15 expression showed that the protein was strongly expressed in the embryo surrounding region (ESR) which was supposed to supply nutrients for the embryo development. These results joined with the proteins sucrose transport capacity and plasma membrane localization suggest that OsSWEET15 plays a prominent role during the caryopsis formation stage probably by releasing sucrose from the ESR to support the embryo development. By contrast, the empty grains were probably caused by the reduced pollen viability of the ossweet15 mutants. Investigation of the makeup of ossweet11 mutant grains revealed similar phenotypes that were observed in the ossweet15 mutants. These results indicate that both OsSWETT15 and OsSWEET11 play important and similar roles during rice pollen development, caryopsis formation, and seed-setting in addition to their function in seed-filling that was demonstrated previously.

plant biology↗

The P132H mutation in the main protease of Omicron SARS-CoV-2 decreases thermal stability without compromising catalysis or small-molecule drug inhibition

The ongoing SARS-CoV-2 pandemic continues to be a significant threat to global health. First reported in November 2021, the Omicron variant (B.1.1.529) is more transmissible and can evade immunity better than previous SARS-CoV-2 variants, fueling an unprecedented surge in cases. To produce functional proteins from this polyprotein, SARS-CoV-2 relies on the cysteine proteases Nsp3/papain-like protease (PLpro) and Nsp5/Main Protease (Mpro)/3C-like protease to cleave at three and more than 11 sites, respectively.1 Therefore, Mpro and PLpro inhibitors are considered to be some of the most promising SARS-CoV-2 antivirals. On December 22, 2021, the Food and Drug Administration (FDA) issued an Emergency Use Authorization (EUA) for PAXLOVID, a ritonavir-boosted formulation of nirmatrelvir. Nirmatrelvir is a first-in-class orally bioavailable SARS-CoV-2 Mpro inhibitor.2 Thus, the scientific community must vigilantly monitor potential mechanisms of drug resistance, especially because SARS-CoV-2 is naive to Mpro inhibitors. Mutations have been well identified in variants to this point.3 Notably, Omicron Mpro (OMpro) harbors a single mutation- P132H. In this study we characterize the enzymatic activity, drug inhibition, and structure of OMpro while evaluating the past and future implications of Mpro mutations.

microbiology↗

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↗

ccnWheat: A Database for Comparing Co-expression Networks Analysis of Allohexaploid Wheat and Its Progenitors

Genetic and epigenetic changes after polyploidization events could result in variable gene expression and modified regulatory networks. Here, using large-scale transcriptome data, we constructed co-expression networks for diploid, tetraploid, and hexaploid wheat species, and built a platform for comparing co-expression networks of allohexaploid wheat and its progenitors, named ccnWheat. ccnWheat is a platform for searching and comparing specific functional co-expression networks, as well as identifying the related functions of the genes clustered therein. Functional annotations like pathway, gene family, protein-protein interactions, microRNA (miRNA), and several lines of epigenome data are integrated in this platform, and Gene Ontology (GO) annotation, gene set enrichment analysis (GSEA), motif identification, and other useful tools are also included. Using ccnWheat, we found that the network of WHEAT ABERRANT PANICLE ORGANIZATION 1 (WAPO1) has more co-expressed genes related to spike development in hexaploid wheat than its progenitors. We also found a novel motif of CArG specifically in the promoter region of WAPO-A1, suggesting that neofunctionalization of the WAPO-A1 gene affects spikelet development in hexaploid wheat. ccnWheat is useful for investigating co-expression networks and conducting other associated analyses, and thus facilitates comparative and functional genomic studies in wheat. ccnWheat is freely available at http://bioinformatics.cau.edu.cn/ccnWheat.

bioinformatics↗

Spatially resolved single-cell deconvolution of bulk RNA-seq using Bulk2Space

Uncovering the tissue molecular architecture at single-cell resolution could help better understand organisms biological and pathological processes. However, bulk RNA-seq can only measure gene expression in cell mixtures, without revealing the transcriptional heterogeneity and spatial patterns of single cells. Herein, we introduce Bulk2Space (https://github.com/ZJUFanLab/bulk2space), a deep learning framework-based spatial deconvolution algorithm that can simultaneously disclose the spatial and cellular heterogeneity of bulk RNA-seq data using existing single-cell and spatial transcriptomics references. The use of bulk transcriptomics to validate Bulk2Space unveils, in particular, the spatial variance of immune cells in different tumor regions, the molecular and spatial heterogeneity of tissues during inflammation-induced tumorigenesis, and spatial patterns of novel genes in different cell types. Moreover, Bulk2Space is utilized to perform spatial deconvolution analysis on bulk transcriptome data from two different mouse brain regions derived from our in-house developed sequencing approach termed Spatial-seq. We have not only reconstructed the hierarchical structure of the mouse isocortex but also further annotated cell types that were not identified by original methods in the mouse hypothalamus.

bioinformatics↗

MERIT: controlling Monte-Carlo error rate in large-scale Monte-Carlo hypothesis testing

The use of Monte-Carlo (MC) p-values when testing the significance of a large number of hypotheses is now commonplace. In large-scale hypothesis testing, we will typically encounter at least some p-values near the threshold of significance, which require a larger number of MC replicates than p-values that are far from the threshold. As a result, the list of detections can vary when different MC replicates are used, resulting in lack of reproducibility. The method of Gandy and Hahn (GH) (2014; 2016; 2017) is the only method that has directly addressed this problem, defining a Monte-Carlo error rate (MCER) to be the probability that any decisions on accepting or rejecting a hypothesis based on MC p-values are different from decisions based on ideal p-values, and then making decisions that control the MCER. Unfortunately, GH is frequently very conservative, often making no rejections at all and leaving a large number of hypotheses "undecided". In this article, we propose MERIT, a method for large-scale MC hypothesis testing that also controls the MCER but is more statistically efficient than the GH method. Through extensive simulation studies, we demonstrated that MERIT controlled the MCER and substantially improved the sensitivity and specificity of detections compared to GH. We also illustrated our method by an analysis of gene expression data from a prostate cancer study.

bioinformatics↗

Systematic histone H4 replacement in Arabidopsis thaliana reveals a role for H4R17 in regulating flowering time

Despite the broad array of roles for epigenetic mechanisms on regulating diverse processes in eukaryotes, no experimental system for the direct assessment of histone function is currently available in plants. In this work, we present the development of a genetic strategy in Arabidopsis thaliana in which modified H4 transgenes can completely replace the expression of endogenous histone H4. Using this strategy, we established a collection of plants expressing different H4 point mutants targeting residues that may be post-translationally modified in vivo. To demonstrate the utility of this new H4 mutant collection, we screened it to uncover substitutions in H4 that alter flowering time. We identified different mutations in the tail (H4R17A) and the globular domain (H4R36A, H4R39K, H4R39A, and H4K44A) of H4 that strongly accelerate the floral transition. Furthermore, we found a conserved regulatory relationship between H4R17 and the ISWI chromatin remodeling complex in plants. Similar to other biological systems, H4R17 regulates nucleosome spacing via ISWI. Overall, this work provides a large set of H4 mutants to the plant epigenetics community that can be used to systematically assess histone H4 function in A. thaliana and a roadmap to replicate this strategy for studying other histone proteins in plants.

plant biology↗

Asymmetric Pendrin Homodimer Reveals its Molecular Mechanism as Anion Exchanger

Pendrin SLC26A4 is an anion exchanger expressed in apical membranes of selected epithelia. Pendrin ablation causes Pendred syndrome, a genetic disorder disease associated with sensorineural hearing loss, hypothyroid goiter, and reduced blood pressure. However, its molecular structure has remained unknown limiting our understanding. Here, we determined the structures of mouse pendrin with symmetric and characteristically asymmetric homodimer conformations by cryo-electron microscopy. The asymmetric homodimer consists of an inward-facing protomer and an intermediate-state protomer, representing the coincident uptake and secretion process, and exhibits the unique state of pendrin as an electroneutral exchanger. This previously unrevealed conformation, together with other conformations we captured, provides an inverted alternate-access mechanism for anion exchange. Furthermore, our structural and functional data disclosed the properties of anion exchange cleft and interpreted the important pathogenetic mutations. These investigations shed light on the pendrin exchange mechanism and extend our structure-guided understanding of pathogenetic mutations. One-Sentence SummaryCryo-EM asymmetric Pendrin homodimer cracks its exchange mechanism and guides our understanding for pathogenetic mutations.

biophysics↗

Horizontal Transfers Lead to the Birth of Momilactone Biosynthetic Gene Clusters in Grass

Momilactone A, an important plant labdane-related diterpenoid, functions as a phytoalexin against pathogens and an allelochemical against neighboring plants. The genes involved in biosynthesis of momilactone A are found in clusters, i.e., MABGCs (Momilactone A biosynthetic gene clusters), in the rice and barnyardgrass genomes. How MABGCs originate and evolve is still not clear. Here, we integrated results from comprehensive phylogeny and comparative genomic analyses of the core genes of MABGC-like clusters and MABGCs in 40 monocot plant genomes, providing convincing evidence for the birth and evolution of MABGCs in grass species. The MABGCs found in the PACMAD clade of the core grass lineage (including Panicoideae and Chloridoideae) originated from a MABGC-like cluster in Triticeae (BOP clade) via horizontal gene transfer (HGT) and followed by recruitment of MAS and CYP76L1 genes. The MABGCs in Oryzoideae originated from PACMAD through another HGT event and lost CYP76L1 afterwards. The Oryza MABGC and another Oryza diterpenoid cluster c2BGC are two distinct clusters, with the latter being originated from gene duplication and relocation within Oryzoideae. Further comparison of the expression patterns of the MABGC genes between rice and barnyardgrass in response to pathogen infection and allelopathy provides novel insights into the functional innovation of MABGCs in plants. Our results demonstrate HGT-mediated origination of MABGCs in grass and shed lights into the evolutionary innovation and optimization of plant biosynthetic pathways.

evolutionary biology↗

Impact of Nosema ceranae invasion on sucrose solution consumption, midgut epithelial cell structure, and lifespan of Apis cerana cerana workers

Nosema ceranae is an intracellular fungal parasite for honeybees, leading to chronic disease named bee nosemosis with worldwide distribution. Asian honeybee (Apis cerana) is the original host for N. ceranae, but the impact of N. ceranae infection on A. cerana physiology is largely unknown. In this current work, workers of Apis cerana cerana, a subspecies of Asian honeybee, were artificially inoculated with N. ceranae spores and reared under lab conditions, followed by detection of fungal spore load as well as host sucrose solution consumption, midgut epithelial cell structure, and lifespan. The result of spore counting suggested that the spore load in the host midgut decreased significantly during 1 dpi-2 dpi, whereas that displayed an elevated trend among 2 dpi-13 dpi. The sucrose solution consumption of workers in N. ceranae-inoculated groups among 1 dpi-20 dpi was always higher than that of workers in un-inoculated groups; additionally, the difference of sucrose solution consumption between these two groups at 4 dpi, 5 dpi, and 13 dpi was of significance. Based on microscopic observation of paraffin sections, darkly stained parasites were clearly detected in the midgut epithelial cells of N. ceranae-inoculated workers at 7 dpi-10 dpi, whereas no parasite was observed in those of un-inoculated workers. In addition, the boundaries of un-inoculated host epithelial cells were intact and the darkly stained nucleus were clear, while the boundaries of midgut epithelial cells of N. ceranae-inoculated workers were blurred, the nucleus were almost disappeared, and the nucleic acid substances were diffused. Moreover, the survival rates of workers in both N. ceranae-inoculated groups and un-inoculated groups at 1 dpi-5 dpi were pretty high and then started to decrease at 5 dpi; the survival rate of workers in N. ceranae-inoculated groups was always lower than that in un-inoculated groups, with significant difference between these two groups during 11 dpi-20 dpi. These results together indicate that the quantity of fungal spores continuously elevated with the microsporidian multiplication, causing energetic stress for workers and host cell structure damage, which further negatively affected the host lifespan. Our findings offer a solid basis not only for exploring the molecular mechanism underlying N. ceranae infection but also for investigating the interaction between N. ceranae and eastern honeybee.

molecular biology↗

A subset of Memory B-derived antibody repertoire from 3-dose vaccinees is ultrapotent against diverse and highly transmissible SARS-CoV-2 variants, including Omicron

Omicron, the most heavily mutated SARS-CoV-2 variant so far, is highly resistant to neutralizing antibodies, raising unprecedented concerns about the effectiveness of antibody therapies and vaccines. We examined whether sera from individuals who received two or three doses of inactivated vaccine, could neutralize authentic Omicron. The seroconversion rates of neutralizing antibodies were 3.3% (2/60) and 95% (57/60) for 2- and 3-dose vaccinees, respectively. For three-dose recipients, the geometric mean neutralization antibody titer (GMT) of Omicron was 15, 16.5-fold lower than that of the ancestral virus (254). We isolated 323 human monoclonal antibodies derived from memory B cells in 3-dose vaccinees, half of which recognize the receptor binding domain (RBD) and show that a subset of them (24/163) neutralize all SARS-CoV-2 variants of concern (VOCs), including Omicron, potently. Therapeutic treatments with representative broadly neutralizing mAbs individually or antibody cocktails were highly protective against SARS-CoV-2 Beta infection in mice. Atomic structures of the Omicron S in complex with three types of all five VOC-reactive antibodies defined the binding and neutralizing determinants and revealed a key antibody escape site, G446S, that confers greater resistance to one major class of antibodies bound at the right shoulder of RBD through altering local conformation at the binding interface. Our results rationalize the use of 3-dose immunization regimens and suggest that the fundamental epitopes revealed by these broadly ultrapotent antibodies are a rational target for a universal sarbecovirus vaccine. One sentence summaryA sub-set of antibodies derived from memory B cells of volunteers vaccinated with 3 doses of an inactivated SARS-CoV-2 vaccine work individually as well as synergistically to keep variants, including Omicron, at bay.

microbiology↗