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Dong, Q.

Publications and source records attributed to Dong, Q..

At least 55 records · Page 3Linked to original sources

In Vivo Plasmonic Enhancement of the Photocycle Dynamics and Fluorescence of Genetically Encoded Voltage Indicators

Plasmonic nanoparticles are key components in nanophotonics1-11 and have applications in molecular detection and diagnostic platforms. 12-14 Coupling of dipoles to plasmonic antennas has allowed engineering of qualitatively altered behavior in isolated quantum systems, 8,15 but this promise has not been fulfilled in living systems, where the use of plasmonics is limited to tissue level applications of plasmonic particles as contrast agents16 or heat sources.17 Here we show that coupling to designed plasmonic nanoparticles can control the electrophysiological function of proteins in living cells. We designed nanostar geometries and achieved robust near-field coupling of these optimized nanoparticles to plasma membrane-localized Archaerhodopsin proteins. We enhanced the fluorescence of the coupled rhodopsins and increased their response speed to membrane voltage. We incorporated this plasmonic enhancement into a Markov chain photocycle model of the Archaerhodopsin mutant QuasAr6a, showing an increased fluorescence emission rate and manipulation of the protein dynamics through a combination of photocycle transition rate enhancements. These results represent the first scalable near-field coupling between plasmonic particles and fluorescent proteins in living cells. They show enhancement of protein function beyond what has been achievable through genetic engineering. This opens up a range of possibilities for engineering biological functionality through plasmonics.

biophysics↗

Whole-Genome Analysis of Stress Resistance-Related Genes in Listeria monocytogenes

Listeria monocytogenes is a crucial foodborne pathogen with significant public health implications. This study analyzed whole-genome sequences (WGS) of L. monocytogenes strains from public databases, examining associations between resistance genes, lineage, strain type, isolation source, and geography. Results revealed that after eliminating duplicates and strains with incomplete WGS, a total of 316 strains were deemed suitable for subsequent analyses. Within these strains, lineages I and II were extensively distributed, predominantly isolated from clinical and food sources. 56.65% of these strains fell into seven major Clonal Complexes (CC), identified by Multilocus Sequence Typing (MLST), correlating significantly with isolation information. Analysis of 46 resistance-related genes showed a high consistency of resistance genes in the same type of strains, hinting at a potential causal chain of habits-foods-environments evolutions. Moreover, the standard strains exhibit similar gene carriage rates as the sample strains, with multiple variations observed in acid-resistance genes. In conclusion, through a comprehensive analysis of the L. monocytogenes genome sequences, this study deepens our understanding of the differences and associations between its lineage, strain typing, isolation sources, geographical distribution, and resistance genes. It has also explored the potential impact of environmental noise on the expression of these genes, offering a scientific foundation for devising more effective prevention and control strategies against L. monocytogenes. Future endeavors should further dissect the functions of stress resistance genes and the variations in their expression, with the aim of gaining a deeper insight into the risks posed by L. monocytogenes to public health safety.

bioinformatics↗

Dual long-axis reorganization of hippocampus in youth

The reorganization of human hippocampus, especially its interaction with cortex, remains largely undefined in youth. The organization of a single hippocampal long-axis has been predominantly characterized as monotonic1-6, despite recent indications of nonmonotonic features in neuron density7 and geometric eigenmodes8. While the human cortical hierarchy has been well recognized for significant developmental and evolutionary advantages9-12, hippocampus has been typically considered an evolutionarily conserved brain structure1,13,14, and overlooked regarding its integrative role of cortical hierarchical processing during development. Here, we corroborated the presence and significance of a dual long-axis representation of the hippocampal connectome and geometry including both linear and quadratic gradients along its long-axis in youth. This finding was robust across two independent large-scale developmental cohorts. Charting development of the dual long-axis gradients underscored their specific contributions to the cortical hierarchy maturation from the frontoparietal and salience/ventral attention networks. The observed developmental variability in spontaneous brain activities in youth parallels the gradients of myelin content. During childhood through adolescence to early adulthood, the hippocampus reorganized the dual long-axis by gradually relaxing its geometric constraints on the intrinsic network organization of cortical spontaneous activity for refined executive functions. Molecular processes underlying such reorganization of the dual long-axis in hippocampus are linked to neural growth, stress hormone regulation, and neuroactive signaling. Our findings enrich the understanding of hippocampal-cortical reorganizational principles across structural, functional, and molecular dimensions as well as its maturation, and define the plasticity distribution within the human hippocampus at systems level, holding potentials to enhance and translate neurodevelopment and neuropsychiatric healthcare.

neuroscience↗

A resource for probing influences of perinatal factors on neurodevelopment in 3-10-years-old Chinese children

Adverse perinatal factors can disrupt the normal development of the brain, with potential long-term impacts on childrens overall development. Currently, the neuropathological mechanisms by which these factors lead to various neurodevelopmental disorders (NDDs) remain largely unknown. An open resource that integrate perinatal factors with brain and mental health development is essential for investigating NDD-related aetiology. In this Data Descriptor, we introduce a multicentre database containing information on perinatal factors that influence childrens brain-mind development, namely, periCBD, that combines neuroimaging and behavioural phenotypes with perinatal factors associated with a high incidence of NDDs at county/region/central district hospitals. PeriCBD was designed to establish a platform for the investigation of individual differences in brain-mind development among children aged 3-10 years are associated with perinatal factors. Ultimately, our goal was to develop an early prediction and screening model for NDDs that leverages normative data to facilitate NDD aetiology research. Herein, we provide a systematic overview of the data acquisition/cleaning/quality control/sharing, processes of periCBD and present preliminary brain-mind associations.

neuroscience↗

Gut microbial genomes with paired isolates from China signify probiotic and cardiometabolic effects

The gut microbiome displays significant genetic differences between populations while systematic characterization of the genomic landscape of the gut microbiome in Asia populations remains limited. Here, we present the Chinese gut microbial reference (CGMR) set, comprising 101,060 high quality metagenomic assembled genomes (MAGs) of 3,707 non-redundant species paired with 1,376 live isolates from a national wide collection of 3,234 fecal samples across China. This improved reference set contains 987 novel species compared with existing resources worldwide. By associating MAGs with geographic and phenotypic characteristics, we observed regional-specific coexisting MAGs and MAGs with probiotic and cardiometabolic functionalities. We further conducted mice experiments to confirm the probiotic effects of two Faecalibacterium intestinalis isolates in alleviating constipation, the cardiometabolic influences of three Bacteroides fragilis_A isolates in obesity, and the functional potential of isolates from the two new species belonging to the genera Parabacteroides and Lactobacillus in host lipids metabolism. Our study not only expands the current microbial genomes with paired isolates but also demonstrates their probiotic and cardiometabolic effects on hosts, contributing to the mechanistic understanding of host-microbe interactions and the translation of microbiome-based personalized therapies.

microbiology↗

SACNet: A Multiscale Diffeomorphic Convolutional Registration Network with Prior Neuroanatomical Constraints for Flexible Susceptibility Artifact Correction in Echo Planar Imaging

Susceptibility artifacts (SAs), inevitable in brain diffusion MR (dMRI) scans acquired using single-shot echo planar imaging (EPI), severely compromise the accurate detection of human brain structure. Existing SA correction (SAC) methods offer inadequate correction quality and limited applicability across diverse datasets with varied acquisition protocols. To address these challenges, we proposed SACNet, a SAC framework based on unsupervised registration convolutional networks, featuring: i) a novel diffeomorphism regularization function to avoid unnatural SAC warps, modified from a potential well function; ii) an integration with prior neuroanatomical constraints and coarse-to-fine processing strategy to enables multi-scale geometric and intensity recoveries in severe distorted areas; iii) a unified registration framework that incorporates multiple phase-encoding (PE) EPI images and structural images, ensuring compatibility with both single- and inverse-PE protocols, with or without field maps. Utilizing simulated dMRI images and over 2000 brain scans from neonatal, child, adult and traveling participants, our method consistently demonstrates state-of-the-art correction performance. Notably, SACNet effectively reduces SAs-related multicenter effects compared to existing methods. We have developed user-friendly tools using containerization techniques, hope to facilitate SAC correction quality across extensive neuroimaging studies.

neuroscience↗

Functional connectome through the human life span

The lifespan growth of the functional connectome remains unknown. Here, we assemble task-free functional and structural magnetic resonance imaging data from 33,250 individuals aged 32 postmenstrual weeks to 80 years from 132 global sites. We report critical inflection points in the nonlinear growth curves of the global mean and variance of the connectome, peaking in the late fourth and late third decades of life, respectively. After constructing a fine-grained, lifespan-wide suite of system-level brain atlases, we show distinct maturation timelines for functional segregation within different systems. Lifespan growth of regional connectivity is organized along a primary-to-association cortical axis. These connectome-based normative models reveal substantial individual heterogeneities in functional brain networks in patients with autism spectrum disorder, major depressive disorder, and Alzheimers disease. These findings elucidate the lifespan evolution of the functional connectome and can serve as a normative reference for quantifying individual variation in development, aging, and neuropsychiatric disorders.

neuroscience↗

Flagellar switch inverted repeat sequence variation impacts Clostridioides difficile RT027/MLST1 virulence.

Clostridioides difficile RT027 strains cause infections that vary in severity from asymptomatic to lethal, but the molecular basis for this variability is poorly understood. Through comparative analyses of RT027 clinical isolates, we determined that isolates that exhibit greater variability in their flagellar gene expression exhibit greater virulence in vivo. C. difficile flagellar genes are phase-variably expressed due to the site-specific inversion of the flgB 5UTR region, which reversibly generates ON vs. OFF orientations for the flagellar switch. We found that longer inverted repeat (IR) sequences in this switch region correlate with greater disease severity, with RT027 strains carrying 6A/6T IR sequences exhibiting greater phenotypic heterogeneity in flagellar gene expression (60%-75% ON) and causing more severe disease than those with shorter IRs (> 99% ON or OFF). Taken together, our results reveal that phenotypic heterogeneity in flagellar gene expression may contribute to the variable disease severity observed in C. difficile patients.

microbiology↗

UniSpec: A Deep Learning Approach for Predicting Energy-Sensitive Peptide Tandem Mass Spectra and Generating Proteomics-Wide In-Silico Spectral Libraries

In this report, we present UniSpec, an attention-based deep neural network designed to predict complete collision-induced fragmentation of tryptic peptides, aimed at enhancing peptide and protein identification in shotgun proteomics studies. We preprocessed spectral data from peptide tandem mass spectral libraries, compiled by the National Institute of Standards and Technology (NIST), utilizing a data approach tailored for model development, resulting in high-quality, energy-consistent spectral datasets. By analyzing all the annotated fragment ions present in these libraries, we constructed an extensive peptide fragment dictionary containing 7919 isotopic ions from sequence ions, neutral loss, internal, iminium, and amino acid fragment ions. The streamlined dictionary-based spectral training data enables UniSpec to efficiently learn the complex intensity patterns of various product ions, resulting in reliable spectral predictions for a wide range of unmodified and modified peptides. We evaluated the models accuracy by comparing its performance across training and testing data, considering diverse peptide characteristics like peptide classes, charge states, and sequence lengths. Our model attained a median cosine similarity score of 0.951 and 0.923 on the training and test data respectively. Contrary to existing deep learning models that often overlook a substantial part of peptide tandem mass spectra beyond the sequence b and y ion series, UniSpec can predict up to 75% of all measured fragment intensities (including unknown signals) in the raw experimental spectra. This represents a marked advancement from the 43.5% coverage achieved solely by b and y sequence ions in the NIST library spectra. For the evaluation of our models practical utility in predicting proteome-wide in-silico spectral libraries, we executed a benchmark test using a dataset of HeLa cells. UniSpec displayed a significant overlap of peptide identifications with the widely used search engine MS-GF+ and the NIST experimental spectral library, demonstrating its robust performance as a standalone peptide identification tool.

bioinformatics↗

Multimodal analysis of neuronal maturation in the developing primate prefrontal cortex

The prefrontal cortex (PFC) is critical for myriad high-cognitive functions and is associated with several neuropsychiatric disorders. Here, using Patch-seq and single-nucleus multiomic analyses, we identified genes and regulatory networks governing the maturation of distinct neuronal populations in the PFC of rhesus macaque. We discovered that specific electrophysiological properties exhibited distinct maturational kinetics and identified key genes underlying these properties. We unveiled that RAPGEF4 is important for the maturation of resting membrane potential and inward sodium current in both macaque and human. We demonstrated that knockdown of CHD8, a high-confidence autism risk gene, in human and macaque organotypic slices led to impaired maturation, via downregulation of key genes, including RAPGEF4. Restoring the expression of RAPGEF4 rescued the proper electrophysiological maturation of CHD8-deficient neurons. Our study revealed regulators of neuronal maturation during a critical period of PFC development in primates and implicated such regulators in molecular processes underlying autism.

neuroscience↗

Developmental Alterations in Brain Network Asymmetry in 3- to 9-Month Infants with Congenital Sensorineural Hearing Loss

Auditory exposure plays crucial roles in shaping healthy brain development and generating lateralization of functional network organization. However, little is known about whether and how an initial lack of auditory exposure in early infancy may disrupt development of functional network lateralization. We addressed this issue by recruiting 55 infants with congenital sensorineural hearing loss (SNHL) and 60 typically developing (TD) controls. Resting-state fNIRS imaging data were acquired to construct hemispheric cerebral networks, and graph theory was applied to quantify the topological characteristics of hemispheric networks. The infants with SNHL exhibited efficient small-world characteristic within each hemispheric network, however, the lateralization of functional network efficiency was substantially disrupted. Compared with TD infants with significantly increased network efficiency lateralized toward left hemisphere with age, the SNHL infants did not exhibit the emergence and development of such cerebral lateralization. Furthermore, the increased leftward asymmetry in nodal efficiency with age was found in TD but not in SNHL infants. Interestingly, the degree of hearing loss had no correlation with lateralization strength in the SNHL group. These results suggest that SNHL infants exhibited disrupted development of cortical lateralization in functional network organization, and highlight the importance of auditory stimulation-promoted multisensory functional integration in early infancy.

neuroscience↗

Uracil-DNA Glycosylase of Murine Gammaherpesvirus 68 Binds Cognate Viral Replication Factors Independently of its Catalytic Residues

Herpesviruses are large double-stranded DNA viruses that encode core replication proteins and accessory factors involved in nucleotide metabolism and DNA repair. Mammalian Uracil-DNA glycosylases (UNG) excise deleterious uracil residues from their genomic DNA. Each herpesvirus UNG studied to date has demonstrated conservation of the enzymatic function to excise uracil residues from DNA. We previously reported that a murine gammaherpesvirus (MHV68) with a stop codon in ORF46 (ORF46.stop) that encodes for vUNG was defective in lytic replication and latency in vivo. However, a mutant virus that expressed a catalytically inactive vUNG (ORF46.CM) had no replication defect, unless coupled with additional mutations in the catalytic motif of the viral dUTPase (ORF54.CM). The disparate phenotypes observed in the vUNG mutants led us to explore the non-enzymatic properties of vUNG. Immunoprecipitation of vUNG followed by mass spectrometry in MHV68-infected fibroblasts identified a complex comprised of the cognate viral DNA polymerase, vPOL encoded by ORF9, and the viral DNA polymerase processivity factor, vPPF encoded by ORF59. MHV68 vUNG colocalized with vPOL and vPPF in subnuclear structures consistent with viral replication compartments. In reciprocal co-immunoprecipitations, the vUNG formed a complex with the vPOL and vPPF upon transfection with either factor alone, or in combination. Last, we determined that key catalytic residues of vUNG are not required for interactions with vPOL and vPPF upon transfection or in the context of infection. We conclude that the vUNG of MHV68 associates with vPOL and vPPF independently of its catalytic activity. IMPORTANCEGammaherpesviruses encode a uracil-DNA glycosylase (vUNG) that is presumed to excise uracil residues from viral genomes. We previously identified the vUNG enzymatic activity, but not the protein itself, as dispensable for gammaherpesvirus replication in vivo. In this study, we report a non-enzymatic role for the viral UNG of a murine gammaherpesvirus to form a complex with two key components of the viral DNA replication machinery. Understanding the role of the vUNG in this viral DNA replication complex may inform the development of antiviral drugs that combat gammaherpesvirus associated cancers.

microbiology↗

A Recombinant Antibody For Tracking Murine Gammaherpesvirus 68 Uracil DNA Glycosylase Expression.

Antibodies are powerful tools to detect expressed proteins. However off-target recognition can confound their use. Therefore, careful characterization is needed to validate specificity in distinct applications. Here we report the sequence and characterization of a mouse recombinant antibody that specifically detects ORF46 of murine gammaherpesvirus 68 (MHV68). This ORF encodes the viral uracil DNA glycosylase (vUNG). The antibody does not recognize murine uracil DNA glycosylase and is useful in detecting vUNG expressed in virally infected cells. It can detect expressed vUNG in cells via immunostaining and microscopy or flow cytometry analysis. The antibody can detect vUNG from lysates of expressing cells via immunoblot under native conditions but not denaturing conditions. This suggests it recognizes a confirmational based epitope. Altogether this manuscript describes the utility of the anti-vUNG antibody and suitability for use in studies of MHV68 infected cells.

molecular biology↗

Ebola Virus Sequesters IRF3 in Viral Inclusion Bodies to Evade Host Antiviral Immunity

Viral inclusion bodies (IBs) commonly form during the replication of Ebola virus (EBOV) in infected cells, but their role in viral immune evasion has rarely been explored. Here, we found that interferon regulatory factor 3 (IRF3), but not TANK-binding kinase 1 (TBK-1) or I{kappa}B kinase epsilon (IKK{varepsilon}), was recruited and sequestered in viral IBs when the cells were infected by EBOV transcription- and replication-competent virus-like particles (trVLPs). NP/VP35-induced IBs formation was critical for IRF3 recruitment and sequestration, probably through interaction with STING. Consequently, the association of TBK1 and IRF3, which plays a vital role in type I interferon (IFN-I) induction, was blocked by EBOV trVLPs infection. Additionally, IRF3 phosphorylation and nuclear translocation induced by Sendai virus (SeV) or poly(I:C) stimulation were suppressed by EBOV trVLPs. Furthermore, downregulation of STING significantly attenuated VP35-induced IRF3 accumulation in IBs. Coexpression of the viral proteins by which IBs-like structures formed was much more potent in antagonizing IFN-I than expression of the IFN-I antagonist VP35 alone. These results suggested a novel immune evasion mechanism by which EBOV evades host innate immunity. Impact statementEbola virus VP35 protein evades host antiviral immunity by interacting with STING to sequester IRF3 into inclusion bodies and inhibit type-I interferon production.

microbiology↗

Temporal colonization of the gut microbiome in neonatal Bos taurus at single nucleotide resolution

BackgroundThe rumen of neonatal calves is underdeveloped and exhibits limited functionality during early life. Thus, the acquisition and colonization of microbes in the gut are key to establishing a healthy host-microbiome symbiosis for neonatal calves. Microbiome-linked health outcomes appear to be the consequences of individual strains of specific microbes. However, the temporal colonization of pioneering microbial strains and their linkages to the health and growth of neonatal calves are poorly understood. ResultsTo address this, we longitudinally profiled the gut microbiome of 36 neonatal calves from birth up to 2 months postpartum and carried out microbial transplantation (MT) to reshape their gut microbiome. Genomic reconstruction of deeply sequenced fecal samples resulted in a total of 3,931 metagenomic assembled genomes (MAGs), of which 397 were identified as new species when compared with existing databases of Bos taurus. Single nucleotide level metagenomic profiling shows a rapid influx of microbes after birth, followed by strong selection during the first few weeks of life. MT was found to reshape the genetic makeup of 33 MAGs (FDR<0.05), mainly from Prevotella and Bacteroides species. We further linked over 20 million microbial single nucleotide variations (SNVs) to 736 plasma metabolites, which enabled us to characterize 24 study-wide significant associations (P < 4.4x10-9) that identify the potential microbial genetic regulation of host immune and neuro-related metabolites, including glutathione and L-dopa. Our integration analyses further revealed that microbial genetic variations may influence the health status and growth performance of neonatal calves by modulating metabolites via structural regulation of their encoded proteins. For instance, we found that the albumin levels and total antioxidant capacity in neonatal calves were correlated with L-dopa, which was determined by SNVs via structural regulations of metabolic enzymes. ConclusionsThe current results indicate that the temporal colonization of microbial strains and MT-induced strain replacement are integral in the development of the gut microbiome of neonatal calves and may help to develop strategies that can improve the health status and growth performance of neonatal calves.

microbiology↗

Early microbial intervention reduces diarrhea while improves later milk production in newborn calves

The rumen of neonatal calves is not well-developed and exhibits limited functionality. Therefore, the establishment of intestinal microbiota may play an instrumental role in their health and performance, but it has been rarely explored. Thus, we aim to explore the temporal colonization of the gut microbiome and the potential benefits of early microbial intervention in newborn calves. We followed up on the temporal dynamics of the gut microbiome and plasma metabolome in 36 newborn calves during the first two months of life and established their relationships with their health status and performance. We also evaluated whether microbiota transplantation (MT) could influence their phenotypes by modulating metabolism and its impact on later milk production performance.We showed that the composition and ecological interactions of the gut microbiome are likely to reach maturity one month after birth. Temporal changes in the gut microbiome of newborn calves are widely associated with changes in their physiological statuses, such as growth and fiber digestion. Importantly, we observed that MT reshapes the gut microbiome of newborns by altering the abundance and interaction of Bacteroides species, as well as amino acid pathways, such as arginine biosynthesis. Two-year follow-up of those calves further showed that MT improves their later milk production. Notably, MT improves fiber digestion, antioxidant capacity of newborns while reducing diarrhea. MT also contributes to significant changes in the metabolomic landscape, and with putative causal mediation analysis, we suggest that altered gut microbial composition in newborns may influence physiological status through microbial-derived metabolites. The data from the study may help develop strategies to manipulate the gut microbiota during early life, which may be significantly relevant to the health and production of newborn calves. HIGHLIGHTSO_LIThe gut microbial composition and ecological interaction in newborn calves reach maturity one month after birth C_LIO_LITemporal shifts in the gut microbiome of newborn calves are associated with phenotypic changes, including growth, digestion, and antioxidative capacity C_LIO_LIEarly microbial intervention in newborn calves reduces diarrhea while improving later milk production C_LIO_LIThe gut microbial impact on newborn calves is mediated by plasma metabolites C_LI

microbiology↗

B cell-intrinsic STAT3-mediated support of latency and interferon suppression during murine gammaherpesvirus 68 infection revealed through an in vivo competition model

Cancers associated with the oncogenic gammaherpesviruses, Epstein-Barr virus and Kaposi sarcoma herpesvirus, are notable for their constitutive activation of the transcription factor STAT3. To better understand the role of STAT3 during gammaherpesvirus latency and immune control, we utilized murine gammaherpesvirus 68 (MHV68) infection. Genetic deletion of STAT3 in B cells of CD19cre/+Stat3f/fmice reduced peak latency approximately 7-fold. However, infected CD19cre/+Stat3f/f mice exhibited disordered germinal centers and heightened virus-specific CD8 T cell responses compared to WT littermates. To circumvent the systemic immune alterations observed in the B cell-STAT3 knockout mice and more directly evaluate intrinsic roles for STAT3, we generated mixed bone marrow chimeras consisting of WT and STAT3-knockout B cells. Using a competitive model of infection, we discovered a dramatic reduction in latency in STAT3-knockout B cells compared to their WT B cell counterparts in the same lymphoid organ. RNA sequencing of sorted germinal center B cells revealed that STAT3 promotes proliferation and B cell processes of the germinal center but does not directly regulate viral gene expression. Last, this analysis uncovered a STAT3-dependent role for dampening type I IFN responses in newly infected B cells. Together, our data provide mechanistic insight into the role of STAT3 as a latency determinant in B cells for oncogenic gammaherpesviruses. IMPORTANCEThere are no directed therapies to the latency program of the gammaherpesviruses, Epstein-Barr virus and Kaposi sarcoma herpesvirus. Activated host factor STAT3 is a hallmark of cancers caused by these viruses. We applied the murine gammaherpesvirus pathogen system to explore STAT3 function upon primary B cell infection in the host. Since STAT3 deletion in all CD19+ B cells of infected mice led to altered B and T cell responses, we generated chimeric mice with both normal and STAT3-deleted B cells. B cells lacking STAT3 failed to support virus latency compared to normal B cells from the same infected animal. Loss of STAT3 impaired B cell proliferation and differentiation and led to a striking upregulation of interferon-stimulated genes. These findings expand our understanding of STAT3-dependent processes key to its function as a pro-viral latency determinant for oncogenic gammaherpesviruses in B cells and may provide novel therapeutic targets.

microbiology↗