Biology subjects

Zhou, L.

Publications and source records attributed to Zhou, L..

At least 199 records · Page 11Linked to original sources

bioRxiv2022

Increased public health threat of avian-origin H3N2 influenza virus during evolution in dogs

Influenza A viruses in animal reservoirs repeatedly cross species barrier to infect humans. Once an animal-borne virus with novel antigenicity acquired the efficient human to human transmissibility, it will become epidemic in the population. Dogs are the closest animal companions to humans and canine respiratory tract expresses both SA2,3-(avian type) and 2,6-Gal (human type) receptors. However, the role of dogs in the ecology of influenza viruses is unclear. H3N2 avian influenza viruses transmitted to dogs around 2006 and have formed stable lineages. The long-term epidemic of avian-origin H3N2 virus in canine offers the best models to investigate the effect of dogs on the evolution of influenza viruses. Here, we carried out a systematic and comparative identification of the biological characteristics of H3N2 canine influenza viruses (CIVs) isolated in the worldwide over 10 years. We found that during the adaptation of H3N2 CIVs to dogs, H3N2 CIVs became to recognize the human-like SA2,6-Gal receptor, gradually increased HA acid stability and replication ability in human airway epithelial cells, and acquired a 100% transmission rate via respiratory droplet in ferret model, which were essential hallmarks of being adapted to humans. We also identified that the frequency of substitutions related to human adaptation has gradually increased in H3N2 CIVs, and determined four cumulative molecular changes responsible for the increased airborne transmission ability in ferrets. Our results suggested that canine may serve as an intermediate for the adaptation of avian influenza virus to human. Continuous surveillance coordinated with risk assessment for CIVs is necessary.

microbiology↗

bioRxiv2022

Umbilical cord blood-derived cell therapy for perinatal brain injury: A systematic review & meta-analysis of preclinical studies - Part A

IntroductionPerinatal brain injury is a major contributor to long-term adverse neurodevelopment. There is mounting preclinical evidence for use of umbilical cord blood (UCB)-derived cell therapy as potential treatment. ObjectivesTo systematically review and analyse effects of UCB-derived cell therapy on brain outcomes in preclinical models of perinatal brain injury. MethodsMEDLINE and Embase databases were searched for relevant studies. Brain injury outcomes were extracted for meta-analysis to calculate standard mean difference (SMD) with 95% confidence interval (CI), using an inverse variance, random effects model. Outcomes were separated based on grey matter (GM) and white matter (WM) regions where applicable. Risk of bias was assessed using SYRCLE, and GRADE was used to summarise certainty of evidence. ResultsFifty-five eligible studies were included (7 large, 48 small animal models). UCB-derived cell therapy significantly improved outcomes across multiple domains, including decreased infarct size (SMD 0.53; 95%CI (0.32, 0.74), P<0.00001), apoptosis (WM, SMD 1.59; 95%CI (0.86, 2.32), P<0.0001), astrogliosis (GM, SMD 0.56; 95%CI (0.12, 1.01), P=0.01), microglial activation (WM, SMD 1.03; 95%CI (0.40, 1.66), P=0.001), neuroinflammation (TNF-, SMD 0.84; 95%CI (0.44, 1.25), P<0.0001); as well as improved neuron number (SMD 0.86; 95%CI (0.39, 1.33), P=0.0003), oligodendrocyte number (GM, SMD 3.35; 95%CI (1.00, 5.69), P=0.005) and motor function (cylinder test, SMD 0.49; 95%CI (0.23, 0.76), P=0.0003). Risk of bias was determined as serious, and overall certainty of evidence was low. ConclusionsUCB-derived cell therapy is an efficacious treatment in pre-clinical models of perinatal brain injury, however findings are limited by low certainty of evidence. SIGNIFICANCE STATEMENTPerinatal brain injury can lead to significant long-term neurodevelopmental deficits. There are limited treatment options available, and new interventions are urgently required. Through assessment of preclinical studies, this systematic review and meta-analysis shows that umbilical cord blood-derived cell therapy is an efficacious treatment for perinatal brain injury across a wide range of neuropathological and functional domains, albeit with low certainty of evidence. It also identified knowledge gaps, including that future studies should focus on non-hypoxic ischemic models, preterm models, large animal models and should explore the heterogeneity that exists in treatment protocols.

neuroscience↗

bioRxiv2022

Robust phenotypic plasticity of symbiotic organs facilitates the adaptation and evolution of deep-sea mussels

The rapid progress of deep-sea methane hydrate exploration and exploitation calls for a thorough evaluation of its potential impact on local chemosynthetic ecosystems, particularly on endemic species. As one dominant megafauna in cold seeps, the deep-sea mussels mainly rely on methanotrophic endosymbionts for nutrition and therefore could serve as a promising model in monitoring the exploitation of methane hydrate. However, knowledge on the long-term responses of deep-sea mussels to environmental stresses induced by methane hydrate exploitation, especially to methane reduction and deprivation, is still lacking. Here, we set up a laboratory system and cultivated methanotrophic deep-sea mussel Gigantidas platifrons without methane supply to survey the phenotypic changes after methane deprivation. While the mussels managed to survive for more than 10 months after the methane deprivation, drastic changes in the metabolism, function, and development of gill tissue, and in the association with methanotrophic symbionts were observed. In detail, the mussel digested all methanotrophic endosymbionts shortly after methane deprivation for nutrition and remodeled the global metabolism of gill to conserve energy. As the methane deprivation continued, the mussel replaced its bacteriocytes with ciliated cells to support filter-feeding, which is an atavistic trait in non-symbiotic mussels. During the long-term methane deprivation assay, the mussel also retained the generation of new cells to support the phenotypic changes of gill and even promoted the activity after being transplanted back to deep-sea, showing the potential resilience after long-term methane deprivation. Evidences further highlighted the participation of symbiont sterol metabolism in regulating these processes, which might be one direct cue for the mussels to respond to methane deprivation. These results collectively show the phenotypic plasticity of deep-sea mussels and their dynamic responses to methane deprivation, providing essential information in assessing the long-term influence of methane hydrate exploitation.

molecular biology↗

bioRxiv2022

Function and Cryo-EM structures of broadly potent bispecific antibodies against multiple SARS-CoV-2 Omicron sublineages

The SARS-CoV-2 variant, Omicron (B.1.1.529), rapidly swept the world since its emergence. Compared with previous variants, Omicron has a high number of mutations, especially those in its spike glycoprotein that drastically dampen or abolish the efficacy of currently available vaccines and therapeutic antibodies. Several major sublineages of Omicron evolved, including BA.1, BA.1.1, BA.2, BA.2.12.1, BA.3, BA.4/5, and BA.2.75, which rapidly changing the global and regional landscape of the pandemic. Although vaccines are available, therapeutic antibodies remain critical for infected and especially hospitalized patients. To address this, we have designed and generated a panel of human/humanized therapeutic bispecific antibodies against Omicron and its sub-lineage variants, with activity spectrum against other lineages. Among these, the top clone CoV2-0213 has broadly potent activities against multiple SARS-CoV-2 ancestral and Omicron lineages, including BA.1, BA.1.1, BA.2, BA.2.12.1, BA.3, BA.4/5, and BA.2.75. We have solved the cryo-EM structure of the lead bi-specific antibody CoV-0213 and its major Fab arm MB.02. Three-dimensional structural analysis shows distinct epitope of antibody - spike receptor binding domain (RBD) interactions and reveals that both Fab fragments of CoV2-0213 can simultaneously target one single spike RBD or two adjacent ones in the same spike trimer, further corroborating its mechanism of action. CoV2-0213 represents a unique and potent broad-spectrum SARS-CoV-2 neutralizing bispecific antibody (nbsAb) against the currently circulating major Omicron variants (BA.1, BA.1.1, BA.2, BA.2.12.1, BA.2.75, BA.3, and BA.4/5). CoV2-0213 is primarily human and ready for translational testing as a countermeasure against the ever-evolving pathogen.

immunology↗

bioRxiv2022

Decoding Subject's Own Name in the Primary Auditory Cortex

Current studies have shown that perception of subjects own name (SON) involves multiple multimodal brain regions, while activities in unimodal sensory regions (i.e., primary auditory cortex) and their interaction with multimodal regions during the self-processing remain unclear. To answer this, we combined multivariate pattern analysis and dynamic causal modelling analysis to explore the regional activation pattern and inter-region effective connection during the perception of SON. We found that SON and other names could be decoded from the activation pattern in the primary auditory cortex. In addition, we found an excitatory effect of SON on connections from the anterior insula/inferior frontal gyrus to the primary auditory cortex, and to the temporal parietal junction. Our findings extended the current knowledge of self-processing by showing that primary auditory cortex could discriminate SON from other names. Furthermore, our findings highlighted the importance of influence of the insula on the primary auditory cortex during self-processing.

neuroscience↗

bioRxiv2022

Nonlinear effect of light intensity on normal axial development of rhesus monkeys

PurposeTo investigate the effects of different indoor lighting intensity (500 lx, 750 lx and 1,000 lx) on normal ocular axial length growth by using juvenal rhesus monkeys. MethodsTwenty-four juvenile monkeys were exposed continuously to normal intensity light (NIL, 500 lx, n=16), medium intensity light (MIL, 750 lx, n=8) and high intensity light (HIL, 1 000 lx, n=8), with a same CCT value (about 3000 K) for 246 days. Axial length, anterior chamber depth, corneal curvature radius were measured at about a monthly interval. ResultsAfter 246 days of light exposure, the growth of axial length of the MIL group (750 lx) were 0.151 {+/-} 0.081 mm and 0.139 {+/-} 0.070 mm in the right and left eyes, respectively, and significantly larger in comparison with the NIL group (500lx, OD: 0.068 {+/-} 0.055 mm, OS: 0.074 {+/-} 0.057 mm) and the HIL group (1000lx,OD:0.063 {+/-} 0.093 mm, OS: 0.084 {+/-} 0.052 mm) monkeys. This effect was stable and robust during the whole experimental period. ConclusionThe effects of different intensity lighting on normal ocular axial development was not linear as most people currently think. We must be cautious when it comes to elevate light intensity in classrooms. Whether this conclusion is correct under lights of other CCT value needs further study.

developmental biology↗

bioRxiv2022

Pick-up Single-Cell Proteomic Analysis for Quantifying up to 3000 Proteins in a Tumor Cell

The shotgun proteomic analysis is currently the most promising single-cell protein sequencing technology, however its identification level of [~]1000 proteins per cell is still insufficient for practical applications. Here, we develop a pick-up single-cell proteomic analysis (PiSPA) workflow to achieve a deep identification capable of quantifying up to 3000 protein groups in a tumor cell using the label-free quantitative method. The PiSPA workflow is specially established for single-cell samples mainly based on a nanoliter-scale microfluidic liquid handling robot, capable of achieving single-cell capture, pretreatment and injection under the pick-up operation strategy. Using this customized workflow with remarkable improvement in protein identification, 1804-3349, 1778-3049 and 1074-2487 protein groups are quantified in single A549 cells (n = 37), HeLa cells (n = 44) and U2OS cells (n = 27), respectively. Benefiting from the flexible cell picking-up ability, we study tumor cell migration at the single cell proteome level, demonstrating the potential in practical biological research from single-cell insight.

cancer biology↗

bioRxiv2022

Aspartate reduces liver inflammation and fibrosis by suppressing the NLRP3 inflammasome pathway via upregulating NS3TP1 expression

Aspartate (Asp) can act on liver Kupffer cells, inhibit NOD-like receptor-P 3 (NLRP3) inflammatory bodies, and improve liver inflammation in acute hepatitis. However, the effect of Asp on the role of hepatic stellate cells (HSCs) in the pathogenesis of liver fibrosis in chronic liver injury remains unexplored. This study aimed to investigate the effects of Asp on CCl4-induced liver fibrosis in mice and HSCs via the NF-{kappa}B/ NLRP3 signaling pathway. Liver fibrosis was induced in C57BL/6J mice by intraperitoneally (IP) injecting 0.5 mL/kg 2% CCl4 three times weekly for 8 weeks. Asp was administered to mice by gavage once every morning for 4 weeks. Massons trichrome staining, Sirius red staining and hematoxylin and eosin staining were used to detect and analyze the pathological changes in liver tissues. Western blot analysis and immunohistochemistry were applied to determine the protein expression levels of -smooth muscle actin (-SMA), collagen III (COL III), NLRP3, and IL-1{beta}. Also, reverse transcription-quantitative PCR was performed to detect the mRNA expression levels. In the liver fibrosis model, the pathological changes in liver tissues improved following treatment with Asp. A marked decrease was observed in protein and mRNA expression levels of -SMA, COL III, NLRP3, and IL-1{beta}. In addition, HSCs were treated with Asp. The expression levels of -SMA, COL III, NLRP3, and IL-1{beta} reduced in dose- and time-dependent manners. Furthermore, Asp upregulated the expression of NS3TP1 in vivo and in vitro, and NS3TP1 had a significant inhibitory effect on liver fibrosis. Asp attenuated liver fibrosis and reduced collagen production by suppressing the NF-{kappa}B/ NLRP3 signaling pathway via upregulating the expression of NS3TP1.

molecular biology↗

bioRxiv2022

A pangenome analysis pipeline (PSVCP) provides insights into rice functional gene identification

BackgroundA pangenome aims to capture the complete genetic diversity within a species and reduce bias in genetic analysis inherent in using a single reference genome. However, the current linear format of most plant pangenomes limits the presentation of position information for novel sequences. Graph pangenomes have been developed to overcome this limitation. However, there is a lack of bioinformatics analysis tools for graph format genomes. ResultsTo overcome this problem, we have developed a novel pangenome construction strategy and a downstream pangenome analysis pipeline that captures position information while maintaining a linearized layout. We applied this strategy to construct a high-quality rice pangenome using 12 representative rice genomes and analyze an international rice panel with 413 diverse accessions using the pangenome reference. Our results provide insights into rice population structure and genomic diversity. Applying the pangenome for PAV-based GWAS analysis can identify causal structural variations for rice grain weight and plant height, while SNP-based GWAS can only identify approximate genomic locations. Additionally, a new locus (qPH8-1) was found to be associated with plant height on chromosome 8 that could not be detected using the SNP-based GWAS. ConclusionsOur results demonstrate that the pangenome constructed by our pipeline combined with PAV-based GWAS can provide additional power for genomic and genetic analysis. The pangenome constructed in this study and associated genome sequence data provide valuable genomic resources for future rice crop improvement.

genetics↗

bioRxiv2022

cAMP-EPAC-PKCε-RIM1α signaling regulates presynaptic long-term potentiation and motor learning

The cerebellum is involved in learning of fine motor skills, yet whether presynaptic plasticity contributes to such learning remains elusive. Here we report that the EPAC-PKC{varepsilon} module has a critical role in a presynaptic form of long-term potentiation in the cerebellum and motor behavior. Presynaptic cAMP-EPAC-PKC{varepsilon} signaling cascade induces a previously unidentified threonine phosphorylation of RIM1, and thereby initiates the assembly of the Rab3A-RIM1-Munc13-1 tripartite complex that facilitates docking and release of synaptic vesicles. Granule cell-specific blocking of EPAC-PKC{varepsilon} signaling abolishes presynaptic long-term potentiation at the parallel fiber to Purkinje cell synapses and impairs basic performance and learning of cerebellar motor behavior. These results unveil a functional relevance of presynaptic plasticity that is regulated through a novel signaling cascade, thereby enriching the spectrum of cerebellar learning mechanisms.

neuroscience↗

bioRxiv2022

SARS-CoV-2 S protein antagonizes type I interferon downstream signal pathway through interacting and attenuating phosphorylation of STAT1/STAT2

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may keep patients in a clinically asymptomatic state by blocking cellular innate antiviral immunity, but the molecular mechanism remains unclear. Here, we screened the viral proteins of SARS-CoV-2 and found that the spike (S) protein inhibits the activation of interferon-stimulated genes (ISGs) and even reduces the expression of these genes to below background values. Mechanistically, the S protein interacted with STAT1, STAT2, and IRF9 and impedes the phosphorylation of STAT1/STAT2, thus preventing the formation of the interferon-stimulating gene factor 3 (ISGF3) complex and inhibiting the downstream production of Interferon-stimulated genes (ISGs). Remarkably, we also have found that the inhibitory mechanism of the S protein was conservative among SARS-CoV-2 variants and other human coronaviruses, including SARS-CoV, MERS-CoV, HCoV-229E, HCoV-NL63, and HCoV-HKU1. Truncation studies indicated that the most conserved S2 domain played a major inhibitory role. Altogether, our findings unveil a new mechanism by which SARS-CoV-2 S protein attenuated the hosts antiviral immune response and provide new insights into the pathogenic mechanism of coronavirus.

microbiology↗

bioRxiv2022

Single-cell perspectives on the function and development of deep-sea mussel bacteriocytes

The authors have withdrawn their manuscript because the authors need to re-organize the data and writing, meanwhile more experimental evidence from more RNA-seq replications, immunofluorescence assay and in vivo knock-down assays will be added to support the viewpoints. In this preprint, only one individual of decolonized mussel was employed for transcriptome sequencing while combined data from single cell transcriptomics with in situ hybridization is not enough convincing to draw some of the conclusion. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.

molecular biology↗

bioRxiv2022

Deformable Mirror based Optimal PSF Engineering for 3D Super-resolution Imaging

Point spread function (PSF) engineering is an important technique to encode the properties (e.g., 3D positions, color, and orientation) of single molecule in the shape of the PSF, often with the help of a programmable phase modulator. Deformable mirror (DM) is currently the most widely used phase modulator for fluorescence detection as it shows negligible photon loss. However, it relies on careful calibration for precise wavefront control. Therefore, design of an optimal PSF not only relies on the theoretical calculation of maximum information content, but also the physical behavior of the phase modulator, which is often ignored during the optimization process. Here, we developed a framework of PSF engineering which could generate a device specific optimal PSF for 3D super-resolution imaging using DM. We used our method to generate two types of PSFs with depths of field comparable to the widely used astigmatism and Tetrapod PSFs, respectively. We demonstrated the superior performance of the DM specific optimal PSF over the conventional astigmatism and Tetrapod PSF both theoretically and experimentally.

biophysics↗

bioRxiv2022

Net-shaped DNA nanostructure designed for rapid/sensitive detection and potential inhibition of SARS-CoV-2 virus

We present a net-shaped DNA nanostructure (called "DNA Net" herein) design strategy for selective recognition and high-affinity capture of the intact SARS-CoV-2 virions through spatial pattern-matching and multivalent interactions between the aptamers (targeting wild type spike-RBD) positioned on the DNA Net and the trimeric spike glycoproteins displayed on the viral outer surface. Carrying a designer nanoswitch, the DNA Net-aptamers releases fluorescent signal upon virus binding that is easily read by a hand-held fluorimeter for a rapid (in 10 mins), simple (mix- and-read), sensitive (PCR equivalent), room temperature compatible, and inexpensive ([~] $1.26/test) COVID-19 test assay. The DNA Net-aptamers also impede authentic wild-type SARS-CoV-2 infection in cell culture with a near 1x103-fold enhancement of the monomeric aptamer. Furthermore, our DNA Net design principle and strategy can be customized to tackle other life-threatening and economically influential viruses like influenza and HIV, whose surfaces carry class-I viral envelope glycoproteins like the SARS-CoV-2 spikes in trimeric forms.

bioengineering↗

bioRxiv2022

FebRNA: an automated fragment-ensemble-based model for building RNA 3D structures

Knowledge of RNA 3-dimensional (3D) structures is critical to understanding the important biological functions of RNAs. Although various structure prediction models have been developed, high accuracy of predicted RNA 3D structures is still limited to the RNAs with short length or with simple topology. In this work, we proposed a new model, namely FebRNA, for building RNA 3D structures through fragment assembly based on coarse-grained (CG) fragment ensembles. Specifically, FebRNA is composed of four processes: establishing the library of different types of CG fragment ensembles, building CG 3D structure ensemble through fragment assembly, identifying top-1 CG structure through a CG scoring function, and rebuilding the all-atom structure from the top-1 CG one. Extensive examination on different types of RNA structures indicates that FebRNA gives consistently reliable predictions on RNA 3D structures including pseudoknots, 3-way junction, 4-way and 5-way junctions, and RNAs in the RNA-Puzzles. FebRNA is available at website: https://github.com/Tan-group/FebRNA.

biophysics↗

bioRxiv2022

ILC3s select for RORγt+ Tregs and establish tolerance to intestinal microbiota

Microbial colonization of the mammalian intestine elicits inflammatory or tolerogenic T cell responses, but the mechanisms controlling these distinct outcomes remain poorly understood and accumulating evidence indicates that aberrant immunity to intestinal microbiota is causally associated with infectious, inflammatory, and malignant diseases1-8. Here, we define a critical pathway controlling the fate of inflammatory versus tolerogenic T cells that are specific for the microbiota and express the transcription factor ROR{gamma}t. We profiled all ROR{gamma}t+ immune cells at single cell resolution from the intestine-draining lymph nodes of mice and reveal a dominant presence of Tregs and lymphoid tissue-induced (LTi)-like group 3 innate lymphoid cells (ILC3s), which co-localize at interfollicular regions. These ILC3s have interconverting potential with ROR{gamma}t+ extrathymic Aire-expressing cells, abundantly express major histocompatibility complex class II, and are necessary and sufficient to promote microbiota-specific ROR{gamma}t+ Tregs and prevent their expansion as inflammatory T helper (Th)17 cells. This occurs through ILC3-mediated antigen-presentation, interleukin-2 gradients, and v integrin. Finally, single-cell analyses demonstrate that ILC3 and ROR{gamma}t+ Treg interactions are impaired in inflammatory bowel disease. Our results define a novel paradigm whereby ILC3s positively select for antigen specific ROR{gamma}t+ Tregs, and against Th17 cells, to establish immune tolerance to the microbiota and intestinal health.

immunology↗

bioRxiv2022

Identification and calibration of ultrabright localizations to eliminate quantification error in SMLM

Single molecule localization microscopy (SMLM) is irreplaceable among super-resolution microscopies in revealing biological ultra-structures, given its unmatched high resolution. However, its sub-optimal quantitative capability, which is critical for characterizing true biomolecular organization of ultra-structures in cells, has hindered its widest application in biomedical research. Here, in SMLM imaging of cellular structures such as lipid rafts and microtubules with saturation labelling, we identified ultra-bright localizations, each of which is contributed by simultaneous emission of multiple molecules within a diffraction-limit region and has been regarded before as a regular localization from single molecule. Consistently, ultra-bright localizations are also observed in simulated SMLM imaging of endoplasmic reticulum or microtubules from public resource. Furthermore, after calibrating each ultrabright localization into multiple single-molecule localizations using the photon-number-based models, the density of total localizations shows linear correlation with the true molecule density, presenting SMLM with new reconstruction method as a quantitative analysis approach. Therefore, identification and dissection of ultra-bright localizations in SMLM enable the close and quantitative estimate of the true biomolecular organization.

biophysics↗

bioRxiv2022

PPML-Omics: a Privacy-Preserving federated Machine Learning system protects patients' privacy from omic data

Modern machine learning models towards various tasks with omic data analysis give rise to threats of privacy leakage of patients involved in those datasets. Despite the advances in different privacy technologies, existing methods tend to introduce too much computational cost (e.g. cryptographic methods) or noise (e.g. differential privacy), which hampers either model usefulness or accuracy in protecting privacy in biological data. Here, we proposed a secure and privacy-preserving machine learning method (PPML-Omics) by designing a decentralized version of the differential private federated learning algorithm. We applied PPML-Omics to analyze data from three sequencing technologies, and addressed the privacy concern in three major tasks of omic data, namely cancer classification with bulk RNA-seq, clustering with single-cell RNA-seq, and the integration of spatial gene expression and tumour morphology with spatial transcriptomics, under three representative deep learning models. We also examined privacy breaches in depth through privacy attack experiments and demonstrated that PPML-Omics could protect patients privacy. In each of these applications, PPML-Omics was able to outperform methods of comparison under the same level of privacy guarantee, demonstrating the versatility of the method in simultaneously balancing the privacy-preserving capability and utility in practical omic data analysis. Furthermore, we gave the theoretical proof of the privacy-preserving capability of PPML-Omics, suggesting the first mathematically guaranteed method with robust and generalizable empirical performance in protecting patients privacy in omic data.

bioinformatics↗