Biology subjects

Chen, S.

Publications and source records attributed to Chen, S..

At least 559 records · Page 31Linked to original sources

bioRxiv2023

Exposure to high-sugar diet induces transgenerational changes in sweet sensitivity and feeding behavior via H3K27me3 reprogramming

Human health is facing a host of new threats linked to unbalanced diets, including high sugar diet (HSD), which contributes to the development of both metabolic and behavioral disorders. Studies have shown that diet-induced metabolic dysfunctions can transmit to multiple generations of offspring and exert long-lasting health burden. Meanwhile, whether and how diet-induced behavioral abnormalities can be transmitted to the offspring remain largely unclear. Here, we showed that ancestral HSD exposure suppressed sweet sensitivity and feeding behavior in the offspring in Drosophila. These behavioral deficits were transmitted through the maternal germline and companied by the enhancement of H3K27me3 modifications. PCL-PRC2 complex, a major driver of H3K27 trimethylation, was upregulated by ancestral HSD exposure, and disrupting its activity eliminated the transgenerational inheritance of sweet sensitivity and feeding behavior deficits. Elevated H3K27me3 inhibited the expression of a transcriptional factor Cad and suppressed sweet sensitivity of the sweet-sensing gustatory neurons, reshaping the sweet perception and feeding behavior of the offspring. Taken together, we uncovered a novel molecular mechanism underlying behavioral abnormalities across multiple generations of offspring upon ancestral HSD exposure, which would contribute to the further understanding of long-term health risk of unbalanced diet.

neuroscience↗

bioRxiv2023

Spike substitution T813S increases Sarbecovirus fusogenicity by enhancing the usage of TMPRSS2.

SARS-CoV Spike (S) protein shares considerable homology with SARS-CoV-2 S, especially in the conserved S2 subunit (S2). S protein mediates coronavirus receptor binding and membrane fusion, and the latter activity can greatly influence coronavirus infection. We observed that SARS-CoV S is less effective in inducing membrane fusion compared with SARS-CoV-2 S. We identify that S813T mutation is sufficient in S2 interfering with the cleavage of SARS-CoV-2 S by TMPRSS2, reducing spike fusogenicity and pseudoparticle entry. Conversely, the mutation of T813S in SARS-CoV S increased fusion ability and viral replication. Our data suggested that residue 813 in the S was critical for the proteolytic activation, and the change from threonine to Serine at 813 position might be an evolutionary feature adopted by SARS-2-related viruses. This finding deepened the understanding of Spike fusogenicity and could provide a new perspective for exploring Sarbecovirus evolution. Author SummaryThe Spike strain of SARS-CoV-2 has accumulated many mutations during its time in circulation, most of which have occurred in the S1 region, and more specifically in the RBD, in an effort to either improve the viruss affinity for the receptor ACE2 or to enhance its ability to evade the immune system. Mutations in the Spike S2 region have more far-reaching effects than those in the S1 region because it is more conserved across sarbecoviruses. By comparing SARS and SARS2, we found that an important substitution at amino acid position 813 in the S2 region (T813S) disrupts the utilization of TMPRSS2 and can significantly influence viral entry into cells. This discovery deepens our knowledge of S proteins and provides new prospects for tracing the evolution of Sarbecoviruses.

microbiology↗

bioRxiv2023

LDL Receptor-Related Protein 5 is a Selective Transporter for Unesterified Polyunsaturated Fatty Acids

Polyunsaturated fatty acids (PUFAs), which cannot be synthesized by animals and must be supplied from the diet, have been strongly associated with human health. However, the mechanisms for their accretion and actions remain poorly understood. Here, we show that LDL receptor-related protein 5 (LRP5), but not its homolog LRP6, selectively transports unesterified PUFAs into a number of cell types. The LDLa ligand-binding repeats of LRP5 directly bind to PUFAs and are required for PUFA transport. LRP5 transports PUFAs via internalization to intracellular compartments including lysosomes, and n-3 PUFAs depends on this transport mechanism to inhibit mTORC1. This LRP5-mediated PUFA transport mechanism suppresses neutrophil extracellular trap formation in neutrophils and protects mice from myocardial injury during ischemia-reperfusion. Thus, this study reveals a previously unknown and biologically important mechanism for PUFA transport and mTORC1 regulation.

cell biology↗

bioRxiv2023

Integration of spatial and single-cell data across modalities with weak linkage

single-cell sequencing methods have enabled the profiling of multiple types of molecular readouts at cellular resolution, and recent developments in spatial barcoding, in situ hybridization, and in situ sequencing allow such molecular readouts to retain their spatial context. Since no technology can provide complete characterization across all layers of biological modalities within the same cell, there is pervasive need for computational cross-modal integration (also called diagonal integration) of single-cell and spatial omics data. For current methods, the feasibility of cross-modal integration relies on the existence of highly correlated, a priori "linked" features. When such linked features are few or uninformative, a scenario that we call "weak linkage", existing methods fail. We developed MaxFuse, a cross-modal data integration method that, through iterative co-embedding, data smoothing, and cell matching, leverages all information in each modality to obtain high-quality integration. MaxFuse is modality-agnostic and, through comprehensive benchmarks on single-cell and spatial ground-truth multiome datasets, demonstrates high robustness and accuracy in the weak linkage scenario. A prototypical example of weak linkage is the integration of spatial proteomic data with single-cell sequencing data. On two example analyses of this type, we demonstrate how MaxFuse enables the spatial consolidation of proteomic, transcriptomic and epigenomic information at single-cell resolution on the same tissue section.

bioinformatics↗

bioRxiv2023

Spatial transcriptomics reveals a conserved segment polarity program that governs muscle patterning in Nematostella vectensis

During early animal evolution, the emergence of axially-polarized segments was central to the diversification of complex bilaterian body plans. Nevertheless, precisely how and when segment polarity pathways arose remains obscure. Here we demonstrate the molecular basis for segment polarization in developing larvae of the pre-bilaterian sea anemone Nematostella vectensis. Utilizing spatial transcriptomics, we first constructed a 3-D gene expression atlas of developing larval segments. Capitalizing on accurate in silico predictions, we identified Lbx and Uncx, conserved homeodomain-containing genes that occupy opposing subsegmental domains under the control of both BMP signaling and the Hox-Gbx cascade. Functionally, Lbx mutagenesis eliminated all molecular evidence of segment polarization at larval stage and caused an aberrant mirror-symmetric pattern of retractor muscles in primary polyps. These results demonstrate the molecular basis for segment polarity in a pre-bilaterian animal, suggesting that polarized metameric structures were present in the Cnidaria-Bilateria common ancestor over 600 million years ago. HighlightsO_LINematostella endomesodermal tissue forms metameric segments and displays a transcriptomic profile similar to that observed in bilaterian mesoderm C_LIO_LIConstruction of a comprehensive 3-D gene expression atlas enables systematic dissection of segmental identity in endomesoderm C_LIO_LILbx and Uncx, two conserved homeobox-containing genes, establish segment polarity in Nematostella C_LIO_LIThe Cnidarian-Bilaterian common ancestor likely possessed the genetic toolkit to generate polarized metameric structures C_LI

evolutionary biology↗

bioRxiv2023

A converged ubiquitin-proteasome pathway for the degradation of TOC and TOM tail-anchored receptors

In plants, thousands of nucleus-encoded proteins translated in the cytosol are sorted to chloroplasts and mitochondria by binding to specific receptors of the TOC (translocon at the outer membranes of chloroplasts) and the TOM (translocon at the outer membranes of mitochondria) complexes for import into those organelles. The degradation pathways for these receptors are unclear. Here, we discovered a converged ubiquitin-proteasome pathway for the degradation of Arabidopsis thaliana TOC and TOM tail-anchored receptors. The receptors are ubiquitinated by E3 ligase(s) and pulled from the outer membranes by the AAA+ ATPase CDC48, after which a previously characterized cytosolic protein, TTOP, binds to the exposed transmembrane domains (TMDs) at the C termini of the receptors and CDC48, and delivers these complexes to the 26S proteasome.

plant biology↗

bioRxiv2022

Comparative analysis of chloroplast genome between wild and cultivated Rehmannia glutinosa Libosch.

Rehmanniae radix, as a tonic Chinese medicine, has a good therapeutic effect on cardiovascular and cerebrovascular diseases and central nervous system diseases, and has a good development prospect in the international market. R.glutinosa Libosch has a large number of source varieties, and the wild and cultivated varieties are different types of R.glutinosa Libosch. There has been a lot of controversy in the formulation of scientific names for wild and cultivated types of R.glutinosa Libosch. In order to learn more about the genetic information of wild R.glutinosa Libosch and explore the phylogenetic relationship between wild R.glutinosa Libosch and cultivated R.glutinosa Libosch. In the current study, we constructed and annotated a complete circular chloroplast genome of wild R.glutinosa Libosch. The chloroplast genome of wild R.glutinosa Libosch. is 153,678 bp in length, including two inverted repeat (IR) regions of 25,759 bp, separated by a large single copy (LSC) region of 84,544 bp and a small single copy (SSC) region of 17,616 bp. The GC content of whole chloroplast genome is 37.9%. The genome contains 133 different genes, including 88 protein-coding genes, 37 tRNA genes, and 8 rRNA genes. Among them, 23 genes contained introns, 50 SSR loci and 49 long repeats were found by Microsatellite scan, and codon use showed obvious A, T base preference. Nine variation regions were screened by mVISTA analysis and combined with DnaSP analysis, and psaJ-rpl33 was finally identified as a region with high variation, which could be used as a candidate DNA barcode for later interspecific identification of R.glutinosa Libosch.. Neighbor-joining method phylogenomic analysis showed that wild R.glutinosa Libosch. formed a monophyletic group, and was sister to other groups of R.glutinosa Libosch.The results of this study revealed the chloroplast genome information of wild R.glutinosa Libosch in detail, and found the genetic information difference between wild and cultivated R.glutinosa Libosch. which laid the foundation for the variety identification, genetic engineering, biosynthesis and other studies.

molecular biology↗

bioRxiv2022

Enhancer-driven gene regulatory networks inference from single-cell RNA-seq and ATAC-seq data

Deciphering the intricate relationships between transcription factors (TFs), enhancers, and genes through the inference of enhancer-driven gene regulatory networks is crucial in understanding gene regulatory programs in a complex biological system. This study introduces STREAM, a novel method that leverages a Steiner Forest Problem model, a hybrid biclustering pipeline, and submodular optimization to infer enhancer-driven gene regulatory networks from jointly profiled single-cell transcriptome and chromatin accessibility data. Compared to existing methods, STREAM demonstrates enhanced performance in terms of TF recovery, TF-enhancer relation prediction, and enhancer-gene discovery. Application of STREAM to an Alzheimers disease dataset and a diffuse small lymphocytic lymphoma dataset reveals its ability to identify TF-enhancer-gene relationships associated with pseudotime, as well as key TF-enhancer-gene relationships and TF cooperation underlying tumor cells.

bioinformatics↗

bioRxiv2022

Intramuscular injection of nerve growth factor as a model of temporomandibular disorder: nature, time-course, and sex differences characterising the pain experience

BackgroundTemporomandibular disorder (TMD) is a common condition that frequently transitions to chronic symptoms. Experimental pain models that mimic the symptoms of clinical TMD may be useful in understanding the mechanisms, and sex differences, present in this disorder. Here we aimed to comprehensively characterise the nature and time-course of pain, functional impairment and hyperalgesia induced by repeated intramuscular injection of nerve growth factor (NGF) into the masseter muscle, and to investigate sex differences in the NGF-induced pain experience. Methods94 healthy individuals participated in a longitudinal observational study with 30-day follow-up. NGF was injected into the right masseter muscle on Day 0 and Day 2. Participants attended laboratory sessions to assess pain (Numerical Rating Scale; NRS), functional limitation (mouth opening distance, Jaw Functional Limitation Scale; JFLS) and mechanical sensitization (pressure pain thresholds; PPTs) on Days 0, 2 and 5 and completed twice daily electronic pain dairies from Day 0 to day 30. ResultsPeak pain averaged 2.0/10 (95 % CI: 1.6-2.4) at rest and 4.3/10 (95 % CI: 3.9-4.8) on chewing. Pain-free mouth opening distance reduced from 5.0 cm (95 % CI: 4.8-5.1 cm) on Day 0 to 3.7 cm (95 % CI: 3.5-3.9 cm) on Day 5. The greatest reduction in PPTs was observed over the masseter muscle. Females experienced higher pain, greater functional impairment, and greater sensitivity to mechanical stimuli than males. ConclusionIntramuscular injection of NGF is a useful model with which to explore the mechanisms, and sex differences, present in clinical TMD.

neuroscience↗

bioRxiv2022

Conditional deletion of LRRC8A in the brain protects against stroke damage independently of effect on swelling-activated glutamate release

The ubiquitous volume-regulated anion channels (VRACs), which are composed of LRRC8 proteins, facilitate cell volume homeostasis, and contribute to many other physiological processes. Prior studies demonstrated that treatment with non-specific VRAC blockers, or brain-specific deletion of the essential VRAC subunit LRRC8A, are highly protective in rodent stroke. In this work, we tested the widely accepted idea that harmful effects of VRACs in the brain are mediated by pathological release of the excitatory transmitter glutamate. We used two molecular genetic strategies to ablate LRRC8A expression in either brain astrocytes only (inducible deletion of Lrrc8aflox/flox with Aldh1l1CreERT2) or the majority of brain cells (neurons, astrocytes, and oligodendrocytes with NestinCre). To produce stroke, genetically modified mice were subjected to a 40-minute occlusion of the middle cerebral artery. The inducible deletion of astrocytic LRRC8A yielded no histological or behavioral protection. In contrast, the brain-wide LRRC8A knockout reduced ischemic infarction by ~50% in both heterozygotes (Het) and the full Lrrc8a knockout (KO) as compared to the control Lrrc8aflox/+ genotype. However, despite identical brain damage, Het and KO mice dramatically differed in their VRAC activities. Het mice had full swelling-activated glutamate release, while KO animals showed its virtual absence. These new findings refute the notion that VRAC-mediated glutamate release plays significant role in ischemic brain injury.

neuroscience↗

bioRxiv2022

Genetically engineered mesenchymal stem cells as a nitric oxide reservoir for acute kidney injury therapy

Nitric oxide (NO), as a gaseous therapeutic agent, shows great potential for the treatment of many kinds of diseases. Although various NO delivery systems have emerged, the immunogenicity and long-term toxicity of artificial carriers hinder the potential clinical translation of this gas therapeutics. Mesenchymal stem cells (MSCs), with the capacities of self-renewal, differentiation, and low immunogenicity, have been used as living carriers. However, MSCs as gaseous signaling molecule (GSM) carriers have not been reported. In this study, MSCs were genetically modified to produce mutant {beta}-galactosidase ({beta}-GALH363A). Furthermore, a new NO prodrug, 6-methyl-galactose-benzyl-oxy NONOate (MGP), was designed. MGP can entrance into cell and selectively trigger the NO release from genetically engineered MSCs (eMSCs) in the presence of {beta}-GALH363A. Moreover, our results revealed that eMSCs can release NO when MGP is systemically administered in a mouse model of acute kidney injury (AKI), which can achieve NO release in a precise spatiotemporal manner and augment the therapeutic efficiency of MSCs. This eMSC and NO prodrug system provides a unique and tunable platform for GSM delivery and holds promise for regenerative therapy by enhancing the therapeutic efficiency of stem cells. SignificanceGaseous signaling molecules (GSMs), such as nitric oxide (NO), hold tremendous potential in regenerative medicine and tissue engineering. However, the delivery of GSMs with stem cells to target tissues or organs in response to demand has never been reported. This study designed engineered mesenchymal stem cells (eMSCs) that produce mutant {beta}-galactosidase ({beta}-GALH363A) and trigger NO release when the NO prodrug is systemically administered, which can achieve NO release in a precise spatiotemporal manner and augment the therapeutic efficiency of MSCs in a mouse model of acute kidney injury (AKI). This eMSC and NO prodrug system provides a unique and tunable platform for GSM delivery and holds promise for regenerative therapy by enhancing the therapeutic efficiency of stem cells. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=128 SRC="FIGDIR/small/519950v1_ufig1.gif" ALT="Figure 1"> View larger version (28K): org.highwire.dtl.DTLVardef@1d8f4e4org.highwire.dtl.DTLVardef@b5e548org.highwire.dtl.DTLVardef@1dff1edorg.highwire.dtl.DTLVardef@184130e_HPS_FORMAT_FIGEXP M_FIG C_FIG

biochemistry↗

bioRxiv2022

Identifying B-cell epitopes using AlphaFold2 predicted structures and pretrained language model

MotivationIdentifying the B-cell epitopes is an essential step for guiding rational vaccine development and immunotherapies. Due to experimental approaches being expensive and time-consuming, many computational methods have been designed to assist B-cell epitope prediction. However, existing sequence-based methods have limited performance since they only use contextual features of the sequential neighbors while neglecting structural information. ResultsBased on the recent breakthrough of AlphaFold2 in protein structure prediction, we propose GraphBepi, a novel graph-based model for accurate B-cell epitope prediction. GraphBepi first generates the effective information sequence representations and protein structures from antigen sequences through the pretrained language model and AlphaFold2, respectively. GraphBepi then applies the edge-enhanced deep graph neural network (EGNN) to capture the spatial information from predicted protein structures and leverages the bidirectional long short-term memory neural networks (BiLSTM) to capture long-range dependencies from sequences. The low-dimensional representation learned by EGNN and BiLSTM is then combined to predict B-cell epitopes through a multilayer perceptron. Through comprehensive tests on the curated epitope dataset, GraphBepi was shown to outperform the state-of-the-art methods by more than 5.5% and 44.0% in terms of AUC and AUPR, respectively. We also provide the GraphBepi web server that is freely available at https://biomed.nscc-gz.cn/apps/GraphBepi. AvailabilityThe datasets, pre-computed features, source codes, and the pretrained model of GraphBepi are available at https://github.com/biomed-AI/GraphBepi. Contactyangyd25@mail.sysu.edu.cn or gaojz@nankai.edu.cn

bioinformatics↗

bioRxiv2022

Hepatitis E virus genome replication is independent of cyclophilins A and B

Hepatitis E virus (HEV) is an emerging pathogen responsible for more than 20 million cases of acute hepatitis globally per annum. Healthy individuals typically have a self-limiting infection, however, mortality rates in some populations such as pregnant women can reach 30%. A detailed understanding of the virus lifecycle is lacking, mainly due to limitations in experimental systems. In this regard, the cyclophilins are an important family of proteins that have peptidyl-prolyl isomerase activity and play roles in the replication of a number of positive-sense RNA viruses, including hepatotropic viruses such as hepatitis C virus (HCV). Cyclophilin A (CypA) and cyclophilin B (CypB) are the two most abundant human cyclophilins in hepatocytes and are therefore potential targets for pan-viral therapeutics. Here, we investigated the importance of CypA and CypB for HEV genome replication using a sub-genomic replicon system. This system removes the requirements for viral entry and packaging and therefore allows for the sensitive measurement of viral genome replication in isolation. Using pharmacological inhibition by cyclosporine A (CsA), known to suppress HCV replication, and silencing by shRNA we find that CypA and CypB are not essential for replication of genotype 1 or 3 HEV replication. However, we find that silencing of CypB reduces replication of genotype 1 HEV in some cells, but not genotype 3. These data suggests HEV is atypical in its requirements for cyclophilin for viral genome replication and that this phenomenon could be genotype specific.

microbiology↗

bioRxiv2022

Comparing Genomic and Epigenomic Features across Species Using the WashU Comparative Epigenome Browser

Genome browsers have become an intuitive and critical tool to visualize and analyze genomic features and data. Conventional genome browsers display data/annotations on a single reference genome/assembly; there are also genomic alignment viewer/browsers that help users visualize alignment, mismatch, and rearrangement between syntenic regions. However, there is a growing need for a comparative epigenome browser that can display genomic and epigenomic datasets across different species and enable users to compare them between syntenic regions. Here, we present the WashU Comparative Epigenome Browser (http://comparativegateway.wustl.edu). It allows users to load functional genomic datasets/annotations mapped to different genomes and display them over syntenic regions simultaneously. The browser also displays genetic differences between the genomes from single nucleotide variants (SNVs) to structural variants (SVs) to visualize the association between epigenomic differences and genetic differences. Instead of anchoring all datasets to the reference genome coordinates, it creates independent coordinates of different genome assemblies to faithfully present features and data mapped to different genomes. It uses a simple, intuitive genome-align track to illustrate the syntenic relationship between different species. It extends the widely used WashU Epigenome Browser infrastructure and can be expanded to support multiple species. This new browser function will greatly facilitate comparative genomic/epigenomic research, as well as support the recent growing needs to directly compare and benchmark the T2T CHM13 assembly and other human genome assemblies.

genomics↗

bioRxiv2022

Rho enhancers play unexpectedly minor roles in Rhodopsin transcription and rod cell integrity

Enhancers function with a basal promoter to control the transcription of target genes. Enhancer regulatory activity is often studied using reporter-based transgene assays. However, unmatched results have been reported when selected enhancers are silenced in situ. In this study, using genomic deletion analysis in mice, we investigated the roles of two previously identified enhancers and the promoter of the Rho gene that codes for the visual pigment rhodopsin. The Rho gene is robustly expressed by rod photoreceptors of the retina, and essential for the subcellular structure and visual function of rod photoreceptors. Mutations in RHO cause severe vision loss in humans. We found that each Rho regulatory region can independently mediate local epigenomic changes, but only the promoter is absolutely required for establishing active Rho chromatin configuration and transcription and maintaining the cell integrity and function of rod photoreceptors. To our surprise, two Rho enhancers that enable strong promoter activation in reporter assays are largely dispensable for Rho expression in vivo. Only small and age-dependent impact is detectable when both enhancers are deleted. Our results demonstrate context-dependent roles of enhancers and highlight the importance of studying functions of cis-regulatory regions in the native genomic context.

genomics↗

bioRxiv2022

The Epithelial Na+ Channel UNC-8 promotes an endocytic mechanism that recycles presynaptic components from old to new boutons in remodeling neurons

SummaryPresynaptic terminals are actively relocated during development to refine circuit function, but the underlying cell biological mechanisms are largely unknown. In C. elegans, the presynaptic boutons of GABAergic DD neurons are moved to new locations during early larval development. We show that developmentally regulated expression of a presynaptic Epithelial Na+ Channel (ENaC), UNC-8, promotes a Ca2+-dependent mechanism, resembling Activity-Dependent Bulk Endocytosis (ADBE), that dismantles presynaptic material for reassembly at nascent DD synapses. ADBE normally functions in highly active neurons to accelerate local recycling of synaptic vesicles. We show that DD presynaptic remodeling depends on canonical features of ADBE including elevated intracellular Ca2+, the phosphatase Calcineurin and its targets, dynamin and the F-BAR protein syndapin, and Arp2/3-driven actin polymerization. Thus, our findings suggest that a native mechanism (ADBE) for maintaining neurotransmitter release at local synapses has been repurposed, in this case, to dismantle presynaptic terminals for reassembly at new locations. HighlightsO_LIDeveloping GABAergic neurons dismantle presynaptic terminals for reassembly at new locations. C_LIO_LIThe DEG/ENaC protein, UNC-8, promotes presynaptic disassembly and recycling C_LIO_LICa2+-dependent endocytosis drives presynaptic disassembly and recycling to new boutons C_LI

neuroscience↗

bioRxiv2022

FMRP phosphorylation modulates neuronal translation through YTHDF1

Translation activation of local synaptic mRNAs is critical to learning and memory1-3. Despite extensive studies on how phosphorylation of ribosomal proteins and translation factors enables timely response to exogenous stimuli4, our knowledge on molecular pathways utilized by RNA binding proteins (RBPs) to control translation of specific mRNAs remains incomplete. We have previously found that YTHDF1 regulates depolarization-induced protein synthesis by promoting translation of N6-methyladenosine (m6A)-modified transcripts5. Here we report an unexpected mechanism that the stimuli-induced neuronal translation is mediated by phosphorylation of a YTHDF1-binding protein FMRP. Phosphorylation of FMRP serine 499 induced by neuronal depolarization alters the condensing behavior of prion-like protein YTHDF1. Unphosphorylated FMRP sequesters YTHDF1 away from the translation initiation complex, whereas the stimulation-induced FMRP phosphorylation releases YTHDF1 to form translational active condensates with the ribosome to activate translation of YTHDF1 target transcripts. In fragile X syndrome (FXS) models characterized by low FMRP expression, we observed YTHDF1-mediated hyperactive translation, which notably impacts FXS pathophysiology. Developmental defects in an FXS forebrain organoid model could be reversed by a selective small-molecule inhibitor of YTHDF1 which acts by suppressing its condensation in neurons. We characterized transcriptome-wide mRNA translation with inhibitor treatment in organoids and identified targets that explain alleviated FXS pathology. Our study thus reveals FMRP and its phosphorylation as an important regulator of the activity-dependent translation during neuronal development and stimulation, and identifies YTHDF1 as a potential therapeutic target for FXS in which developmental defects caused by FMRP depletion could be reversed through YTHDF1 inhibition.

molecular biology↗

bioRxiv2022

Polyvalent mRNA vaccination elicited potent immune response to monkeypox surface antigens

The soaring global monkeypox cases lead to a surge in demand for monkeypox vaccine, which far exceeds the supply. mRNA vaccine has achieved great success in prevention of coronavirus disease and holds promise against diverse pathogens. In this study, we generate a polyvalent lipid nanoparticle (LNP) mRNA vaccine candidate for monkeypox virus (MPXV) and evaluate its immunogenicity in animal models. This polyvalent MPXV mRNA vaccine candidate, MPXVac-097, encodes five 2022 MPXV targets that are important surface antigens. Three-dose (prime-boost-booster) MPXVac-097 vaccination elicits strong antibody response to A35R and E8L antigens, moderate response to M1R, but not B6R or A29, highlighting the differences in immunogenicity. Bulk T cell receptor (TCR) sequencing reveals preferential usage of VJ combinations and clonal expansion of peripheral T cells after MPXVac-097 vaccination. These data demonstrate initial feasibility of developing MPXV mRNA vaccine and pave the way for its future optimization.

immunology↗