Biology subjects

Ma, S.

Publications and source records attributed to Ma, S..

At least 181 records · Page 10Linked to original sources

bioRxiv2022

A Neural Index Reflecting the Amount of Cognitive Resources Available during Memory Encoding: A Model-based Approach

Humans have a limited amount of cognitive resources to process various cognitive operations at a given moment. The Source of Activation Confusion (SAC) model of episodic memory proposes that resources are consumed during each processing and once depleted they need time to recover gradually. This has been supported by a series of behavioral findings in the past. However, the neural substrate of the resources is not known. In the present study, over an existing EEG dataset of a free recall task (Kahana et al., 2022), we provided a neural index reflecting the amount of cognitive resources available for forming new memory traces. Unique to our approach, we obtained the neural index not through correlating neural patterns with behavior outcomes or experimental conditions, but by demonstrating its alignment with a latent quantity of cognitive resources inferred from the SAC model. In addition, we showed that the identified neural index can be used to propose novel hypothesis regarding other long-term memory phenomena. Specifically, we found that according to the neural index, neural encoding patterns for subsequently recalled items correspond to greater available cognitive resources compared with that for subsequently unrecalled items. This provides a mechanistic account for the long-established subsequent memory effects (SMEs, i.e. differential neural encoding patterns between subsequently recalled versus subsequently unrecalled items), which has been previously associated with attention, fatigue and properties of the stimuli.

neuroscience↗

bioRxiv2022

A microglia-CD4+ T cell partnership generates protective anti-tumor immunity to glioblastoma

The limited efficacy of immunotherapies against glioblastoma illustrates the urgent need to better understand the interactions between the central nervous system and the immune system. Here, we showed that a protective response to CTLA-4 therapy depended on a mutualistic relationship between microglia and CD4+ T cells. Suppression of gliomas by CD4+ T cells did not require tumor-intrinsic MHC-II expression, but rather was dependent on the selective expression of MHC-II and antigen presentation by local microglia that in turn, sustained CD4+ T cell tumoricidal effector functions. CD4+ T cell secretion of IFN{gamma} made the glioma cells vulnerable to enhanced tumor surveillance and phagocytosis by microglia via the AXL/MER tyrosine kinase receptors that were necessary for tumor suppression. This work illustrates a novel partnership between CD4+ T cells and microglia that unleashes the tumoricidal properties of microglia that can be harnessed to improve immunotherapies for glioblastoma.

immunology↗

bioRxiv2022

Molecular atlas reveals the tri-sectional spinning mechanism of spider dragline silk

We performed the first molecular atlas of natural spider dragline silk production using genome assembly for the golden orb-web spider Trichonephila clavata and multiomics defining for the segmented major ampullate (Ma) gland: Tail, Sac, and Duct. We uncovered a hierarchical biosynthesis of spidroins, organic acids, lipids, and chitin in the sectionalized Ma gland dedicated to fine silk constitution. The ordered secretion of spidroins was achieved by the synergetic regulation of epigenetic and ceRNA signatures for genomic group-distributed spidroin genes. Single-cellular and spatial RNA profiling identified ten cell types with partitioned functional division determining the tri-sectional organization of the Ma gland. Convergent evolution and genetic manipulation analyses further validated that this tri-sectional architecture of the silk gland was analogous in silk-spinning animals and inextricably linked with silk formation. Our study provided multiple levels of data that significantly expand the knowledge of spider dragline silk generation and may eventually benefit spider-inspired fiber innovations.

genomics↗

bioRxiv2022

Two ligand-binding sites on SARS-CoV-2 non-structural protein 1 revealed by fragment-based x-ray screening

The regular reappearance of coronavirus (CoV) outbreaks over the past 20 years has caused significant health consequences and financial burdens worldwide. The most recent and still ongoing novel CoV pandemic, caused by Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) has brought a range of devastating consequences. Due to the exceptionally fast development of vaccines, the mortality rate of the virus has been curbed to a significant extent. However, the limitations of vaccination efficiency and applicability, coupled with the still high infection rate, emphasise the urgent need for discovering safe and effective antivirals against SARS-CoV-2 through suppressing its replication and or attenuating its virulence. Non-structural protein 1 (nsp1), a unique viral and conserved leader protein, is a crucial virulence factor for causing host mRNA degradation, suppressing interferon (IFN) expression and host antiviral signalling pathways. In view of the essential role of nsp1 in the CoV life cycle, it is regarded as an exploitable target for antiviral drug discovery. Here, we report a variety of fragment hits against SARS-CoV-2 nsp1 identified by fragment-based screening via X-ray crystallography. We also determined the structure of nsp1 at atomic resolution (0.95 [A]). Binding affinities of hits against nsp1 were determined by orthogonal biophysical assays such as microscale thermophoresis and thermal sift assays. We identified two ligand-binding sites on nsp1, one deep and one shallow pocket, which are not conserved between the three medially relevant SARS, SARS-CoV-2 and MERS coronaviruses. Our study provides an excellent starting point for the development of more potent nsp1-targeting inhibitors and functional studies on SARS-CoV-2 nsp1.

biochemistry↗

bioRxiv2022

Innate and adaptive immune basis of mental health effect on Alzheimer's disease progression

Mental health has long been suspected to be highly associated with neurodegenerative disease, but it lacks experimental evidence to elaborate the link and immunological mechanism between them. In this work, we studied the progression of Alzheimers disease (AD) and its associated immune activity by using the transgenic mice under negative (depression) and positive (environmental enrichment, EE) mental health intervention. The tissue pathology, resident and peripheral immunity and behavioral characteristics were investigated. The transgenic mice undergoing depression treatment was featured with aggravated AD pathology, elevated activation of microglia in the brains, more abundance of Treg cells and cytotoxic T cells, and higher ratios of central memory T cells to effector memory T (TCM-to-TEM) cells in the peripheral blood and spleens. The EE treated mice were featured with alleviated AD pathology, reduced activation of microglia, less amounts of Treg and cytotoxic T cells and lower ratios of TCM-to-TEM cells. This study may provide strategies for immunity regulation and mental health intervention that benefit AD therapy. Significance statementMental health is suspected to regulate AD progression, but its validation in histology examination and the regulatory mechanism remains unclear. Here, we prove that both innate and adaptive immunity are playing important roles and mental health-immunity-AD progression forms a triad. More active microglia, Treg, and cytotoxic T cells, and higher TCM-to-TEM feature negative mental health and severer AD progress, and vice versa. The findings in adaptive immunity and the triad may inspire AD regulation.

animal behavior and cognition↗

bioRxiv2022

Excessive Mechanotransduction in Sensory Neurons Causes Joint Contractures in a Mouse Model of Arthrogryposis

Distal arthrogryposis (DA) is a collection of rare disorders characterized by congenital joint contractures. Most DA mutations are in muscle- and joint-related genes, and the anatomical defects originate cell-autonomously within the musculoskeletal system. However, gain-of-function (GOF) mutations in PIEZO2, a principal mechanosensor in somatosensation, cause DA subtype 5 via unknown mechanisms. We show that expression of a GOF PIEZO2 mutation in proprioceptive sensory neurons mainly innervating muscle spindles and tendons is sufficient to induce DA5-like phenotypes in mice. Overactive PIEZO2 causes anatomical defects via increased activity within the peripheral nervous system during postnatal development. Remarkably, Botox and a dietary fatty acid that modulates PIEZO2 activity markedly reduce DA5-like deficits. This reveals an unexpected role for somatosensory neurons: excessive mechanosensation within these neurons disrupts musculoskeletal development.

neuroscience↗

bioRxiv2022

Revealing druggable cryptic pockets in the Nsp-1 of SARS-CoV-2 and other β-coronaviruses by simulations and crystallography

Non-structural protein 1 (Nsp1) is a main pathogenicity factor of - and {beta}-coronaviruses. Nsp1 of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) suppresses the host gene expression by sterically blocking 40S host ribosomal subunits and promoting host mRNA degradation. This mechanism leads to the downregulation of the translation-mediated innate immune response in host cells, ultimately mediating the observed immune evasion capabilities of SARS-CoV-2. Here, by combining extensive Molecular Dynamics simulations, fragment screening and crystallography, we reveal druggable pockets in Nsp1. Structural and computational solvent mapping analyses indicate the partial crypticity of these newly discovered and druggable binding sites. The results of fragment-based screening via X-ray crystallography confirm the druggability of the major pocket of Nsp1. Finally, we show how the targeting of this pocket could disrupt the Nsp1-mRNA complex and open a novel avenue to design new inhibitors for other Nsp1s present in homologous {beta}-coronaviruses.

biophysics↗

bioRxiv2022

Intrinsic RNA targeting constrains the utility of CRISPR-Cas13 systems

CRISPR-Cas13 systems have been adapted as versatile toolkits for RNA-related applications. Here we systematically evaluate the performance of several popular Cas13 family effectors (Cas13a, Cas13b and Cas13d) under lentiviral vectors and reveal surprisingly differential defects and characteristics of these systems. Using RNA immunoprecipitation sequencing, transcriptome profiling, biochemistry analysis, high-throughput CRISPR-Cas13 screening and machine learning approaches, we determine that each Cas13 system has its intrinsic RNA targets in mammalian cells. Viral process-related host genes can be targeted by Cas13 and affect production of fertile lentiviral particles, thereby restricting the utility of lentiviral Cas13 systems. Multiple RNase activities of Cas13 are involved in endogenous RNA targeting. Unlike target-induced nonspecific collateral effect, intrinsic RNA cleavage can be specific, target-independent and dynamically tuned by varied states of Cas13 nucleases. Our work provides guidance on appropriate use of lentiviral Cas13 systems and further raises cautions about intrinsic RNA targeting during Cas13-based basic and therapeutic applications.

molecular biology↗

bioRxiv2022

TIR-catalyzed ADP-ribosylation reactions produce signaling molecules for plant immunity

Plant pathogen-activated immune signaling by nucleotide-binding leucine-rich repeat (NLR) receptors with an N-terminal Toll/Interleukin-1 receptor (TIR) domain converges on Enhanced Disease Susceptibility 1 (EDS1) and its direct partners Phytoalexin Deficient 4 (PAD4) or Senescence-Associated Gene 101 (SAG101). TIR-encoded NADases produce signaling molecules to promote exclusive EDS1-PAD4 and EDS1-SAG101 interactions with helper NLR sub-classes. Here we show that TIR-containing proteins catalyze adenosine diphosphate (ADP)-ribosylation of adenosine triphosphate (ATP) and ADP ribose (ADPR) via ADPR polymerase-like and NADase activity, forming ADP-ribosylated ATP (ADPr-ATP) and ADPr-ADPR (di-ADPR), respectively. Specific binding of di-ADPR or ADPr-ATP allosterically promotes EDS1-SAG101 interaction with helper NLR N requirement gene 1A (NRG1A) in vitro and in planta. Our data reveal an enzymatic activity of TIRs that enables specific activation of the EDS1-SAG101-NRG1 immunity branch.

plant biology↗

bioRxiv2022

Identification and receptor mechanism of TIR-catalyzed small molecules in plant immunity

Plant nucleotide-binding leucine-rich-repeat receptors (NLRs) with an N-terminal toll/interleukin-1 receptor (TIR) domain sense pathogen effectors to enable TIR-encoded NADase activity for immune signaling. TIR-NLR (TNL) signaling requires conserved helper NLRs NRG1 and ADR1 and the lipase-like protein EDS1 that functions as a heterodimer with each of its paralogs PAD4 and SAG101. We show that TIR-containing proteins catalyze production of 2-(5-phosphoribosyl)-5-adenosine mono-/di-phosphate (pRib-AMP/ADP) in vitro and in planta. Biochemical and structural data demonstrate that EDS1-PAD4 is a receptor complex for pRib-AMP/ADP. pRib-ADP binding triggers a conformational change in the PAD4 C-terminal domain to allosterically promote EDS1-PAD4 interaction with ADR1-L1 but not NRG1A. Our study identifies TIR-catalyzed pRib-AMP/ADP as a missing link in TIR signaling via EDS1-PAD4 and as likely second messengers for plant immunity.

plant biology↗

bioRxiv2022

Chromatin-associated lncRNA Malat1 regulates Th17 effector program and promotes intestinal inflammation

Interleukin IL-17 cytokines are central regulators of mucosal homeostasis and disease. In mouse models of colonic tissue injury, IL-17A promotes epithelial barrier functions and restricts local inflammation. Here, we report that IL-17A production by the diverse T lymphocyte subsets is dynamically regulated at different stages of colitis pathogenesis. During the onset and peak of the disease, T{gamma}{delta}17 cells are the major IL-17A producers, while Th17 activity is temporally restricted by long non-coding RNA (lncRNA) Malat1. In response to IL-6 and TGF{beta} signaling, Malat1 is recruited to the Th17-specific cis-regulatory elements, CNS3 and CNS4, of the Il17a locus to fine-tune bivalent super-enhancer activities and repress local transcription. During the resolution phase of inflammation, Malat1 expression is down-regulated to enhance Th17 activities, allowing Th17 cells to emerge as the main producers of IL-17A in the colonic lamina propria. Genetic ablation of Malat1 potentiates IL-17A production in Th17 cells and improves disease outcomes in mouse models of colitis. These findings uncover a surprising role of a chromatin-associated lncRNA in regulating colonic Th17-specific responses to control the timing of inflammation resolution. Significance StatementT cells are critical modulators of mucosal barrier function and inflammation. The function of long-noncoding RNAs (lncRNAs) in T cells and their role in mucosal inflammation remain elusive. Here, we identify an essential role of the lncRNA Malat1 restricting transcription of the Il17a locus in Th17 cells encoding a cytokine implicated in epithelial barrier function post-injury. By controlling the activity of the bivalent super-enhancer at the Il17a locus, Malat1 regulates the timing of inflammation resolution in the intestine. The Malat1-Il17a pathway reveals new targets for combating mucosal diseases. Graphic Abstract O_FIG_DISPLAY_L [Figure 1] M_FIG_DISPLAY C_FIG_DISPLAY

immunology↗

bioRxiv2022

The chromatin landscape of Th17 cells reveals mechanisms of diversification of regulatory and pro-inflammatory states

Th17 cells are a heterogenous cell population consisting of non-pathogenic Th17 cells (npTh17) that contribute to tissue homeostasis and pathogenic Th17 cells (pTh17) that are potent mediators of tissue inflammation. To reveal regulatory mechanisms underlying Th17 heterogeneity, we performed combined ATAC-seq and RNA-seq and discovered substantial differences in the chromatin landscape of npTh17 and pTh17 cells both in vitro and in vivo. Compared to other CD4+ T cell subsets, npTh17 cells share accessible chromatin programs with Tregs, and pTh17 cells have an intermediate profile spanning features of npTh17 cells and Th1 cells. Integrating single-cell ATAC-seq and single-cell RNA-seq, we inferred self-reinforcing and mutually exclusive regulatory networks controlling the different cell states and predicted transcription factors (TFs) shaping the chromatin landscape of Th17 cell pathogenicity. We validated one novel TF, BACH2, which promotes immunomodulatory npTh17 programs and restrains pro-inflammatory Th1-like programs in Th17 cells and showed genetic evidence for protective variants in the human BACH2 locus associated with multiple sclerosis. Our work uncovered mechanisms that regulate Th17 heterogeneity, revealed shared regulatory programs with other CD4+ T cell subsets, and identified novel drivers of Th17 pathogenicity as potential targets to mitigate autoimmunity.

immunology↗

bioRxiv2022

Hinokitiol alters Gene Expression in Aspergillus fumigatus, protects against fungal keratitis by Reducing Fungal Load, LOX-1, Proinflammatory cytokines and Neutrophil Infiltration

Hinokitiol (HK), a tropolone-related compound found in cupressaceous plants, has antifungal and anti-inflammatory properties. But its roles in Aspergillus fumigatus ( A.F. ) keratitis remains unknown. This study examined the antifungal activity of HK against A.F. and investigated its possible mechanisms at the ultrastructural and transcriptional levels. We tested the minimum inhibitory concentration (MIC) of HK against A.F.. Our data showed that the MIC50 was 2 g/ml and MIC90 was 8 g/ml, and HK could significantly inhibit the spore germination and mycelial growth of A.F.. Scanning electron microscopy (SEM) and transmission electron microscopy (TEM) observations showed that HK induced significant changes in hyphal morphology and microstructure, including cell membrane rupture and intracellular structural disorder. Adhesion assay and biofilm assay experiments showed that HK reduced the adhesion of spores to human corneal epithelial cells (HCECs) and inhibited the formation of biofilms. The genetic changes of A.F. after HK treatment were analyzed by RNA sequencing, and a total of 2487 differentially expressed genes (DEGs) were identified, including the down-regulated DEGs related to carbohydrate and various amino acid metabolism, ribosome biogenesis, asexual reproduction, and up-regulated DEGs related to steroid biosynthesis through GO and KEGG enrichment analysis. RNA-seq results suggested that HK may play an antifungal effect by destroying the structural integrity of its wall and membrane, inhibiting protein biosynthesis and the growth and reproduction of A.F..10 g/ml HK, which had no effect on proliferation and migration of HCECs, was used in the treatment of murine fungal keratitis (FK). We found that HK eyedrop treatment could reduce the severity of FK by reducing corneal fungal burden, neutrophil infiltration, and the expression of LOX-1 and pro-inflammatory factors. HK is expected to be a safe and effective new drug for FK treatment. Author summaryFK is a serious common blind-causing eye disease. The current clinical antifungal drugs have the disadvantages of low bioavailability and high corneal toxicity, which greatly limit the clinical effectiveness. Therefore, there is an urgent need for a new, safe and effective treatment for FK. HK had shown great antifungal capacity against A.F., amazingly well anti-inflammatory effect and real improvement in murine FK in our research. These findings provide a theoretical basis for the application of HK as an antifungal drug and reveal the potential of HK to be applied in the clinical treatment of FK.

microbiology↗

bioRxiv2022

The Mycobacterium tuberculosis protein O-phosphorylation landscape

Bacterial phosphosignaling has long been synonymous with the histidine kinases of the two component systems, but many bacteria, including Mycobacterium tuberculosis (Mtb), also code for Ser/Thr protein kinases (STPKs). STPKs are the main phosphosignaling enzymes in eukaryotes, but the full extent of phosphorylation on protein Ser/Thr and Tyr (O-phosphorylation) in bacteria remains unclear. Here, we explored the global signaling capacity of the STPKs in Mtb. We generated STPK loss-and gain-of-function strains and measured the resulting O-phosphorylation and transcriptional changes. This deep phosphoproteome shows that O-phosphorylation in Mtb is an underexplored protein modification that affects >70% of the proteome. The substrate-STPK interactions show an extensive interface with the transcriptional machinery, resulting in regulation of gene expression of [~]30% of Mtb genes. Mtb O-phosphorylation gives rise to an expansive, distributed, and cooperative network of a complexity that has previously only been associated with eukaryotic phosphosignaling networks.

microbiology↗

bioRxiv2022

Epigenetic Memory of COVID-19 in Innate Immune Cells and Their Progenitors

Severe coronavirus disease 2019 (COVID-19) is characterized by systemic inflammation and can result in protracted symptoms. Robust systemic inflammation may trigger persistent changes in hematopoietic cells and innate immune memory through epigenetic mechanisms. We reveal that rare circulating hematopoietic stem and progenitor cells (HSPC), enriched from human blood, match the diversity of HSPC in bone marrow, enabling investigation of hematopoiesis and HSPC epigenomics. Following COVID-19, HSPC retain epigenomic alterations that are conveyed, through differentiation, to progeny innate immune cells. Epigenomic changes vary with disease severity, persist for months to a year, and are associated with increased myeloid cell differentiation and inflammatory or antiviral programs. Epigenetic reprogramming of HSPC may underly altered immune function following infection and be broadly relevant, especially for millions of COVID-19 survivors. One Sentence SummaryTranscriptomic and epigenomic analysis of blood reveal sustained changes in hematopoiesis and innate immunity after COVID-19. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=197 HEIGHT=200 SRC="FIGDIR/small/479588v1_ufig1.gif" ALT="Figure 1"> View larger version (54K): org.highwire.dtl.DTLVardef@1ffe42dorg.highwire.dtl.DTLVardef@dd4868org.highwire.dtl.DTLVardef@1bcae8borg.highwire.dtl.DTLVardef@674e85_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2021

Summary statistics knockoff inference empowers identification of putative causal variants in genome-wide association studies

Recent advances in genome sequencing and imputation technologies provide an exciting opportunity to comprehensively study the contribution of genetic variants to complex phenotypes. However, our ability to translate genetic discoveries into mechanistic insights remains limited at this point. In this paper, we propose an efficient knockoff-based method, GhostKnockoff, for genome-wide association studies (GWAS) that leads to improved power and ability to prioritize putative causal variants relative to conventional GWAS approaches. The method requires only Z-scores from conventional GWAS and hence can be easily applied to enhance existing and future studies. The method can also be applied to meta-analysis of multiple GWAS allowing for arbitrary sample overlap. We demonstrate its performance using empirical simulations and two applications: (1) analysis of 1,403 binary phenotypes from the UK Biobank data in 408,961 samples of European ancestry, and (2) a meta-analysis for Alzheimers disease (AD) comprising nine overlapping large-scale GWAS, whole-exome and whole-genome sequencing studies. The UK Biobank analysis demonstrates superior performance of the proposed method compared to conventional GWAS in both statistical power (2.05-fold more discoveries) and localization of putative causal variants at each locus (46% less proxy variants due to linkage disequilibrium). The AD meta-analysis identified 55 risk loci (including 31 new loci) with ~70% of the proximal genes at these loci showing suggestive signal in downstream single-cell transcriptomic analyses. Our results demonstrate that GhostKnockoff can identify putatively functional variants with weaker statistical effects that are missed by conventional association tests.

genetics↗

bioRxiv2021

Structural insights into the mechanism of nucleotide regulation of pancreatic KATP channel

ATP-sensitive potassium channels (KATP) are metabolic sensors that convert the intracellular ATP/ADP ratio to the excitability of cells. They are involved in many physiological processes and implicated in several human diseases. Here we present the cryo-EM structures of the pancreatic KATP channel in both the closed state and the pre-open state, resolved in the same sample. The nucleotides bind at the inhibitory sites of the Kir6.2 channel in the closed state but not in the pre-open state. Structural comparisons reveal the mechanism for ATP inhibition and Mg-ADP activation, two fundamental properties of KATP channels. Moreover, the structure also uncovers the activation mechanism of diazoxide-type KATP openers.

biophysics↗

bioRxiv2021

Awake ripples enhance emotional memory encoding in the human brain

Intracranial recordings from the human amygdala and the hippocampus during an emotional memory encoding and discrimination task reveal increased awake sharp-wave/ripples (aSWR) after encoding of emotional compared to neutral stimuli. Further, post-encoding aSWR-locked memory reinstatement in the amygdala and the hippocampus was predictive of later memory discrimination. These findings provide electrophysiological evidence that post-encoding aSWRs enhance memory for emotional events.

neuroscience↗