Biology subjects

Jiang, X.

Publications and source records attributed to Jiang, X..

30 records · Page 2Linked to original sources

bioRxiv2018

Endogenous protection from ischemic brain injury by preconditioned monocytes

Exposure to low dose lipopolysaccharide prior to cerebral ischemia is neuroprotective in stroke models, a phenomenon termed preconditioning. While it is well established that lipopolysaccharide-preconditioning induces central and peripheral immune responses, the cellular mechanisms modulating ischemic injury remain unclear. Here, we investigated the role of immune cells in the brain protection afforded by preconditioning and we tested whether monocytes may be reprogrammed by ex vivo lipopolysaccharide exposure thus modulating the inflammatory injury after cerebral ischemia in male mice. We found that systemic injection of low-dose lipopolysaccharide induces a distinct subclass of CD115+Ly6Chi monocytes that protect the brain after transient middle cerebral artery occlusion in mice. Remarkably, adoptive transfer of monocytes isolated from preconditioned mice into naive mice 7 hours after transient middle cerebral artery occlusion reduced brain injury. Gene expression and functional studies showed that IL-10, iNOS and CCR2 in monocytes are essential for the neuroprotection. This protective activity was elicited even if mouse or human monocytes were exposed ex vivo to lipopolysaccharide and then injected into male mice after stroke. Cell tracking studies showed that protective monocytes are mobilized from the spleen and reach brain and meninges, wherein they suppressed post-ischemic inflammation and neutrophils influx into the brain parenchyma. Our findings unveil a previously unrecognized subpopulation of splenic monocytes capable to protect the brain with an extended therapeutic window, and provide the rationale for cell therapies based on the delivery of autologous or allogeneic protective monocytes into patients with ischemic stroke.\n\nSignificance StatementInflammation is a key component of the pathophysiology of the brain in stroke, a leading cause of death and disability with limited therapeutic options. Here, we investigate endogenous mechanisms of protection against cerebral ischemia. Using LPS preconditioning as an approach to induce ischemic tolerance in mice, we found the generation of neuroprotective monocytes within the spleen from where they traffic to the brain and meninges suppressing post-ischemic inflammation. Importantly, systemic LPS preconditioning can be mimicked by adoptive transfer of in vitro-preconditioned mouse or human monocytes at translational relevant time points after stroke. This model of neuroprotection may facilitate clinical efforts to increase the efficacy of bone marrow mononuclear cell treatments in acute neurological diseases such as cerebral ischemia.

neuroscience↗

bioRxiv2017

Replay of large-scale spatio-temporal patterns from waking during subsequent slow-wave sleep in human cortex

Animal studies support the hypothesis that in slow-wave sleep, replay of waking neocortical activity under hippocampal guidance leads to memory consolidation. However, no intracranial electrophysiological evidence for replay exists in humans. We identified consistent sequences of population firing peaks across widespread cortical regions during complete waking periods. The occurrence of these Motifs were compared between sleeps preceding the waking period (Sleep-Pre) when the Motifs were identified, and those following (Sleep-Post). In all subjects, the majority of waking Motifs (most of which were novel) had more matches in Sleep-Post than in Sleep-Pre. In rodents, hippocampal replay occurs during local sharp-wave ripples, and the associated neocortical replay tends to occur during local sleep spindles and down-to-up transitions. These waves may facilitate consolidation by sequencing cell-firing and encouraging plasticity. Similarly, we found that Motifs were coupled to neocortical spindles, down-to-up transitions, theta bursts, and hippocampal sharp-wave ripples. While Motifs occurring during cognitive task performance were more likely to have more matches in subsequent sleep, our studies provide no direct demonstration that the replay of Motifs contributes to consolidation. Nonetheless, these results confirm a core prediction of the dominant neurobiological theory of human memory consolidation.

neuroscience↗

bioRxiv2017

Comprehensive analysis of mobile genetic elements in the gut microbiome reveals a phylum-level niche-adaptive gene pool

Mobile genetic elements (MGEs) drive extensive horizontal transfer in the gut microbiome. This transfer could benefit human health by conferring new metabolic capabilities to commensal microbes, or it could threaten human health by spreading antibiotic resistance genes to pathogens. Despite their biological importance and medical relevance, MGEs from the gut microbiome have not been systematically characterized. Here, we present a comprehensive analysis of chromosomal MGEs in the gut microbiome using a method called Split Read Insertion Detection (SRID) that enables the identification of the exact mobilizable unit of MGEs. Leveraging the SRID method, we curated a database of 5600 putative MGEs encompassing seven MGE classes called ImmeDB (Intestinal microbiome mobile element database) (https://immedb.mit.edu/). We observed that many MGEs carry genes that confer an adaptive advantage to the gut environment including gene families involved in antibiotic resistance, bile salt detoxification, mucus degradation, capsular polysaccharide biosynthesis, polysaccharide utilization, and sporulation. We find that antibiotic resistance genes are more likely to be spread by conjugation via integrative conjugative elements or integrative mobilizable elements than transduction via prophages. Additionally, we observed that horizontal transfer of MGEs is extensive within phyla but rare across phyla. Taken together, our findings support a phylum level niche-adaptive gene pools in the gut microbiome. ImmeDB will be a valuable resource for future fundamental and translational studies on the gut microbiome and MGE communities.

bioinformatics↗

bioRxiv2017

Predominant Patterns of Splicing Evolution on Human, Chimpanzee, and Macaque Evolutionary Lineages

Although splicing is widespread and evolves rapidly among species, the mechanisms driving this evolution, as well as its functional implications, are not yet fully understood. We analyzed the evolution of splicing patterns based on transcriptome data from five tissues of humans, chimpanzees, rhesus macaques, and mice. In total, 1,526 exons and exon sets from 1,236 genes showed significant splicing differences among primates. More than 60% of these differences represent constitutive-to-alternative exon transitions while an additional 25% represent changes in exon inclusion frequency. These two dominant evolutionary patterns have contrasting conservation, regulation, and functional features. The sum of these features indicates that, despite their prevalence, constitutive-to-alternative exon transitions do not substantially contribute to long-term functional transcriptome changes. Conversely, changes in exon inclusion frequency appear to be functionally relevant, especially for changes taking place in the brain on the human evolutionary lineage.

evolutionary biology↗

bioRxiv2017

Two SecA/SecY Systems with Distinct Roles in the Ecological Adaptations of Bacteria

Bacteria interact with their environment through the secretion of a specific set of proteins (known as secretome) through various secretion systems. Molecular modifications of these secretion systems may lead to the emergence of new bacterial-environment interactions, although this remains unexplored. In this study we investigate the possible link between molecular and functional changes in secretion proteins and the ecological diversity of bacteria. We studied functional modifications in secretion proteins by identifying events of functional evolutionary divergence--that is, changes at the molecular level that have driven changes of proteins function. We present data supporting that these functional diversifications occurred in essential secretion proteins in bacteria. In particular, functional divergence of the two most important secretion proteins SecA and SecY in pathogenic bacteria suggests that molecular changes at these proteins are responsible for their adaptations to the host. Functional divergence has mainly occurred at protein domains involved in ATP hydrolysis in SecA and membrane pore formation in SecY. This divergence is stronger in pathogenic bacteria for protein copies resulting from the duplication of SecA/SecY, known as SecA2/SecY2. In concert with these results, we find that the secretome of bacteria with the strongest functional divergence is enriched for proteins specialized in the interaction with specific environments. We unravel evolutionary signatures that link mutations at secretion proteins to the ecological diversification of bacteria.

microbiology↗

bioRxiv2017

De novo assemblies of high-quality reference transcriptomes identifies Rosaceae-common and Rosa-specific encoding genes

Roses are important plants for human beings with important economical and biological traits like continuous flowering, flower architecture, color and scent, that current model plants do not feature, thus are becoming ideal models for studying these traits. Due to high heterozygosity of rose genomes likely caused by frequent inter-species hybridization, a high-quality and well-annotated genome for Rosa plants is not available yet. Developing genetic and genomic tools with high quality has become necessary for further roses breeding and for disentangling the molecular genetic mechanisms underlying roses domestication. We here generated the high quality and comprehensive reference transcriptomes for Rosa chinensis Old Blush (OB) and R. wichuriana Basyes Thornless (BT), two roses contrasting at several important traits. These reference transcriptomes showed transcripts N50 above 2000bp. The two species shared about 23310 transcripts (N50 = 2364bp), among which about 8975 orthologs were conserved within genera of Rosa. Rosa plants shared about 5049 transcripts (Rosaceae-common) with these from Malus, Prunus, Rubus, and Fragaria. Finally, a pool of 417 transcripts unique to Rosa plants (Rosa-specific) was identified. These Rosaceae-common and Rosa-specific transcripts should facilitate the phylogenetic analysis of Rosaceae plants and investigation of Rosa-specific traits. The data reported here should provide the fundamental genomic tools and knowledge critical for understanding the biology and domestication of roses.

plant biology↗

bioRxiv2017

Impact of spatial organization on a novel auxotrophic interaction among soil microbes

A key prerequisite to achieve a deeper understanding of microbial communities and to engineer synthetic ones is to identify the individual metabolic interactions among key species and how these interactions are affected by different environmental factors. Deciphering the physiological basis of species-species and species-environment interactions in spatially organized environment requires reductionist approaches using ecologically and functionally relevant species. To this end, we focus here on a specific defined system to study the metabolic interactions in a spatial context among a plant-beneficial endophytic fungus Serendipita indica, and the soil-dwelling model bacterium Bacillus subtilis. Focusing on the growth dynamics of S. indica under defined conditions, we identified an auxotrophy in this organism for thiamine, which is a key co-factor for essential reactions in the central carbon metabolism. We found that S. indica growth is restored in thiamine-free media, when co-cultured with B. subtilis. The success of this auxotrophic interaction, however, was dependent on the spatial and temporal organization of the system; the beneficial impact of B. subtilis was only visible when its inoculation was separated from that of S. indica either in time or space. These findings describe a key auxotrophic interaction in the soil among organisms that are shown to be important for plant ecosystem functioning, and point to the potential importance of spatial and temporal organization for the success of auxotrophic interactions. These points can be particularly important for engineering of minimal functional synthetic communities as plant-seed treatments and for vertical farming under defined conditions.

systems biology↗

bioRxiv2017

Sodium valproate rescues expression of TRANK1 in iPSC-derived neural cells that carry a genetic variant associated with serious mental illness

Biological characterization of genetic variants identified in genome-wide association studies (GWAS) remains a substantial challenge. Here we used human induced pluripotent stem cells (hiPSC) and their neural derivatives to characterize common variants on chromosome 3p22 that have been associated by GWAS with major mental illnesses. HiPSC-derived neural progenitor cells carrying the risk allele of the single nucleotide polymorphism (SNP), rs9834970, displayed lower baseline TRANK1 expression that was rescued by chronic treatment with therapeutic dosages of valproic acid (VPA). Although rs9834970 has no known function, we demonstrated that a nearby SNP, rs90832, strongly affects binding by the transcription factor, CTCF, and that the high-affinity allele usually occurs on haplotypes carrying the rs9834970 risk allele. Decreased expression of TRANK1 perturbed expression of many genes involved in neural development and differentiation. These findings have important implications for the pathophysiology of major mental illnesses and the development of novel therapeutics.\n\nHighlightsO_LIhiPSC-derived neural cells carrying a mental illness risk allele showed lower expression of TRANK1\nC_LIO_LIValproic acid rescued TRANK1expression in cells carrying the risk allele\nC_LIO_LIRisk haplotypes usually carry an allele that increased CTCF binding\nC_LIO_LIReduced expression of TRANK1 perturbed genes involved in neural development and differentiation\nC_LI\n\nIn BriefUsing neural derivatives of human induced pluripotent stem cells, Jiang et al. demonstrate that genetic variants associated with mental illness alter transcription factor binding and decrease expression of a nearby gene, an effect which is rescued by valproic acid.

genetics↗

bioRxiv2017

Protein Structural Disorder Of The Envelope V3 Loop Contributes To The Switch In Human Immunodeficiency Virus Type 1 Cell Tropism

Human immunodeficiency virus type 1 (HIV-1) envelope gp120 is partly an intrinsically disordered (unstructured/disordered) protein as it contains regions that do not fold into well-defined protein structures. These disordered regions play important roles in HIVs life cycle, particularly, V3 loop-dependent cell entry, which determines how the virus uses two coreceptors on immune cells, the chemokine receptors CCR5 (R5), CXCR4 (X4) or both (R5X4 virus). Most infecting HIV-1 variants utilise CCR5, while a switch to CXCR4-use occurs in the majority of infections. Why does this rewiring event occur in HIV-1 infected patients? As changes in the charge of the V3 loop are associated with this receptor switch and it has been suggested that charged residues promote structure disorder, we hypothesise that the intrinsic disorder of the V3 loop plays a role in determining cell tropism. To test this we use three independent data sets of gp120 to analyse V3 loop disorder. We find that the V3 loop of X4 virus has significantly higher intrinsic disorder tendency than R5 and R5X4 virus, while R5X4 virus has the lowest. These results indicate that structural disorder plays an important role in determining HIV-1 cell tropism and CXCR4 binding. We speculate that changes in N-linked glycosylation associated with tropism change (from R5 to X4) are required to stabilise the V3 loop with increased disorder tendency during HIV-1 evolution. We discuss the potential evolutionary mechanisms leading to the fixation of disorder promoting mutations and the adaptive potential of protein structural disorder in viral host adaptation.\n\nIMPORTANCEHIV-1 cell entry relies on the V3 loop of its heavily glycosylated envelope protein gp120 to bind to a host coreceptor CCR5 or CXCR4. Unraveling the mechanism whereby HIV-1 switches host coreceptor is critical to understanding HIV-1 pathogenesis and development of novel intervention strategies. However, a mechanistic understanding of the switch is limited as no gp120-CCR5/CXCR4 complex is available, due to the intrinsically disordered nature of the V3 loop responsible for coreceotor swtich. We hypothesise that shifts of V3 disorder may contribute to HIV-1 coreceptor switch and cell tropism. In this study we compared the disorder tendency of the V3 loop before and after the coreceptor switch. We find that the coreceptor switch is associated with a significant increase of V3 loop disorder from CCR5 to CXCR4 using. This result provides a mechanistic explanation of coreceptor switch that increasingly disordered V3 loop results in use of a different host coreceptor.

bioinformatics↗

bioRxiv2017

Mapping Human Hematopoietic Hierarchy At Single Cell Resolution By Microwell-seq

The classical hematopoietic hierarchy, which is mainly built with fluorescence-activated cell sorting (FACS) technology, proves to be inaccurate in recent studies. Single cell RNA-seq (scRNA-seq) analysis provides a solution to overcome the limit of FACS-based cell type definition system for the dissection of complex cellular hierarchy. However, large-scale scRNA-seq is constrained by the throughput and cost of traditional methods. Here, we developed Microwell-seq, a high-throughput and low-cost scRNA-seq platform using extremely simple devices. Using Microwell-seq, we constructed a single-cell resolution transcriptome atlas of human hematopoietic differentiation hierarchy by profiling more than 50,000 single cells throughout adult human hematopoietic system. We found that adult human hematopoietic stem and progenitor cell (HSPC) compartment is dominated by progenitors primed with lineage specific regulators. Our analysis revealed differentiation pathways for each cell types, through which HSPCs directly progress to lineage biased progenitors before differentiation. We propose a revised adult human hematopoietic hierarchy independent of oligopotent progenitors. Our study also demonstrates the broad applicability of Microwell-seq technology.

cell biology↗

bioRxiv2017

Resolving Drug Effects In Patient-Derived Cancer Cells Links Organoid Responses To Genome Alterations

Cancer drug screening in patient-derived cells holds great promise for personalized oncology and drug discovery but lacks standardization. Whether cells are cultured as conventional monolayer or advanced organoid cultures influences drug effects and thereby drug selection and clinical success. To precisely compare drug profiles in differently cultured primary cells, we developed DeathPro, an automated microscopy-based assay to resolve drug-induced cell death and proliferation inhibition. Using DeathPro, we screened cells from ovarian cancer patients in monolayer or organoid culture with clinically relevant drugs. Drug-induced growth arrest and efficacy of cytostatic drugs differed between the two culture systems. Interestingly, drug effects in organoids were more diverse and had lower therapeutic potential. Genomic analysis revealed novel links between drug sensitivity and DNA repair deficiency in organoids that were undetectable in monolayers. Thus, our results highlight the dependency of cytostatic drugs and pharmacogenomic associations on culture systems, and guide culture selection for drug tests.

cancer biology↗

bioRxiv2017

Bacterial outer membrane homeostasis via retrograde phospholipid transport

Biogenesis of the outer membrane (OM) in Gram-negative bacteria, which is essential for viability, requires the coordinated transport and assembly of proteins and lipids, including lipopolysaccharides (LPS) and phospholipids (PLs), into the membrane. While pathways for LPS and OM protein assembly are well-studied, how PLs are transported to and from the OM is not clear. Mechanisms that ensure OM stability and homeostasis are also unknown. The trans-envelope Tol-Pal complex, whose physiological role has remained elusive, is important for OM stability. Here, we establish that the Tol-Pal complex is required for PL transport and OM lipid homeostasis in Escherichia coli. Cells lacking the complex exhibit defects in lipid asymmetry and accumulate excess phospholipids (PLs) in the OM. This imbalance in OM lipids is due to defective retrograde PL transport in the absence of a functional Tol-Pal complex. Thus, cells ensure the assembly of a stable OM by maintaining an excess flux of PLs to the OM only to return the surplus to the inner membrane. Our findings also provide insights into the mechanism by which the Tol-Pal complex may promote OM invagination during cell division.

microbiology↗