Biology subjects

Ju, Y.

Publications and source records attributed to Ju, Y..

At least 37 records · Page 2Linked to original sources

bioRxiv2024

Disrupting Homologous Recombination or Single-Strand Annealing Significantly Hinders CRISPR-Cas12a-Assisted Nonhomologous End-Joining Gene Editing Efficiency in Mycobacterium abscessus

Mycobacterium abscessus, a fast-growing, non-tuberculous mycobacterium resistant to most antimicrobial drugs, causes many types of serious infections in humans, posing a significant public health challenge. Currently, effective genetic manipulation tools for M. abscessus are still being developed, which hampers research and therapeutic development. However, the clustered regularly interspaced short palindromic repeats (CRISPR) - associated protein (Cas) systems have emerged as promising methods for generating highly specific double-strand breaks (DSBs) in its genome. These DSBs can be repaired by the error-prone nonhomologous end joining (NHEJ) mechanism, facilitating targeted gene editing. Here, our study marks a pioneering application of the CRISPR-NHEJ strategy in M. abscessus. Additionally, we discovered that NrgA from Mycobacterium marinum is crucial for the repair of DSBs caused by the CRISPR-Cas system in M. abscessus. Finally, contrary to previous findings, our study also indicates that inhibiting or overexpressing homologous recombination/single-strand annealing significantly decreases the efficiency of NHEJ repair in M. abscessus. This discovery challenges established perspectives and suggests that the NHEJ repair in M. abscessus may require the involvement of components from homologous recombination and single-strand annealing, demonstrating the complex interactions among the three DSB repair pathways in M. abscessus. Impact statementThere are still very few genetic manipulation tools available for Mycobacterium abscessus. Here we report the successful application of CRISPR-Cas12a-assisted nonhomologous end joining (NHEJ) in efficient gene editing in M. abscessus. Contrary to previous research suggesting that homologous recombination (HR) inhibition may enhance such editing efficiency in other Mycobacterium species, our results showed that disruption or overexpression of either HR or single-strand annealing not only failed to enhance but also significantly reduced the gene editing efficiency in M. abscessus. This suggests that NHEJ repair in M. abscessus may require components from both HR and single-strand annealing, highlighting a complex interaction among the DSB repair pathways in M. abscessus.

microbiology↗

bioRxiv2023

Intermediate basal cell population in prostate homeostasis and cancer initiation

Many glandular epithelia are mainly composed of basal cells and luminal cells, including the prostate gland. Adult prostate basal and luminal cells are independently self-sustained by unipotent stem cells that can reactivate multipotency under prostate inflammation and carcinogenesis contexts. However, the defined basal stem cell populations responsible for prostate regeneration and their cell fates in prostate homeostasis, inflammation and carcinogenesis remain unclear. Using a genetic proliferation tracer (ProTracer) system, we found that basal cells exhibited extensive cell loss and proliferation during androgen-mediated prostate regression and regeneration, respectively. A rare intermediate basal cell population that expresses luminal cell markers (Nkx3.1 and Pbsn) (termed Basal-B) and a large basal cell population (termed Basal-A) were identified in mouse prostates by single-cell RNA sequencing. Basal-B cells exhibited a greater capacity for organoid formation and luminal cell differentiation in vitro. Genetic lineage tracing using dual recombinases showed that prostate homeostasis and regeneration are not driven by specific basal cell types. Fate-mapping results showed that Basal-B cells had a greater tendency to generate luminal cells under bacteria-induced prostate inflammation. Deletion of Pten in basal cells resulted in Basal-A-to-Basal-B-to-luminal transition and prostatic intraepithelial neoplasia. Moreover, the human Basal-B-cell population was significantly increased in human benign prostate hyperplasia and prostatic intraepithelial neoplasia samples compared with normal prostate samples. This study identifies intermediate Basal-B cells as a potential stem cell population and provides genetic evidence of prostate basal cell lineage plasticity under physiological and pathological contexts.

developmental biology↗

bioRxiv2023

The eccDNA mediated spread and rapid evolution of herbicide resistance in pigweed interspecific hybrids

Extrachromosomal circular DNAs (eccDNAs) are found in many eukaryotic organisms. The eccDNA-powered copy number variation plays diverse roles from oncogenesis in humans to herbicide resistance in crop weeds. Here we report interspecific eccDNA flow and its dynamic behavior in soma cells of natural populations and F1 hybrids of Amaranthus sp. The glyphosate resistance (GR) trait is controlled by eccDNA-based amplification harboring the 5-enolpyruvylshikimate-3-phosphate synthase (EPSPS) gene (EPSPS-eccDNA), the molecular target of glyphosate. We documented pollen-mediated transfer of eccDNA in experimental hybrids between GS A. tuberculatus x GR A. palmeri. Experimental hybridization and fluorescence in situ hybridization (FISH) analysis revealed that the EPSPS-eccDNA present in A. spinosus was derived from GR A. palmeri by natural hybridization. FISH analysis also revealed random chromosome anchoring and massive EPSPS-eccDNA copy number variation in soma cells of weedy hybrids. The results suggest that eccDNAs are inheritable across compatible species contributing to genome plasticity and rapid adaptive evolution.

genetics↗

bioRxiv2022

The evolution of two transmissible leukaemias colonizing the coasts of Europe

Transmissible cancers are malignant cell clones that spread among individuals through transfer of living cancer cells. Several such cancers, collectively known as bivalve transmissible neoplasia (BTN), are known to infect and cause leukaemia in marine bivalve molluscs. This is the case of BTN clones affecting the common cockle, Cerastoderma edule, which inhabits the Atlantic coasts of Europe and north-west Africa. To investigate the origin and evolution of contagious cancers in common cockles, we collected 6,854 C. edule specimens and diagnosed 390 cases of BTN. We then generated a reference genome for the species and assessed genomic variation in the genomes of 61 BTN tumours. Analysis of tumour-specific variants confirmed the existence of two cockle BTN lineages with independent clonal origins, and gene expression patterns supported their status as haemocyte-derived marine leukaemias. Examination of mitochondrial DNA sequences revealed several mitochondrial capture events in BTN, as well as co-infection of cockles by different tumour lineages. Mutational analyses identified two lineage-specific mutational signatures, one of which resembles a signature associated with DNA alkylation. Karyotypic and copy number analyses uncovered genomes marked by pervasive instability and polyploidy. Whole-genome duplication, amplification of oncogenes CCND3 and MDM2, and deletion of the DNA alkylation repair gene MGMT, are likely drivers of BTN evolution. Characterization of satellite DNA identified elements with vast expansions in the cockle germ line, yet absent from BTN tumours, suggesting ancient clonal origins. Our study illuminates the evolution of contagious cancers under the sea, and reveals long-term tolerance of extreme instability in neoplastic genomes.

evolutionary biology↗

bioRxiv2022

Sex differences in the nasal microbiome of healthy young adults

Respiratory diseases impose an immense health burden worldwide. Epidemiological studies have revealed extensive disparities in the incidence and severity of respiratory tract infections (RTIs) between males and females. It is recently hypothesized that there might also be a nasal microbiome axis contributing to the observed sex disparities, but without evidence. In this work, we study the nasal microbiome of healthy young adults in, as of today, the largest cohort based on deep shot-gun metagenomic sequencing. We mainly focus on the bacteriome, but also integrate the mycobiome to get a more holistic perspective. De novo assembly is performed to catalog the nasal bacterial colonizers/residents, which also identify and therefore account for uncharacterized components of the community. The bacteriome is then profiled based on the non-redundant metagenome-assembled genomes (MAGs) catalog constructed therefrom. Unsupervised clustering reveals clearly separable structural patterns in the nasal microbiome between the two sexes. Following this link, we systematically evaluate sex differences for the first time and reveal extensive sex-specific features in the nasal microbiome composition. More importantly, through network analyses, we capture markedly higher ecological stability and antagonistic potentials in the nasal microbiome of females than that of males. The analysis of the keystone bacteria of the communities reveal that the sex-dependent evolutionary characteristics might have contributed to this difference. HighlightsThe non-redundant nasal bacterial MAGs catalog constructed from ultra-deeply sequenced metagenomic data provides a valuable resource. Integrating nasal bacteriome and mycobiome data provides a more holistic perspective for the understudied human nasal microbiome. Unsupervised clustering helps uncover extensive sex differences in the nasal microbiome compositions. Network analyses capture markedly higher ecological stability and antagonistic potentials in the nasal microbiome of females than that of males. Sex-dependent genetic evolutionary forces play a role in the shaping of keystones in the nasal microbial community.

microbiology↗

bioRxiv2022

Human Digital Twin: Automated Cell Type Distance Computation and 3D Atlas Construction in Multiplexed Skin Biopsies

Mapping the human body at single cell resolution in three-dimensions (3D) is an important step toward a "digital twin" model that captures important structure and dynamics of cell-cell interactions. Current 3D imaging methods suffer from low resolution and are limited in their ability to distinguish cell types and their spatial relationships. We present a novel 3D workflow: MATRICS-A (Multiplexed Image Three-D Reconstruction and Integrated Cell Spatial - Analysis) that generates a 3D map of cells from multiplexed images and calculates cell type distance from endothelial cells and other features of interest. We applied this workflow to multiplexed data from sequential skin sections from younger and older donors (n=10; 33-72 years) with biopsies from ten anatomical regions with different sun exposure effects (mild, moderate-marked). Up to 26 sequential sections from each sample underwent multiplexed imaging with 18 biomarkers covering 12 cell types (keratinocytes (granular, spinous, basal), epithelial and myoepithelial cells, fibroblasts, macrophages, T helpers, T killers, T regs, neurons and endothelial cells, markers of DNA damage and repair (p53, DDB2) and cell proliferation (Ki67). Following cell classification, the tissue and classified cells were reconstructed into 3D volumes. A significant inverse correlation between DDB2 positive cells and age was found (corr= -0.78, adj. p=0.047). This suggests reduced capacity for repair in non-cancer older sun-exposed individuals. While absolute immune cell count did not differ by age or sun exposure, the ratio of T Helper/T Killer cells was positively correlated with age (corr=0.82, adj. p=0.048) This is the first such 3D study in skin and paves the way for cataloging more cell types and spatial relationships in aging and disease in skin and other organs.

cell biology↗

bioRxiv2021

Tissue Registration and Exploration User Interfaces in support of a Human Reference Atlas

Several international consortia are collaborating to construct a human reference atlas, which is a comprehensive, high-resolution, three-dimensional atlas of all the cells in the healthy human body. Laboratories around the world are collecting tissue specimens from donors varying in sex, age, ethnicity, and body mass index. However, integrating and harmonizing tissue data across 20+ organs and more than 15 bulk and spatial single-cell assay types poses diverse challenges. Here we present the software tools and user interfaces developed to annotate ("register") and explore the collected tissue data. A key part of these tools is a common coordinate framework, which provides standard terminologies and data structures for describing specimens, biological structures, and spatial positions linked to existing ontologies. As of December 2021, the "registration" user interface has been used to harmonize and make publicly available data on 6,178 tissue sections from 2,698 tissue blocks collected by the Human Biomolecular Atlas Program, the Stimulating Peripheral Activity to Relieve Conditions program, the Human Cell Atlas, the Kidney Precision Medicine Project, and the Genotype Tissue Expression project. The second "exploration" user interface enables consortia to evaluate data quality and coverage, explore tissue data in the context of the human body, and guide data acquisition.

bioinformatics↗

bioRxiv2021

Robust and generalizable segmentation of human functional tissue units

The Human BioMolecular Atlas Program aims to compile a reference atlas for the healthy human adult body at the cellular level. Functional tissue units (FTU, e.g., renal glomeruli and colonic crypts) are of pathobiological significance and relevant for modeling and understanding disease progression. Yet, annotation of FTUs is time consuming and expensive when done manually and existing algorithms achieve low accuracy and do not generalize well. This paper compares the five winning algorithms from the "Hacking the Kidney" Kaggle competition to which more than a thousand teams from sixty countries contributed. We compare the accuracy and performance of the algorithms on a large-scale renal glomerulus Periodic acid-Schiff stain dataset and their generalizability to a colonic crypts hematoxylin and eosin stain dataset. Results help to characterize how the number of FTUs per unit area differs in relationship to their position in kidney and colon with respect to age, sex, body mass index (BMI), and other clinical data and are relevant for advancing pathology, anatomy, and surgery.

bioinformatics↗

bioRxiv2021

TopoRoot: A method for computing hierarchy and fine-grained traits of maize roots from X-ray CT images

Background3D imaging, such as X-ray CT and MRI, has been widely deployed to study plant root structures. Many computational tools exist to extract coarse-grained features from 3D root images, such as total volume, root number and total root length. However, methods that can accurately and efficiently compute fine-grained root traits, such as root number and geometry at each hierarchy level, are still lacking. These traits would allow biologists to gain deeper insights into the root system architecture (RSA). ResultsWe present TopoRoot, a high-throughput computational method that computes fine-grained architectural traits from 3D X-ray CT images of field-excavated maize root crowns. These traits include the number, length, thickness, angle, tortuosity, and number of children for the roots at each level of the hierarchy. TopoRoot combines state-of-the-art algorithms in computer graphics, such as topological simplification and geometric skeletonization, with customized heuristics for robustly obtaining the branching structure and hierarchical information. TopoRoot is validated on both real and simulated root images, and in both cases it was shown to improve the accuracy of traits over existing methods. We also demonstrate TopoRoot in differentiating a maize root mutant from its wild type segregant using fine-grained traits. TopoRoot runs within a few minutes on a desktop workstation for volumes at the resolution range of 400^3, without need for human intervention. ConclusionsTopoRoot improves the state-of-the-art methods in obtaining more accurate and comprehensive fine-grained traits of maize roots from 3D CT images. The automation and efficiency makes TopoRoot suitable for batch processing on a large number of root images. Our method is thus useful for phenomic studies aimed at finding the genetic basis behind root system architecture and the subsequent development of more productive crops.

plant biology↗

bioRxiv2021

The First High-Quality Reference Genome of Sika Deer Provides Insights for High-Tannin Adaptation

Sika deer are known to prefer oak leaves, which are rich in tannins and toxic to most mammals; however, the genetic mechanisms underlying their unique ability to adapt to living in the jungle are still unclear. In identifying the mechanism responsible for the tolerance of a highly toxic diet, we have made a major advancement in the elucidation of the genomics of sika deer. We generated the first high-quality, chromosome-level genome assembly of sika deer and measured the correlation between tannin intake and RNA expression in 15 tissues through 180 experiments. Comparative genome analyses showed that the UGT and CYP gene families are functionally involved in the adaptation of sika deer to high-tannin food, especially the expansion of UGT genes in a subfamily. The first chromosome-level assembly and genetic characterization of the tolerance toa highly toxic diet suggest that the sika deer genome will serve as an essential resource for understanding evolutionary events and tannin adaptation. Our study provides a paradigm of comparative expressive genomics that can be applied to the study of unique biological features in non-model animals.

genomics↗

bioRxiv2021

Metagenome-genome-wide association studies reveal human genetic impact on the oral microbiome

The oral microbiota contains billions of microbial cells, which could contribute to diseases in a number of body sites. Challenged by eating, drinking and dental hygiene on a daily basis, the oral microbiota is regarded as highly dynamic. Here, we report significant human genomic associations with the oral metagenome from more than 1,915 individuals, for both the tongue dorsum and saliva. We identified five genetic loci associated with oral microbiota at study-wide significance (p < 3.16 x 10-11). Four of the five associations were well replicated in an independent cohort of 1,439 individuals: rs1196764 at APPL2 with Prevotella jejuni, Oribacterium uSGB 3339 and Solobacterium uSGB 315; rs3775944 at the serum uric acid transporter SLC2A9 with Oribacterium uSGB 1215, Oribacterium uSGB 489 and Lachnoanaerobaculum umeaense; rs4911713 near OR11H1 with species F0422 uSGB 392; and rs36186689 at LOC105371703 with Eggerthia. Further analyses confirmed 84% (386/455 for tongue dorsum) and 85% (391/466 for saliva) of genetic-microbiota associations including 6 genome-wide significant associations mutually validated between the two niches. Human genetics accounted for at least 10% of oral microbiome compositions between individuals. Machine learning models showed that polygenetic risk score dominated over oral microbiome in predicting predisposing risk of dental diseases such as dental calculus and gingival bleeding. These findings indicate that human genetic differences are one explanation for a stable or recurrent oral microbiome in each individual.

genetics↗

bioRxiv2021

Three bacterium-plasmid golden combinations facilitate the spread of ST11/CG258 carbapenemase-producing Klebsiella pneumoniae in China

Carbapenemase-producing Klebsiella pneumoniae (cpKP) poses serious threats to public health. Previous studies showed that only ST11/CG258-cpKP successfully disseminated in China, however, the underlying genetic bases are still unknown. We conducted a comprehensive genomic-epidemiology analysis on 420 cpKP isolates from 70 hospitals in 24 Chinese provinces during 2009-2017 based on short-/long-reads sequencing. Three golden combinations of host--blaKPC-carrying plasmids (Clade 3.1+3.2--IncFIIpHN7A8, Clade 3.1+3.2--IncFIIpHN7A8:IncR, Clade 3.3--IncFIIpHN7A8:IncpA1763-KPC) endowed cpKP with advantages both in genotypes (strong-correlation/co-evolution) and phenotypes (resistance/growth/competition), thereby facilitating nationwide spread of ST11/CG258-cpKP. Intriguingly, Bayesian skyline illustrated that the three golden combinations might directly lead to the strong population expansion during 2007-2008 and subsequent maintenance of the dissemination of ST11/CG258-cpKP after 2008. We tested drug-resistance profiles and proposed combination treatment regimens for CG258/non-CG258 cpKP. Our findings systematically revealed the molecular-epidemiology and genetic-basis for dissemination of Chinese ST11/CG258 cpKP and reminded us to monitor the golden combinations of cpKP- plasmid closely.

microbiology↗

bioRxiv2021

Visualization of reactive astrocytes in living brain of Alzheimer's disease patient

An early appearance of reactive astrocytes is a hallmark of Alzheimers disease (AD)1,2, providing a substrate for early diagnostic neuroimaging targets. However, there is no clinically validated neuroimaging probe to visualize the reactive astrogliosis in the human brain in vivo. Here, we report that PET/CT imaging with 11C-acetate and 18F-fluorodeoxyglucose (18F-FDG) functionally visualizes the reactive astrocyte-mediated neuronal hypometabolism in the brains with neuroinflammation and AD. We demonstrate that reactive astrocytes excessively absorb acetate through elevated monocarboxylate transporter-1 (MCT1), leading to aberrant GABA synthesis and release which suppresses neuronal glucose uptake through decreased glucose transporter-3 (GLUT3) in both animal and human brains. We propose the non-invasive functional PET/CT imaging for astrocytic acetate-hypermetabolism and neuronal glucose-hypometabolism as an advanced diagnostic strategy for early stages of AD.

neuroscience↗

bioRxiv2021

Visualizing reactive astrogliosis extends survival in glioblastoma patients

Glioblastoma multiforme (GBM) is a devastating brain tumor with dismal prognosis of only 15-month survival regardless of surgical resection. Here, we report an advanced neuroimaging technique combining 11C-acetate PET and MRI (AcePET), visualizing the boundary beyond the MRI-defined tumor. Targeted biopsy of the regions with increased 11C-acetate uptake revealed the presence of reactive astrocytes with enhanced acetate-transporter MCT1, along with cancer stem cells. Reactive astrogliosis and MCT1-dependent 11C-acetate-uptake were recapitulated in U87MG-orthotopic models. Mechanistically, glycolytic tumor cells release excessive acetate causing reactive astrogliosis, leading to the release of aberrant astrocytic GABA and H2O2, which further down-regulate the neuronal glucose uptake through GLUT3. Clincally, AcePET-guided surgery allows complete tumor resection of infiltrating cancer stem cells and extends the overall survival of patients by 5.25 months compared to conventional MRI-guided surgery. We established a new concept of the metabolic interactions between GBM cells and neighboring neurons through reactive astrocytes and developed AcePET-guided surgery to fight against GBM.

cancer biology↗

bioRxiv2020

Alisertib exerts KRAS allele specific anticancer effects in colorectal cancer

Colorectal cancer (CRC) is a common cancer causing substantial mortality and morbidity worldwide. Oncogene RAS mutations occur notably in [~]45% of CRCs, associated with a poor prognosis. KRAS is subject to multiple tiers of regulation, including kinase. Aurora kinases has been implicated in many types of tumor onsets and progression, making them as a promising therapeutic targets. Alisertib (ALS), selectively inhibits Aurora kinase A (AURKA) and exerts potent anticancer activities in vitro and in vivo studies, but the latent anticancer effect of ALS on CRC remains unclear in the context of different KRAS mutations. This study aimed to assess the effects of ALS on RAS signaling pathway in a panel of CRC lines expressing different KRAS alleles, including Caco-2 (KRAS WT), Colo-678 (KRAS G12D), SK-CO-1 (KRAS G12V), HCT116 (KRAS G13D), CCCL-18 (KRAS A146T), and HT29 (BRAF V600E). The results showed that ALS modulated the active form of KRAS in a RAS allele specific manner across the panel of CRC lines; ALS differentially regulated RAS signal via PI3K/Akt and MAPK pathways; and ALS induced apoptosis and autophagy in a RAS allele specific manner. Of note, in combination of ALS and MEK inhibitor, selumetinib, enhanced ALS regulatory effects in CRC lines in a RAS allele specific manner on apoptosis, autophagy, and cell growth. Taken together, this study suggests that ALS differentially regulates RAS signaling pathway and manipulates cell apoptosis and autophagy in RAS allele specific manner. The combinatorial approach of ALS and MEK inhibitor may represent a new therapeutic strategy for precision therapy of CRC in a RAS allele manner.

cancer biology↗

bioRxiv2020

Role of short-chain fatty acids in the gut-brain axis in schizophrenia: contribution to immune activation and pathophysiology in humans and mice

ObjectiveGut microbiota dysbiosis and aberrant gut-brain functional modules including short-chain fatty acid (SCFA) production and long-lasting immune activation (IA) are presented in schizophrenia. Given the key roles of gut microbiota and SCFA in shaping immunity, we propose that dysbiosis-induced SCFA upregulation could contribute to IA and behavioral symptoms in schizophrenia. DesignGut microbiota, SCFA, and IA biomarkers were compared between schizophrenic patients and healthy controls. The roles of SCFA in schizophrenia-related IA were analyzed in cultured peripheral blood mononuclear cells (PBMCs) and a mouse model of schizophrenia. The effects of SCFAs on schizophrenia-related phenotypes were analyzed in both human and mouse. ResultsBoth microbial-derived SCFA and SCFA-producing bacteria were elevated in the guts of schizophrenic patients, and this increased SCFA production in gut was associated with IA in schizophrenia. The microbiome signature underpinning schizophrenia-related IA includes increased diversity and increased SCFA-producing bacteria and inflammation-associated bacteria. The impact of SCFAs on immune responses of cultured PBMC depend on the diagnosis and IA status of donors. Small-molecule serum filtrates from immune-activated schizophrenic patients increased the inflammatory response of PBMCs from healthy volunteers, which can be enhanced and attenuated by SCFAs supplementation and inhibition of SCFA signaling, respectively. Chronically elevated SCFAs in adolescence induced neuroinflammation and schizophrenia-like behaviors in adult mice. Moreover, chronically elevated SCFAs in adult mice prenatally exposed to IA potentiated their expression of schizophrenia-like behaviors. Conclusionmicrobiota-derived SCFAs are important mediators of dysregulated gut-brain axis and participant in pathogenesis via enhance IA in schizophrenia. SummaryO_ST_ABSSignificance of this studyC_ST_ABSO_LIWhat is already known about this subject? [tpltrtarr]Schizophrenia pathogenesis goes beyond the brain since increasing peripheral abnormalities are revealed including gut microbiota dysbiosis, GI dysfunction, and systemic immune activation (IA). [tpltrtarr]Systemic IA/inflammation contributes to the neuroinflammation and brain impairment underlying schizophrenia, and adjunctive immunotherapy can improve psychotic symptoms. [tpltrtarr]Short-chain fatty acids (SCFA) mediate the microbiota-gut-brain communication and modulate several pathways involved in schizophrenia, including pathways of immunity and neurotransmitters. C_LIO_LIWhat are the new findings? [tpltrtarr]Patients with schizophrenia displayed increased rates of IA and increased SCFA production compared with healthy controls, and increased SCFA is associated with IA in patients. [tpltrtarr]A unique microbiota signature including enriched SCFA-producing bacterial species can distinguish patients with IA from other patients and controls. [tpltrtarr]Small molecules in the serum of immune-activated patients with schizophrenia enhance LPS-induced immune response of cultured peripheral blood mononuclear cell (PBMCs), which is partially mediated by SCFA signaling. [tpltrtarr]SCFA intake upregulates both peripheral and brain inflammation and potentiates the expression of schizophrenia-like behaviors in mice prenatally exposed to IA. C_LIO_LIHow might it impact on clinical practice in the foreseeable future? [tpltrtarr]Interference of SCFA signaling or targeted destruction of SCFA-producing bacteria may provide a new approach for the prevention and treatment of schizophrenia. [tpltrtarr]Immune activation status of patients should be an important condition considered when selecting immunotherapy for future precision psychiatric therapy. C_LI

neuroscience↗

bioRxiv2019

Identification of gut microbiome markers for schizophrenia delineates a potential role of Streptococcus

Emerging evidence has linked the gut microbiota to schizophrenia. However, the functional changes in the gut microbiota and the biological role of individual bacterial species in schizophrenia have not been explored systematically. Here, we characterized the gut microbiota in schizophrenia using shotgun metagenomic sequencing of feces from a discovery cohort of 90 drug-free patients and 81 controls, as well as a validation cohort of 45 patients taking antipsychotics and 45 controls. We screened 83 schizophrenia-associated bacterial species and constructed a classifier comprising 26 microbial biomarkers that distinguished patients from controls with a 0.896 area under the receiver operating characteristics curve (AUC) in the discovery cohort and 0.765 AUC in the validation cohort. Our analysis of fecal metagenomes revealed that schizophrenia-associated gut-brain modules included short-chain fatty acids synthesis, tryptophan metabolism, and synthesis/degradation of neurotransmitters including glutamate, {gamma}-aminobutyric acid, and nitric oxide. The schizophrenia-enriched gut bacterial species include several oral cavity-resident microbes, such as Streptococcus vestibularis. We transplanted Streptococcus vestibularis into the gut of the mice with antibiotic-induced microbiota depletion to explore its functional role. We observed that this microbe transiently inhabited the mouse gut and this was followed by hyperactivity and deficit in social behaviors, accompanied with altered neurotransmitter levels in peripheral tissues. In conclusion, our study identified 26 schizophrenia-associated bacterial species representing potential microbial targets for future treatment, as well as gut-brain modules, some of which may give rise to new microbial metabolites involved in the development of schizophrenia.

microbiology↗

bioRxiv2019

Inhibiting Mycobacterium tuberculosis ClpP1P2 by addressing the equatorial handle domain of ClpP1 subunit

Unlike other bacterial ClpP systems, mycobacterial ClpP1P2 complex is essential for mycobacterial survival. The functional details of Mycobacterium tuberculosis (Mtb) ClpP1P2 remains largely elusive and selectively targeting ClpP of different species is a big challenge. In this work, cediranib was demonstrated to significantly decrease the activity of MtbClpP1P2. By solving the crystal structure of cediranib-bound MtbClpP1P2, we found that cediranib dysregulates MtbClpP1P2 by interfering with handle domain of the equatorial region of MtbClpP1, indicating that the inter-ring dynamics are crucial for its function. This finding provides direct evidence for the notion that a conformational switch in the equatorial handle domain is essential for ClpP activity. We also present biochemical data to interpret the distinct interaction pattern and inhibitory properties of cediranib toward MtbClpP1P2. These results suggest that the variable handle domain region is responsible for the species-selectivity of cediranib, which suggests the equatorial handle domain as a potential region for screening pathogen-specific ClpP inhibitors.

biochemistry↗