Biology subjects

Chen, X.

Publications and source records attributed to Chen, X..

At least 667 records · Page 37Linked to original sources

bioRxiv2024

MtrAB two-component system is crucial for the intrinsic resistance and virulence of Mycobacterium abscessus

Mycobacterium abscessus (Mab) poses serious therapeutic challenges, principally due to its intrinsic resistance to a wide array of antibiotics. The pressing issue of drug resistance has spurred an urgent need to explore novel targets and develop new therapeutic agents against Mab. The MtrAB two-component system, conserved among Actinobacteria, is pivotal for regulating various metabolic processes. Nevertheless, the role of MtrAB in Mab remains elusive. In this study, we uncovered that Mab strains with disrupted mtrA, mtrB or both exhibited heightened susceptibility to a variety of antibiotics with diverse mechanisms of action, in contrast to the wild-type strain. In a murine model, rifabutin, bedaquiline, and amikacin, which were inactive against the wild-type Mab strain, demonstrated efficacy against all the mtrA, mtrB and mtrAB knockout strains, significantly reducing pulmonary bacterial burdens compared to vehicle controls after ten days of treatment. Notably, the virulence of all the mtrA, mtrB, and mtrAB knockout strains was highly diminished in the murine model, as evidenced by a substantial decrease in bacterial load in the lungs of mice after 16 days. We observed that all three knockout strains exhibited a significantly reduced growth rate compared to the wild-type strain. We discovered that cells lacking mtrA, mtrB or both exhibited an elongated cell length and had multiple septa, suggesting that both MtrA and MtrB regulate cell division of Mab. Subsequently, an ethidium bromide accumulation assay disclosed that the absence of either mtrA or mtrB or both significantly increased cell envelope permeability. In summary, this study suggests that mtrA and mtrB play an important role in the intrinsic resistance and virulence of Mab by affecting cell division and altering cell permeability. Consequently, MtrA and MtrB represent promising targets for the discovery of anti-Mab drugs. HIGHLIGHTSO_LIKnockout of mtrA, mtrB or mtrAB leads to increased sensitivity of M. abscessus in vitro and in vivo. C_LIO_LIThe mtrA, mtrB or mtrAB knockout M. abscessus strains exhibit highly reduced virulence. C_LIO_LIMtrA and MtrB are potential targets for anti-M. abscessus drug discovery. C_LIO_LIKnockout of mtrA, mtrB or mtrAB results in defective cell division in M. abscessus. C_LI

microbiology↗

bioRxiv2024

Discovery of orally bioavailable SARS-CoV-2 papain-like protease inhibitor as a potential treatment for COVID-19

The RNA-dependent RNA polymerase (RdRp), 3C-like protease (3CLpro), and papain-like protease (PLpro) are pivotal components in the viral life cycle of SARS-CoV-2, presenting as promising therapeutic targets. Currently, all FDA-approved antiviral drugs against SARS-CoV-2 are RdRp or 3CLpro inhibitors. However, the mutations causing drug resistance have been observed in RdRp and 3CLpro from SARS-CoV-2, which makes it necessary to develop antivirals with novel mechanisms. Through the application of a structure-based drug design (SBDD) approach, we discovered a series of novel potent non-covalent PLpro inhibitors with remarkable in vitro potency and in vivo PK properties. The co-crystal structures of PLpro with leads revealed that the residues D164 and Q269 around the S2 site are critical for improving the inhibitors potency. The lead compound GZNL-P36 not only inhibited SARS-CoV-2 and its variants at the cellular level with EC50 ranging from 58.2 nM to 306.2 nM, but also inhibited HCoV-NL63 and HCoV-229E with EC50 of 81.6 nM and 2.66 M, respectively. Oral administration of the compound resulted in significantly improved survival and notable reductions in lung viral loads and lesions in SARS- CoV-2 infection mouse model, consistent with RNA-seq data analysis. Our results indicate that PLpro inhibitor is a promising SARS-CoV-2 therapy.

microbiology↗

bioRxiv2024

Bidirectional Translation of Transcriptomic Profiles between Liver and Kidney under Drug Treatment Using Generative Adversarial Networks (GANs)

Translational research in toxicology has significantly benefited from transcriptomic profiling, particularly in drug safety. However, its application has predominantly focused on limited organs, notably the liver, due to resource constraints. This paper presents TransTox, an innovative AI model using a Generative Adversarial Network (GAN) method to facilitate bidirectional translation of transcriptomic profiles between the liver and kidney under drug treatment. TransTox demonstrates robust performance, validated across independent datasets and laboratories. Firstly, the concordance between real experimental data and synthetic data generated by TransTox was demonstrated in characterizing toxicity mechanisms compared to real experimental settings. Secondly, TransTox proved valuable in gene expression predictive models, where synthetic data could be used to develop gene expression predictive models or serve as "digital twins" for diagnostic applications. The TransTox approach holds potential for multi-organ toxicity assessment with AI and advancing the field of precision toxicology.

bioinformatics↗

bioRxiv2024

Negative regulation of APC/C activation by MAPK-mediated attenuation of Cdc20Slp1 under stress

Mitotic anaphase onset is a key cellular process tightly regulated by multiple kinases. The involvement of mitogen-activated protein kinases (MAPKs) in this process has been established in Xenopus egg extracts. However, the detailed regulatory cascade remains elusive, and also it is unknown whether the MAPKs-dependent mitotic regulation is evolutionarily conserved in the single cell eukaryotic organism such as fission yeast (Schizosaccharomyces pombe). Here we show that two MAPKs in S. pombe indeed act in concert to restrain anaphase-promoting complex/cyclosome (APC/C) activity upon activation of the spindle assembly checkpoint (SAC). One MAPK, Pmk1, binds and phosphorylates Slp1Cdc20, the co-activator of APC/C. Phosphorylation of Slp1Cdc20 by Pmk1, but not by Cdk1, promotes its subsequent ubiquitylation and degradation. Intriguingly, Pmk1-mediated phosphorylation event is also required to sustain SAC under environmental stress. Thus, our study establishes a new underlying molecular mechanism of negative regulation of APC/C by MAPK upon stress stimuli, and provides an unappreciated framework for regulation of anaphase entry in eukaryotic cells. One-sentence summaryInhibitory effect on the activation of anaphase promoting complex/cyclosome (APC/C) by MAPK Pmk1

cell biology↗

bioRxiv2024

Temporal Ablation of Primary Cilia Impairs Brainwave Patterns Implicated in Memory Formation

The primary cilium is a hair-like organelle that hosts molecular machinery for various developmental and homeostatic signaling pathways. Its alteration can cause rare ciliopathies such as the Bardet-Biedl and Joubert syndromes, but is also linked to Alzheimers disease, clinical depression, and autism spectrum disorder. These afflictions are caused by disturbances in a wide variety of genes but a common phenotype amongst them is cognitive impairment. While cilia-mediated neural function has been widely examined in early neurodevelopment, their function in the adult brain is not well understood. To help elucidate the role of cilia in neural activity, we temporally induced the ablation of IFT88, a gene encoding the intraflagellar transport 88 protein which is neccessary for ciliogenesis, in adult mice before performing memory-related behavioral assays and electroencephalogram/electromyogram (EEG/EMG) recordings. Inducible IFT88 KO mice exhibited severe learning deficits in trace fear conditioning and Morris water maze tests. They had strongly affected brainwave activity both under isoflurane induced anesthesia and during normal activity. And additionally, inducible IFT88 KO mice had altered sleep architecture and attenuated phase-amplitude coupling, a process that underlies learning and memory formation. These results highlight the growing significance of primary cilia for healthy neural function in the adult brain.

animal behavior and cognition↗

bioRxiv2024

Non-invasive and painless mid-infrared modulation increases collagen in human and mouse skin

Stimulating collagen production in skin helps to enhance vitality while decelerating aging- associated processes in skin tissue. However, current approaches to enhancing collagen production are commonly limited by accompanying pain and trauma. Here, we report that mid-infrared modulation (MIMO) at an intensity of 70 mW/cm2 promotes collagen production in human or mouse skin in vivo without generating excessive heat. We found that protein levels of the collagen- degrading endopeptidase, MMP-1, were decreased in the skin of mice following MIMO treatment, whereas the collagen synthesis-related factors, TGF-{beta}, HSP47, and HSP70, were all increased. In addition, MIMO stimulated collagen secretion in human dermal fibroblasts in vitro. This work demonstrates that MIMO is an effective, non-invasive, and painless intervention for in vivo enhancement of collagen production in the skin. One Sentence SummaryMid-infrared modulation promotes collagen production

molecular biology↗

bioRxiv2024

Exploring Pathogenic Mutation in Allosteric Proteins: the Prediction and Beyond

Allosteric regulation that triggers the functional activity of a protein through conformational changes is an inherent function of the protein in numerous physiological and pathological scenarios. In the post-genomic era, a central challenge for disease genomes is the identification of the biological effects of specific somatic variants on allosteric proteins and the phenotypes they influence during the initiation and progression of diseases. Here, we analyzed more than 38539 mutations observed in 90 human genes with 740 allosteric protein chains. We found that existing allosteric protein mutations are associated with many diseases, but the clinical significance of the majority of mutations in allosteric proteins remains unclear. Next, we developed a machine-learning-based model for pathogenic mutation prediction of allosteric proteins based on the intrinsic characteristics of proteins and the prediction results from existed methods. When tested on the benchmark allosteric protein dataset, the proposed method achieves AUCs of 0.868 and AUPR of 0.894 on allosteric proteins. Furthermore, we explored the performance of existing methods in predicting the pathogenicity of mutations at allosteric sites and identified potential significant pathogenic mutations at allosteric sites using the proposed method. In summary, these findings illuminate the significance of allosteric mutation in disease processes, and contribute a valuable tool for the identification of pathogenic mutations as well as previously unknown disease-causing allosteric-protein-encoded genes.

bioinformatics↗

bioRxiv2024

Compartmentalized localization of perinuclear proteins within germ granules in C. elegans

Biomolecular condensates are nonmembrane-enclosed organelles that play important roles in distinct biological processes. Germ granules are RNA-rich condensates that are often docked on the cytoplasmic surface of germline nuclei and exist in a variety of organisms. The C. elegans germ granule is a condensate that is subcompartmentalized into at least 6 distinct regions, including the P granule, Z granule, E granule, Mutator foci, SIMR foci and P-body. Although a number of perinuclear proteins have been found to be enriched in germ granules, their precise localization within the subcompartments of germ granules is still unclear. Here, we systematically labeled perinuclear localized proteins with fluorescent proteins via CRISPR/Cas9 technology and further explored the perinuclear localization of these proteins. Using this nematode strain library, we identified a series of proteins localized in Z or E granules. We found that proteins that participate in distinct piRNA processing steps were localized in particular subcompartments, including the P-, Z-, and E-granules. We further identified a novel subcompartment, the D granule, which was enriched between the P granule and the nuclear pore complex. Finally, we analyzed the perinuclear localization of these germ granule subcompartments in mip-1/eggd-1 mutants and found that the LOTUS domain protein MIP-1/EDDG-1 was required for the establishment of the multiphase architecture of germ granules. Overall, our work revealed germ granule architecture and redefined the localization of perinuclear proteins within germ granules. Additionally, the library of genetically modified nematode strains expressing peri-nuclear proteins labeled with fluorescent tags will facilitate research on germ granules in C. elegans.

cell biology↗

bioRxiv2024

A Comparative Study on the Superiority of AOS DP3-7 Over 5-ALA in Facilitating Pigment Change in Peppers

This study investigates the impact of Alginate Oligosaccharides (AOS) and 5-Aminolevulinic Acid (5-ALA) on the maturation process of red peppers, focusing on color transformation, weight gain, seed density, and skin thickness. Treatments included foliar applications of 100 ppm solutions of AOS and 5-ALA, compared with a control group, over a period of two weeks in a controlled environment. Results indicated that AOS and 5-ALA treatments accelerated the ripening process, as evidenced by increased uniformity in color transformation and significant weight gain in treated groups. Further examination revealed notable differences in seed distribution and skin thickness, with AOS and 5-ALA peppers exhibiting a denser seed population and variations in skin thickness. Biochemical pathway analysis suggested that these biostimulants could modulate ethylene signaling and other ripening-related processes, influencing both external fruit characteristics and internal development. This comprehensive study offers valuable insights into the complex mechanisms of fruit ripening and the application of biostimulants to enhance crop quality and market value.

plant biology↗

bioRxiv2024

Seaweed Amino Acid and L-Amino Acid Improve Coriander Growth

This study investigates the impact of Seaweed amino acid (SG) and L-amino acid (LG) treatments on the growth and root development of coriander plants compared to a control group (CG). The results from Figure 1 illustrate a significant increase in biomass and foliage density for the SG and LG groups, suggesting an enhanced nutritional uptake resulting from these amino acid treatments. Both SG and LG treatments produced more vigorous growth and higher plant height compared to the CG, which received only water. Additionally, a closer inspection of coriander root systems in Figure 2 reveals an improvement in root biomass and architecture, indicating that both SG and LG applications contribute positively to root development, potentially enhancing plant resilience and yield. While both treatments showed comparable effects on root morphology, further research is required to determine if one has superior long-term benefits over the other. The findings point towards the efficacy of using amino acid treatments as bio-stimulants in agricultural practices to improve crop yield, especially in challenging growth conditions such as those found in Guangzhou, China. O_FIG O_LINKSMALLFIG WIDTH=185 HEIGHT=200 SRC="FIGDIR/small/585645v1_fig1.gif" ALT="Figure 1"> View larger version (144K): org.highwire.dtl.DTLVardef@84ada8org.highwire.dtl.DTLVardef@a51dfeorg.highwire.dtl.DTLVardef@544772org.highwire.dtl.DTLVardef@11e9adf_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOFigure 1:C_FLOATNO Comparative Analysis of Coriander Growth Response to Root Applications of Seaweed Amino Acid (SG) and L-amino Acid (LG). Top Left (SG): Coriander plants treated with seaweed amino acid at 100 ppm, showing dense foliage. Top Right (LG): Coriander plants treated with L-amino acid at 100 ppm, exhibiting similar vegetative growth. Bottom Left (CG): Control coriander plants irrigated only with water, with noticeably less growth. Bottom Right: Comparative height analysis of harvested coriander plants, demonstrating the impact of SG and LG treatments versus the control group. C_FIG O_FIG O_LINKSMALLFIG WIDTH=120 HEIGHT=200 SRC="FIGDIR/small/585645v1_fig2.gif" ALT="Figure 2"> View larger version (92K): org.highwire.dtl.DTLVardef@49b047org.highwire.dtl.DTLVardef@1d42543org.highwire.dtl.DTLVardef@da7ec1org.highwire.dtl.DTLVardef@b7c5db_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOFigure 2.C_FLOATNO Differential Impact of Seaweed Amino Acid (SG) and L-amino Acid (LG) Treatments on Coriander Root Morphology. The image presents a comparative view of coriander root systems after treatment with Seaweed amino acids (SG) and L-amino acids (LG) against a control group (CG). The control group roots (top row) display a baseline development, having been irrigated solely with water. The SG group roots (middle row) exhibit enhanced development, indicative of the positive influence of Seaweed amino acid treatment. In contrast, the LG group roots (bottom row) show a comparable advancement in root structure to the SG group, suggesting both amino acid treatments contribute to improved root architecture and possibly, plant resilience at harvest. C_FIG

plant biology↗

bioRxiv2024

CLigOpt: Controllable Ligand Design through Target-Specific Optimisation

AO_SCPCAPBSTRACTC_SCPCAPO_ST_ABSMotivationC_ST_ABSKey challenge in deep generative models for molecular design is to navigate random sampling of the vast molecular space, and produce promising molecules that compromise property controls across multiple chemical criteria. Fragment-based drug design (FBDD), using fragments as starting points, is an effective way to constrain chemical space and improve generation of biologically active molecules. Furthermore, optimisation approaches are often implemented with generative models to search through chemical space, and identify promising samples which satisfy specific properties. Controllable FBDD has promising potential in efficient target-specific ligand design. ResultsWe propose a controllable FBDD model, CLigOpt, which can generate molecules with desired properties from a given fragment pair. CLigOpt is a Variational AutoEncoder-based model which utilises co-embeddings of node and edge features to fully mine information from molecular graphs, as well as a multi-objective Controllable Generation Module to generate molecules under property controls. CLigOpt achieves consistently strong performance in generating structurally and chemically valid molecules, as evaluated across six metrics. Applicability is illustrated through ligand candidates for hDHFR and it is shown that the proportion of feasible active molecules from the generated set is increased by 10%. Molecular docking and synthesisability prediction tasks are conducted to prioritise generated molecules to derive potential lead compounds. Availability and ImplementationThe source code is available via https://github.com/yutongLi1997/CLigOpt-Controllable-Ligand-Design-through-Target-Specific-Optimisation.

bioinformatics↗

bioRxiv2024

Non-invasive laser speckle imaging of extra-embryonic blood vessels in intact few-days-old avian eggs

Imaging blood vessels in early-stage avian embryos has a wide range of practical applications for developmental biology studies, drug and vaccine testing, and early sex determination. Optical imaging such as brightfield transmission imaging offers a compelling solution due to its safe non-ionizing radiation, and operational benefits. However, it comes with challenges such as eggshell opacity and light scattering. To address these, we have revisited an approach based on laser speckle contrast imaging (LSCI) and demonstrated a high quality, comprehensive and non-invasive visualization of blood vessels in few-days-old chicken eggs, with blood vessel as small as 100 {micro}m in diameter (with LSCI profile full-width-at-half-maximum of 275 {micro}m). We present its non-invasive use for monitoring blood flow, measuring the embryos heartbeat, and determining the embryos developmental stages using machine learning with 85% accuracy from stage HH15 to HH22. This method can potentially be used for non-invasive longitudinal studies of cardiovascular development and angiogenesis, as well as egg screening for the poultry industry.

bioengineering↗

bioRxiv2024

Conditional c-MYC activation in catecholaminergic cells drives distinct neuroendocrine tumors: neuroblastoma vs somatostatinoma

The MYC proto-oncogenes (c-MYC, MYCN, MYCL) are among the most deregulated oncogenic drivers in human malignancies including high-risk neuroblastoma, 50% of which are MYCN-amplified. Genetically engineered mouse models (GEMMs) based on the MYCN transgene have greatly expanded the understanding of neuroblastoma biology and are powerful tools for testing new therapies. However, a lack of c-MYC-driven GEMMs has hampered the ability to better understand mechanisms of neuroblastoma oncogenesis and therapy development given that c-MYC is also an important driver of many high-risk neuroblastomas. In this study, we report two transgenic murine neuroendocrine models driven by conditional c-MYC induction in tyrosine hydroxylase (Th) and dopamine {beta}-hydroxylase (Dbh)-expressing cells. c-MYC induction in Th-expressing cells leads to a preponderance of Pdx1+ somatostatinomas, a type of pancreatic neuroendocrine tumor (PNET), resembling human somatostatinoma with highly expressed gene signatures of {delta} cells and potassium channels. In contrast, c-MYC induction in Dbh-expressing cells leads to onset of neuroblastomas, showing a better transforming capacity than MYCN in a comparable C57BL/6 genetic background. The c-MYC murine neuroblastoma tumors recapitulate the pathologic and genetic features of human neuroblastoma, express GD2, and respond to anti-GD2 immunotherapy. This model also responds to DFMO, an FDA-approved inhibitor targeting ODC1, which is a known MYC transcriptional target. Thus, establishing c-MYC-overexpressing GEMMs resulted in different but related tumor types depending on the targeted cell and provide useful tools for testing immunotherapies and targeted therapies for these diseases.

cancer biology↗

bioRxiv2024

Detection of spatial chromatin accessibility patterns with inter-cellular correlations

Recent advances in spatial sequencing technologies enable simultaneous capture of spatial location and chromatin accessibility of cells within intact tissue slices. Identifying peaks that display spatial variation and cellular heterogeneity is the first and key analytic task for characterizing the spatial chromatin accessibility landscape of complex tissues. Here we propose an efficient and iterative model, Descartes, for spatially variable peaks identification based on the graph of inter-cellular correlations. Through the comprehensive benchmarking for spatially variable peaks identification, we demonstrate the superiority of Descartes in revealing cellular heterogeneity and capturing tissue structure. In terms of computational efficiency, Descartes also outperforms existing methods with spatial assumptions. Utilizing the graph of inter-cellular correlations, Descartes denoises and imputes data via the neighboring relationships, enhancing the precision of downstream analysis. We further demonstrate the ability of Descartes for peak module identification by using peak-peak correlations within the graph. When applied to spatial multi-omics data, Descartes show its potential to detect gene-peak interactions, offering valuable insights into the construction of gene regulatory networks.

bioinformatics↗

bioRxiv2024

MYT1L deficiency impairs excitatory neuron trajectory during cortical development

Mutations that reduce the function of MYT1L, a neuron-specific transcription factor, are associated with a syndromic neurodevelopmental disorder. Furthermore, MYT1L is routinely used as a proneural factor in fibroblast-to-neuron transdifferentiation. MYT1L has been hypothesized to play a role in the trajectory of neuronal specification and subtype specific maturation, but this hypothesis has not been directly tested, nor is it clear which neuron types are most impacted by MYT1L loss. In this study, we profiled 313,335 nuclei from the forebrains of wild-type and MYT1L-deficient mice at two developmental stages: E14 at the peak of neurogenesis and P21, when neurogenesis is complete, to examine the role of MYT1L levels in the trajectory of neuronal development. We found that MYT1L deficiency significantly disrupted the relative proportion of cortical excitatory neurons at E14 and P21. Significant changes in gene expression were largely concentrated in excitatory neurons, suggesting that transcriptional effects of MYT1L deficiency are largely due to disruption of neuronal maturation programs. Most effects on gene expression were cell autonomous and persistent through development. In addition, while MYT1L can both activate and repress gene expression, the repressive effects were most sensitive to haploinsufficiency, and thus more likely mediate MYT1L syndrome. These findings illuminate the intricate role of MYT1L in orchestrating gene expression dynamics during neuronal development, providing insights into the molecular underpinnings of MYT1L syndrome.

neuroscience↗

bioRxiv2024

HER2 Prognostic Significance and Therapeutic Implications in Gastric Cardia Adenocarcinoma: Insights from Multi-Omics Profiling

Therapeutic targets for Gastric Cardia Adenocarcinoma (GCA), particularly for HER2- negative patients, are lacking. Here, we conducted multi-omics profiling on 128 GCA patients using mass spectrometry, whole-exome sequencing, RNA-Seq, and metabolomics. We found HER2 to be a favorable prognostic marker for GCA. Employing molecular counting, we categorized patients into HER2-high, -low, and -negative groups. We uncovered an enrichment of DNA repair features in the HER2-high group, while HER2-low and -negative groups exhibited strong inflammation. We found that tumor mutation burden may not be the distinguishing factor among these three groups. We revealed that the HER2-negative and -low groups have a tumor-suppressive immune microenvironment, and HER2 expression is associated with fatty acid metabolic profiles and inflammation in the blood of patients. Our study revealed anti-inflammatory and immune checkpoint inhibition, targeting PD-L2 and the CD47/SIRPA pair, as therapeutic strategies for HER2-negative GCA patients. These findings highlight promising avenues for personalized treatment for GCA.

cancer biology↗

bioRxiv2024

Targeting G9a translational mechanism of SARS-CoV-2 pathogenesis for multifaceted therapeutics of COVID-19 and its sequalae

By largely unknown mechanism(s), SARS-CoV-2 hijacks the host translation apparatus to promote COVID-19 pathogenesis. We report that the histone methyltransferase G9a noncanonically regulates viral hijacking of the translation machinery to bring about COVID-19 symptoms of hyperinflammation, lymphopenia, and blood coagulation. Chemoproteomic analysis of COVID-19 patient peripheral mononuclear blood cells (PBMC) identified enhanced interactions between SARS-CoV-2-upregulated G9a and distinct translation regulators, particularly the N6-methyladenosine (m6A) RNA methylase METTL3. These interactions with translation regulators implicated G9a in translational regulation of COVID-19. Inhibition of G9a activity suppressed SARS-CoV-2 replication in human alveolar epithelial cells. Accordingly, multi-omics analysis of the same alveolar cells identified SARS-CoV-2-induced changes at the transcriptional, m6A-epitranscriptional, translational, and post-translational (phosphorylation or secretion) levels that were reversed by inhibitor treatment. As suggested by the aforesaid chemoproteomic analysis, these multi-omics-correlated changes revealed a G9a-regulated translational mechanism of COVID-19 pathogenesis in which G9a directs translation of viral and host proteins associated with SARS-CoV-2 replication and with dysregulation of host response. Comparison of proteomic analyses of G9a inhibitor-treated, SARS-CoV-2 infected cells, or ex vivo culture of patient PBMCs, with COVID-19 patient data revealed that G9a inhibition reversed the patient proteomic landscape that correlated with COVID-19 pathology/symptoms. These data also indicated that the G9a-regulated, inhibitor-reversed, translational mechanism outperformed G9a-transcriptional suppression to ultimately determine COVID-19 pathogenesis and to define the inhibitor action, from which biomarkers of serve symptom vulnerability were mechanistically derived. This cell line-to-patient conservation of G9a-translated, COVID-19 proteome suggests that G9a inhibitors can be used to treat patients with COVID-19, particularly patients with long-lasting COVID-19 sequelae.

immunology↗

bioRxiv2024

Gut Microbiome-Driven Metabolites Influence Skin Pigmentation in TYRP1 Mutant Oujiang Color Common Carp

The gut microbiome is one of the major regulators of the gut-skin axis and is partly regulated by host genetics. In the present study, using comparative high-throughput omics data on CRISPR/Cas9-mediated TYRP1 mutant and wild-color common carp populations, we quantified the proportion of inter-individual variation in the skin transcriptome and blood metabolome by genetic architecture and gut microbiomes. We found 525 differential metabolites (DMs) and 45 differential gut microbial genera in TYRP1 mutant fishes relative to the wild type. Through interaction analysis and causal mediation analyses, we revealed that the TYRP1-mutant derived genetic background may exert an inflammatory Acinetobacter - Leukotrience-C4 and - Spermine metabolic pathway under the regulation of an anti-inflammatory cardio-vascular genetic network underlying the upregulating expression of COMT, PLG, C2, C3, F10, TDO2, MHC1, and SERPINF2 gene for evolving unusual coffee-like color phenotype. This unique network appears to underlie the "coffee-like" color phenotype. We propose that the COMT-mediated causal effect of the unusual gut microbiome on the atypical skin gene expression patterns through the gut-skin metabolic pathway. Article SummaryR.N. Mandal et al. report on the causal effect of gut microbiome-driven metabolites on the expression pattern of regulatory genes underlying an unusual color phenotype. It suggests that TYRP1 Mutation may rise an unusual inflammatory gut microbiome-skin metabolic pathway that may be balanced by an anti-inflammatory cardio-vascular genetic network leading to unique coloration in Oujiang Color Common Carp.

genetics↗