Sci Rep. 2023 Aug 28;13(1):14046. doi: 10.1038/s41598-023-41037-0.

ABSTRACT

Uremic cardiomyopathy is characterized by diastolic dysfunction, left ventricular hypertrophy (LVH), and fibrosis. Dysregulation of the kisspeptin receptor (KISS1R)-mediated pathways are associated with the development of fibrosis in cancerous diseases. Here, we investigated the effects of the KISS1R antagonist peptide-234 (P234) on the development of uremic cardiomyopathy. Male Wistar rats (300-350 g) were randomized into four groups: (i) Sham, (ii) chronic kidney disease (CKD) induced by 5/6 nephrectomy, (iii) CKD treated with a lower dose of P234 (ip. 13 µg/day), (iv) CKD treated with a higher dose of P234 (ip. 26 µg/day). Treatments were administered daily from week 3 for 10 days. At week 13, the P234 administration did not influence the creatinine clearance and urinary protein excretion. However, the higher dose of P234 led to reduced anterior and posterior wall thicknesses, more severe interstitial fibrosis, and overexpression of genes associated with left ventricular remodeling (Ctgf, Tgfb, Col3a1, Mmp9), stretch (Nppa), and apoptosis (Bax, Bcl2, Casp7) compared to the CKD group. In contrast, no significant differences were found in the expressions of apoptosis-associated proteins between the groups. Our results suggest that the higher dose of P234 hastens the development and pathophysiology of uremic cardiomyopathy by activating the fibrotic TGF-β-mediated pathways.

PMID:37640761 | DOI:10.1038/s41598-023-41037-0

Proc Natl Acad Sci U S A. 2023 Sep 5;120(36):e2303758120. doi: 10.1073/pnas.2303758120. Epub 2023 Aug 28.

ABSTRACT

In Arabidopsis thaliana, brassinosteroid (BR) signaling and stomatal development are connected through the SHAGGY/GSK3-like kinase BR INSENSITIVE2 (BIN2). BIN2 is a key negative regulator of BR signaling but it plays a dual role in stomatal development. BIN2 promotes or restricts stomatal asymmetric cell division (ACD) depending on its subcellular localization, which is regulated by the stomatal lineage-specific scaffold protein POLAR. BRs inactivate BIN2, but how they govern stomatal development remains unclear. Mapping the single-cell transcriptome of stomatal lineages after triggering BR signaling with either exogenous BRs or the specific BIN2 inhibitor, bikinin, revealed that the two modes of BR signaling activation generate spatiotemporally distinct transcriptional responses. We established that BIN2 is always sensitive to the inhibitor but, when in a complex with POLAR and its closest homolog POLAR-LIKE1, it becomes protected from BR-mediated inactivation. Subsequently, BR signaling in ACD precursors is attenuated, while it remains active in epidermal cells devoid of scaffolds and undergoing differentiation. Our study demonstrates how scaffold proteins contribute to cellular signal specificity of hormonal responses in plants.

PMID:37639582 | DOI:10.1073/pnas.2303758120

Adv Sci (Weinh). 2023 Aug 28:e2303207. doi: 10.1002/advs.202303207. Online ahead of print.

ABSTRACT

Tissue-infiltrating neutrophils (TINs) secrete various signaling molecules to establish paracrine communication within the inflammatory milieu. It is imperative to identify molecular mediators that control this secretory phenotype of TINs. The present study uncovers a secretory neutrophil subset that exhibits increased pro-inflammatory cytokine production and enhanced migratory capacity which is highly related with periodontal pathogenesis. Further analysis identifies the OTU domain-containing protein 1 (OTUD1) plays a regulatory role in this secretory neutrophil polarization. In human and mouse periodontitis, the waning of inflammation is correlated with OTUD1 upregulation, whereas severe periodontitis is induced when neutrophil-intrinsic OTUD1 is depleted. Mechanistically, OTUD1 interacts with SEC23B, a component of the coat protein II complex (COPII). By removing the K63-linked polyubiquitin chains on SEC23B Lysine 81, the deubiquitinase OTUD1 negatively regulates the COPII secretory machinery and limits protein ER-to-Golgi trafficking, thus restricting the surface expression of integrin-regulated proteins, CD9 and CD47. Accordingly, blockade of protein transport by Brefeldin A (BFA) curbs recruitment of Otud1-deficient TINs and attenuates inflammation-induced alveolar bone destruction. The results thus identify OTUD1 signaling as a negative feedback loop that limits the polarization of neutrophils with secretory phenotype and highlight the potential application of BFA in the treatment of periodontal inflammation.

PMID:37639212 | DOI:10.1002/advs.202303207

Methods Mol Biol. 2024;2713:281-296. doi: 10.1007/978-1-0716-3437-0_19.

ABSTRACT

Macrophages display a high degree of phenotypic diversity and plasticity, which is influenced by their location within the tissue microenvironment. Co-Detection by Indexing (CODEX), a multiplexed imaging technique, allows the simultaneous detection of multiple membrane and cellular markers that enable the accurate identification of tissue-resident hematopoietic and non-hematopoietic cells, while conferring spatial information at a single-cell level. Here we describe the use of CODEX to visualize the phenotypic and spatial heterogeneity of murine tissue-resident macrophages in several organs, and a pipeline to characterize their cellular microenvironments and interactions.

PMID:37639130 | DOI:10.1007/978-1-0716-3437-0_19

mSystems. 2023 Aug 28:e0043723. doi: 10.1128/msystems.00437-23. Online ahead of print.

ABSTRACT

The transcriptional regulatory network (TRN) of the phytopathogen Pseudomonas syringae pv. tomato DC3000 regulates its response to environmental stimuli, including interactions with hosts and neighboring bacteria. Despite the importance of transcriptional regulation during these agriculturally significant interactions, a comprehensive understanding of the TRN of P. syringae is yet to be achieved. Here, we collected and decomposed a compendium of public RNA-seq data from P. syringae to obtain 45 independently modulated gene sets (iModulons) that quantitatively describe the TRN and its activity state across diverse conditions. Through iModulon analysis, we (i) untangle the complex interspecies interactions between P. syringae and other terrestrial bacteria in cocultures, (ii) expand the current understanding of the Arabidopsis thaliana-P. syringae interaction, and (iii) elucidate the AlgU-dependent regulation of flagellar gene expression. The modularized TRN yields a unique understanding of interaction-specific transcriptional regulation in P. syringae. IMPORTANCE Pseudomonas syringae pv. tomato DC3000 is a model plant pathogen that infects tomatoes and Arabidopsis thaliana. The current understanding of global transcriptional regulation in the pathogen is limited. Here, we applied iModulon analysis to a compendium of RNA-seq data to unravel its transcriptional regulatory network. We characterize each co-regulated gene set, revealing the activity of major regulators across diverse conditions. We provide new insights on the transcriptional dynamics in interactions with the plant immune system and with other bacterial species, such as AlgU-dependent regulation of flagellar genes during plant infection and downregulation of siderophore production in the presence of a siderophore cheater. This study demonstrates the novel application of iModulons in studying temporal dynamics during host-pathogen and microbe-microbe interactions, and reveals specific insights of interest.

PMID:37638727 | DOI:10.1128/msystems.00437-23

Biotechnol Bioeng. 2023 Aug 28. doi: 10.1002/bit.28532. Online ahead of print.

ABSTRACT

Species of bacteria from the genus Cupriavidus are known, in part, for their ability to produce high amounts of poly-hydroxybutyrate (PHB) making them attractive candidates for bioplastic production. The native synthesis of PHB occurs during periods of metabolic stress, and the process regulating the initiation of PHB accumulation in these organisms is not fully understood. Screening an RB-TnSeq transposon library of Cupriavidus basilensis 4G11 allowed us to identify two genes of an apparent, uncharacterized two-component system, which when omitted from the genome enable increased PHB productivity in balanced, nonstress growth conditions. We observe average increases in PHB productivity of 56% and 41% relative to the wildtype parent strain upon deleting each gene individually from the genome. The increased PHB phenotype disappears, however, in nitrogen-free unbalanced growth conditions suggesting the phenotype is specific to fast-growing, replete, nonstress growth. Bioproduction modeling suggests this phenotype could be due to a decreased reliance on metabolic stress induced by nitrogen limitation to initiate PHB production in the mutant strains. Due to uncertainty in the two-component system's input signal and regulon, the mechanism by which these genes impart this phenotype remains unclear. Such strains may allow for the use of single-stage, continuous bioreactor systems, which are far simpler than many PHB bioproduction schemes used previously, given a similar product yield to batch systems in such a configuration. Bioproductivity modeling suggests that omitting this regulation in the cells may increase PHB productivity up to 24% relative to the wildtype organism when using single-stage continuous systems. This work expands our understanding of the regulation of PHB accumulation in Cupriavidus, in particular the initiation of this process upon transition into unbalanced growth regimes.

PMID:37638652 | DOI:10.1002/bit.28532

Front Immunol. 2023 Aug 10;14:1243516. doi: 10.3389/fimmu.2023.1243516. eCollection 2023.

ABSTRACT

Dengue virus (DENV) infection manifests as a febrile illness with three distinct phases: early acute, late acute, and convalescent. Dengue can result in clinical manifestations with different degrees of severity, dengue fever, dengue hemorrhagic fever, and dengue shock syndrome. Interferons (IFNs) are antiviral cytokines central to the anti-DENV immune response. Notably, the distinct global signature of type I, II, and III interferon-regulated genes (the interferome) remains uncharacterized in dengue patients to date. Therefore, we performed an in-depth cross-study for the integrative analysis of transcriptome data related to DENV infection. Our systems biology analysis shows that the anti-dengue immune response is characterized by the modulation of numerous interferon-regulated genes (IRGs) enriching, for instance, cytokine-mediated signaling (e.g., type I and II IFNs) and chemotaxis, which is then followed by a transcriptional wave of genes associated with cell cycle, also regulated by the IFN cascade. The adjunct analysis of disease stratification potential, followed by a transcriptional meta-analysis of the interferome, indicated genes such as IFI27, ISG15, and CYBRD1 as potential suitable biomarkers of disease severity. Thus, this study characterizes the landscape of the interferome signature in DENV infection, indicating that interferome dynamics are a crucial and central part of the anti-dengue immune response.

PMID:37638052 | PMC:PMC10449254 | DOI:10.3389/fimmu.2023.1243516

Front Immunol. 2023 Aug 10;14:1216379. doi: 10.3389/fimmu.2023.1216379. eCollection 2023.

ABSTRACT

BACKGROUND: Primary Sjogren Syndrome (pSS) is an autoimmune disease characterized by immune cell infiltration. While the presence of follicular T helper (Tfh) cells in the glandular microenvironment has been observed, their biological functions and clinical significance remain poorly understood.

METHODS: We enrolled a total of 106 patients with pSS and 46 patients without pSS for this study. Clinical data and labial salivary gland (LSG) biopsies were collected from all participants. Histological staining was performed to assess the distribution of Tfh cells and B cells. Transcriptome analysis using RNA-sequencing (RNA-seq) was conducted on 56 patients with pSS and 26 patients without pSS to uncover the underlying molecular mechanisms of Tfh cells. To categorize patients, we employed the single-sample gene set enrichment analysis (ssGSEA) algorithm, dividing them into low- and high-Tfh groups. We then utilized gene set enrichment analysis (GSEA), weighted gene co-expression network analysis (WGCNA), and deconvolution tools to explore functional and immune infiltration differences between the low- and high-Tfh groups.

RESULTS: Patients with pSS had a higher positive rate of the antinuclear antibody (ANA), anti-Ro52, anti-SSA, anti-SSB and hypergammaglobulinaemia and higher levels of serum IgG compared to the non-pSS. Histopathologic analyses revealed the presence of Tfh cells (CD4+CXCR5+ICOS+) in germinal centers (GC) within the labial glands of pSS patients. GSEA, WGCNA, and correlation analysis indicated that the high-Tfh group was associated with an immune response related to virus-mediated IFN response and metabolic processes, primarily characterized by hypoxia, elevated glycolysis, and oxidative phosphorylation levels. In pSS, most immune cell types exhibited significantly higher infiltration levels in the high-Tfh group compared to the low-Tfh group. Additionally, patients in the Tfh-high group demonstrated a higher positive rate of the ANA, rheumatoid factor (RF), and hypergammaglobulinaemia, as well as higher serum IgG levels.

CONCLUSION: Our study suggests that Tfh cells may play a crucial role in the pathogenesis of pSS and could serve as potential therapeutic targets in pSS patients.

PMID:37638029 | PMC:PMC10448518 | DOI:10.3389/fimmu.2023.1216379

Front Pharmacol. 2023 Aug 11;14:1229297. doi: 10.3389/fphar.2023.1229297. eCollection 2023.

ABSTRACT

Copper (Cu) is a vital trace element for maintaining human health. Current evidence suggests that genes responsible for regulating copper influx and detoxification help preserve its homeostasis. Adequate Cu levels sustain normal cardiac and blood vessel activity by maintaining mitochondrial function. Cuproptosis, unlike other forms of cell death, is characterized by alterations in mitochondrial enzymes. Therapeutics targeting cuproptosis in cardiovascular diseases (CVDs) mainly include copper chelators, inhibitors of copper chaperone proteins, and copper ionophores. In this review, we expound on the primary mechanisms, critical proteins, and signaling pathways involved in cuproptosis, along with its impact on CVDs and the role it plays in different types of cells. Additionally, we explored the influence of key regulatory proteins and signaling pathways associated with cuproptosis on CVDs and determined whether intervening in copper metabolism and cuproptosis can enhance the outcomes of CVDs. The insights from this review provide a fresh perspective on the pathogenesis of CVDs and new targets for intervention in these diseases.

PMID:37637426 | PMC:PMC10450925 | DOI:10.3389/fphar.2023.1229297

J Immunother Precis Oncol. 2023 May 15;6(3):127-132. doi: 10.36401/JIPO-22-19. eCollection 2023 Aug.

ABSTRACT

INTRODUCTION: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) can cure patients with high-risk myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). However, many patients relapse or develop debilitating graft-versus-host disease. Transplant restores T-cell reactivity against tumor cells, implicating patient human leukocyte antigen (HLA)-dependent antigen presentation via the major histocompatibility complex as a determinant of response. We sought to identify characteristics of the HLA genotype that influence response in allo-HSCT patients.

METHODS: We collected HLA genotype and panel-based somatic mutation profiles for 55 patients with AML and MDS and available data treated at the University of California San Diego Moores Cancer Center between May 2012 and January 2019. We evaluated characteristics of the HLA genotype relative to relapse-free time and overall survival (OS) post-allo-HSCT using univariable and multivariable regression.

RESULTS: In multivariable regression, the presence of an autoimmune allele was significantly associated with relapse-free time (hazard ratio [HR], 0.25; p = 0.01) and OS (HR, 0.16; p < 0.005). The better potential of the donor HLA type to present peptides harboring driver mutations trended toward better relapse-free survival (HR, 0.45; p = 0.07) and significantly correlated with longer OS (HR, 0.33; p = 0.01) though only a minority of cases had an HLA mismatch.

CONCLUSION: In this single institution retrospective study of patients receiving allo-HSCT for relapsed AML/MDS, characteristics of an individual's HLA genotype (presence of an autoimmune allele and potential of the donor HLA to better present peptides representing driver mutations) were significantly associated with better outcomes. These findings suggest that HLA type may guide the optimal application of allo-HSCT and merit evaluation in larger cohorts. ClinicalTrials.gov Identifier: NCT02478931.

PMID:37637234 | PMC:PMC10448732 | DOI:10.36401/JIPO-22-19

Front Oncol. 2023 Aug 11;13:1174831. doi: 10.3389/fonc.2023.1174831. eCollection 2023.

ABSTRACT

INTRODUCTION: Lynch syndrome (LS) is the most common hereditary cause of colorectal cancer (CRC), increasing lifetime risk of CRC by up to 70%. Despite this higher lifetime risk, disease penetrance in LS patients is highly variable and most LS patients undergoing CRC surveillance will not develop CRC. Therefore, biomarkers that can correctly and consistently predict CRC risk in LS patients are needed to both optimize LS patient surveillance and help identify better prevention strategies that reduce risk of CRC development in the subset of high-risk LS patients.

METHODS: Normal-appearing colorectal tissue biopsies were obtained during repeat surveillance colonoscopies of LS patients with and without a history of CRC, healthy controls (HC), and patients with a history of sporadic CRC. Biopsies were cultured in an ex-vivo explant system and their supernatants were assayed via multiplexed ELISA to profile the local immune signaling microenvironment. High quality cytokines were identified using the rxCOV fidelity metric. These cytokines were used to perform elastic-net penalized logistic regression-based biomarker selection by computing a new measure - overall selection probability - that quantifies the ability of each marker to discriminate between patient cohorts being compared.

RESULTS: Our study demonstrated that cytokine based local immune microenvironment profiling was reproducible over repeat visits and sensitive to patient LS-status and CRC history. Furthermore, we identified sets of cytokines whose differential expression was predictive of LS-status in patients when compared to sporadic CRC patients and in identifying those LS patients with or without a history of CRC. Enrichment analysis based on these biomarkers revealed an LS and CRC status dependent constitutive inflammatory state of the normal appearing colonic mucosa.

DISCUSSION: This prospective pilot study demonstrated that immune profiling of normal appearing colonic mucosa discriminates LS patients with a prior history of CRC from those without it, as well as patients with a history of sporadic CRC from HC. Importantly, it suggests the existence of immune signatures specific to LS-status and CRC history. We anticipate that our findings have the potential to assess CRC risk in individuals with LS and help in preemptively mitigating it by optimizing surveillance and identifying candidate prevention targets. Further studies are required to validate our findings in an independent cohort of LS patients over multiple visits.

PMID:37637062 | PMC:PMC10457127 | DOI:10.3389/fonc.2023.1174831

RSC Adv. 2023 Aug 24;13(36):25218-25228. doi: 10.1039/d3ra03796g. eCollection 2023 Aug 21.

ABSTRACT

Artificial intelligence has become more prevalent in broad fields, including drug discovery, in which the process is costly and time-consuming when conducted through wet experiments. As a result, drug repurposing, which tries to utilize approved and low-risk drugs for a new purpose, becomes more attractive. However, screening candidates from many drugs for specific protein targets is still expensive and tedious. This study aims to leverage computational resources to aid drug discovery by utilizing drug-protein interaction data and estimating their interaction strength, so-called binding affinity. Our estimation approach addresses multiple challenges encountered in the field. First, we employed a graph-based deep learning technique to overcome the limitations of drug compounds represented in string format by incorporating background knowledge of node and edge information as separate multi-dimensional features. Second, we tackled the complexities associated with extracting the representation and structure of proteins by utilizing a pre-trained model for feature extraction. Also, we employed graph operations over the 1D representation of a protein sequence to overcome the fixed-length problem typically encountered in language model tasks. In addition, we conducted a comparative analysis with a baseline model that creates a protein graph from a contact map prediction model, giving valuable insights into the performance and effectiveness of our proposed method. We evaluated the performance of our model using the same benchmark datasets with a variety of matrices as other previous work, and the results show that our model achieved the best prediction results while requiring no contact map information compared to other graph-based methods.

PMID:37636509 | PMC:PMC10448119 | DOI:10.1039/d3ra03796g

Heliyon. 2023 Aug 2;9(8):e18869. doi: 10.1016/j.heliyon.2023.e18869. eCollection 2023 Aug.

ABSTRACT

Preoperative radiochemotherapy is a promising therapeutic method for locally advanced rectal cancer patients. However, the response of colorectal cancer (CRC) patients to preoperative radiotherapy varies widely. In this study, we aimed to identify novel biomarkers that could predict the response of colorectal tumors to treatment using a systems biology approach. We applied the Weighted Gene Co-Expression Network Analysis to construct co-expression networks and evaluated the correlation of these networks with radiation using the module-trait relationship. We then identified hub genes and related transcription factors in the selected co-expression module. Our analysis of seven constructed modules revealed that one module, which contained 113 nodes and 6066 edges, had the strongest correlation with radiation effects on CRC (correlation = 0.85; p-value = 6e-7). By analyzing the selected module with the CytoHubba plugin, we identified four hub genes, including ZEB2, JAM2, NDN, and PPAP2A. We also identified seven important transcription factors, including KLF4, SUZ12, TCF4, NANOG, POU5F1, SOX2, and SMARCA4, which may play essential roles in regulating the four hub genes. In summary, our findings suggest that ZEB2, JAM2, NDN, and PPAP2A, along with the seven transcription factors related to these hub genes, may be associated with the response of colorectal tumors to chemoradiotherapy.

PMID:37636389 | PMC:PMC10447927 | DOI:10.1016/j.heliyon.2023.e18869

iScience. 2023 Jul 25;26(9):107472. doi: 10.1016/j.isci.2023.107472. eCollection 2023 Sep 15.

ABSTRACT

Evidence is mounting for cross-resistance between immune checkpoint and targeted kinase inhibitor therapies in cutaneous melanoma patients. Since the loss of the transcription factor, SOX10, causes tolerance to MAPK pathway inhibitors, we used bioinformatic techniques to determine if reduced SOX10 expression/activity is associated with immune checkpoint inhibitor resistance. We integrated SOX10 ChIP-seq, knockout RNA-seq, and knockdown ATAC-seq data from melanoma cell models to develop a robust SOX10 gene signature. We used computational methods to validate this signature as a measure of SOX10-dependent activity in independent single-cell and bulk RNA-seq SOX10 knockdown, cell line panel, and MAPK inhibitor drug-resistant datasets. Evaluation of patient single-cell RNA-seq data revealed lower levels of SOX10-dependent transcripts in immune checkpoint inhibitor-resistant tumors. Our results suggest that SOX10-deficient melanoma cells are associated with cross-resistance between targeted and immune checkpoint inhibitors and highlight the need to identify therapeutic strategies that target this subpopulation.

PMID:37636077 | PMC:PMC10450419 | DOI:10.1016/j.isci.2023.107472

iScience. 2023 Jul 28;26(9):107500. doi: 10.1016/j.isci.2023.107500. eCollection 2023 Sep 15.

ABSTRACT

The bacterial strain JCVI-syn3.0 stands as the first example of a living organism with a minimized synthetic genome, derived from the Mycoplasma mycoides genome and chemically synthesized in vitro. Here, we report the experimental evolution of a syn3.0- derived strain. Ten independent replicates were evolved for several hundred generations, leading to growth rate improvements of > 15%. Endpoint strains possessed an average of 8 mutations composed of indels and SNPs, with a pronounced C/G- > A/T transversion bias. Multiple genes were repeated mutational targets across the independent lineages, including phase variable lipoprotein activation, 5 distinct; nonsynonymous substitutions in the same membrane transporter protein, and inactivation of an uncharacterized gene. Transcriptomic analysis revealed an overall tradeoff reflected in upregulated ribosomal proteins and downregulated DNA and RNA related proteins during adaptation. This work establishes the suitability of synthetic, minimal strains for laboratory evolution, providing a means to optimize strain growth characteristics and elucidate gene functionality.

PMID:37636038 | PMC:PMC10448532 | DOI:10.1016/j.isci.2023.107500

iScience. 2023 Jul 26;26(9):107466. doi: 10.1016/j.isci.2023.107466. eCollection 2023 Sep 15.

ABSTRACT

Comprehensive multiplatform analysis of Luminal B breast cancer (LBBC) specimens identifies two molecularly distinct, clinically relevant subtypes: Cluster A associated with cell cycle and metabolic signaling and Cluster B with predominant epithelial mesenchymal transition (EMT) and immune response pathways. Whole-exome sequencing identified significantly mutated genes including TP53, PIK3CA, ERBB2, and GATA3 with recurrent somatic mutations. Alterations in DNA methylation or transcriptomic regulation in genes (FN1, ESR1, CCND1, and YAP1) result in tumor microenvironment reprogramming. Integrated analysis revealed enriched biological pathways and unexplored druggable targets (cancer-testis antigens, metabolic enzymes, kinases, and transcription regulators). A systematic comparison between mRNA and protein displayed emerging expression patterns of key therapeutic targets (CD274, YAP1, AKT1, and CDH1). A potential ceRNA network was developed with a significantly different prognosis between the two subtypes. This integrated analysis reveals a complex molecular landscape of LBBC and provides the utility of targets and signaling pathways for precision medicine.

PMID:37636034 | PMC:PMC10448479 | DOI:10.1016/j.isci.2023.107466

Front Endocrinol (Lausanne). 2023 Aug 10;14:1232569. doi: 10.3389/fendo.2023.1232569. eCollection 2023.

ABSTRACT

Hepatocyte nuclear factor 4-alpha (HNF4α) drives a complex array of transcriptional programs across multiple organs. Beyond its previously documented function in the liver, HNF4α has crucial roles in the kidney, intestine, and pancreas. In the intestine, a multitude of functions have been attributed to HNF4 and its accessory transcription factors, including but not limited to, intestinal maturation, differentiation, regeneration, and stem cell renewal. Functional redundancy between HNF4α and its intestine-restricted paralog HNF4γ, and co-regulation with other transcription factors drive these functions. Dysregulated expression of HNF4 results in a wide range of disease manifestations, including the development of a chronic inflammatory state in the intestine. In this review, we focus on the multiple molecular mechanisms of HNF4 in the intestine and explore translational opportunities. We aim to introduce new perspectives in understanding intestinal genetics and the complexity of gastrointestinal disorders through the lens of HNF4 transcription factors.

PMID:37635981 | PMC:PMC10450339 | DOI:10.3389/fendo.2023.1232569

Environ Sci Ecotechnol. 2023 Jul 26;17:100304. doi: 10.1016/j.ese.2023.100304. eCollection 2024 Jan.

ABSTRACT

Microbiome research has generated an extensive amount of data, resulting in a wealth of publicly accessible samples. Accurate annotation of these samples is crucial for effectively utilizing microbiome data across scientific disciplines. However, a notable challenge arises from the lack of essential annotations, particularly regarding collection location and sample biome information, which significantly hinders environmental microbiome research. In this study, we introduce Meta-Sorter, a novel approach utilizing neural networks and transfer learning, to enhance biome labeling for thousands of microbiome samples in the MGnify database that have incomplete information. Our findings demonstrate that Meta-Sorter achieved a remarkable accuracy rate of 96.7% in classifying samples among the 16,507 lacking detailed biome annotations. Notably, Meta-Sorter provides precise classifications for representative environmental samples that were previously ambiguously labeled as "Marine" in MGnify, thereby elucidating their specific origins in benthic and water column environments. Moreover, Meta-Sorter effectively distinguishes samples derived from human-environment interactions, enabling clear differentiation between environmental and human-related studies. By improving the completeness of biome label information for numerous microbial community samples, our research facilitates more accurate knowledge discovery across diverse disciplines, with particular implications for environmental research.

PMID:37635952 | PMC:PMC10457426 | DOI:10.1016/j.ese.2023.100304

F1000Res. 2023 Jul 25;12:884. doi: 10.12688/f1000research.139755.1. eCollection 2023.

ABSTRACT

Charged multivesicular body protein 2B is a subunit of the endosomal sorting complex required for transport III (ESRCT-III), a complex implicated in the lysosomal degradation pathway and formation of multivesicular bodies. Mutations to the CHMP2B gene can result in abnormal protein aggregates in neurons and is therefore predicted to be associated in neurodegenerative diseases, including across the ALS-FTD spectrum. Through our standardized experimental protocol which compares read-outs in knockout cell lines and isogenic parental controls, this study aims to enhance the reproducibility of research on this target by characterizing eight commercial antibodies against charged multivesicular body protein 2b using Western Blot, immunoprecipitation, and immunofluorescence. We identified many high-performing antibodies and encourage readers to use this report as a guide to select the most appropriate antibody for their specific needs.

PMID:37635943 | PMC:PMC10448144 | DOI:10.12688/f1000research.139755.1

Clin Cosmet Investig Dermatol. 2023 Aug 22;16:2283-2295. doi: 10.2147/CCID.S421193. eCollection 2023.

ABSTRACT

OBJECTIVE: This study aimed to identify hub genes and common pathways shared between psoriasis and cardiovascular disease (CVD) using bioinformatics analysis and predict the transcription factors (TFs) of hub genes.

METHODS: GSE133555 data from the Gene Expression Omnibus (GEO) database were used to identify differentially expressed genes (DEGs) between involved and uninvolved skin lesions in psoriasis, employing the limma package in R. Additionally, CVD-related genes were obtained from the GeneCards database. The intersection of DEGs and CVD-related genes yielded CVD-DEGs. Gene Ontology and signaling pathway analyses were performed using the clusterProfiler package in R. Hub genes were identified by intersecting six algorithms in the CytoHubba plugin of Cytoscape. To identify potential biomarkers, the GSE14905 dataset was subjected to receiver operating characteristic analysis, resulting in the identification of eight central hub genes. Finally, the NetworkAnalyst web tool was used to identify the TFs of the eight hub genes.

RESULTS: We identified 92 significant DEGs out of 1825 CVD-related genes in psoriasis obtained from the GSE13355 and GeneCard data. Functional enrichment analysis revealed the involvement of these genes in various signaling pathways, including the interleukin-17 signaling, tumor necrosis factor signaling, lipid and atherosclerosis, chemokine signaling, and cytokine signaling pathways in the immune system. The eight hub genes identified included interleukin-1 beta, C-X-C motif chemokine ligand 8, signal transducer and activator of transcription 3, C-C motif chemokine ligand 2, arginase 1, C-X-C motif chemokine receptor 4, cyclin D1, and matrix metallopeptidase 9, with forkhead box C1 also identified as an associated TF of these genes. These hub genes and TF may act as key regulators in the context of CVD.

CONCLUSION: This study identified several hub genes and signaling pathways associated with both CVD and psoriasis. These findings lay the groundwork for potential therapeutic interventions for patients with psoriasis affected by CVD.

PMID:37635735 | PMC:PMC10460209 | DOI:10.2147/CCID.S421193