Toxics. 2025 Feb 19;13(2):142. doi: 10.3390/toxics13020142.

ABSTRACT

Chemical exposure in the environment can adversely affect the biodiversity of living organisms, particularly when persistent chemicals accumulate over time and disrupt the balance of microbial populations. In this study, we examined how chemical contaminants influence microorganisms in sediment and overlaying water samples collected from the Kinnickinnic, Milwaukee, and Menomonee Rivers near Milwaukee, Wisconsin, USA. We characterized these samples using shotgun metagenomic sequencing to assess microbiome diversity and employed chemical analyses to quantify more than 200 compounds spanning 16 broad classes, including pesticides, industrial products, personal care products, and pharmaceuticals. Integrative and differential comparative analyses of the combined datasets revealed that microbial density, approximated by adjusted total sequence reads, declined with increasing total chemical concentrations. Protozoan, metazoan, and fungal populations were negatively correlated with higher chemical concentrations, whereas certain bacterial (particularly Proteobacteria) and archaeal populations showed positive correlations. As expected, sediment samples exhibited higher concentrations and a wider dynamic range of chemicals compared to water samples. Varying levels of chemical contamination appeared to shape the distribution of microbial taxa, with some bacterial, metazoan, and protozoan populations present only at certain sites or in specific sample types (sediment versus water). These findings suggest that microbial diversity may be linked to both the type and concentration of chemicals present. Additionally, this study demonstrates the potential roles of multiple microbial kingdoms in degrading environmental pollutants, emphasizing the metabolic versatility of bacteria and archaea in processing complex contaminants such as polyaromatic hydrocarbons and bisphenols. Through functional and resistance gene profiling, we observed that multi-kingdom microbial consortia-including bacteria, fungi, and protozoa-can contribute to bioremediation strategies and help restore ecological balance in contaminated ecosystems. This approach may also serve as a valuable proxy for assessing the types and levels of chemical pollutants, as well as their effects on biodiversity.

PMID:39997957 | DOI:10.3390/toxics13020142

Metabolites. 2025 Feb 6;15(2):101. doi: 10.3390/metabo15020101.

ABSTRACT

Background/Objectives: Determining appropriate cellular objectives is crucial for the system-scale modeling of biological networks for metabolic engineering, cellular reprogramming, and drug discovery applications. The mathematical representation of metabolic objectives can describe how cells manage limited resources to achieve biological goals within mechanistic and environmental constraints. While rapidly proliferating cells like tumors are often assumed to prioritize biomass production, mammalian cell types can exhibit objectives beyond growth, such as supporting tissue functions, developmental processes, and redox homeostasis. Methods: This review addresses the challenge of determining metabolic objectives and trade-offs from multiomics data. Results: Recent advances in single-cell omics, metabolic modeling, and machine/deep learning methods have enabled the inference of cellular objectives at both the transcriptomic and metabolic levels, bridging gene expression patterns with metabolic phenotypes. Conclusions: These in silico models provide insights into how cells adapt to changing environments, drug treatments, and genetic manipulations. We further explore the potential application of incorporating cellular objectives into personalized medicine, drug discovery, tissue engineering, and systems biology.

PMID:39997726 | DOI:10.3390/metabo15020101

Metabolites. 2025 Jan 26;15(2):76. doi: 10.3390/metabo15020076.

ABSTRACT

Background: Elevated choline kinase alpha (ChoK) levels are observed in most solid tumors, including glioblastomas (GBM), and ChoK inhibitors have demonstrated limited efficacy in GBM models. Given that hypoxia is associated with resistance to GBM therapy, we hypothesized that tumor hypoxia could be responsible for the limited response. Therefore, we evaluated the effects of hypoxia on the function of JAS239, a potent ChoK inhibitor in four GBM cell lines. Methods: Rodent (F98 and 9L) and human (U-87 MG and U-251 MG) GBM cell lines were subjected to 72 h of hypoxic conditioning and treated with JAS239 for 24 h. NMR metabolomic measurements and analyses were performed to evaluate the signaling pathways involved. In addition, cell proliferation, cell cycle progression, and cell invasion parameters were measured in 2D cell monolayers as well as in 3D cell spheroids, with or without JAS239 treatment, in normoxic or hypoxic cells to assess the effect of hypoxia on JAS239 function. Results: Hypoxia and JAS239 treatment led to significant changes in the cellular metabolic pathways, specifically the phospholipid and glycolytic pathways, associated with a reduction in cell proliferation via induced cell cycle arrest. Interestingly, JAS239 also impaired GBM invasion. However, effects from JAS239 were variable depending on the cell line, reflecting the inherent heterogeneity of GBMs. Conclusions: Our findings indicate that JAS239 and hypoxia can deregulate cellular metabolism, inhibit cell proliferation, and alter cell invasion. These results may be useful for designing new therapeutic strategies based on ChoK inhibition, which can act on multiple pro-tumorigenic features.

PMID:39997701 | DOI:10.3390/metabo15020076

Healthcare (Basel). 2025 Feb 10;13(4):376. doi: 10.3390/healthcare13040376.

ABSTRACT

Background: The risk of dying from chronic liver diseases (CLDs) is two to three times higher for patients with diabetes (DM). Nonalcoholic fatty liver disease (NAFLD) is the primary cause of this increased risk, which has an etiology unrelated to alcohol or viruses. Previous research reported that diabetes and CLD are related, since they influence each other. Aim: Estimation of the impact of diabetes (DM) on liver diseases (LD), and of the impact of liver diseases on DM among Egyptian and Saudi patients. It is a descriptive and prospective analytical study design. The investigation was carried out in Saudi Arabia and Egypt at gastroenterology outpatient clinics. Methods: Prospective data were collected through face-to-face patient interviews during clinic visits between June 2021 and June 2023. The interviews covered the patients' basic characteristics and information on DM and LD. Certain laboratory tests were conducted on these patients, such as liver function, glucose level, lipid profile, INR, and prothrombin time. Results: The total of 2748 participants in this study included 1242 diabetic patients of both genders from Saudi Arabia and 1506 from Egypt. Most Saudis had between 10 and 20 years' duration of DM (35.5%), with HbA1c (7-10%) values of 47.8%, while the Egyptian patients had >20 years' duration of DM (39.8%), with HbA1c (7-10%) values of 49.8%. Regarding the impact of DM on the development of liver diseases, about 35.5% (Saudis) vs. 23.5% (Egyptians) had liver diseases due to DM, a significant difference (p-value = 0.011). Liver enzymes were increased in many of the Egyptian and Saudi patients (41.4% vs. 33%), while the presence of fatty liver (28.2% vs. 35.7%) and hepatocellular carcinoma (13.7% vs. 6.1%) were also significantly different (p-value = 0.047). While the impact of liver diseases on DM was observed more among Egyptian (59%) than among Saudi (46.4%) patients because of liver cirrhosis (HCV or HBV), known to be a reason for diabetes in Egyptians (27.9%) vs. Saudis (8.0%), a higher incidence of fatty liver leading to DM was observed in Saudis than in Egyptians (15.9% vs. 11.6%) (p-value = 0.000. Obesity was more prevalent among Saudi patients (63.8%) than among Egyptian patients (48.6%) (p-value = 0.019). Fewer Egyptians (about 65%) suffered from dyslipidemia than Saudis (about 80%). Higher INR and longer prothrombin times were observed in Egyptians (29.9% and 29.1%, respectively) than in Saudis (20.3% and 18.8%, respectively), with a significant difference between the two nations (p-value < 0.050). Conclusions: We may conclude that diabetes in most patients has a negative impact on the development of liver diseases (particularly fatty liver in Saudi patients). In addition, most liver diseases (liver cirrhosis) have a negative influence on the development of DM (more so in Egyptian patients). There is a link between DM and liver disease. In particular, liver cirrhosis and diabetes were found to influence each other. Therefore, correct medication, adherence to treatment, lifestyle modifications, successful cirrhosis control (in patients with liver diseases), and diabetic control (in diabetic patients) could lead to effective management of both diseases. The negative fallouts in the two cases were prompted by obesity, morbid eating, and poor quality of life.

PMID:39997251 | DOI:10.3390/healthcare13040376

Cells. 2025 Feb 12;14(4):266. doi: 10.3390/cells14040266.

ABSTRACT

Liver fibrosis, a consequence of chronic liver injury, represents a major global health burden and is the leading cause of liver failure, morbidity, and mortality. The pathological hallmark of this condition is excessive extracellular matrix deposition, driven primarily by integrin-mediated mechanotransduction. Integrins, transmembrane heterodimeric proteins that serve as primary ECM receptors, orchestrate complex mechanosignaling networks that regulate the activation, differentiation, and proliferation of hepatic stellate cells and other ECM-secreting myofibroblasts. These mechanical signals create self-reinforcing feedback loops that perpetuate the fibrotic response. Recent advances have provided insight into the roles of specific integrin subtypes in liver fibrosis and revealed their regulation of key downstream effectors-including transforming growth factor beta, focal adhesion kinase, RhoA/Rho-associated, coiled-coil containing protein kinase, and the mechanosensitive Hippo pathway. Understanding these mechanotransduction networks has opened new therapeutic possibilities through pharmacological manipulation of integrin-dependent signaling.

PMID:39996739 | DOI:10.3390/cells14040266

Cells. 2025 Feb 11;14(4):257. doi: 10.3390/cells14040257.

ABSTRACT

Cells in heart muscle need to generate ATP at or near peak capacity to meet their energy demands. Over 90% of this ATP comes from mitochondria, strategically located near myofibrils and densely packed with cristae to concentrate ATP generation per unit volume. However, a consequence of dense inner membrane (IM) packing is that restricted metabolite diffusion inside mitochondria may limit ATP production. Under physiological conditions, the flux of ATP synthase is set by ADP levels in the matrix, which in turn depends on diffusion-dependent concentration of ADP inside cristae. Computer simulations show how ADP diffusion and consequently rates of ATP synthesis are modulated by IM topology, in particular (i) number, size, and positioning of crista junctions that connect cristae to the IM boundary region, and (ii) branching of cristae. Predictions are compared with the actual IM topology of a cardiomyocyte mitochondrion in which cristae vary systematically in length and morphology. The analysis indicates that this IM topology decreases but does not eliminate the "diffusion penalty" on ATP output. It is proposed that IM topology normally attenuates mitochondrial ATP output under conditions of low workload and can be regulated by the cell to better match ATP supply to demand.

PMID:39996730 | DOI:10.3390/cells14040257

J Exp Bot. 2025 Feb 25;76(4):899-903. doi: 10.1093/jxb/erae411.

NO ABSTRACT

PMID:39996292 | DOI:10.1093/jxb/erae411

JHEP Rep. 2024 Nov 12;7(3):101267. doi: 10.1016/j.jhepr.2024.101267. eCollection 2025 Mar.

ABSTRACT

BACKGROUND & AIMS: Primary sclerosing cholangitis (PSC) is a chronic heterogenous cholangiopathy with unknown etiology where chronic inflammation of the bile ducts leads to multifocal biliary strictures and biliary fibrosis with consecutive cirrhosis development. We here aimed to identify a PSC-specific gene signature associated with biliary fibrosis development.

METHODS: We performed RNA-sequencing of 47 liver biopsies from people with PSC (n = 16), primary biliary cholangitis (PBC, n = 15), and metabolic dysfunction-associated steatotic liver disease (MASLD, n = 16) with different fibrosis stages to identify a PSC-specific gene signature associated with biliary fibrosis progression. For validation, we compared an external transcriptome data set of liver biopsies from people with PSC (n = 73) with different fibrosis stages (baseline samples from NCT01672853).

RESULTS: Differential gene expression analysis of the liver transcriptome from patients with PSC with advanced vs. early fibrosis revealed 431 genes associated with fibrosis development. Of those, 367 were identified as PSC-associated when compared with PBC or MASLD. Validation against an external data set of 73 liver biopsies from patients with PSC with different fibrosis stages led to a condensed set of 150 (out of 367) differentially expressed genes. Cell type specificity assignment of those genes by using published single-cell RNA-Seq data revealed genetic disease drivers expressed by cholangiocytes (e.g. CXCL1, SPP1), fibroblasts, innate, and adaptive immune cells while deconvolution along fibrosis progression of the PSC, PBC, and MASLD samples highlighted an early involvement of macrophage- and neutrophil-associated genes in PSC fibrosis.

CONCLUSIONS: We reveal a PSC-attributed gene signature associated with biliary fibrosis development that may enable the identification of potential new biomarkers and therapeutic targets in PSC-related fibrogenesis.

IMPACT AND IMPLICATIONS: Primary sclerosing cholangitis (PSC) is an inflammatory liver disease that is characterized by multifocal inflammation of bile ducts and subsequent biliary fibrosis. Herein, we identify a PSC-specific gene set of biliary fibrosis progression attributing to a uniquely complex milieu of different cell types, including innate and adaptive immune cells while neutrophils and macrophages showed an earlier involvement in fibrosis initiation in PSC in contrast to PBC and metabolic dysfunction-associated steatotic liver disease. Thus, our unbiased approach lays an important groundwork for further mechanistic studies for research into PSC-specific fibrosis.

PMID:39996122 | PMC:PMC11848773 | DOI:10.1016/j.jhepr.2024.101267

iScience. 2025 Jan 27;28(2):111808. doi: 10.1016/j.isci.2025.111808. eCollection 2025 Feb 21.

ABSTRACT

Intracrinology-wherein hormones are synthesized in the organ where they exert their effect without release into circulation-has been described. However, molecular mechanisms of hormone deactivation within intracrine tissue are still largely unknown. The meibomian glands in the eyelids produce oil (meibum) to the ocular surface to prevent dehydration (dry eye). Androgens are generated inside this gland and are crucial for its tissue-homeostasis. However, there is no data showing the presence of androgens in meibum, implying local conversion/deactivation into unknown metabolites. Here, we performed radioactive tracer studies in combination with pharmacological enzyme inhibition, followed by targeted liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis, and found three androgen metabolites-androstanedione, androsterone, and epiandrosterone-in mouse and human meibomian glands. Accounting for the enzymatic conversion, we show tissue-endogenous 3α/3β-ketosteroid reductase expression. We therefore reinforce the idea that androgens are metabolically inactivated within the glands. These metabolite markers may help to assess meibomian local androgen activity using meibum.

PMID:39995859 | PMC:PMC11848505 | DOI:10.1016/j.isci.2025.111808

Int J Cardiol Heart Vasc. 2025 Feb 5;57:101621. doi: 10.1016/j.ijcha.2025.101621. eCollection 2025 Apr.

ABSTRACT

BACKGROUND: Atrial fibrillation Better Care (ABC) pathway is recommended by guidelines on atrial fibrillation (AF) and exerts a protective role against adverse outcomes of AF patients. But the possible differences in its effectiveness across the diverse range of patients in China have not been systematically evaluated. We aim to comprehensively evaluate multiple clinical characteristics of patients, and probe clusters of ABC criteria efficacy in patients with AF.

METHODS: We used data from an observational cohort that included 2,016 patients with AF. We utilized 45 baseline variables for cluster analysis. We evaluated the management patterns and adverse outcomes of identified phenotypes. We assessed the effectiveness of adherence to the ABC criteria at reducing adverse outcomes of phenotypes.

RESULTS: Cluster analysis identified AF patients into three distinct groups. The clusters include Cluster 1: old patients with the highest prevalence rates of atherosclerotic and/or other comorbidities (n = 964), Cluster 2: valve-comorbidities AF in young females (n = 407), and Cluster 3: low comorbidity patients with paroxysmal AF (n = 644). The clusters showed significant differences in MACNE, all-cause death, stroke, and cardiovascular death. All clusters showed that full adherence to the ABC pathway was associated with a significant reduction in the risk of MACNE (all P < 0.05). For three clusters, adherence to the different 'A'/'B'/'C' criterion alone showed differential clinic impact.

CONCLUSION: Our study suggested specific optimization strategies of risk stratification and integrated management for different groups of AF patients considering multiple clinical, genetic and socioeconomic factors.

PMID:39995811 | PMC:PMC11848476 | DOI:10.1016/j.ijcha.2025.101621

Rep Biochem Mol Biol. 2024 Jul;13(2):281-300. doi: 10.61186/rbmb.13.2.281.

ABSTRACT

BACKGROUND: Gastric cancer (GC) is a prevalent malignancy with high recurrence. Advances in systems biology have identified molecular pathways and biomarkers. This study focuses on discovering gene and miRNA biomarkers for diagnosing and predicting survival in GC patients.

METHODS: Three sets of genes (GSE19826, GSE81948, and GSE112369) and two sets of miRNA expression (GSE26595, GSE78775) were obtained from the Gene Expression Omnibus (GEO), and subsequently, differentially expressed genes (DEGs) and miRNAs (DEMs) were identified. Functional pathway enrichment, DEG-miR-TF-protein-protein interaction network, DEM-mRNA network, ROC curve, and survival analyses were performed. Finally, qRT-PCR was applied to validate our results.

RESULTS: From the high-throughput profiling studies of GC, we investigated 10 candidate mRNA and 7 candidate miRNAs as potential biomarkers. Expression analysis of these hubs revealed that 5 miRNAs (including miR-141-3p, miR-204-5p, miR-338-3p, miR-609, and miR-369-5p) were significantly upregulated compared to the controls. The genes with the highest degree included 6 upregulated and 4 downregulated genes in tumor samples compared to controls. The expression of miR-141-3p, miR-204-5p, SESTD1, and ANTXR1 were verified in vitro from these hub DEMs and DEGs. The findings indicated a decrease in the expression of miR-141-3p and miR-204-5p and increased expression of SESTD1 and ANTXR1 in GC cell lines compared to the GES-1 cell line.

CONCLUSIONS: The current investigation successfully recognized a set of prospective miRNAs and genes that may serve as potential biomarkers for GC's early diagnosis and prognosis.

PMID:39995653 | PMC:PMC11847593 | DOI:10.61186/rbmb.13.2.281

J Vis Exp. 2025 Feb 7;(216). doi: 10.3791/67892.

ABSTRACT

Systematic screening of gain- or loss-of-function genetic perturbations can be used to characterize the genetic dependencies and mechanisms of regulation for essentially any cellular process of interest. These experiments typically involve profiling from a pool of single gene perturbations and how each genetic perturbation affects the relative cell fitness. When applied in the context of drug efficacy studies, often called chemo-genetic profiling, these methods should be effective at identifying drug mechanisms of action. Unfortunately, fitness-based chemo-genetic profiling studies are ineffective at identifying all components of a drug response. For instance, these studies generally fail to identify which genes regulate drug-induced cell death. Several issues contribute to obscuring death regulation in fitness-based screens, including the confounding effects of proliferation rate variation, variation in the drug-induced coordination between growth and death, and, in some cases, the inability to separate DNA from live and dead cells. MEDUSA is an analytical method for identifying death-regulatory genes in conventional chemo-genetic profiling data. It works by using computational simulations to estimate the growth and death rates that created an observed fitness profile rather than scoring fitness itself. Effective use of the method depends on optimal tittering of experimental conditions, including the drug dose, starting population size, and length of the assay. This manuscript will describe how to set up a chemo-genetic profiling study for MEDUSA-based analysis, and we will demonstrate how to use the method to quantify death rates in chemo-genetic profiling data.

PMID:39995184 | DOI:10.3791/67892

BMC Plant Biol. 2025 Feb 25;25(1):254. doi: 10.1186/s12870-025-06242-1.

ABSTRACT

BACKGROUND: Papaya exhibits three sex types: female (XX), male (XY), and hermaphrodite (XYh), making it an unusual trioecious model for studying sex determination. A critical aspect of papaya sex determination is the pistil abortion in male flowers. However, the regulatory networks that control the development of pistils and stamens in papaya remain incompletely understood.

RESULTS: In this study, we identified three organ-specific clusters involved in papaya pistils and stamens development. We found that pistil development is primarily characterized by the significant expression of auxin-related genes, while the pistil abortion genes in males is mainly associated with cytokinin, gibberellin, and auxin pathways. Additionally, we constructed expression regulatory networks for the development of female pistils, aborted pistils and stamens in male flowers, revealing key regulatory genes and signaling pathways involved in papaya organ development. Furthermore, we systematically identified 65 members of the MADS-box gene family and 10 ABCDE subfamily MADS-box genes in papaya. By constructing a phylogenetic tree of the ABCDE subfamily, we uncovered gene contraction and expansion in papaya, providing an improved understanding of the developmental mechanisms and evolutionary history of papaya floral organs.

CONCLUSIONS: These findings provide a robust framework for identifying candidate sex-determining genes and constructing the sex determination regulatory network in papaya, providing insights and genomic resources for papaya breeding.

PMID:39994552 | DOI:10.1186/s12870-025-06242-1

Nat Cardiovasc Res. 2025 Feb 24. doi: 10.1038/s44161-025-00612-6. Online ahead of print.

ABSTRACT

Myocarditis, characterized by inflammatory cell infiltration, can have multiple etiologies, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection or, rarely, mRNA-based coronavirus disease 2019 (COVID-19) vaccination. The underlying cellular and molecular mechanisms remain poorly understood. In this study, we performed single-nucleus RNA sequencing on left ventricular endomyocardial biopsies from patients with myocarditis unrelated to COVID-19 (Non-COVID-19), after SARS-CoV-2 infection (Post-COVID-19) and after COVID-19 vaccination (Post-Vaccination). We identified distinct cytokine expression patterns, with interferon-γ playing a key role in Post-COVID-19, and upregulated IL16 and IL18 expression serving as a hallmark of Post-Vaccination myocarditis. Although myeloid responses were similar across all groups, the Post-Vaccination group showed a higher proportion of CD4+ T cells, and the Post-COVID-19 group exhibited an expansion of cytotoxic CD8+ T and natural killer cells. Endothelial cells showed gene expression changes indicative of vascular barrier dysfunction in the Post-COVID-19 group and ongoing angiogenesis across all groups. These findings highlight shared and distinct mechanisms driving myocarditis in patients with and without a history of SARS-CoV-2 infection or vaccination.

PMID:39994453 | DOI:10.1038/s44161-025-00612-6

Mol Syst Biol. 2025 Feb 24. doi: 10.1038/s44320-025-00092-7. Online ahead of print.

ABSTRACT

The circadian clock regulates key physiological processes, including cellular responses to DNA damage. Circadian-based therapeutic strategies optimize treatment timing to enhance drug efficacy and minimize side effects, offering potential for precision cancer treatment. However, applying these strategies in cancer remains limited due to a lack of understanding of the clock's function across cancer types and incomplete insights into how the circadian clock affects drug responses. To address this, we conducted deep circadian phenotyping across a panel of breast cancer cell lines. Observing diverse circadian dynamics, we characterized metrics to assess circadian rhythm strength and stability in vitro. This led to the identification of four distinct circadian-based phenotypes among 14 breast cancer cell models: functional, weak, unstable, and dysfunctional clocks. Furthermore, we demonstrate that the circadian clock plays a critical role in shaping pharmacological responses to various anti-cancer drugs and we identify circadian features descriptive of drug sensitivity. Collectively, our findings establish a foundation for implementing circadian-based treatment strategies in breast cancer, leveraging clock phenotypes and drug sensitivity patterns to optimize therapeutic outcomes.

PMID:39994450 | DOI:10.1038/s44320-025-00092-7

Commun Biol. 2025 Feb 24;8(1):297. doi: 10.1038/s42003-025-07743-3.

ABSTRACT

The NADase activity of the defense-associated sirtuins (DSRs) is activated by the phage tail tube protein (TTP). Herein, we report cryo-EM structures of a free-state Bacillus subtilis DSR2 tetramer and a fragment of the tetramer, a phage SPR tail tube, and two DSR2-TTP complexes. DSR2 contains an N-terminal SIR2 domain, a middle domain (MID) and a C-terminal domain (CTD). The DSR2 CTD harbors the α-solenoid tandem-repeats like the HEAT-repeat proteins. DSR2 assembles into a tetramer with four SIR2 clustered at the center, and two intertwined MID-CTD chains flank the SIR2 core. SPR TTPs self-assemble into a tube-like complex. Upon DSR2 binding, the D1 domain of SPR TTP is captured between the HEAT-repeats domains of DSR2, which conflicts with TTPs self-assembly. Binding of TTPs induces conformational changes in DSR2 tetramer, resulting in increase of the NAD+ pocket volume in SIR2, thus activates the NADase activity and leads to cellular NAD+ depletion.

PMID:39994439 | DOI:10.1038/s42003-025-07743-3

Nat Neurosci. 2025 Feb 24. doi: 10.1038/s41593-024-01865-3. Online ahead of print.

ABSTRACT

Enlargement of the cerebrospinal fluid (CSF)-filled brain ventricles (ventriculomegaly) is a defining feature of congenital hydrocephalus (CH) and an under-recognized concomitant of autism. Here, we show that de novo mutations in the autism risk gene PTEN are among the most frequent monogenic causes of CH and primary ventriculomegaly. Mouse Pten-mutant ventriculomegaly results from aqueductal stenosis due to hyperproliferation of periventricular Nkx2.1+ neural progenitor cells (NPCs) and increased CSF production from hyperplastic choroid plexus. Pten-mutant ventriculomegalic cortices exhibit network dysfunction from increased activity of Nkx2.1+ NPC-derived inhibitory interneurons. Raptor deletion or postnatal everolimus treatment corrects ventriculomegaly, rescues cortical deficits and increases survival by antagonizing mTORC1-dependent Nkx2.1+ NPC pathology. Thus, PTEN mutations concurrently alter CSF dynamics and cortical networks by dysregulating Nkx2.1+ NPCs. These results implicate a nonsurgical treatment for CH, demonstrate a genetic association of ventriculomegaly and ASD, and help explain neurodevelopmental phenotypes refractory to CSF shunting in select individuals with CH.

PMID:39994410 | DOI:10.1038/s41593-024-01865-3

Sci Rep. 2025 Feb 24;15(1):6658. doi: 10.1038/s41598-025-91022-y.

ABSTRACT

Metformin, widely used for the treatment of type 2 diabetes, has recently gained attention for its potential anticancer properties. Several studies have shown that metformin treatment inhibits cell viability in colon adenocarcinoma (COAD); however, the research related to the tumor-node-metastasis (TNM) stage is limited. As COAD is frequently diagnosed at an advanced stage, understanding the genetic factors that regulate the pathogenesis of COAD at each TNM stage and the effects of metformin for potential treatment. Therefore, we identified differentially expressed factors at the TNM stage in metformin-treated COAD cells and investigated their regulatory mechanisms using microRNAs (miRNAs). Through bioinformatics analyses, four-jointed box kinase 1 (FJX1) and hsa-miR-1306-3p were identified as differentially expressed in COAD upon metformin treatment. Metformin treatment significantly reduced cell viability, with an observed decrease of approximately 50%. Analysis using quantitative real-time PCR showed an increase in hsa-miR-1306-3p and a decrease in FJX1 expression upon metformin treatment compared to untreated cells. Luciferase assay confirmed the sequence-specific binding of hsa-miR-1306-3p to FJX1. These findings highlight the potential of metformin as a therapeutic agent for COAD by modulating FJX1 expression via upregulation of hsa-miR-1306-3p, revealing novel avenues for COAD treatment.

PMID:39994354 | DOI:10.1038/s41598-025-91022-y

Nat Commun. 2025 Feb 24;16(1):1942. doi: 10.1038/s41467-025-57170-5.

ABSTRACT

This study showcases an integrative mass spectrometry-based strategy combining systems antigenomics and systems serology to characterize human antibodies in clinical samples. This strategy involves using antibodies circulating in plasma to affinity-enrich antigenic proteins in biochemically fractionated pools of bacterial proteins, followed by their identification and quantification using mass spectrometry. A selected subset of the identified antigens is then expressed recombinantly to isolate antigen-specific IgG, followed by characterization of the structural and functional properties of these antibodies. We focused on Group A streptococcus (GAS), a major human pathogen lacking an approved vaccine. The data shows that both healthy and GAS-infected individuals have circulating IgG against conserved streptococcal proteins, including toxins and virulence factors. The antigenic breadth of these antibodies remains relatively constant across healthy individuals but changes considerably in GAS bacteremia. Moreover, antigen-specific IgG analysis reveals individual variation in titers, subclass distributions, and Fc-signaling capacity, despite similar epitope and Fc-glycosylation patterns. Finally, we show that GAS antibodies may cross-react with Streptococcus dysgalactiae (SD), a bacterial pathogen that occupies similar niches and causes comparable infections. Collectively, our results highlight the complexity of GAS-specific antibody responses and the versatility of our methodology to characterize immune responses to bacterial pathogens.

PMID:39994218 | DOI:10.1038/s41467-025-57170-5

Cancer Genomics Proteomics. 2025 Mar-Apr;22(2):285-305. doi: 10.21873/cgp.20502.

ABSTRACT

BACKGROUND/AIM: Oncogenic processes are delineated by metabolic dysregulation. Drug likeness is pharmacokinetically tested through the CYP450 enzymatic system, whose genetic aberrations under epigenetic stress could shift male organisms into prostate cancer pathways. Our objective was to predict the susceptibility to prostate neoplasia, focused on benign prostatic hyperplasia (BPH) and prostate cancer (PCa), based on the pharmacoepigenetic and the metabolic profile of Caucasians.

MATERIALS AND METHODS: Two independent cohorts of 47,389 individuals in total were assessed to find risk associations of CYP450 genes with prostatic neoplasia. The metabolic profile of the first cohort was statistically evaluated and frequencies of absorption-distribution-metabolism-excretion-toxicity (ADMET) properties were calculated. Prediction of miRNA pharmacoepigenetic targeting was performed.

RESULTS: We found that prostate cancer and benign prostatic hyperplasia patients of the first cohort shared common cardiometabolic trends. Drug classes C08CA, C09AA, C09CA, C10AA, C10AX of the cardiovascular, and G04CA, G04CB of the genitourinary systems, were associated with increased prostate cancer risk, while C03CA and N06AB of the cardiovascular and nervous systems were associated with low-risk for PCa. CYP3A4*1B was the most related pharmacogenetic polymorphism associated with prostate cancer susceptibility. miRNA-200c-3p and miRNA-27b-3p seem to be associated with CYP3A4 targeting and prostate cancer predisposition. Metabolomic analysis indicated that 11β-OHT, 2β-OHT, 15β-OHT, 2α-OHT and 6β-OHT had a high risk, and 16α-OHT, and 16β-OHT had an intermediate disease-risk.

CONCLUSION: These findings constitute a novel integrated signature for prostate cancer susceptibility. Further studies are required to assess their predictive value more fully.

PMID:39993800 | DOI:10.21873/cgp.20502