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

Proc Natl Acad Sci U S A. 2025 Mar 4;122(9):e2415475122. doi: 10.1073/pnas.2415475122. Epub 2025 Feb 24.

ABSTRACT

The most common chemotherapeutics induce DNA damage to eradicate cancer cells, yet defective DNA repair can propagate mutations, instigating therapy resistance and secondary malignancies. Structural variants (SVs), arising from copy-number-imbalanced and -balanced DNA rearrangements, are a major driver of tumor evolution, yet understudied posttherapy. Here, we adapted single-cell template-strand sequencing (Strand-seq) to a HER2+ breast cancer model to investigate the formation of doxorubicin-induced de novo SVs. We coupled this approach with nucleosome occupancy (NO) measurements obtained from the same single cell to enable simultaneous SV detection and cell-type classification. Using organoids from TetO-CMYC/TetO-Neu/MMTV-rtTA mice modeling HER2+ breast cancer, we generated 459 Strand-seq libraries spanning various tumorigenesis stages, identifying a 7.4-fold increase in large chromosomal alterations post-doxorubicin. Complex DNA rearrangements, deletions, and duplications were prevalent across basal, luminal progenitor (LP), and mature luminal (ML) cells, indicating uniform susceptibility of these cell types to SV formation. Doxorubicin further elevated sister chromatid exchanges (SCEs), indicative of genomic stress persisting posttreatment. Altered nucleosome occupancy levels on distinct cancer-related genes further underscore the broad genomic impact of doxorubicin. The organoid-based system for single-cell multiomics established in this study paves the way for unraveling the most important therapy-associated SV mutational signatures, enabling systematic studies of the effect of therapy on cancer evolution.

PMID:39993200 | DOI:10.1073/pnas.2415475122

Ann Hematol. 2025 Feb 24. doi: 10.1007/s00277-025-06274-5. Online ahead of print.

ABSTRACT

In classic Hodgkin-lymphoma (cHL), only a few cases recur, and only a limited fraction of patients is primary-refractory to standard-polychemotherapy. Underlying genomic features of unfavorable clinical courses remain sparsely characterized. Here, we investigated the genomic characteristics of primary-refractory/relapsed cHL in contrast with responders. Therefore, ultra-deep next-generation panel-sequencing was performed on a total of 59 FFPE-samples (20 responders, 26 relapsed (rHL: 11 initial-diagnosis, 15 relapse) and 13 primary-refractory (prHL: 8 initial-diagnosis, 5 progression) from 44 cHL-patients applying a hybrid-capture approach. We compared samples associated with distinct disease courses concerning their oncogenic drivers, mutational signatures, and perturbed pathways. Compared to responders, mutations in genes such as PMS2, PDGFRB, KAT6A, EPHB1, and HGF were detected more frequently in prHL/rHL. Additionally, we observed that in rHL or prHL, BARD1-mutations occur, whereas ETV1, NF1, and MET-mutations were eliminated through clonal selection. A significant enrichment of non-synonymous variants was detected in prHL compared to responders and a significant selection process in favor of NOTCH-pathway mutations driving rHL or prHL was observed. However, our analysis revealed a negative selection process for non-synonymous variants affecting the hippo-pathway. This study delineates distinct mutational signatures between responders and rHL/prHL, whilst illustrating longitudinal dynamics in mutational profiles using paired samples. Further, several exploitable therapeutic vulnerabilities for rHL and prHL were identified.

PMID:39992429 | DOI:10.1007/s00277-025-06274-5

Neurochem Res. 2025 Feb 24;50(2):103. doi: 10.1007/s11064-025-04357-3.

ABSTRACT

Human immunodeficiency virus (HIV) infections remain a significant public health burden globally with infected individuals at high risk for cognitive decline and memory loss even on combination antiretroviral therapy. Almost half of HIV infected individuals smoke, which drives poorer health outcomes including a higher dementia rate. Microglia are the brain's immune cells that serve as a persistent HIV reservoir contributing to neuroinflammatory signaling. We examined interactions between the HIV envelope glycoprotein gp120 and nicotine within human microglia cells (HMC3) that endogenously express chemokine receptor 5 (CCR5) and nicotinic acetylcholine receptors (nAChRs). Liquid chromatography coupled to electrospray ionization mass spectrometry (LC-ESI/MS) shows that gp120 alters mitochondria proteins within HMC3 cells. In the presence of nicotine, gp120 increased the expression of mitochondrial prohibitin 2 (PHB2), cytochrome c (cyt c), and mitofusin 2 (MFN2) but decreased fission 1 (FIS1) levels. An analysis of mito-YFP expression confirms that interaction between nicotine and gp120 increases the size and branching of mitochondrial networks. Interaction between nicotine and gp120 is also surprisingly found to promote the release of amyloid precursor protein (APP) peptides from microglia. This was accompanied by visualization of amyloid containing vesicles that colocalized with the autophagy protein LC3B-II in the cell. Taken together, our findings show that interaction between nicotine and gp120 impact microglia in a manner that regulates mitochondrial proteins and network properties and impacts amyloid protein management and release within microglia. These mechanisms may contribute to understanding neuroinflammatory signaling in smokers with HIV.

PMID:39992414 | DOI:10.1007/s11064-025-04357-3

Front Genet. 2025 Feb 7;16:1558406. doi: 10.3389/fgene.2025.1558406. eCollection 2025.

NO ABSTRACT

PMID:39991320 | PMC:PMC11842322 | DOI:10.3389/fgene.2025.1558406

ISME Commun. 2025 Jan 29;5(1):ycaf006. doi: 10.1093/ismeco/ycaf006. eCollection 2025 Jan.

ABSTRACT

The role of microbial necromass (nonliving microbial biomass), a significant component of belowground organic carbon, in nutrient cycling and its impact on the dynamics of microbial communities in subsurface systems remains poorly understood. It is currently unclear whether necromass metabolites from various microbes are different, whether certain groups of metabolites are preferentially utilized over others, or whether different microbial species respond to various necromass metabolites. In this study, we aimed to fill these knowledge gaps by designing enrichments with necromass as the sole nutrient source for subsurface microbial communities. We used the soluble fraction of necromass from bacterial isolates belonging to Arthrobacter, Agrobacterium, and Pseudomonas genera, and our results indicate that metabolite composition of necromass varied slightly across different strains but generally included amino acids, organic acids, and nucleic acid constituents. Arthrobacter-derived necromass appeared more recalcitrant. Necromass metabolites enriched diverse microbial genera, particularly Massilia sp. responded quickly regardless of the necromass source. Despite differences in necromass utilization, microbial community composition converged rapidly over time across the three different necromass amendments. Uracil, xanthine, valine, and phosphate-containing isomers were generally depleted over time, indicating microbial assimilation for maintenance and growth. However, numerous easily assimilable metabolites were not significantly depleted, suggesting efficient necromass recycling and the potential for necromass stabilization in systems. This study highlights the dynamic interactions between microbial necromass metabolites and subsurface microbial communities, revealing both selective utilization and rapid community and necromass convergence regardless of the necromass source.

PMID:39991274 | PMC:PMC11843093 | DOI:10.1093/ismeco/ycaf006

ACS Meas Sci Au. 2024 Dec 27;5(1):109-119. doi: 10.1021/acsmeasuresciau.4c00077. eCollection 2025 Feb 19.

ABSTRACT

Direct-infusion mass spectrometry (DI-MS) and mass spectrometry imaging (MSI) are powerful techniques for lipidomics research. However, annotating isomeric and isobaric lipids with these methods is challenging due to the absence of chromatographic separation. Recently, cyclic ion mobility mass spectrometry (cIM-MS) has been proposed to overcome this limitation. However, fluctuations in room conditions can affect ion mobility multipass arrival times, potentially reducing annotation confidence. In this study, we developed a multipass arrival time correction method that proved effective across various dates, room temperatures, ion mobility settings, and laboratories using mixtures of reference standards. We observed slight variations in the linear correction lines between lipid and nonlipid molecules, underscoring the importance of choosing appropriate reference molecules. Based on these results, we demonstrated that an accurate multipass arrival time database can be constructed from corrected t 0 and t p for interlaboratory use and can effectively identify isomeric lipids in MSI using only a single measurement. This approach significantly simplifies the identification process compared to determining multipass collision cross-section, which requires multiple measurements that are both sample- and time-intensive for MSI. Additionally, we validated our multipass drift time correction method in shotgun lipidomics analyses of human and mouse serum samples and observed no matrix effect for the analysis. Despite variations in dates, room temperatures, instruments, and ion mobility settings, our approach reduced the mean drift time differences from over 2% to below 0.2%.

PMID:39991034 | PMC:PMC11843504 | DOI:10.1021/acsmeasuresciau.4c00077

bioRxiv [Preprint]. 2025 Feb 15:2025.02.11.637731. doi: 10.1101/2025.02.11.637731.

ABSTRACT

MicroRNA (miRNA) induced silencing complex (miRISC) is the targeting apparatus and arguably rate-limiting step of the miRNA-mediated regulatory subsystem - the major noise reducing though metabolically wasteful mechanism. Recently, we reported that miRISC channels miRNA-mediated regulatory activity back onto their own mRNAs to form negative self-feedback loops, a noise-reduction technique in engineering and synthetic/systems biology. Here, we describe mathematical modeling that predicts mRNA expression noise to correlate negatively with degradation rate (K deg ) and noise reduction by self-feedback control of K deg . We also calculated K deg and expression noise of mRNAs detected in a cutting-edge total-RNA single-cell RNA-seq (scRNA-seq) dataset. As predicted, miRNA-targeted mRNAs exhibited higher K deg values in conjunction with lower inter-cell expression noise. Moreover, as predicted by our self-feedback loop model, miRISC mRNAs (AGO1/2/3 and TNRC6A/B/C) exhibited further reduced expression noise. In short, mathematical-modeling and total-RNA scRNA-seq data-analysis shed insight into operational trade-off between noise reduction and metabolic/energetic expenditure in producing miRNA-targeted mRNAs destined for enhanced degradation and translational inhibition, as well as negative self-feedback loop reinforcement of miRISC - the core of miRNA-mediated noise-reduction subsystem. To our knowledge, this is the first report of concurrent mRNA degradation and expression noise analyses and of noise reduction by self-feedback control of mRNA degradation.

PMID:39990448 | PMC:PMC11844488 | DOI:10.1101/2025.02.11.637731