Small Methods. 2025 Jun 2:e2401900. doi: 10.1002/smtd.202401900. Online ahead of print.

ABSTRACT

It is shown that regularizing the signal gradient statistics during training of deep-learning models of super-resolution fluorescence microscopy improves the generated images. Specifically, regularizing the images in the training data set is proposed to have gradient and Laplacian statistics closer to those expected for natural-scene images. The BioSR data set of matched pairs of diffraction-limited and super-resolution images is used to evaluate the proposed regularization in a state-of-the-art generative deep-learning model of super-resolution microscopy, the Conditional Variational Diffusion Model (CVDM). Since the proposed regularization is applied as a preprocessing step to the training data, it can be used in conjunction with any supervised machine-learning model. However, its utility is limited to images for which the prior is appropriate, which in the BioSR data set are the images of filamentous structures. The quality and generalization power of CVDM trained with and without the proposed regularization are compared, showing that the new prior yields images with clearer visual detail and better small-scale structure.

PMID:40454902 | DOI:10.1002/smtd.202401900

J Phycol. 2025 Jun 2. doi: 10.1111/jpy.70040. Online ahead of print.

ABSTRACT

The transition from interbreeding populations to species continues to represent difficult terrain for phylogenetic investigations. Genotyping entire genomes holds promise for enhancing insights into the process of speciation and evolutionary relationships among recently speciated taxa. Northeast Pacific ribbon kelp was once recognized as four species before they were folded into Alaria marginata based on DNA barcodes, although several lineages continue to be recognized. We used whole genome sequencing to determine whether these lineages represente species. Whole genomes of 69 individuals from five genetically distinctive lineages in the Gulf of Alaska (United States) and Salish Sea (Canada) were analyzed, along with 63 genomes from three other species of Alaria. Our analysis of >3.4 million single nucleotide polymorphisms reaffirmed that organellar and nuclear phylogenetic signals are incongruent in Alaria, producing different topologies among five organellar and six nuclear A. marginata lineages. Lineages appeared to be reproductively isolated, as evidenced by strong clustering and lack of recent admixture across nuclear genomes. Genetic divergence between A. marginata lineages also exceeded intra-lineage divergence, proxied by A. esculenta populations, but fell short of distances observed across other species of Alaria. Despite the genomic data supporting predictions of the biological and genetic species concepts, we encountered inherent limitations in declaring species status. While our work shifts taxonomic conversations toward a genome-scale framework that provides a more comprehensive picture of divergence and connectivity, our work also highlights that philosophical challenges inherent to defining species persist and that integrative approaches continue to be necessary in the genomic era.

PMID:40454788 | DOI:10.1111/jpy.70040

Curr Med Chem. 2025 May 29. doi: 10.2174/0109298673410629250520111827. Online ahead of print.

NO ABSTRACT

PMID:40454496 | DOI:10.2174/0109298673410629250520111827

iScience. 2025 Apr 18;28(5):112488. doi: 10.1016/j.isci.2025.112488. eCollection 2025 May 16.

ABSTRACT

Steroid hormones regulate cell physiology and immune function, with dysregulated steroidogenesis promoting cancer progression by supporting tumor growth and suppressing anti-tumor immunity. Targeting CYP11A1, the first and rate-limiting enzyme in steroid biosynthesis, has shown promise in cancer therapy, but safe and effective inhibitors remain an unmet need. Undertaking in silico structure-based drug repurposing approach, we found posaconazole as an inhibitor of CYP11A1. The docking pose analysis showed that posaconazole can form multiple hydrogen bonds and hydrophobic interactions with the key residues at the binding site and the cofactor, stabilizing the protein-ligand complex. We validated its inhibition efficiency in cell-based assays. In a mouse model of lung metastasis, we demonstrated that posaconazole restricts metastasis by stimulating anti-tumor immunity. These findings highlight posaconazole's potential as a research tool to study steroidogenesis and as a candidate for further preclinical and clinical evaluation in pathologies associated with local steroidogenesis, such as steroidogenic tumors.

PMID:40454094 | PMC:PMC12124671 | DOI:10.1016/j.isci.2025.112488

iScience. 2025 Apr 23;28(5):112505. doi: 10.1016/j.isci.2025.112505. eCollection 2025 May 16.

ABSTRACT

Gallbladder cancer (GBC) is a highly aggressive tumor associated with risk factors, such as chronic infection, gallstones, and exposure to harmful chemicals. Our study explores the role of polycyclic aromatic hydrocarbons (PAHs) and long noncoding RNA HEGBC in GBC progression. We found that PAHs activate the aryl hydrocarbon receptor (AhR), which enhances HEGBC expression and promotes GBC cell proliferation, invasion, and metastasis both in vitro and in vivo. Mechanistically, AhR binds to the HEGBC promoter, establishing a positive feedback loop that further activates AhR transcription. Moreover, CYP1A1 was identified as a key downstream effector of PAHs-AhR/HEGBC-mediated proliferation, migration, and invasion of GBC cells in vitro and in vivo. These findings provide the integrative view of a molecular mechanism loop for regulating the malignant progression of GBC centered by PAHs/AhR/HEGBC, which represents a promising strategy for the treatment of GBC.

PMID:40454092 | PMC:PMC12124655 | DOI:10.1016/j.isci.2025.112505

Vet World. 2025 Apr;18(4):763-772. doi: 10.14202/vetworld.2025.763-772. Epub 2025 Apr 7.

ABSTRACT

BACKGROUND AND AIM: Electroejaculation (EE) is widely used for semen collection in bulls but raises concerns about animal welfare due to potential pain and stress. The physiological impact of EE on bulls remains a topic of debate, with previous studies yielding inconclusive results. This study aims to objectively evaluate pain and stress responses in bulls subjected to EE using electroencephalography (EEG) alongside hormonal, behavioral, and metabolite profiling.

MATERIALS AND METHODS: Eight bulls were subjected to EE in three replicates, with physiological and behavioral data collected before, during, and after the procedure. EEG parameters, including median frequency (MF) and total power (Ptot), were analyzed to assess cortical activity indicative of pain and stress. Blood samples were evaluated for stress-related hormones (adrenaline, noradrenaline, β-endorphin, and dopamine), while metabolomic analysis was conducted to identify biochemical alterations associated with stress. Behavioral indicators, including vocalization and muscle spasms, were recorded.

RESULTS: EE induced significant increases (p < 0.05) in stress hormones at ejaculation, which gradually returned to baseline 20 min post-procedure. EEG metrics, such as MF and Ptot, significantly increased during EE (p < 0.05), indicating heightened cortical activity associated with nociception. Metabolomic analysis revealed distinct biochemical shifts, with variations in glucose, taurine, and norepinephrine profiles across baseline, stimulation, and recovery phases. Behavioral observations corroborated physiological findings, with bulls exhibiting signs of discomfort, such as struggling, arched back posture, and excessive salivation.

CONCLUSION: The combined EEG, hormonal, and metabolomic findings confirm that EE is a stressful and painful procedure for bulls. The study provides robust evidence of neurophysiological and biochemical responses indicative of pain. These findings highlight the need for alternative semen collection methods to minimize animal distress and improve welfare standards.

PMID:40453932 | PMC:PMC12123290 | DOI:10.14202/vetworld.2025.763-772

Blood Neoplasia. 2024 Feb 15;1(1):100004. doi: 10.1016/j.bneo.2024.100004. eCollection 2024 Mar.

ABSTRACT

TP53 mutation predicts adverse prognosis in many cancers, including myeloid neoplasms, but the mechanisms by which specific mutations affect disease biology, and whether they differ between disease categories, remain unknown. We analyzed TP53 mutations in 4 myeloid neoplasm subtypes (myelodysplastic syndrome [MDS], acute myeloid leukemia [AML], AML with myelodysplasia-related changes [AML-MRC], and therapy-related AML), and identified differences in mutation types, spectrum, and hot spots between disease categories and in comparison to solid tumors. Missense mutations in the DNA-binding domain were most common across all categories, whereas inactivating mutations and mutations outside the DNA binding domain were more common in AML-MRC than in MDS. TP53 mutations in MDS were more likely to retain transcriptional activity, and comutation profiles were distinct between disease categories and mutation types. Our findings suggest that mutated TP53 contributes to initiation and progression of neoplasia via distinct mechanisms, and support the utility of specific identification of TP53 mutations in myeloid malignancies.

PMID:40453522 | PMC:PMC12082110 | DOI:10.1016/j.bneo.2024.100004

Comput Struct Biotechnol J. 2025 May 1;27:1754-1771. doi: 10.1016/j.csbj.2025.04.040. eCollection 2025.

ABSTRACT

BACKGROUND: The interaction between HIV-1 and host immune cells, particularly macrophages, is crucial in understanding viral persistence and pathogenesis. This study aims to explore the impact of HIV-1 infection on macrophage microRNA (miRNA) expression profiles using a systems biology approach to uncover the potential role of miRNAs in modulating macrophage functionality and identify key miRNA targets that may serve as therapeutic avenues.

METHODS: PMA-differentiated THP-1 cells were used to model macrophage infection with HIV-1. A custom miRNA microarray was performed to identify dysregulated miRNAs following infection. miRTarBase was utilized for miRNA target identification, revealing gene targets associated with the dysregulated miRNAs. A protein-protein interaction (PPI) map of miRNA targets and their first interactors was constructed, with key nodes identified based on a calculated disease score, which considered degree, betweenness centrality, average shortest path length, and clustering coefficient. Gene Ontology molecular function analysis was also conducted on the identified targets.

RESULTS: The miRNA microarray identified 23 dysregulated miRNAs in HIV-1-infected macrophages, with 8 upregulated and 15 downregulated. Among these, the top 10 dysregulated miRNAs targeted over 2000 unique genes. PPI analysis revealed key nodes in the upregulated miRNA network, including APP, MYC, ESR2, RAF1, and HIST1H4A, while ZRANB1, HSPA8, TGOLN2, HSPA5, and BRD4 were prominent in the downregulated miRNA network. Notably, KRAS, CUL3, TP53, ESR1, and PARP1 were influenced by both upregulated and downregulated miRNAs. Gene Ontology analysis indicated that the targeted genes were involved in processes such as protein and RNA binding, ATPase activity, and ribosomal function.

CONCLUSIONS: HIV-1 infection induces significant dysregulation of miRNAs in macrophages, impacting a wide array of gene targets and molecular functions. These findings suggest that miRNA-mediated regulation may play a crucial role in HIV-1 pathogenesis within macrophages and present potential targets for miRNA-based therapeutic strategies.

PMID:40453371 | PMC:PMC12124685 | DOI:10.1016/j.csbj.2025.04.040

Blood Neoplasia. 2025 Mar 3;2(2):100083. doi: 10.1016/j.bneo.2025.100083. eCollection 2025 May.

ABSTRACT

Loss of all or part of chromosome 7 [-7/del(7q)] is recurrent in myeloid neoplasms and associated with a poor response to chemotherapy. Chromosome 7-encoded genes driving drug resistance and the consequences of combinatorial 7q tumor suppressor gene loss have remained unclear, the latter question largely because of the challenges of modeling aneuploidy. Here, we use in silico data mining to uncover 7q genes involved in chemotherapy resistance. We establish murine models of del(7q) clonal hematopoiesis and drug resistance with multiplex CRISPR-Cas9 (CRISPR-associated protein 9)-mediated inactivation of 4 genes, Cux1, Ezh2, Kmt2c, and Kmt2e. Postgenotoxic exposure, combined deficiency of Cux1 and Ezh2 preferentially promotes clonal myeloid expansion in vivo, with compounding defects in DNA damage recognition and repair. Human acute myeloid leukemia cell lines similarly illustrate central roles for CUX1 and EZH2 loss in survival and DNA damage resolution after chemotherapy exposure. Transcriptome analysis reveals combined Cux1 and Ezh2 loss recapitulates gene signatures of -7 patients and defective DNA damage response pathways, to a greater extent than single gene loss. This work reveals a genetic interaction between CUX1 and EZH2, and sheds light on how -7/del(7q) contributes to leukemogenesis and drug resistance characteristic of these adverse-risk neoplasms. These data support the concept of 7q as a contiguous gene syndrome region, in which combined loss of multiple gene drives pathogenesis. Furthermore, our CRISPR-based approach may serve as a framework for interrogating other recurrent aneuploid events in cancer.

PMID:40453147 | PMC:PMC12067884 | DOI:10.1016/j.bneo.2025.100083

J Endocr Soc. 2025 Apr 18;9(7):bvaf068. doi: 10.1210/jendso/bvaf068. eCollection 2025 Jul.

ABSTRACT

OBJECTIVE: We evaluated provider sentiments and practices that influence recommendations for insulin pump use.

METHODS: We surveyed US adult endocrinologists and used descriptive statistics to assess guideline adherence and criteria for insulin pump candidacy. Providers were categorized as permissive or selective prescribers based on reliance on criteria outside of clinical guidelines. Adjusted logistic regression identified factors associated with selective prescribing.

RESULTS: In 2023, we emailed surveys to 5684 endocrinologists, and 299 (5%) responded. Criteria for insulin pump use varied across providers: carbohydrate counting (55%), a minimum number of daily glucose checks (51%), a minimum number of clinic visits (48%), continuous glucose monitor use (42%), a minimum duration after diagnosis (20%), and a specific A1c (8%). While 94% reported being aware of diabetes care guidelines, 52% almost never referenced guidelines when determining insulin pump candidacy. The majority reported relying on their own judgment about insulin pump candidacy when it conflicted with clinical guidelines. Selective prescribers were more likely to report using guidelines sometimes or more (vs not often/never), have a low proportion of diabetes in their clinical case mix, and see patients primarily with public insurance.

CONCLUSION: Less than half of endocrinologists referenced national guidelines for pump candidacy, with many relying on nonevidence-based criteria. These findings demonstrate an important disconnect between guideline recommendations and clinical practice that may lead to underutilization of insulin pumps, which can enhance diabetes care and outcomes. Additional work is needed to better align clinical practice with current recommendations.

PMID:40452799 | PMC:PMC12123061 | DOI:10.1210/jendso/bvaf068

Microbiologyopen. 2025 Jun;14(3):e70015. doi: 10.1002/mbo3.70015.

ABSTRACT

SCOPE: Iron deficiency (ID) is the most common nutritional deficiency worldwide, impacting gut bacteria's metabolism and cellular biochemistry, but its effects on the microbiota-gut-brain axis (MGB) are poorly understood. Early-life ID-related dysbiosis is linked to neurodevelopmental impairments like autism and attention deficit hyperactivity disorder. Studying ID's impact on bacterial signaling can guide interventions to target MGB in iron-deficient populations. This study examined the responses of Escherichia coli (E. coli) and Limosilactobacillus reuteri (L. reuteri) to in-vitro ID conditions using the iron chelator 2,2'-Bipyridyl (BP).

METHODS AND RESULTS: We assessed and modeled their growth and cultivability and explored their bioelectric profiles using the voltage-sensitive dye DiBAC4(3). Results showed differential responses: L. reuteri's growth and cultivability were unaffected by BP, while E. coli's growth rate and cultivability decreased under ID. Additionally, we created a deterministic mathematical model that demonstrated a decrease in the population's average reproduction rate in E. coli under ID. Only E. coli exhibited an altered bioelectric profile, marked by increased cell depolarization in ID conditions, which was largely rescued upon the addition of a saturating concentration of iron.

CONCLUSION: These findings highlight specific bioelectrical responses in gut bacteria to ID. Understanding this variability is crucial for deciphering the microbiota's role in health and disease, particularly concerning nutritional iron imbalance and bacterial signaling in the MGB.

PMID:40452591 | DOI:10.1002/mbo3.70015

Mol Biol Evol. 2025 Jun 2:msaf129. doi: 10.1093/molbev/msaf129. Online ahead of print.

ABSTRACT

Shikimate kinase-like 1 (SKL1) plays an essential role in chloroplast biogenesis in Arabidopsis thaliana whereby mutants present a pigment-defective phenotype. The inability to identify SKL1 in organisms pre-dating land plants suggests an important role for this gene coinciding with the emergence of terrestrial plants. A role for SKL1 in chloroplast biogenesis has previously been determined in Arabidopsis, however the biological function for SKL1 has not been established in early land plants. In the present study, we provided functional and evolutionary insights into the diversification of SKL1 in the early land plant Marchantia polymorpha. We identified the SK gene homologues common to all land plants, two of which were shown to have high sequence similarity to SK. We confirmed that one member possessed kinase activity shikimate, whereas the second member is inactive. These findings led us to identify MpSK (Mp3g21830) and infer the identity of MpSKL1 (Mp6g03600). Consistent with previous studies in Arabidopsis, disruption of MpSKL1 in Marchantia resulted in a pigment-defective phenotype with abnormal chloroplast morphology and thylakoid network organization. Given an early origin of SKL1 in land plant evolution, we investigated requisite structural modifications to an ancestral SK that led to the functional diversification of SKL1. We provided evidence that SKL1 displays an open and accessible substrate binding pocket, conferring its biological function for chloroplast biogenesis. Together, our results demonstrate that the acquisition of SKL1 corresponds with the emergence of terrestrial land plants and that this biological function is conserved across distant plant lineages.

PMID:40452216 | DOI:10.1093/molbev/msaf129

Brief Bioinform. 2025 May 1;26(3):bbaf252. doi: 10.1093/bib/bbaf252.

ABSTRACT

CpG island hypermethylation, a hallmark of cancer, exhibits substantial heterogeneity across tumors, presenting both opportunities and challenges for cancer diagnostics and therapeutics. While this heterogeneity offers potential for patient stratification to predict clinical outcomes and personalize treatments, it complicates the development of robust biomarkers for early detection. Understanding the mechanisms driving this heterogeneity is essential for advancing biomarker design. Here, simulation-based analyses demonstrate that tumor purity and the high prevalence of low epi-mutation samples significantly obscure the identification of negative, rather than positive, regulators of CpG island hypermethylation, limiting a comprehensive understanding of heterogeneity sources. By addressing these confounders, we identify impaired DNA methylation maintenance, as indicated by global hypomethylation levels, as the primary contributor to CpG island hypermethylation variability among known regulators. This finding is supported by integrative analyses of datasets from The Cancer Genome Atlas (TCGA) Pan-Cancer Atlas, Genomics of Drug Sensitivity in Cancer (GDSC1000) cancer cell lines, and epi-allele analyses of two independent whole-genome bisulfite sequencing cohorts, using a newly developed method, MeHist (https://github.com/vhang072/MeHist). Furthermore, we assess widely used hypermethylation biomarkers across ten cancer types and find that 65 out of 246 (26.4%) are significantly influenced by impaired methylation maintenance. Incorporating hypomethylation and hypermethylation markers improves the robustness of cancer detection, as validated across multiple plasma cell-free DNA datasets. In summary, our findings highlight the value of simulation-guided integrative analysis in mitigating confounding effects and identify impaired DNA methylation maintenance as a key regulator of CpG island hypermethylation heterogeneity.

PMID:40452146 | DOI:10.1093/bib/bbaf252

J Sci Med Sport. 2025 May 20:S1440-2440(25)00155-0. doi: 10.1016/j.jsams.2025.05.009. Online ahead of print.

ABSTRACT

OBJECTIVES: Childhood cancer treatment has long-term health sequelae but there is more controversy for physical fitness. We compared fitness and echocardiographic variables in childhood cancer survivors (CCSs) and controls. A secondary aim was to determine the potential role of previous enrollment in inpatient exercise, and of current physical activity (PA) levels.

DESIGN: Cross-sectional.

METHODS: CCSs (age = 5-18 yrs, ≥4 yrs since diagnosis) and controls (no cancer history) were recruited. Outcomes included anthropometric, cardiorespiratory fitness (CRF)-related variables, upper/lower-body muscle strength (5-repetition maximum), functional mobility (timed up and down stairs [TUDS] test), and echocardiography. We performed sub-analyses attending to previous enrollment in supervised exercise training during intensive treatment and current accelerometer-determined PA.

RESULTS: 126 CCSs (12.8 ± 3.2 yrs, 41 % female) and 497 controls (11.2 ± 3.3 yrs, 40 % female) were studied. CCSs had a higher body mass index (+1.6 kg/m2, p < 0.001). Despite no significant differences in peak oxygen uptake (-0.5 %, p = 0.900), CCSs had lower ventilatory threshold (-9.8 %, p = 0.018), strength (-42.9 to -52.2 % depending on the analyzed exercise, p < 0.001 for most exercises) and TUDS performance (-23 %, p < 0.001) values than controls. CCSs showed a higher prevalence of left-ventricle hypertrophy and concentric cardiac remodeling. These results were independent of inpatient exercise background. CCSs showed lower levels of moderate-to-vigorous PA (MVPA) and vigorous PA (VPA) (p < 0.005). In CCSs, a positive correlation was found between MVPA/VPA levels and CRF or strength-related variables (all r > 0.4, p < 0.05).

CONCLUSIONS: CCSs showed impairments in some physical fitness and cardiac parameters ≥4 yrs posttreatment, which seemed independent of previous inpatient exercise background but not of MVPA/VPA levels after treatment.

PMID:40450428 | DOI:10.1016/j.jsams.2025.05.009

FEBS J. 2025 Jun 1. doi: 10.1111/febs.70140. Online ahead of print.

ABSTRACT

The fruit fly Drosophila melanogaster has emerged as an important model organism to shed light on neurodegeneration. Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder, the cause of which is still mostly unclear. The long-term use of available PD drugs may have major side effects, and they only target the symptoms without providing any effective cure for the disease. Therefore, in vivo and in silico approaches are extensively used to model PD-like phenotypes in Drosophila and investigate cellular alterations underlying PD pathogenesis. In vivo models are particularly crucial to provide insight into the PD-related molecular processes. It has been a preferred approach to investigate these models by collecting omics datasets, which can be further analysed using in silico modeling such as genome-scale metabolic models and artificial intelligence applications. This review aims to summarise in vivo and in silico modeling studies in the literature to illustrate the potential of the Drosophila in the characterisation of PD-related biological mechanisms towards providing early biomarkers and novel treatment options for PD.

PMID:40451947 | DOI:10.1111/febs.70140

Comput Methods Programs Biomed. 2025 May 23;269:108840. doi: 10.1016/j.cmpb.2025.108840. Online ahead of print.

ABSTRACT

BACKGROUND: Radiomic features, derived from a region of interest (ROI) in medical images, are valuable as prognostic factors. Selecting an appropriate ROI is critical, and many recent studies have focused on leveraging multiple ROIs by segmenting analogous regions across patients - such as the primary tumour and peritumoral area or subregions of the tumour. These can be straightforwardly incorporated into models as additional features. However, a more complex scenario arises, for example, in a regionally disseminated disease, when multiple distinct lesions are present.

AIM: This study aims to evaluate the feasibility of integrating radiomic data from multiple lesions into survival models. We explore strategies for incorporating these ROIs and hypothesize that including all available lesions can improve model performance.

METHODS: While each lesion produces a feature vector, the desired result is a unified prediction. We propose methods to aggregate either the feature vectors to form a representative one or the modelling results to compute a consolidated risk score. As a proof of concept, we apply these strategies to predict distant metastasis risk in a cohort of 115 non-small cell lung cancer patients, 60% of whom exhibit regionally advanced disease. Two feature sets (radiomics extracted from PET and PET interpolated to CT resolution) are tested across various survival models using a Monte Carlo Cross-Validation framework.

RESULTS: Across both feature sets, incorporating all available lesions - rather than limiting analysis to the primary tumour - consistently improved the c-index, irrespective of the survival model used. The highest c-Index obtained by a primary tumour-only model was 0.611 for the PET dataset and 0.614 for the PET_CT dataset, while by using all lesions we were able to achieve c-Indices of 0.632 and 0.634.

CONCLUSION: Lesions beyond the primary tumour carry information that should be utilized in radiomics-based models to enhance predictive ability.

PMID:40451095 | DOI:10.1016/j.cmpb.2025.108840

Brain Behav Immun. 2025 May 30:S0889-1591(25)00204-1. doi: 10.1016/j.bbi.2025.05.027. Online ahead of print.

ABSTRACT

Disease-associated microglia (DAM), initially described in mouse models of neurodegenerative diseases, have been classified into two related states; starting from a TREM2-independent DAM1 state to a TREM2 dependent state termed DAM2, with each state being characterized by the expression of specific marker genes (Keren-Shaul, 2017). Recently, single-cell (sc)RNA-Seq studies have reported the existence of DAMs in humans (Pettas, 2022; Jauregui, 2023; Friedman, 2018; Mathys, 2019; Tuddenham, 2024); however, whether DAMs play beneficial or detrimental roles in the context of neurodegeneration is still under debate (Butovsky and Weiner, 2018; Wang and Colonna, 2019). Here, we present a pharmacological approach to mimic human DAM in vitro: we validated in silico predictions that two different histone deacetylase (HDAC) inhibitors, Entinostat and Vorinostat, recapitulate aspects of the DAM signature in two human microglia-like model systems. HDAC inhibition increases RNA expression of MITF, a transcription factor previously described as a regulator of the DAM signature (Dolan, 2023). This engagement of MITF appears to be associated with one part of the DAM signature, refining our understanding of the DAM signature as a combination of at least two transcriptional programs that appear to be correlated in vivo. Further, we functionally characterized our DAM-like model system, showing that the upregulation of this transcriptional program by HDAC inhibitors leads to an upregulation of amyloid β and pHrodo Dextran uptake - while E.coli uptake is reduced - and a specific reduction of MCP1 secretion in response to IFN-γ and TNF-α. Overall, our strategy for compound-driven microglial polarization offers potential for exploring the function of human DAM and for an immunomodulatory strategy around HDAC inhibition.

PMID:40451396 | DOI:10.1016/j.bbi.2025.05.027

Cell Commun Signal. 2025 May 31;23(1):256. doi: 10.1186/s12964-025-02240-w.

ABSTRACT

INTRODUCTION: Cardiac mitochondrial function is intricately regulated by various processes, ultimately impacting metabolic performance. Additionally, protein turnover is crucial for sustained metabolic homeostasis in cardiomyocytes.

OBJECTIVE: Here, we studied the role of mTOR in OPA-1 cleavage and its consequent effects on mitochondrial dynamics and energetics in cardiomyocytes.

RESULTS: Cultured rat cardiomyocytes treated with rapamycin for 6-24 h showed a significant reduction in phosphorylation of p70S6K, indicative of sustained inhibition of mTOR. Structural and functional analysis revealed increased mitochondrial fragmentation and impaired bioenergetics characterized by decreases in ROS production, oxygen consumption, and cellular ATP. Depletion of either the mitochondrial protease OMA1 or the mTOR regulator TSC2 by siRNA, coupled with an inducible, cardiomyocyte-specific knockout of mTOR in vivo, suggested that inhibition of mTOR promotes mitochondrial fragmentation through a mechanism involving OMA1 processing of OPA-1. Under homeostatic conditions, OMA1 activity is kept under check through an interaction with microdomains in the inner mitochondrial membrane that requires prohibitin proteins (PHB). Loss of these microdomains releases OMA1 to cleave its substrates. We found that rapamycin both increased ubiquitination of PHB1 and decreased its abundance, suggesting proteasomal degradation. Consistent with this, the proteasome inhibitor MG-132 maintained OPA-1 content in rapamycin-treated cardiomyocytes. Using pharmacological activation and inhibition of AMPK our data supports the hypothesis that this mTOR-PHB1-OMA-OPA-1 pathway impacts mitochondrial morphology under stress conditions, where it mediates dynamic changes in metabolic status.

CONCLUSIONS: These data suggest that mTOR inhibition disrupts mitochondrial integrity in cardiomyocytes by promoting the degradation of prohibitins and OPA-1, leading to mitochondrial fragmentation and metabolic dysfunction, particularly under conditions of metabolic stress.

PMID:40450326 | DOI:10.1186/s12964-025-02240-w

Sci Rep. 2025 May 31;15(1):19148. doi: 10.1038/s41598-025-03339-3.

ABSTRACT

This cross-sectional observational study aimed to identify the predictors of sleep bruxism (SB) in patients with temporomandibular disorder (TMD) and to comprehensively investigate its association with clinical, sleep-related, psychological, and hematological factors. Seventy-nine patients with TMD (69 females and 10 males; mean age 45.46 ± 14.46 years) were divided into two groups based on the presence or absence of SB: TMD_nonbruxer and TMD_bruxer. Descriptive statistics, correlation analyses, and multivariate stepwise logistic regression were conducted; p < 0.05 was considered statistically significant. In Cramer's V, SB was correlated with several clinical and sleep-related factors, including TMJ noise (r = 0.52), TMD pain (r = 0.48), craniomandibular index (r = 0.32), limited mouth opening (r = 0.29), tinnitus (r = 0.29), an increase in the Pittsburgh sleep quality index (PSQI) global score (r = 0.24), and poor sleep quality, defined as a PSQI global score ≥ 5 (r = 0.19) (all p < 0.05). SB was also associated with psychological distress. Regarding hematological factors, elevated levels of cortisol (r = 0.30), adrenocorticotropic hormone (ACTH) (r = 0.34), and cortisol/ACTH ratio (r = 0.35) were also associated with SB (all p < 0.05). The factors associated with an increased likelihood of SB ranked in terms of the odds ratio (OR) were: craniomandibular index (OR = 18.400, p = 0.006), poor sleep quality with a PSQI global score ≥ 5 (OR = 11.425, p = 0.027), depression (OR = 1.189, p = 0.014), cortisol/ACTH ratio (OR = 1.151, p = 0.007), anxiety (OR = 1.081, p = 0.040), and adrenocorticotropic hormone (OR = 1.073, p = 0.019). Notably, an increase in age was associated with a decreased likelihood of SB (OR = 0.905, p = 0.006), with a cut-off value of 50 years (AUC = 0.259, 95% CI: 0.149-0.368, p = 0.024), indicating a significant decrease in bruxism occurrence in individuals aged ≥ 50 years. Further analysis revealed complex interconnections between SB and its predictors. In conclusion, SB in TMD patients was associated with age < 50 years, various clinical factors, such as TMD pain and TMJ noise, poor sleep quality, psychological deterioration, and elevated cortisol and ACTH levels.

PMID:40450081 | DOI:10.1038/s41598-025-03339-3

Nat Commun. 2025 May 31;16(1):5061. doi: 10.1038/s41467-025-59653-x.

ABSTRACT

Base editors enable the direct conversion of target nucleotides without introducing DNA double strand breaks, making them a powerful tool for creating point mutations in a human genome. However, current Cas9-derived base editing technologies have limited ability to simultaneously edit multiple loci with base-pair level precision, hindering the generation of polygenic phenotypes. Here, we test the ability of six Cas12a-derived base editing systems to process multiple gRNAs from a single transcript. We identify base editor variants capable of multiplexed base editing and improve the design of the respective gRNA array expression cassette, enabling multiplexed editing of 15 target sites in multiple human cell lines, increasing state-of-the-art in multiplexing by three-fold in the field of mammalian genome engineering. To reduce bystander mutations, we also develop a Cas12a gRNA engineering approach that directs editing outcomes towards a single base-pair conversion. We combine these advances to demonstrate that both strategies can be combined to drive multiplex base editing with greater precision and reduced bystander mutation rates. Overcoming these key obstacles of mammalian genome engineering technologies will be critical for their use in studying single nucleotide variant-associated diseases and engineering synthetic mammalian genomes.

PMID:40449999 | DOI:10.1038/s41467-025-59653-x