Nat Genet. 2025 Jul 3. doi: 10.1038/s41588-025-02217-y. Online ahead of print.

ABSTRACT

As DNA variants accumulate in somatic stem cells, become selected or evolve neutrally, they may ultimately alter tissue function. When, and how, selection occurs in homeostatic tissues is incompletely understood. Here, we introduce SCIFER, a scalable method that identifies selection in an individual tissue, without requiring knowledge of the driver event. SCIFER also infers self-renewal and mutation dynamics of the tissue's stem cells, and the size and age of selected clones. Probing bulk whole-genome sequencing data of nonmalignant human bone marrow and brain, we detected pervasive selection in both tissues. Selected clones in hematopoiesis, with or without known drivers, were initiated uniformly across life. In the brain, we found pre-malignant clones with glioma-initiating mutations and clones without known drivers. In contrast to hematopoiesis, selected clones in the brain originated preferentially from childhood to young adulthood. SCIFER is broadly applicable to renewing somatic tissues to detect and quantify selection.

PMID:40610627 | DOI:10.1038/s41588-025-02217-y

Sci Data. 2025 Jul 3;12(1):1139. doi: 10.1038/s41597-025-05318-9.

ABSTRACT

Freshwater bivalves (FWB) are attracting scientific and societal attention given their essential ecosystem services, ecological functions, and poor conservation status. Current knowledge of the spatial distribution of West Palearctic FWB is poor preventing the understanding of biogeography and conservation planning. One of the priorities of the pan-European networking project "CONFREMU - Conservation of freshwater mussels: a pan-European approach" funded by the European Union, was to fill the knowledge gap on the distribution of FWB in Europe and adjacent regions. Based on the efforts of this network of scientists, we provide the most complete, taxonomically, and geographically accurate distribution of FWB species for the entire West Palearctic. The dataset contains 270,287 geo-referenced records of 93 native and 8 non-native FWB from 1674 to 2023. The dataset compiles information from private records from 82 specialists and multiple sources (e.g., published articles, grey literature, biodiversity databases, and scientific collections). This dataset, available online, represents an important data source for future studies on the biodiversity, biogeography, and conservation of these important organisms.

PMID:40610536 | DOI:10.1038/s41597-025-05318-9

Nat Commun. 2025 Jul 3;16(1):6125. doi: 10.1038/s41467-025-61156-8.

ABSTRACT

Prader-Willi Syndrome (PWS) is caused by the loss of expression of paternally expressed genes in the human 15q11.2-q13 imprinting domain. A set of imprinted genes that are active on the paternal but silenced on the maternal chromosome are intricately regulated by a bipartite imprinting center (PWS-IC) located in the PWS imprinting domain. We previously discovered that euchromatic histone lysine N-methyltransferase-2 (EHMT2/G9a) inhibitors are capable of un-silencing PWS-associated genes by restoring their expression from the maternal chromosome. Here, in mice lacking the Ehmt2 gene, we document un-silencing of the imprinted Snrpn/Snhg14 gene on the maternal chromosome in the late embryonic and postnatal brain. Using PWS and Angelman syndrome patient derived cells with either paternal or maternal deletion of 15q11.2-q13, we have found that chromatin of maternal PWS-IC is closed and has compact 3D folding confirmation. We further show that a distinct noncoding RNA (TSS4-280118) preferentially transcribed from the upstream of the PWS-IC of maternal chromosome interacts with EHMT2 and forms a heterochromatin complex in CIS on the maternal chromosome. Inactivation of TSS4-280118 by CRISPR/Cas9 editing results in unsilencing of the expression of SNRPN and SNORD116 from the maternal chromosome. Taken together, these findings demonstrate that allele-specific recruitment of EHMT2 is required to maintain the maternal imprints. Our findings provide mechanistic insights and support a model for imprinting maintenance of the PWS imprinted domain.

PMID:40610428 | DOI:10.1038/s41467-025-61156-8

Semin Cell Dev Biol. 2025 Jul 2:103623. doi: 10.1016/j.semcdb.2025.103623. Online ahead of print.

ABSTRACT

Endothelial cells (ECs), which line the inner surface of blood vessels, continuously respond to biomechanical forces from blood flow, extracellular matrix, and intracellular tension. Recent advances have highlighted the pivotal role of these forces in regulating cellular plasticity during endothelial-to-hematopoietic transition (EHT) and endothelial-to-mesenchymal transition (EndMT), two processes essential for embryogenesis, tissue repair, and disease progression. EHT contributes to hematopoietic stem cell formation, and EndMT to valve formation and vessel sprouting. When misregulated, both processes cause vascular pathologies such as fibrosis, cancer metastasis, and atherosclerosis. This review provides an overview of how biomechanical cues influence EC fate decisions and behavioral transitions. We explore how external biomechanical forces are sensed at the endothelial cell surface, transmitted through intracellular adaptors, and affect changes at the transcriptional level. Understanding these mechanotransduction pathways during cell fate transition not only deepens our knowledge of endothelial cell plasticity but also provides insight into potential root causes of and treatments for vascular diseases.

PMID:40610306 | DOI:10.1016/j.semcdb.2025.103623

Redox Biol. 2025 Jun 24;85:103739. doi: 10.1016/j.redox.2025.103739. Online ahead of print.

ABSTRACT

Pathogenic variants in BRCA2 are hereditary risks for various cancers, including breast, ovary, pancreas and prostate. Genomic instability due to insufficient homologous recombination is thought as responsible for carcinogenesis. Reportedly, endogenous or exogenous aldehydes, including formaldehyde and acetaldehyde, suppress BRCA2 function. However, molecular sequences how BRCA2 insufficiency leads to carcinogenesis remains unelucidated. To assess whether Fenton reaction-based oxidative stress is a promotional risk factor of carcinogenesis in BRCA2 haploinsufficiency, we here applied iron-induced renal carcinogenesis to a newly established rat heterozygous mutation model of Brca2 (mutant, T1942Kfs/+; MUT). Rat MUT model, despite significant increase in spontaneous malignant tumors, showed no promotional effect on renal carcinogenesis induced by ferric nitrilotriacetate (Fe-NTA) in contrast to our previous study using Brca1 mutant rats. Array-based comparative genome hybridization of renal cell carcinoma in MUT revealed significant increase in the frequency of homozygous Cdkn2A deletion. Whereas acute-phase analysis of the kidney after single or 1-week Fe-NTA administration to MUT showed suppressed lipid peroxidation, consistent with ferroptosis-resistance, ferroptosis and regeneration of tubular cells were coexistent with higher cytoplasmic catalytic Fe(II) levels in the subacute phase of MUT after 3-week Fe-NTA administration. Mechanistically, mitochondrial dysfunction with excess iron, promoted by insufficient BRCA2 presumably for maintaining DNA integrity, eventually initiated ferroptotic process. In conclusion, iron-dependent oxidative stress plays double-edged roles either for cell death or proliferation in carcinogenesis and its biological consequences are distinct between BRCA2 and BRCA1 haploinsufficiency. Our results suggest that iron-catalyzed oxidative stress is not a major driving force of carcinogenesis in BRCA2 pathogenic variants.

PMID:40609478 | DOI:10.1016/j.redox.2025.103739

Sci Total Environ. 2025 Jul 2;993:179971. doi: 10.1016/j.scitotenv.2025.179971. Online ahead of print.

ABSTRACT

Microplastic (MP) pollution is an increasing environmental concern due to its persistence and potential risks to both ecosystems and human health. Additionally, MPs can adsorb and become vehicle of other pollutants and hazardous chemicals. Among these, Bisphenol A (BPA) is a well-known endocrine disruptor. This study investigates the effects of MPs exposure in multiple cell types (preadipocytes, hepatocytes, hypothalamic neurons, and endothelial cells), the adsorption/desorption dynamics of BPA on MPs and the biological effects of BPA-sorbed MPs. We employed 5 μm commercial polystyrene microplastics (PS-MPs), both in their pristine form and with carboxyl (-COOH) functionalization, mimicking surface oxidation resulting from environmental weathering. While exposure to a wide range of pristine PS-MPs concentrations did not affect cell viability, COOH-functionalized PS-MPs induced significant toxicity in neurons and endothelial cells at high concentrations (>100 μg/mL). Furthermore, COOH-functionalized MPs altered lipid accumulation during preadipocyte to adipocyte differentiation. Using an optimized HPLC-MS/MS method with online SPE, we quantified the adsorption of BPA onto PS-MPs in water and its subsequent desorption under physiological conditions, achieving detection and quantification limits (3 ng/mL and 10 ng/mL, respectively) that enabled accurate BPA measurements, particularly in desorption studies. COOH-functionalized PS-MPs exhibited higher BPA adsorption efficiency and an increased desorption in cell culture media (29 % adsorption; 45 % desorption) compared to pristine PS-MPs (23 % adsorption; 13 % desorption), suggesting that oxidized MPs may act as more effective carriers for toxic chemicals. However, when cells were exposed to BPA-sorbed PS-MPs, no synergistic effects between the two pollutants were observed. These findings underscore the pivotal role of MP surface chemistry in governing pollutant interactions and shaping biological responses. Additionally, they emphasize the importance of assessing pollutant adsorption onto MPs; this approach, rather than using simple co-exposure methods, is essential for studying the role of MPs as carriers of environmental pollutants in biological systems.

PMID:40609415 | DOI:10.1016/j.scitotenv.2025.179971

Blood Adv. 2025 Jul 3:bloodadvances.2024015185. doi: 10.1182/bloodadvances.2024015185. Online ahead of print.

NO ABSTRACT

PMID:40609078 | DOI:10.1182/bloodadvances.2024015185

PLoS Comput Biol. 2025 Jul 3;21(7):e1013253. doi: 10.1371/journal.pcbi.1013253. Online ahead of print.

ABSTRACT

The colonic epithelium plays a key role in the host-microbiome interactions, allowing uptake of various nutrients and driving important metabolic processes. To unravel detailed metabolic activities in the human colonic epithelium, our present study focuses on the generation of the first cell-type specific genome-scale metabolic model (GEM) of human colonic epithelial cells, named iColonEpithelium. GEMs are powerful tools for exploring reactions and metabolites at the systems level and predicting the flux distributions at steady state. Our cell-type-specific iColonEpithelium metabolic reconstruction captures genes specifically expressed in the human colonic epithelial cells. iColonEpithelium is also capable of performing metabolic tasks specific to the colonic epithelium. A unique transport reaction compartment has been included to allow for the simulation of metabolic interactions with the gut microbiome. We used iColonEpithelium to identify metabolic signatures associated with inflammatory bowel disease. We used single-cell RNA sequencing data from Crohn's Diseases (CD) and ulcerative colitis (UC) samples to build disease-specific iColonEpithelium metabolic networks in order to predict metabolic signatures of colonocytes in both healthy and disease states. We identified reactions in nucleotide interconversion, fatty acid synthesis and tryptophan metabolism were differentially regulated in CD and UC conditions, relative to healthy control, which were in accordance with experimental results. The iColonEpithelium metabolic network can be used to identify mechanisms at the cellular level, and we show an initial proof-of-concept for how our tool can be leveraged to explore the metabolic interactions between host and gut microbiota.

PMID:40609069 | DOI:10.1371/journal.pcbi.1013253

Elife. 2025 Jul 3;13:RP101850. doi: 10.7554/eLife.101850.

ABSTRACT

Synaptic plasticity underlies the brain's ability to learn and adapt. While experiments in brain slices have revealed mechanisms and protocols for the induction of plasticity between pairs of neurons, how these synaptic changes are coordinated in biological neuronal networks to ensure the emergence of learning remains poorly understood. Simulation and modeling have emerged as important tools to study learning in plastic networks, but have yet to achieve a scale that incorporates realistic network structure, active dendrites, and multi-synapse interactions, key determinants of synaptic plasticity. To rise to this challenge, we endowed an existing large-scale cortical network model, incorporating data-constrained dendritic processing and multi-synaptic connections, with a calcium-based model of functional plasticity that captures the diversity of excitatory connections extrapolated to in vivo-like conditions. This allowed us to study how dendrites and network structure interact with plasticity to shape stimulus representations at the microcircuit level. In our exploratory simulations, plasticity acted sparsely and specifically, firing rates and weight distributions remained stable without additional homeostatic mechanisms. At the circuit level, we found plasticity was driven by co-firing stimulus-evoked functional assemblies, spatial clustering of synapses on dendrites, and the topology of the network connectivity. As a result of the plastic changes, the network became more reliable with more stimulus-specific responses. We confirmed our testable predictions in the MICrONS datasets, an openly available electron microscopic reconstruction of a large volume of cortical tissue. Our results quantify at a large scale how the dendritic architecture and higher-order structure of cortical microcircuits play a central role in functional plasticity and provide a foundation for elucidating their role in learning.

PMID:40608402 | DOI:10.7554/eLife.101850

mBio. 2025 Jul 3:e0124925. doi: 10.1128/mbio.01249-25. Online ahead of print.

ABSTRACT

Cerebral malaria (CM) is a severe and often fatal complication of Plasmodium falciparum infection. Although much progress has been made in understanding CM, the precise pathogenesis remains elusive. The olfactory bulb (OB) has emerged as a critical site of immunopathology in experimental cerebral malaria (ECM) models, but its contribution to disease progression is not fully understood. To investigate the molecular mechanisms driving early ECM pathogenesis, we conducted transcriptomic profiling of the OB to identify key genes associated with disease onset. Our analysis revealed significant early upregulation of interferon (IFN)-inducible GTPases, particularly Irgb6 and Gbp4, effectors downstream of IFN-γ but not IFN-α/β signaling, suggesting their involvement in ECM pathology. Using Gbp4-/-, Irgb6-/-, and double knockout (Irgb6-/- Gbp4-/-) mice, we identified a pathological role for these GTPases. Mechanistically, we found that double-knockout mice exhibited increased infiltration of CD4+ and CD8+ T cells into the brain but with reduced T cell functionality and impaired antigen presentation by endothelial cells, leading to enhanced parasite accumulation in the OB. This disruption in immune regulation ultimately conferred improved survival in the Irgb6-/- Gbp4-/- mice and indicated the pathological impact of Gbp4 and Irgb6 in ECM. These findings reveal that Gbp4 and Irgb6 play important roles in the early immunopathogenesis of ECM by modulating antigen processing and presentation in the OB, thereby shaping immune cell dynamics. Our work shows the dual role of Irgb6 and Gbp4 GTPases in host defence and immunopathology and offers new insights into ECM mechanisms and antigen presentation.IMPORTANCECerebral malaria (CM) arises from an excessive inflammatory response and blood-brain-barrier (BBB) dysfunction in Plasmodium-infected hosts, but the precise mechanisms driving early-stage pathogenesis remain unclear. Through RNA sequencing of the olfactory bulb (OB) in a murine experimental cerebral malaria (ECM) model, we identified the early upregulation of interferon (IFN)-inducible GTPases, Irgb6 and Gbp4, key effectors downstream of IFN-γ signaling. Our results demonstrate that Gbp4 and Irgb6 synergistically contribute to ECM pathology by regulating antigen cross-presentation in endothelial cells. This dysregulation leads to abnormal parasite burden and alters the accumulation of CD4+ and CD8+ T cells in the brain via the OB, further perturbing inflammation. Our findings suggest a novel mechanism in CM and emphasize the pivotal roles of Gbp4 and Irgb6 in promoting cell-autonomous immune responses that, in turn, escalate pathological inflammation. Our study offers insights into how dysregulated immune responses drive CM progression and suggests potential therapeutic targets to mitigate fatal outcomes.

PMID:40607809 | DOI:10.1128/mbio.01249-25

J Integr Plant Biol. 2025 Jul 3. doi: 10.1111/jipb.13963. Online ahead of print.

ABSTRACT

INOSITOL-REQUIRING ENZYME 1 (IRE1) is conserved in plants and mammals to regulate stress responses. Here, we found that TaIRE1 is involved in the unconventional splicing of cell membrane-localized TabZIP60 messenger RNA (mRNA), which results in a nucleus resident protein form (TabZIP60s), and enhanced heat stress tolerance. Transcriptome analysis together with binding element prediction revealed 121 high-confidence targets of TabZIP60s responsive to heat stress in wheat (Triticum aestivum), including heat shock protein genes. Interestingly, we found that an asparagine to glutamic acid substitution, located next to DNA-binding domain of TabZIP60s, results in reduced binding affinity and transcriptional activity to downstream targets, and this heat stress tolerance inferior allele was positively selected during modern wheat breeding programs in China, possibly due to their negative effects on yield potential. Finally, we showed that TaIRE1 is also responsible for the mis-cleavage of miR172 precursors, and consequently contribute to heat stress tolerance. To the best of our knowledge, this represents the first report showing that, like in mammals, IRE1 also regulates miRNA cleavage in response to heat stress in plants. Together, this coordinate control of two signaling pathways provides new insights into heat stress tolerance regulation in wheat.

PMID:40607649 | DOI:10.1111/jipb.13963

Front Mol Biosci. 2025 Jun 18;12:1607583. doi: 10.3389/fmolb.2025.1607583. eCollection 2025.

ABSTRACT

INTRODUCTION: As of mid-2024, COVID-19 has affected over 676 million people worldwide, leading to more than 6.8 million deaths. Numerous studies have documented metabolic changes occurring during both the acute phase of the disease and the recovery phase, which, in some cases, contribute to the development of long COVID syndrome.

AIMS AND METHODS: In this study, we aimed to evaluate clinical, laboratory, and comprehensive metabolomic data from hospitalized COVID-19 patients during the second, third and fourth waves (Alpha, Delta, and Omicron). A targeted, fully quantitative metabolomics assay (TMIC MEGA Assay) was used to measure 529 metabolites and lipids in plasma samples. The metabolomic profiles of these patients were compared according to different and relevant factors impacting COVID-19 outcome, such as age, sex, comorbidities, and vaccination status.

RESULTS: Among the 21 classes of compounds evaluated in this study, amino acids and lipids were the most dysregulated when comparing age, sex, comorbidities, vaccination status, and the different epidemiological waves. This is the most comprehensive analysis in Mexico providing absolute quantitative data for 529 metabolites and lipids measured in hospitalized COVID-19 patients, which could be used to monitor their metabolic status and clinical outcomes associated with COVID-19 infection or with long COVID syndrome.

PMID:40607062 | PMC:PMC12214581 | DOI:10.3389/fmolb.2025.1607583

Phenomics. 2025 Mar 7;5(2):208-211. doi: 10.1007/s43657-024-00168-8. eCollection 2025 Apr.

ABSTRACT

Metagenomics and metabolomics technologies have been widely used to investigate the microbe-metabolite interactions in vivo. However, the computational methods that accurately infer the microbe-metabolite interactions are lacking. We present a context-aware framework for graph representation learning, NetNiche, which predicts microbe-metabolite and microbe-microbe interactions in an accurate manner, by integrating their abundance data with prior knowledge. We applied NetNiche to datasets on gut and soil microbiome, and demonstrated that NetNiche can outperform the state-of-the-art methods, such as SParse InversE Covariance Estimation for Ecological Association Inference (SPIEC-EASI), Sparse Correlations for Compositional data (SparCC) and microbe-metabolite vectors (mmvec). NetNiche is an effective tool with wide applicability for the multi-omics study of human microbiome.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s43657-024-00168-8.

PMID:40606566 | PMC:PMC12209087 | DOI:10.1007/s43657-024-00168-8

Phenomics. 2025 Apr 9;5(2):212-215. doi: 10.1007/s43657-024-00174-w. eCollection 2025 Apr.

ABSTRACT

Previous observational and genomic-wide association studies (GWAS) suggested the association between several phenotypic factors and keratinocyte carcinoma, including lifestyle and dietary, photodamage-related conditions and socioeconomic status. The causal effect of these phenotypic factors in keratinocytes carcinoma etiology remains unclear. In this study, we utilized two-sample mendelian randomization analysis from multiple large-scale GWAS datasets of keratinocytes carcinoma including more than 300,000 patients. Genetic instrumental variables (IVs) were constructed by identifying single nucleotide polymorphisms (SNPs) that associate with corresponding factors. The inverse variance weighted (IVW) method and four robust MR approaches, including weighted median estimator, MR-Egger regression, simple mode and weighted mode were implemented for causal inferences and assess the sensitivity across findings. In this analysis, ease of skin tanning was identified as casual protective factor of keratinocyte carcinoma (Basal cell carcinoma: IVW OR = 0.718, 95% CI 0.654-0.788, p < 0.001; Cutaneous squamous cell carcinoma: IVW OR = 0.601, 95% CI 0.516-0.701, p < 0.001). Other phenotypic factors, such as coffee intake, alcohol consumption, smoking and socioeconomic status, indicated insignificant effects on keratinocyte carcinoma risk in the analysis, and therefore, our study does not support their roles in modifying keratinocytes carcinoma risks. Our extensive analysis provides strong evidence of the causative protective effect of ease of skin tanning in keratinocyte carcinoma. The findings suggest that individuals who are less prone to tanning may need to pay greater attention to sun protection in their daily activities to reduce the potential risk of keratinocyte cancers.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s43657-024-00174-w.

PMID:40606559 | PMC:PMC12209071 | DOI:10.1007/s43657-024-00174-w

ACS Cent Sci. 2025 Jun 17;11(6):823-825. doi: 10.1021/acscentsci.5c00917. eCollection 2025 Jun 25.

ABSTRACT

Screening the tetrazine-protein interactome finds the balance needed for high-performance fluorescent probes.

PMID:40606006 | PMC:PMC12220826 | DOI:10.1021/acscentsci.5c00917

Data Brief. 2025 Jun 9;61:111763. doi: 10.1016/j.dib.2025.111763. eCollection 2025 Aug.

ABSTRACT

Analysis of bacterial biofilms is particularly challenging and important with diverse applications from systems biology to biotechnology. Among the variety of techniques that have been applied, time-of-flight secondary ion mass spectrometry (ToF-SIMS) has many promising features in studying the surface characteristics of biofilms. ToF-SIMS offers high spatial resolution and high mass accuracy, which permit surface sensitive analysis of biofilm components. Thus, ToF-SIMS provides a powerful solution to addressing the challenge of bacterial biofilm analysis. This dataset covers ToF-SIMS analysis of Paenibacillus sp. 300A (300A) isolated from the Hanford site in Richland, WA. The strain is known to have metal and sulfur reducing properties and can be used for bioremediation, wastewater treatment, bioengineering and technology development. There is a current need to identify small molecules and fragments produced from bacterial biofilms. Static ToF-SIMS spectra of 300A were obtained using an IONTOF TOF-SIMS V instrument equipped with a 25 keV Bi3 + metal ion gun. Identified molecules and molecular fragments are compared against known biological databases and the reported peaks have at least 65 ppm mass accuracy. These molecules range from lipids and fatty acids to flavonoids, quinolones, and other naturally occurring organic compounds. It is anticipated that the spectral identification of key peaks will assist detection of metabolites, extracellular polymeric substance molecules like polysaccharides, and biologically relevant small molecules using ToF-SIMS in future surface and interface research of bacterial biofilms.

PMID:40605852 | PMC:PMC12221530 | DOI:10.1016/j.dib.2025.111763

Adv Mater. 2025 Jul 3:e2419870. doi: 10.1002/adma.202419870. Online ahead of print.

ABSTRACT

Immune checkpoint inhibitors have revolutionized cancer therapy; however, many patients exhibit suboptimal responses, which is due to inadequate T cell priming by the innate immune response. Metal ions play a critical role in modulating the innate immune response. However, the mechanisms by which metal ions facilitate dendritic cell maturation through the activation of interferon remain poorly understood. This research identifies a nanomaterial Calcium phosphate-containing liposome (NanoCa), characterized by an atypical crystal structure and pH-responsive profile. NanoCa promotes bone marrow-derived dendritic cell maturation and exhibits antiviral effects and anti-tumor properties in different tumor models. Also, NanoCa acts as an immunostimulant by fostering antibody production. Furthermore, when combined with programmed cell death 1 receptor (PD-1) blocking antibodies, NanoCa synergistically enhances anti-tumor efficacy in CT26 models. Mechanistically, NanoCa rapidly releases Ca2+ via the lysosome pathway post-endocytosis, subsequently triggering interferon through the Ca2+-calcineurin (CaN) - nuclear factor of activated T cells 2 (NFATc2) - protein kinase C beta (PKCβ) - interferon regulatory factor 3 (IRF3) signal pathway. Single-cell RNA sequencing (scRNA-seq) shows NanoCa increases the population of tumoral infiltrating dendritic cell (DC), C1qc+ TAM, and CD8T_eff cells and decreases the CD8T_ex and immunosuppressive SPP1+ TAM population in tumor-draining lymph nodes. Overall, NanoCa shows translational potential for anti-tumor immune therapeutics.

PMID:40605669 | DOI:10.1002/adma.202419870

Cereb Cortex. 2025 Jul 1;35(7):bhaf140. doi: 10.1093/cercor/bhaf140.

ABSTRACT

Older adults with mild cognitive impairment (MCI) exhibit a reduction in trust propensity (TP), which is correlated with heightened affective sensitivity to betrayal. However, the mediating role of this affective component in declining TP in MCI and the influence of structural brain alterations on reduced TP via affect warrant further investigation. We conducted multiple mediation analyses to assess whether differences in TP between MCI and normal healthy controls (NHCs) were mediated by affect, motivation, executive function, and social cognition. Whole-brain mediation analyses identified neural substrates and moderated mediation analyses examined whether structural brain changes influenced TP via affect differently between the two groups. Our results revealed a significant mediating effect of affect on the group difference in TP. Atrophy within the thalamus and anterior insula (AI) in the MCI group was found to contribute to their diminished TP. Furthermore, moderated mediation analysis showed that the influence of the thalamus and AI on TP was mediated by affect within the MCI group but not NHCs. These findings suggest that reduced TP in MCI is primarily driven by the increased sensitivity to betrayal, which is underpinned by structural alterations within salience network regions rather than alterations in other trust-related cognitive domains.

PMID:40605311 | DOI:10.1093/cercor/bhaf140

Gut Microbes. 2025 Dec;17(1):2525478. doi: 10.1080/19490976.2025.2525478. Epub 2025 Jul 2.

ABSTRACT

Fecal Microbiota Transplant (FMT) is a treatment for recurrent Clostridium difficile infections and is being explored for other clinical applications, from alleviating digestive and neurological disorders, to restoring microbiomes impacted by cancer treatment. Quantifying the extent of engraftment following an FMT is important in understanding a recipient's response to treatment. Engraftment and clinical response need to be investigated independently to evaluate an FMT's role (or lack thereof) in achieving a clinical response. Standardized bioinformatics methodologies for quantifying engraftment extent would not only improve assessment and understanding of FMT outcomes, but also facilitate comparison of FMT results and protocols across studies. Here we review FMT studies, integrating three concepts from microbial ecology as framework to discuss how these studies approached assessing engraftment extent: 1) Community Coalescence investigates microbiome shifts following FMT engraftment, 2) Indicator Features tracks specific microbiome features as a signal of engraftment, and 3) Resilience examines how resistant post-FMT recipients' microbiomes are to reverting back to baseline. These concepts explore subtly different questions about the microbiome following FMT. Taken together, they provide holistic insight into how an FMT alters a recipient's microbiome composition and provide a clear framework for quantifying and communicating about microbiome engraftment.

PMID:40605266 | DOI:10.1080/19490976.2025.2525478

RNA Biol. 2025 Dec;22(1):1-20. doi: 10.1080/15476286.2025.2502719. Epub 2025 Jul 2.

ABSTRACT

CD4+ regulatory T cells (TREGS) are critical for immune tolerance and the transcription factor Forkhead Box P3 (FOXP3) plays a crucial role in their differentiation and function. Recently, an alternative promoter has been reported for FOXP3, which is active only in TREGS and could have profound implications for the output of the locus, and therefore, for the functionality of these cells. By direct RNA sequencing we identified multiple novel FOXP3 transcriptional products, including one relatively abundant isoform with an extended 5' UTR that we named 'longFOXP3'. Western blotting, analysis of public mass spectrometry data, and transfection of in vitro transcribed RNA suggested that longFOXP3 is not coding. Furthermore, we show using two distinct RNA single-molecule fluorescence in situ hybridization technologies that transcription from the upstream promoter correlates with decreased levels of FOXP3 at the mRNA and protein levels. Together, we provide compelling evidence that the transcriptional output of the human FOXP3 locus is far more complex than that of the current annotation and warrants a more detailed analysis to identify coding and non-coding transcript isoforms. Furthermore, the alternative promoter may interfere with the activity of the canonical promoter, evoking intragenic transcriptional interference, and in this way, fine-tune the levels of FOXP3 in human TREGS.

PMID:40605177 | DOI:10.1080/15476286.2025.2502719