Neurogenetics. 2025 Mar 5;26(1):34. doi: 10.1007/s10048-025-00816-9.

ABSTRACT

Schizophrenia (SCZ) is a chronic and severe mental disorder with a complex molecular aetiology. Emerging evidence indicates a potential association between the gut microbiome and the development of SCZ. Considering the under-representation of African populations in SCZ research, this study aimed to explore the association between the gut microbiome and SCZ within a South African cohort. Gut microbial DNA was obtained from 89 participants (n = 41 SCZ cases; n = 48 controls) and underwent 16S rRNA (V4) sequencing. Data preparation and taxa classification were performed with the DADA2 pipeline in R studio followed by diversity analysis using QIIME2. Analysis of Compositions of Microbiomes with Bias Correction (ANCOM-BC) was utilised to identify differentially abundant taxa. No statistically significant differences were observed between SCZ patients and controls in terms of alpha-diversity (Shannon q = 0.09; Simpson q = 0.174) or beta-diversity (p = 0.547). Five taxa, namely Prevotella (p = 0.037), Faecalibacterium (p = 0.032), Phascolarctobacterium (p = 0.002), Dialister (p = 0.043), and SMB53 (p = 0.012), were differentially abundant in cases compared to controls, but this observation did not survive correction for multiple testing. This exploratory study suggests a potential association between the relative abundance of Prevotella, Faecalibacterium, Phascolarctobacterium, Dialister, and SMB53 with SCZ case-control status. Given the lack of significance after correcting for multiple testing, these results should be interpreted with caution. Mechanistic studies in larger samples are warranted to confirm these findings and better understand the association between the gut microbiome and SCZ.

PMID:40042645 | DOI:10.1007/s10048-025-00816-9

Elife. 2025 Mar 5;13:RP102986. doi: 10.7554/eLife.102986.

ABSTRACT

Outcomes can vary even when choices are repeated. Such ambiguity necessitates adjusting how much to learn from each outcome by tracking its variability. The medial prefrontal cortex (mPFC) has been reported to signal the expected outcome and its discrepancy from the actual outcome (prediction error), two variables essential for controlling the learning rate. However, the source of signals that shape these coding properties remains unknown. Here, we investigated the contribution of cholinergic projections from the basal forebrain because they carry precisely timed signals about outcomes. One-photon calcium imaging revealed that as mice learned different probabilities of threat occurrence on two paths, some mPFC cells responded to threats on one of the paths, while other cells gained responses to threat omission. These threat- and omission-evoked responses were scaled to the unexpectedness of outcomes, some exhibiting a reversal in response direction when encountering surprising threats as opposed to surprising omissions. This selectivity for signed prediction errors was enhanced by optogenetic stimulation of local cholinergic terminals during threats. The enhanced threat-evoked cholinergic signals also made mice erroneously abandon the correct choice after a single threat that violated expectations, thereby decoupling their path choice from the history of threat occurrence on each path. Thus, acetylcholine modulates the encoding of surprising outcomes in the mPFC to control how much they dictate future decisions.

PMID:40042523 | DOI:10.7554/eLife.102986

Elife. 2025 Mar 5;13:RP100949. doi: 10.7554/eLife.100949.

ABSTRACT

Root causal gene expression levels - or root causal genes for short - correspond to the initial changes to gene expression that generate patient symptoms as a downstream effect. Identifying root causal genes is critical towards developing treatments that modify disease near its onset, but no existing algorithms attempt to identify root causal genes from data. RNA-sequencing (RNA-seq) data introduces challenges such as measurement error, high dimensionality and non-linearity that compromise accurate estimation of root causal effects even with state-of-the-art approaches. We therefore instead leverage Perturb-seq, or high-throughput perturbations with single-cell RNA-seq readout, to learn the causal order between the genes. We then transfer the causal order to bulk RNA-seq and identify root causal genes specific to a given patient for the first time using a novel statistic. Experiments demonstrate large improvements in performance. Applications to macular degeneration and multiple sclerosis also reveal root causal genes that lie on known pathogenic pathways, delineate patient subgroups and implicate a newly defined omnigenic root causal model.

PMID:40042510 | DOI:10.7554/eLife.100949

Alzheimers Dement. 2025 Mar;21(3):e14493. doi: 10.1002/alz.14493.

ABSTRACT

INTRODUCTION: Late-life cognitive impairment and depression frequently co-occur and share many symptoms. However, the specific neural and clinical factors contributing to both their common and distinct profiles in older adults remain unclear.

METHODS: We investigated resting-state correlates of cognitive and depressive symptoms in older adults (n = 248 and n = 95) using clinical, blood, and neuroimaging data. We computed a connectivity matrix across default mode, executive control, and salience networks. Cross-validated elastic net regression identified features reflecting cognitive function and depressive symptoms. These features were validated on a held-out dataset.

RESULTS: We discovered that white matter hyperintensities and nine overlapping nodes spanning all three networks are associated with both cognitive function and depressive symptoms, including left amygdala, left hippocampus, and bilateral ventral tegmental area.

DISCUSSION: Our findings reveal intertwined neural nodes influencing cognitive impairment and depressive symptoms in late life, offering insights into shared characteristics and potential therapeutic targets.

HIGHLIGHTS: Resting-state neuroimaging markers are associated with symptoms of cognitive decline and late-life depression. Symptom-associated connectivity alterations were present across three major brain networks of interest, including the salience, default mode, and executive control networks. Some regions of interest are associated with both cognitive function and depressive symptoms, including the left amygdala, left hippocampus, and bilateral ventral tegmental area.

PMID:40042417 | DOI:10.1002/alz.14493

Cardiovasc Res. 2025 Mar 5:cvaf016. doi: 10.1093/cvr/cvaf016. Online ahead of print.

ABSTRACT

AIMS: Patients with chronic kidney disease (CKD) show a high risk of cardiovascular diseases, predominantly caused by accelerated vascular calcification. Vascular calcification is a highly regulated process with no current treatment. The vasoconstriction-inhibiting factor (VIF) peptide was recently discovered with vasoregulatory properties, but no information regarding calcification has been described.

METHODS AND RESULTS: In the present work, the inhibitory calcification effect of the VIF peptide was analysed in vitro in vascular smooth muscle cells (VSMCs), ex vivo in rat aortic rings, as well as in vivo in rats treated with vitamin D and nicotine (VDN). The VIF peptide inhibits vascular calcification by acting as a calcimimetic for the calcium-sensing receptor, increasing carboxylated matrix Gla protein production and blocking the activation of calcification pathways. The VIF peptide decreased calcium influx, the production of reactive oxygen species, and the activation of multiple kinases in VSMCs. Furthermore, calcium deposition in the aortas of patients with CKD negatively correlates with the VIF peptide concentration. Moreover, we show the cleavage of the VIF peptide from chromogranin-A by 'proprotein convertase subtilisin/kexin type 2' and 'carboxypeptidase E' enzymes. In addition, 'cathepsin K' degrades the VIF peptide. The active site of the native 35 amino acid-sequence long VIF peptide was identified with seven amino acids, constituting a promising drug candidate with promise for clinical translation.

CONCLUSION: The elucidation of the underlying mechanism by which the VIF peptide inhibits vascular calcification, as well as the active sequence and the cleavage and degradation enzymes, forms the basis for developing preventive and therapeutic measures to counteract vascular calcification.

PMID:40042167 | DOI:10.1093/cvr/cvaf016

Allergy. 2025 Mar 5. doi: 10.1111/all.16521. Online ahead of print.

NO ABSTRACT

PMID:40042067 | DOI:10.1111/all.16521

Acta Pharm Sin B. 2025 Jan;15(1):133-150. doi: 10.1016/j.apsb.2024.08.017. Epub 2024 Aug 24.

ABSTRACT

Pharmacotranscriptomic profiles, which capture drug-induced changes in gene expression, offer vast potential for computational drug discovery and are widely used in modern medicine. However, current computational approaches neglected the associations within gene‒gene functional networks and unrevealed the systematic relationship between drug efficacy and the reversal effect. Here, we developed a new genome-scale functional module (GSFM) transformation framework to quantitatively evaluate drug efficacy for in silico drug discovery. GSFM employs four biologically interpretable quantifiers: GSFM_Up, GSFM_Down, GSFM_ssGSEA, and GSFM_TF to comprehensively evaluate the multi-dimension activities of each functional module (FM) at gene-level, pathway-level, and transcriptional regulatory network-level. Through a data transformation strategy, GSFM effectively converts noisy and potentially unreliable gene expression data into a more dependable FM active matrix, significantly outperforming other methods in terms of both robustness and accuracy. Besides, we found a positive correlation between RSGSFM and drug efficacy, suggesting that RSGSFM could serve as representative measure of drug efficacy. Furthermore, we identified WYE-354, perhexiline, and NTNCB as candidate therapeutic agents for the treatment of breast-invasive carcinoma, lung adenocarcinoma, and castration-resistant prostate cancer, respectively. The results from in vitro and in vivo experiments have validated that all identified compounds exhibit potent anti-tumor effects, providing proof-of-concept for our computational approach.

PMID:40041913 | PMC:PMC11873659 | DOI:10.1016/j.apsb.2024.08.017

Front Endocrinol (Lausanne). 2025 Feb 18;16:1472754. doi: 10.3389/fendo.2025.1472754. eCollection 2025.

ABSTRACT

INTRODUCTION: Endocrine system disorders are a serious public health burden and can be caused by deleterious genetic variants in single genes or by the combined effects of multiple variants along with environmental and lifestyle factors.

METHODS: The EndoGene database presents the results of next-generation sequencing assays used to genetically profile 5,926 patients who were diagnosed with 450 endocrine and concomitant diseases and were examined and treated at the National Medical Research Center for Endocrinology between November 2017 and January 2024. Among them, 494, 1,785, 692, and 1,941 patients were profiled using four internally developed genetic panels including 220, 250, 376, and 382 genes, respectively, selected based on a literature analysis and clinical recommendations, and 1,245 patients were profiled by whole exome sequencing covering 31,969 genes.

RESULTS: 2,711 genetic variants were reported as clinically relevant by medical geneticists and are presented here along with genomic, technical, and clinical annotations.

DISCUSSION: This publicly accessible database will be useful to those interested in genetics, epidemiology, population statistics, and a better understanding of the molecular basis of endocrine disorders.

PMID:40041282 | PMC:PMC11876052 | DOI:10.3389/fendo.2025.1472754

Heliyon. 2025 Feb 14;11(4):e42719. doi: 10.1016/j.heliyon.2025.e42719. eCollection 2025 Feb 28.

ABSTRACT

Preventing exacerbations in Chronic Obstructive Pulmonary Disease (COPD) is crucial due to the high mortality rate and the associated costs of hospitalization for patients during exacerbations. Despite the proven influence of the lung microbiome on disease control, the dynamics of bacterial communication in different stages of COPD remain unknown. This study aimed to propose a group of candidate bacteria for the differential diagnosis of different states of COPD based on the relative abundance correlation of bacteria in lung sputum samples. We compared microbiome data collected from 101 COPD patients in stable and exacerbation states, as well as 124 healthy controls from two separate general cohorts, to determine the major microbiome and keystone genera. To validate our findings, we utilized two additional distinct public datasets, each comprising 81 healthy subjects and 87 COPD patients in stable condition, exacerbation, and post-treatment phases. During COPD exacerbation, Porphyromonas, Clostridium, Moryella, and Megasphaera were identified as phenotype-specific keystone genera, while Prevotella, Streptococcus, Haemophilus, and Veillonella were consistently present across all datasets as core microbiome members. Changes in keystone genera during different COPD stages indicate rewiring of bacterial interactions, with increased keystone bacteria and network connectivity observed during dysbiosis and more severe COPD. Bifidobacterium showed probiotic potential, positively correlating with Lactobacillus during exacerbation, while Neisseria and Haemophilus increased in abundance, and negatively correlated with key probiotic bacteria. These findings indicate promising potential for the simultaneous use of Bifidobacterium along with Lactobacillus as a therapeutic candidate to prevent COPD exacerbations in lung health, underscoring the need for further research in future clinical studies.

PMID:40040961 | PMC:PMC11876909 | DOI:10.1016/j.heliyon.2025.e42719

iScience. 2025 Feb 5;28(3):111961. doi: 10.1016/j.isci.2025.111961. eCollection 2025 Mar 21.

ABSTRACT

Existing research has proven difficult to understand the interplay between upstream signaling events during NLRP3 inflammasome activation. Additionally, events downstream of inflammasome complex formation such as cytokine release and pyroptosis can exhibit variation, further complicating matters. Cell Painting has emerged as a prominent tool for unbiased evaluation of the effect of perturbations on cell morphological phenotypes. Using this technique, phenotypic fingerprints can be generated that reveal connections between phenotypes and possible modes of action. To the best of our knowledge, this was the first study that utilized Cell Painting on human THP-1 macrophages to generate phenotypic fingerprints in response to different endogenous and exogenous NLRP3 inflammasome triggers and to identify phenotypic features specific to NLRP3 inflammasome complex formation. Our results demonstrated that not only can Cell Painting generate morphological fingerprints that are NLRP3 trigger-specific but it can also identify cellular fingerprints associated with NLRP3 inflammasome activation.

PMID:40040812 | PMC:PMC11876907 | DOI:10.1016/j.isci.2025.111961

Anal Chem. 2025 Mar 4. doi: 10.1021/acs.analchem.4c05138. Online ahead of print.

ABSTRACT

Therapy resistance in breast cancer is increasingly attributed to polyploid giant cancer cells (PGCCs), which arise through whole genome doubling and exhibit heightened resilience to standard treatments. Characterized by enlarged nuclei and increased DNA content, these cells tend to be dormant under therapeutic stress, driving disease relapse. Despite their critical role in resistance, strategies to effectively target PGCCs are limited, largely due to the lack of high-throughput methods for assessing their viability. Traditional assays lack the sensitivity needed to detect PGCC-specific elimination, prompting the development of novel approaches. To address this challenge, we developed a high-throughput single-cell morphological analysis workflow designed to differentiate compounds that selectively inhibit non-PGCCs, PGCCs, or both. Using this method, we screened a library of 2726 FDA Phase 1-approved drugs, identifying promising anti-PGCC candidates, including proteasome inhibitors, FOXM1, CHK, and macrocyclic lactones. Notably, RNA-Seq analysis of cells treated with the macrocyclic lactone Pyronaridine revealed AXL inhibition as a potential strategy for targeting PGCCs. Although our single-cell morphological analysis pipeline is powerful, empirical testing of all existing compounds is impractical and inefficient. To overcome this limitation, we trained a machine learning model to predict anti-PGCC efficacy in silico, integrating chemical fingerprints and compound descriptions from prior publications and databases. The model demonstrated a high correlation with experimental outcomes and predicted efficacious compounds in an expanded library of over 6,000 drugs. Among the top-ranked predictions, we experimentally validated five compounds as potent PGCC inhibitors using cell lines and patient-derived models. These findings underscore the synergistic potential of integrating high-throughput empirical screening with machine learning-based virtual screening to accelerate the discovery of novel therapies, particularly for targeting therapy-resistant PGCCs in breast cancer.

PMID:40040372 | DOI:10.1021/acs.analchem.4c05138

Annu Int Conf IEEE Eng Med Biol Soc. 2024 Jul;2024:1-4. doi: 10.1109/EMBC53108.2024.10782823.

ABSTRACT

Tuberculosis, caused by Mycobacterium tuberculosis (Mtb), is a highly infectious disease mainly affecting the lungs. Macrophages are key phagocytic immune cells and the preferred hosts for intracellular bacteria growth. Macrophages are also important sites of vitamin D3 synthesis, with vitamin D3 deficiency associated with increased risk of developing active TB. There is great interest in vitamin D3 as adjunctive therapy due to its immunomodulatory and antimicrobial properties, particularly the effect on proinflammatory effectors like bactericidal nitric oxide (NO). NO production requires inducible nitric oxide synthase expression, which is regulated by IFN-γ, a pro-inflammatory cytokine upregulated by IL-12. Vitamin D3 serves an important host protective function to regulate NO production to a level that is sufficient to restrict Mtb growth while avoiding uncontrolled inflammation. While previous in vitro studies have shown that vitamin D3 modulates NO levels and IL-12, in an infection dose-dependent manner, to date, there are no computational models that capture the mechanisms by which vitamin D3 regulates NO production during high and low Mtb infection. Using an integrative systems biology approach, we define key signaling pathways involved in vitamin D3 immunometabolism and determine the impact of vitamin D3 sufficiency/deficiency given infection dosage. Data from multiple computational models and in vitro infection studies are integrated into a mechanistic model, and simulation results compared to in vitro IL-12 and NO concentrations from our in vitro models of infection. Concurrence between our in-silico and in vitro models demonstrates the feasibility of NO modulation in a vitamin D3 and infection level dependent manner.

PMID:40039981 | DOI:10.1109/EMBC53108.2024.10782823

Plant J. 2025 Mar;121(5):e70046. doi: 10.1111/tpj.70046.

ABSTRACT

Spider mites (Tetranychus urticae) are a major threat to economically important crops. Here, we investigated the potential of tetranins, in particular Tet3 and Tet4, as T. urticae protein-type elicitors that stimulate plant defense. Truncated Tet3 and Tet4 proteins showed efficacy in activating the defense gene pathogenesis-related 1 (PR1) and inducing phytohormone production in leaves of Phaseolus vulgaris. In particular, Tet3 caused a drastically higher Ca2+ influx in leaves, but a lower reactive oxygen species (ROS) generation compared to other tetranins, whereas Tet4 caused a low Ca2+ influx and a high ROS generation in the host plants. Such specific and non-specific elicitor activities were examined by knockdown of Tet3 and Tet4 expressions in mites, confirming their respective activities and in particular showing that they function additively or synergistically to induce defense responses. Of great interest is the fact that Tet3 and Tet4 expression levels were higher in mites on their preferred host, P. vulgaris, compared to the levels in mites on the less-preferred host, Cucumis sativus, whereas Tet1 and Tet2 were constitutively expressed regardless of their host. Furthermore, mites that had been hosted on C. sativus induced lower levels of PR1 expression, Ca2+ influx and ROS generation, i.e., Tet3- and Tet4-responsive defense responses, in both P. vulgaris and C. sativus leaves compared to the levels induced by mites that had been hosted on P. vulgaris. Taken together, these findings show that selected tetranins respond to variable host cues that may optimize herbivore fitness by altering the anti-mite response of the host plant.

PMID:40038832 | DOI:10.1111/tpj.70046

Stem Cell Res Ther. 2025 Mar 5;16(1):111. doi: 10.1186/s13287-025-04144-5.

ABSTRACT

BACKGROUND: Rheumatoid arthritis (RA) is a chronic autoimmune disease and the integrity of CX3CR1+ synovial macrophage barrier significantly impacts its progression. However, the mechanisms driving the dynamic changes of this macrophage barrier remain unclear. Traditional drug therapies for RA have substantial limitations. Mesenchymal stem cells (MSCs)-based cell therapy, especially adipose-derived stem cells (ADSCs), hold therapeutic promise. Nevertheless, the underlying therapeutic mechanism of ADSCs, especially their interactions with CX3CR1+ macrophages, require further investigation.

METHODS: To explore the interaction between ADSCs and CX3CR1+ synovial macrophages during barrier reconstruction, underlying the therapeutic mechanism of ADSCs and the mechanisms on the dynamic changes of the macrophage barrier, scRNA-seq analysis was conducted 4 days after ADSCs injection in serum transfer-induced arthritis model mice. The roles of mitochondria transfer and ADSCs transplantation were also explored. Bulk RNA-seq analysis was performed after the co-culture of ADSCs and CX3CR1+ synovial macrophages. To study the in vivo fate of ADSCs, bulk RNA-seq was performed on ADSCs retrieved at 0, 2, 4, and 7 days post-injection.

RESULTS: Intra-articular injection of ADSCs effectively attenuated the pathological progression of mice with serum transfer-induced arthritis. ADSCs gradually adhered to CX3CR1+ macrophages, facilitating the restore of the macrophage barrier, while the absence of this barrier greatly weakened the therapeutic effect of ADSCs. scRNA-seq analysis revealed an Atf3high Ccl3high subset of CX3CR1+ macrophages with impaired oxidative phosphorylation that increased during RA progression. ADSCs-mediated reduction of this subset appeared to be linked to mitochondrial transfer, and transplantation of isolated ADSCs-derived mitochondria also proved effective in treating RA. Both bulk RNA-seq and scRNA-seq analyses revealed multiple interaction mechanisms between ADSCs and CX3CR1+ macrophages, including Cd74/Mif axis and GAS6/MERTK axis, which contribute to barrier restoration and therapeutic effects. Furthermore, bulk RNA-seq analysis showed that ADSCs primarily contribute to tissue repair and immune regulation subsequently.

CONCLUSIONS: Our results suggest that ADSCs ameliorated the energy metabolism signature of CX3CR1+ lining macrophages and may promote barrier restoration through mitochondria transfer. In addition, we elucidated the fate of ADSCs and the therapeutic potential of mitochondria in RA treatment.

PMID:40038808 | DOI:10.1186/s13287-025-04144-5

BMC Genomics. 2025 Mar 4;26(1):215. doi: 10.1186/s12864-025-11250-4.

ABSTRACT

BACKGROUND: Integrating germplasm populations genotyped by different genotyping platforms via genotype imputation is a way to utilize accumulated genetic resources. In this study, we used 278 canola samples genotyped via whole-genome sequencing (WGS) at 10× coverage to evaluate the imputation accuracy of three imputation approaches. The optimal imputation methods were used to impute and integrate two Canola genotype datasets: a diverse canola collection genotyped by genotyping-by-sequencing via transcriptome (GBS-t) and a double haploid (DH) line collection genotyped with low-coverage WGS (skim-WGS). The genomic predictive ability (GP) and detection power of marker‒trait association (GWAS) of the combined population for blackleg resistance were evaluated.

RESULTS: The empirical imputation accuracy (r2) measured as the squared correlation between observed and imputed genotypes was moderate for Minimac3 when imputing from the GBS-t density to the WGS. The accuracy dramatically improved from 0.64 to 0.82 by removing SNPs with poor Minimac3-reported Rsq (Rsq < 0.2) quality statistics. The r2 for GLIMPSE was higher than that for Beagle when imputing from different low-coverage to full-coverage WGS. We imputed and integrated the diverse canola collection and the DH lines, and the combined population showed similar or slightly greater predictive ability (PA) for blackleg resistance traits than did each of the single populations with ~ 921 K SNPs. Higher marker-trait association (MTA) detection powers were indicated with the combined population; however, similar numbers of MTAs were discovered when each single population was combined in a meta-GWAS.

CONCLUSION: It is feasible to impute and integrate germplasms from different sequencing platforms for downstream analyses. However, genetic heterogeneity across populations could add complexity to the analysis. Increasing the sample size by combining datasets showed slightly greater predictive ability and greater detection power in GWASs in the present study.

PMID:40038585 | DOI:10.1186/s12864-025-11250-4

Commun Biol. 2025 Mar 4;8(1):361. doi: 10.1038/s42003-025-07796-4.

ABSTRACT

Chromosomal instability (CIN) is a hallmark of cancer that drives metastasis, immune evasion and treatment resistance. CIN may result from chromosome mis-segregation errors and excessive chromatin is frequently packaged in micronuclei (MN), which can be enumerated to quantify CIN. The assessment of CIN remains a predominantly manual and time-consuming task. Here, we present micronuclAI, a pipeline for automated and reliable quantification of MN of varying size and morphology in cells stained only for DNA. micronuclAI can achieve close to human-level performance on various human and murine cancer cell line datasets. The pipeline achieved a Pearson's correlation of 0.9278 on images obtained at 10X magnification. We tested the approach in otherwise isogenic cell lines in which we genetically dialed up or down CIN rates, and on several publicly available image datasets where we achieved a Pearson's correlation of 0.9620. Given the increasing interest in developing therapies for CIN-driven cancers, this method provides an important, scalable, and rapid approach to quantifying CIN on images that are routinely obtained for research purposes. We release a GUI-implementation for easy access and utilization of the pipeline.

PMID:40038430 | DOI:10.1038/s42003-025-07796-4

Geroscience. 2025 Mar 4. doi: 10.1007/s11357-025-01571-3. Online ahead of print.

ABSTRACT

A significant challenge in multi-omic geroscience research is the collection of high quality, fit-for-purpose biospecimens from a diverse and well-characterized study population with sufficient sample size to detect age-related changes in physiological biomarkers. The Dog Aging Project designed the precision cohort to study the mechanisms underlying age-related change in the metabolome, microbiome, and epigenome in companion dogs, an emerging model system for translational geroscience research. One thousand dog-owner pairs were recruited into cohort strata based on life stage, sex, size, and geography. We designed and built a novel implementation of the REDCap electronic data capture system to manage study participants, logistics, and biospecimen and survey data collection in a secure online platform. In collaboration with primary care veterinarians, we collected and processed blood, urine, fecal, and hair samples from 976 dogs. The resulting data include complete blood count, chemistry profile, immunophenotyping by flow cytometry, metabolite quantification, fecal microbiome characterization, epigenomic profile, urinalysis, and associated metadata characterizing sample conditions at collection and during lab processing. The project, which has already begun collecting second- and third-year samples from precision cohort dogs, demonstrates that scientifically useful biospecimens can be collected from a geographically dispersed population through collaboration with private veterinary clinics and downstream labs. The data collection infrastructure developed for the precision cohort can be leveraged for future studies. Most important, the Dog Aging Project is an open data project. We encourage researchers around the world to apply for data access and utilize this rich, constantly growing dataset in their own work.

PMID:40038157 | DOI:10.1007/s11357-025-01571-3

Plant Cell. 2025 Mar 4:koaf041. doi: 10.1093/plcell/koaf041. Online ahead of print.

ABSTRACT

Powdery mildews are obligate biotrophic fungi that manipulate plant metabolism to supply lipids to the fungus, particularly during fungal asexual reproduction when lipid demand is high. We found levels of leaf storage lipids (triacylglycerols, TAGs) are 3.5-fold higher in whole Arabidopsis (Arabidopsis thaliana) leaves with a 15-fold increase in storage lipids at the infection site during fungal asexual reproduction. Lipid bodies, not observable in uninfected mature leaves, were found in and external to chloroplasts in mesophyll cells underlying the fungal feeding structure. Concomitantly, thylakoid disassembly occurred and thylakoid membrane lipid levels decreased. Genetic analyses showed that canonical endoplasmic reticulum TAG biosynthesis does not support powdery mildew spore production. Instead, Arabidopsis chloroplast-localized DIACYLGLYCEROL ACYLTRANSFERASE 3 (DGAT3) promoted fungal asexual reproduction. Consistent with the reported AtDGAT3 preference for 18:3 and 18:2 acyl substrates, which are dominant in thylakoid membrane lipids, dgat3 mutants exhibited a dramatic reduction in powdery mildew-induced chloroplast TAGs, attributable to decreases in TAG species largely comprised of 18:3 and 18:2 acyl substrates. This pathway for TAG biosynthesis in the chloroplast at the expense of thylakoids provides insights into obligate biotrophy and plant lipid metabolism, plasticity and function. By understanding how photosynthetically active leaves can be converted into TAG producers, more sustainable and environmentally friendly plant oil production may be developed.

PMID:40037697 | DOI:10.1093/plcell/koaf041

Plant Physiol. 2025 Mar 4:kiaf066. doi: 10.1093/plphys/kiaf066. Online ahead of print.

NO ABSTRACT

PMID:40037614 | DOI:10.1093/plphys/kiaf066

G3 (Bethesda). 2025 Mar 3:jkaf047. doi: 10.1093/g3journal/jkaf047. Online ahead of print.

ABSTRACT

Genetic suppression occurs when the phenotypic defects caused by a deleterious mutation are rescued by another mutation. Suppression interactions are of particular interest for genetic diseases, as they identify ways to reduce disease severity, thereby potentially highlighting avenues for therapeutic intervention. To what extent suppression interactions are influenced by the genetic background in which they operate remains largely unknown. However, a high degree of suppression conservation would be crucial for developing therapeutic strategies that target suppressors. To gain an understanding of the effect of the genetic context on suppression, we isolated spontaneous suppressor mutations of temperature sensitive alleles of SEC17, TAO3, and GLN1 in three genetically diverse natural isolates of the budding yeast Saccharomyces cerevisiae. After identifying and validating the genomic variants responsible for suppression, we introduced the suppressors in all three genetic backgrounds, as well as in a laboratory strain, to assess their specificity. Ten out of eleven tested suppression interactions were conserved in the four yeast strains, although the extent to which a suppressor could rescue the temperature sensitive mutant varied across genetic backgrounds. These results suggest that suppression mechanisms are highly conserved across genetic contexts, a finding that is potentially reassuring for the development of therapeutics that mimic genetic suppressors.

PMID:40037589 | DOI:10.1093/g3journal/jkaf047