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

Plant Physiol. 2025 Mar 4:kiaf064. doi: 10.1093/plphys/kiaf064. Online ahead of print.

NO ABSTRACT

PMID:40037583 | DOI:10.1093/plphys/kiaf064

Open Biol. 2025 Mar;15(3):240231. doi: 10.1098/rsob.240231. Epub 2025 Mar 5.

ABSTRACT

The lung microbiome has recently gained attention for potentially affecting respiratory viral infections, including influenza A virus, respiratory syncytial virus (RSV) and SARS-CoV-2. We will discuss the complexities of the lung microenvironment in the context of viral infections and the use of organ-on-chip (OoC) models in replicating the respiratory tract milieu to aid in understanding the role of temporary microbial colonization. Leveraging the innovative capabilities of OoC, particularly through integrating gut and lung models, opens new avenues to understand the mechanisms linking inter-organ crosstalk and respiratory infections. We will discuss technical aspects of OoC lung models, ranging from the selection of cell substrates for extracellular matrix mimicry, mechanical strain, breathing mechanisms and air-liquid interface to the integration of immune cells and use of microscopy tools for algorithm-based image analysis and systems biology to study viral infection in vitro. OoC offers exciting new options to study viral infections across host species and to investigate human cellular physiology at a personalized level. This review bridges the gap between complex biological phenomena and the technical prowess of OoC models, providing a comprehensive roadmap for researchers in the field.

PMID:40037530 | DOI:10.1098/rsob.240231

J Clin Endocrinol Metab. 2025 Mar 3:dgaf131. doi: 10.1210/clinem/dgaf131. Online ahead of print.

ABSTRACT

CONTEXT: Tangier disease (TD) is a rare, autosomal recessive genetic disorder associated with a deficiency in cellular cholesterol export leading to cholesterol accumulation in peripheral tissues. With approximately 150 described cases, the disease is significantly understudied, and the clinical presentation appears to be heterogenous.

OBJECTIVE: To investigate the phenotype and lipid metabolism in TD.

DESIGN: Multicenter cohort study.

PATIENTS: Four patients with TD.

MAIN OUTCOME MEASURES: Nuclear magnetic resonance (NMR)-based lipidomic and metabolomic analyses were performed in patients with TD and healthy controls.

RESULTS: While showing similar laboratory patterns with respect to high-density lipoprotein depletion, the clinical phenotypes of four TD patients were heterogenous with two patients diagnosed at 47 and 72 years having predominantly gastrointestinal and neurological phenotypes. Two previously undescribed variants (c.2418G>A, c.5055.del) were reported.Apart from pathognomonic changes in HDL composition, NMR spectroscopy revealed an increased abundance of VLDL with higher total lipid and cholesterol concentrations, pointing towards an impaired clearance of triglyceride-rich lipoproteins. Increased triglyceride-rich IDL supports impaired hepatic lipase activity, together with a CETP-mediated increase in LDL-triglycerides at higher abundance of large LDL subtypes and decreased small dense LDL.The lipid composition of HDL particles and LDL-1/LDL-4 remained the strongest differentiating factors as compared to healthy controls.

CONCLUSIONS: Clinical phenotypes of TD can be heterogeneous including gastrointestinal and neurological manifestations. Impaired triglyceride-rich lipoprotein clearance and hepatic lipase activity could be a pathophysiological hallmark of TD.

PMID:40037526 | DOI:10.1210/clinem/dgaf131

Prog Neuropsychopharmacol Biol Psychiatry. 2025 Mar 2:111309. doi: 10.1016/j.pnpbp.2025.111309. Online ahead of print.

ABSTRACT

BACKGROUND: The diagnosis and treatment of Alzheimer's disease (AD) is challenging due to the complexity of its pathogenesis. Although research suggests a link between circulating metabolites and AD, their causal relationship is not fully understood.

METHODS: Based on publicly available genome-wide association study data, we investigated the causative relationship between AD (7759 cases and 334,740 controls) and 233 traits describing circulating metabolites (136,016 participants) using a two-sample Mendelian randomization (MR) method. We adopted the inverse variance weighted approach as the priority and performed sensitivity analyses with MR-Egger intercept method and Cochran's Q test.

RESULTS: The overall causal effect of circulating metabolic traits on AD was significantly higher than the inverse effect (beta: 0.15 ± 0.42 vs. 0.04 ± 0.07; p < 0.05). A total of 72 circulating metabolic traits (odd ratio (OR): 1.16-2.48) had a significant positive causal effect on AD, while a total of 16 circulating metabolic traits with significant negative causal effects on AD were detected (OR: 0.38-0.88). AD had a significant positive causal effect (OR: 1.02-1.17) on 142 circulating metabolic traits and a negative causal effect (OR: 0.87-0.99) on 43 circulating metabolic traits. Circulating metabolites that have a bi-directional causative relationship with AD mainly include apolipoprotein B levels, total cholesterol levels, total triglycerides levels, and omega-6 fatty acids levels.

CONCLUSION: The causative relationship between AD and the circulating metabolic traits is complex and bidirectional. Analyzing metabolites causally involved in the development of AD may provide clues for identifying preventive and therapeutic targets for this disorder.

PMID:40037511 | DOI:10.1016/j.pnpbp.2025.111309

Neuron. 2025 Feb 25:S0896-6273(25)00076-5. doi: 10.1016/j.neuron.2025.01.028. Online ahead of print.

ABSTRACT

In this NeuroView, we discuss challenges and best practices when dealing with disease-detection AI models that are trained on heterogeneous clinical data, focusing on the interrelated problems of model bias, causality, and rare diseases.

PMID:40037359 | DOI:10.1016/j.neuron.2025.01.028

Cell Host Microbe. 2025 Feb 26:S1931-3128(25)00053-8. doi: 10.1016/j.chom.2025.02.005. Online ahead of print.

ABSTRACT

Diarrhea is the predominant symptom of acute gastroenteritis resulting from enteric infections and a leading cause of death in infants and young children. However, the role of the host response in diarrhea pathogenesis is unclear. Using rotavirus and neonatal mice as a model, we found that oral inoculation of UV-inactivated replication-defective rotavirus consistently induced watery diarrhea by robust activation of cytosolic double-stranded RNA sensing pathways and type III interferon (IFN-λ) secretion. Diarrhea was significantly diminished in mice lacking the IFN-λ receptor. Mechanistically, IFN-λ signaling downregulates the expression of Dra, a chloride and bicarbonate exchanger, which contributes to reduced water absorption. We confirmed these findings in mice inoculated with reovirus, as well as in donor-derived human intestinal organoids and human biopsy samples. Our data highlight a mechanism of rapid diarrhea induction by host innate immune sensing in the gastrointestinal tract and suggest that diarrhea induction is an active host defense strategy to eliminate the pathogen.

PMID:40037352 | DOI:10.1016/j.chom.2025.02.005

G3 (Bethesda). 2025 Feb 28:jkaf045. doi: 10.1093/g3journal/jkaf045. Online ahead of print.

ABSTRACT

During mammalian reproduction, sperm are delivered to the female reproductive tract bathed in a complex medium known as seminal fluid, which plays key roles in signaling to the female reproductive tract and in nourishing sperm for their onwards journey. Along with minor contributions from the prostate and the epididymis, the majority of seminal fluid is produced by a somewhat understudied organ known as the seminal vesicle. Here, we report the first single-cell RNA-seq atlas of the mouse seminal vesicle, generated using tissues obtained from 23 mice of varying ages, exposed to a range of dietary challenges. We define the transcriptome of the secretory cells in this tissue, identifying a relatively homogeneous population of the epithelial cells which are responsible for producing the majority of seminal fluid. We also define the immune cell populations - including large populations of macrophages, dendritic cells, T cells, and NKT cells - which have the potential to play roles in producing the various immune mediators present in seminal plasma. Together, our data provide a resource for understanding the composition of an understudied reproductive tissue, with potential implications for paternal control of offspring development and metabolism.

PMID:40036847 | DOI:10.1093/g3journal/jkaf045

J Proteome Res. 2025 Mar 4. doi: 10.1021/acs.jproteome.4c00795. Online ahead of print.

ABSTRACT

A nanosheath-flow capillary electrophoresis mass spectrometry (CE-MS) system with electrospray ionization was used to profile cationic metabolite cargo in exosomes secreted by nontumorigenic MCF-10A and tumorigenic MDA-MB-231 breast epithelial cells. An in-house-produced sheath liquid interface was developed and machined from PEEK to enable nanoflow volumes. Normalization of CE-MS peak areas to the total UV signal was employed to enhance quantitative accuracy and reduce variability. CE-MS-based metabolomics revealed increased purine synthesis intermediates and increased carnitine synthesis metabolites in MDA-MB-231-derived exosomes, with pathway enrichment indicating the activation of de novo purine pathways and upregulation of carnitine metabolism. In addition, nano-LC-MS-based proteomics revealed differential expression of ecto-5'-nucleotidase (NT5E) and mitochondrial aldehyde dehydrogenase (ALDH9A1), demonstrating metabolic alterations in related enzymatic steps. This study demonstrates the application of nanosheath-flow CE-MS for comprehensive and quantitative exosome metabolomics, uncovering metabolic reprogramming in purine and carnitine pathways between normal and cancerous breast cell lines and providing insight into exosome-mediated signaling of breast cancer metabolism.

PMID:40036676 | DOI:10.1021/acs.jproteome.4c00795

J Proteome Res. 2025 Mar 4. doi: 10.1021/acs.jproteome.4c00968. Online ahead of print.

ABSTRACT

Liquid chromatography-tandem mass spectrometry employing data-dependent acquisition (DDA) is a mature, widely used proteomics technique routinely applied to proteome profiling, protein-protein interaction studies, biomarker discovery, and protein modification analysis. Numerous tools exist for searching DDA data and myriad file formats are output as results. While some search and post processing tools include data visualization features to aid biological interpretation, they are often limited or tied to specific software pipelines. This restricts the accessibility, sharing and interpretation of data, and hinders comparison of results between different software pipelines. We developed Limelight, an easy-to-use, open-source, freely available tool that provides data sharing, analysis and visualization and is not tied to any specific software pipeline. Limelight is a data visualization tool specifically designed to provide access to the whole "data stack", from raw and annotated scan data to peptide-spectrum matches, quality control, peptides, proteins, and modifications. Limelight is designed from the ground up for sharing and collaboration and to support data from any DDA workflow. We provide tools to import data from many widely used open-mass and closed-mass search software workflows. Limelight helps maximize the utility of data by providing an easy-to-use interface for finding and interpreting data, all using the native scores from respective workflows.

PMID:40036265 | DOI:10.1021/acs.jproteome.4c00968

Proc Natl Acad Sci U S A. 2025 Mar 11;122(10):e2420499122. doi: 10.1073/pnas.2420499122. Epub 2025 Mar 4.

ABSTRACT

Cardiomyocyte hypertrophy is a key clinical predictor of heart failure. High-throughput and AI-driven screens have the potential to identify drugs and downstream pathways that modulate cardiomyocyte hypertrophy. Here, we developed LogiRx, a logic-based mechanistic machine learning method that predicts drug-induced pathways. We applied LogiRx to discover how drugs discovered in a previous compound screen attenuate cardiomyocyte hypertrophy. We experimentally validated LogiRx predictions in neonatal cardiomyocytes, adult mice, and two patient databases. Using LogiRx, we predicted antihypertrophic pathways for seven drugs currently used to treat noncardiac disease. We experimentally validated that escitalopram (Lexapro) and mifepristone inhibit hypertrophy of cultured cardiomyocytes in two contexts. The LogiRx model predicted that escitalopram prevents hypertrophy through an "off-target" serotonin receptor/PI3Kγ pathway, mechanistically validated using additional investigational drugs. Further, escitalopram reduced cardiomyocyte hypertrophy in a mouse model of hypertrophy and fibrosis. Finally, mining of both FDA and University of Virginia databases showed that patients with depression on escitalopram have a lower incidence of cardiac hypertrophy than those prescribed other serotonin reuptake inhibitors that do not target the serotonin receptor. Mechanistic machine learning by LogiRx discovers drug pathways that perturb cell states, which may enable repurposing of escitalopram and other drugs to limit cardiac remodeling through off-target pathways.

PMID:40035765 | DOI:10.1073/pnas.2420499122

FASEB J. 2025 Mar 15;39(5):e70443. doi: 10.1096/fj.202403156R.

ABSTRACT

AGGF1 encodes an angiogenic factor that causes vascular disease Klippel-Trenaunay syndrome when mutated. AGGF1 also acts at the top of the genetic regulatory hierarchy for mesodermal differentiation of hemangioblasts, multipotent stem cells for differentiation of blood cells and vascular cells. Alternative splicing (AS) is a post-transcriptional process that generates multiple mature mRNAs from a single primary transcript (pre-mRNA), producing protein diversity. Deregulation of AS leads to many human diseases. The physiological role and mechanism of AGGF1 in AS are not clear. Full-length transcriptome sequencing of human pulmonary artery endothelial cells (HPAECs) with AGGF1 silencing revealed 63 121 genes, including 1144 new unannotated genes, and showed that AGGF1 is a general splicing factor regulating AS of 436 genes, including SRSF6 regulating AS of many target genes. AGGF1 promoted the skipping of exon 3 that produces the full-length SRSF6 protein, an evolutionarily conserved AS event. Overexpression of full-length SRSF6 reversed the reduced cell proliferation, migration, and capillary tube formation of HPAECs with AGGF1 silencing. Knockdown of SRSF6 and overexpression of the shorter, alternatively spliced isoform of SRSF6 both inhibited HPAEC proliferation, migration, and capillary tube formation, whereas opposite results were obtained for overexpression of full-length SRSF6. Knockdown of srsf6 impaired development of ISVs in zebrafish, whereas overexpression of srsf6 enhanced vascular development and partially rescued impaired ISV development in zebrafish embryos with aggf1 knockdown. Overall, our findings reveal that AGGF1 is a general splicing factor, and that AGGF1-mediated exon 3 skipping of SRSF6 pre-mRNA is important for endothelial cell functions, angiogenesis, and vascular development.

PMID:40035560 | DOI:10.1096/fj.202403156R

Biotechnol Rep (Amst). 2025 Feb 9;45:e00882. doi: 10.1016/j.btre.2025.e00882. eCollection 2025 Mar.

ABSTRACT

Quality by design (QbD) is applied to the upstream process to maximize the RBD-Fc fusion protein production in CHO cells. The three factors (culture duration, temperature, and polyethyleneimine to plasmid DNA (PEI-Max/pDNA) ratio) were identified as critical process attributes based on risk analysis (FMEA) and further optimized by response surface to maximize the protein yields. Using a Box-Behnken design, the optimal conditions for RBD-Fc production were determined to be a culture duration of 5 days, a culture temperature of 34.4 °C, and a PEI-Max/pDNA ratio of 4.2:1 (w/w) with a predictive value of 48 mg/L (desirability of 92.8 %). The PEI-Max/pDNA ratio and its interaction with culture duration to express the highest yield (47.78 ± 2.30 mg/l). In addition, the purified CHO-produced RBD-Fc fusion protein was highly pure and strongly bound to its receptor, ACE2. Our finding demonstrated that the QBD tools can identify the critical parameters to facilitate scaling-up production.

PMID:40034964 | PMC:PMC11872631 | DOI:10.1016/j.btre.2025.e00882

J Pharm Anal. 2025 Feb;15(2):101047. doi: 10.1016/j.jpha.2024.101047. Epub 2024 Jul 25.

ABSTRACT

Image 1.

PMID:40034864 | PMC:PMC11874559 | DOI:10.1016/j.jpha.2024.101047

Front Immunol. 2025 Feb 17;16:1488851. doi: 10.3389/fimmu.2025.1488851. eCollection 2025.

ABSTRACT

We describe the establishment and current content of the ImmuneCODE™ database, which includes hundreds of millions of T-cell Receptor (TCR) sequences from over 1,400 subjects exposed to or infected with the SARS-CoV-2 virus, as well as over 160,000 high-confidence SARS-CoV-2-associated TCRs. This database is made freely available, and the data contained in it can be used to assist with global efforts to understand the immune response to the SARS-CoV-2 virus and develop new interventions.

PMID:40034696 | PMC:PMC11873104 | DOI:10.3389/fimmu.2025.1488851

Bioinform Biol Insights. 2025 Mar 2;19:11779322241271565. doi: 10.1177/11779322241271565. eCollection 2025.

ABSTRACT

Breast cancer is a highly heterogeneous disorder characterized by dysregulated expression of number of genes and their cascades. It is one of the most common types of cancer in women posing serious health concerns globally. Recent developments and discovery of specific prognostic biomarkers have enabled its application toward developing personalized therapies. The basic premise of this study was to investigate key signature genes and signaling pathways involved in triple-negative breast cancer using bioinformatics approach. Microarray data set GSE65194 from the National Center for Biotechnology Information (NCBI) Gene Expression Omnibus was used for identification of differentially expressed genes (DEGs) using R software. Gene ontology and Kyoto Encyclopedia of Genes and Genome (KEGG) pathway enrichment analyses were carried out using the ClueGO plugin in Cytoscape software. The up-regulated DEGs were primarily engaged in the regulation of cell cycle, overexpression of spindle assembly checkpoint, and so on, whereas down-regulated DEGs were employed in alteration to major signaling pathways and metabolic reprogramming. The hub genes were identified using cytoHubba from protein-protein interaction (PPI) network for top up-regulated and down-regulated DEG's plugin in Cytoscape software. The hub genes were validated as potential signature biomarkers by evaluating the overall survival percentage in breast cancer patients.

PMID:40034579 | PMC:PMC11873876 | DOI:10.1177/11779322241271565

Synth Syst Biotechnol. 2025 Feb 8;10(2):511-522. doi: 10.1016/j.synbio.2025.02.002. eCollection 2025 Jun.

ABSTRACT

Corynebacterium glutamicum is a versatile industrial microorganism for producing various amino acids. However, there have been no reports of well-defined C. glutamicum strains capable of hyperproducing l-tryptophan. This study presents a comprehensive metabolic engineering approach to establish robust C. glutamicum strains for l-tryptophan biosynthesis, including: (1) identification of potential targets by enzyme-constrained genome-scale modeling; (2) enhancement of the l-tryptophan biosynthetic pathway; (3) reconfiguration of central metabolic pathways; (4) identification of metabolic bottlenecks through comparative metabolome analysis; (5) engineering of the transport system, shikimate pathway, and precursor supply; and (6) repression of competing pathways and iterative optimization of key targets. The resulting C. glutamicum strain achieved a remarkable l-tryptophan titer of 50.5 g/L in 48h with a yield of 0.17 g/g glucose in fed-batch fermentation. This study highlights the efficacy of integrating computational modeling with systems metabolic engineering for significantly enhancing the production capabilities of industrial microorganisms.

PMID:40034180 | PMC:PMC11872490 | DOI:10.1016/j.synbio.2025.02.002

ArXiv [Preprint]. 2025 Feb 21:arXiv:2502.15597v1.

ABSTRACT

Guidelines for managing scientific data have been established under the FAIR principles requiring that data be Findable, Accessible, Interoperable, and Reusable. In many scientific disciplines, especially computational biology, both data and models are key to progress. For this reason, and recognizing that such models are a very special type of 'data', we argue that computational models, especially mechanistic models prevalent in medicine, physiology and systems biology, deserve a complementary set of guidelines. We propose the CURE principles, emphasizing that models should be Credible, Understandable, Reproducible, and Extensible. We delve into each principle, discussing verification, validation, and uncertainty quantification for model credibility; the clarity of model descriptions and annotations for understandability; adherence to standards and open science practices for reproducibility; and the use of open standards and modular code for extensibility and reuse. We outline recommended and baseline requirements for each aspect of CURE, aiming to enhance the impact and trustworthiness of computational models, particularly in biomedical applications where credibility is paramount. Our perspective underscores the need for a more disciplined approach to modeling, aligning with emerging trends such as Digital Twins and emphasizing the importance of data and modeling standards for interoperability and reuse. Finally, we emphasize that given the non-trivial effort required to implement the guidelines, the community moves to automate as many of the guidelines as possible.

PMID:40034129 | PMC:PMC11875277

New Phytol. 2025 Mar 3. doi: 10.1111/nph.20446. Online ahead of print.

ABSTRACT

Drought stress imposes severe challenges on agriculture by impacting crop performance. Understanding drought responses in plants at a cellular level is a crucial first step toward engineering improved drought resilience. However, the molecular responses to drought are complex as they depend on multiple factors, including the severity of drought, the profiled organ, its developmental stage or even the cell types therein. Thus, deciphering the transcriptional responses to drought is especially challenging. In this study, we investigated tissue-specific responses to mild drought (MD) in young Arabidopsis thaliana (Arabidopsis) leaves using single-cell RNA sequencing (scRNA-seq). To preserve transcriptional integrity during cell isolation, we inhibited RNA synthesis using the transcription inhibitor actinomycin D, and demonstrated the benefits of transcriptome fixation for studying mild stress responses at a single-cell level. We present a curated and validated single-cell atlas, comprising 50 797 high-quality cells from almost all known cell types present in the leaf. All cell type annotations were validated with a new library of reporter lines. The curated data are available to the broad community in an intuitive tool and a browsable single-cell atlas (http://www.single-cell.be/plant/leaf-drought). We show that the mesophyll contains two spatially separated cell populations with distinct responses to drought: one enriched in canonical abscisic acid-related drought-responsive genes, and another one enriched in genes involved in iron starvation responses. Our study thus reveals a dual adaptive mechanism of the leaf mesophyll in response to MD and provides a valuable resource for future research on stress responses.

PMID:40033544 | DOI:10.1111/nph.20446