Stem Cell Reports. 2025 Mar 12:102447. doi: 10.1016/j.stemcr.2025.102447. Online ahead of print.

ABSTRACT

Nuclear reprogramming can change cellular fates. Yet, reprogramming efficiency is low, and the resulting cell types are often not functional. Here, we used nuclear transfer to eggs to follow single cells during reprogramming in vivo. We show that the differentiation success of reprogrammed cells varies across cell types and depends on the expression of genes specific to the previous cellular identity. We find subsets of reprogramming-resistant cells that fail to form functional cell types, undergo cell death, or disrupt normal body patterning. Reducing expression levels of genes specific to the cell type of origin leads to better reprogramming and improved differentiation trajectories. Thus, our work demonstrates that failing to reprogram in vivo is cell type specific and emphasizes the necessity of minimizing aberrant transcripts of the previous somatic identity for improving reprogramming.

PMID:40086446 | DOI:10.1016/j.stemcr.2025.102447

Cell Syst. 2025 Mar 11:101205. doi: 10.1016/j.cels.2025.101205. Online ahead of print.

ABSTRACT

The sparse and stochastic nature of conversion has obscured our understanding of how transcription factors (TFs) drive cells to new identities. To overcome this limit, we develop a tailored, high-efficiency conversion system that increases the direct conversion of fibroblasts to motor neurons 100-fold. By tailoring the cocktail to a minimal set of transcripts, we reduce extrinsic variation, allowing us to examine how proliferation and TFs synergistically drive conversion. We show that cell state-as set by proliferation history-defines how cells interpret the levels of TFs. Controlling for proliferation history and titrating each TF, we find that conversion correlates with levels of the pioneer TF Ngn2. By isolating cells by both their proliferation history and Ngn2 levels, we demonstrate that levels of Ngn2 expression alone are insufficient to predict conversion rates. Rather, proliferation history and TF levels combine to drive direct conversion. Finally, increasing the proliferation rate of adult human fibroblasts generates morphologically mature induced human motor neurons at high rates.

PMID:40086434 | DOI:10.1016/j.cels.2025.101205

Transl Oncol. 2025 Mar 13;55:102347. doi: 10.1016/j.tranon.2025.102347. Online ahead of print.

ABSTRACT

Patients with liver metastatic colorectal cancer (mCRC) have a poor prognosis and are the leading cause of death in colorectal cancer (CRC) patients, but the mechanisms associated with CRC metastasis have not been fully elucidated. In this study, we obtained data from the Gene Expression Omnibus database and characterized the single-cell profiles of CRC, mCRC and healthy samples at single-cell resolution, and explored the cells that influence CRC metastasis. We find that AQP1+ CRC identified as highly malignant tumor cells exhibited proliferative and metastatic characteristics. Immunosuppressive properties are present in the tumor microenvironment (TME), while NOTCH3+ Fib is identified to play a facilitating role in the metastatic colonization of CRC. Importantly, we reveal that tumor-associated macrophages (TAM) characterized by SPP1-specific high expression may be involved in TME remodeling through intercellular communication. Specifically, SPP1+ TAM mediates the generation of Fib-derived extracellular vesicle through the APOE-LRP1 axis, which in turn delivers tumor growth-promoting factors in the TME. This study deepens the understanding of the mechanism of TME in mCRC and lays the scientific foundation for the development of therapeutic regimens for mCRC patients.

PMID:40086324 | DOI:10.1016/j.tranon.2025.102347

Sci Adv. 2025 Mar 14;11(11):eads6004. doi: 10.1126/sciadv.ads6004. Epub 2025 Mar 14.

ABSTRACT

NALCN (sodium leak channel, nonselective) is vital for regulating electrical activity in neurons and other excitable cells, and mutations in the channel or its auxiliary proteins lead to severe neurodevelopmental disorders. Here, we show that the neuronal SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptors) complex proteins syntaxin and SNAP25 (synaptosome-associated protein 25), which enable synaptic transmission in the nervous system, inhibit the activity of the NALCN channel complex in both heterologous systems and primary neurons. The existence of this interaction suggests that the neurotransmitter release machinery can regulate electrical signaling directly and therefore modulate the threshold for its own activity. We further find that reduction of NALCN currents is sufficient to promote cell survival in syntaxin-depleted cells. This suggests that disinhibited NALCN may cause the puzzling phenomenon of rapid neuronal cell death in the absence of syntaxin. This interaction could offer opportunities for future drug development against genetic diseases linked to both NALCN- and SNARE protein-containing complexes.

PMID:40085699 | DOI:10.1126/sciadv.ads6004

Int J Syst Evol Microbiol. 2025 Mar;75(3). doi: 10.1099/ijsem.0.006716.

ABSTRACT

Streptomyces strains DSM 116494T and DSM 116496T were isolated from sediment samples of the River Oker in Braunschweig, Germany, and subjected to a polyphasic taxonomic study and genome mining for specialized secondary metabolites. Phenotypic, genetic and genomic data confirmed the assignment of these strains to the Streptomyces genus. Pairwise 16S rRNA gene sequence similarity values between the strains and validly named Streptomyces species reached 99.5 and 99.7% for strains DSM 116494T and DSM 116496T, respectively. Genome-based phylogeny demonstrated that Streptomyces pilosus and Streptomyces griseoflavus species were the close relatives to strain DSM 116494T, while Streptomyces vinaceus species was the nearest neighbour to strain DSM 116496T. Digital DNA-DNA hybridization and average nucleotide identity comparisons of the genomic sequence of the strains and their close phylogenomic relatives revealed that values were below the determined threshold of 70 and 95-96% for prokaryotic species demarcation, respectively. The strains were distinguished from their close neighbours based on biochemical, chemotaxonomic and enzymatic data. Given these results, the strains merit being affiliated to novel species within the genus Streptomyces, for which the names Streptomyces okerensis sp. nov. (=OG2.3T=DSM 116494T=KCTC 59408T) and Streptomyces stoeckheimensis sp. nov. (=OG3.14T=DSM 116496T=KCTC 59410T) are proposed. Strains DSM 116494T and DSM 116496T harboured several biosynthetic gene clusters encoding potentially novel antimicrobial and anticancer compounds. Crude extracts of strains DSM 116494T and DSM 116496T inhibited the growth of Gram-negative bacteria (Escherichia coli ΔtolC, Proteus vulgaris) and a multi-drug-resistant Gram-positive, Staphylococcus aureus.

PMID:40085491 | DOI:10.1099/ijsem.0.006716

Neurol Sci. 2025 Mar 14. doi: 10.1007/s10072-025-08114-w. Online ahead of print.

ABSTRACT

Parkinson's disease (PD) is a neurodegenerative disorder primarily characterized by motor impairment, resulting from the accumulation of α-synuclein and neuronal cell death in the substantia nigra of the midbrain. Emerging evidence suggests that α-synuclein aggregation may originate in the enteric nervous system (ENS) and subsequently propagate to the brain via the vagus nerve. Clinical observations, such as prodromal gastrointestinal dysfunction in PD patients and the increased incidence of PD among individuals with inflammatory bowel disease, support the hypothesis that abnormal intestinal inflammation may contribute to the onset of motor dysfunction and neuropathology in PD. This review examines recent findings on the interplay between intestinal immune cells and α-synuclein aggregation within the framework of gut-originated PD pathogenesis. It begins by discussing evidence linking dysbiosis and intestinal inflammation to α-synuclein aggregation in the ENS. Additionally, it explores the potential role of intestinal immune cells in influencing enteric neurons and α-synuclein aggregation, furthering the understanding of PD development.

PMID:40085320 | DOI:10.1007/s10072-025-08114-w

Cancer Immunol Res. 2025 Mar 14:OF1-OF20. doi: 10.1158/2326-6066.CIR-24-0151. Online ahead of print.

ABSTRACT

Immunotherapies have had unprecedented success in the treatment of multiple cancer types, albeit with variable response rates. Unraveling the complex network of immune cells within the tumor microenvironment (TME) may provide additional insights to enhance antitumor immunity and improve clinical response. Many studies have shown that NK cells or innate lymphoid cells (ILC) have regulatory capacity. Here, we identified CD103 as a marker that was found on CD56+ cells that were associated with a poor proliferative capacity of tumor-infiltrating lymphocytes in culture. We further demonstrated that CD103+CD56+ ILCs isolated directly from tumors represented a distinct ILC population that expressed unique surface markers (such as CD49a and CD101), transcription factor networks, and transcriptomic profiles compared with CD103-CD56+ NK cells. Using single-cell multiomic and spatial approaches, we found that these CD103+CD56+ ILCs were associated with CD8+ T cells with reduced expression of granzyme B. Thus, this study identifies a population of CD103+CD56+ ILCs with potentially inhibitory functions that are associated with a TME that includes CD8+ T cells with poor antitumor activity. Further studies focusing on these cells may provide additional insights into the biology of an inhibitory TME.

PMID:40084939 | DOI:10.1158/2326-6066.CIR-24-0151

J Proteome Res. 2025 Mar 14. doi: 10.1021/acs.jproteome.4c01020. Online ahead of print.

ABSTRACT

We describe a new release of the Candida albicans PeptideAtlas proteomics spectral resource (build 2024-03), providing a sequence coverage of 79.5% at the canonical protein level, matched mass spectrometry spectra, and experimental evidence identifying 3382 and 536 phosphorylated serine and threonine sites with false localization rates of 1% and 5.3%, respectively. We provide a tutorial on how to use the PeptideAtlas and associated tools to access this information. The C. albicans PeptideAtlas summary web page provides "Build overview", "PTM coverage", "Experiment contribution", and "Data set contribution" information. The protein and peptide information can also be accessed via the Candida Genome Database via hyperlinks on each protein page. This allows users to peruse identified peptides, protein coverage, post-translational modifications (PTMs), and experiments that identify each protein. Given the value of understanding the PTM landscape in the sequence of each protein, a more detailed explanation of how to interpret and analyze PTM results is provided in the PeptideAtlas of this important pathogen. Candida albicans PeptideAtlas web page: https://db.systemsbiology.net/sbeams/cgi/PeptideAtlas/buildDetails?atlas_build_id=578.

PMID:40084908 | DOI:10.1021/acs.jproteome.4c01020

Bio Protoc. 2025 Mar 5;15(5):e5223. doi: 10.21769/BioProtoc.5223. eCollection 2025 Mar 5.

ABSTRACT

Non-small cell lung cancer (NSCLC) is the most common type of lung cancer. According to 2020 reports, globally, 2.2 million cases are reported every year, with the mortality number being as high as 1.8 million patients. To study NSCLC, systems biology offers mathematical modeling as a tool to understand complex pathways and provide insights into the identification of biomarkers and potential therapeutic targets, which aids precision therapy. Mathematical modeling, specifically ordinary differential equations (ODEs), is used to better understand the dynamics of cancer growth and immunological interactions in the tumor microenvironment. This study highlighted the dual role of the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS/STING) pathway's classical involvement in regulating type 1 interferon (IFN I) and pro-inflammatory responses to promote tumor regression through senescence and apoptosis. Alternative signaling was induced by nuclear factor kappa B (NF-κB), mutated tumor protein p53 (p53), and programmed death-ligand1 (PD-L1), which lead to tumor growth. We identified key regulators in cancer progression by simulating the model and validating it with the following model estimation parameters: local sensitivity analysis, principal component analysis, rate of flow of metabolites, and model reduction. Integration of multiple signaling axes revealed that cGAS-STING, phosphoinositide 3-kinases (PI3K), and Ak strain transforming (AKT) may be potential targets that can be validated for cancer therapy. Key features • Procedures for the reconstruction of a robust and steady-state mathematical model with respective analysis in order to provide mechanistic insights. • The dynamic mathematical model allows an understanding of the multifaceted dual roles of cGAS-STING in NSCLC promotion and inhibition. • The inherent statistical tool in systems biology provides a novel immunotherapeutic target.

PMID:40084069 | PMC:PMC11896782 | DOI:10.21769/BioProtoc.5223

Front Immunol. 2025 Feb 27;16:1530053. doi: 10.3389/fimmu.2025.1530053. eCollection 2025.

ABSTRACT

OBJECTIVE: To observe the inhibitory effect and potential mechanism of Yiqi Huayu Jiedu Decoction (YHJD) on liver metastasis of colorectal cancer (CRC).

METHODS: We compared the changes of liver weight and liver index before and after YHJD treatment in CRC liver metastasis mouse models. HE staining was employed to observe the pathological changes in mouse liver tissue sections. Flow cytometry was used to analyze the number and marker of neutrophils treated with YHJD. Transcriptomics, proteomics, and multiplex cytokine array analyses were conducted to further verify the role of YHJD on CXCL1. Differential gene analysis was performed to further explore the mechanism by which YHJD inhibits liver metastasis of CRC.

RESULTS: Animal studies demonstrated that YHJD reduces liver metastases. Flow cytometry results revealed that YHJD promotes N1 neutrophils in liver. Combining multi-omics and multiple cytokine arrays, we observed a significant increase in the expression of CXCL1 in the liver and plasma. GO and KEGG enrichment analyses indicated that YHJD may regulate the chemotaxis of neutrophils to inhibit the liver metastasis of CRC by participating in the regulation of cell adhesion molecule binding, adhesion protein binding, and multiple metabolic pathways.

CONCLUSIONS: YHJD inhibits CRC liver metastasis by upregulating CXCL1, thereby promoting N1 neutrophil chemotaxis towards the liver, and concurrently raising the expression of N1 neutrophil markers.

PMID:40083557 | PMC:PMC11903724 | DOI:10.3389/fimmu.2025.1530053

J Public Health Afr. 2025 Feb 25;16(1):690. doi: 10.4102/jphia.v16i1.690. eCollection 2025.

ABSTRACT

BACKGROUND: Human immunodeficiency viruses (HIV) and acquired immunodeficiency syndrome (AIDS) remain a global public health problem. Other sexually transmitted infections (STIs) are aggravating factors.

AIM: This study aimed to assess the prevalence and identify new cases of HIV and STIs, as well as their associated risk factors.

SETTING: Political insecurity in the northern regions of Cameroon has led to population displacement, weakening an already fragile health system.

METHODS: A cohort of 684 consenting participants from the north and far north were enrolled in 2021 and followed up in 2022. Socio-demographic variables and risk behaviours were collected. Anti-HIV Ab, hepatitis B surface antigen, Treponema pallidum haemagglutination tests were performed. The data were analysed using Epi Info 7.5.2. The associations between variables were evaluated using the Chi-square test with a 95% confidence interval.

RESULTS: The new cases of HIV rate and overall prevalence were 1.63% (95% confidence interval [CI]: 0.83% - 2.41%) and 3.8% (95% CI: 2.01% - 3.97%), respectively. New HIV cases increased from 0.27% (2017, Demographic and Health Survey [DHS]) to 1.63%. The prevalence of syphilis and hepatitis B was 1.03% (95% CI: 0.98% - 1.09%) and 4.56% (95% CI: 4.51% - 4.66%), respectively. Factors associated with HIV included religion (p = 0.027), unprotected sex (p = 0.006), sex with a sex worker (p = 0.00009), and co-infection with syphilis and hepatitis B (p = 0.033). New HIV infections may also be associated with population displacement.

CONCLUSION: HIV infection, syphilis and hepatitis B are on the rise in the Northern Cameroon.

CONTRIBUTION: Future HIV prevention strategies should consider population displacement and HIV-associated infections such as hepatitis B and syphilis in order to secure achievements in HIV programme and further curb the burden of these infections in the country.

PMID:40083464 | PMC:PMC11905195 | DOI:10.4102/jphia.v16i1.690

Aging Cell. 2025 Mar 13:e70043. doi: 10.1111/acel.70043. Online ahead of print.

ABSTRACT

The lymphatic vasculature plays essential roles in fluid balance, immunity, and lipid transport. Chronic, low-grade inflammation in peripheral tissues develops when lymphatic structure or function is impaired, as observed during aging. While aging has been associated with a broad range of heart pathophysiology, its effect on cardiac lymphatic vasculature has not been characterized. Here, we analyzed cardiac lymphatics in aged 20-month-old mice versus young 2-month-old mice. Aged hearts showed reduced lymphatic vascular density, more dilated vessels, and increased inflammation and fibrosis in peri-lymphatic zones. As exercise has shown benefits in several different models of age-related heart disease, we further investigated the effects of aerobic training on cardiac lymphatics. Eight weeks of voluntary wheel running attenuated age-associated adverse remodeling of the cardiac lymphatics, including reversing their dilation, increasing lymph vessel density and branching, and reducing perilymphatic inflammation and fibrosis. Intravital lymphangiography demonstrated improved cardiac lymphatic flow after exercise training. Our findings illustrate that aging leads to cardiac lymphatic dysfunction, and that exercise can improve lymphatic health in aged animals.

PMID:40083143 | DOI:10.1111/acel.70043

FEMS Yeast Res. 2025 Mar 13:foaf011. doi: 10.1093/femsyr/foaf011. Online ahead of print.

ABSTRACT

The formation of hyphae is one of the most crucial virulence traits the human pathogenic fungus Candida albicans possesses. The assessment of hyphal length in response to various stimuli, such as exposure to human serum, provides valuable insights into the adaptation strategies of C. albicans to the host environment. Despite the increasing high-throughput capacity live-cell imaging and data generation, the accurate analysis of hyphal growth has remained a laborious, error-prone, and subjective manual process. We developed an analysis pipeline utilizing the open-source visual programming language JIPipe to overcome the limitations associated with manual analysis of hyphal growth. By comparing our automated approach with manual analysis, we refined the strategies to achieve accurate differentiation between yeast cells and hyphae. The automated method enables length measurements of individual hyphae, facilitating a time-efficient, high-throughput, and user-friendly analysis. By utilizing this JIPipe analysis approach, we obtained insights into the filamentation behavior of two C. albicans strains when exposed to human serum albumin (HSA), the most abundant protein in human serum. Our findings indicate that despite the known role of HSA in stimulating fungal growth, it reduces filamentous growth. The implementation of our automated JIPipe analysis approach for hyphal growth represents a long-awaited and time-efficient solution to meet the demand of high-throughput data generation. This tool can benefit different research areas investigating the virulence aspects of C. albicans.

PMID:40082735 | DOI:10.1093/femsyr/foaf011

EMBO J. 2025 Mar 13. doi: 10.1038/s44318-025-00408-1. Online ahead of print.

ABSTRACT

The AAA protease FtsH associates with HflK/C subunits to form a megadalton-size complex that spans the inner membrane and extends into the periplasm of E. coli. How this bacterial complex and homologous assemblies in eukaryotic organelles recruit, extract, and degrade membrane-embedded substrates is unclear. Following the overproduction of protein components, recent cryo-EM structures showed symmetric HflK/C cages surrounding FtsH in a manner proposed to inhibit the degradation of membrane-embedded substrates. Here, we present structures of native protein complexes, in which HflK/C instead forms an asymmetric nautilus-shaped assembly with an entryway for membrane-embedded substrates to reach and be engaged by FtsH. Consistent with this nautilus-like structure, proteomic assays suggest that HflK/C enhances FtsH degradation of certain membrane-embedded substrates. Membrane curvature in our FtsH•HflK/C complexes is opposite that of surrounding membrane regions, a property that correlates with lipid scramblase activity and possibly with FtsH's function in the degradation of membrane-embedded proteins.

PMID:40082723 | DOI:10.1038/s44318-025-00408-1

Nat Aging. 2025 Mar 13. doi: 10.1038/s43587-025-00816-2. Online ahead of print.

ABSTRACT

Neuroinflammation including interleukin (IL)-12/IL-23-signaling is central to Alzheimer's disease (AD) pathology. Inhibition of p40, a subunit of IL-12/IL-23, attenuates pathology in AD-like mice; however, its signaling mechanism and expression pattern remained elusive. Here we show that IL-12 receptors are predominantly expressed in neurons and oligodendrocytes in AD-like APPPS1 mice and in patients with AD, whereas IL-23 receptor transcripts are barely detectable. Consistently, deletion of the IL-12 receptor in neuroectodermal cells ameliorated AD pathology in APPPS1 mice, whereas removal of IL-23 receptors had no effect. Genetic ablation of IL-12 signaling alone reverted the loss of mature oligodendrocytes, restored myelin homeostasis, rescued the amyloid-β-dependent reduction of parvalbumin-positive interneurons and restored phagocytosis-related changes in microglia of APPPS1 mice. Furthermore, IL-12 protein expression was increased in human AD brains compared to healthy age-matched controls, and human oligodendrocyte-like cells responded profoundly to IL-12 stimulation. We conclude that oligodendroglial and neuronal IL-12 signaling, but not IL-23 signaling, are key in orchestrating AD-related neuroimmune crosstalk and that IL-12 represents an attractive therapeutic target in AD.

PMID:40082619 | DOI:10.1038/s43587-025-00816-2

Metabolomics. 2025 Mar 13;21(2):40. doi: 10.1007/s11306-025-02228-0.

ABSTRACT

BACKGROUND: Advancements in the research of intracellular metabolome have the potential to affect our understanding of biological processes. The applications and findings of intracellular metabolome analysis are useful in understanding cellular pathways, microbial interactions, and the detection of secreted metabolites and their functions.

AIM OF REVIEW: This work focuses on the analysis of intracellular metabolomes in microorganisms. The techniques used for analyzing the intracellular metabolomes including metabolomics approaches such as mass spectrometry, nuclear magnetic resonance, liquid chromatography, and gas chromatography are discussed.

KEY SCIENTIFIC CONCEPTS OF REVIEW: Challenges such as sample preparation, data analysis, metabolite extraction, sample storage and collection, and processing techniques were investigated, as they can highlight emerging technologies and advancements in metabolome analysis, future applications in drug discovery, personalized medicine, systems biology, and the limitations and challenges in studying the metabolome of microorganisms.

PMID:40082321 | DOI:10.1007/s11306-025-02228-0

Trends Cell Biol. 2025 Mar 12:S0962-8924(25)00040-6. doi: 10.1016/j.tcb.2025.02.006. Online ahead of print.

ABSTRACT

Aging is a dynamic process that is driven by cellular damage and disruption of homeostatic gene regulatory networks (GRNs). Traditional studies often focus on individual genes, but understanding their interplay is key to unraveling the mechanisms of aging. This review explores the gene circuits that influence longevity and highlights the role of feedback loops in maintaining cellular balance. The SIR2-HAP circuit in yeast serves as a model to explore how mutual inhibition between pathways influences aging trajectories and how engineering stable fixed points or oscillations within these circuits can extend lifespan. Feedback loops crucial for maintaining homeostasis are also reviewed, and we highlight how their destabilization accelerates aging. By leveraging systems and synthetic biology, strategies are proposed that may stabilize these loops within single cells, thereby enhancing their resilience to aging-related damage.

PMID:40082090 | DOI:10.1016/j.tcb.2025.02.006

J Microbiol Biotechnol. 2025 Mar 13;35:e2411058. doi: 10.4014/jmb.2411.11058.

ABSTRACT

Polyethylene (PE) is among the most widely used synthetic plastics globally, serving as an essential material in daily life and numerous industries, such as packaging for bottles and food, as well as in the production of toys and pipes. PE is used for various purposes owing to its high durability and low production costs, leading to a steadily increasing demand. However, PE waste is a significant contributor to environmental pollution, posing serious threats to marine and soil ecosystems. Therefore, the efficient decomposition of PE, a synthetic polymer known for its resistance to degradation, using bacteria offers a sustainable and effective method for reusing PE. In this study, we isolated a novel species of Kosakonia, designated Kosakonia cowanii JNU01, from a landfill site, capable of biodegrading PE. K. cowanii JNU01 exhibited the highest cell growth rate in media containing PE, indicating its effectiveness in decomposing PE for use as a sole carbon source in its metabolic pathway. Treatment of PE with K. cowanii JNU01 resulted in the emergence of new chemical functional groups, including hydroxyl, carboxyl, amide, and ether groups, within the inert hydrocarbon structure. Analysis of the PE film treated with K. cowanii JNU01 revealed considerable physical degradation on the film's surface. Additionally, various metabolites released from PE by K. cowanii JNU01 were identified. These findings suggest that K. cowanii JNU01 proves to be an effective candidate bacterium for PE degradation.

PMID:40081902 | DOI:10.4014/jmb.2411.11058

J Mol Biol. 2025 Mar 11:169087. doi: 10.1016/j.jmb.2025.169087. Online ahead of print.

ABSTRACT

I started my faculty career in 1981 at the UW-Madison in the Department of Bacteriology and moved to the University of California, San Francisco in 1993, where I am a Professor in the Departments of Microbiology and Immunology and Cell and Tissue Biology. In this article, I first review my contributions to understanding the molecular biology of bacterial transcriptional apparatus and the global role of alternative sigmas (σs), a major pillar of bacterial transcriptional control. I then discuss my role in spearheading the development of bacterial systems biology, specifically to the genome-wide phenotyping approaches necessary for rapid understanding of gene function and the molecular basis of pathway connections across the bacterial universe.

PMID:40081792 | DOI:10.1016/j.jmb.2025.169087

J Affect Disord. 2025 Mar 11:S0165-0327(25)00370-2. doi: 10.1016/j.jad.2025.03.032. Online ahead of print.

ABSTRACT

BACKGROUND: Recent studies have linked branched-chain amino acids (BCAAs) metabolism with the risk of major depressive disorder (MDD). However, it is unclear whether associations of plasma BCAA levels with MDD are causal or driven by reverse causality.

METHODS: Mendelian randomization (MR) was used to investigate the causal association of genetically determined BCAA levels with the risk of MDD. The large genome-wide association study (GWAS) datasets on plasma BCAA levels (n = 115,051) were obtained from the UK Biobank. The summary GWAS dataset for MDD was obtained from the Psychiatric Genomics Consortium (n = 1,035,760). We applied the inverse variance-weighted (IVW) method to explore the causal relationships between BCAA levels and MDD, followed by multiple pleiotropy and heterogeneity tests.

RESULTS: Our results demonstrated that genetically determined circulating total BCAAs (odds ratio (OR): 1.05, 95 % confidence interval (CI): 1.01-1.10, P = 0.016), leucine (OR: 1.06, 95 % CI: 1.02-1.11, P = 7.22 × 10-3), and isoleucine (OR: 1.08, 95 % CI: 1.01-1.16, P = 0.032) levels were associated with an increased risk of MDD. There was suggestive evidence supporting the causal effect of valine levels on MDD (OR: 1.04, 95 % CI: 1.00-1.08, P = 0.075). Bidirectional MR analysis did not provide evidence of reverse causality.

CONCLUSIONS: We report evidence supporting the causal role of BCAAs in the development of MDD. This study offers new insights into the mechanisms and treatment of MDD.

PMID:40081595 | DOI:10.1016/j.jad.2025.03.032