BMC Genomics. 2025 Feb 5;26(1):110. doi: 10.1186/s12864-025-11301-w.

ABSTRACT

Small proteins with fewer than 100, particularly fewer than 50, amino acids are still largely unexplored. Nonetheless, they represent an essential part of bacteria's often neglected genetic repertoire. In recent years, the development of ribosome profiling protocols has led to the detection of an increasing number of previously unknown small proteins. Despite this, they are overlooked in many cases by automated genome annotation pipelines, and often, no functional descriptions can be assigned due to a lack of known homologs. To understand and overcome these limitations, the current abundance of small proteins in existing databases was evaluated, and a new dedicated database for small proteins and their potential functions, called 'sORFdb', was created. To this end, small proteins were extracted from annotated bacterial genomes in the GenBank database. Subsequently, they were quality-filtered, compared, and complemented with proteins from Swiss-Prot, UniProt, and SmProt to ensure reliable identification and characterization of small proteins. Families of similar small proteins were created using bidirectional best BLAST hits followed by Markov clustering. Analysis of small proteins in public databases revealed that their number is still limited due to historical and technical constraints. Additionally, functional descriptions were often missing despite the presence of potential homologs. As expected, a taxonomic bias was evident in over-represented clinically relevant bacteria. This new and comprehensive database is accessible via a feature-rich website providing specialized search features for sORFs and small proteins of high quality. Additionally, small protein families with Hidden Markov Models and information on taxonomic distribution and other physicochemical properties are available. In conclusion, the novel small protein database sORFdb is a specialized, taxonomy-independent database that improves the findability and classification of sORFs, small proteins, and their functions in bacteria, thereby supporting their future detection and consistent annotation. All sORFdb data is freely accessible via https://sorfdb.computational.bio .

PMID:39910485 | DOI:10.1186/s12864-025-11301-w

Int J Food Sci Nutr. 2025 Feb 5:1-11. doi: 10.1080/09637486.2025.2461144. Online ahead of print.

ABSTRACT

Our study examined the relationship between diet quality and the prevalence of metabolic syndrome (MetS) among 1779 U.S. cancer survivors using data from the National Health and Nutrition Examination Survey (NHANES, 2005-2016). Diet quality was assessed using the Healthy Eating Index 2015 (HEI-2015). Higher HEI-2015 scores were linked to significantly lower MetS prevalence (OR: 0.51, 95% CI: 0.32-0.80). Specifically, a higher intake of seafood and plant proteins, and fatty acids, coupled with a reduced intake of added sugars, was associated with decreased odds of MetS prevalence (OR: 0.93; 95% CI, 0.86-0.99) in cancer survivors. Additionally, a better diet quality was linked to lower prevalence of high waist circumference, elevated triglycerides, reduced high-density lipoprotein (HDL) cholesterol and high fasting glucose levels (OR, 0.44; 95% CI, 0.27-0.72). These results suggest that adopting healthy dietary habits may prevent MetS in cancer survivors.

PMID:39910439 | DOI:10.1080/09637486.2025.2461144

Nat Biomed Eng. 2025 Feb 5. doi: 10.1038/s41551-025-01359-y. Online ahead of print.

NO ABSTRACT

PMID:39910377 | DOI:10.1038/s41551-025-01359-y

Nature. 2025 Feb 5. doi: 10.1038/s41586-024-08501-x. Online ahead of print.

ABSTRACT

The genetic code is conserved across all domains of life, yet exceptions have revealed variations in codon assignments and associated translation factors1-3. Inspired by this natural malleability, synthetic approaches have demonstrated whole-genome replacement of synonymous codons to construct genomically recoded organisms (GROs)4,5 with alternative genetic codes. However, no efforts have fully leveraged translation factor plasticity and codon degeneracy to compress translation function to a single codon and assess the possibility of a non-degenerate code. Here we describe construction and characterization of Ochre, a GRO that fully compresses a translational function into a single codon. We replaced 1,195 TGA stop codons with the synonymous TAA in ∆TAG Escherichia coli C321.∆A4. We then engineered release factor 2 (RF2) and tRNATrp to mitigate native UGA recognition, translationally isolating four codons for non-degenerate functions. Ochre thus utilizes UAA as the sole stop codon, with UGG encoding tryptophan and UAG and UGA reassigned for multi-site incorporation of two distinct non-standard amino acids into single proteins with more than 99% accuracy. Ochre fully compresses degenerate stop codons into a single codon and represents an important step toward a 64-codon non-degenerate code that will enable precise production of multi-functional synthetic proteins with unnatural encoded chemistries and broad utility in biotechnology and biotherapeutics.

PMID:39910296 | DOI:10.1038/s41586-024-08501-x

Sci Rep. 2025 Feb 5;15(1):4306. doi: 10.1038/s41598-025-88465-8.

ABSTRACT

The genetic contributions to early onset heart failure (HF) are incompletely understood. Genetic testing in advanced HF patients undergoing heart transplantation (HTx) may yield clinical benefits, but data is limited. We performed deep-coverage whole genome sequencing (WGS) in 102 Swedish HTx recipients. Gene lists were compiled through a systematic literature review. Variants were prioritized for pathogenicity and classified manually. We also compared polygenic HF risk scores to a population-based cohort. We found a pathogenic (LP/P) variant in 34 individuals (34%). Testing yield was highest in hypertrophic (63% LP/P carriers), dilated (40%) and arrhythmogenic right ventricular (33%) cardiomyopathy and lower in ischemic cardiomyopathy (10%). A family history was more common in LP/P variant carriers than in non-carriers but was present in less than half of carriers (44% vs 13%, P < 0.001), whereas age was similar. Polygenic risk scores were similar in HTx recipients and the population cohort. In conclusion, we observed a high prevalence of pathogenic cardiomyopathy gene variants in individuals with early-onset advanced HF, which could not accurately be ruled out by family history and age. In contrast, we did not observe higher polygenic risk scores in early onset advanced HF cases than in the general population.

PMID:39910139 | DOI:10.1038/s41598-025-88465-8

NPJ Syst Biol Appl. 2025 Feb 4;11(1):15. doi: 10.1038/s41540-025-00496-z.

ABSTRACT

Predictive mathematical modeling is an essential part of systems biology and is interconnected with information management. Systems biology information is often stored in specialized formats to facilitate data storage and analysis. These formats are not designed for easy human readability and thus require specialized software to visualize and interpret results. Therefore, comprehending modeling and underlying networks and pathways is contingent on mastering systems biology tools, which is particularly challenging for users with no or little background in data science or system biology. To address this challenge, we investigated the usage of public Artificial Intelligence (AI) tools in exploring systems biology resources in mathematical modeling. We tested public AI's understanding of mathematics in models, related systems biology data, and the complexity of model structures. Our approach can enhance the accessibility of systems biology for non-system biologists and help them understand systems biology without a deep learning curve.

PMID:39910106 | DOI:10.1038/s41540-025-00496-z

Gut Microbes. 2025 Dec;17(1):2455506. doi: 10.1080/19490976.2025.2455506. Epub 2025 Feb 5.

ABSTRACT

The relationship between bacteria, cognitive function and obesity is well established, yet the role of archaeal species remains underexplored. We used shotgun metagenomics and neuropsychological tests to identify microbial species associated with cognition in a discovery cohort (IRONMET, n = 125). Interestingly, methanogen archaeas exhibited the strongest positive associations with cognition, particularly Methanobrevibacter smithii (M. smithii). Stratifying individuals by median-centered log ratios (CLR) of M. smithii (low and high M. smithii groups: LMs and HMs) revealed that HMs exhibited better cognition and distinct gut bacterial profiles (PERMANOVA p = 0.001), characterized by increased levels of Verrucomicrobia, Synergistetes and Lentisphaerae species and reduced levels of Bacteroidetes and Proteobacteria. Several of these species were linked to the cognitive test scores. These findings were replicated in a large-scale validation cohort (Aging Imageomics, n = 942). Functional analyses revealed an enrichment of energy, butyrate, and bile acid metabolism in HMs in both cohorts. Global plasma metabolomics by CIL LC-MS in IRONMET identified an enrichment of methylhistidine, phenylacetate, alpha-linolenic and linoleic acid, and secondary bile acid metabolism associated with increased levels of 3-methylhistidine, phenylacetylgluamine, adrenic acid, and isolithocholic acid in the HMs group. Phenylacetate and linoleic acid metabolism also emerged in the Aging Imageomics cohort performing untargeted HPLC-ESI-MS/MS metabolic profiling, while a targeted bile acid profiling identified again isolithocholic acid as one of the most significant bile acid increased in the HMs. 3-Methylhistidine levels were also associated with intense physical activity in a second validation cohort (IRONMET-CGM, n = 116). Finally, FMT from HMs donors improved cognitive flexibility, reduced weight, and altered SCFAs, histidine-, linoleic acid- and phenylalanine-related metabolites in the dorsal striatum of recipient mice. M. smithii seems to interact with the bacterial ecosystem affecting butyrate, histidine, phenylalanine, and linoleic acid metabolism with a positive impact on cognition, constituting a promising therapeutic target to enhance cognitive performance, especially in subjects with obesity.

PMID:39910065 | DOI:10.1080/19490976.2025.2455506

Life Sci Alliance. 2025 Feb 5;8(4):e202402956. doi: 10.26508/lsa.202402956. Print 2025 Apr.

ABSTRACT

The transition of an embryo from gastrulation to organogenesis requires precisely coordinated changes in gene expression, but the underlying mechanisms remain unclear. The RNA-binding protein Trim71 is essential for development and serves as a potent regulator of post-transcriptional gene expression. Here, we show that global deficiency of Trim71 induces severe defects in mesoderm-derived cells at the onset of organogenesis. Murine Trim71-KO embryos displayed impaired primitive erythropoiesis, yolk sac vasculature, heart function, and circulation, explaining the embryonic lethality of these mice. Tie2 Cre Trim71 conditional knockout did not induce strong defects, showing that Trim71 expression in endothelial cells and their immediate progenitors is dispensable for embryonic survival. scRNA-seq of E7.5 global Trim71-KO embryos revealed that transcriptomic changes arise already at gastrulation, showing a strong up-regulation of the mesodermal pioneer transcription factor Eomes. We identify Eomes as a direct target of Trim71-mediated mRNA repression via the NHL domain, demonstrating a functional link between these important regulatory genes. Taken together, our data suggest that Trim71-dependent control of gene expression at gastrulation establishes a framework for proper development during organogenesis.

PMID:39909558 | DOI:10.26508/lsa.202402956

Mitochondrion. 2025 Feb 3:102008. doi: 10.1016/j.mito.2025.102008. Online ahead of print.

ABSTRACT

Mitochondrial dynamics is crucial for cellular homeostasis. However, not all proteins involved are known. Using a protein-protein interaction (PPI) approach, we identified ITPRIPL2 for involvement in mitochondrial dynamics. ITPRIPL2 co-localizes with intermediate filament protein vimentin, supported by protein simulations. ITPRIPL2 knockdown reveals mitochondrial elongation, disrupts vimentin processing, intermediate filament formation, and alters vimentin-related pathways. Interestingly, vimentin knockdown also leads to mitochondrial elongation. These findings highlight ITPRIPL2 as vimentin-associated protein essential for intermediate filament structure and suggest a role for intermediate filaments in mitochondrial morphology. Our study demonstrates that PPI analysis is a powerful approach for identifying novel mitochondrial dynamics proteins.

PMID:39909388 | DOI:10.1016/j.mito.2025.102008

Cell. 2025 Jan 10:S0092-8674(24)01420-X. doi: 10.1016/j.cell.2024.12.007. Online ahead of print.

ABSTRACT

Ubiquinone (UQ), the only known electron carrier in the mammalian electron transport chain (ETC), preferentially delivers electrons to the terminal electron acceptor oxygen (O2). In hypoxia, ubiquinol (UQH2) diverts these electrons onto fumarate instead. Here, we identify rhodoquinone (RQ), an electron carrier detected in mitochondria purified from certain mouse and human tissues that preferentially delivers electrons to fumarate through the reversal of succinate dehydrogenase, independent of environmental O2 levels. The RQ/fumarate ETC is strictly present in vivo and is undetectable in cultured mammalian cells. Using genetic and pharmacologic tools that reprogram the ETC from the UQ/O2 to the RQ/fumarate pathway, we establish that these distinct ETCs support unique programs of mitochondrial function and that RQ confers protection upon hypoxia exposure in vitro and in vivo. Thus, in discovering the presence of RQ in mammals, we unveil a tractable therapeutic strategy that exploits flexibility in the ETC to ameliorate hypoxia-related conditions.

PMID:39909039 | DOI:10.1016/j.cell.2024.12.007

J Environ Manage. 2025 Feb 4;375:124396. doi: 10.1016/j.jenvman.2025.124396. Online ahead of print.

ABSTRACT

Innovative technological solutions are needed for water decontamination to combat the diverse pollutants present in water systems, as no single optimal decontamination technique is appropriate for all circumstances. Vacuum-ultraviolet (V-UV) radiation is a source of energetic photons that break molecular bonds, producing a plethora of chemically reactive agents, most notably OH● radicals, which can cause the degradation of harmful pollutants. Low-pressure gaseous plasma is a good source of V-UV radiation; however, its application to liquid water poses challenges. We constructed an inductively coupled radiofrequency plasma to produce high-intensity V-UV radiation, which was applied to contaminated water via a V-UV-transparent window. Plasma was sustained in hydrogen, as it produces the highest V-UV intensity among all gases at selected discharge parameters. Bacteriophage MS2 was used as an indicator of microbial decontamination efficiency. Reactive oxygen and nitrogen species were measured at various treatment setups to quantify their effect on MS2 inactivation and elucidate the primary inactivation factors. At optimal conditions, the concentration of active virus dropped by 9 log10 PFU/mL in 60 s. The optimal experimental setup was then used to treat bacteria E. coli, S. aureus, antibiotic tetracycline, and synthetic dye methylene blue as representatives of other types of pollutants, all of which were effectively removed/degraded within 10 min of treatment. A comparison of energy efficiency (EEO) to other disinfection setups was made for bacteriophage inactivation. With a low EEO value, we showcase the potential of this technique for further work in this field.

PMID:39908620 | DOI:10.1016/j.jenvman.2025.124396

N Engl J Med. 2025 Feb 6;392(6):577-583. doi: 10.1056/NEJMoa2411507.

ABSTRACT

Malignant T-cell transformation after chimeric antigen receptor (CAR) T-cell therapy has been described, but the contribution of CAR integration to oncogenesis is not clear. Here we report a case of a T-cell lymphoma harboring a lentiviral integration in a known tumor suppressor, TP53, which developed in a patient with multiple myeloma after B-cell maturation antigen (BCMA) CAR T-cell therapy.

PMID:39908432 | DOI:10.1056/NEJMoa2411507

Sci Transl Med. 2025 Feb 5;17(784):eadp8913. doi: 10.1126/scitranslmed.adp8913. Epub 2025 Feb 5.

ABSTRACT

Although oncogenic NRAS activates mitogen-activated protein kinase (MAPK) signaling, inhibition of the MAPK pathway is not therapeutically efficacious in NRAS-mutant (NRASMUT) tumors. Here, we report that selectively silencing the ribosomal protein S6 kinase 2 (S6K2) while preserving the activity of S6K1 perturbs lipid metabolism, enhances fatty acid unsaturation, and triggers lethal lipid peroxidation in NRASMUT melanoma cells that are resistant to MAPK inhibition. S6K2 depletion induces endoplasmic reticulum stress and peroxisome proliferator-activated receptor α (PPARα) activation, triggering cell death selectively in MAPK inhibitor-resistant melanoma. We found that combining PPARα agonists and polyunsaturated fatty acids phenocopied the effects of S6K2 abrogation, blocking tumor growth in both patient-derived xenografts and immunocompetent murine melanoma models. Collectively, our study establishes S6K2 and its effector subnetwork as promising targets for NRASMUT melanomas that are resistant to global MAPK pathway inhibitors.

PMID:39908352 | DOI:10.1126/scitranslmed.adp8913

Cell Rep. 2025 Feb 4;44(2):115274. doi: 10.1016/j.celrep.2025.115274. Online ahead of print.

ABSTRACT

The mechanism by which Wnt signaling, an essential pathway controlling development and disease, stabilizes β-catenin has been a subject of debate over the last four decades. Casein kinase 1α (CK1α) functions as a pivotal negative regulator of this signaling pathway, initiating the events that destabilize β-catenin. However, whether and how CK1α activity is regulated in Wnt-off and Wnt-on states remains poorly understood. We now show that CK1α activity requires its association with the α catalytic subunit of protein phosphatase 2A (PPP2CA) on AXIN, the scaffold protein of the β-catenin destruction complex. Wnt stimulation induces the dissociation of PPP2CA from CK1α, resulting in CK1α autophosphorylation and its consequent inactivation. Moreover, autophosphorylated CK1α is enriched in a subset of colorectal cancers (CRCs) harboring constitutive Wnt activation. Our findings identify a mechanism by which Wnt stimulation inactivates CK1α, filling a critical gap in our understanding of Wnt signaling, with relevance for CRC.

PMID:39908140 | DOI:10.1016/j.celrep.2025.115274

J Proteome Res. 2025 Feb 5. doi: 10.1021/acs.jproteome.4c00907. Online ahead of print.

ABSTRACT

Protein sulfation can be crucial in regulating protein-protein interactions but remains largely underexplored. Sulfation is nearly isobaric to phosphorylation, making it particularly challenging to investigate using mass spectrometry. The degree to which tyrosine sulfation (sY) is misidentified as phosphorylation (pY) is, thus, an unresolved concern. This study explores the extent of sY misidentification within the human phosphoproteome by distinguishing between sulfation and phosphorylation based on their mass difference. Using Gaussian mixture models (GMMs), we screened ∼45 M peptide-spectrum matches (PSMs) from the PeptideAtlas human phosphoproteome build for peptidoforms with mass error shifts indicative of sulfation. This analysis pinpointed 104 candidate sulfated peptidoforms, backed up by Gene Ontology (GO) terms and custom terms linked to sulfation. False positive filtering by manual annotation resulted in 31 convincing peptidoforms spanning 7 known and 7 novel sY sites. Y47 in calumenin was particularly intriguing since mass error shifts, acidic motif conservation, and MS2 neutral loss patterns characteristic of sulfation provided strong evidence that this site is sulfated rather than phosphorylated. Overall, although misidentification of sulfation in phosphoproteomics data sets derived from cell and tissue intracellular extracts can occur, it appears relatively rare and should not be considered a substantive confounding factor in high-quality phosphoproteomics data sets.

PMID:39907647 | DOI:10.1021/acs.jproteome.4c00907

Elife. 2025 Feb 5;13:RP97424. doi: 10.7554/eLife.97424.

ABSTRACT

Manifold-learning is particularly useful to resolve the complex cellular state space from single-cell RNA sequences. While current manifold-learning methods provide insights into cell fate by inferring graph-based trajectory at cell level, challenges remain to retrieve interpretable biology underlying the diverse cellular states. Here, we described MGPfactXMBD, a model-based manifold-learning framework and capable to factorize complex development trajectories into independent bifurcation processes of gene sets, and thus enables trajectory inference based on relevant features. MGPfactXMBD offers a more nuanced understanding of the biological processes underlying cellular trajectories with potential determinants. When bench-tested across 239 datasets, MGPfactXMBD showed advantages in major quantity-control metrics, such as branch division accuracy and trajectory topology, outperforming most established methods. In real datasets, MGPfactXMBD recovered the critical pathways and cell types in microglia development with experimentally valid regulons and markers. Furthermore, MGPfactXMBD discovered evolutionary trajectories of tumor-associated CD8+ T cells and yielded new subtypes of CD8+ T cells with gene expression signatures significantly predictive of the responses to immune checkpoint inhibitor in independent cohorts. In summary, MGPfactXMBD offers a manifold-learning framework in scRNA-seq data which enables feature selection for specific biological processes and contributing to advance our understanding of biological determination of cell fate.

PMID:39907554 | DOI:10.7554/eLife.97424

Plant Physiol. 2025 Feb 5:kiaf050. doi: 10.1093/plphys/kiaf050. Online ahead of print.

NO ABSTRACT

PMID:39907471 | DOI:10.1093/plphys/kiaf050

Appl Environ Microbiol. 2025 Feb 5:e0213424. doi: 10.1128/aem.02134-24. Online ahead of print.

ABSTRACT

Beauveria bassiana (Bb) is one of the most widely used biocontrol agents, and its products constitute more than one-third of the global market share of fungal insecticides. Solid-state fermentation (SSF) is widely used in the production of Beauveria bassiana (Bb) because of its economic practicality and high production efficiency. However, the heat generated during fermentation can sharply reduce both the yield and quality of Bb, and current industrial methods to mitigate high temperatures during fermentation are inadequate, leading to increased production costs. Thus, exploring the underlying mechanism of how heat is produced by Bb is crucial for improving the SSF procedure and yield. This study employed multiomics data analysis of Bb during SSF to explore the relationships between fungal fermentation and environmental factors. We found that the heat production period for SSF was 12 hours to 48 hours post-inoculation. To further explore the underlying mechanism during this heating period, we identified 454 temperature-correlated metabolites (TCMs) and 1,994 temperature-correlated genes (TCGs). Annotations of the above TCMs and TCGs revealed significant enrichment in the arginine biosynthesis pathway; specifically, the expression level of glutamine synthetase, a TCG, decreased with fermentation time, whereas the expression levels of the TCGs L-arginine and L-glutamine increased with fermentation time, and glutamine synthetase and L-glutamine in the arginine biosynthesis pathway cycle produced the end product L-arginine. Furthermore, when the substrates of the SSF were treated with exogenous arginine, the temperature peak of the SSF significantly decreased with increasing concentration of exogenously added arginine.IMPORTANCEA large amount of experimental evidence from the field has shown that Bb is an irreplaceable mature product that protects the health of our agriculture and ecosystem. In addition to high efficiency and host extensiveness, low cost is a critical merit that makes Bb products frequently used in the field. However, the growing cost of power and labor in the Bb industry, especially the SSF procedure, has significantly increased the price of its products, thus restricting the use of Bb in the field. This study not only fills the theoretical knowledge gaps concerning the molecular basis of the interrelationship between Bb and the fermentation environment during SSF but also provides an economical and applicable strategy (the addition of arginine to the fermentation media) to further lower the cost and increase the yield of Bb during SSF at the industrial level.

PMID:39907454 | DOI:10.1128/aem.02134-24

Bioinformatics. 2025 Feb 5:btaf048. doi: 10.1093/bioinformatics/btaf048. Online ahead of print.

ABSTRACT

SUMMARY: We present NetworkCommons, a platform for integrating prior knowledge, omics data, and network inference methods, facilitating their usage and evaluation. NetworkCommons aims to be an infrastructure for the network biology community that supports the development of better methods and benchmarks, by enhancing interoperability and integration.

AVAILABILITY AND IMPLEMENTATION: NetworkCommons is implemented in Python and offers programmatic access to multiple omics datasets, network inference methods, and benchmarking setups. It is a free software, available at https://github.com/saezlab/networkcommons, and deposited in Zenodo at https://doi.org/10.5281/zenodo.14719118 .

SUPPLEMENTARY DATA: Contribution guidelines, additional figures, and descriptions for data, knowledge, methods, evaluation strategies and their implementation are available in the Supplementary Data and in the NetworkCommons documentation at https://networkcommons.readthedocs.io/.

PMID:39907203 | DOI:10.1093/bioinformatics/btaf048

iScience. 2025 Jan 4;28(2):111758. doi: 10.1016/j.isci.2025.111758. eCollection 2025 Feb 21.

ABSTRACT

Bladder tumors with aggressive characteristics often present microenvironmental niches marked by low oxygen levels (hypoxia) and limited glucose supply due to inadequate vascularization. The molecular mechanisms facilitating cellular adaptation to these stimuli remain largely elusive. Employing a multi-omics approach, we discovered that hypoxic and glucose-deprived cancer cells enter a quiescent state supported by mitophagy, fatty acid β-oxidation, and amino acid catabolism, concurrently enhancing their invasive capabilities. Reoxygenation and glucose restoration efficiently reversed cell quiescence without affecting cellular viability, highlighting significant molecular plasticity in adapting to microenvironmental challenges. Furthermore, cancer cells exhibited substantial perturbation of protein O-glycosylation, leading to simplified glycophenotypes with shorter glycosidic chains. Exploiting glycoengineered cell models, we established that immature glycosylation contributes to reduced cell proliferation and increased invasion. Our findings collectively indicate that hypoxia and glucose deprivation trigger cancer aggressiveness, reflecting an adaptive escape mechanism underpinned by altered metabolism and protein glycosylation, providing grounds for clinical intervention.

PMID:39906564 | PMC:PMC11791300 | DOI:10.1016/j.isci.2025.111758