Cell Syst. 2025 Jun 16:101297. doi: 10.1016/j.cels.2025.101297. Online ahead of print.

ABSTRACT

Does an ecological community allow stable species coexistence? Identifying the general effects of competitive, mutualistic, and predator-prey interactions on stability remains a central problem of systems ecology because established approaches cannot account for the full network arrangement of these interactions. Here, we therefore analyze all interaction networks of N≤5 species with Lotka-Volterra dynamics by combining exact results and numerical exploration. We find that a very small subset of these networks is "impossible ecologies," in which stable coexistence is non-trivially impossible. We prove that the possibility of stable coexistence is determined by similarly rare "irreducible ecologies." Statistical sampling shows that this probability varies over orders of magnitude even in ecologies that differ only in the network arrangement of identical interactions. Thus, our approach reveals that the full network structure of interactions can influence stability of coexistence more than the established effect of interaction-type proportions. A record of this paper's transparent peer review process is included in the supplemental information.

PMID:40527317 | DOI:10.1016/j.cels.2025.101297

Eur J Obstet Gynecol Reprod Biol. 2025 Jun 10;312:114525. doi: 10.1016/j.ejogrb.2025.114525. Online ahead of print.

ABSTRACT

OBJECTIVE: To evaluate diagnostic accuracy of novel nanoparticle immunoassays across different histotypes of tubo-ovarian carcinoma (TOC) at diagnosis.

METHOD: This multicenter observational study consisted of consecutive patients (n = 1,312) having surgery due to suspected ovarian pathology. Serum were analyzed with Sialyl-Thomsen-nouveau (STn) antibody and Macrophage-Galactose-Lectin (MGL) for the detection of cancer antigen 125 (CA125) and 15-3 (CA15-3) glycoforms using CA125 enzyme immunoassay (EIA), CA15-3EIA and HE4EIA as references. Receiver operating characteristics (ROC) were applied and sensitivity at 75 % and 98 % specificity were calculated across histotypes.

RESULT: TOC was present in 596 patients and 716 had benign disease. CA125STn showed higher sensitivity at 98 % specificity compared with CA125EIA for high grade serous ovarian carcinoma (HGSC) (0.85 vs 0.62, p < 0.001), HGSC early-stage (0.66 vs 0.24, p = 0.003), and HGSC late-stage (0.90 vs 0.69, p < 0.001). CA15-3STn showed higher sensitivity at 98 % specificity compared to CA125EIA for mucinous ovarian carcinoma (0.50 vs 0.16, p = 0.038). No improvements were found for low grade serous carcinoma (LGSC), endometrioid and clear cell histotypes. The best performing combined biomarker test was CA125STn + HE4EIA with higher sensitivity at 98 % specificity for HGSC (0.93 vs 0.86, p < 0.001) and HGSC late-stage (0.97 vs 0.91p < 0.001) compared with CA125EIA + HE4EIA.

CONCLUSION: The STn glycovariants of CA125 and CA15-3 have improved sensitivity at high specificity for high grade serous and mucinous ovarian carcinoma and often perform better than the commonly used biomarker CA125EIA.

PMID:40527115 | DOI:10.1016/j.ejogrb.2025.114525

Elife. 2025 Jun 17;13:RP100604. doi: 10.7554/eLife.100604.

ABSTRACT

Metabolic pathways are remodeled in response to energy and other homeostatic demands and are dynamically regulated during embryonic development, suggesting a role in guiding cellular differentiation. Here, we show that glycolytic flux is required and sufficient to bias multipotent retinal progenitor cells (RPCs) to acquire a rod photoreceptor fate in the murine retina. In RPC-specific Phosphatase and tensin homolog conditional knockout (Pten-cKO) and RPC-specific conditional gain-of-function of dominant active PFKFB3 (cytoPFKFB3) mice, glycolytic gene expression and activity are elevated, correlating with precocious rod photoreceptor differentiation and outer segment (OS) maturation. Conversely, glycolytic inhibition in retinal explants suppresses RPC proliferation and photoreceptor differentiation, achieved either with 2-deoxy-D-glucose, a competitive inhibitor of glucose metabolism, by lowering media pH, which disables PKM2, a rate-limiting enzyme, or by inhibiting lactate/H+ symporters, which lowers intracellular pH. Mechanistically, we show that Wnt signaling, the top-upregulated pathway in Pten-cKO retinas, is a glycolysis-dependent pathway. Pharmacological and genetic perturbation of Wnt signaling by knocking-out Ctnnb1, encoding β-catenin, phenocopies glycolytic inhibition, suppressing RPC proliferation, photoreceptor differentiation, and OS maturation. Thus, developmental rewiring of glycolytic flux modulates Wnt signaling to drive rod photoreceptor differentiation and maturation, an instructive role that may be exploited therapeutically for cell replacement strategies.

PMID:40526494 | DOI:10.7554/eLife.100604

J Proteome Res. 2025 Jun 17. doi: 10.1021/acs.jproteome.5c00191. Online ahead of print.

ABSTRACT

Neuroblastoma, a prevalent and aggressive childhood cancer, lacks effective treatments. Recent research highlights the repurposing of existing drugs as a strategy for breakthroughs in combating this disease. We systematically analyzed small-molecule perturbation gene expression data from the Library of Integrated Network-Based Cellular Signatures (LINCS), identifying pyrvinium pamoate and sirolimus, two FDA-approved drugs, as potential candidates for neuroblastoma combination therapy. Colony formation assays and organoid culture confirmed that the therapeutic effect of combining these two drugs exceeded that of either drug alone. The mRNA expression levels of several genes predicted by LINCS also decreased. To comprehensively understand the mechanism behind superior efficacy of the combination therapy compared to monotherapy, we performed quantitative proteomics with tandem mass tag labeling and identified 3416 proteins from 20,623 peptides. Gene set enrichment analysis and Database for Annotation, Visualization, and Integrated Discovery revealed that combination therapy significantly decreased cytoskeleton formation compared with monotherapy, reflecting dramatic reduction in cell migration. Additionally, the research indicated that cell cycle arrest occurred under combination therapy. Furthermore, we confirmed that the extent of autophagy significantly increased after the combination treatment. In summary, this study elucidates the mechanisms and therapeutic potential of combining sirolimus and pyrvinium pamoate for treating neuroblastoma, offering new advancements for this challenging disease.

PMID:40526398 | DOI:10.1021/acs.jproteome.5c00191

Radiology. 2025 Jun;315(3):e242634. doi: 10.1148/radiol.242634.

ABSTRACT

Background Many state laws require insurance coverage for supplemental screening MRI in women at elevated risk for breast cancer, but MRI capacity is limited. Purpose To evaluate the impact of contrast-enhanced mammography (CEM) on incremental cancer detection rate (ICDR), false-positive rate (FPR) due to recall, and positive predictive value of biopsies performed (PPV3) when added to digital breast tomosynthesis (DBT) in women eligible for screening MRI. Materials and Methods From March 2021 to December 2022, 615 eligible women were prospectively recruited and consented to a single screening CEM examination with clinical DBT. Two radiologists interpreted each imaging study: Reader 1 recorded DBT findings first, and reader 2 recorded CEM findings first. Incremental cancer detection rate, cancer type and/or nodal status, FPR, PPV3, interval cancer rate, and areas under receiver operating characteristic curve (AUCs) based on forced Breast Imaging Reporting and Data System assessments were evaluated. Results Six hundred one women (mean age, 56 years [range: 30-75 years]) completed CEM. Twelve of the 601 women (2.0%) were diagnosed with 16 malignant lesions; cancers in five of the 12 women (42%) were detected by reader 1 at DBT, and one was detected at DBT by reader 2 (also seen on CEM by both observers). Cancers in the other six women were identified only with CEM (ICDR, six per 601 or 10.0 per 1000 women [95% CI: 3.3, 18.3]): five had invasive disease, all node negative, with a median lesion size of 0.7 cm (range: 0.4-1.1 cm); three were lobular. The FPR of combined DBT plus CEM was 127 of 589 (21.6%) for reader 1, which was an increase of 13.4% (95% CI: 10.8, 16.4) over DBT alone at 48 of 589 (8.1%). Despite increased FPR, the addition of CEM improved the overall AUC for reader 1 to 0.92 versus 0.73 for DBT alone (P = .016). Among the 601 women, 50 (8.3%) were recommended for biopsy according to CEM by reader 1, and six of the 50 (12%) were diagnosed with cancer. At the lesion level, the PPV3 was seven of 62 (11%) for biopsies prompted only with CEM by reader 1. There were no interval cancers at 1 year. Conclusion A significant increase in the detection of early-stage breast cancer was achieved using CEM after DBT. Despite substantially increasing the FPR, adding CEM to DBT improved the overall AUC by 0.19. ClinicalTrials.gov registration no.: NCT04764292 © RSNA, 2025 Supplemental material is available for this article.

PMID:40525975 | DOI:10.1148/radiol.242634

iScience. 2025 May 19;28(6):112698. doi: 10.1016/j.isci.2025.112698. eCollection 2025 Jun 20.

ABSTRACT

Streptomyces tsukubaensis NRRL 18488, the primary producer of the immunosuppressant FK506, was analyzed to elucidate regulatory features of secondary metabolism. Completion of its 7.9-Mb linear genome enabled accurate re-annotation of the FK506 biosynthetic gene cluster (BGC). Transcriptome analysis during BGC activation revealed major transcriptional shifts from primary to secondary metabolism, especially in genes involved in FK506 biosynthesis and lysine metabolism. Primary transcriptome mapping identified 1,225 transcription units and uncovered post-transcriptional regulation of allylmalonyl-CoA production, a key FK506 precursor. Ribosome profiling demonstrated that AT-rich codons reduce translational efficiency in S. tsukubaensis, with pronounced ribosome pausing at the TTA codon within the FK506 BGC. Substituting this codon relieved pausing and improved FK506 production. Together, these integrative genomic, transcriptomic, and translatomic analyses highlight how multi-level regulatory mechanisms shape secondary metabolism in Streptomyces. This work offers insights into metabolic control that could inform future efforts in strain improvement for efficient natural products production.

PMID:40524956 | PMC:PMC12167820 | DOI:10.1016/j.isci.2025.112698

Br J Nutr. 2025 Jun 17:1-42. doi: 10.1017/S0007114525103668. Online ahead of print.

ABSTRACT

Food insecurity affects the health of college-aged individuals, but its impact on the gut microbiome (GM) over time is poorly understood. This study explored the association between food insecurity and the GM in 85 college students, identifying microbial taxa, metabolites, and pathways linked to food security status and examining GM stability and microbe-metabolite interactions. Longitudinal GM and metabolomic data were collected from first-year students over an academic year, encompassing periods of variable food security status. Participants were categorized into three groups: food insecure (FI, n=13), food secure (FS, n=44), and variable (VAR, n=28) status. GM composition varied significantly between FS classifications (Bray-Curtis dissimilarity, P ≤ 0.005). Stability analysis revealed correlations between stability scores and microbial features, pathways, and metabolites. Specific microbes (e.g., Bifidobacterium species, Faecalibacterium prausnitizii D, and Lachnospiraceae), pathways (energy and microbial turnover), and metabolites (cadaverine, N-acetylcadaverine, putrescine, testosterone sulfate, and creatine) associated with FI status were identified. Multi-omic integration revealed metabolic pathways influenced by differentially abundant microbial species and co-occurring fecal metabolites in food-insecure participants related to the microbial production of polyamines, detoxification, and energy metabolism. The transition from FS to FI showed no significant differences at specific taxonomic, functional, or metabolite levels. This study uncovers complex interactions between food security, GM composition, and metabolism. Significant differences were found in microbial community variability and metabolic pathways associated with food security status, but the transition from food security to insecurity disrupted the GM without clear taxonomic or functional distinctions, emphasizing the need for further research into these mechanisms.

PMID:40524571 | DOI:10.1017/S0007114525103668

J Tradit Chin Med. 2025 Jun;45(3):610-617. doi: 10.19852/j.cnki.jtcm.20250103.001.

ABSTRACT

OBJECTIVE: To take Baihui (GV20) and Fengchi (GB20) targeting inflammatory response to regulate migraine as an example to describe a new method for studying the mechanism of stimulating acupoints.

METHODS: The target information of Baihui (GV20) and Fengchi (GB20) was retrieved, and after intersection with migraine, Kyoto Encyclopedia of Genes and Genomes (KEGG), Reactome, and UniProt Keywords were used for functional enrichment. After selecting the main pathway, rats were selected and nitroglycerin was used for modeling, and the behavioral scores, inflammatory factors, heme oxygenase 1 (HMOX1), protein kinase B (AKT1), signal transducer and activator of transcription 3 (STAT3), phosphorylated extracellular signal-regulated kinase 1/2 (P-ERK1/ERK2) and other states of the rats in the acupuncture, twisting, and electroacupuncture groups were compared.

RESULTS: A total of 135 Baihui (GV20) targets and 27 Fengchi (GB20) targets were collected. A total of 73 target information were obtained after the intersection of these targets in migraine. These 73 targets have three main pathways: hypoxia-inducible factor 1 (HIF-1) signaling pathway, signaling by interleukins and inflammatory response. The main targets in the pathway were verified and found that interleukin-1 beta (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α) and HMOX1, AKT1, STAT3, P-ERK1/ERK2 can be regulated by Baihui (GV20) and Fengchi (GB20).

CONCLUSION: Baihui (GV20) and Fengchi (GB20) can regulate migraine by regulating inflammatory factors and HMOX1, AKT1, STAT3, P-ERK1/ERK2 and other changes in HIF-1 signaling pathway, Signaling by Interleukins and Inflammatory response pathways. Based on systems biology and network pharmacology, and with the model of "acupoint-target-disease", explore the research methods of systematic acupuncture and moxibustion. We believe this is a usable research direction for exploring the mechanism of acupuncture stimulation.

PMID:40524299 | DOI:10.19852/j.cnki.jtcm.20250103.001

Cancer Metab. 2025 Jun 16;13(1):28. doi: 10.1186/s40170-025-00400-7.

ABSTRACT

BACKGROUND: Targeted therapy interventions using tyrosine kinase inhibitors (TKIs) provide encouraging treatment responses in patients with ALK-rearranged lung adenocarcinomas, yet resistance occurs almost inevitably. In addition to tumor cell-intrinsic resistance mechanisms, accumulating evidence suggests that cancer-associated fibroblasts (CAFs) within the tumor microenvironment contribute to therapy resistance. This study aimed to investigate CAF-driven molecular networks that shape the therapeutic susceptibility of ALK-driven lung adenocarcinoma cells.

METHODS: Three-dimensional (3D) spheroid co-cultures comprising ALK-rearranged lung adenocarcinoma cells and CAFs were utilized to model the tumor microenvironment. Single-cell RNA sequencing was performed to uncover transcriptional differences between TKI-treated homotypic and heterotypic spheroids. Functional assays assessed the effects of CAF-conditioned medium and CAF-secreted factors on tumor cell survival, proliferation, lipid metabolism, and downstream AKT signaling. The therapeutic potential of targeting metabolic vulnerabilities was evaluated using pharmacological inhibition of lipid metabolism and by ferroptosis induction.

RESULTS: CAFs significantly diminished the apoptotic response of lung tumor cells to ALK inhibitors while simultaneously enhancing their proliferative capacity. Single-cell RNA sequencing identified lipogenesis-associated genes as a key transcriptional difference between TKI-treated homotypic and heterotypic lung tumor spheroids. CAF-conditioned medium and the CAF-secreted factors HGF and NRG1 activated AKT signaling in 3D-cultured ALK-rearranged lung tumor cells, leading to increased de novo lipogenesis and suppression of lipid peroxidation. These metabolic adaptations were critical for promoting tumor cell survival and fostering therapy resistance. Notably, both dual inhibition of ALK and the lipid-regulatory factor SREBP-1, as well as co-treatment with ferroptosis inducers such as erastin or RSL3, effectively disrupted the CAF-driven metabolic-supportive niche and restored sensitivity of resistant lung tumor spheroids to ALK inhibition.

CONCLUSIONS: This study highlights a critical role for CAFs in mediating resistance to ALK-TKIs by reprogramming lipid metabolism in ALK-rearranged lung cancer cells. It suggests that targeting these metabolic vulnerabilities, particularly through inhibition of lipid metabolism or induction of ferroptosis, could provide a novel therapeutic approach to overcome resistance and improve patient outcomes.

PMID:40524253 | DOI:10.1186/s40170-025-00400-7

J Pharmacokinet Pharmacodyn. 2025 Jun 16;52(4):36. doi: 10.1007/s10928-025-09984-5.

ABSTRACT

Quantitative Systems Pharmacology (QSP) has emerged as a cornerstone of modern drug development, providing a robust framework to integrate data from preclinical and clinical studies, enhance decision-making, and optimize therapeutic strategies. By modeling biological systems and drug interactions, QSP enables predictions of outcomes, optimization of dosing regimens, and personalized medicine applications. Recent advancements in artificial intelligence (AI) and machine learning (ML) hold the potential to significantly transform QSP by enabling enhanced data extraction, fostering the development of hybrid mechanistic ML models, and supporting the introduction of surrogate models and digital twins. This manuscript explores the transformative role of AI and ML in reshaping QSP modeling workflows. AI/ML tools now enable automated literature mining, the generation of dynamic models from data, and the creation of hybrid frameworks that blend mechanistic insights with data-driven approaches. Large Language Models (LLMs) further revolutionize the field by transitioning AI/ML from merely a tool to becoming an active partner in QSP modeling. By facilitating interdisciplinary collaboration, lowering barriers to entry, and democratizing QSP workflows, LLMs empower researchers without deep coding expertise to engage in complex modeling tasks. Additionally, the integration of Artificial General Intelligence (AGI) holds the potential to autonomously propose, refine, and validate models, further accelerating innovation across multiscale biological processes. Key challenges remain in integrating AI/ML into QSP workflows, particularly in ensuring rigorous validation pipelines, addressing ethical considerations, and establishing robust regulatory frameworks to address the reliability and reproducibility of AI-assisted models. Moreover, the complexity of multiscale biological integration, effective data management, and fostering interdisciplinary collaboration present ongoing hurdles. Despite these challenges, the potential of AI/ML to enhance hybrid model development, improve model interpretability, and democratize QSP modeling offers an exciting opportunity to revolutionize drug development and therapeutic innovation. This work highlights a pathway toward a transformative era for QSP, leveraging advancements in AI and ML to address these challenges and drive innovation in the field.

PMID:40524056 | DOI:10.1007/s10928-025-09984-5

NPJ Precis Oncol. 2025 Jun 16;9(1):188. doi: 10.1038/s41698-025-00973-y.

ABSTRACT

Patients with high-grade serous ovarian cancer (HGSOC) typically present with widespread metastasis, obscuring a temporal understanding of tumor-immune dynamics. To address this, we perform multi-site global proteomics alongside matched immunohistochemistry (IHC) for CD4⁺ and CD8⁺ tumor-infiltrating lymphocytes (TILs) in patient samples. We order the protein expression profiles using an unbiased pseudotime analysis, recapitulating clinical observations of metastatic progression, and providing a framework to explore tumor-immune dynamics from localized to metastatic disease. Metastatic progression correlates with immune cell infiltration, the recruitment of regulatory T cells (Tregs) to counterbalance γδ T cell abundance, and an increased abundance of exhausted CD8⁺ T cells. The accumulation of Tregs at metastatic sites correlates with SNX8 expression, a critical regulator of the STING pathway. In early-stage tumors, keratin-expressing cancer cells recruit Tregs via MHC class II, fostering an inflammatory phenotype with limited IFNγ production and non-clonally expanded T cells. Together, our findings reveal novel mechanisms of immune escape associated with both localized disease and metastatic progression in HGSOC.

PMID:40523956 | DOI:10.1038/s41698-025-00973-y

Nat Commun. 2025 Jun 16;16(1):5317. doi: 10.1038/s41467-025-60575-x.

ABSTRACT

Spatial multi-slice multi-omics (SMSMO) integration has transformed our understanding of cellular niches, particularly in tumors. However, challenges like data scale and diversity, disease heterogeneity, and limited sample population size, impede the derivation of clinical insights. Here, we propose stClinic, a dynamic graph model that integrates SMSMO and phenotype data to uncover clinically relevant niches. stClinic aggregates information from evolving neighboring nodes with similar-profiles across slices, aided by a Mixture-of-Gaussians prior on latent features. Furthermore, stClinic directly links niches to clinical manifestations by characterizing each slice with attention-based geometric statistical measures, relative to the population. In cancer studies, stClinic uses survival time to assess niche malignancy, identifying aggressive niches enriched with tumor-associated macrophages, alongside favorable prognostic niches abundant in B and plasma cells. Additionally, stClinic identifies a niche abundant in SPP1+ MTRNR2L12+ myeloid cells and cancer-associated fibroblasts driving colorectal cancer cell adaptation and invasion in healthy liver tissue. These findings are supported by independent functional and clinical data. Notably, stClinic excels in label annotation through zero-shot learning and facilitates multi-omics integration by relying on other tools for latent feature initialization.

PMID:40523901 | DOI:10.1038/s41467-025-60575-x

J Biol Chem. 2025 Jun 14:110379. doi: 10.1016/j.jbc.2025.110379. Online ahead of print.

ABSTRACT

Protein-carbohydrate binding plays an essential role in biological processes including cellular recognition and immune signaling. However, glycans are hydrophilic with limited hydrophobic surfaces, a challenge for selective recognition by proteins. CH-π stacking interactions are pervasive in protein-carbohydrate binding sites and have emerged as critical drivers of protein-carbohydrate recognition. They are highly favorable and have a broad orientational landscape. However, it is unknown how CH-π stacking interaction orientational dynamics are influenced by the protein environment and what their functional interplay is with hydrogen bonds in protein-carbohydrate binding. Here, we employ well-tempered metadynamics simulations to obtain binding free energy landscapes for a set of protein-β-D-galactoside complexes with CH-π stacking interactions. Our data show that the favored orientation of a CH-π stacking interaction is controlled by the location of hydrogen bonds in the protein binding site. Complexes with extended carbohydrate ligands that form additional hydrogen bonds have more specific orientational dependences, while protein variant complexes with fewer hydrogen bonds have broader free energy landscapes with glycan ligands adopting multiple CH-π stacking interaction orientations. We also show that forming multiple CH-π stacking interactions facilitates the dynamics necessary for the translocation of oligosaccharide ligands within a processive enzyme. Our findings underscore the cooperative nature of hydrogen bonds and CH-π stacking interactions, demonstrating that tuning the number and positions of these interactions through evolution or protein engineering can alter ligand recognition or support ligand movement in protein binding sites.

PMID:40523618 | DOI:10.1016/j.jbc.2025.110379

Proc Natl Acad Sci U S A. 2025 Jun 24;122(25):e2510268122. doi: 10.1073/pnas.2510268122. Epub 2025 Jun 16.

NO ABSTRACT

PMID:40523194 | DOI:10.1073/pnas.2510268122

Proc Natl Acad Sci U S A. 2025 Jun 24;122(25):e2500621122. doi: 10.1073/pnas.2500621122. Epub 2025 Jun 16.

ABSTRACT

Iron (Fe) availability limits photosynthesis at a global scale where Fe-rich photosystem (PS) I abundance is drastically reduced in Fe-poor environments. We used single-particle cryoelectron microscopy to reveal a unique Fe starvation-dependent arrangement of light-harvesting chlorophyll (LHC) proteins where Fe starvation-induced TIDI1 is found in an additional tetramer of LHC proteins associated with PSI in Dunaliella tertiolecta and Dunaliella salina. These cosmopolitan green algae are resilient to poor Fe nutrition. TIDI1 is a distinct LHC protein that co-occurs in diverse algae with flavodoxin (an Fe-independent replacement for the Fe-containing ferredoxin). The antenna expansion in eukaryotic algae we describe here is reminiscent of the iron-starvation induced (isiA-encoding) antenna ring in cyanobacteria, which typically co-occurs with isiB, encoding flavodoxin. Our work showcases the convergent strategies that evolved after the Great Oxidation Event to maintain PSI capacity.

PMID:40523173 | DOI:10.1073/pnas.2500621122

Med Oncol. 2025 Jun 16;42(7):266. doi: 10.1007/s12032-025-02831-0.

ABSTRACT

Lung cancers, including small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), remain the leading cause of cancer-related mortality worldwide, with the tumor microenvironment (TME) playing a crucial role in disease progression. Among the immune components of the TME, tumor-associated neutrophils (TANs) and neutrophil extracellular traps (NETs) have garnered increasing attention due to their complex and sometimes contrasting roles in tumor biology. TANs exhibit both protumor and antitumor functions, either promoting lung cancer progression through enhanced tumor cell proliferation, invasion, angiogenesis, and metastasis or exerting antitumor effects by stimulating immune responses and cytotoxicity. Their impact is largely context-dependent and influenced by interactions with other immune cells, particularly T cells, within the lung cancer TME. Additionally, NETs, secreted by neutrophils, play a pivotal role in tumor progression by facilitating tumor growth, invasion, metastasis, and cancer-associated thrombosis. Although the precise mechanisms underlying NET-mediated tumor promotion are not yet fully elucidated, accumulating evidence suggests their significant contribution to lung cancer pathophysiology. This review synthesizes recent findings on the dual roles of TANs, their interactions with T cells, and the emerging molecular insights into NETs in lung cancer. By elucidating the intricate interplay between TANs, NETs, and immune cells, we aim to provide a foundation for the development of novel therapeutic strategies targeting neutrophil-mediated tumor dynamics.

PMID:40522596 | DOI:10.1007/s12032-025-02831-0

J Comput Aided Mol Des. 2025 Jun 16;39(1):32. doi: 10.1007/s10822-025-00604-5.

ABSTRACT

Designing reaction pathways that maximize the production of a target compound in a given metabolic network is a fundamental problem in systems biology. In this study, we systematically explore the non-oxidative glycolysis metabolic network, guided by the principle that reactions with negative Gibbs free energy differences are thermodynamically favored. We enumerate alternative pathways that implement the net non-oxidative glycolysis reaction, categorized by their length. Our analysis reveals several alternative thermodynamically favorable pathways beyond the experimentally reported ones. Additionally, we identify molecules within the network, such as 3-hydroxypropionic acid, that may have significant potential for further investigation.

PMID:40522364 | DOI:10.1007/s10822-025-00604-5

Elife. 2025 Jun 16;13:RP96803. doi: 10.7554/eLife.96803.

ABSTRACT

Motivational deficits are common in several brain disorders, and motivational syndromes like apathy and anhedonia predict worse outcomes. Disrupted effort-based decision-making may represent a neurobiological underpinning of motivational deficits, shared across neuropsychiatric disorders. We measured effort-based decision-making in 994 participants using a gamified online task, combined with computational modelling, and validated offline for test-retest reliability. In two pre-registered studies, we first replicated studies linking impaired effort-based decision-making to neuropsychiatric syndromes, taking both a transdiagnostic and a diagnostic-criteria approach. Next, testing participants with early and late circadian rhythms in the morning and evening, we find circadian rhythm interacts with time-of-testing to produce parallel effects on effort-based decision-making. Circadian rhythm may be an important variable in computational psychiatry, decreasing reliability or distorting results when left unaccounted for. Disentangling effects of neuropsychiatric syndromes and circadian rhythm on effort-based decision-making will be essential to understand motivational pathologies and to develop tailored clinical interventions.

PMID:40522113 | DOI:10.7554/eLife.96803

Proteins. 2025 Jun 16. doi: 10.1002/prot.26852. Online ahead of print.

ABSTRACT

EgLIP1 is an oil-body lipase (EC 3.1.1.3) overexpressed in the fruit mesocarp of Elaeis guineensis (oil palm). Despite its significant role in fruit ripening and the hydrolysis of of triacylglycerol into free fatty acids (FFA) in oil palm, the molecular structure and functional understanding of EgLIP1 are yet to be fully elucidated. Phylogenetic analysis reveals that EgLIP1 shares homology with several plant oil-body lipases. The 3D structure of EgLIP1 was modeled using AlphaFold 2 with high confidence (pLDDT score of 89.7). Structural comparison with Rhizomucor miehei triacylglycerol lipase (RML) reveals that the regions β1, η1, α1, η2, β2, α2, α3, α4, α15, α16, and β15 represent novel insertions unique to EgLIP1, while the overall fold in other regions of the protein remains highly conserved in comparison to RML. Notably, an insertion of residue "PF" was also found in EgLIP1 and its plant orthologs. This insertion is located immediately before the lid domain helix, forming a kink facing toward the active lipase site. Enzyme-membrane surface interaction prediction suggests that α1, α3, α4, α15, and α16 are likely involved in anchoring EgLIP1 at the interface of the phospholipid monolayer of oil bodies. Molecular docking and molecular dynamics (MD) simulation analyses of EgLIP1 with its potential substrate, 1-palmitoylglycerol, demonstrate that the catalytic serine residue S308 and the GX oxyanion hole motif residue T223 can form hydrogen bonds with the carbonyl group of the ligand to initiate a nucleophilic attack on the substrate. Our structure-guided functional studies provide molecular insights into how EgLIP1 associates with oil bodies and catalyzes its potential substrates.

PMID:40521868 | DOI:10.1002/prot.26852

Curr Res Microb Sci. 2025 May 23;9:100410. doi: 10.1016/j.crmicr.2025.100410. eCollection 2025.

ABSTRACT

Winemaking is influenced by many factors, from the vineyard to the fermentation process. While traditional approaches have focused on vineyard treatments and controlled fermentations to ensure a stable product, global warming has made it necessary to reassess the effects of these factors on winemaking. This study aimed to evaluate the impact of vintage, management, and environmental settings on the composition of yeast populations driving grape spontaneous fermentations and defining the characteristics of the final product. Our results emphasize how climate change and the vineyard's yeast populations influence fermentation, showing that while the vintage plays a key role in grape composition, it s not the sole determinant of fermentation. The geographical location of the vineyard, alongside the management practices and vintage, shapes the composition and dynamics of yeast populations. Specific vineyard conditions sometimes lead to stable and unique yeast populations. Furthermore, the grape origin affects both the yeast population and the wine's volatile compounds, with certain yeast species, like Saccharomyces cerevisiae, being linked to specific environmental features. While vintage and climate change impact a smaller portion of the yeast population, the environment remains a significant influence. As fermentation progresses, the yeast populations retain vineyard-specific characteristics, underlining the strong connection between yeast dynamics and environmental factors. Understanding these interactions is crucial for adapting to global warming and optimizing wine fermentation processes. It will help improve wine quality, innovation, and specific wine characteristics through better management of microbial communities in the grape-wine ecosystem.

PMID:40521374 | PMC:PMC12164235 | DOI:10.1016/j.crmicr.2025.100410