Alzheimers Dement. 2025 Aug;21(8):e70519. doi: 10.1002/alz.70519.

ABSTRACT

INTRODUCTION: Mitochondrial dysfunction is implicated in Alzheimer's disease (AD), but whether it drives AD-associated changes is unclear. We assessed transcriptomic alterations in the brains of Ndufs4-/- mice, a model of mitochondrial complex I (mtCI) deficiency, and evaluated the therapeutic effects of the neuroprotective mtCI inhibitor CP2.

METHODS: Cortico-hippocampal tissue from Ndufs4-/- and wild-type mice was subjected to transcriptomic analysis, followed by cross-species comparisons to human late-onset AD and familial AD mouse datasets.

RESULTS: Knockout of Ndufs4-mediated mtCI deficiency disrupted mitochondrial homeostasis, energy metabolism, and synaptic gene expression, recapitulating transcriptomic signatures of AD. CP2 treatment partially reversed these changes, with female Ndufs4-/- mice showing greater compensatory adaptations and treatment responses.

DISCUSSION: Loss of mtCI activity alone is sufficient to induce AD-like molecular changes in the brain, independent of amyloid beta or phosphorylated tau. CP2-mediated rescue highlights the potential of targeting mitochondria as a therapeutic strategy for AD. Sex-specific responses suggest important considerations for personalized therapeutics.

HIGHLIGHTS: Activity of mitochondrial complex I (mtCI) affects broad mitochondrial and neuronal transcriptional networks. A reduction of mtCI activity is sufficient to induce transcriptomic changes reminiscent of those observed in late-onset Alsheimer's disease (AD) patients and familial mouse models of AD. Pharmacological targeting of mtCI mediates neuroprotective signaling. Male and female mice have differential responses to the loss of mtCI activity and to the mitochondria-targeted therapeutics. Mitochondria play a key role in AD development and treatment.

PMID:40731203 | DOI:10.1002/alz.70519

Nat Microbiol. 2025 Jul 29. doi: 10.1038/s41564-025-02070-z. Online ahead of print.

ABSTRACT

The global surge in antimicrobial resistance presents a critical threat to public health, emphasizing the urgent need for the development of new and more effective bacterial vaccines. Since the success of mRNA vaccines during the COVID-19 pandemic, this vaccine strategy has rapidly advanced, with most efforts focused on cancer immunotherapy and targeting viral pathogens. Recently, mRNA vaccines have entered the early phases of clinical development for bacterial diseases. However, bacteria present greater biological complexity compared with viruses, posing additional challenges for vaccine design, such as antigen selection, immune response and mRNA construct design. Here, we discuss critical aspects in the development of bacterial mRNA vaccines, from antigen selection to construct design. We also highlight the current preclinical landscape and discuss remaining translational challenges and future potential for mRNA vaccines against bacterial infections.

PMID:40730911 | DOI:10.1038/s41564-025-02070-z

Nat Commun. 2025 Jul 29;16(1):6948. doi: 10.1038/s41467-025-62066-5.

ABSTRACT

Pre- and post-transcriptional mechanisms, including alternative promoters, termination signals, and splicing, play essential roles in diversifying protein output by generating distinct RNA and protein isoforms. Two major challenges in characterizing the cellular function of alternative isoforms are the lack of experimental methods to specifically and efficiently modulate isoform expression and computational tools for complex experimental design and analysis. To address these gaps, we develop and methodically test an isoform-specific knockdown strategy which pairs the RNA-targeting CRISPR/Cas13d system with guide RNAs that span exon-exon junctions. In parallel, we provide computational tools for experimental design and analysis. In this study, we demonstrate that junction-targeting achieves robust and isoform-specific RNA knockdown across diverse alternative isoform events, genes, and cell types.

PMID:40730819 | DOI:10.1038/s41467-025-62066-5

Mol Divers. 2025 Jul 29. doi: 10.1007/s11030-025-11300-9. Online ahead of print.

ABSTRACT

Tuberculosis, caused by Mycobacterium tuberculosis (Mtb), remains a critical global health challenge due to rising drug resistance and the pathogen's ability to persist in hostile host environments. Identifying novel molecular targets that underlie Mtb's unique survival mechanisms is essential for developing more effective therapies. In this study, we developed an integrative computational pipeline combining genome-scale metabolic modeling, flux balance analysis (FBA), comparative genomics, and network-based prioritization to uncover metabolic vulnerabilities specific to Mtb. Comparative analysis with the reductively evolved Mycobacterium leprae revealed significant differences in pathways involved in pantothenate biosynthesis (PanB), peptidoglycan synthesis (GlmU), and branched-chain amino acid metabolism (IlvN). These targets were prioritized based on gene essentiality, dormancy-associated expression, druggability, and absence of human homologs to maximize therapeutic selectivity. Molecular docking, followed by MM-GBSA binding free energy calculations, identified high-affinity ligands from LifeChemicals and ChEMBL libraries interacting strongly with active-site residues. Molecular dynamics simulations were performed to further validate target engagement and ligand retention, revealing stable conformational behavior and persistent protein-ligand interactions across 300 ns. Similarly, metabolite flux analysis and pathway enrichment highlighted adaptive rewiring in glycine, serine, pyruvate, and nitrogen metabolism, reflecting Mtb's persistence strategies under host-imposed stress. This study provides a robust, generalizable pipeline for pathogen-specific drug target and ligand discovery and supports the rational development of new therapies against drug-resistant tuberculosis.

PMID:40730708 | DOI:10.1007/s11030-025-11300-9

Cell Rep Methods. 2025 Jul 23:101117. doi: 10.1016/j.crmeth.2025.101117. Online ahead of print.

ABSTRACT

This paper reports a 3D-printed plug as a meso-scale interface solution that minimizes sample loss and enhances cell usage efficiency, seamlessly connecting microfluidic systems to conventional well plates. The plug concentrates cells near the region of interest for chemotaxis, reducing cell number requirements and featuring tapered structures for efficient manual or robotic liquid handling. Comprehensive testing showed that the plug increased cell usage efficiency in single-cell migration assays by 8-fold, maintaining accuracy and sensitivity. We also extended our approach to neuron axon guidance assays, where limited cell availability is a constraint, and observed substantial improvements in assay outcomes. This integration of 3D printing with microfluidics establishes low-loss interfaces for precious samples, advancing the capabilities of microfluidic technology.

PMID:40730156 | DOI:10.1016/j.crmeth.2025.101117

Plant Physiol Biochem. 2025 Jul 25;228:110298. doi: 10.1016/j.plaphy.2025.110298. Online ahead of print.

ABSTRACT

Water stress challenges global crop productivity, particularly for perennial species such as grapevines, where effective water management is crucial for berry quality and yield. Aquaporins, a family of water channel proteins, play a key role in regulating water transport within plant cells, affecting water uptake and redistribution. Although the transcriptional response of aquaporin genes to water stress in grapevines has been documented, their translational regulation remains less explored. This study investigates the transcriptional and translational dynamics of three Plasma Membrane Intrinsic Proteins and three Tonoplast Intrinsic Proteins in leaves and roots of a grafted 'Pinot Noir' on 'Kober 5BB' rootstock during water deficit conditions and recovery. Aquaporin translation analyzed by polysome profiling and co-sedimentation analysis of their transcripts highlighted that water stress had a general negative effect, although significant only for VviTIP1-3. Conversely, recovery measured at 6 h after rewatering was characterized by a boost of translation reactivation for all but one aquaporins. Transcriptional profiling of the same aquaporins revealed significant down-regulation at prolonged stress in roots, highlighting the contribution of aquaporins to osmoregulation and drought tolerance. Moreover, transcriptional modulation resembles a long-term adaptative response to limit water loss. In the leaf, only two specific genes, VviPIP2-5 and VviTIP2-1, were modulated during water deficit and even more during recovery and positively correlated with stomatal conductance and leaf water potential. They represent important regulators of water homeostasis and good candidates for breeding programs. This study uncovered an additional level of aquaporin post-transcriptional control finely tuning vines to changing external conditions.

PMID:40729951 | DOI:10.1016/j.plaphy.2025.110298

J Hazard Mater. 2025 Jul 26;496:139367. doi: 10.1016/j.jhazmat.2025.139367. Online ahead of print.

ABSTRACT

Abelmoschus manihot is a promising cadmium (Cd) hyperaccumulator for phytoremediation, but its endophytic bacterial community diversity and the bioremediation potential of its culturable endophytes remain underexplored. In this study, we employed high-throughput sequencing technology to comprehensively analyze the diversity, structure, and composition of endophytic bacteria in A. manihot under different levels of Cd stress. Our results showed that the root endosphere community was more strongly affected by Cd stress than the aboveground endosphere. Cd exposure markedly reduced bacterial diversity and altered the composition of the dominant genera in the root endosphere across different Cd concentrations. Network analysis revealed that Cd stress increased microbial connectivity in root communities while reducing network complexity in aboveground communities, indicating tissue-specific microbial adaptation. In the microbial networks, keystone taxa, primarily from the phyla Proteobacteria and Firmicutes, played essential roles in microbial interactions. Functional profiling through PICRUSt2 prediction revealed significant differences in the metabolic pathways of endophytic bacteria between plant compartments. Interestingly, pathways associated with transcription factors, quorum sensing, and glyoxylate and dicarboxylate metabolism were upregulated in both the root and leaf microbiomes under Cd stress. Furthermore, a core microbiome of 33 amplicon sequence variants (ASVs), dominated by Proteobacteria and Firmicutes, was consistently present across both root and aboveground tissues. 41 Cd-resistant endophytic strains were further isolated, among which the Bacillus strain BL-61 demonstrated strong potential for promoting plant growth and Cd accumulation. These findings underscore the critical roles of endophytic bacteria in hyperaccumulator adaptation to heavy metal stress and provide a foundation for developing microbe-assisted phytoremediation strategies.

PMID:40729874 | DOI:10.1016/j.jhazmat.2025.139367

J Reprod Immunol. 2025 Jul 18;171:104621. doi: 10.1016/j.jri.2025.104621. Online ahead of print.

ABSTRACT

Cellular senescence is a well-established biological phenomenon in eukaryotes. It involves DNA damage, telomere shortening, a senescence-associated secretory phenotype (SASP), and the inability of cells to replicate. It is associated with ageing, and also with oxidative stress. Given the importance of oxidative stress in pre-eclampsia, there is considerable evidence, that we review, that senescence plays an important role in both normal placental development and in the development of both early- and late-term pre-eclampsia. Autophagy is capable of delaying or even reversing the development of senescence, and certain small molecules such as sulforaphane and spermidine can stimulate autophagy, including via the redox-sensitive transcription factor Nrf2. Ergothioneine is a thiohistidine antioxidant that is protective against a variety of cardiovascular and other diseases. Ergothioneine also interacts with Nrf2, and pre-eclampsia occurs far less frequently in individuals with higher plasma ergothioneine levels. Together, these elements provide a self-consistent, molecular and systems biology explanation for at least one mechanism by which ergothioneine may be protective against pre-eclampsia.

PMID:40729821 | DOI:10.1016/j.jri.2025.104621

Plant Biotechnol J. 2025 Jul 29. doi: 10.1111/pbi.70282. Online ahead of print.

ABSTRACT

Chitin triggers localised and systemic plant immune responses, making it a promising treatment for sustainable disease resistance. However, the precise molecular mechanisms underlying chitin-induced systemic effects in plants remain unknown. In this study, we investigated the effects of soil amendment with crab chitin flakes (hereafter chitin) on pattern-triggered immunity (PTI) and systemic disease resistance in various plant species. We found that soil amendment with chitin potentiates PTI and disease resistance against the bacterial pathogen Pseudomonas syringae pv. tomato DC3000 in lettuce, tomato and Arabidopsis as well as against the fungal pathogen Blumeria graminis f. sp. tritici (Bgt), which causes powdery mildew in wheat. Using micrografting in Arabidopsis, we demonstrated that this systemic effect is dependent on active chitin perception in the roots. We also showed that induced systemic resistance (ISR) and pattern-recognition receptors (PRRs)/coreceptors, but not systemic acquired resistance (SAR), are involved in the systemic effects triggered by chitin soil amendment. These systemic effects correlated with the transcriptional upregulation of key PTI regulators in distal leaves upon chitin soil amendment. Notably, chitin-triggered systemic immunity was independent of microbes present in soil or chitin flakes. Together, these findings contribute to a better understanding of chitin-triggered systemic immunity, from active chitin perception in roots to the potentiation of PTI in the leaves, ultimately priming plants to mount enhanced defence responses against pathogen attacks. Our study provides valuable insights into the molecular mechanisms of chitin soil amendment and resulting induced immunity and highlights its potential use for sustainable crop protection strategies.

PMID:40729549 | DOI:10.1111/pbi.70282

Cell Prolif. 2025 Jul 29:e70103. doi: 10.1111/cpr.70103. Online ahead of print.

ABSTRACT

Differences in gene expression, which arise from divergence in cis-regulatory elements or alterations in transcription factors (TFs) binding specificity, are one of the most important causes of phenotypic diversity during evolution. On one hand, changes in the cis-elements located in the vicinity of target genes affect TF binding and/or local chromatin environment, thereby modulating gene expression in cis. On the other hand, alterations in trans-factors influence the expression of their target genes in a more pleiotropic fashion. Although the evolution of amino acid sequences is much slower than that of non-coding regulatory elements, particularly for the TF DNA binding domains (DBDs), it is still possible that changes in TF-DBD might have the potential to drive large phenotypic changes if the resulting effects have a net positive effect on the organism's fitness. If so, species-specific changes in TF-DBD might be positively selected. So far, however, this possibility has been largely unexplored. By protein sequence analysis, we observed high sequence conservation in the DBD of the TF caudal-type homeobox 2 across many vertebrates, whereas three amino acid changes were exclusively found in mouse Cdx2 (mCdx2), suggesting potential positive selection in the mouse lineage. Multi-omics analyses were then carried out to investigate the effects of these changes. Surprisingly, there were no significant functional differences between mCdx2 and its rat homologue (rCdx2), and none of the three amino acid changes had any impact on its function. Finally, we used rat-mouse allodiploid embryonic stem cells to study the cis effects of Cdx2-mediated gene regulation between the two rodents. Interestingly, whereas Cdx2 binding is largely divergent between mouse and rat, the transcriptional effect induced by Cdx2 is conserved to a much larger extent. There were no significant functional differences between mCdx2 and its rat homologue (rCdx2), and none of the three amino acid changes had any impact on its function. Moreover, Cdx2 binding is largely divergent between mouse and rat; the transcriptional effect induced by Cdx2 is conserved to a much larger extent.

PMID:40729530 | DOI:10.1111/cpr.70103

Plant Biotechnol J. 2025 Jul 29. doi: 10.1111/pbi.70279. Online ahead of print.

ABSTRACT

Botrytis cinerea (Bc) is a major pathogen of cultivated grapevine (Vitis vinifera L.), with cell wall (CW) remodelling playing a critical role in fungal colonisation. CW-modifying enzymes, particularly pectin methylesterases (PMEs), produced by both host and pathogen, influence CW integrity and the outcome of infection. To explore the role of CW composition and remodelling in grapevine's response to Bc, we inoculated three genotypes with varying susceptibility at full flowering. Biochemical analysis of flowers and ripe berry skins revealed that the tolerant genotype exhibited significantly higher PME activity postinfection compared with the susceptible ones. Unbiased transcriptome analysis of infected flower tissues showed a more intense transcriptional response in the susceptible genotype, suggesting an ultimately ineffective attempt to restrict fungus spread. Expression profiling of 62 PME genes in this data set and public Bc-infected berry transcriptomes identified PME10 as the most strongly induced gene upon infection. PME10 knockout mutants displayed reduced PME activity and heightened susceptibility, while overexpression lines showed enhanced PME activity and reduced disease symptoms. Gene co-expression network analysis highlighted WRKY03, a defence-related transcription factor, as a putative regulator of PME10. DAP-seq, DAP-qPCR and dual luciferase assays confirmed direct binding and activation of the PME10 promoter by WRKY03. Altogether, this study demonstrates that PME10 is a functional PME contributing to grapevine immunity against B. cinerea, establishing it as a key component of the grapevine defence machinery against fungal pathogens.

PMID:40729521 | DOI:10.1111/pbi.70279

PLoS Biol. 2025 Jul 29;23(7):e3003287. doi: 10.1371/journal.pbio.3003287. eCollection 2025 Jul.

ABSTRACT

Metabolic cross-feeding networks are central to shaping microbial community dynamics in environments ranging from the rhizosphere, gut, and marine carbon cycling. Yet cross-feeding has predominantly been viewed by examining exchanged small metabolites. In contrast, the role of extracellular polymeric substance (EPS)-a complex mixture of proteins, polysaccharides, DNA, and humic-like compounds-in cross-feeding remains poorly understood, mainly due to technical challenges in measuring their secretion relative to small metabolites. Using chitin-degrading microbes as a model system, we used a bicarbonate-buffered bioreactor coupled with elemental analysis, which allowed us to quantify both EPS and small metabolite secretion. This revealed that ~25% of carbon exuded by a chitin degrader is in the form of EPS. EPS was produced at similar levels across marine chitin-degrading isolates and seawater communities, underscoring its importance relative to small metabolites. Notably, different sources of EPS were found to select for distinct and diverse microbial communities. Combining in vitro enzyme assays and untargeted metabolomics, we show that EPS undergoes sequential degradation-from large oligomers to smaller, broadly accessible monomers. This sequential breakdown creates a temporal succession of metabolic niches, potentially fueling a shift from specialist species degrading complex substrates to a more diverse community of generalists using simpler monomers. By identifying EPS as a major and dynamic contributor to cross-feeding networks, our findings reveal a hidden layer of complexity in how microbial communities assemble and function across ecosystems.

PMID:40729313 | DOI:10.1371/journal.pbio.3003287

Asian Pac J Cancer Prev. 2025 Jul 1;26(7):2511-2520. doi: 10.31557/APJCP.2025.26.7.2511.

ABSTRACT

BACKGROUND: Colorectal cancer (CRC) is intricately influenced by dysregulated microRNAs (miRNAs) targeting the Wnt signaling pathway, a phenomenon pivotal in CRC initiation and progression. The exploration of miRNA-Wnt interactions holds promise for innovative therapeutic strategies in CRC treatment.

METHODS: a comprehensive list of genes influenced by dysregulated miRNAs targeting the Wnt pathway was compiled. High-scoring genes from the miRDB database underwent further analysis. Protein-protein interaction networks were constructed using Cytoscape and StringApp 2.0, with hub proteins identified through MCC, MNC, DMNC, and Degree algorithms. Gene ontology, KEGG enrichment analysis, CytoCluster, and promoter motif analysis were employed to characterize gene functions, associations, dysregulated clusters, and regulatory elements.

RESULTS: Protein-protein interaction networks unveiled 15 central hub proteins, including EP300, , NRAS, NF1, CCND1, SMAD4, SOCS7, SOCS6, NECAP1, MBTD1, ACVR1C, ESR1, CREBBP, and PIK3CA. Gene ontology and KEGG analysis revealed their involvement in critical biological processes, cellular components, and molecular functions. CytoCluster analysis identified dysregulated miRNA-targeted gene clusters linked to cancer-related pathways. Promoter motif analysis provided insights into regulatory elements governing hub protein expression.

CONCLUSION: The identified hub proteins, enriched in cancer-related pathways, offer potential therapeutic targets. These findings pave the way for future research, enhancing our ability to develop targeted interventions for improved outcomes in CRC treatment.

PMID:40729072 | DOI:10.31557/APJCP.2025.26.7.2511

Curr Issues Mol Biol. 2025 Jul 21;47(7):575. doi: 10.3390/cimb47070575.

ABSTRACT

Vibrio parahaemolyticus is a pathogenic bacterium widely distributed in marine environments, posing significant threats to aquatic organisms and human health. The overuse and misuse of antibiotics has led to the development of multidrug- and pan-resistant V. parahaemolyticus strains. There is an urgent need for novel antibacterial therapies with innovative mechanisms of action. In this work, a genome-scale metabolic network model (GMSN) of V. parahaemolyticus, named VPA2061, was reconstructed to predict the metabolites that can be explored as potential drug targets for eliminating V. parahaemolyticus infections. The model comprises 2061 reactions and 1812 metabolites. Through essential metabolite analysis and pathogen-host association screening with VPA2061, 10 essential metabolites critical for the survival of V. parahaemolyticus were identified, which may serve as key candidates for developing new antimicrobial strategies. Additionally, 39 structural analogs were found for these essential metabolites. The molecular docking analysis of the essential metabolites and structural analogs further investigated the potential value of these metabolites for drug design. The GSMN reconstructed in this work provides a new tool for understanding the pathogenic mechanisms of V. parahaemolyticus. Furthermore, the analysis results regarding the essential metabolites hold profound implications for the development of novel antibacterial therapies for V. parahaemolyticus-related disease.

PMID:40729044 | DOI:10.3390/cimb47070575

Acta Neuropathol. 2025 Jul 29;150(1):10. doi: 10.1007/s00401-025-02913-3.

ABSTRACT

Development of therapeutic approaches that target specific microglia responses in amyotrophic lateral sclerosis (ALS) is crucial due to the involvement of microglia in ALS progression. Our study identifies the predominant microglia subset in human ALS primary motor cortex and spinal cord as an undifferentiated phenotype with dysregulated respiratory electron transport. Moreover, we find that the interferon response microglia subset is enriched in donors with aggressive disease progression, while a previously described potentially protective microglia phenotype is depleted in ALS. Additionally, we observe an enrichment of non-microglial immune cell, mainly NK/T cells, in the ALS central nervous system, primarily in the spinal cord. These findings pave the way for the development of microglia subset-specific therapeutic interventions to slow or even stop ALS progression.

PMID:40728732 | DOI:10.1007/s00401-025-02913-3

J Proteome Res. 2025 Jul 29. doi: 10.1021/acs.jproteome.5c00278. Online ahead of print.

ABSTRACT

Protein phosphorylation, a key post-translational modification, is central to cellular signaling and disease pathogenesis. The development of high-throughput proteomics pipelines has led to the discovery of large numbers of phosphorylated protein motifs and sites (phosphosites) across many eukaryotic species. However, the majority of phosphosites are reported from human samples, with most species having a few experimentally confirmed or computationally predicted phosphosites. Furthermore, only a small fraction of the characterized human phosphoproteome has an annotated functional role. A common way of predicting functional phosphosites is through conservation-based sequence analysis, but large-scale evolutionary studies are scarce. In this study, we explore the conservation of 20,751 confident human phosphosites across 100 eukaryotic species and investigate the evolution of associated protein domains and kinases. We categorize protein functions based on phosphosite conservation patterns and demonstrate the importance of conservation analysis in identifying organisms suitable as biological models for studying conserved signaling pathways relevant to human biology and disease. Finally, we use human protein sequences as a reference for propagating over 1,000,000 potential phosphosites to other eukaryotes. Our results can improve proteome annotations of several species and help direct research aimed at exploring the evolution and functional relevance of phosphorylation.

PMID:40728433 | DOI:10.1021/acs.jproteome.5c00278

MedComm (2020). 2025 Jul 27;6(8):e70300. doi: 10.1002/mco2.70300. eCollection 2025 Aug.

ABSTRACT

This study aimed to investigate the efficacy, safety, and predictors of camrelizumab combined with carboplatin and nab-paclitaxel as first-line setting for patients with extensive-stage small-cell lung cancer (ES-SCLC). Camrelizumab plus carboplatin and nab-paclitaxel were administrated every 3 weeks for four to six cycles, followed by maintenance camrelizumab until intolerable toxicity or disease progression. The primary endpoint was 6-month progression-free survival (PFS) rate and secondary endpoints were objective response rate (ORR), disease control rate (DCR), PFS, overall survival (OS), and safety. We conducted the whole-exome and transcriptomic sequencing on available tumor samples to explore the potential predictive biomarkers. A total of 60 patients were included. Primary endpoint was met with 6-month PFS rate of 52.2%. The median PFS and OS were 7.1 and 18.1 months, respectively. The confirmed ORR and DCR were 73.3% and 93.3%, respectively. No unexpected adverse events were observed. Exploratory analysis showed that MUC17 alterations or high NEUROG1 expression were correlated with markedly shorter PFS and OS. Deeper investigation of transcriptomic data reveals two subsets with distinct immune features and therapeutic vulnerabilities. Collectively, this trial suggested that camrelizumab plus carboplatin and nab-paclitaxel might be an alternative first-line setting for ES-SCLC. Integration of multiomic data could highlight the complex mechanisms underlying chemo-immunotherapy responses.

PMID:40727251 | PMC:PMC12301171 | DOI:10.1002/mco2.70300

Curr Opin Syst Biol. 2023 Dec;36:100482. doi: 10.1016/j.coisb.2023.100482. Epub 2023 Oct 31.

ABSTRACT

Anthropogenic carbon emissions are driving rapid changes to the earth's climate, disrupting whole ecosystems and endangering the stability of human society. Innovations in engineered microbial fermentation enable the fossil resource-free production of fuels, commodity chemicals, and materials, thereby reducing the carbon emissions associated with these products. Microorganisms have been engineered to catabolize sustainable sources of carbon and energy (i.e., plant biomass, plastic waste, and one-carbon feedstocks) and biosynthesize carbon-neutral or carbon-negative products. These engineering efforts exploit and optimize natural biological pathways or generate unnatural pathways which can biosynthesize chemicals that have not yet been accessed using synthetic chemistry. Recent advances in microbial fermentation seek not only to maximize the titer, rate, and yield of desired products, but also to tailor microbial catabolism to utilize inexpensive feedstocks. Ultimately, these advances aim to lower the cost of bioproduction so that microorganism-derived chemicals can be economically competitive with fossil-derived chemicals.

PMID:40726999 | PMC:PMC12302915 | DOI:10.1016/j.coisb.2023.100482

Front Immunol. 2025 Jul 14;16:1543529. doi: 10.3389/fimmu.2025.1543529. eCollection 2025.

ABSTRACT

INTRODUCTION: Ovarian cancer (OVCA) has a five-year survival rate of approximately 45%, with little improvement over recent decades. Although anti-PD-L1 therapies have shown substantial efficacy in other solid tumors, their effectiveness in OVCA has been limited. These treatments target only membranous and soluble forms of PD-L1, without addressing nuclear-localized PD-L1. The role of nuclear PD-L1 in OVCA chemoresistance, however, remains largely unexplored. In this study, we examined the prognostic significance of nuclear PD-L1 and its interactions with plasma gelsolin (pGSN) and CD8+ T cells within the tumor microenvironment.

METHODS: Using immunofluorescence, we quantified nuclear PD-L1, pGSN, and additional markers in OVCA samples. Statistical analyses and machine learning approaches were employed to assess associations between marker expression, patient outcomes, and chemoresistance.

RESULTS: Increased nuclear PD-L1 was associated with disease recurrence, chemoresistance and poor overall survival. Although CD8+ T cells provided survival benefits to patients, elevated PD-L1 hindered these benefits resulting in shortened disease free (DFS) and overall survival (OS). Co-expression of PD-L1 and pGSN was also associated with shortened DFS, OS and chemoresistance.

DISCUSSION: These findings indicate that nuclear PD-L1 serves as a poor prognostic marker in OVCA, being associated with tumor recurrence, chemoresistance, and reduced overall survival. Targeting nuclear PD-L1 may represent a novel therapeutic strategy to improve outcomes in patients with OVCA.

PMID:40726982 | PMC:PMC12301380 | DOI:10.3389/fimmu.2025.1543529

J Proteome Res. 2025 Jul 29. doi: 10.1021/acs.jproteome.5c00203. Online ahead of print.

ABSTRACT

Poor therapeutic indexes are a principal cause of drug attrition during development. To develop multiomic methods for elucidating potentially targetable mechanisms of drug toxicity, we performed profiling of the response to subtoxic and toxic doses of l-Asparaginase (ASNase) in immune-compromised mice. ASNase is an enzyme-drug approved for the treatment of pediatric acute lymphoblastic leukemia (ALL) but too toxic for use in adults, making it an ideal test case. We collected 20-μL whole blood samples longitudinally, processed them to plasma, and extracted three molecule types (metabolites, lipids, and proteins) from each sample. We then analyzed the extracts using multiple reaction monitoring (MRM) of 500+ water-soluble metabolites, 750+ lipids, and 375 peptides on a triple quadrupole LC-MS/MS platform. Metabolites, lipids, and peptides that were modulated in a dose-dependent manner appeared to converge on antioxidation, inflammation, autophagy, and cell death pathways, prompting the hypothesis that inhibiting one or more of those pathways might decrease ASNase toxicity while preserving anticancer activity. The present studies were not designed to address therapeutic index directly, because efficacy was not studied. We provide here a streamlined, three-in-one LC-MS/MS workflow for targeted metabolomics, lipidomics, and proteomics and, as a proof of principle, demonstrate its ability to generate new hypotheses about mechanisms of ASNase toxicity.

PMID:40726195 | DOI:10.1021/acs.jproteome.5c00203