Development. 2025 Mar 17:dev.204367. doi: 10.1242/dev.204367. Online ahead of print.

ABSTRACT

Differentiation of prohaemocytes, the precursors of Drosophila blood cells (haemocytes), and the release of haemocytes from the lymph gland, a major larval haematopoietic organ, are vital responses to wasp infestation or tissue degeneration. While cells and extracellular matrices (ECMs) in the lymph gland play a crucial role in haemocyte differentiation, the underlying mechanisms remain unclear. Here, we show that the matrix glycoprotein Papilin (Ppn) is essential for maintaining the prohaemocyte population in lymph glands. In Ppn-depleted larvae, haemocyte differentiation increased with a reduction in the prohaemocyte-containing medullary zone, and lymph gland lobes dispersed prematurely. Ppn was synthesised by plasmatocytes, forming lamellae mainly in the medullary zone. Microbial infection or wasp infestation disrupted the Ppn meshwork within lymph glands. Ppn colocalised with collagen, laminin, nidogen, and perlecan. Ppn depletion disrupted the ECM structure, including perlecan organisation. Phenotypes caused by Ppn depletion were partially rescued by perlecan overexpression or inactivation of the epidermal growth factor receptor (EGFR) pathway. Thus, Ppn is critical in maintaining lymph gland architecture and regulating haemocyte differentiation, highlighting an intricate interaction between ECMs and signalling pathways in haematopoiesis.

PMID:40094323 | DOI:10.1242/dev.204367

Theranostics. 2025 Feb 26;15(8):3673-3692. doi: 10.7150/thno.91873. eCollection 2025.

ABSTRACT

Rationale: Neurons producing Gonadotropin-Releasing Hormone (GnRH) are essential for human reproduction and have to migrate from nose to brain during prenatal life. Impaired GnRH neuron biology results in alterations of the reproductive axis, including delayed puberty and infertility, with considerable effects on quality of life and metabolic health. Although various genes have been implicated, the molecular causes of these conditions remain elusive, with most patients lacking a genetic diagnosis. Methods: GnRH neurons and non-GnRH cells were FACS-isolated from mouse embryo microdissections to perform high-resolution transcriptomic profiling during mouse embryonic development. We analyzed our dataset to reveal GnRH neuron molecular identity, gene expression dynamics, and cell-to-cell communication. The spatial context of candidate genes was validated using in situ hybridization and spatial transcriptomic analysis. The possible links with human reproduction in health and disease were explored using enrichment analysis on GWAS data and analyzing the genetic burden of patients with congenital GnRH deficiency. Results: GnRH neurons undergo a profound transcriptional shift as they migrate from the nose to the brain and display expression trajectories associating with distinct biological processes, including cell migration, neuronal projections, and synapse formation. We revealed a timely and spatially restricted modulation of signaling pathways involving known and novel molecules, including Semaphorins and Neurexins, respectively. A particular set of genes, whose expression in GnRH neurons timely rises in late developmental stages, showed a strong association with GWAS genes linked with human reproductive onset. Finally, some of the identified trajectories harbor a diagnostic potential for congenital hypogonadism. This is supported by genetic analysis in a large cohort of patients affected by congenital GnRH deficiency, revealing a high mutation burden in patients compared to healthy controls. Conclusion: We charted the landscape of gene expression dynamics underlying murine GnRH neuron embryonic development. Our study highlights new genes in GnRH neuron development and provides novel insights linking those genes with human reproduction.

PMID:40093908 | PMC:PMC11905127 | DOI:10.7150/thno.91873

Theranostics. 2025 Feb 18;15(8):3234-3256. doi: 10.7150/thno.100295. eCollection 2025.

ABSTRACT

Rationale: Despite substantial advancement in the treatment of B-cell acute lymphoblastic leukemia (B-ALL), it remains a leading cause of cancer mortality in children due to the high relapse rate. Moreover, the long-term survival rates for adult B-ALL patients are still less than 40%. The B-ALL patients carrying MLL rearrangements or BCR-ABL fusion represent high-risk B-ALL subtypes that face particularly dismal prognoses. This study aims to identify innovative therapeutic vulnerability for high-risk B-ALL. Methods: The CRISPR-Cas9 screen was conducted to pinpoint genes essential for high-risk B-ALL cell survival/growth. Both in vitro and in vivo models were then employed to investigate the pathological role of ZNF217 in high-risk B-ALL. To characterize the downstream functionally essential targets of ZNF217, we performed RNA-seq and CUT&RUN-seq, followed by integrative bioinformatics analysis and experimental validation. Results: Through the focused CRISPR-Cas9 screening, ZNF217 emerged as the most essential gene for the cell survival/growth of B-ALL driven by MLL rearrangement or BCR-ABL. Through in vitro gain- and loss-of-function assays, we demonstrated that ZNF217 is indeed required for B-ALL cell survival/growth. Moreover, we established the B-ALL xenograft model and patient-derived xenograft (PDX) model and demonstrated that ZNF217 depletion significantly suppressed B-ALL progression and substantially extended the survival of recipient mice. Through integrative multiple-omics analysis, we elucidated that ZNF217 exerts its oncogenic role in B-ALL through both CoREST-dependent and CoREST-independent mechanisms. Furthermore, we characterized FOS as a functionally essential downstream target of ZNF217, and ZNF217 inhibited FOS expression in a CoREST-independent manner. Conclusions: Our findings highlight ZNF217 as a promising therapeutic target for the treatment of high-risk B-ALL, such as those carrying MLL-rearrangements or BCR-ABL fusion.

PMID:40093906 | PMC:PMC11905140 | DOI:10.7150/thno.100295

Int J Med Sci. 2025 Feb 26;22(7):1493-1503. doi: 10.7150/ijms.106518. eCollection 2025.

ABSTRACT

Background: Aortic dissection is a life-threatening condition associated with polycystic kidney disease (PKD). Additionally, PKD often progresses to chronic kidney disease (CKD), a known risk factor for cardiovascular disease. However, the impact of CKD on aortic dissection, particularly in patients with PKD, remains unclear. This study aims to investigate the effects of both CKD and PKD on aortic dissection. Materials and methods: This nationwide, population-based, retrospective cohort study used data from the National Health Insurance Research Database (NHIRD) in Taiwan. The primary outcome evaluated in this study was the cumulative incidence of aortic dissection, compared between PKD patients and a control group without PKD over a 15-year follow-up period. CKD subgroup analyses were performed to further assess the impact of CKD progression on the development of aortic dissection. Results: From 2000 to 2015, this study included 9,192 PKD patients and 36,768 matched controls without PKD from the NHIRD. Our findings demonstrated that PKD patients who developed aortic dissection had a higher incidence of comorbidities, including hypertension and coronary artery disease. Aortic dissection was more prevalent among male patients, individuals over 45 years of age, and those in the lowest insured premium group. PKD patients had a 2.53-fold higher adjusted hazard ratio (HR) for developing aortic dissection compared to the control group (95% CI: 1.74 to 3.66, p < 0.001). Notably, PKD patients with concurrent hypertension had a 7.77-fold increased risk of aortic dissection (95% CI: 4.97 to 12.13, p < 0.001). In CKD subgroup analyses, PKD patients without CKD and those with CKD had adjusted HRs of 1.74 and 3.38, respectively (p < 0.001). Among PKD patients with CKD, those who initiated hemodialysis (HD) and those who did not showed adjusted HRs of 3.95 and 2.74, respectively, for aortic dissection (p < 0.001). Conclusion: These findings indicate that the risk of aortic dissection in PKD patients significantly increases with CKD progression. Additionally, hypertension is an independent risk factor for aortic dissection in PKD patients. Careful management of blood pressure and strategies to prevent CKD progression may reduce the incidence of aortic dissection in this population.

PMID:40093803 | PMC:PMC11905265 | DOI:10.7150/ijms.106518

Iran J Psychiatry. 2025 Jan;20(1):1-2. doi: 10.18502/ijps.v20i1.17407.

NO ABSTRACT

PMID:40093520 | PMC:PMC11904747 | DOI:10.18502/ijps.v20i1.17407

bioRxiv [Preprint]. 2025 Mar 4:2025.02.27.640640. doi: 10.1101/2025.02.27.640640.

ABSTRACT

Angiogenesis, the formation of new vessels from existing vessels, is mediated by vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF). Despite discoveries supporting the cross-family interactions between VEGF and PDGF families, sharing the binding partners between them makes it challenging to identify growth factors that predominantly affect angiogenesis. Systems biology offers promises to untangle this complexity. Thus, in this study, we developed a mass-action kinetics-based computational model for cross-family interactions between VEGFs (VEGF-A, VEGF-B, and PlGF) and PDGFs (PDGF-AA, PDGF-AB, and PDGF-BB) with their receptors (VEGFR1, VEGFR2, NRP1, PDGFRα, and PDGFRβ). The model, parametrized with our literature mining and surface resonance plasmon assays, was validated by comparing the concentration of VEGFR1 complexes with a previously constructed angiogenesis model. The model predictions include five outcomes: 1) the percentage of free or bound ligands and 2) receptors, 3) the concentration of free ligands, 4) the percentage of ligands occupying each receptor, and 5) the concentration of ligands that is bound to each receptor. We found that at equimolar ligand concentrations (1 nM), PlGF and VEGF-A were the main binding partners of VEGFR1 and VEGFR2, respectively. Varying the density of receptors resulted in the following five outcomes: 1) Increasing VEGFR1 density depletes the free PlGF concentration, 2) increasing VEGFR2 density decreases PDGF:PDGFRα complexes, 3) increased NRP1 density generates a biphasic concentration of the free PlGF, 4) increased PDGFRα density increases PDGFs:PDGFRα binding, and 5) increasing PDGFRβ density increases VEGF-A:PDGFRβ. Our model offers a reproducible, fundamental framework for exploring cross-family interactions that can be extended to the tissue level or intracellular molecular level. Also, our model may help develop therapeutic strategies in pathological angiogenesis by identifying the dominant complex in the cell signaling.

AUTHOR SUMMARY: New blood vessel formation from existing ones is essential for growth, healing, and reproduction. However, when this process is disrupted-either too much or too little-it can contribute to diseases such as cancer and peripheral arterial disease. Two key families of proteins, vascular endothelial growth factors (VEGFs) and platelet-derived growth factors (PDGFs), regulate this process. Traditionally, scientists believed that VEGFs only bind to VEGF receptors and PDGFs to PDGF receptors. However, recent findings show that these proteins can interact with each other's receptors, making it more challenging to understand and control blood vessel formation. To clarify these complex interactions, we combined computer modeling with biological data to map out which proteins bind to which receptors and to what extent. Our findings show that when VEGFs and PDGFs are present in equal amounts, VEGFs are the primary binding partners for VEGF receptors. We also explored how changes in receptor levels affect these interactions in disease-like conditions. This work provides a foundational computational model for studying cross-family interactions, which can be expanded to investigate tissue-level effects and processes inside cells. Ultimately, our model may help develop better treatments for diseases linked to abnormal blood vessel growth by identifying key protein-receptor interactions.

PMID:40093087 | PMC:PMC11908192 | DOI:10.1101/2025.02.27.640640

Front Immunol. 2025 Feb 28;16:1474575. doi: 10.3389/fimmu.2025.1474575. eCollection 2025.

ABSTRACT

BACKGROUND: Currently available schistosomiasis diagnostic and monitoring tools are limited, and the development of novel technologies is necessary to enhance disease diagnostic and surveillance by supporting elimination efforts. Novel disease-specific biomarkers can facilitate the development of these technologies. Through the comparison of parasite burden and host factors, we assessed whether host plasma cytokines could be used as robust biomarkers for intestinal schistosomiasis and associated pathology in school-aged children (SAC) living in endemic areas.

METHODS: Levels of host plasma cytokines were measured in SAC from a low-to-moderate burden region five months deworming with praziquantel, using Luminex assay for exploration analysis and ELISA for validation.

RESULTS: The concentration of GM-CSF, IL-2, and VEGF in plasma was significantly lower in schistosome-infected compared to non-infected children, as determined by Luminex assay. Further evaluation by ELISA revealed a negative correlation between GM-CSF plasma levels, but not those of IL-2 or VEGF, and S. mansoni egg burdens in infected individuals. Common coinfections in the study area such as geohelminths, hepatitis or malaria failed to alter plasma GM-CSF levels arguing in favor of a potential specific effect of S. mansoni infection on this cytokine. Receiver operating characteristic analysis confirmed GM-CSF as an acceptable predictive marker of S. mansoni infection, with an area under the curve (AUC) of 75%. Finally, the adjunct use of plasmatic GM-CSF thresholds for screening S. mansoni at-risk children and identify S. mansoni-infected ones increased the sensitivity of a single Kato-Katz test by averagely 15%.

CONCLUSIONS: Our findings highlight the potential of using plasma GM-CSF levels to biomark S. mansoni infection and improve the sensitivity of single Kato-Katz based diagnostic for low- to-moderate burden infections.

PMID:40092989 | PMC:PMC11906694 | DOI:10.3389/fimmu.2025.1474575

Cell Investig. 2025 Mar;1(1):100008. doi: 10.1016/j.clnves.2025.100008. Epub 2025 Feb 26.

ABSTRACT

RNA N 6-methyladenosine (m6A) modification has been identified as the most abundant RNA modification and plays crucial roles in both physiological and pathological processes. YTHDF2 was the first identified reader protein that can recognize m6A modification and recent studies also revealed its ability to bind 5-methylcytidine (m5C) modification. YTHDF2 shows a dual binding capacity to both m6A and m5C, which leads to opposite mRNA outcomes. Multiple studies have highlighted the critical roles of YTHDF2 in tumor development and tumor microenvironment. Emerging findings showed that YTHDF2 plays critical roles in immune regulation, impacting T cell, B cell, NK cell, macrophage, innate/adaptive anti-tumor immune responses, and T-cell based immunotherapy. Inhibitors have been developed to target YTHDF2, which showed potential efficacy in tumor treatment. Herein, we reviewed the molecular mechanism of YTHDF2 and its roles in tumors, immune cells, and tumor microenvironment.

PMID:40092843 | PMC:PMC11908620 | DOI:10.1016/j.clnves.2025.100008

Front Mol Biosci. 2025 Feb 28;12:1562357. doi: 10.3389/fmolb.2025.1562357. eCollection 2025.

ABSTRACT

INTRODUCTION: The recombinant human p53 adenovirus (Ad-p53) offers a promising approach for cancer therapy, yet its chromatin structure and effects on host chromatin organization and gene expression are not fully understood.

METHODS: In this study, we employed in situ ChIA-PET to investigate the colorectal cancer cell line HCT116 with p53 knockout, comparing them to cells infected with the adenovirus-vector expressing p53. We examined alterations in chromatin interactions and gene expression following treatment with the anti-cancer drug 5-fluorouracil (5-FU).

RESULTS: Our results indicate that Ad-p53 forms a specific chromatin architecture within the vector and mainly interacts with repressive or inactive regions of host chromatin, without significantly affecting the expression of associated genes. Additionally, Ad-p53 does not affect topologically associating domains (TADs) or A/B compartments in the host genome.

DISCUSSION: These findings suggest that while Ad-p53 boosts p53 expression, enhancing drug sensitivity without substantially altering host HCT116 chromatin architecture.

PMID:40092712 | PMC:PMC11906465 | DOI:10.3389/fmolb.2025.1562357

Front Physiol. 2025 Feb 28;16:1539615. doi: 10.3389/fphys.2025.1539615. eCollection 2025.

ABSTRACT

INTRODUCTION: As a basis for performance optimal nutritional balance is key to keep the body functioning at homeostatic capacity. When environmental circumstances become challenging such as in a cold environment extraordinary performance is requested specifically for physiological (i.e., vascular response, diet induced thermogenesis, immune response), and cognitive mechanisms (i.e., cognitive function, psychological and cognitive wellbeing) of the human body. In this review we describe which nutritional strategies could enhance military performance in the cold by mitigation of CWIs.

METHODS: We will first describe how exposure to cold affects the physiological or cognitive mechanisms itself and then we will explain how nutrition can be used to optimize these affected mechanisms. We will discuss long-term nutritional solutions preventing shortfalls and potential direct quick fixes for physiological and cognitive mechanisms.

RESULTS: For optimal functioning of the immune system and infection prevention, absence of micronutrient deficiencies is key and should be pursued amongst military personnel. For the effectivity of PUFA's, Echinacea purpurea and probiotics in immune functioning, more research is needed in the CWO context. A multitude of micronutrients (i.e., nitrate, L-citrulline, L-arginine) appears to be able to enhance vasodilation, perhaps partially offsetting the detrimental effect of cold on peripheral blood circulation. Although the direct effect of diet induced thermogenesis is small in comparison to being physically active, it is of interest to investigate the effects of adding a combination of spices to the rations, such as capsaicin from red pepper, cinnamon, ginger, and menthol. Also, of interest for stimulation of thermogenesis are caffeine, and polyphenolic compounds. Caffeine and tyrosine supplementation 1 h, resp. 2 h before a cognitively demanding task during CWOs could be used to mitigate decreases in cognitive performance. Alternatives that are of interest, but need more research, include chocolate polyphenols and omega-3 fatty acids.

CONCLUSION: Even though some recommendations can be provided, it is evident that much information regarding the effectiveness and application of micronutrients in cold weather operations is still lacking. More focus should be placed on investigating (micro)nutritional solutions, practical feasibility, and implementation in operational military personnel to better understand the magnitude of the possible benefits in cold conditions.

PMID:40092148 | PMC:PMC11907006 | DOI:10.3389/fphys.2025.1539615

Infect Dis Model. 2025 Feb 13;10(2):702-715. doi: 10.1016/j.idm.2025.02.006. eCollection 2025 Jun.

NO ABSTRACT

PMID:40091911 | PMC:PMC11907466 | DOI:10.1016/j.idm.2025.02.006

J Allergy Clin Immunol Glob. 2025 Jan 30;4(2):100434. doi: 10.1016/j.jacig.2025.100434. eCollection 2025 May.

ABSTRACT

BACKGROUND: Food protein-induced enterocolitis syndrome (FPIES) is a non-IgE-mediated food allergy typically presenting in infancy but has also been recognized in adults. FPIES is an allergic emergency due to severe vomiting occurring 1 to 4 hours after ingesting the causative food protein. Since the 2017 FPIES guidelines, no prospective data exist on the prevalence, incidence, and clinical characteristics of FPIES.

OBJECTIVE: We established a multicenter FPIES registry to systematically collect clinical data and biospecimens on FPIES patients.

METHODS: The FPIES registry is a US multicenter REDCap database collecting epidemiologic data to support the evolving FPIES landscape in relation to age at diagnosis, triggers and coreactivity, disease resolution, and risk of disease conversion to IgE allergy. Questionnaire and biosampling strategies have been developed using a systems biology approach to identify determinants of FPIES.

RESULTS: The registry includes patients with physician diagnosis of FPIES (ICD-10 code K52.21) from January 2015. Longitudinal REDCap instruments for FPIES data collection include: age at first reaction, age at diagnosis, reaction timing, symptoms, treatment, medical care or hospitalization for reaction, dietary triggers, atopic comorbidities, family history of atopy and FPIES, oral food challenge procedures (eg, intravenous line placement, dosing protocol, observation period, reaction timing, symptoms and treatment), age at food trigger resolution, food-trigger IgE, cases converting from atypical FPIES to IgE-mediated food allergy, and sample collection data.

CONCLUSIONS: The registry will provide a multicenter repository of data and biospecimens, enabling identification of clinical determinants and phenotypes of FPIES, better understanding of conversion risks, and identification of biomarkers and mechanisms associated with FPIES.

PMID:40091881 | PMC:PMC11909745 | DOI:10.1016/j.jacig.2025.100434

J Clin Invest. 2025 Mar 17;135(6):e181671. doi: 10.1172/JCI181671.

ABSTRACT

BACKGROUNDImmune checkpoint blockade (ICB) is an effective treatment in a subset of patients diagnosed with head and neck squamous cell carcinoma (HNSCC); however, the majority of patients are refractory.METHODSIn a nonrandomized, open-label Phase 1b clinical trial, participants with recurrent and/or metastatic (R/M) HNSCC were treated with low-dose 5-azacytidine (5-aza) daily for either 5 or 10 days in combination with durvalumab and tremelimumab after progression on ICB. The primary objective was to assess the biologically effective dose of 5-aza as determined by molecular changes in paired baseline and on-treatment tumor biopsies; the secondary objective was safety.RESULTSThirty-eight percent (3 of 8) of participants with evaluable paired tissue samples had a greater-than 2-fold increase from baseline in IFN-γ signature and CD274 (programmed cell death protein 1 ligand, PD-L1) expression within the tumor microenvironment (TME), which was associated with increased CD8+ T cell infiltration and decreased infiltration of CD4+ T regulatory cells. The mean neutrophil-to-lymphocyte ratio (NLR) decreased by greater than 50%, from 14.2 (SD 22.6) to 6.9 (SD 5.2). Median overall survival (OS) was 16.3 months (95% CI 1.9, NA), 2-year OS rate was 24.7% (95% CI: 4.5%, 53.2%), and 58% (7 of 12) of treated participants demonstrated prolonged OS of greater than 12 months.CONCLUSIONOur findings suggest that low-dose 5-aza can reprogram systemic host immune responses and the local TME to increase IFN-γ and PD-L1 expression. The increased expression of these established biomarkers correlated with prolonged OS upon ICB rechallenge.TRIAL REGISTRATIONClinicalTrials.gov NCT03019003.FUNDINGNIH/NCI P01 CA240239.

PMID:40091844 | DOI:10.1172/JCI181671

Adv Sci (Weinh). 2025 Mar 17:e2404938. doi: 10.1002/advs.202404938. Online ahead of print.

ABSTRACT

Prostate cancer (PCa) stands as a leading cause of cancer-related mortality among men, with treatment-induced neuroendocrine prostate cancer (NEPC) posing a challenge as an ARPI-resistant subtype. The role of transcription factors (TFs) in PCa progression and NEPC transdifferentiation remains inadequately understood, underscoring a critical gap in current research. In this study, an internal Z score-based approach is developed to identify lineage-specific TF profiles in prostatic adenocarcinoma and NEPC for a nuanced understanding of TF expression dynamics. Distinct TF profiles for adenocarcinoma and NEPC are unveiled, identifying 126 shared TFs, 46 adenocarcinoma-TFs, and 56 NEPC-TFs, validated across multiple cohorts. Gene Ontology is employed to validate their biological and functional roles in PCa progression. Implications are revealed in cell development, differentiation, and lineage determination. Knockdown experiments suggest that lineage-TFs are functionally important in maintaining lineage-specific cell proliferation. Additionally, a longitudinal study on NE transdifferentiation highlights dynamic TF expression shifts, proposing a three-phases hypothesis for PCa progression mechanisms. This study introduces a groundbreaking approach for deciphering the TF landscape in PCa, providing a molecular basis for adenocarcinoma to NEPC progression, and paving the way for innovative treatment strategies with potential impact on patient outcomes.

PMID:40091506 | DOI:10.1002/advs.202404938

ACS Chem Neurosci. 2025 Mar 17. doi: 10.1021/acschemneuro.5c00006. Online ahead of print.

ABSTRACT

Cerebral dysfunctions give rise to a wide range of neurological diseases due to the structural and functional complexity of the human brain stemming from the interactive cellular metabolism of its specific cells, including neurons and glial cells. In parallel with advances in isolation and measurement technologies, genome-scale metabolic models (GEMs) have become a powerful tool in the studies of systems biology to provide critical insights into the understanding of sophisticated eukaryotic systems. In this study, brain cell-specific GEMs were reconstructed for neurons, astrocytes, microglia, oligodendrocytes, and oligodendrocyte precursor cells by integrating single-cell RNA-seq data and global Human1 via a task-driven integrative network inference for tissues (tINIT) algorithm. Then, intercellular reactions among neurons, astrocytes, microglia, and oligodendrocytes were added to generate a combined brain model, iHumanBrain2690. This brain network was used in the prediction of metabolic alterations in glucose, ketone bodies, oxygen change, and reporter metabolites. Glucose supplementation increased the subsystems' activities in glycolysis, and ketone bodies elevated those in the TCA cycle and oxidative phosphorylation. Reporter metabolite analysis identified L-carnitine and arachidonate as the top reporter metabolites in gray and white matter microglia in multiple sclerosis (MS), respectively. Carbamoyl-phosphate was found to be the top reporter metabolite in primary progressive MS. Taken together, single and integrated iHumanBrain2690 metabolic networks help us elucidate complex metabolism in brain physiology and homeostasis in health and disease.

PMID:40091499 | DOI:10.1021/acschemneuro.5c00006

Anim Microbiome. 2025 Mar 16;7(1):28. doi: 10.1186/s42523-025-00391-2.

ABSTRACT

BACKGROUND: Antibiotics and antiparasitics are essential tools in controlling infectious disease outbreaks in commercial aquaculture. While the negative effects of antimicrobials on the gut microbiome of various farmed fish species are well documented, the influence of underlying host factors, such as age, on microbiome responses remains poorly understood. This is especially evident for peracetic acid, whose impact on the gut microbiome has not yet been studied. Understanding how microbiome dynamics vary by host age is critical to improving antibiotic stewardship in aquaculture. In this study, juvenile and sexually mature brown trout (Salmo trutta) were used as a model to investigate the age-dependent effects of florfenicol and peracetic acid on the gut microbiome using a 16S rRNA metabarcoding approach.

RESULTS: Fish age significantly shaped taxonomic composition and microbial co-occurrence network structure of the gut microbiome, regardless of treatment. Juvenile trout exhibited greater microbiome volatility and a stronger response to both florfenicol and peracetic acid compared to adult fish, with disruptions persisting up to 11 days post-treatment. Temporal dynamics were also evident, with microbial shifts characterized by a decline in beneficial commensals like Cetobacterium and Lactococcus. Although overall abundance recovered by 18 days post-treatment, network positions of key microbial community members remained altered, particularly in juvenile fish. Opportunistic pathogens, including Aeromonas and Streptococcus, were enriched and assumed more central roles within the microbial networks in treated fish.

CONCLUSION: The initial composition of the gut microbiome in brown trout is strongly influenced by fish age, which in turn affects the microbiome's response to antibiotic disruption. Juveniles displayed higher susceptibility to microbiome perturbation, and although recovery was observed at the community level, network properties remained altered. This study also provides the first evidence that external peracetic acid application can disrupt gut microbial communities. Since compositional shifts are often linked to functional alterations, even short-term disruptions may have important consequences for host health in developing fish. These findings emphasize the importance of considering gut microbial community structure in relation to fish age in aquaculture management practices.

PMID:40091084 | DOI:10.1186/s42523-025-00391-2

Cell Death Discov. 2025 Mar 16;11(1):106. doi: 10.1038/s41420-025-02382-3.

ABSTRACT

The RAD51-BRCA2 interaction is central to DNA repair through homologous recombination. Emerging evidence indicates RAD51 overexpression and its correlation with chemoresistance in various cancers, suggesting RAD51-BRCA2 inhibition as a compelling avenue for intervention. We previously showed that combining olaparib (a PARP inhibitor (PARPi)) with RS-35d (a BRCA2-RAD51 inhibitor) was efficient in killing pancreatic ductal adenocarcinoma (PDAC) cells. However, RS-35d impaired cell viability even when administered alone, suggesting potential off-target effects. Here, through multiple, integrated orthogonal biological approaches in different 2D and 3D PDAC cultures, we characterised RS-35d enantiomers, in terms of mode of action and single contributions. By differentially inhibiting both RAD51-BRCA2 interaction and sensor kinases ATM, ATR and DNA-PK, RS-35d enantiomers exhibit a 'within-pathway synthetic lethality' profile. To the best of our knowledge, this is the first reported proof-of-concept single small molecule capable of demonstrating this built-in synergism. In addition, RS-35d effect on BRCA2-mutated, olaparib-resistant PDAC cells suggests that this compound may be effective as an anticancer agent possibly capable of overcoming PARPi resistance. Our results demonstrate the potential of synthetic lethality, with its diversified applications, to propose new and concrete opportunities to effectively kill cancer cells while limiting side effects and potentially overcoming emerging drug resistance.

PMID:40091075 | DOI:10.1038/s41420-025-02382-3

J Pharm Technol. 2025 Mar 14:87551225251324856. doi: 10.1177/87551225251324856. Online ahead of print.

ABSTRACT

STUDY OBJECTIVES: Zolpidem is a widely prescribed medication for treating insomnia due to its effectiveness as a sedative-hypnotic. This study aimed to estimate the incidence of potential adverse effects associated with the use and misuse of zolpidem.

METHODS: Retrospective cohort study. Participants were selected from consumers who had purchased zolpidem in a commercial pharmacy in Brazil and submitted an interviewed. Descriptive analysis was used to present the results. Pearson's chi-square tests were used to compare adverse reactions to zolpidem with categorical variables, and Student's t-tests were used to compare means. The significance level adopted was 5%.

RESULTS: The study involved 65 participants, with a mean age of 52.7 years, 76.9% of whom were women. Of the total sample, 69.2% used zolpidem for the treatment of long-term insomnia, and 77.4% used it continuously. Among the interviewees, 55.4% reported experiencing adverse reactions, with amnesia, insomnia, and sleepwalking being the most reported. A statistically significant association was found between the occurrence of adverse reactions and continuous use (P value = 0.048), as well as among those with lower mean age (P value = 0.042).

CONCLUSION: Despite being a prescription-controlled medication, zolpidem was used excessively and inappropriately in the studied sample. Given the high prevalence of adverse effects identified in this study, the risk/benefit ratio of pharmacological treatments for insomnia warrants careful evaluation during prescription and dispensing. Incidence of adverse effects and misuse of zolpidem.

PMID:40092895 | PMC:PMC11909643 | DOI:10.1177/87551225251324856

J Parkinsons Dis. 2025 Mar 16:1877718X251323922. doi: 10.1177/1877718X251323922. Online ahead of print.

ABSTRACT

BackgroundImpulsive-compulsive disorders (ICDs) are commonly acknowledged as side effects of dopaminergic therapy in Parkinson's disease (PD). While many large-scale studies have focused on prevalences and high-risk treatments, little is known about practical management of ICDs in clinical care and patients' experiences.ObjectiveTo investigate how ICDs are recognized in clinical PD care, clinical features of patients with ICDs, and how patients are impacted by their ICD.MethodsQuestionnaires were sent to all patients who reported ICD symptoms in the Swedish quality register for PD in Skåne County (n = 170) and patients' medical records were screened for mention of ICDs. Core subjects were communication between clinician and patient, course and management of ICDs, and impact on different life domains.ResultsDespite sufficient awareness of the ICD risk during PD treatment, there was limited communication between clinical care staff and patients regarding ICDs. Only 49% of patients had reported their ICD as part of clinical care, and only 14% had been asked about it. Additionally, collaboration with psychiatry was rare (12%). ICD severity increased over time with ongoing PD treatment, and most patients reported a mild to moderate impact of their ICD on close relationships, family, mental and physical health.ConclusionsThis study identified insufficient communication about ICDs as part of clinical care in PD and a very limited involvement of mental health services. Thus, to improve prevention and treatment, ICDs should be recognized, monitored and treated more systematically in routine clinical care, and collaboration with mental health services should be increased.

PMID:40091420 | DOI:10.1177/1877718X251323922

CNS Neurosci Ther. 2025 Mar;31(3):e70330. doi: 10.1111/cns.70330.

ABSTRACT

BACKGROUND: Gliomas represent the most aggressive malignancies of the central nervous system, with posttranslational modifications (PTMs) emerging as critical regulators of oncogenic processes through dynamic protein functional modulation. Despite their established role in tumor biology, the systematic characterization of PTM-mediated molecular mechanisms driving glioma progression remains unexplored. This study aims to uncover the molecular mechanisms of glioma, with a focus on the role of PTMs.

METHODS: We analyzed the PTM pathway to classify glioma patients into distinct clusters. Comprehensive analyses compared intercluster differences in clinical outcomes, mutational landscapes, and immune microenvironment profiles. Differentially expressed genes (DEGs) were identified to construct a robust prognostic prediction model with machine learning approaches. Among the genes included in the model, TOM1L1 (Target of Myb1 Like 1 Membrane Trafficking Protein) was selected for in vitro experimental validation to assess its role in glioma progression.

RESULTS: PTMs were found to influence glioma prognosis significantly. Dysregulation in specific pathways, such as glutathionylation and citrullination, was correlated with more aggressive clinical features. The prognostic model, comprising DEGs such as TOM1L1, demonstrated high predictive accuracy (c-index = 0.867)-the scores derived from the model strongly correlated with glioma progression indicators. In vitro experiments revealed that TOM1L1 facilitates malignant progression by modulating PTM pathways, confirming its functional role in glioma.

CONCLUSION: Our study establishes the first comprehensive PTM atlas in gliomas, revealing subtype-specific modification patterns with clinical and therapeutic implications. TOM1L1 emerges as a promising prognostic biomarker and a potential therapeutic intervention target. Targeting PTM pathways may offer novel strategies for glioma treatment, enhancing patient outcomes.

PMID:40090864 | DOI:10.1111/cns.70330