Front Med (Lausanne). 2025 Mar 27;12:1589992. doi: 10.3389/fmed.2025.1589992. eCollection 2025.

NO ABSTRACT

PMID:40201325 | PMC:PMC11977388 | DOI:10.3389/fmed.2025.1589992

J Biol Methods. 2025 Jan 16;12(1):e99010049. doi: 10.14440/jbm.2025.0094. eCollection 2025.

ABSTRACT

BACKGROUND: Lipids are crucial signaling molecules or cellular membrane components orchestrating biological processes. To gain insights into lipid functions and the communication between organelles, it is essential to understand the subcellular localization of individual lipids. Advancements in lipid quantification techniques, improvements in chemical and spatial resolution for detecting various lipid species, and enhancements in organelle isolation speed have allowed for profiling of the organelle lipidome, capturing its temporal-spatial distribution.

OBJECTIVE: This review examined approaches used to develop organelle lipidome and aimed to gain insights into cellular lipid homeostasis from an organelle perspective. In addition, this review discussed the advancements in lipid-mediated inter-organelle communication within complex physiological and pathological processes.

CONCLUSION: With the advancement of lipidomic technologies, more detailed explorations of organelle structures and the specific lipid-mediating functions they perform are feasible.

PMID:40200947 | PMC:PMC11973048 | DOI:10.14440/jbm.2025.0094

Stud Health Technol Inform. 2025 Apr 8;323:149-153. doi: 10.3233/SHTI250067.

ABSTRACT

PM-TOM (Personalized Medicine-Therapy Optimization Method) is a clinical decision-support tool designed to optimize polypharmacy treatments by minimizing their adverse drug reactions (ADRs) caused by individual drugs or drug interactions (DDIs, DCIs, DFIs, DGIs), along with the risks identified by the STOPP and Beers criteria. On the other hand, AI tools like ChatGPT 4.0, trained on medical literature texts, can provide broader clinical reasoning and insights tailored to individual patient contexts. By referring to a documented deprescribing case, this study demonstrates the synergistic power of PM-TOM and ChatGPT in optimizing potentially inappropriate medication (PIM) treatments. A malnourished older woman was admitted to a deprescribing facility with recurrent falls, hypertension, ischemic heart disease, depression, osteoarthritis, osteoporosis, and GERD. She was initially prescribed acetaminophen, alendronate, omeprazole, lisinopril, metoprolol, aspirin, citalopram, and vitamin D, which were assessed as inadequate. While the discharge regimen improved some conditions by replacing alendronate with zoledronic acid and reducing some drug dosages, PM-TOM revealed that key risks, stemming primarily from omeprazole, aspirin, and citalopram, remained unaddressed. The discharge treatment was optimized with PM-TOM after considering alternative drug classes suggested by ChatGPT and elaborated in the available medical literature. In the optimized treatment, omeprazole (PPI) was replaced with famotidine (H2-blocker), citalopram (SSRI) with agomelatine (atypical antidepressant), zoledronic acid (bisphosphonate) with denosumab (RANK ligand inhibitor), aspirin (NSAID) with ticagrelor (antiplatelet), and lisinopril with benazepril (ACE inhibitor). These changes significantly reduced possible ADRs and the geriatric care criteria risks. Finally, ChatGPT validated the proposed adjustments, confirming their alignment with the guidelines and highlighting the potential for longer-term benefits. This case study illustrates how a combined use of PM-TOM and AI tools can effectively support the clinical decision-making process by optimizing polypharmacy treatments and minimizing their PIMs, major contributors to morbidity in older adults and high healthcare costs.

PMID:40200464 | DOI:10.3233/SHTI250067

Front Public Health. 2025 Mar 24;13:1531583. doi: 10.3389/fpubh.2025.1531583. eCollection 2025.

ABSTRACT

Rare diseases, also known as orphan diseases, are a group of disorders that affect a small percentage of the population. Despite individually affecting a small number of people, collectively, they impact millions worldwide. This is particularly significant in paediatric patients, highlighting the global scale of the issue. This review delves into the exact prevalence of rare diseases among children and adolescents and their diverse impact on the quality of life of patients and their families. The review sheds light on the complex interplay of genetic and environmental factors contributing to these conditions and the diagnostic challenges and delays often encountered in identifying and categorising these diseases. It is noted that although there have been significant strides in the field of genomic medicine and the development of orphan drugs, effective treatments remain limited. This necessitates a comprehensive, multidisciplinary approach to management involving various specialities working closely together to provide holistic care. Furthermore, the review addresses the psychosocial and economic burdens faced by families with paediatric patients suffering from rare diseases, highlighting the urgent need for enhanced support mechanisms. Recent technological and therapeutic advancements, including genomic sequencing and personalized medicine, offer promising avenues for improving patient outcomes. Additionally, the review underscores the role of policy and advocacy in advancing research, ensuring healthcare access, and supporting affected families. It emphasises the importance of increased awareness, education, and collaboration among healthcare providers, researchers, policymakers, and patient advocacy groups. It stresses the pivotal role each group plays in improving the diagnosis, treatment, and overall quality of life for paediatric patients with rare diseases.

PMID:40196857 | PMC:PMC11973084 | DOI:10.3389/fpubh.2025.1531583

J Mol Graph Model. 2025 Apr 5;138:109036. doi: 10.1016/j.jmgm.2025.109036. Online ahead of print.

ABSTRACT

The effective treatment of neurological diseases, particularly Alzheimer's disease (AD), is a significant source of frustration for drug discovery scientists. The lengthy process of drug discovery further makes this task exceedingly challenging. To enable a rapid stride in drug discovery, we focused on the drug repurposing strategy to identify new N-methyl-D-aspartate receptor (NMDAR) inhibitors from the pool of 1827 approved USFDA drugs. The high throughput virtual screening (HTVS) followed by molecular docking and molecular mechanics studies enabled us to identify two drugs, Ertugliflozin (Dock Score: -9.43 kcal/mol, MMGBSA: -104.50 kcal/mol) and Selpercatinib (Dock Score: 8.11 kcal/mol, MMGBSA: 83.62 kcal/mol), with a high affinity towards the NMDAR. The molecular dynamics analysis on these identified drugs led us to choose Ertugliflozin for its better stability as a lead for further studies. The corroboration of in silico findings led us to deduce that Ertugliflozin can inhibit NMDAR with an IC50 of 613.19 nM. These results were confirmed by the anti-NMDAR ELISA-based analysis, which was further deduced via western blotting. The work is further supported by strong literature evidence that concludes the impact of antidiabetic molecules on AD progression, along with the evidence that Ertugliflozin possesses efficacy against AD with unequivocal evidence on the biological target and the mechanism. Further work, however, is required to establish this association in the in vivo or suitable model that could mimic the AD microenvironment as a part of future research.

PMID:40199086 | DOI:10.1016/j.jmgm.2025.109036

Am J Respir Cell Mol Biol. 2025 Apr 8. doi: 10.1165/rcmb.2024-0303OC. Online ahead of print.

ABSTRACT

Chronic obstructive pulmonary disease (COPD) is a prevalent respiratory disease lacking effective treatment. Focusing on early COPD should help to discover disease modifying therapies. We examined the role of the CXCL12/CXCR4 axis in early COPD using human samples and murine models. Blood samples and lung tissues from both individuals with early COPD and controls were analyzed for CXCL12 and CXCR4 levels. To generate an early-like COPD model, 10-week-old male C57BL/6J mice were exposed to cigarette smoke (CS) for 10 weeks and intranasal instillations of polyinosinic-polycytidylic acid (poly(I:C)) for the last five weeks to mimic exacerbations. The number of cells expressing CXCR4 was increased in the blood of individuals with COPD, as well as in the blood of exposed mice. Lung CXCL12 expression was higher in both early COPD patients and exposed mice. Exposed mice presented mild airflow obstruction, peri-bronchial fibrosis, and right heart thickening. The density of fibrocyte-like cells expressing CXCR4 increased in the bronchial submucosa of these mice. Conditional inactivation of CXCR4 as well as pharmacological inhibition of CXCR4 with plerixafor injections improved lung function, reduced inflammation, and protected against CS and poly-(I:C)-induced airway and cardiac remodeling. CXCR4-/- and plerixafor-treated mice also had fewer CXCR4-expressing circulating cells and a lower density of peri-bronchial fibrocyte-like cells. We demonstrate that targeting CXCR4 has beneficial effects in an animal model mimicking early COPD. While these preclinical findings are encouraging, further research is needed to explore the potential for transferring these insights into clinical applications, including drug repurposing.

PMID:40198797 | DOI:10.1165/rcmb.2024-0303OC

Orphanet J Rare Dis. 2025 Apr 8;20(1):166. doi: 10.1186/s13023-025-03629-z.

ABSTRACT

BACKGROUND: Rare diseases (RDs) clinical care and research face several challenges. Patients are dispersed over large geographic areas, their number per disease is limited, just like the number of researchers involved. Current databases as well as biological collections, when existing, are generally local, of modest size, incomplete, of uneven quality, heterogeneous in format and content, and rarely accessible or standardised to support interoperability. Most disease phenotypes are complex corresponding to multi-systemic conditions, with insufficient interdisciplinary cooperation. Thus emerged the need to generate, within a coordinated, mutualised, secure and interoperable framework, high-quality data from national or international RD cohorts, based on deep phenotyping, including molecular analysis data, notably genotypic. The RaDiCo program objective was to create, under the umbrella of Inserm, a national operational platform dedicated to the development of RD e-cohorts. Its Information System (IS) is presented here.

MATERIAL AND METHODS: Constructed on the cloud computing principle, the RaDiCo platform was designed to promote mutualization and factorization of processes and services, for both clinical epidemiology support and IS. RaDiCo IS is based on an interoperability framework combining a unique RD identifier, data standardisation, FAIR principles, data exchange flows/processes and data security principles compliant with the European GDPR.

RESULTS: RaDiCo IS favours a secure, open-source web application in order to implement and manage online databases and give patients themselves the opportunity to collect their data. It ensures a continuous monitoring of data quality and consistency over time. RaDiCo IS proved to be efficient, currently hosting 13 e-cohorts, covering 67 distinct RDs. As of April 2024, 8063 patients were recruited from 180 specialised RD sites spread across the national territory.

DISCUSSION: The RaDiCo operational platform is equivalent to a national infrastructure. Its IS enables RD e-cohorts to be developed on a shared platform with no limit on size or number. Compliant with the GDPR, it is compatible with the French National Health Data Hub and can be extended to the RDs European Reference Networks (ERNs).

CONCLUSION: RaDiCo provides a robust IS, compatible with the French Data Hub and RDs ERNs, integrated on a RD platform that enables e-cohorts creation, monitoring and analysis.

PMID:40200372 | DOI:10.1186/s13023-025-03629-z

Orphanet J Rare Dis. 2025 Apr 8;20(1):163. doi: 10.1186/s13023-025-03704-5.

ABSTRACT

BACKGROUND: Rare neurological diseases (RNDs) result in severe health burdens worldwide. Data from China are limited. We aimed to investigate the health burden of 20 RNDs in Guangdong Province (GD), which contains two-thirds of the population of South China.

METHODS: The hospitalization data of 20 RNDs were described using hospital-based front sheet data from 3,037 hospitals of GD from 2016 to 2022. The 20 RNDs included amyotrophic lateral sclerosis (ALS), Charcot-Marie-Tooth Disease, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, congenital myotonia, congenital myasthenic syndrome, Dravet syndrome, Fabry disease, hereditary spastic paraplegia, Huntington disease, Leber hereditary optic neuropathy, mitochondrial encephalopathy (ME), multi-focal motor neuropathy, myotonic dystrophy, primary hereditary dystonia, progressive muscular dystrophy (PMD), spinal and bulbar muscular atrophy, spinal muscular atrophy (SMA), spinocerebellar ataxia, Wilson disease (WD) and X-linked adrenoleukodystrophy. Age were presented as mean and standard deviation while length of hospital stay as median and interquartile range (25th and 75th percentiles). The other variables were described as number and percentage. The data were analyzed by Joinpoint regression.

RESULTS: There were 9,351 cases, including 330 ICU and 155 death cases. The average age was 33.7 ± 22.0 y, and 63.8% of patients were male. From 2016 to 2022, the number of RND (and juvenile RND) cases were 1034 (184), 1174 (293), 1443 (374), 1422 (320), 1331 (337), 1432 (409) to 1515 (515). ICU (and juvenile ICU) cases rose from 28 (3), 34 (6), 24 (4), 38 (11), 46 (13), 54 (24) to 106 (56). Joinpoint regression showed significant upward trend in percentages of juvenile and juvenile ICU cases (APC = 8.13, P< 0.05; APC = 28.42, P< 0.05). The fop five RNDs were WD, ASL, PMD, ME, and SMA, which accounted for 79.7% of all, 99.1% of ICU, and 94.8% of death cases.

CONCLUSIONS: We demonstrated that the increase in health burden of RNDs was mainly evident in juveniles in South China from 2016 to 2022. The top 5 RNDs accounted for majority of the critical patients.

PMID:40200352 | DOI:10.1186/s13023-025-03704-5

Biochem Pharmacol. 2025 Apr 6:116921. doi: 10.1016/j.bcp.2025.116921. Online ahead of print.

ABSTRACT

Oxidative stress-induced growth inhibitors (OSGINs) represent a new category of proteins that respond to oxidative stress and modulate redox balance. Growing evidence indicates that OSGINs have extensive physiological and pathological functions by regulating essential cellular processes, including proliferation, autophagy, apoptosis, and ferroptosis, thus influencing the progression of various diseases such as cancer, atherosclerosis, and pulmonary fibrosis. Moreover, research indicates that some contaminants, biomaterials, active compounds, and drugs can induce the expression of OSGINs, thereby exerting toxicity or therapeutic effects on the organism. These many functions make OSGINs attractive targets. However, a thorough analysis of the topic is still lacking. This paper presents a systematic review of current OSGINs research, with an emphasis on their molecular functions, regulatory mechanisms, disease roles, and environmental stressors. Furthermore, using virtual screening tools, we identified a series of active molecules with potential inhibitory effects on OSGINs, providing valuable references for further drug development. Our review presents novel insights and guidance for the ongoing investigation of the biological significance and potential clinical applications of OSGINs.

PMID:40199404 | DOI:10.1016/j.bcp.2025.116921

Yearb Med Inform. 2024 Aug;33(1):168-174. doi: 10.1055/s-0044-1800738. Epub 2025 Apr 8.

ABSTRACT

OBJECTIVES: Objective: Precision medicine uses individualized patient data, including genomic and social determinants of health SDoH), to provide optimized personalized patient treatment. In this scoping review, we summarize studies published in the last two years that reported on implementation of precision medicine in clinical decision support (CDS) related to precision medicine.

METHODS: We searched PubMed for manuscripts published in 2022 and 2023 to retrieve publications that included CDS and precision medicine keywords and Mesh terms. We reviewed the abstracts and full texts to apply the inclusion criteria that the study must have described the implementation of precision medicine related CDS within electronic health records. We extracted the domain, type of data used in CDS, target population included in the implementation from the final set of included manuscripts.

RESULTS: Our search retrieved 285 manuscripts and papers. Sixteen (16) papers met inclusion criteria after manual review of the full text. Eight of the reviewed papers studied the successful implementation of pharmacogenomics in CDS, four studies investigated the implementation of disease risk, and only one paper described the implementation of CDS integrating social determinants of health.

CONCLUSION: Our scoping review of recent literature highlighted several findings. Pharmacogenomics is the most implemented precision medicine intervention based on published studies. Few reports describing disease risk and polygenic risk scores were found and no study addressed CDS for continuous biometric monitoring. Despite the increasing attention to social determinants of health as a key predictor of health outcomes, only one CDS incorporating SDoH have been publicly reported. Regular updates to scoping reviews can investigate barriers to implementation and identify solutions.

PMID:40199302 | DOI:10.1055/s-0044-1800738

Support Care Cancer. 2025 Apr 8;33(5):362. doi: 10.1007/s00520-025-09392-y.

ABSTRACT

PURPOSE: Prior studies evaluating the genetic predisposition to chemotherapy induced peripheral neuropathy (CIPN) have been limited by small populations due to difficulty with real-world data extraction. This genome-wide association study (GWAS) evaluates the genetic differences between patients who developed CIPN against those unaffected, using an electronic health record (EHR) definition of CIPN.

METHODS: This study included all patients who received chemotherapy associated with CIPN and had germline genetic data within the biobank at the Colorado Center for Personalized Medicine. CIPN was defined by a new neuropathic pain medication or an ICD-diagnosis of neuropathy after specified chemotherapy initiation. GWAS were stratified by (1) total population, (2) platinum chemotherapy, (3) taxane chemotherapy, and (4) vinca alkaloid chemotherapy. Genes previously associated with CIPN were analyzed within each GWAS.

RESULTS: Nine hundred fifteen patients received chemotherapy associated with CIPN, with 528 patients (57%) developing CIPN. Median age at chemotherapy initiation was 60.5 years; female sex (n = 517, 56.5%) and White or Caucasian race (n = 822, 89.8%) were most common. Among single nucleotide polymorphisms (SNPs) that reached suggestive levels of genome-wide significance (p < 1 × 10-5), 60 SNPs occurred within 11 genes that may play a role in the development of or protection against CIPN, including RCOR1, CLDN14, TRIM5, and TMC2. No SNPs previously associated with CIPN achieved genome-wide significance in this population.

CONCLUSION: This pharmacogenomic study suggests several genomic loci that may modulate the development of CIPN. This EHR-definition may allow for increased sample sizes and improved statistical power in future genetic studies of CIPN.

PMID:40198382 | DOI:10.1007/s00520-025-09392-y

Physiotherapy. 2025 Feb 13:101772. doi: 10.1016/j.physio.2025.101772. Online ahead of print.

ABSTRACT

OBJECTIVE: To assess the impact of combining positive expiratory pressure (PEP) and nebulisation on lung delivery by measuring the urinary concentration of amikacin, used as a biomarker in people with cystic fibrosis.

DESIGN: Randomised crossover study.

PARTICIPANTS: Nine people with cystic fibrosis.

INTERVENTION: A solution of amikacin was nebulised using a nebuliser alone or a nebuliser in combination with a PEP device.

OUTCOME MEASURES: After nebulisation, urine samples were collected over 24 hours. The total amount of amikacin excreted in urine was calculated, reflecting the lung dose. The elimination rate constant was also calculated, and represents total drug elimination by excretion and metabolism.

RESULTS: No differences in lung dose, half-life or elimination rate constant were observed between the two methods of nebulisation. Lung dose divided by respiratory rate was significantly greater for nebulisation in combination with PEP.

CONCLUSION: The use of nebulisation in combination with PEP does not result in clinically significant improvements in drug delivery in people with mild-to-moderate cystic fibrosis. However, this combination can be used safely to reduce the duration of physiotherapy sessions without compromising drug delivery.

TRIAL REGISTRATION: NCT02535130. CONTRIBUTION OF THE PAPER.

PMID:40199650 | DOI:10.1016/j.physio.2025.101772

Pulm Ther. 2025 Apr 8. doi: 10.1007/s41030-025-00293-3. Online ahead of print.

ABSTRACT

INTRODUCTION: ARISE was a global clinical trial designed to generate evidence demonstrating the utility of the patient-reported outcome instruments Quality of Life-Bronchiectasis (QOL-B) [Respiratory Domain (RD) only] and Patient-Reported Outcomes Measurement Information System Short Form v1.0-Fatigue 7a (PROMIS F SF-7a) in patients with newly diagnosed or recurrent Mycobacterium avium complex lung disease (MACLD). Here, we describe trial conduct, patient characteristics, and patient-reported symptoms at baseline among patients enrolled in ARISE.

METHODS: Adult patients with newly diagnosed or recurrent non-cavitary MACLD who had not initiated antibiotic treatment for their current MAC infection were enrolled; data including comorbidities and prior MACLD history were collected during screening. Symptom burden was assessed using QOL-B, PROMIS F SF-7a, and Functional Assessment of Chronic Illness Therapy (FACIT) questionnaires.

RESULTS: Of 99 patients from 12 countries enrolled in ARISE, the median age was 69.0 years; most were white (80.8%) and female (77.8%). This was the first diagnosis of MACLD for 72.7% of patients. Patients frequently reported having a comorbid respiratory disorder: bronchiectasis (49.5%), asthma (21.2%), and chronic obstructive pulmonary disease (16.2%). At baseline, mean (± SD) and median QOL-B RD scores were 65.0 (± 15.3) and 66.7; PROMIS F SF-7a T-scores were 53.8 (± 8.2) and 55.1; and FACIT-Fatigue scores were 35.0 (± 9.6) and 37.0.

CONCLUSIONS: Patients in ARISE were representative of a real-world patient population with MACLD. Comorbid chronic respiratory diseases were common in patients with new or recurrent MACLD, and substantial disease burden at the time physicians initiated MACLD treatment was evidenced by impairment across measures of fatigue and QOL-B domains.

GOV IDENTIFIER: NCT04677543.

PMID:40198465 | DOI:10.1007/s41030-025-00293-3

Curr Microbiol. 2025 Apr 8;82(6):236. doi: 10.1007/s00284-025-04167-4.

ABSTRACT

Cystic fibrosis (CF) is a polymicrobial infection characterized by interactions among various bacterial species that affect one another's cohabitation. The investigation of interspecies interactions in dual infections is essential to understand their reaction in the environment better and assist in the development of treatment regimens and innovative disease control approaches. Our hypothesis posits that co-infection interactions promote the adaptation of Staphylococcus aureus and Pseudomonas aeruginosa, potentially leading to synergistic action. To explore this, we examined dual-species interactions in co-isolated pairs of these organisms from Egyptian CF patients using laboratory media and artificial sputum media (ASM). Based on demographic data, 82 collected bacterial isolates from single, dual, and triple cultures were identified from 50 enrolled patients. In the interaction of the pairs in mimic media, P. aeruginosa exo-products significantly enhanced the biofilm formation and growth of S. aureus. Conversely, S. aureus did not inhibit P. aeruginosa biofilm formation. Furthermore, the biofilm mode of dual-organism growth provides protection in the CF context, as bacterial biofilms can withstand much higher antimicrobial levels compared to planktonically grown bacteria. Additionally, key biofilm genes regulated by quorum sensing were differentially expressed in both species in an isolate-dependent manner, highlighting their significant role in coexistence dual-species biofilm coexistence. In conclusion, our study illuminates the competitive and cooperative interactions between these two pathogens, which impact their coexistence and encourage biofilm production. This, in turn, accelerates disease progression and compromises patient health.

PMID:40198369 | DOI:10.1007/s00284-025-04167-4

BMJ Case Rep. 2025 Apr 8;18(4):e265092. doi: 10.1136/bcr-2025-265092.

ABSTRACT

A subset of idiopathic pulmonary fibrosis cases has a familial component. Telomeric mutations, such as those in the Regulator of Telomere Elongation Helicase 1 (RTEL1) gene, have been associated with lung fibrosis and a minority of dyskeratosis congenita (DC) cases.We present the case of a A male in his 50s with pulmonary fibrosis, cryptogenic hepatic cirrhosis, chronic anaemia and thrombocytopenia, lacy skin hyperpigmentation, dystrophic nails and canities. Family history included pulmonary fibrosis in two brothers. Genetic testing identified a RTEL1 mutation (c.3730T>C, p.Cys1244Arg) in heterozygosity, linked to a few cases of pulmonary fibrosis and DC. This mutation was confirmed in one brother and two sons. The patient was started on pirfenidone and referred for respiratory rehabilitation, haematological and transplant evaluations.Recognising family history and extrapulmonary manifestations in familial pulmonary fibrosis can expedite diagnosis, treatment and genetic counselling. Early detection of DC allows timely management of bone marrow failure and malignancy screening.

PMID:40199602 | DOI:10.1136/bcr-2025-265092

Cell Commun Signal. 2025 Apr 8;23(1):174. doi: 10.1186/s12964-025-02141-y.

ABSTRACT

STX12 (syntaxin12 or syntaxin13), a member of the SNARE protein family, plays a crucial role in intracellular vesicle transport and membrane fusion. Our previous research demonstrated that Stx12 knockout mice exhibit perinatal lethality with iron deficiency anemia. Despite its importance, the comprehensive physiological and pathological mechanism of STX12 remains largely unknown. Here, we revealed that STX12 deficiency causes the depolarization of mitochondrial membrane potential in zebrafish embryos and mouse embryonic fibroblasts. Additionally, the loss of STX12 decreased the levels of mitochondrial complex subunits, accompanied by mitochondrial DNA (mtDNA) release and activated cGAS-STING pathway and Type I interferon pathway in the lung tissue of Stx12-/- mice. Additionally, we observed a substantial increase in cytokines and neutrophil infiltration within the lung tissues of Stx12 knockout mice, indicating severe inflammation, which could be a contributing factor for Stx12-/- mortality. Various interventions have failed to rescue the lethal phenotype, suggesting that systemic effects may contribute to lethality. Further research is warranted to elucidate potential intervention strategies. Overall, our findings uncover the critical role of STX12 in maintaining mitochondrial function and mtDNA stability in pulmonary cells, and reveal that STX12 depletion results in pulmonary mtDNA release and activates mtDNA-dependent innate immunity.

PMID:40200300 | DOI:10.1186/s12964-025-02141-y

BMC Bioinformatics. 2025 Apr 8;26(1):100. doi: 10.1186/s12859-025-06104-5.

ABSTRACT

BACKGROUND: Bayesian Network (BN) modeling is a prominent methodology in computational systems biology. However, the incommensurability of datasets frequently encountered in life science domains gives rise to contextual dependence and numerical irregularities in the behavior of model selection criteria (such as MDL, Minimum Description Length) used in BN reconstruction. This renders model features, first and foremost dependency strengths, incomparable and difficult to interpret. In this study, we derive and evaluate a model selection principle that addresses these problems.

RESULTS: The objective of the study is attained by (i) approaching model evaluation as a misspecification problem, (ii) estimating the effect that sampling error has on the satisfiability of conditional independence criterion, as reflected by Mutual Information, and (iii) utilizing this error estimate to penalize uncertainty with the novel Minimum Uncertainty (MU) model selection principle. We validate our findings numerically and demonstrate the performance advantages of the MU criterion. Finally, we illustrate the advantages of the new model evaluation framework on real data examples.

CONCLUSIONS: The new BN model selection principle successfully overcomes performance irregularities observed with MDL, offers a superior average convergence rate in BN reconstruction, and improves the interpretability and universality of resulting BNs, thus enabling direct inter-BN comparisons and evaluations.

PMID:40200184 | DOI:10.1186/s12859-025-06104-5

Cell Death Differ. 2025 Apr 8. doi: 10.1038/s41418-025-01509-4. Online ahead of print.

ABSTRACT

Accumulating evidence indicates that metabolic enzymes can directly couple metabolic signals to transcriptional adaptation and cell differentiation. Glycogen synthase 1 (GYS1), the key metabolic enzyme for glycogenesis, is a nucleocytoplasmic shuttling protein compartmentalized in the cytosol and nucleus. However, the spatiotemporal regulation and biological function of nuclear GYS1 (nGYS1) microcompartments remain unclear. Here, we show that GYS1 dynamically reorganizes into nuclear condensates under conditions of glycogen depletion or transcription inhibition. nGYS1 complexes with the transcription factor NONO/p54nrb and undergoes liquid-liquid phase separation to form biomolecular condensates, leading to its nuclear retention and inhibition of glycogen biosynthesis. Compared to their wild-type littermates, Nono-deficient mice exhibit exercise intolerance, higher muscle glycogen content, and smaller myofibers. Additionally, Gys1 or Nono deficiency prevents C2C12 differentiation and cardiotoxin-induced muscle regeneration in mice. Mechanistically, nGYS1 and NONO co-condense with the myogenic transcription factor MyoD and preinitiation complex (PIC) proteins to form transcriptional condensates, driving myogenic gene expression during myoblast differentiation. These results reveal the spatiotemporal regulation and subcellular function of nuclear GYS1 condensates in glycogenesis and myogenesis, providing mechanistic insights into glycogenoses and muscular dystrophy.

PMID:40200092 | DOI:10.1038/s41418-025-01509-4

Nat Protoc. 2025 Apr 8. doi: 10.1038/s41596-025-01150-y. Online ahead of print.

ABSTRACT

Spheroids are reaggregated multicellular three-dimensional structures generated from cells or cell cultures of healthy as well as pathological tissue. Basic and translational spheroid application across academia and industry have led to the development of multiple setups and analysis methods, which mostly lack the modularity to maximally phenotype spheroids. Here we present the self-assembly of single-cell suspensions into spheroids by the liquid overlay method, followed by a modular framework for a multifaceted phenotyping of spheroids. Cell seeding, supernatant handling and compound administration are elaborated by both manual and automated procedures. The phenotyping modules contain a suite of orthogonal assays to analyze spheroids longitudinally and/or at an endpoint. Longitudinal analyses include morphometry with or without spheroid or cell state specific information and supernatant evaluation (nutrient consumption and metabolite/cytokine production). Spheroids can also be used as a starting point to monitor single and collective cell migration and invasion. At an endpoint, spheroids are lysed, fixed or dissociated into single cells. Endpoint analyses allow the investigation of molecular content, single-cell composition and state and architecture with spatial cell and subcellular specific information. Each module addresses time requirements and quality control indicators to support reproducibility. The presented complementary techniques can be readily adopted by researchers experienced in cell culture and basic molecular biology. We anticipate that this modular protocol will advance the application of three-dimensional biology by providing scalable and complementary methods.

PMID:40200041 | DOI:10.1038/s41596-025-01150-y