Nat Aging. 2025 Mar 13. doi: 10.1038/s43587-025-00816-2. Online ahead of print.

ABSTRACT

Neuroinflammation including interleukin (IL)-12/IL-23-signaling is central to Alzheimer's disease (AD) pathology. Inhibition of p40, a subunit of IL-12/IL-23, attenuates pathology in AD-like mice; however, its signaling mechanism and expression pattern remained elusive. Here we show that IL-12 receptors are predominantly expressed in neurons and oligodendrocytes in AD-like APPPS1 mice and in patients with AD, whereas IL-23 receptor transcripts are barely detectable. Consistently, deletion of the IL-12 receptor in neuroectodermal cells ameliorated AD pathology in APPPS1 mice, whereas removal of IL-23 receptors had no effect. Genetic ablation of IL-12 signaling alone reverted the loss of mature oligodendrocytes, restored myelin homeostasis, rescued the amyloid-β-dependent reduction of parvalbumin-positive interneurons and restored phagocytosis-related changes in microglia of APPPS1 mice. Furthermore, IL-12 protein expression was increased in human AD brains compared to healthy age-matched controls, and human oligodendrocyte-like cells responded profoundly to IL-12 stimulation. We conclude that oligodendroglial and neuronal IL-12 signaling, but not IL-23 signaling, are key in orchestrating AD-related neuroimmune crosstalk and that IL-12 represents an attractive therapeutic target in AD.

PMID:40082619 | DOI:10.1038/s43587-025-00816-2

Metabolomics. 2025 Mar 13;21(2):40. doi: 10.1007/s11306-025-02228-0.

ABSTRACT

BACKGROUND: Advancements in the research of intracellular metabolome have the potential to affect our understanding of biological processes. The applications and findings of intracellular metabolome analysis are useful in understanding cellular pathways, microbial interactions, and the detection of secreted metabolites and their functions.

AIM OF REVIEW: This work focuses on the analysis of intracellular metabolomes in microorganisms. The techniques used for analyzing the intracellular metabolomes including metabolomics approaches such as mass spectrometry, nuclear magnetic resonance, liquid chromatography, and gas chromatography are discussed.

KEY SCIENTIFIC CONCEPTS OF REVIEW: Challenges such as sample preparation, data analysis, metabolite extraction, sample storage and collection, and processing techniques were investigated, as they can highlight emerging technologies and advancements in metabolome analysis, future applications in drug discovery, personalized medicine, systems biology, and the limitations and challenges in studying the metabolome of microorganisms.

PMID:40082321 | DOI:10.1007/s11306-025-02228-0

Drug Des Devel Ther. 2025 Mar 8;19:1655-1668. doi: 10.2147/DDDT.S508773. eCollection 2025.

ABSTRACT

Trastuzumab deruxtecan (T-DXd) has been approved to treat various tumors. While most adverse events (AEs) associated with T-DXd are manageable, interstitial lung disease (ILD)/pneumonitis is a notable AE of special concern. This review describes the incidence, severity, and management of T-DXd-induced ILD/pneumonitis across different tumors. We conducted a systematic search of PubMed, Embase, Cochrane Library, and Web of Science for literature published up to 13 September 2024, regarding the use of T-DXd in the treatment of HER2-positive tumors. Studies included were clinical trials involving HER2-positive tumors with reported ILD/pneumonitis cases.The main data extracted from the full-text articles included the incidence and severity of T-DXd-induced ILD. 18 studies involving 3380 patients with various advanced solid malignancies were included in our review. The overall incidence of adjudicated drug-related ILD/pneumonitis was 12.40%. Although most ILD/pneumonitis cases were low-grade, the risk of ILD/pneumonitis-related death should not be overlooked. Given the prolonged exposure to the drug, careful monitoring and management of T-DXd-induced ILD/pneumonitis are critical. Management strategies include dose reduction, treatment interruption, discontinuation, corticosteroids, and supportive care. Further research is needed to clarify the risk factors and mechanisms underlying T-DXd-induced ILD/pneumonitis. This review highlights critical gaps in understanding the risk factors and mechanisms of T-DXd-induced ILD, underscoring the need for further research.

PMID:40083848 | PMC:PMC11904318 | DOI:10.2147/DDDT.S508773

Allergol Select. 2025 Mar 6;9:28-39. doi: 10.5414/ALX02531E. eCollection 2025.

ABSTRACT

β-lactam antibiotics (BLAs) are still the antibiotics of first choice for the treatment of many bacterial infections. Treatment with a BLA is often hindered by a suspected allergy, up to 10% of the population report an allergy to penicillin. After allergological evaluation of the suspected allergic reaction to a BLA, most patients show a low probability of a BLA allergy; only in a minority of cases an allergic reaction to the repeated administration of a BLA appear likely in view of the previous history. In > 90% of cases, the suspected BLA allergy can be ruled out by allergy diagnostics. We recommend a risk-stratified approach in the context of an urgent need for BLA, which should enable most patients to receive a BLA therapy. After acute therapy, allergy diagnostics have to be done to clearly prove or reliably rule out a BLA allergy.

PMID:40083843 | PMC:PMC11905010 | DOI:10.5414/ALX02531E

JAMA Netw Open. 2025 Mar 3;8(3):e250572. doi: 10.1001/jamanetworkopen.2025.0572.

ABSTRACT

IMPORTANCE: Inequitable access to transplant in the US is well recognized, yet the nature and extent of upstream disparities in care prior to transplant are unknown.

OBJECTIVE: To understand patterns of referral for lung transplant by race, ethnicity, and neighborhood-level socioeconomic status.

DESIGN, SETTING, AND PARTICIPANTS: This retrospective cohort study included adults aged 18 to 80 years with obstructive and restrictive lung disease from a single large-volume transplant center in Cleveland, Ohio, who were diagnosed between January 1, 2006, and May 11, 2023.

EXPOSURES: Neighborhood resources.

MAIN OUTCOMES AND MEASURES: The main outcome was the transition to the next stage of the transplant care continuum, death, or a lapse in care. Cause-specific Cox proportional hazards regression models were used to account for death as a competing risk, adjusting for age at index encounter (respective to each cohort), diagnosis, and sex as covariates.

RESULTS: This study included 30 050 patients with obstructive and restrictive lung disease with primary care encounters (mean [SD] age, 65 [13] years; 56.1% female), 73 817 with a pulmonary medicine encounter, 4198 undergoing lung transplant evaluation, and 1378 on the lung transplant waiting list. In a multivariable model including age, diagnosis, sex, area deprivation index, and race and ethnicity (including 3.3% Hispanic, 15.2% non-Hispanic Black, and 81.5% non-Hispanic White individuals), patients residing in the least-resourced neighborhoods were 97% more likely to die without transitioning to pulmonary medicine (hazard ratio [HR], 1.97 [95% CI, 1.78-2.17]), 90% more likely to die prior to lung transplant evaluation (HR, 1.90 [95% CI, 1.77-2.04]), 40% more likely to die prior to placement on the waiting list (HR, 1.40 [95% CI, 1.11-1.76]), and 97% more likely to die prior to transplant (HR, 1.97 [95% CI, 1.18-3.29]) compared with patients residing in the most-resourced neighborhoods. These patients were also 13% less likely to transition to pulmonary medicine (HR, 0.87 [95% CI, 0.82-0.92]) and 45% less likely to be placed on the waiting list (HR, 0.55 [95% CI, 0.44-0.68]) despite a 69% increased likelihood of transplant evaluation (HR, 1.69 [95% CI, 1.36-2.09]). While non-Hispanic Black patients had lower risks of death across all stages of care, they experienced a 39% lower likelihood of proceeding to lung transplant evaluation (HR, 0.61 [95% CI, 0.51-0.74]). Racial differences in the cumulative incidence of waiting list placement were found, but differences were not consistent across levels of neighborhood resources.

CONCLUSIONS AND RELEVANCE: In this retrospective cohort study of patients diagnosed with restrictive and obstructive pulmonary disease, increased mortality risks and decreased likelihood of care escalations for patients who were socioeconomically disadvantaged and for racial and ethnic minority patients were found. These results suggest potential interventions for advancing equitable access to lung transplant.

PMID:40080022 | PMC:PMC11907320 | DOI:10.1001/jamanetworkopen.2025.0572

Drug Discov Today. 2025 Mar 11:104327. doi: 10.1016/j.drudis.2025.104327. Online ahead of print.

ABSTRACT

Rheumatoid arthritis (RA) presents a significant challenge in clinical management because of the dearth of effective drugs despite advances in understanding its mechanisms. Drug repurposing has emerged as a promising strategy to address this gap, offering potential cost savings and expediting drug discovery. Notably, computational methods, particularly machine learning (ML), have shown promise in RA drug repurposing. In this review, we survey various drug-repurposing approaches, both classical and contemporary, highlighting the pivotal role of ML. We summarize RA candidate drugs identified through computational strategies and discuss prevailing challenges in this domain. Leveraging ML, alongside a deepening understanding of RA mechanisms, holds promise for enhancing pharmacological treatment options for patients with RA.

PMID:40081521 | DOI:10.1016/j.drudis.2025.104327

Gene. 2025 Mar 11:149386. doi: 10.1016/j.gene.2025.149386. Online ahead of print.

ABSTRACT

Vancomycin is a commonly administered antibiotic for various Gram-positive infections in critically ill patients. Vancomycin has a narrow therapeutic index and its main adverse drug reaction is acute kidney injury (AKI). In this regard, various pharmacokinetic parameters have been widely considered for therapeutic drug monitoring (TDM) purposes. Higher vancomycin trough concentration and area under the curve (AUC) values would be associated with higher rates of AKI. Therefore, dose adjustment based on targeted pharmacokinetic values would be essential to avoid toxicity and achieve optimal clinical response. However, there are numerous reports regarding the discrepancy between pharmacokinetic parameter values and AKI. In this regard, we examined the possible role of pharmacogenetics in vancomycin-induced AKI to distinguish patients who are genetically prone to AKI. In this cross-sectional study, polymorphisms of osteopontin (OPN) and Apolipoprotein E (APOE) along with pharmacokinetic parameters were assessed in 87 critically ill patients admitted to ICU wards and received vancomycin. The results indicated a significant difference in OPN and APOE genotype distribution between AKI and non-AKI patients (P = 0.001 and 0.02, respectively). Stepwise multivariate logistic regression analysis showed that patients with e2e3 genotype were 4.2-fold more prone to AKI (P = 0.029; OR = 4.2; 95 %CI = 1.2-15.7). Moreover, there was a significant correlation between pharmacokinetic parameters (calculated trough concentration, AUCτ, AUC24h, and t1/2) and vancomycin-induced AKI. Genotyping the patients for OPN and APOE polymorphisms before vancomycin initiation would be promising as a routine clinical practice to obtain an efficient clinical response and prevent vancomycin-induced AKI, especially in critically ill patients.

PMID:40081681 | DOI:10.1016/j.gene.2025.149386

Biochim Biophys Acta Mol Basis Dis. 2025 Mar 12;1871(5):167755. doi: 10.1016/j.bbadis.2025.167755. Online ahead of print.

ABSTRACT

The Arylamine-N-acetyltransferase-2 (NAT2) enzyme is involved in metabolism of commonly used drugs driving differences in efficacy and tolerability of treatments. To bridge the current knowledge gap on metabolism of cytotoxic drugs by NAT2, and identify anticancer agents whose effects depend on NAT2 activity, we assessed 147 clinically used drugs. Hit compounds were evaluated for metabolic conversion by acetylation in presence of recombinant NAT2. Among those 147 drugs we found doxorubicin, daunorubicin, epirubicin, valrubicin, teniposide, afatinib, carmustine, vincristine, panobinostat, and vorinostat to have increased toxicity to cancer cells expressing the rapid NAT2 allele. Additionally, we report NAT2-mediated acetylation of idarubicin, daunorubicin, doxorubicin, vorinostat, and CUDC-101. These findings have implications for pharmacogenomics and cancer precision medicine using conventional chemotherapeutic drugs, as improving their efficacy and safety may affect >4 million cancer patients worldwide that receive these drugs as standard of care.

PMID:40081304 | DOI:10.1016/j.bbadis.2025.167755

Forensic Sci Int. 2025 Mar 7;370:112445. doi: 10.1016/j.forsciint.2025.112445. Online ahead of print.

ABSTRACT

Methadone is a synthetic opioid that is often used for prevention of withdrawal symptoms and for management of chronic pain. In concentrations above the therapeutic level however, methadone can lead to detrimental side effects, such as respiratory depression. Several cytochrome P450 (CYP) enzymes are involved in methadone metabolism, foremost in building the main metabolite 2-ethylidene-1,5-dimethyl-3,3diphenylpyrrolidine (EDDP). It is well known that genetic polymorphisms within the CYPs can lead to an altered metabolism, affecting methadone elimination and peak concentrations. The metabolic ratio, in forensic toxicology suggested to assist in distinguishing between chronic and acute intake, can also be affected by genetic variations in CYP genes. The aim of the study was therefor to examine, whether the metabolizer type of CYP2D6, CYP2C19 and CYP2B6 can be associated with a certain type of intoxication, methadone concentration or metabolic ratio in postmortem blood samples of methadone intakers. The metabolic ratio of EDDP/methadone was determined in 37 blood samples from deceased methadone intakers in 2023. These cases were genotyped for CYP2D6, CYP2C19 and CYP2B6 via SNaPshot analysis. In case of CYP2D6 a copy number variations analysis was applied using qPCR. Metabolizer phenotypes were determined according to guidelines by the Dutch Pharmacogenetics Working Group (DPWG) and the Clinical Pharmacogenetics Implementation Consortium (CPIC). Our results show a significantly increased metabolic ratio of EDDP/methadone in the CYP2D6 intermediate metabolizer (IM) group, compared to the CYP2D6 normal metabolizer (NM) group. Further, when separating the methadone intakers by type of intoxication, CYP2D6 IM had a significantly higher metabolic ratio in the mix intoxication and the non-intoxication group compared to NM, poor and ultrarapid metabolizers (PM, UM).

PMID:40080971 | DOI:10.1016/j.forsciint.2025.112445

Mol Oncol. 2025 Mar 13. doi: 10.1002/1878-0261.70008. Online ahead of print.

ABSTRACT

Ewing sarcoma (EwS) is a rare and aggressive malignancy, which frequently affects children. One of the few recurrent genomic variants in EwS is genomic copy number deletion of CDKN2A; however, the clinical consequences of dysregulation of CDKN2A in EwS are unclear. In this study, we revisit CDKN2A to investigate its role as a potential prognostic biomarker in EwS using data from EwS pre-clinical models as well as clinical samples from patients with EwS. We demonstrate the potential essentiality of CDKN2A dysregulation and sustained downstream CDK4/CCND1 activity. Finally, we present evidence that high expression of CDKN2A is a negative prognostic biomarker at diagnosis in EwS in three independent datasets. Our data may suggest that the role of CDKN2A may change across the clinical context of EwS, however, further study is necessary to validate the function of CDKN2A expression in EwS.

PMID:40080912 | DOI:10.1002/1878-0261.70008

Microb Pathog. 2025 Mar 11:107473. doi: 10.1016/j.micpath.2025.107473. Online ahead of print.

ABSTRACT

Pseudomonas aeruginosa is a prominent bacterial pathogen that causes several nosocomial infections and is notorious for its environmental resilience and rapid development of resistance to frontline antibiotics. A major cause of mortality and morbidity among cystic fibrosis patients, multidrug-resistant P. aeruginosa is often targeted with the antibiotic colistin as a last option. However, increasing reports of colistin resistance among P. aeruginosa is a significant concern. Though the molecular mechanisms responsible for the development of colistin resistance are well known, the evolutionary trajectory to colistin resistance is an important area of investigation. In this work, using the adaptive laboratory evolution (ALE) approach we have evolved a colistin-sensitive P. aeruginosa ancestral strain to a resistant one. During the process of laboratory evolution in 106 generations, colistin MIC was increased 32-fold. The evolved strain had lower fitness than the ancestral strain, as evidenced by a lower growth rate. Moreover, the evolved strain produced more biofilm and less pyocyanin pigment. Interestingly, the evolved strain showed collateral sensitivity to several antibiotics, including ampicillin, tetracycline, streptomycin, gentamycin, nalidixic acid, trimethoprim, rifampicin, and chloramphenicol. On analysing various TCS modules involved in the development of colistin resistance, a novel missense mutation (V136G) was detected in the PmrB sensor kinase. In silico analysis indicated that the V136G substitution would destabilize the PmrB kinase structure, making the mutation deleterious. However, the functionality of the PmrB mutant remains to be validated experimentally.

PMID:40081679 | DOI:10.1016/j.micpath.2025.107473

Respir Med. 2025 Mar 11:108036. doi: 10.1016/j.rmed.2025.108036. Online ahead of print.

ABSTRACT

BACKGROUND: Lung ultrasound is becoming increasingly important in the diagnosis of acute and chronic lung disease, especially in children and adolescents. In children with cystic fibrosis (CF), conventional radiography or computed tomography (CT) has been the main modality used to evaluate acute pneumonia or the progression of chronic lung disease. This Study aimed to evaluate Lung-Ultrasound as a diagnostic tool for children and adolescents with CF.

METHODS: We examined 30 CF patients with lung ultrasound before and after spirometry and compared them with lung ultrasounds of 15 lung-healthy children. We used a comprehensive and complete examination procedure with 12 probe positions to determine the best examination procedure in retrospect. In addition, an acceptance survey was conducted among the children and adolescents after the examination.

RESULTS: There was a significant difference in pleural irregularities, B-lines, consolidations and the adapted Peixoto et al. score between CF patients and healthy children before spirometry. We found excellent discrimination between patients and lung-healthy subjects using the Peixoto-score (AUC 0.968), pleural irregularities (AUC 0.890. CF patients had more B-lines, more consolidations, and a higher Peixoto score (mean difference 7.7 points).There was no significant difference in lung ultrasound results in children with CF before and after spirometry. Shortening our extended examination procedure would minimally compromise diagnostic accuracy. The lung ultrasound examination was well accepted by the children.

CONCLUSION: We could demonstrate that lung ultrasound is a sensitive and reliable method for assessing pulmonary changes in cystic fibrosis.

PMID:40081670 | DOI:10.1016/j.rmed.2025.108036

JBRA Assist Reprod. 2025 Mar 13. doi: 10.5935/1518-0557.20240102. Online ahead of print.

ABSTRACT

OBJECTIVE: To determine the carrier frequency of X-linked and autosomal recessive diseases in patients attending a human fertility institute in Colombia.

METHODS: This retrospective observational study included patients and gamete donors attending a Human Fertility Institute in Colombia between January 2017 and June 2023. Sociodemographic data and results of Next Generation Sequencing laboratory panels for screening of recessive disease-causing mutations were collected and analyzed.

RESULTS: Data from 746 samples were analyzed; 599 (80.3%) were Colombian origin individuals and 147 (19.7%) were foreigners. At least one mutation was detected in 526 (70.5%) individuals. Of note, 893 pathogenic genetic variants were identified.The genetic variants most frequently observed in all the individuals studied were associated with the following diseases (carrier frequency): alpha thalassemia (10.5%), alpha-1 antitrypsin deficiency (10%), congenital adrenal hyperplasia due to 21-hydroxylase deficiency (9.4%), cystic fibrosis (7.3%), spinal muscular atrophy type 1 (5.6%) and Stargardt disease type 1 (5.0%). The most frequent genetic variant observed in the subgroup of Colombian origin individuals was associated with alpha-1 antitrypsin deficiency (11.3%).

CONCLUSIONS: Information on the frequency of recessive diseases in Colombia is limited. This pioneering carrier genetic screening identified a high percentage of carriers for at least one recessive autosomal or X-linked in the population evaluated. Screening for recessive mutations could lead to an evolution in family planning programs and a decrease in the number of patients affected by recessive disorders. Furthermore, it could become a routine test not only in cases of assisted reproduction but also in cases of natural gestation.

PMID:40080775 | DOI:10.5935/1518-0557.20240102

Thorax. 2025 Mar 13:thorax-2024-221537. doi: 10.1136/thorax-2024-221537. Online ahead of print.

ABSTRACT

BACKGROUND: The diagnosis of interstitial lung disease (ILD) can pose a challenge as the pulmonary function test (PFT) is only minimally affected at the onset. To improve early diagnosis, this study aims to explore the potential of artificial intelligence (AI) software in assisting pulmonologists with PFT interpretation for ILD diagnosis. The software provides an automated description of PFT and disease probabilities computed from an AI model.

STUDY METHODS: In study phase 1, a cohort of 60 patients, 30 of whom had ILD, were retrospectively diagnosed by 25 pulmonologists (8 junior physicians and 17 experienced pneumologists) by evaluating a PFT (body plethysmography and diffusion capacity) and a short medical history. The experts screened the cohort twice, without and with the aid of AI (ArtiQ.PFT, V.1.4.0, ArtiQ, BE) software and provided a primary diagnosis and up to three differential diagnoses for each case. In study phase 2, 19 pulmonologists repeated the protocol after using ArtiQ.PFT for 4-6 months.

RESULTS: Overall, AI increased the diagnostic accuracy for various lung diseases from 41.8% to 62.3% in study phase 1. Focusing on ILD, AI improved the detection of lung fibrosis as the primary diagnosis from 42.8% without AI to 72.1% with AI (p<0.0001). Phase 2 yielded a similar outcome: using AI increased ILD diagnosis based on primary diagnosis (53.2% to 75.1%; p<0.0001). ILD detections without AI support significantly increased between phase 1 and phase 2 (p=0.028) but not with AI (p=0.24).

INTERPRETATION: This study shows that AI-based decision support on PFT interpretation improves accurate and early ILD diagnosis.

PMID:40081903 | DOI:10.1136/thorax-2024-221537

Tuberc Respir Dis (Seoul). 2025 Mar 13. doi: 10.4046/trd.2024.0181. Online ahead of print.

ABSTRACT

Rare forms of interstitial lung diseases (ILDs) present with unique clinical features and require different treatment strategies. Respiratory bronchiolitis-associated ILD mainly affects smokers, showing ground-glass opacities on chest computed tomography (CT) scans and pigmented macrophages in the bronchoalveolar lavage fluid. Smoking cessation is essential for treatment, with corticosteroids used for severe cases. Desquamative interstitial pneumonia, also related to smoking, is characterized by exertional dyspnea, dry cough, restrictive lung function, and ground-glass opacities on high-resolution CT. Lymphoid interstitial pneumonia involves lymphocytic proliferation and is associated with autoimmune diseases or infections, treated with corticosteroids. Acute interstitial pneumonia resembles acute respiratory distress syndrome but occurs without a clear cause and is managed with supportive care. Idiopathic pleuroparenchymal fibroelastosis results in fibrosis in the upper lobes, primarily in nonsmokers, and is diagnosed through clinical and imaging findings, with no effective treatment to improve survival. Each condition has distinct pathological features, clinical presentations, and treatment approaches, along with variable prognoses.

PMID:40081337 | DOI:10.4046/trd.2024.0181

Respir Investig. 2025 Mar 12;63(3):334-341. doi: 10.1016/j.resinv.2025.03.005. Online ahead of print.

ABSTRACT

BACKGROUND: The 6-min walk test (6MWT) is frequently used in pulmonary fibrosis (PF) research. It evaluates an individual's sub-maximal exercise performance by measuring the distance they walk and their vital signs across 6 min. In research studies, the 6-min walk distance (6MWD) is often used as a surrogate marker for disease progression. The aim of this study was to systematically assess the association between 6MWT parameters and mortality in PF.

METHODS: MEDLINE, EMBASE, CINAHL, and CENTRAL databases were searched for studies reporting mortality and 6MWD in patients with PF. Study quality was assessed using a modified Newcastle-Ottawa Scale. Studies were included if they reported associations between the 6MWT in pulmonary fibrosis and mortality. Results were presented as a narrative synthesis.

RESULTS: 2312 studies were identified, 22 studies met the pre-defined inclusion criteria, comprising 5940 Idiopathic PF patients. Baseline 6MWD was found to be loosely associated with mortality (Ranges: univariate HR 0.89-4.72, multivariate HR 0.96-2.65), while a decrease in 6MWD across 24-weeks was correlated with a higher risk of mortality (Ranges: univariate HR 2.25-4.81, multivariate HR 1.72-4.3).

DISCUSSION: This review found that a low baseline 6MWD, and a 6-month decrease in 6MWD were strongly correlated with increased mortality in Idiopathic PF patients. As the 6MWT is a safe, easy-to-conduct test, it is appropriate for use as a marker of patient prognosis, in both clinical and research settings.

OPEN SCIENCE FRAMEWORK PROTOCOL REGISTRATION: DOI 10.17605/OSF.IO/3D7BV.

PMID:40081204 | DOI:10.1016/j.resinv.2025.03.005

Funct Integr Genomics. 2025 Mar 13;25(1):62. doi: 10.1007/s10142-025-01571-8.

NO ABSTRACT

PMID:40080215 | DOI:10.1007/s10142-025-01571-8

Trends Cell Biol. 2025 Mar 12:S0962-8924(25)00040-6. doi: 10.1016/j.tcb.2025.02.006. Online ahead of print.

ABSTRACT

Aging is a dynamic process that is driven by cellular damage and disruption of homeostatic gene regulatory networks (GRNs). Traditional studies often focus on individual genes, but understanding their interplay is key to unraveling the mechanisms of aging. This review explores the gene circuits that influence longevity and highlights the role of feedback loops in maintaining cellular balance. The SIR2-HAP circuit in yeast serves as a model to explore how mutual inhibition between pathways influences aging trajectories and how engineering stable fixed points or oscillations within these circuits can extend lifespan. Feedback loops crucial for maintaining homeostasis are also reviewed, and we highlight how their destabilization accelerates aging. By leveraging systems and synthetic biology, strategies are proposed that may stabilize these loops within single cells, thereby enhancing their resilience to aging-related damage.

PMID:40082090 | DOI:10.1016/j.tcb.2025.02.006

J Microbiol Biotechnol. 2025 Mar 13;35:e2411058. doi: 10.4014/jmb.2411.11058.

ABSTRACT

Polyethylene (PE) is among the most widely used synthetic plastics globally, serving as an essential material in daily life and numerous industries, such as packaging for bottles and food, as well as in the production of toys and pipes. PE is used for various purposes owing to its high durability and low production costs, leading to a steadily increasing demand. However, PE waste is a significant contributor to environmental pollution, posing serious threats to marine and soil ecosystems. Therefore, the efficient decomposition of PE, a synthetic polymer known for its resistance to degradation, using bacteria offers a sustainable and effective method for reusing PE. In this study, we isolated a novel species of Kosakonia, designated Kosakonia cowanii JNU01, from a landfill site, capable of biodegrading PE. K. cowanii JNU01 exhibited the highest cell growth rate in media containing PE, indicating its effectiveness in decomposing PE for use as a sole carbon source in its metabolic pathway. Treatment of PE with K. cowanii JNU01 resulted in the emergence of new chemical functional groups, including hydroxyl, carboxyl, amide, and ether groups, within the inert hydrocarbon structure. Analysis of the PE film treated with K. cowanii JNU01 revealed considerable physical degradation on the film's surface. Additionally, various metabolites released from PE by K. cowanii JNU01 were identified. These findings suggest that K. cowanii JNU01 proves to be an effective candidate bacterium for PE degradation.

PMID:40081902 | DOI:10.4014/jmb.2411.11058

J Mol Biol. 2025 Mar 11:169087. doi: 10.1016/j.jmb.2025.169087. Online ahead of print.

ABSTRACT

I started my faculty career in 1981 at the UW-Madison in the Department of Bacteriology and moved to the University of California, San Francisco in 1993, where I am a Professor in the Departments of Microbiology and Immunology and Cell and Tissue Biology. In this article, I first review my contributions to understanding the molecular biology of bacterial transcriptional apparatus and the global role of alternative sigmas (σs), a major pillar of bacterial transcriptional control. I then discuss my role in spearheading the development of bacterial systems biology, specifically to the genome-wide phenotyping approaches necessary for rapid understanding of gene function and the molecular basis of pathway connections across the bacterial universe.

PMID:40081792 | DOI:10.1016/j.jmb.2025.169087