FASEB J. 2025 Jan 15;39(1):e70306. doi: 10.1096/fj.202402813R.

ABSTRACT

Obstructive sleep apnea (OSA) is increasingly recognized for its link to idiopathic pulmonary fibrosis (IPF), though the underlying mechanisms remain poorly understood. Histone lysine demethylase 6B (KDM6B) may either prevent or promote organ fibrosis, but its specific role in IPF is yet to be clarified. This study aimed to investigate the function and mechanisms of KDM6B in IPF and the exacerbating effects of OSA. We assessed KDM6B levels in lung tissues from IPF patients, IPF mouse models, and a dual-hit model combining OSA-associated intermittent hypoxia (IH) with bleomycin (BLM) or TGF-β1. We evaluated pulmonary fibrosis, myofibroblast activation, and oxidative stress. KDM6B levels were elevated in lung tissues from IPF patients and BLM-treated mice, as well as in TGF-β1-stimulated myofibroblasts. Importantly, IH significantly worsened BLM-induced pulmonary fibrosis and TGF-β1-induced myofibroblast activation, further amplifying KDM6B expression both in vivo and in vitro. Inhibition of KDM6B reduced pulmonary fibrosis and decreased fibroblast activation and migration in IPF and dual-hit models. Mechanistically, KDM6B inhibition led to decreased NOX4 expression and reduced oxidative stress. KDM6B plays a critical role in promoting pulmonary fibrosis and mediating the exacerbating effects of OSA on this condition. Our findings identify KDM6B as a novel potential therapeutic target for IPF.

PMID:39781582 | DOI:10.1096/fj.202402813R

Int J Biol Sci. 2025 Jan 1;21(2):685-707. doi: 10.7150/ijbs.105826. eCollection 2025.

ABSTRACT

Pulmonary fibrosis (PF) is a high-mortality lung disease with limited treatment options, highlighting the need for new therapies. Cyclin-dependent kinase 8 (CDK8) is a promising target due to its role in regulating transcription via the TGF-β/Smad pathway, though CDK8 inhibitors have not been thoroughly studied for PF. This study aims to evaluate the potential of E966-0530-45418, a novel CDK8 inhibitor, in mitigating PF progression and explores its underlying mechanisms. We discovered that CDK8 is upregulated in lung tissues from idiopathic pulmonary fibrosis patients and in a bleomycin-induced PF mouse model. Our study further revealed that E966-0530-45418 inhibits PF progression by attenuating the activity of the transcription factor Smad3, which is involved in TGF-β1/Smad signaling, along with RNA polymerase II to downregulate fibrosis-associated protein expression in alveolar epithelia and lung fibroblasts and consequently mitigate myofibroblast differentiation and collagen deposition. E966-0530-45418 also blocks STAT3 signaling to obstruct M2 macrophage polarization, further suppressing PF progression. Moreover, E966-0530-45418 administration ameliorated lung function deterioration and lung parenchymal destruction in the bleomycin-induced PF mouse model. These findings indicate that E966-0530-45418 holds promise as a pioneering CDK8 inhibitor for treating PF.

PMID:39781457 | PMC:PMC11705631 | DOI:10.7150/ijbs.105826

Ther Adv Rare Dis. 2025 Jan 6;6:26330040241311621. doi: 10.1177/26330040241311621. eCollection 2025 Jan-Dec.

ABSTRACT

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening systemic hyperinflammatory syndrome, rarely associated with bone marrow failure (BMF). Telomere biology disorders (TBD) are caused by inherited defects in telomerase processes and can have heterogeneous presentations including idiopathic pulmonary fibrosis, cirrhosis, and BMF. We report a case of a 10-year-old male from Lima, Peru, who presented with HLH as the initial manifestation of a TBD. He experienced fever, gastrointestinal symptoms, and mucocutaneous involvement. Initial laboratory analyses revealed pancytopenia and elevated inflammatory markers. Despite symptomatic and antibiotic treatment, his clinical condition persisted leading to a suspicion of Kawasaki disease and, subsequently, HLH. Immunomodulatory treatment was initiated with a good clinical response. Bone marrow aspiration revealed severe hypocellular bone marrow and cytophagocytosis. Genetic studies identified a pathogenic variant in the TERC gene (n.110_113del), which was also found in the patient's mother and brother. HLH as the initial manifestation of BMF is rare. This case highlights the importance of considering TBD in children with BMF of unclear etiology and the value of genetic testing in such cases.

PMID:39780848 | PMC:PMC11705338 | DOI:10.1177/26330040241311621

Front Plant Sci. 2024 Dec 23;15:1385414. doi: 10.3389/fpls.2024.1385414. eCollection 2024.

ABSTRACT

Drought conditions severely curtail the ability of plants to accumulate biomass due to the closure of stomata and the decrease of photosynthetic assimilation rate. Additionally, there is a shift in the plant's metabolic processes toward the production of metabolites that offer protection and aid in osmoadaptation, as opposed to those required for development and growth. To limit water loss via non-stomatal transpiration, plants adjust the load and composition of cuticle waxes, which act as an additional barrier. This study investigates the impact of soil water deficit on stomatal and epicuticular water losses, as well as metabolic adjustments in two canola (Brassica napus L.) cultivars-one drought-tolerant and the other drought-sensitive. Specifically, we examined the effect of a drought treatment, which involved reducing water holding capacity to 40%, on the levels of cysteine, sucrose, and abscisic acid (ABA) in the leaves of both cultivars. Next, we looked for potential differences in night, predawn, and early morning transpiration rates and the epicuticular wax load and composition in response to drought. A substantial rise in leaf cysteine was observed in both canola cultivars in response to drought, and a strong correlation was found between cysteine, ABA, and stomatal conductance, indicating that cysteine and sulfur may play a role in controlling stomatal movement during drought stress. Attributes related to CO2 diffusion (stomatal and mesophyll conductance) and photosynthetic capacity were different between the two canola cultivars suggesting a better management of water relations under stress by the drought-tolerant cultivar. Epicuticular waxes were found to adjust in response to drought, acting as an additional barrier against water loss. Surprisingly, both canola cultivars responded similarly to the metabolites (cysteine, sucrose, and ABA) and epicuticular waxes, indicating that they were not reliable stress markers in our test setup. However, the higher level of phenylalanine in the drought-tolerant canola cultivar is suggestive that this amino acid is important for adaptation to drier climates. Furthermore, a multitrait genotype-ideotype distance index (MGIDI) revealed the likely role of aspartic acid in sustaining nitrogen and carbon for immediate photosynthetic resumption after drought episodes. In conclusion, leveraging amino acid knowledge in agriculture can enhance crop yield and bolster resistance to environmental challenges.

PMID:39781188 | PMC:PMC11707614 | DOI:10.3389/fpls.2024.1385414

J Gerontol A Biol Sci Med Sci. 2025 Jan 9:glae255. doi: 10.1093/gerona/glae255. Online ahead of print.

ABSTRACT

The African turquoise killifish Nothobranchius furzeri represents an emerging short-lived model for aging research. Captive strains of this species are characterized by large differences in lifespan. To identify the gene expression correlates of this lifespan differences, we analyzed a public transcriptomic dataset consisting of four different tissues in addition to embryos. We focused on the GRZ and the MZM0410 captive strains, which show a near twofold difference in lifespan, but similar growth and maturation and validated the results in a newly-generated dataset from a third longer-lived strain. The two strains show distinct transcriptome expression patterns already as embryos and the genotype has a larger effect than age on gene expression, both in terms of number of differentially expressed genes and magnitude of regulation. Network analysis detected RNA processing and histone modifications as the most prominent categories upregulated in GRZ that also showed idiosyncratic expression patterns such as high expression of DND is somatic tissues. The short-lived GRZ strain shows transcriptional aging signatures already at sexual maturity (anticipated aging) in all four tissues suggesting that short lifespan is the results of events that occur early in life rather than the progressive accumulation of strain-dependent differences. The GRZ strain is the most commonly used N. furzeri strain in intervention studies and our results warrant replication of at least key intervention studies in longer-lived strains.

PMID:39780413 | DOI:10.1093/gerona/glae255

Immunology. 2025 Jan 8. doi: 10.1111/imm.13895. Online ahead of print.

ABSTRACT

Enterovirus A71 (EV-A71) has caused hand, foot, and mouth disease with an increased prevalence of neurological complications and acute mortality, threatening young children around the globe. By provoking mucosal immunity, intranasal vaccination has been suggested to prevent EV-A71 infection. However, antigens delivered via the nasal route usually fail to induce a protective memory response. Zymosan has been identified to activate multiple pattern recognition receptors to orchestrate innate and adaptive immunity. Herein, we aimed to investigate the capacity of zymosan to strengthen the vaccine response induced by an intranasal EV-A71 vaccine. First, we confirmed its remarkable capacity to ignite innate signaling by upregulating cytokine production in primary DCs in vitro. Second, we verified its capacity to promote the vaccine immunogenicity in vivo after triple vaccination with EV-A71, especially with the notable induction of virus-specific IgA at multiple mucosae and the IL-17-producing splenic population after antigen reencounter. Lastly, we validated its capacity to improve vaccine efficacy in vivo after dual vaccination by furnishing neonatal protection against lethal infection. Our findings show that zymosan, at a preferable dosage, could augment the benefits of the intranasal vaccination to tackle EV-A71 infection. This research provides a feasible strategy for preventing EV-A71 infection with severe complications and contributes to the development of nasal spray vaccination.

PMID:39780346 | DOI:10.1111/imm.13895

Alzheimers Dement. 2024 Dec;20 Suppl 5:e086936. doi: 10.1002/alz.086936.

ABSTRACT

BACKGROUND: The use of potentially inappropriate medications (PIMs) in older adults with dementia and/or Mild Cognitive Impairment (MCI) has been associated with increased adverse events, drug-related problems (DRPs), prolonged hospitalization, risk of falls, and increased length of stay. This study aimed to identify which explicit tool, Beers criteria 2023 or Screening Tool of Older Persons Potentially Inappropriate Prescriptions (STOPP) 2023, identifies more PIM use among older adults with MCI or dementia.

METHODS: A cross-sectional study was conducted at a Multispecialty Interprofessional Team-based (MINT) memory clinic. Patients with MCI or dementia were recruited between Jan and August 2023. Patient medical records were reviewed for PIMs using Beers Criteria 2023 and STOPP criteria 2023. Bivariate logistic regression analysis was employed to identify potential factors associated with the use of PIMs.

RESULTS: Overall, 44 participants were enrolled in the study, with a mean age of 80.2± 6.2 years. Among 44 patients, 36.4% (n = 16) patients had MCI, followed by one-fifth of patients (n = 9) who had mixed dementia and 11.4% (n = 5) with vascular cognitive impairment. At least one PIM was identified in 47.7% (n = 21) and 27.2% (n = 12) of the study participants based on Beers' and STOPP's criteria, respectively. Using the Beers criteria, 50 PIMs were found, with an average of 0.9 PIMs for each patient, while a total of 31 PIMs were identified using the STOPP criteria, with an average of 0.6 PIMs per patient. There was a significant association between ≥ 9 number of comorbidities and PIMs as per Beers criteria (OR = 8.4, 95% Confidence interval: 1.27- 55.39, P = 0.027). However, no statistically significant association was observed with PIMs as per STOPP criteria.

CONCLUSION: The frequency of PIMs identified using Beers and STOPP criteria highlights the importance of identifying and addressing PIMs in this population. This study adds valuable insights to the progressing comprehension of medication-related complexities in older adults living with MCI or dementia.

PMID:39781973 | DOI:10.1002/alz.086936

Alzheimers Dement. 2024 Dec;20 Suppl 5:e086917. doi: 10.1002/alz.086917.

ABSTRACT

BACKGROUND: Up to 30% of hospitalizations in older adults living with Mild Cognitive Impairment (MCI) and dementia are attributed to drug-related problems (DRPs), including adverse drug reactions, drug interactions, potentially inappropriate medication (PIM) use, and medication non-adherence. This study categorizes the identified DRPs according to the Pharmaceutical Care Network Europe (PCNE) Classification for DRPs version 9.1.

METHODS: A cross-sectional study was carried out with older adults receiving care for MCI or dementia at an Interdisciplinary memory clinic over eight months. The study employed four tools: the Medication Appropriateness Index (MAI), and the Medication Review in Cognitive Impairment and Dementia (MedRevCiD) checklist, Beers Criteria 2023, and Screening Tool of Older Persons Potentially Inappropriate Prescription (STOPP) 2023 to conduct a medication review. Identified DRPs were categorized according to their types and root causes with the PCNE classification system, version 9.1.

RESULTS: Forty-four participants (45.5% female, n = 20) were enrolled. The average age of the study participants was 80.2 years (standard deviation (SD) 6.2). Most of the participants (61.4%, n = 28) had six or more comorbidities ((mean ± SD) 6.7 ± 3.4). A total of 375 medications were prescribed to the 44 study participants. The median number of medications per day was 7.5 (interquartile range (IQR): 6 per day). A total of 119 DRPs were detected in 36 patients, with an average of 2.7 DRPs per patient. The most common type of DRP was within the classification of treatment safety, accounting for 63% of the reported DRPs (n = 75), followed by treatment effectiveness (15.9%, n = 19). The most common cause of DRPs noted was inappropriate drugs according to guidelines/formulary (43.6%, n = 52), followed by an inappropriate combination of drugs, or drugs and herbal or drug-drug interaction (21%, n = 25) from the drug selection category. A total of 53 recommendations were made by the pharmacist in the medical records for the study participants.

CONCLUSION: The high prevalence of DRPs, notably those involving treatment safety and inappropriate drug selection, emphasizes the importance of medication reviews and tailored interventions to improve medication management and safety in this at-risk population.

PMID:39781930 | DOI:10.1002/alz.086917

Alzheimers Res Ther. 2025 Jan 8;17(1):15. doi: 10.1186/s13195-024-01669-4.

ABSTRACT

BACKGROUND: The safety data of lecanemab in the post-marketing period has yet to be fully investigated in the current literature. We aimed to identify and characterise the safety profile of lecanemab in the post-marketing period.

METHODS: We searched and reviewed the reports submitted to the FDA's Adverse Event Reporting System (FAERS). We used a case/non-case approach to estimate the reporting odds ratio (ROR) and information component (IC) with 95% confidence intervals (CI) for lecanemab-related adverse events (AEs) reported at least four counts. We compared the difference between serious and non-serious reports using non-parametric tests.

RESULTS: The FAERS recorded 1,986 lecanemab-related AEs affecting 868 patients. Two hundred and three patients experienced serious AEs, including 22 deaths. The most frequently reported AEs were headache (n = 193), chills (n = 100), fatigue (n = 93), and amyloid-related imaging abnormality-oedema/effusion (ARIA-E) (n = 91). Safety signals were detected, such as headache (ROR: 10.4, 95%CI: 8.97, 12.07; IC: 3.25, 95%CI: 2.97, 3.40), ARIA-E (ROR: 18,299.69, 95%CI: 14,001.27, 23,917.73; IC: 13.37, 95%CI: 6.15, 6.87), and infusion-related reaction (ROR: 35.25, 95CI 27.58, 45.07; IC: 5.09, 95CI 4.15, 4.87). We also identified several new AEs, such as migraine and pancreatic carcinoma. Patients with serious AEs were more likely to be on polypharmacy for Alzheimer's disease and use aspirin, acid-suppressing medications, statins, antidepressants, or benzodiazepines compared to those with non-serious AEs.

CONCLUSIONS: Lecanemab may have a significant potential for AEs. Our results provide evidence for healthcare professionals and patients to weigh the risks and benefits of lecanemab treatment. Further prospective studies are needed to explore rare and unexpected AEs.

PMID:39780222 | DOI:10.1186/s13195-024-01669-4

Funding Opportunity PAR-25-068 from the NIH Guide for Grants and Contracts. This Notice of Funding Opportunity (NOFO) invites applications for innovative basic and translational pilot research projects within the mission of the NIDDK that are aligned with NIH HIV/AIDS research priorities. These priorities were most recently outlined by the NIH Office of AIDS Research (OAR) in NOT-20-018, UPDATE: NIH HIV/AIDS Research Priorities and Guidelines for Determining HIV/AIDS Funding, scientific priorities. Potential topics could address multiple overarching priorities. These include elucidation of unique pathophysiological mechanisms contributing to HIV comorbidities, coinfections, and complications (CCCs) affecting organs, tissues, and processes within the mission of the NIDDK. Likewise, interrogations into biological mechanisms underlying HIV reservoirs in NIDDK-relevant tissues are important for developing strategies for long-term viral suppression or eradication. Finally, health-impeding social determinants of health may affect CCCs or viral reservoirs within NIDDK's mission through multiple pathways.

Funding Opportunity PAR-25-097 from the NIH Guide for Grants and Contracts. The purpose of this Notice of Funding Opportunity (NOFO) is to provide support for new investigators from diverse backgrounds, including from groups nationally underrepresented in biomedical research, to conduct small research projects in the scientific mission areas of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and participating Institutes and Centers. New investigators at the time of award under this NOFO will have/have had less than $125,000 direct costs of combined research funding (excluding NIH training and NIH career awards). This R21 will support small research projects that can be carried out in a short period of time with limited resources and seeks to facilitate transition to research independence. The R21 grant mechanism supports different types of projects including pilot and feasibility studies; secondary analysis of existing data; small, self-contained research projects; development of research methodology; and development of new research technology.

Funding Opportunity PA-25-150 from the NIH Guide for Grants and Contracts. The Joint NINDS/NIMH Exploratory Neuroscience Research Grant program supports exploratory and innovative research projects, which fall within the missions of the NINDS and NIMH. Awards will provide support for the early and conceptual stages of projects. These studies often assess the feasibility of a novel avenue of investigation and involve considerable risk, but have the potential to bring about breakthroughs in the understanding of important areas of neuroscience, or to the development of novel techniques, agents, methodologies, or models, of high value to the neuroscience community. While this funding opportunity also accepts clinical trials, only applications proposing mechanistic clinical trials or studies or basic experimental studies with humans (BESH) will be considered for funding. For information on the types of clinical trial that are within scope of this funding opportunity announcement, refer to Funding Opportunity Description, below.

Funding Opportunity PAR-25-318 from the NIH Guide for Grants and Contracts. The purpose of this Notice of Funding Opportunity (NOFO) is to stimulate HIV/AIDS research within the scientific mission areas of the National Institute on Deafness and Other Communications Disorders (NIDCD). Applications should address high priority HIV/AIDS research outlined by the NIH Office of AIDS Research (OAR) (https://www.oar.nih.gov/hiv-policy-and-research/research-priorities) in the areas of hearing, balance, taste, smell, voice, speech, and language. For applications proposing a clinical trial, only low risk clinical trials will be supported.

Funding Opportunity PAR-25-319 from the NIH Guide for Grants and Contracts. The purpose of this Funding Opportunity Announcement (FOA) is to stimulate HIV/AIDS research within the scientific mission areas of the National Institute on Deafness and Other Communications Disorders (NIDCD). Applications should address high priority HIV/AIDS research outlined by the NIH Office of AIDS Research (OAR) [https://www.oar.nih.gov/hiv-policy-and-research/research-priorities] in the areas of hearing, balance, taste, smell, voice, speech, and language. For applications proposing a clinical trial, only low risk clinical trials will be supported.

Funding Opportunity PAR-25-355 from the NIH Guide for Grants and Contracts. This NOFO invites applications at the intersection of HIV and aging by proposing research that aims to meet the following objectives: 1) Improve the understanding of biological, clinical, and socio-behavioral aspects of aging through the lens of HIV infection and its treatment; and 2) Improve approaches for testing, preventing, and treating HIV infection, and managing HIV-related comorbidities, co-infections, and complications in different populations and cultural settings by applying current aging science approaches. Proposed research must be consistent with the HIV/AIDS Research Priorities outlined by NIHs Office of AIDS Research (OAR), as described inNOT-OD-20-018.

Funding Opportunity PAR-25-354 from the NIH Guide for Grants and Contracts. This NOFO invites applications at the intersection of HIV and aging by proposing research that aims to meet the following objectives: 1) Improve the understanding of biological, clinical, and socio-behavioral aspects of aging through the lens of HIV infection and its treatment; and 2) Improve approaches for testing, preventing, and treating HIV infection, and managing HIV-related comorbidities, co-infections, and complications in different populations and cultural settings by applying current aging science approaches. Proposed research must be consistent with the HIV/AIDS Research Priorities outlined by NIHs Office of AIDS Research (OAR), as described inNOT-OD-20-018.

Funding Opportunity PA-25-169 from the NIH Guide for Grants and Contracts. This Trailblazer Award is an opportunity for NIH-defined New and Early Stage Investigators (https://grants.nih.gov/policy/early-investigators/index.htm) to pursue research programs that integrate engineering and the physical sciences with the life and/or biomedical sciences. A Trailblazer project may be exploratory, developmental, proof of concept, or high risk-high impact, and may be technology design-directed, discovery-driven, or hypothesis-driven. Importantly, applicants must propose research approaches for which there are minimal or no preliminary data. A distinct feature for this FOA is that no preliminary data are required, expected, or encouraged. However, if available, minimal preliminary data are allowed. Preliminary data are defined as material which the applicant has independently produced and not yet published in a peer-reviewed journal. All preliminary data should be clearly marked and limited to one-half page, which may include one figure. Applications including data more than one-half page or more than one figure will be considered noncompliant with the FOA instructions and will not go forward to review.

Funding Opportunity PAR-25-250 from the NIH Guide for Grants and Contracts. The purpose of the NIDCD Research Dissertation Fellowship for Au.D. Audiologists (F32) program is to support a comprehensive, rigorous biomedical research training, and dissertation research leading to a research doctorate (i.e., Ph.D.) in the biomedical, behavioral, or clinical sciences.

Notice NOT-AG-24-042 from the NIH Guide for Grants and Contracts

Notice NOT-AG-24-030 from the NIH Guide for Grants and Contracts