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Androgen membrane receptor modulates muscle strength
A conserved phosphorylation mechanism for regulating the interaction between the CMG replicative helicase and its forked DNA substrate
Return to Play With Genetic Heart Disease: The Importance of Developing a Personalized Emergency Action Plan
Targeting HNRNPA2B1 to overcome chemotherapy resistance in gastric cancer stem cells: Mechanisms and therapeutic potential
Withdrawal of Guideline-Directed Medical Therapy in Patients With Heart Failure and Improved Ejection Fraction
BACKGROUND: Limited evidence exists on the prognostic role of continuing medical therapy in patients with heart failure (HF) and an ejection fraction (EF) that has improved over time. This study assessed rates of, patient profiles, and associations with morbidity/mortality of renin-angiotensin inhibitors (RASi), angiotensin receptor–neprilysin inhibitors (ARNi), beta-blockers (BBL), and mineralocorticoid receptor antagonists (MRA) withdrawal in patients with HF with improved EF. METHODS: Patients with a first recorded EF <40% and a later EF ≥40% from the Swedish HF registry between June 11, 2000, and December 31, 2023, were included in this retrospective observational study. Withdrawal was defined as a patient on treatment at the first (reduced) but not at the second (improved) registration. The association between withdrawal and time to first cardiovascular mortality/hospitalization for HF with censoring at 1 year was assessed by Cox regression model using overlap weighting. RESULTS: Of 8728 patients with HF with improved EF (median age, 70 years [25th to 75th percentile, 61–78], 2611 [29.9%] women), 96%, 94%, and 46% received RASi/ARNi, BBL, and MRA, respectively, when EF was <40%. The withdrawal rates at the time of the improved EF registration were 4.4% for RASi/ARNi, 3.3% for BBL, and 17.2% for MRA. Predictors of withdrawal included lower use of other HF medications, higher EF at the later EF registration, and a longer time between the 2 EF assessments. After weighting, withdrawal was independently associated with a higher risk of cardiovascular mortality/hospitalization for HF by 38% for RASi/ARNi and 36% for MRA, but not for BBL. Withdrawal of BBL was associated with a higher risk of the primary outcome in the subgroup of patients with an improved EF of 40% to 49% versus ≥50% ( P -interaction 0.03). CONCLUSIONS: In patients with HF with improved EF, HF therapy withdrawal was rare. Withdrawing RASi/ARNi and MRA was associated with higher mortality/morbidity at 1 year. No association was found for BBL withdrawal, albeit with a significant heterogeneity for EF at improvement, suggesting better outcomes with continuing BBL only until EF improves up to 50%. These results are hypothesis-generating and highlight the need for randomized controlled trials testing BBL withdrawal in patients with HF with improved EF.
Enlargement of microvascular dropout toward the disc-fovea axis indicates new central visual field defect in glaucoma
Declining activity of serum response factor in aging aorta in relation to aneurysm progression
Reactivation of Oxidized Soluble Guanylate Cyclase as a Novel Treatment Strategy to Slow Progression of Calcific Aortic Valve Stenosis: Preclinical and Randomized Clinical Trials to Assess Safety and Efficacy
BACKGROUND: Pharmacological treatments for fibrocalcific aortic valve stenosis (FCAVS) have been elusive for >50 years. Here, we tested the hypothesis that reactivation of oxidized sGC (soluble guanylate cyclase), the primary receptor for nitric oxide, with ataciguat is a safe and efficacious strategy to slow progression of FCAVS. METHODS: We used quantitative real-time reverse transcription polymerase chain reaction, Western blotting, and immunohistochemistry to characterize sGC signaling and the biological effects of ataciguat on signaling cascades related to nitric oxide, calcification, and fibrosis in excised human aortic valve tissue, aortic valve interstitial cells, and mouse aortic valves. We then conducted randomized, placebo-controlled phase I (14-day safety/tolerance) and phase II (6-month efficacy) trials in patients with moderate aortic valve stenosis. RESULTS: In excised human tissue, we found robust losses in sGC signaling despite upregulation of sGC subunits. In vitro, ataciguat increased sGC signaling and reduced BMP2 (bone morphogenetic protein 2) signaling in aortic valve interstitial cells. In mice with established FCAVS, treatment with ataciguat attenuated BMP signaling and slowed progression of valve calcification and dysfunction. In a phase I, randomized, placebo-controlled trial, treatment with ataciguat for 2 weeks was safe and well tolerated in patients with moderate FCAVS ( https://www.clinicaltrials.gov ; Unique identifier: NCT02049203). In a separate phase II, randomized, placebo-controlled trial, treatment with ataciguat for 6 months slowed the progression of aortic valve calcification and tended to slow the progression of valvular and ventricular dysfunction in patients with moderate FCAVS ( https://www.clinicaltrials.gov ; Unique identifier: NCT02481258). CONCLUSIONS: Collectively, this study highlights the therapeutic potential of the targeted restoration of the diseased/inactive form of sGC for treatment of FCAVS. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02049203. URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02481258.
Children’s gendered expectations of moral parties
Antimicrobial peptides selectively target malaria parasites by a cholesterol-dependent mechanism
METTL4-Mediated Mitochondrial DNA N6-Methyldeoxyadenosine Promoting Macrophage Inflammation and Atherosclerosis
BACKGROUND: Mitochondrial dysfunction is a key factor in the development of atherogenesis. METTL4 (methyltransferase-like protein 4) mediates N6- methyldeoxyadenosine (6mA) of mammalian mitochondrial DNA (mtDNA). However, the role of METTL4-mediated mitoepigenetic regulation in atherosclerosis is still unknown. This study aims to investigate the potential involvement of METTL4 in atherosclerosis, explore the underlying mechanism, and develop targeted strategies for treating atherosclerosis. METHODS: Expression levels of mtDNA 6mA and METTL4 were determined in atherosclerotic lesions. We explored the mechanism of METTL4 involvement in atherosclerosis using Mettl4 Mac -KO - Apoe -/ - and Mettl4 MUT - Apoe -/ - mice and cell models, as well as bone marrow transplantation. Natural compound libraries were screened to identify potent METTL4 antagonists. In addition, bioinspired proteolysis targeting chimera technology targeting macrophages within plaques was used to increase the efficacy of the METTL4 antagonist. RESULTS: The expression levels of mtDNA 6mA and METTL4 were significantly increased in plaque macrophages. Mettl4 Mac-KO - Apoe -/ - mice displayed suppressed mtDNA 6mA levels and atherosclerotic progression, which were reversed by METTL4 restoration through bone marrow transplantation (n=6). Mechanistically, elevated METTL4 expression reduces mitochondrial ATP6 (MT-ATP6) expression by suppressing its transcription, thereby impairing the activity of mitochondrial respiration chain complex V. This disruption leads to the accumulation of excess protons in the mitochondrial intermembrane space, causing mitochondrial dysfunction. Consequently, mtDNA is released into the cytoplasm, ultimately triggering inflammasome activation. All results were reversed by the mutation in the METTL4 methyltransferase active site. Mettl4 MUT - Apoe -/ - mice showed suppressed mtDNA 6mA levels and atherosclerotic progression and repaired mitochondrial function of macrophage, which were reversed by METTL4 restoration through bone marrow transplantation (n=6). Pemetrexed was identified as the first METTL4 antagonist to effectively alleviate atherosclerotic progression. Furthermore, we generated a proteolysis targeting chimera drug based on pemetrexed that specifically targeted METTL4 in macrophages within plaques, showing a promising therapeutic effect on atherosclerosis. CONCLUSIONS: This study revealed a novel mechanism by which mtDNA 6mA orchestrated mitochondrial function–related gene expression in macrophages, thereby promoting atherosclerosis. Through various experimental techniques, such as gene manipulation, pharmacological inhibition, and proteolysis targeting chimera, this study demonstrated that mtDNA 6mA and its specific enzyme METTL4 hold potential as therapeutic targets for atherosclerosis.
Physiological regulation underlying the alleviation of cadmium stress in maize seedlings by exogenous glycerol
Abstract Cadmium (Cd) contamination in maize poses a significant threat to global food security due to its persistent accumulation in crops. In this study, the effects of foliar application of glycerol on Cd accumulation in maize seedlings were studied. Our results demonstrated that under Cd treatment, biomass, total chlorophyll content, net photosynthetic rate (Pn), Ribulose-1,5-bisphosphate carboxylase/oxygenase (RuBisCO) activity, Phosphoenolpyruvate carboxylase (PEPC) activity, sucrose levels, and carbohydrate levels in maize seedlings significantly increased after glycerol application. H2O2 and MDA levels in both the aboveground and belowground portions of the maize plants significantly decreased. Moreover, superoxide dismutase (SOD), peroxidase (POD), and catalase (CAT) activities in the aboveground parts significantly increased. Notably, maize plants used glycerol to chelate Cd, which was fixed within the cell wall and soluble fraction of the roots, reducing Cd transport to the shoots and significantly lowering the Cd transport coefficient (TF). Transcriptomic data suggested that glycerol-mediated alleviation of Cd stress in maize seedlings may be associated with phenylpropanoid biosynthesis, plant-pathogen interactions and photosynthesis pathways. These molecular patterns align with the observed physiological improvements. This study provided a novel approach to effectively alleviate excessive Cd in maize and suggested possible applications of glycerol in cultivating plant resistance to heavy metals.