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Heart failure (HF) is an increasing global health crisis, affecting 40 million people and causing 50% mortality within 5 years of diagnosis. A fuller understanding of the genetic and environmental factors underlying HF, and novel therapeutic approaches to address it, are urgently warranted. Here, we discovered that cardiac-specific germline deletion in mice of potassium channel β subunit-encoding Kcne2 (Kcne2CS-/- ) causes dilated cardiomyopathy and terminal HF (median longevity, 28 weeks). Mice with global Kcne2 deletion (Kcne2Glo-/- ) exhibit multiple HF risk factors, yet, paradoxically survived over twice as long as Kcne2CS-/- mice. Global Kcne2 deletion, which inhibits gastric acid secretion, reduced the relative abundance of species within Bacteroidales, a bacterial order that positively correlates with increased lifetime risk of human cardiovascular disease. Strikingly, the proton-pump inhibitor omeprazole similarly altered the microbiome and delayed terminal HF in Kcne2CS-/- mice, increasing survival 10-fold at 44 weeks. Thus, genetic or pharmacologic induction of hypochlorhydria and decreased gut Bacteroidales species are associated with lifespan extension in a novel HF model.

Molecular chirality is represented as broken mirror symmetry in the structural orientation of constituent atoms and plays a pivotal role at every scale of nature. Since the discovery of the chiroptic property of chiral molecules, the characterization of molecular chirality is important in the fields of biology, physics, and chemistry. Over the centuries, the field of optical chiral sensing was based on chiral light–matter interactions between chiral molecules and polarized light. Starting from simple optics-based sensing, the utilization of plasmonic materials that could control local chiral light–matter interactions by squeezing light into molecules successfully facilitated chiral sensing into noninvasive, ultrasensitive, and accurate detection. In this Review, the importance of plasmonic materials and their engineering in chiral sensing are discussed based on the principle of chiral light–matter interactions and the theory of optical chirality and chiral perturbation; thus, this Review can serve as a milestone for the proper design and utilization of plasmonic nanostructures for improved chiral sensing. [ABSTRACT FROM AUTHOR]

Backgroud: Orthodontic treatment plans face challenges when deciding on tooth extraction, particularly when the retraction of incisors leads to a flattening of the lip curvature. Despite the significance of this issue, quantitative measurements of curvature have not been previously undertaken. This study presents novel soft tissue measurements, namely SAL (A'toSn-Ls) depth, SAL angle, PBL (B'toLi-Pg) depth, and angle, as tools for assessing lip curvature. The aim of this study was to assess whether new parameters demonstrated more pronounced flattening of the upper and lower lips in the extraction group compared to the non-extraction group. Methods: A total of sixty-two patients diagnosed with skeletal Class I malocclusion and treated with extraction or non-extraction orthodontic treatment were included and compared. Cephalometric measurements were analyzed and compared between the initial and final stages of treatment. Results: The difference in SAL (1.99°) and PBL (4.41°) angles and other soft tissue measurements between the groups was not statistically significant. Multiple regression analysis yielded the equation: ΔSAL = 0.66ΔU1 tip – 0.98ΔL1 tip – 1.58. Conclusions: Flattening of the upper lip was not significantly displayed on moderate anchorage. Consequently, orthodontic treatment accompanying the retraction of the upper incisors does not always result in obtuse lip profiles. [ABSTRACT FROM AUTHOR]

Herein, we investigate micro-light-emitting diodes (μLEDs) ranging in size from 160 × 160 to 10 × 10 μm2 and report that the differences in the behavior of InGaN-based blue (∼460 nm) and red (∼600 nm) μLEDs are related to carrier localization. The external quantum efficiency (EQE) of blue μLEDs decreases with size regardless of sidewall conditions, whereas that of red μLEDs is insignificant due to carrier localization. Atomic probe tomography examination of 30%, 15%, and 7.5% indium-concentrated InGaN layers used in red μLEDs shows that higher indium concentrations result in greater indium fluctuations, which promote carrier localization and thus shorten the diffusion length of carriers. Finally, by observing the peak wavelength of electroluminescence and the current density at peak EQE for both blue and red μLEDs, we find that radiative recombination rate in μLEDs is likely to be chip size dependent. [ABSTRACT FROM AUTHOR]

Background/Objectives: Perillyl alcohol (POH), a monoterpene natural product derived from the essential oils of plants such as perilla (Perilla frutescens), is currently in phase I and II clinical trials as a chemotherapeutic agent. In this study, we investigated the effect of POH on cytochrome P450 (CYP) activity for evaluating POH–drug interaction potential. Methods: The investigation was conducted using pooled human liver microsomes (HLMs), recombinant CYP3A4 (rCYP3A4) enzymes, and human pluripotent stem cell-derived hepatic organoids (hHOs) employing liquid chromatography-tandem mass spectrometry. Results: POH inhibited the activities of CYP2A6 and CYP2B6 with Ki of 6.35 and 3.78 μM, respectively, whereas it stimulated CYP3A4 activity in pooled HLMs incubated with midazolam (MDZ). In a direct CYP inhibition assay using HLMs, activities of CYP2C9, CYP2C19, and CYP2E1 were also inhibited by POH, with IC50 values greater than 50 μM, but those of CYP1A2, CYP2C8, CYP2D6, and CYP3A4 (testosterone) were not significantly inhibited. In pooled HLMs, the Vmax/Km value of 1′-hydroxy MDZ, but not that of 4-hydroxy MDZ, was increased 2.7-fold by 100 μM POH compared with that in the absence of POH. Moreover, stimulation of MDZ 1′-hydroxylation by CYP3A4 was observed in hHOs and rCYP3A4 with cytochrome b5 but not rCYP3A4 without cytochrome b5. Furthermore, activation of CYP3A4-mediated metabolism by POH was observed in HLMs incubated with fimasartan but not atorvastatin, buspirone, donepezil, nifedipine, or tadalafil, suggesting a substrate-dependent activation of CYP3A4 by POH. Conclusions: POH inhibits CYP2A6 and CYP2B6, but it activates CYP3A4. These findings underscore the need for further evaluation of the interactions of clinical drugs with POH. [ABSTRACT FROM AUTHOR]

Type 2 diabetes mellitus (T2DM) represents a rapidly increasing threat to global public health. T2DM arises largely from obesity, poor diet, and lack of exercise, but it also involves genetic predisposition. Here we report that the KCNE2 potassium channel transmembrane regulatory subunit is expressed in human and mouse pancreatic β cells. Kcne2 deletion in mice impaired glucose tolerance as early as 5 wk of age in pups fed a Western diet, ultimately causing diabetes. In adult mice fed normal chow, skeletal muscle expression of insulin receptor β and insulin receptor substrate 1 were down-regulated 2-fold by Kcne2 deletion, characteristic of T2DM. Kcne2 deletion also caused extensive pancreatic transcriptome changes consistent with facets of T2DM, including endoplasmic reticulum stress, inflammation, and hyperproliferation. Kcne2 deletion impaired β-cell insulin secretion in vitro up to 8-fold and diminished β-cell peak outward K+ current at positive membrane potentials, but also left-shifted its voltage dependence and slowed inactivation. Interestingly, we also observed an aging-dependent reduction in β-cell outward currents in both Kcne2+/+ and Kcne2-/- mice. Our results demonstrate that KCNE2 is required for normal β-cell electrical activity and insulin secretion, and that Kcne2 deletion causes T2DM. KCNE2 may regulate multiple K+ channels in β cells, including the T2DM-linked KCNQ1 potassium channel α subunit.-Lee, S. M., Baik, J., Nguyen, D., Nguyen, V., Liu, S., Hu, Z., Abbott, G. W. Kcne2 deletion impairs insulin secretion and causes type 2 diabetes mellitus.

This study aimed to identify hub genes involved in regulatory T cell (Treg) function and migration, offering insights into potential therapeutic targets for cancer immunotherapy. We performed a comprehensive bioinformatics analysis using three gene expression microarray datasets from the GEO database. Differentially expressed genes (DEGs) were identified to pathway enrichment analysis to explore their functional roles and potential pathways. A protein-protein interaction network was constructed to identify hub genes critical for Treg activity. We further evaluated the co-expression of these hub genes with immune checkpoint proteins (PD-1, PD-L1, CTLA4) and assessed their prognostic significance. Through this comprehensive analysis, we identified CCR8 as a key player in Treg migration and explored its potential synergistic effects with ICIs. Our findings suggest that CCR8-targeted therapies could enhance cancer immunotherapy outcomes, with breast invasive carcinoma (BRCA) emerging as a promising indication for combination therapy. This study highlights the potential of CCR8 as a biomarker and therapeutic target, contributing to the development of targeted cancer treatment strategies. [ABSTRACT FROM AUTHOR]

Highlights: Blue micro-light-emitting diodes (μLED)-integrated gas sensors were fabricated as monolithic structure by directly loading sensing materials onto the μLED. SnO2 nanoparticles are activated by blue μLED and exhibit outstanding sensitivity to NO2 at μ-Watt power levels. Noble metal (Au, Pd, Pt)-decorated SnO2 showed the tunable gas selectivity for 4 target gases under blue light illumination. Micro-light-emitting diodes (μLEDs) have gained significant interest as an activation source for gas sensors owing to their advantages, including room temperature operation and low power consumption. However, despite these benefits, challenges still exist such as a limited range of detectable gases and slow response. In this study, we present a blue μLED-integrated light-activated gas sensor array based on SnO2 nanoparticles (NPs) that exhibit excellent sensitivity, tunable selectivity, and rapid detection with micro-watt level power consumption. The optimal power for μLED is observed at the highest gas response, supported by finite-difference time-domain simulation. Additionally, we first report the visible light-activated selective detection of reducing gases using noble metal-decorated SnO2 NPs. The noble metals induce catalytic interaction with reducing gases, clearly distinguishing NH3, H2, and C2H5OH. Real-time gas monitoring based on a fully hardware-implemented light-activated sensing array was demonstrated, opening up new avenues for advancements in light-activated electronic nose technologies. [ABSTRACT FROM AUTHOR]

Nonalcoholic fatty liver disease (NAFLD) is an increasing health problem worldwide, with genetic, epigenetic, and environmental components. Here, we describe the first example of NAFLD caused by genetic disruption of a mammalian potassium channel subunit. Mice with germline deletion of the KCNE2 potassium channel β subunit exhibited NAFLD as early as postnatal day 7. Using mouse genetics, histology, liver damage assays and transcriptomics we discovered that iron deficiency arising from KCNE2-dependent achlorhydria is a major factor in early-onset NAFLD in Kcne2(─/─) mice, while two other KCNE2-dependent defects did not initiate NAFLD. The findings uncover a novel genetic basis for NAFLD and an unexpected potential factor in human KCNE2-associated cardiovascular pathologies, including atherosclerosis.

Coronary artery disease (CAD) is the leading cause of death worldwide. An estimated half of cases involve genetic predisposition. Sequence variants in human KCNE2, which encodes a cardiac and epithelial K(+) channel β subunit, cause inherited cardiac arrhythmias. Unexpectedly, human KCNE2 polymorphisms also associate with predisposition to atherosclerosis, with unestablished causality or mechanisms. Here, we report that germline Kcne2 deletion promotes atherosclerosis in mice, overcoming the relative resistance of this species to plaque deposition. In female western diet-fed mice, Kcne2 deletion increased plaque deposition >6-fold and also caused premature ventricular complexes and sudden death. The data establish causality for the first example of ion channel-linked atherosclerosis, and demonstrate that the severity of Kcne2-linked cardiac arrhythmias is strongly diet-dependent.