NDUFS4 Regulates Cristae Remodeling in Diabetic Kidney Disease

The mitochondrial electron transport chain (ETC) is a highly adaptive process to meet metabolic demands of the cell, and its dysregulation has been associated with diverse clinical pathologies. However, the role and nature of impaired ETC in kidney diseases remains poorly understood. Here, we generated diabetic mice with podocyte-specific overexpression of Ndufs4, an accessory subunit of mitochondrial complex I, as a model to investigate the role of ETC integrity in diabetic kidney disease (DKD). We find that these conditional mice exhibit significant improvements in cristae morphology, mitochondrial dynamics, and albuminuria. By coupling proximity labeling with super-resolution imaging, we also identify the role of cristae shaping proteins in linking NDUFS4 with improved cristae morphology. Taken together, we discover the central role of NDUFS4 as a powerful regulator of cristae remodeling, respiratory supercomplexes assembly, and mitochondrial ultrastructur

Alkali Metal Bismuth(III) Chloride Double Salts

Evaporative co-crystallization of MCl (M = Na, K, Rb, Cs) with BiOCl in aqueous HCl produces double salts: MxBiyCl(x+3y)·zH2O. The sodium salt, Na2BiCl5·5H2O (monoclinic P21/c, a = 8.6983(7) Å, b = 21.7779(17) Å, c = 7.1831(6) Å, β = 103.0540(10)°, V = 1325.54(19) Å3, Z = 4) is composed of zigzag chains of μ2-Cl-cis-linked (BiCl5)n2n– chains. Edge-sharing chains of NaCln(OH2)6−n octahedra (n = 0, 2, 3) are linked through μ3-Cl to Bi. The potassium salt, K7Bi3Cl16 (trigonal R−3c, a = 12.7053(9) Å, b = 12.7053(9) Å, c = 99.794(7) Å, V = 13,951(2) Å3, Z = 18) contains (Bi2Cl10)4– edge-sharing dimers of octahedra and simple (BiCl6)3– octahedra. The K+ ions are 5- to 8-coordinate and the chlorides are 3-, 4-, or 5-coordinate. The rubidium salt, Rb3BiCl6·0.5H2O (orthorhombic Pnma, a = 12.6778(10) Å, b = 25.326(2) Å, c = 8.1498(7) Å, V = 2616.8(4) Å3, Z = 8) contains (BiCl6)3– octahedra. The Rb+ ions are 6-, 8-, and 9-coordinate, and the chlorides are 4- or 5-coordinate. Two cesium salts were formed: Cs3BiCl6 (orthorhombic Pbcm, a = 8.2463(9) Å, b = 12.9980(15) Å, c = 26.481(3) Å, V = 2838.4(6) Å3, Z = 8) being comprised of (BiCl6)3– octahedra, 8-coordinate Cs+, and 3-, 4-, and 5-coordinate Cl−. In Cs3Bi2Cl9 (orthorhombic Pnma, a = 18.4615(15) Å, b = 7.5752(6) Å, c = 13.0807(11) Å, V = 1818.87(11) Å3, Z = 4) Bi octahedra are linked by μ2-bridged Cl into edge-sharing Bi4 squares which form zigzag (Bi2Cl9)n3n– ladders. The 12-coordinate Cs+ ions bridge the ladders, and the Cl− ions are 5- and 6-coordinate. Four of the double salts are weakly photoluminescent at 78 K, each showing a series of three excitation peaks near 295, 340, and 380 nm and a broad emission near 440 nm

Bench to Bed Evidences for Pharmacokinetic and Pharmacodynamic Interactions Involving Oseltamivir and Chinese Medicine

Oseltamivir (OA), an ethyl ester prodrug of oseltamivir carboxylate (OC), is clinically used as a potent and selective inhibitor of neuraminidase. Chinese medicines have been advocated to combine with conventional drug for avian influenza. The current study aims to investigate the potential pharmacokinetic and pharmacodynamic interactions of a Chinese medicine formula, namely, Yin Qiao San and Sang Ju Yin (CMF1), commonly used for anti-influenza in combination with OA in both rat and human, and to reveal the underlined mechanisms. It was found that although Cmax, AUC and urinary recovery of OC, as well as metabolic ratio (AUCOC/AUCOA), were significantly decreased in a dose-dependent manner following combination use of CMF1 and OA in rat studies (P<0.01), such coadministration in 14 healthy volunteers only resulted in a trend of minor decrease in the related parameters. Further mechanistic studies found that although CMF1 could reduce absorption and metabolism of OA, it appears to enhance viral inhibition of OA (P<0.01). In summary, although there was potential interaction between OA and CMF1 found in rat studies, its clinical impact was expected to be minimal. The coadministration of OA and CMF1 at the clinical recommended dosages is, therefore, considered to be safe

A population of luminous accreting black holes with hidden mergers

Major galaxy mergers are thought to play an important part in fuelling the growth of supermassive black holes. However, observational support for this hypothesis is mixed, with some studies showing a correlation between merging galaxies and luminous quasars and others showing no such association. Recent observations have shown that a black hole is likely to become heavily obscured behind merger-driven gas and dust, even in the early stages of the merger, when the galaxies are well separated (5 to 40 kiloparsecs). Merger simulations further suggest that such obscuration and black-hole accretion peaks in the final merger stage, when the two galactic nuclei are closely separated (less than 3 kiloparsecs). Resolving this final stage requires a combination of high-spatial-resolution infrared imaging and high-sensitivity hard-X-ray observations to detect highly obscured sources. However, large numbers of obscured luminous accreting supermassive black holes have been recently detected nearby (distances below 250 megaparsecs) in X-ray observations. Here we report high-resolution infrared observations of hard-X-ray-selected black holes and the discovery of obscured nuclear mergers, the parent populations of supermassive-black-hole mergers. We find that obscured luminous black holes (bolometric luminosity higher than 2x10^44 ergs per second) show a significant (P<0.001) excess of late-stage nuclear mergers (17.6 per cent) compared to a sample of inactive galaxies with matching stellar masses and star formation rates (1.1 per cent), in agreement with theoretical predictions. Using hydrodynamic simulations, we confirm that the excess of nuclear mergers is indeed strongest for gas-rich major-merger hosts of obscured luminous black holes in this final stage.Comment: To appear in the 8 November 2018 issue of Nature. This is the authors' version of the wor

Perilipin 2 (PLIN2)-Deficiency Does Not Increase Cholesterol-Induced Toxicity in Macrophages

Interventions on macrophages/foam cells to redirect intracellular cholesterol towards efflux pathways could become a very valuable addition to our therapeutic arsenal against atherosclerosis. However, certain manipulations of the cholesteryl ester cycle, such as the inhibition of ACAT1, an ER-resident enzyme that re-esterifies cholesterol, are not well tolerated. Previously we showed that targeting perilipin-2 (PLIN2), a major lipid droplet (LD)-associated protein in macrophages, prevents foam cell formation and protects against atherosclerosis. Here we have assessed the tolerance of PLIN2-deficient bone marrow derived macrophages (BMM) to several lipid loading conditions similar to the found during atherosclerosis development, including exposure to modified low-density lipoprotein (mLDL) and 7-ketocholesterol (7-KC), a free cholesterol (FC) metabolite, in media with or without cholesterol acceptors. BMM isolated from mice that do or do not express PLIN2 were tested for apoptosis (TUNEL and cleaved caspase-3), ER stress (CHOP induction and XBP-1 splicing), and inflammation (TNF-α and IL-6 mRNA levels). Like in other cell types, PLIN2 deficiency impairs LD buildup in BMM. However, while most stress parameters were elevated in macrophages under ACAT inhibition and 7-KC loading, PLIN2 inactivation was well tolerated. The data support the safety of targeting PLIN2 to prevent foam cell formation and atherosclerosis

Spatial, temporal, and demographic patterns in prevalence of chewing tobacco use in 204 countries and territories, 1990-2019 : a systematic analysis from the Global Burden of Disease Study 2019

Interpretation Chewing tobacco remains a substantial public health problem in several regions of the world, and predominantly in south Asia. We found little change in the prevalence of chewing tobacco use between 1990 and 2019, and that control efforts have had much larger effects on the prevalence of smoking tobacco use than on chewing tobacco use in some countries. Mitigating the health effects of chewing tobacco requires stronger regulations and policies that specifically target use of chewing tobacco, especially in countries with high prevalence. Findings In 2019, 273 center dot 9 million (95% uncertainty interval 258 center dot 5 to 290 center dot 9) people aged 15 years and older used chewing tobacco, and the global age-standardised prevalence of chewing tobacco use was 4 center dot 72% (4 center dot 46 to 5 center dot 01). 228 center dot 2 million (213 center dot 6 to 244 center dot 7; 83 center dot 29% [82 center dot 15 to 84 center dot 42]) chewing tobacco users lived in the south Asia region. Prevalence among young people aged 15-19 years was over 10% in seven locations in 2019. Although global agestandardised prevalence of smoking tobacco use decreased significantly between 1990 and 2019 (annualised rate of change: -1 center dot 21% [-1 center dot 26 to -1 center dot 16]), similar progress was not observed for chewing tobacco (0 center dot 46% [0 center dot 13 to 0 center dot 79]). Among the 12 highest prevalence countries (Bangladesh, Bhutan, Cambodia, India, Madagascar, Marshall Islands, Myanmar, Nepal, Pakistan, Palau, Sri Lanka, and Yemen), only Yemen had a significant decrease in the prevalence of chewing tobacco use, which was among males between 1990 and 2019 (-0 center dot 94% [-1 center dot 72 to -0 center dot 14]), compared with nine of 12 countries that had significant decreases in the prevalence of smoking tobacco. Among females, none of these 12 countries had significant decreases in prevalence of chewing tobacco use, whereas seven of 12 countries had a significant decrease in the prevalence of tobacco smoking use for the period. Summary Background Chewing tobacco and other types of smokeless tobacco use have had less attention from the global health community than smoked tobacco use. However, the practice is popular in many parts of the world and has been linked to several adverse health outcomes. Understanding trends in prevalence with age, over time, and by location and sex is important for policy setting and in relation to monitoring and assessing commitment to the WHO Framework Convention on Tobacco Control. Methods We estimated prevalence of chewing tobacco use as part of the Global Burden of Diseases, Injuries, and Risk Factors Study 2019 using a modelling strategy that used information on multiple types of smokeless tobacco products. We generated a time series of prevalence of chewing tobacco use among individuals aged 15 years and older from 1990 to 2019 in 204 countries and territories, including age-sex specific estimates. We also compared these trends to those of smoked tobacco over the same time period. Findings In 2019, 273 & middot;9 million (95% uncertainty interval 258 & middot;5 to 290 & middot;9) people aged 15 years and older used chewing tobacco, and the global age-standardised prevalence of chewing tobacco use was 4 & middot;72% (4 & middot;46 to 5 & middot;01). 228 & middot;2 million (213 & middot;6 to 244 & middot;7; 83 & middot;29% [82 & middot;15 to 84 & middot;42]) chewing tobacco users lived in the south Asia region. Prevalence among young people aged 15-19 years was over 10% in seven locations in 2019. Although global age standardised prevalence of smoking tobacco use decreased significantly between 1990 and 2019 (annualised rate of change: -1 & middot;21% [-1 & middot;26 to -1 & middot;16]), similar progress was not observed for chewing tobacco (0 & middot;46% [0 & middot;13 to 0 & middot;79]). Among the 12 highest prevalence countries (Bangladesh, Bhutan, Cambodia, India, Madagascar, Marshall Islands, Myanmar, Nepal, Pakistan, Palau, Sri Lanka, and Yemen), only Yemen had a significant decrease in the prevalence of chewing tobacco use, which was among males between 1990 and 2019 (-0 & middot;94% [-1 & middot;72 to -0 & middot;14]), compared with nine of 12 countries that had significant decreases in the prevalence of smoking tobacco. Among females, none of these 12 countries had significant decreases in prevalence of chewing tobacco use, whereas seven of 12 countries had a significant decrease in the prevalence of tobacco smoking use for the period. Interpretation Chewing tobacco remains a substantial public health problem in several regions of the world, and predominantly in south Asia. We found little change in the prevalence of chewing tobacco use between 1990 and 2019, and that control efforts have had much larger effects on the prevalence of smoking tobacco use than on chewing tobacco use in some countries. Mitigating the health effects of chewing tobacco requires stronger regulations and policies that specifically target use of chewing tobacco, especially in countries with high prevalence. Copyright (c) 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license.Peer reviewe

Spatial, temporal, and demographic patterns in prevalence of smoking tobacco use and attributable disease burden in 204 countries and territories, 1990-2019 : a systematic analysis from the Global Burden of Disease Study 2019

Background Ending the global tobacco epidemic is a defining challenge in global health. Timely and comprehensive estimates of the prevalence of smoking tobacco use and attributable disease burden are needed to guide tobacco control efforts nationally and globally. Methods We estimated the prevalence of smoking tobacco use and attributable disease burden for 204 countries and territories, by age and sex, from 1990 to 2019 as part of the Global Burden of Diseases, Injuries, and Risk Factors Study. We modelled multiple smoking-related indicators from 3625 nationally representative surveys. We completed systematic reviews and did Bayesian meta-regressions for 36 causally linked health outcomes to estimate non-linear dose-response risk curves for current and former smokers. We used a direct estimation approach to estimate attributable burden, providing more comprehensive estimates of the health effects of smoking than previously available. Findings Globally in 2019, 1.14 billion (95% uncertainty interval 1.13-1.16) individuals were current smokers, who consumed 7.41 trillion (7.11-7.74) cigarette-equivalents of tobacco in 2019. Although prevalence of smoking had decreased significantly since 1990 among both males (27.5% [26. 5-28.5] reduction) and females (37.7% [35.4-39.9] reduction) aged 15 years and older, population growth has led to a significant increase in the total number of smokers from 0.99 billion (0.98-1.00) in 1990. Globally in 2019, smoking tobacco use accounted for 7.69 million (7.16-8.20) deaths and 200 million (185-214) disability-adjusted life-years, and was the leading risk factor for death among males (20.2% [19.3-21.1] of male deaths). 6.68 million [86.9%] of 7.69 million deaths attributable to smoking tobacco use were among current smokers. Interpretation In the absence of intervention, the annual toll of 7.69 million deaths and 200 million disability-adjusted life-years attributable to smoking will increase over the coming decades. Substantial progress in reducing the prevalence of smoking tobacco use has been observed in countries from all regions and at all stages of development, but a large implementation gap remains for tobacco control. Countries have a dear and urgent opportunity to pass strong, evidence-based policies to accelerate reductions in the prevalence of smoking and reap massive health benefits for their citizens. Copyright (C) 2021 The Author(s). Published by Elsevier Ltd.Peer reviewe