3-Hydroxyisobutyryl-CoA hydrolase involved in isoleucine catabolism regulates triacylglycerol accumulation in Phaeodactylum tricornutum

Since methylmalonyl-CoA epimerase appears to be absent in the majority of photosynthetic organisms, including diatoms, (S)-methylmalonyl-CoA, the intermediate of isoleucine (Ile) catabolism, cannot be metabolized to (R)methylmalonyl-CoA then to succinyl-CoA. In this study, propionyl-CoA carboxylase (PCC) RNAi silenced strains and 3-hydroxyisobutyryl-CoA hydrolase (HIBCH) overexpression strains were constructed to elucidate the Ile degradation pathway and its influence on lipid accumulation in Phaeodactylum tricornutum based on growth, neutral lipid content and metabolite profile analysis. Knockdown of PCC disturbed the metabolism of Ile through propionyl-CoA to methylmalonyl-CoA, as illustrated by much higher Ile content at day 6. However, Ile decreased to comparable levels to the wild-type at day 10. PCC silencing redirected propionyl-CoA to acetyl-CoA via a modified beta-oxidation pathway, and transcript levels for some branched-chain amino acid (BCAA) degradation-related genes, especially HIBCH, significantly upregulated in the PCC mutant, which enhanced the BCAA degradations and thus resulted in higher triacylglycerol (TAG) content. Overexpression of HIBCH accelerates Ile degradation and results in a lowered Ile content in the overexpression strains, thus enhancing carbon skeletons to the tricarboxylic acid cycle and giving rise to increasing TAG accumulation. Our study provides a good strategy to obtain high-lipid-yield transgenic diatoms by modifying the propionyl-CoA metabolism. This article is part of the themed issue &#39;The peculiar carbon metabolism in diatoms&#39;.</p

Spermidine endows macrophages anti-inflammatory properties by inducing mitochondrial superoxide-dependent AMPK activation, Hif-1α upregulation and autophagy.

Distinct metabolic programs, either energy-consuming anabolism or energy-generating catabolism, were required for different biological functions. Macrophages can adopt different immune phenotypes in response to various cues and exhibit anti- or pro-inflammatory properties relying on catabolic pathways associated with oxidative phosphorylation (OXPHOS) or glycolysis. Spermidine, a natural polyamine, has been reported to regulate inflammation through inducing anti-inflammatory (M2) macrophages. However, the underlying mechanisms remain elusive. We show here that the M2-polarization induced by spermidine is mediated by mitochondrial reactive oxygen species (mtROS). The levels of mitochondrial superoxide and H2O2 were markedly elevated by spermidine. Mechanistically, mtROS were found to activate AMP-activated protein kinase (AMPK), which in turn enhanced mitochondrial function. Furthermore, hypoxia-inducible factor-1α (Hif-1α) was upregulated by the AMPK activation and mtROS and was required for the expression of anti-inflammatory genes and induction of autophagy. Consistent with previous report that autophagy is required for the M2 polarization, we found that the M2 polarization induced by spermidine was also mediated by increased autophagy. The macrophages treated with spermidine in vitro were found to ameliorate Dextran Sulfate Sodium (DSS)-induced inflammatory bowel disease (IBD) in mice. Thus, spermidine can elicit an anti-inflammatory program driven by mtROS-dependent AMPK activation, Hif-1α stabilization and autophagy induction in macrophages. Our studies revealed a critical role of mtROS in shaping macrophages into M2-like phenotype and provided novel information for management of inflammatory disease by spermidine

Soil Moisture but Not Warming Dominates Nitrous Oxide Emissions During Freeze–Thaw Cycles in a Qinghai–Tibetan Plateau Alpine Meadow With Discontinuous Permafrost

Large quantities of organic matter are stored in frozen soils (permafrost) within the Qinghai–Tibetan Plateau (QTP). The most of QTP regions in particular have experienced significant warming and wetting over the past 50 years, and this warming trend is projected to intensify in the future. Such climate change will likely alter the soil freeze–thaw pattern in permafrost active layer and toward significant greenhouse gas nitrous oxide (N2O) release. However, the interaction effect of warming and altered soil moisture on N2O emission during freezing and thawing is unclear. Here, we used simulation experiments to test how changes in N2O flux relate to different thawing temperatures (T5–5°C, T10–10°C, and T20–20°C) and soil volumetric water contents (VWCs, W15–15%, W30–30%, and W45–45%) under 165 F–T cycles in topsoil (0–20 cm) of an alpine meadow with discontinuous permafrost in the QTP. First, in contrast to the prevailing view, soil moisture but not thawing temperature dominated the large N2O pulses during F–T events. The maximum emissions, 1,123.16–5,849.54 μg m–2 h–1, appeared in the range of soil VWC from 17% to 38%. However, the mean N2O fluxes had no significant difference between different thawing temperatures when soil was dry or waterlogged. Second, in medium soil moisture, low thawing temperature is more able to promote soil N2O emission than high temperature. For example, the peak value (5,849.54 μg m–2 h–1) and cumulative emissions (366.6 mg m–2) of W30T5 treatment were five times and two to four times higher than W30T10 and W30T20, respectively. Third, during long-term freeze–thaw cycles, the patterns of cumulative N2O emissions were related to soil moisture. treatments; on the contrary, the cumulative emissions of W45 treatments slowly increased until more than 80 cycles. Finally, long-term freeze–thaw cycles could improve nitrogen availability, prolong N2O release time, and increase N2O cumulative emission in permafrost active layer. Particularly, the high emission was concentrated in the first 27 and 48 cycles in W15 and W30, respectively. Overall, our study highlighted that large emissions of N2O in F–T events tend to occur in medium moisture soil at lower thawing temperature; the increased number of F–T cycles may enhance N2O emission and nitrogen mineralization in permafrost active layer

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts

Expression of Foxm1 Transcription Factor in Cardiomyocytes Is Required for Myocardial Development

Forkhead Box M1 (Foxm1) is a transcription factor essential for organ morphogenesis and development of various cancers. Although complete deletion of Foxm1 in Foxm1−/− mice caused embryonic lethality due to severe abnormalities in multiple organ systems, requirements for Foxm1 in cardiomyocytes remain to be determined. This study was designed to elucidate the cardiomyocyte-autonomous role of Foxm1 signaling in heart development. We generated a new mouse model in which Foxm1 was specifically deleted from cardiomyocytes (Nkx2.5-Cre/Foxm1fl/f mice). Deletion of Foxm1 from cardiomyocytes was sufficient to disrupt heart morphogenesis and induce embryonic lethality in late gestation. Nkx2.5-Cre/Foxm1fl/fl hearts were dilated with thinning of the ventricular walls and interventricular septum, as well as disorganization of the myocardium which culminated in cardiac fibrosis and decreased capillary density. Cardiomyocyte proliferation was diminished in Nkx2.5-Cre/Foxm1fl/fl hearts owing to altered expression of multiple cell cycle regulatory genes, such as Cdc25B, Cyclin B1, Plk-1, nMyc and p21cip1. In addition, Foxm1 deficient hearts displayed reduced expression of CaMKIIδ, Hey2 and myocardin, which are critical mediators of cardiac function and myocardial growth. Our results indicate that Foxm1 expression in cardiomyocytes is critical for proper heart development and required for cardiomyocyte proliferation and myocardial growth

Which health-related quality of life score? A comparison of alternative utility measures in patients with Type 2 diabetes in the ADVANCE trial.

BACKGROUND: Diabetes has a high burden of illness both in life years lost and in disability through related co-morbidities. Accurate assessment of the non-mortality burden requires appropriate health-related quality of life and summary utility measures of which there are several contenders. The study aimed to measure the impact of diabetes on various health-related quality of life domains, and compare several summary utility measures. METHODS: In the ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation) study, 978 Australian patients with Type 2 diabetes completed two health-related quality of life questionnaires at baseline: the EQ-5D and the SF-36v2, from which nine summary utility measures were calculated, and compared. The algorithms were grouped into four classes: (i) based on the EQ-5D; (ii) using fewer items than those in the SF-12 (iii) using the items in the SF-12; and (iv) using all items of the SF-36. RESULTS: Overall health-related quality of life of the subjects was good (mean utility ranged from 0.68 (+/-0.08) to 0.85(+/-0.14) over the nine utility measures) and comparable to patients without diabetes. Summary indices were well correlated with each other (r = 0.76 to 0.99), and showed lower health-related quality of life in patients with major diabetes-related events such as stroke or myocardial infarction. Despite the smaller number of items used in the scoring of the EQ-5D, it generally performed at least as well as SF-36 based methods. However, all utility measures had some limitation such as limited range or ceiling effects. CONCLUSION: The summary utility measures showed good agreement, and showed good discrimination between major and minor health state changes. However, EQ-5D based measures performed as well and are generally simpler to use

Contributions of mean and shape of blood pressure distribution to worldwide trends and variations in raised blood pressure: A pooled analysis of 1018 population-based measurement studies with 88.6 million participants

© The Author(s) 2018. Background: Change in the prevalence of raised blood pressure could be due to both shifts in the entire distribution of blood pressure (representing the combined effects of public health interventions and secular trends) and changes in its high-blood-pressure tail (representing successful clinical interventions to control blood pressure in the hypertensive population). Our aim was to quantify the contributions of these two phenomena to the worldwide trends in the prevalence of raised blood pressure. Methods: We pooled 1018 population-based studies with blood pressure measurements on 88.6 million participants from 1985 to 2016. We first calculated mean systolic blood pressure (SBP), mean diastolic blood pressure (DBP) and prevalence of raised blood pressure by sex and 10-year age group from 20-29 years to 70-79 years in each study, taking into account complex survey design and survey sample weights, where relevant. We used a linear mixed effect model to quantify the association between (probittransformed) prevalence of raised blood pressure and age-group- and sex-specific mean blood pressure. We calculated the contributions of change in mean SBP and DBP, and of change in the prevalence-mean association, to the change in prevalence of raised blood pressure. Results: In 2005-16, at the same level of population mean SBP and DBP, men and women in South Asia and in Central Asia, the Middle East and North Africa would have the highest prevalence of raised blood pressure, and men and women in the highincome Asia Pacific and high-income Western regions would have the lowest. In most region-sex-age groups where the prevalence of raised blood pressure declined, one half or more of the decline was due to the decline in mean blood pressure. Where prevalence of raised blood pressure has increased, the change was entirely driven by increasing mean blood pressure, offset partly by the change in the prevalence-mean association. Conclusions: Change in mean blood pressure is the main driver of the worldwide change in the prevalence of raised blood pressure, but change in the high-blood-pressure tail of the distribution has also contributed to the change in prevalence, especially in older age groups

Repositioning of the global epicentre of non-optimal cholesterol

High blood cholesterol is typically considered a feature of wealthy western countries(1,2). However, dietary and behavioural determinants of blood cholesterol are changing rapidly throughout the world(3) and countries are using lipid-lowering medications at varying rates. These changes can have distinct effects on the levels of high-density lipoprotein (HDL) cholesterol and non-HDL cholesterol, which have different effects on human health(4,5). However, the trends of HDL and non-HDL cholesterol levels over time have not been previously reported in a global analysis. Here we pooled 1,127 population-based studies that measured blood lipids in 102.6 million individuals aged 18 years and older to estimate trends from 1980 to 2018 in mean total, non-HDL and HDL cholesterol levels for 200 countries. Globally, there was little change in total or non-HDL cholesterol from 1980 to 2018. This was a net effect of increases in low- and middle-income countries, especially in east and southeast Asia, and decreases in high-income western countries, especially those in northwestern Europe, and in central and eastern Europe. As a result, countries with the highest level of non-HDL cholesterol-which is a marker of cardiovascular riskchanged from those in western Europe such as Belgium, Finland, Greenland, Iceland, Norway, Sweden, Switzerland and Malta in 1980 to those in Asia and the Pacific, such as Tokelau, Malaysia, The Philippines and Thailand. In 2017, high non-HDL cholesterol was responsible for an estimated 3.9 million (95% credible interval 3.7 million-4.2 million) worldwide deaths, half of which occurred in east, southeast and south Asia. The global repositioning of lipid-related risk, with non-optimal cholesterol shifting from a distinct feature of high-income countries in northwestern Europe, north America and Australasia to one that affects countries in east and southeast Asia and Oceania should motivate the use of population-based policies and personal interventions to improve nutrition and enhance access to treatment throughout the world.Peer reviewe

Height and body-mass index trajectories of school-aged children and adolescents from 1985 to 2019 in 200 countries and territories: a pooled analysis of 2181 population-based studies with 65 million participants

Summary Background Comparable global data on health and nutrition of school-aged children and adolescents are scarce. We aimed to estimate age trajectories and time trends in mean height and mean body-mass index (BMI), which measures weight gain beyond what is expected from height gain, for school-aged children and adolescents. Methods For this pooled analysis, we used a database of cardiometabolic risk factors collated by the Non-Communicable Disease Risk Factor Collaboration. We applied a Bayesian hierarchical model to estimate trends from 1985 to 2019 in mean height and mean BMI in 1-year age groups for ages 5–19 years. The model allowed for non-linear changes over time in mean height and mean BMI and for non-linear changes with age of children and adolescents, including periods of rapid growth during adolescence. Findings We pooled data from 2181 population-based studies, with measurements of height and weight in 65 million participants in 200 countries and territories. In 2019, we estimated a difference of 20 cm or higher in mean height of 19-year-old adolescents between countries with the tallest populations (the Netherlands, Montenegro, Estonia, and Bosnia and Herzegovina for boys; and the Netherlands, Montenegro, Denmark, and Iceland for girls) and those with the shortest populations (Timor-Leste, Laos, Solomon Islands, and Papua New Guinea for boys; and Guatemala, Bangladesh, Nepal, and Timor-Leste for girls). In the same year, the difference between the highest mean BMI (in Pacific island countries, Kuwait, Bahrain, The Bahamas, Chile, the USA, and New Zealand for both boys and girls and in South Africa for girls) and lowest mean BMI (in India, Bangladesh, Timor-Leste, Ethiopia, and Chad for boys and girls; and in Japan and Romania for girls) was approximately 9–10 kg/m2. In some countries, children aged 5 years started with healthier height or BMI than the global median and, in some cases, as healthy as the best performing countries, but they became progressively less healthy compared with their comparators as they grew older by not growing as tall (eg, boys in Austria and Barbados, and girls in Belgium and Puerto Rico) or gaining too much weight for their height (eg, girls and boys in Kuwait, Bahrain, Fiji, Jamaica, and Mexico; and girls in South Africa and New Zealand). In other countries, growing children overtook the height of their comparators (eg, Latvia, Czech Republic, Morocco, and Iran) or curbed their weight gain (eg, Italy, France, and Croatia) in late childhood and adolescence. When changes in both height and BMI were considered, girls in South Korea, Vietnam, Saudi Arabia, Turkey, and some central Asian countries (eg, Armenia and Azerbaijan), and boys in central and western Europe (eg, Portugal, Denmark, Poland, and Montenegro) had the healthiest changes in anthropometric status over the past 3·5 decades because, compared with children and adolescents in other countries, they had a much larger gain in height than they did in BMI. The unhealthiest changes—gaining too little height, too much weight for their height compared with children in other countries, or both—occurred in many countries in sub-Saharan Africa, New Zealand, and the USA for boys and girls; in Malaysia and some Pacific island nations for boys; and in Mexico for girls. Interpretation The height and BMI trajectories over age and time of school-aged children and adolescents are highly variable across countries, which indicates heterogeneous nutritional quality and lifelong health advantages and risks