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SIRT3 regulation of fatty acid oxidation The sirtuin family of regulatory proteins has been implicated in various biological pathways including responses to calorie restriction and metabolic stress. Work in mice now shows that sirtuin 3 (SIRT3), which mediates deacetylation of several mitochondrial proteins, is induced in liver and brown adipose tissue during fasting. One of SIRT3's substrates is shown to be long-chain acyl co-enzyme A dehydrogenase (LCAD). Without SIRT3, LCAD becomes hyperacetylated, which diminishes its activity, and reduces fatty acid oxidation. Mice without SIRT3 have all the hallmarks of fatty acid oxidation disorders during fasting, including reduced ATP levels and intolerance to cold. These findings suggest that acetylation is a novel regulatory mechanism for fatty acid oxidation. During fasting SIRT3 is induced in liver and brown adipose tissue. One of SIRT3's substrates is shown to be long–chain acyl co-enzyme A dehydrogenase (LCAD). Without SIRT3 LCAD becomes hyperacetylated, which diminishes its activity, and reduces fatty acid oxidation. Mice without SIRT3 have all the hallmarks of fatty acid oxidation disorders during fasting, including reduced ATP levels and intolerance to cold. Thus, acetylation is a novel regulatory mechanism for fatty acid oxidation. Sirtuins are NAD + -dependent protein deacetylases. They mediate adaptive responses to a variety of stresses, including calorie restriction and metabolic stress. Sirtuin 3 (SIRT3) is localized in the mitochondrial matrix, where it regulates the acetylation levels of metabolic enzymes, including acetyl coenzyme A synthetase 2 (refs 1 , 2 ). Mice lacking both Sirt3 alleles appear phenotypically normal under basal conditions, but show marked hyperacetylation of several mitochondrial proteins 3 . Here we report that SIRT3 expression is upregulated during fasting in liver and brown adipose tissues. During fasting, livers from mice lacking SIRT3 had higher levels of fatty-acid oxidation intermediate products and triglycerides, associated with decreased levels of fatty-acid oxidation, compared to livers from wild-type mice. Mass spectrometry of mitochondrial proteins shows that long-chain acyl coenzyme A dehydrogenase (LCAD) is hyperacetylated at lysine 42 in the absence of SIRT3. LCAD is deacetylated in wild-type mice under fasted conditions and by SIRT3 in vitro and in vivo ; and hyperacetylation of LCAD reduces its enzymatic activity. Mice lacking SIRT3 exhibit hallmarks of fatty-acid oxidation disorders during fasting, including reduced ATP levels and intolerance to cold exposure. These findings identify acetylation as a novel regulatory mechanism for mitochondrial fatty-acid oxidation and demonstrate that SIRT3 modulates mitochondrial intermediary metabolism and fatty-acid use during fasting.

This randomized trial assessed whether urate-lowering treatment with allopurinol could attenuate eGFR decline in at-risk patients with stage 3 or 4 chronic kidney disease. Allopurinol did not slow the decline in eGFR as compared with placebo.

Characterising associations between the methylome, proteome and phenome may provide insight into biological pathways governing brain health. Here, we report an integrated DNA methylation and phenotypic study of the circulating proteome in relation to brain health. Methylome-wide association studies of 4058 plasma proteins are performed ( N  = 774), identifying 2928 CpG-protein associations after adjustment for multiple testing. These are independent of known genetic protein quantitative trait loci (pQTLs) and common lifestyle effects. Phenome-wide association studies of each protein are then performed in relation to 15 neurological traits ( N  = 1,065), identifying 405 associations between the levels of 191 proteins and cognitive scores, brain imaging measures or APOE e4 status. We uncover 35 previously unreported DNA methylation signatures for 17 protein markers of brain health. The epigenetic and proteomic markers we identify are pertinent to understanding and stratifying brain health. Characterising associations between the methylome, proteome and phenome may provide insight into biological pathways governing brain health. Here, blood protein markers of brain health are integrated with omics data to reveal DNA methylation differences that associate with these protein markers.

Clonal hematopoiesis of indeterminate potential (CHIP) increases rapidly in prevalence beyond age 60 and has been associated with increased risk for malignancy, heart disease and ischemic stroke. CHIP is driven by somatic mutations in hematopoietic stem and progenitor cells (HSPCs). Because mutations in HSPCs often drive leukemia, we hypothesized that HSPC fitness substantially contributes to transformation from CHIP to leukemia. HSPC fitness is defined as the proliferative advantage over cells carrying no or only neutral mutations. If mutations in different genes lead to distinct fitness advantages, this could enable patient stratification. We quantified the fitness effects of mutations over 12 years in older age using longitudinal sequencing and developed a filtering method that considers individual mutational context alongside mutation co-occurrence to quantify the growth potential of variants within individuals. We found that gene-specific fitness differences can outweigh inter-individual variation and, therefore, could form the basis for personalized clinical management. An analysis of blood samples from longitudinal cohorts reveals insights on the dynamics of clonal hematopoiesis of indeterminate potential and proposes a model that could be used for individualized clone monitoring over time.

Models predicting individual body weights over time clarify patient expectations in weight loss programs. The accuracy of two commonly used weight prediction models in community living people is unclear. All eligible people entering a weight management program between 1992 and 2015 were included. Patients’ diet was 1200 kcal/day for week 0 followed by 900 kcal/day for weeks 1–7 and were excluded from the analysis if they were nonadherent. We generated expected weights using the National Institutes of Health Body Weight Planner (NIH-BWP) and the Pennington Biomedical Research Center Weight Loss Predictor (PBRC-WLP). 3703 adherent people were included (mean age 46 years, 72.6% women, mean [SD] weight 262.3 pounds [54.2], mean [SD] BMI 42.4 [7.6]). Mean (SD) relative body weight differences (100*[observed−expected]/expected) for NIH-BWP and PBRC-WLP models was − 1.5% (3.8) and − 2.9% (3.2), respectively. At week 7, mean squared error with NIH-BWP (98.8, 83%CI 89.7–108.8) was significantly lower than that with PBRC-WLP (117.7, 83%CI 112.4–123.4). Notable variation in relative weight difference were seen (for NIH-BWP, 5th–95th percentile was − 6.2%, + 3.7%; Δ 9.9%). During the first 7 weeks of a weight loss program, both weight prediction models returned expected weights that were very close to observed values with the NIH-BWP being more accurate. However, notable variability between expected and observed weights in individual patients were seen. Clinicians can monitor patients in weight loss programs by comparing their progress with these data.

High methane (CH4) mixing ratios (up to 4 ppm) have occurred sporadically at our measurement site in Haddenham, Cambridgeshire, since July 2012. Isotopic measurements and back trajectories show that the source is the Waterbeach Waste Management Park 7 km SE of Haddenham. To investigate this further, measurements were made on 30 June and 1 July 2015 at other locations nearer to the source. Landfill emissions have been estimated using three different approaches at different scales; near source using the WindTrax inversion dispersion model, middle distance using a Gaussian plume (GP) model and at the landscape scale using the Numerical Atmospheric Modelling Environment (NAME) Inversion Technique for Emission Modelling (InTEM) inversion. The emission estimates derived using the WindTrax and Gaussian plume (GP) approaches agree well for the period of intense observations. Applying the Gaussian plume approach to all periods of elevated measurements seen at Haddenham produces year-round and monthly landfill emission estimates with an estimated annual emission of 11.6 GgCH(4) yr(-1). The monthly emission estimates are highest in winter (2160 kg h(-1) in February) and lowest in summer (620 kg h(-1) in July). These data identify the effects of environmental conditions on landfill CH4 production and highlight the importance of year-round measurements to capture seasonal variability in CH4 emission.

Nicholas Feasey and colleagues report whole-genome sequence analysis of 675 isolates of Salmonella enterica serovar Enteritidis from 45 countries. They find evidence for a global epidemic clade associated with enterocolitis and two novel clades restricted to distinct regions of Africa and associated with invasive disease. An epidemiological paradox surrounds Salmonella enterica serovar Enteritidis. In high-income settings, it has been responsible for an epidemic of poultry-associated, self-limiting enterocolitis, whereas in sub-Saharan Africa it is a major cause of invasive nontyphoidal Salmonella disease, associated with high case fatality. By whole-genome sequence analysis of 675 isolates of S. Enteritidis from 45 countries, we show the existence of a global epidemic clade and two new clades of S. Enteritidis that are geographically restricted to distinct regions of Africa. The African isolates display genomic degradation, a novel prophage repertoire, and an expanded multidrug resistance plasmid. S. Enteritidis is a further example of a Salmonella serotype that displays niche plasticity, with distinct clades that enable it to become a prominent cause of gastroenteritis in association with the industrial production of eggs and of multidrug-resistant, bloodstream-invasive infection in Africa.

Objective To test whether community mobilization adds effectiveness to conventional dengue control.Design Pragmatic open label parallel group cluster randomized controlled trial. Those assessing the outcomes and analyzing the data were blinded to group assignment. Centralized computerized randomization after the baseline study allocated half the sites to intervention, stratified by country, evidence of recent dengue virus infection in children aged 3-9, and vector indices.Setting Random sample of communities in Managua, capital of Nicaragua, and three coastal regions in Guerrero State in the south of Mexico.Participants Residents in a random sample of census enumeration areas across both countries: 75 intervention and 75 control clusters (about 140 households each) were randomized and analyzed (60 clusters in Nicaragua and 90 in Mexico), including 85 182 residents in 18 838 households.Interventions A community mobilization protocol began with community discussion of baseline results. Each intervention cluster adapted the basic intervention—chemical-free prevention of mosquito reproduction—to its own circumstances. All clusters continued the government run dengue control program.Main outcome measures Primary outcomes per protocol were self reported cases of dengue, serological evidence of recent dengue virus infection, and conventional entomological indices (house index: households with larvae or pupae/households examined; container index: containers with larvae or pupae/containers examined; Breteau index: containers with larvae or pupae/households examined; and pupae per person: pupae found/number of residents). Per protocol secondary analysis examined the effect of Camino Verde in the context of temephos use.Results With cluster as the unit of analysis, serological evidence from intervention sites showed a lower risk of infection with dengue virus in children (relative risk reduction 29.5%, 95% confidence interval 3.8% to 55.3%), fewer reports of dengue illness (24.7%, 1.8% to 51.2%), fewer houses with larvae or pupae among houses visited (house index) (44.1%, 13.6% to 74.7%), fewer containers with larvae or pupae among containers examined (container index) (36.7%, 24.5% to 44.8%), fewer containers with larvae or pupae among houses visited (Breteau index) (35.1%, 16.7% to 55.5%), and fewer pupae per person (51.7%, 36.2% to 76.1%). The numbers needed to treat were 30 (95% confidence interval 20 to 59) for a lower risk of infection in children, 71 (48 to 143) for fewer reports of dengue illness, 17 (14 to 20) for the house index, 37 (35 to 67) for the container index, 10 (6 to 29) for the Breteau index, and 12 (7 to 31) for fewer pupae per person. Secondary per protocol analysis showed no serological evidence of a protective effect of temephos.Conclusions Evidence based community mobilization can add effectiveness to dengue vector control. Each site implementing the intervention in its own way has the advantage of local customization and strong community engagement. Trial registration ISRCTN27581154