IRS1 Genotype Modulates Metabolic Syndrome Reversion in Response to 2-Year Weight-Loss Diet Intervention: The POUNDS LOST trial

OBJECTIVE Genetic variants near IRS1 are associated with features of the metabolic syndrome (MetS). We examined whether genetic variants near IRS1 might modulate the effects of diets varying in fat content on the MetS status in a 2-year weight-loss trial. RESEARCH DESIGN AND METHODS Two variants near IRS1, rs1522813 and rs2943641, were genotyped in 738 overweight/obese adults (age 60 ± 9 years; BMI 32.7 ± 3.9 kg/m2) randomly assigned to one of four weight-loss diets (a deficit of 750 kcal/day of caloric intake from baseline) varying in macronutrient contents for 2 years. We compared MetS status of high-fat (40% of caloric intake; n = 370) and low-fat (20% caloric intake; n = 368) diet groups differentiated by genotypes (rs1522813 A-allele carriers and noncarriers and rs2943641T-allele carriers and noncarriers). RESULTS Among rs1522813 A-allele carriers, the reversion rates of the MetS were higher in the high-fat diet group than those in the low-fat diet group over the 2-year intervention (P = 0.002), while no significant difference between diet groups was observed among noncarriers (P = 0.27). The genetic modulation on dietary effect was independent of weight changes. The odds ratio (OR) for the 2-year reversion of the MetS was 2.88 (95% CI 1.25–6.67) comparing the high-fat and low-fat diets among rs1522813 A-allele carriers, while the corresponding OR was 0.83 (0.36–1.92) in noncarriers. The variant rs2943641 was not observed to modulate dietary effects on the MetS status. CONCLUSIONS Our data suggest that high-fat weight-loss diets might be more effective in the management of the MetS compared with low-fat diets among individuals with the A-allele of the rs1522813 variant near IRS1

Synthesis of the elements in stars: forty years of progress

Forty years ago Burbidge, Burbidge, Fowler, and Hoyle combined what we would now call fragmentary evidence from nuclear physics, stellar evolution and the abundances of elements and isotopes in the solar system as well as a few stars into a synthesis of remarkable ingenuity. Their review provided a foundation for forty years of research in all of the aspects of low energy nuclear experiments and theory, stellar modeling over a wide range of mass and composition, and abundance studies of many hundreds of stars, many of which have shown distinct evidence of the processes suggested by B2FH. In this review we summarize progress in each of these fields with emphasis on the most recent developments

Effect of diet composition and weight loss on resting energy expenditure in the POUNDS LOST study

Weight loss reduces energy expenditure, but it is unclear whether dietary macronutrient composition affects this reduction. We hypothesized that energy expenditure might be modulated by macronutrient composition of the diet. The POUNDS LOST study, a prospective, randomized controlled trial in 811 overweight/obese people who were randomized in a 2×2 design to diets containing 20en% or 40en% fat and 15en% or 25en% (diets with 65%, 55%, 45% and 35% carbohydrate) provided the data to test this hypothesis. Resting energy expenditure (REE) was measured at baseline, 6 and 24 months using a ventilated hood. REE declined at 6 months by 99.5±8.0 kcal/d in men and 55.2±10.6 kcal/d in women during the first 6 months. This decline was related to the weight loss, and there was no difference between the diets. REE had returned to baseline by 24 months, but body weight was still 60% below baseline. Measured REE at 6 months was significantly lower than the predicted (−18.2±6.7 kcal/d) and was the result of significant reductions from baseline in the low fat diets (65% or 55% carbohydrate), but not in the high fat diet groups. By 24 months the difference had reversed with measured REE being slightly but significantly higher than predicted (21.8±10.1 kcal/d). In conclusion, we found that REE fell significantly after weight loss but was not related to diet composition. Adaptive thermogenesis was evident at 6 months, but not at 24 months

Land management explains major trends in forest structure and composition over the last millennium in California's Klamath Mountains

For millennia, forest ecosystems in California have been shaped by fire from both natural processes and Indigenous land management, but the notion of climatic variation as a primary controller of the pre-colonial landscape remains pervasive. Understanding the relative influence of climate and Indigenous burning on the fire regime is key because contemporary forest policy and management are informed by historical baselines. This need is particularly acute in California, where 20th-century fire suppression, coupled with a warming climate, has caused forest densification and increasingly large wildfires that threaten forest ecosystem integrity and management of the forests as part of climate mitigation efforts. We examine climatic versus anthropogenic influence on forest conditions over 3 millennia in the western Klamath Mountains—the ancestral territories of the Karuk and Yurok Tribes—by combining paleoenvironmental data with Western and Indigenous knowledge. A fire regime consisting of tribal burning practices and lightning were associated with long-term stability of forest biomass. Before Euro-American colonization, the long-term median forest biomass was between 104 and 128 Mg/ha, compared to values over 250 Mg/ha today. Indigenous depopulation after AD 1800, coupled with 20th-century fire suppression, likely allowed biomass to increase, culminating in the current landscape: a closed Douglas fir–dominant forest unlike any seen in the preceding 3,000 y. These findings are consistent with precontact forest conditions being influenced by Indigenous land management and suggest large-scale interventions could be needed to return to historic forest biomass levels

Effect of monocytes/macrophages on the early osteogenic differentiation of hBMSCs

Heterotypic cell interactions are essential for the homeostasis of bone tissue, in particular the widely studied interaction between osteoblasts and osteoclasts. Closely related with osteoclasts are monocytes/macrophages. These have been shown to produce osteogenic factors, e.g. BMP-2, which plays a key role in bone metabolism. However, the mechanisms through which monocytes/macrophages interact with osteoblasts are still elusive. The aim of this work was to assess the influence of human peripheral blood monocytes/macrophages over the early osteogenic differentiation of human bone marrow stromal cells (hBMSCs) in the presence of dexamethasone-supplemented medium. The co-cultures were performed using porous transwells that allowed the interaction between both cell types through the production of paracrine factors. The potential effect of BMP-2 produced by monocytes/macrophages was addressed by adding an anti-BMP-2 antibody to the co-cultures. hBMSCs cultured in the presence of monocytes/macrophages had a higher proliferation rate than hBMSCs monocultures. The quantification of early osteogenic marker alkaline phosphatase (ALP) revealed higher activity of this enzyme in cells in the co-culture throughout the time of culture. Both of these effects were inhibited by adding an anti-BMP-2 antibody to the cultures. Moreover, qRTPCR for osteocalcin and osteopontin transcripts showed overexpression of both markers. Once again, the effect of monocytes/macrophages over hBMSC osteogenic differentiation was completely inhibited in the co-cultures by blocking BMP-2. The present report confirmed that monocytes/macrophages produce BMP-2, which promotes osteogenic differentiation and proliferation of hBMSCs cumulatively to dexamethasone-supplemented medium. This potentially implies that monocyte/macrophages play a stronger role in bone homeostasis than so far supposed

Neonatal overfeeding by small-litter rearing sensitises hippocampal microglial responses to immune challenge:Reversal with neonatal repeated injections of saline or minocycline

The early-life period is extremely vulnerable to programming effects from the environment, many of which persist into adulthood. We have previously demonstrated that adult rats overfed as neonates have hypothalamic microglia that are hyper-responsive to an immune challenge, as well as hippocampal microglia that respond less efficiently to learning. We therefore hypothesised that neonatal overfeeding would alter the ability of hippocampal microglia to respond to an immune challenge with lipopolysaccharide (LPS) and that concomitant minocycline, a tetracycline antibiotic that suppresses microglial activity, could restore these responses. We induced neonatal overfeeding by manipulating the litter sizes in which Wistar rat pups were raised, so the pups were suckled in litters of four (neonatally overfed) or 12 (control-fed). We then examined the hippocampal microglial profiles 24 hour after an immune challenge with LPS and found that the neonatally overfed rats had dramatically increased microglial numbers in the hippocampus after immune challenge compared to control-fed rats. Attempts to reverse these effects with minocycline revealed repeated that neonatal injections, whether with minocycline or with saline, markedly suppressed microglial number and density throughout the hippocampus and abolished the difference between the groups in their responses to LPS. These data suggest that neonatal overfeeding not only can have lasting effects on hippocampal immune responses, but also that neonatal exposure to a protocol of repeated injections, irrespective of treatment, has a pronounced long-term impact, highlighting the importance of considering these effects when interpreting experimental data

The Personalized Nutrition Study (POINTS): evaluation of a genetically informed weight loss approach, a randomized clinical trial

Weight loss (WL) differences between isocaloric high-carbohydrate and high-fat diets are generally small; however, individual WL varies within diet groups. Genotype patterns may modify diet effects, with carbohydrate-responsive genotypes losing more weight on high-carbohydrate diets (and vice versa for fat-responsive genotypes). We investigated whether 12-week WL (kg, primary outcome) differs between genotype-concordant and genotype-discordant diets. In this 12-week single-center WL trial, 145 participants with overweight/obesity were identified a priori as fat-responders or carbohydrate-responders based on their combined genotypes at ten genetic variants and randomized to a high-fat (n = 73) or high-carbohydrate diet (n = 72), yielding 4 groups: (1) fat-responders receiving high-fat diet, (2) fat-responders receiving high-carbohydrate diet, (3) carbohydrate-responders receiving high-fat diet, (4) carbohydrate-responders receiving high-carbohydrate diet. Dietitians delivered the WL intervention via 12 weekly diet-specific small group sessions. Outcome assessors were blind to diet assignment and genotype patterns. We included 122 participants (54.4 [SD:13.2] years, BMI 34.9 [SD:5.1] kg/m2, 84% women) in the analyses. Twelve-week WL did not differ between the genotype-concordant (−5.3 kg [SD:1.0]) and genotype-discordant diets (−4.8 kg [SD:1.1]; adjusted difference: −0.6 kg [95% CI: −2.1,0.9], p = 0.50). With the current ability to genotype participants as fat- or carbohydrate-responders, evidence does not support greater WL on genotype-concordant diets. ClinicalTrials identifier: NCT04145466

Catching Element Formation In The Act

Gamma-ray astronomy explores the most energetic photons in nature to address some of the most pressing puzzles in contemporary astrophysics. It encompasses a wide range of objects and phenomena: stars, supernovae, novae, neutron stars, stellar-mass black holes, nucleosynthesis, the interstellar medium, cosmic rays and relativistic-particle acceleration, and the evolution of galaxies. MeV gamma-rays provide a unique probe of nuclear processes in astronomy, directly measuring radioactive decay, nuclear de-excitation, and positron annihilation. The substantial information carried by gamma-ray photons allows us to see deeper into these objects, the bulk of the power is often emitted at gamma-ray energies, and radioactivity provides a natural physical clock that adds unique information. New science will be driven by time-domain population studies at gamma-ray energies. This science is enabled by next-generation gamma-ray instruments with one to two orders of magnitude better sensitivity, larger sky coverage, and faster cadence than all previous gamma-ray instruments. This transformative capability permits: (a) the accurate identification of the gamma-ray emitting objects and correlations with observations taken at other wavelengths and with other messengers; (b) construction of new gamma-ray maps of the Milky Way and other nearby galaxies where extended regions are distinguished from point sources; and (c) considerable serendipitous science of scarce events -- nearby neutron star mergers, for example. Advances in technology push the performance of new gamma-ray instruments to address a wide set of astrophysical questions.Comment: 14 pages including 3 figure

Rice consumption and risk of cardiovascular disease: results from a pooled analysis of 3 U.S. cohorts.

BACKGROUND: Health concerns have been raised about rice consumption, which may significantly contribute to arsenic exposure. However, little is known regarding whether habitual rice consumption is associated with cardiovascular disease (CVD) risk. OBJECTIVE: We examined prospectively the association of white rice and brown rice consumption with CVD risk. DESIGN: We followed a total of 207,556 women and men [73,228 women from the Nurses' Health Study (1984-2010), 92,158 women from the Nurses' Health Study II (1991-2011), and 42,170 men from the Health Professionals Follow-Up Study (1986-2010)] who were free of CVD and cancer at baseline. Validated semiquantitative food-frequency questionnaires were used to assess consumption of white rice, brown rice, and other food items. Fatal and nonfatal CVD (coronary artery disease and stroke) was confirmed by medical records or self-reports. RESULTS: During 4,393,130 person-years of follow-up, 12,391 cases of CVD were identified. After adjustment for major CVD risk factors, including demographics, lifestyle, and other dietary intakes, rice consumption was not associated with CVD risk. The multivariable-adjuted HR of developing CVD comparing ≥5 servings/wk with <1 serving/wk was 0.98 (95% CI: 0.84, 1.14) for white rice, 1.01 (0.79, 1.28) for brown rice, and 0.99 (0.90, 1.08) for total rice. To minimize the potential impact of racial difference in rice consumption, we restricted the analyses to whites only and obtained similar results: the HRs of CVD for ≥5 servings/wk compared with <1 serving/wk were 1.04 (95% CI: 0.88, 1.22) for white rice and 1.01 (0.78, 1.31) for brown rice. CONCLUSIONS: Greater habitual consumption of white rice or brown rice is not associated with CVD risk. These findings suggest that rice consumption may not pose a significant CVD risk among the U.S. population when consumed at current amounts. More prospective studies are needed to explore these associations in other populations.Supported by NIH grants CA50385, CA87969, CA176726, CA167552, HL60712, HL034594, HL088521, and HL35464. QS was supported by a career development grant R00HL098459 sponsored by the National Heart, Lung, and Blood Institute. FI was supported by Medical Research Council Epidemiology Unit Core Support (MC_UU_12015/5).This article was originally published in The American Journal of Clinical Nutrition (I Muraki, H Wu, F Imamura, F Laden, EB Rimm, FB Hu, WC Willett, Q Sun, The American Journal of Clinical Nutrition 2015, 101, 164-172

miR-873-5p targets mitochondrialGNMT-Complex II interface contributing tonon-alcoholic fatty liver disease

Objective:Non-alcoholic fatty liver disease (NAFLD) is a complex pathology in which several dysfunctions, including alterations in metabolicpathways, mitochondrial functionality and unbalanced lipid import/export, lead to lipid accumulation and progression to inflammation andfibrosis.The enzyme glycine N-methyltransferase (GNMT), the most important enzyme implicated in S-adenosylmethionine catabolism in the liver, isdownregulated during NAFLD progression. We have studied the mechanism involved in GNMT downregulation by its repressor microRNA miR-873-5p and the metabolic pathways affected in NAFLD as well as the benefit of recovery GNMT expression.Methods:miR-873-5p and GNMT expression were evaluated in liver biopsies of NAFLD/NASH patients. Differentin vitroandin vivoNAFLD murinemodels were used to assess miR-873-5p/GNMT involvement in fatty liver progression through targeting of the miR-873-5p as NAFLD therapy.Results:We describe a new function of GNMT as an essential regulator of Complex II activity in the electron transport chain in the mitochondria.In NAFLD, GNMT expression is controlled by miR-873-5p in the hepatocytes, leading to disruptions in mitochondrial functionality in a preclinicalmurine non-alcoholic steatohepatitis (NASH) model. Upregulation of miR-873-5p is shown in the liver of NAFLD/NASH patients, correlating withhepatic GNMT depletion. Importantly, NASH therapies based on anti-miR-873-5p resolve lipid accumulation, inflammation andfibrosis byenhancing fatty acidb-oxidation in the mitochondria. Therefore, miR-873-5p inhibitor emerges as a potential tool for NASH treatment.Conclusion:GNMT participates in the regulation of metabolic pathways and mitochondrial functionality through the regulation of Complex II activityin the electron transport chain. In NAFLD, GNMT is repressed by miR-873-5p and its targeting arises as a valuable therapeutic option for treatment