Summary Background Excessive weight gain during pregnancy seems to increase birthweight and the offspring's risk of obesity later in life. However, this association might be confounded by genetic and ...other shared effects. We aimed to examine the association between maternal weight gain and birthweight using state-based birth registry data that allowed us to compare several pregnancies in the same mother. Methods In this population-based cohort study, we used vital statistics natality records to examine all known births in Michigan and New Jersey, USA, between Jan 1, 1989, and Dec 31, 2003. From an initial sample of women with more than one singleton birth in the database, we made the following exclusions: gestation less than 37 weeks or 41 weeks or more; maternal diabetes; birthweight less than 500 g or more than 7000 g; and missing data for pregnancy weight gain. We examined how differences in weight gain that occurred during two or more pregnancies for each woman predicted the birthweight of her offspring, using a within-subject design to reduce confounding to a minimum. Findings Our analysis included 513 501 women and their 1 164 750 offspring. We noted a consistent association between pregnancy weight gain and birthweight (β 7·35, 95% CI 7·10–7·59, p<0·0001). Infants of women who gained more than 24 kg during pregnancy were 148·9 g (141·7–156·0) heavier at birth than were infants of women who gained 8–10 kg. The odds ratio of giving birth to an infant weighing more than 4000 g was 2·26 (2·09–2·44) for women who gained more than 24 kg during pregnancy compared with women who gained 8–10 kg. Interpretation Maternal weight gain during pregnancy increases birthweight independently of genetic factors. In view of the apparent association between birthweight and adult weight, obesity prevention efforts targeted at women during pregnancy might be beneficial for offspring. Funding US National Institutes of Health.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Dietary fat: From foe to friend? Ludwig, David S; Willett, Walter C; Volek, Jeff S ...
Science (American Association for the Advancement of Science),
11/2018, Volume:
362, Issue:
6416
Journal Article
Peer reviewed
Open access
For decades, dietary advice was based on the premise that high intakes of fat cause obesity, diabetes, heart disease, and possibly cancer. Recently, evidence for the adverse metabolic effects of ...processed carbohydrate has led to a resurgence in interest in lower-carbohydrate and ketogenic diets with high fat content. However, some argue that the relative quantity of dietary fat and carbohydrate has little relevance to health and that focus should instead be placed on which particular fat or carbohydrate sources are consumed. This review, by nutrition scientists with widely varying perspectives, summarizes existing evidence to identify areas of broad consensus amid ongoing controversy regarding macronutrients and chronic disease.
Current dietary guidelines recommend eating a variety of fruits and vegetables. However, based on nutrient composition, some particular fruits and vegetables may be more or less beneficial for ...maintaining or achieving a healthy weight. We hypothesized that greater consumption of fruits and vegetables with a higher fiber content or lower glycemic load would be more strongly associated with a healthy weight.
We examined the association between change in intake of specific fruits and vegetables and change in weight in three large, prospective cohorts of 133,468 United States men and women. From 1986 to 2010, these associations were examined within multiple 4-y time intervals, adjusting for simultaneous changes in other lifestyle factors, including other aspects of diet, smoking status, and physical activity. Results were combined using a random effects meta-analysis. Increased intake of fruits was inversely associated with 4-y weight change: total fruits -0.53 lb per daily serving (95% CI -0.61, -0.44), berries -1.11 lb (95% CI -1.45, -0.78), and apples/pears -1.24 lb (95% CI -1.62, -0.86). Increased intake of several vegetables was also inversely associated with weight change: total vegetables -0.25 lb per daily serving (95% CI -0.35, -0.14), tofu/soy -2.47 lb (95% CI, -3.09 to -1.85 lb) and cauliflower -1.37 lb (95% CI -2.27, -0.47). On the other hand, increased intake of starchy vegetables, including corn, peas, and potatoes, was associated with weight gain. Vegetables having both higher fiber and lower glycemic load were more strongly inversely associated with weight change compared with lower-fiber, higher-glycemic-load vegetables (p < 0.0001). Despite the measurement of key confounders in our analyses, the potential for residual confounding cannot be ruled out, and although our food frequency questionnaire specified portion size, the assessment of diet using any method will have measurement error.
Increased consumption of fruits and non-starchy vegetables is inversely associated with weight change, with important differences by type suggesting that other characteristics of these foods influence the magnitude of their association with weight change.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Integrins have been extensively investigated as therapeutic targets over the last decades, which has been inspired by their multiple functions in cancer progression, metastasis, and angiogenesis as ...well as a continuously expanding number of other diseases, e.g., sepsis, fibrosis, and viral infections, possibly also Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-2). Although integrin-targeted (cancer) therapy trials did not meet the high expectations yet, integrins are still valid and promising targets due to their elevated expression and surface accessibility on diseased cells. Thus, for the future successful clinical translation of integrin-targeted compounds, revisited and innovative treatment strategies have to be explored based on accumulated knowledge of integrin biology. For this, refined approaches are demanded aiming at alternative and improved preclinical models, optimized selectivity and pharmacological properties of integrin ligands, as well as more sophisticated treatment protocols considering dose fine-tuning of compounds. Moreover, integrin ligands exert high accuracy in disease monitoring as diagnostic molecular imaging tools, enabling patient selection for individualized integrin-targeted therapy. The present review comprehensively analyzes the state-of-the-art knowledge on the roles of RGD-binding integrin subtypes in cancer and non-cancerous diseases and outlines the latest achievements in the design and development of synthetic ligands and their application in biomedical, translational, and molecular imaging approaches. Indeed, substantial progress has already been made, including advanced ligand designs, numerous elaborated pre-clinical and first-in-human studies, while the discovery of novel applications for integrin ligands remains to be explored.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Clonal expansion of cells with somatically diversified receptors and their long-term maintenance as memory cells is a hallmark of adaptive immunity. Here, we studied pathogen-specific adaptation ...within the innate immune system, tracking natural killer (NK) cell memory to human cytomegalovirus (HCMV) infection. Leveraging single-cell multiomic maps of ex vivo NK cells and somatic mitochondrial DNA mutations as endogenous barcodes, we reveal substantial clonal expansion of adaptive NK cells in HCMV
individuals. NK cell clonotypes were characterized by a convergent inflammatory memory signature enriched for AP1 motifs superimposed on a private set of clone-specific accessible chromatin regions. NK cell clones were stably maintained in specific epigenetic states over time, revealing that clonal inheritance of chromatin accessibility shapes the epigenetic memory repertoire. Together, we identify clonal expansion and persistence within the human innate immune system, suggesting that these mechanisms have evolved independent of antigen-receptor diversification.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Recent technological advances have enabled massively parallel chromatin profiling with scATAC-seq (single-cell assay for transposase accessible chromatin by sequencing). Here we present ATAC with ...select antigen profiling by sequencing (ASAP-seq), a tool to simultaneously profile accessible chromatin and protein levels. Our approach pairs sparse scATAC-seq data with robust detection of hundreds of cell surface and intracellular protein markers and optional capture of mitochondrial DNA for clonal tracking, capturing three distinct modalities in single cells. ASAP-seq uses a bridging approach that repurposes antibody:oligonucleotide conjugates designed for existing technologies that pair protein measurements with single-cell RNA sequencing. Together with DOGMA-seq, an adaptation of CITE-seq (cellular indexing of transcriptomes and epitopes by sequencing) for measuring gene activity across the central dogma of gene regulation, we demonstrate the utility of systematic multi-omic profiling by revealing coordinated and distinct changes in chromatin, RNA and surface proteins during native hematopoietic differentiation and peripheral blood mononuclear cell stimulation and as a combinatorial decoder and reporter of multiplexed perturbations in primary T cells.
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GEOZS, IJS, IMTLJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK, ZAGLJ
The effectiveness of low-fat diets for long-term weight loss has been debated for decades, with many randomised controlled trials (RCTs) and recent reviews giving mixed results. We aimed to summarise ...the large body of evidence from RCTs to determine whether low-fat diets contribute to greater weight loss than participants' usual diet, low-carbohydrate diets, and other higher-fat dietary interventions.
We did a systematic review and random effects meta-analysis of RCTs comparing the long-term effect (≥1 year) of low-fat and higher-fat dietary interventions on weight loss by searching MEDLINE, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), and Cochrane Database of Systematic Reviews to identify eligible trials published from database inception up until July 31, 2014. We excluded trials if one intervention group included a non-dietary weight loss component but the other did not, and trials of dietary supplements or meal replacement drink interventions. Data including the main outcome measure of mean difference in weight change between interventions, and whether interventions were intended to lead to weight loss, weight maintenance, or neither, were extracted from published reports. We estimated the pooled weighted mean difference (WMD) with a DerSimonian and Laird random effects method.
3517 citations were identified by the search and 53 studies met our inclusion criteria, including 68 128 participants (69 comparisons). In weight loss trials, low-carbohydrate interventions led to significantly greater weight loss than did low-fat interventions (18 comparisons; WMD 1·15 kg 95% CI 0·52 to 1·79; I(2)=10%). Low-fat interventions did not lead to differences in weight change compared with other higher-fat weight loss interventions (19 comparisons; WMD 0·36 kg -0·66 to 1·37; I(2)=82%), and led to a greater weight decrease only when compared with a usual diet (eight comparisons; -5·41 kg -7·29 to -3·54; I(2)=68%). Similarly, results of non-weight-loss trials and weight maintenance trials, for which no low-carbohydrate comparisons were made, showed that low-fat versus higher-fat interventions have a similar effect on weight loss, and that low-fat interventions led to greater weight loss only when compared with usual diet. In weight loss trials, higher-fat weight loss interventions led to significantly greater weight loss than low-fat interventions when groups differed by more than 5% of calories obtained from fat at follow-up (18 comparisons; WMD 1·04 kg 95% CI 0·06 to 2·03; I(2)=78%), and when the difference in serum triglycerides between the two interventions at follow-up was at least 0·06 mmol/L (17 comparisons; 1·38 kg 0·50 to 2·25; I(2)=62%).
These findings suggest that the long-term effect of low-fat diet intervention on bodyweight depends on the intensity of the intervention in the comparison group. When compared with dietary interventions of similar intensity, evidence from RCTs does not support low-fat diets over other dietary interventions for long-term weight loss.
National Institutes of Health and American Diabetes Association.
In this trial, overweight and obese adolescents were assigned to a 1-year intervention to decrease consumption of sugar-sweetened beverages or not; there was 1 year of additional follow-up without ...intervention. BMI increased less in the intervention group at 1 year but not at 2 years.
The consumption of sugar-sweetened beverages among adolescents
1
has increased in tandem with the prevalence of pediatric obesity in the United States,
2
suggesting a causal relationship. At present, a substantial proportion of high-school students habitually consume sugar-sweetened beverages, including carbonated soda, sports drinks, energy drinks, and highly sweetened coffees and teas.
3
Sugar-sweetened beverages are the leading source of added sugar in the diet of a wide range of racial and ethnic groups.
4
According to nationally representative data, overweight and obese adolescents obtain more than 300 kcal per day from these products, amounting to an average of 15% of their total daily . . .
Lineage tracing provides key insights into the fate of individual cells in complex organisms. Although effective genetic labeling approaches are available in model systems, in humans, most approaches ...require detection of nuclear somatic mutations, which have high error rates, limited scale, and do not capture cell state information. Here, we show that somatic mutations in mtDNA can be tracked by single-cell RNA or assay for transposase accessible chromatin (ATAC) sequencing. We leverage somatic mtDNA mutations as natural genetic barcodes and demonstrate their utility as highly accurate clonal markers to infer cellular relationships. We track native human cells both in vitro and in vivo and relate clonal dynamics to gene expression and chromatin accessibility. Our approach should allow clonal tracking at a 1,000-fold greater scale than with nuclear genome sequencing, with simultaneous information on cell state, opening the way to chart cellular dynamics in human health and disease.
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•Somatic mtDNA mutations can track cellular relationships and hierarchies in vitro•Single-cell genomic assays faithfully detect mtDNA mutations•Lineage inference can be combined with gene expression or chromatin state profiles•mtDNA mutations enable studies of clonal architecture in human health and disease
Using single-cell sequencing technologies, somatic mutations in mtDNA can be used as natural genetic barcodes to study cellular states and clonal dynamics.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
To determine the effects of diets varying in carbohydrate to fat ratio on total energy expenditure.
Randomized trial.
Multicenter collaboration at US two sites, August 2014 to May 2017.
164 adults ...aged 18-65 years with a body mass index of 25 or more.
After 12% (within 2%) weight loss on a run-in diet, participants were randomly assigned to one of three test diets according to carbohydrate content (high, 60%, n=54; moderate, 40%, n=53; or low, 20%, n=57) for 20 weeks. Test diets were controlled for protein and were energy adjusted to maintain weight loss within 2 kg. To test for effect modification predicted by the carbohydrate-insulin model, the sample was divided into thirds of pre-weight loss insulin secretion (insulin concentration 30 minutes after oral glucose).
The primary outcome was total energy expenditure, measured with doubly labeled water, by intention-to-treat analysis. Per protocol analysis included participants who maintained target weight loss, potentially providing a more precise effect estimate. Secondary outcomes were resting energy expenditure, measures of physical activity, and levels of the metabolic hormones leptin and ghrelin.
Total energy expenditure differed by diet in the intention-to-treat analysis (n=162, P=0.002), with a linear trend of 52 kcal/d (95% confidence interval 23 to 82) for every 10% decrease in the contribution of carbohydrate to total energy intake (1 kcal=4.18 kJ=0.00418 MJ). Change in total energy expenditure was 91 kcal/d (95% confidence interval -29 to 210) greater in participants assigned to the moderate carbohydrate diet and 209 kcal/d (91 to 326) greater in those assigned to the low carbohydrate diet compared with the high carbohydrate diet. In the per protocol analysis (n=120, P<0.001), the respective differences were 131 kcal/d (-6 to 267) and 278 kcal/d (144 to 411). Among participants in the highest third of pre-weight loss insulin secretion, the difference between the low and high carbohydrate diet was 308 kcal/d in the intention-to-treat analysis and 478 kcal/d in the per protocol analysis (P<0.004). Ghrelin was significantly lower in participants assigned to the low carbohydrate diet compared with those assigned to the high carbohydrate diet (both analyses). Leptin was also significantly lower in participants assigned to the low carbohydrate diet (per protocol).
Consistent with the carbohydrate-insulin model, lowering dietary carbohydrate increased energy expenditure during weight loss maintenance. This metabolic effect may improve the success of obesity treatment, especially among those with high insulin secretion.
ClinicalTrials.gov NCT02068885.
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BFBNIB, CMK, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
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