Severe obesity is a rapidly growing global health threat. Although often attributed to unhealthy lifestyle choices or environmental factors, obesity is known to be heritable and highly polygenic; the ...majority of inherited susceptibility is related to the cumulative effect of many common DNA variants. Here we derive and validate a new polygenic predictor comprised of 2.1 million common variants to quantify this susceptibility and test this predictor in more than 300,000 individuals ranging from middle age to birth. Among middle-aged adults, we observe a 13-kg gradient in weight and a 25-fold gradient in risk of severe obesity across polygenic score deciles. In a longitudinal birth cohort, we note minimal differences in birthweight across score deciles, but a significant gradient emerged in early childhood and reached 12 kg by 18 years of age. This new approach to quantify inherited susceptibility to obesity affords new opportunities for clinical prevention and mechanistic assessment.
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•A genome-wide polygenic score can quantify inherited susceptibility to obesity•Polygenic score effect on weight emerges early in life and increases into adulthood•Effect of polygenic score can be similar to a rare, monogenic obesity mutation•High polygenic score is a strong risk factor for severe obesity and associated diseases
A genome-wide polygenic score quantifies inherited susceptibility to obesity, integrating information from 2.1 million common genetic variants to identify adults at risk of severe obesity.
A key public health need is to identify individuals at high risk for a given disease to enable enhanced screening or preventive therapies. Because most common diseases have a genetic component, one ...important approach is to stratify individuals based on inherited DNA variation
. Proposed clinical applications have largely focused on finding carriers of rare monogenic mutations at several-fold increased risk. Although most disease risk is polygenic in nature
, it has not yet been possible to use polygenic predictors to identify individuals at risk comparable to monogenic mutations. Here, we develop and validate genome-wide polygenic scores for five common diseases. The approach identifies 8.0, 6.1, 3.5, 3.2, and 1.5% of the population at greater than threefold increased risk for coronary artery disease, atrial fibrillation, type 2 diabetes, inflammatory bowel disease, and breast cancer, respectively. For coronary artery disease, this prevalence is 20-fold higher than the carrier frequency of rare monogenic mutations conferring comparable risk
. We propose that it is time to contemplate the inclusion of polygenic risk prediction in clinical care, and discuss relevant issues.
Dissecting the role of insulin in the complex regulation of triglyceride metabolism is necessary for understanding dyslipidemia and steatosis. Liver insulin receptor knockout (LIRKO) mice show that ...in the physiological context of feeding, hepatic insulin signaling is not required for the induction of mTORC1, an upstream activator of the lipogenic regulator, SREBP-1c. Feeding induces SREBP-1c mRNA in LIRKO livers, though not to the extent observed in controls. A high fructose diet also partially induces SREBP-1c and lipogenic gene expression in LIRKO livers. Insulin signaling becomes more important in the pathological context of obesity, as knockdown of the insulin receptor in ob/ob mice, a model of Type 2 diabetes, using antisense oligonucleotides, abolishes the induction of SREBP-1c and its targets by obesity and ameliorates steatosis. Thus, insulin-independent signaling pathways can partially compensate for insulin in the induction of SREBP-1c by feeding but the further induction by obesity/Type 2 diabetes is entirely dependent upon insulin.
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► Hepatic insulin signaling is not required for activation of mTORC1 by feeding ► SREBP-1c mRNA is partially induced by feeding in absence of insulin ► Induction of SREBP-1c by obesity is entirely dependent upon insulin signaling
Delusional parasitosis manifests as a fixed, false belief that an individual is infested by living organisms. Primary delusional parasitosis is a psychiatric disorder with the delusion as an isolated ...manifestation, whereas secondary delusional parasitosis is a delusion occurring secondary to a psychiatric disorder, substance use, or medical illness. A 62-year-old woman with no psychiatric history presented to the Emergency Department with two to three months of “whole body itching” and seeing small insects crawling on her skin and in her hair. Exam of her skin and scalp was notable for no appreciable lesions, rashes, excoriations, or insects. Her neurologic exam was notable for full visual fields, and no localizing deficits. A non-contrast head CT demonstrated a nonspecific heterogeneous low-attenuation lesion within the medial right occipital lobe, and a follow up MRI confirmed a right posterior cerebral artery distribution subacute infarction. She was admitted for two days, and ultimately was discharged on aspirin and atorvastatin for secondary prevention. An emergency physician should remain vigilant in his/her assessment of patients with seemingly psychiatric symptoms, in particular elderly patients with no known psychiatric illnesses. Neuroimaging should be amongst studies considered in the evaluation of elderly patients presenting with new onset psychiatric complaints.
Lactation benefits both lactating individuals and their infants. Despite high rates of breastfeeding initiation, physicians are a high-risk group for early cessation. Barriers to meeting lactation ...goals for physicians include lack of protected time, dedicated space, and collegial support. The emergency department (ED) is a uniquely challenging setting for lactating emergency physicians, given the high-stress, high-acuity environment that lacks predictability or scheduled breaks. This article presents an overview of relevant lactation physiology and evidence for specific strategies that the lactating emergency physician, colleagues, and ED leadership can implement to overcome barriers and facilitate meeting lactation goals.
Podcasts are commonly used by residents as part of their learning, with many listening concomitantly with other activities (e.g., driving and exercise). The effects of exercise on learning are ...controversial, with some suggesting potential benefit and others suggesting impaired learning. This study examined whether exercise influences knowledge acquisition and retention among resident physicians listening to a podcast while exercising versus those with undistracted listening.
This multicenter, randomized, crossover trial assessed emergency medicine residents across 5 U.S. institutions from September 2022 to January 2023. Residents were randomized to a group that listened to one 30-minute podcast while seated or a group that listened to a 30-minute podcast while engaging in 30 minutes of continuous aerobic exercise, with stratification by site and postgraduate year. Within 30 minutes of completing the podcast, they completed a 20-question multiple-choice test. They subsequently crossed over to the other intervention and listened to a different 30-minute podcast followed by another 20-question test. Each podcast focused on emergency medicine-relevant journal articles that had not been covered in journal club or curriculum at any sites. Residents also completed a 40-question delayed recall test with separate questions on both podcasts at 30 days.
Ninety-six residents were recruited for the study, with 95 (99.0%) completing the initial recall portion and 92 (97.0%) completing the delayed recall tests. No statistically significant differences were found between the exercise and seated cohorts on initial recall (74.4% vs 76.3%; d = -0.12; 95% CI, -0.33 to 0.08; P = .12) or delayed recall (52.3% vs 52.5%; d = -0.01; 95% CI, -0.22 to -0.19; P = .46).
Exercising while listening to podcasts did not appear to meaningfully affect knowledge acquisition or retention at 30 days when compared with listening while seated and undistracted.
The regulation of ApoB metabolism by insulin Haas, Mary E; Attie, Alan D; Biddinger, Sudha B
Trends in endocrinology and metabolism,
08/2013, Letnik:
24, Številka:
8
Journal Article
Recenzirano
Odprti dostop
Highlights • In the liver, insulin antagonizes ApoB secretion at multiple sites. • Insulin promotes ApoB clearance via multiple hepatic receptor systems. • In diabetes, ApoB secretion is increased, ...and ApoB clearance is decreased. • Changes in ApoB metabolism may drive cardiovascular disease in the diabetic state.
Abstract
The mammalian mitochondrial proteome is under dual genomic control, with 99% of proteins encoded by the nuclear genome and 13 originating from the mitochondrial DNA (mtDNA). We previously ...developed MitoCarta, a catalogue of over 1000 genes encoding the mammalian mitochondrial proteome. This catalogue was compiled using a Bayesian integration of multiple sequence features and experimental datasets, notably protein mass spectrometry of mitochondria isolated from fourteen murine tissues. Here, we introduce MitoCarta3.0. Beginning with the MitoCarta2.0 inventory, we performed manual review to remove 100 genes and introduce 78 additional genes, arriving at an updated inventory of 1136 human genes. We now include manually curated annotations of sub-mitochondrial localization (matrix, inner membrane, intermembrane space, outer membrane) as well as assignment to 149 hierarchical ‘MitoPathways’ spanning seven broad functional categories relevant to mitochondria. MitoCarta3.0, including sub-mitochondrial localization and MitoPathway annotations, is freely available at http://www.broadinstitute.org/mitocarta and should serve as a continued community resource for mitochondrial biology and medicine.
Insulin receptor (IR) plays a key role in the control of glucose homeostasis; however, the regulation of its cellular expression remains poorly understood. Here we show that the amount of ...biologically active IR is regulated by the cleavage of its ectodomain, by the β-site amyloid precursor protein cleaving enzyme 1 (BACE1), in a glucose concentration-dependent manner. In vivo studies demonstrate that BACE1 regulates the amount of IR and insulin signaling in the liver. During diabetes, BACE1-dependent cleavage of IR is increased and the amount of IR in the liver is reduced, whereas infusion of a BACE1 inhibitor partially restores liver IR. We suggest the potential use of BACE1 inhibitors to enhance insulin signaling during diabetes. Additionally, we show that plasma levels of cleaved IR reflect IR isoform A expression levels in liver tumors, which prompts us to propose that the measurement of circulating cleaved IR may assist hepatic cancer detection and management.
Analyzing 12,361 all-cause cirrhosis cases and 790,095 controls from eight cohorts, we identify a common missense variant in the Mitochondrial Amidoxime Reducing Component 1 gene (MARC1 p.A165T) that ...associates with protection from all-cause cirrhosis (OR 0.91, p = 2.3*10-11). This same variant also associates with lower levels of hepatic fat on computed tomographic imaging and lower odds of physician-diagnosed fatty liver as well as lower blood levels of alanine transaminase (-0.025 SD, 3.7*10-43), alkaline phosphatase (-0.025 SD, 1.2*10-37), total cholesterol (-0.030 SD, p = 1.9*10-36) and LDL cholesterol (-0.027 SD, p = 5.1*10-30) levels. We identified a series of additional MARC1 alleles (low-frequency missense p.M187K and rare protein-truncating p.R200Ter) that also associated with lower cholesterol levels, liver enzyme levels and reduced risk of cirrhosis (0 cirrhosis cases for 238 R200Ter carriers versus 17,046 cases of cirrhosis among 759,027 non-carriers, p = 0.04) suggesting that deficiency of the MARC1 enzyme may lower blood cholesterol levels and protect against cirrhosis.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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