Dynamic RNA polymerase II occupancy drives differentiation of the intestine under the direction of HNF4.

Terminal differentiation requires massive restructuring of the transcriptome. During intestinal differentiation, the expression patterns of nearly 4,000 genes are altered as cells transition from progenitor cells in crypts to differentiated cells in villi. We identify dynamic occupancy of RNA polymerase II (Pol II) to gene promoters as the primary driver of transcriptomic shifts during intestinal differentiation in vivo.

Extracellular Vesicles in Metabolic and Vascular Insulin Resistance.

Background: Insulin resistance is a major etiological factor in obesity, type 2 diabetes, and cardiovascular disease (CVD). Endothelial dysfunction may precede impairments in insulin-stimulated glucose uptake, thereby making it a key feature in development of CVD. However, the mechanism by which vascular tissue becomes dysfunctional is not clear.

Exercise increases TCA intermediate concentrations during low-calorie diet independent of insulin resistance among women with obesity.

Tricarboxylic acid cycle intermediates (TCAi) have been proposed to act as myokines that influence energy metabolism. We determined if 2-weeks of low-calorie diet with interval exercise (LCD + INT) would increase TCAi more than a low-calorie diet (LCD). Twenty-three women were randomized to 2-weeks of LCD (n = 12, 48.

Impact of Insulin-Induced Relative Hypoglycemia on Vascular Insulin Sensitivity and Central Hemodynamics in Prediabetes.

Context: Relative hypoglycemia (RH) is linked to sympathetic responses that can alter vascular function in individuals with type 2 diabetes. However, less is known about the role of RH on hemodynamics or metabolic insulin sensitivity in prediabetes.

Objective: Determine if RH alters peripheral endothelial function or central hemodynamics to a greater extent in those with prediabetes (PD) versus normoglycemia (NG).

Preconception Micronutrient Supplementation Affects Maternal BMI and Body Composition Postpartum: A Randomized Controlled Trial in Vietnam.

Background: Although there is growing evidence on the role of preconception nutrition for birth outcomes, limited evidence exists for its effects on maternal health.

Objectives: This study evaluates the impact of preconception micronutrient supplementation on maternal BMI (kg/m) and body composition at 6 to 7 y postpartum (PP).

Methods: We followed females who participated in a randomized controlled trial of preconception supplementation in Vietnam and delivered live offspring (n = 1599).

Early chronotype favors appetite and reduced later day caloric intake among adults with obesity.

Late chronotype (LC) is related to obesity and altered food intake throughout the day. But whether appetite perception and gut hormones differ among chronotypes is unclear. Thus, we examined if early chronotype (EC) have different appetite responses in relation to food intake than LC.

Intermediate versus morning chronotype has lower vascular insulin sensitivity in adults with obesity.

Aim: Chronotype reflects a circadian rhythmicity that regulates endothelial function. While the morning chronotype (MORN) usually has low cardiovascular disease risk, no study has examined insulin action on endothelial function between chronotypes. We hypothesized intermediate chronotypes (INT) would have lower vascular insulin sensitivity than morning chronotype (MORN).

Catalytic activity of OGG1 is impaired by Zinc deficiency.

Oxidative stress-induced DNA base modifications, if unrepaired, can increase mutagenesis and genomic instability, ultimately leading to cell death. Cells predominantly use the base excision repair (BER) pathway to repair oxidatively-induced non-helix distorting lesions. BER is initiated by DNA glycosylases, such as 8-oxoguanine DNA glycosylase (OGG1), which repairs oxidatively modified guanine bases, including 7,8-dihydro-8-oxoguanine (8-oxoG) and ring-opened formamidopyrimidine lesions, 2,6-diamino-4-hydroxy-5-formamidopyrimidine (FapyG).

A Small-Molecule Approach to Bypass In Vitro Selection of New Aptamers: Designer Pre-Ligands Turn Baby Spinach into Sensors for Reactive Inorganic Targets.

Fluorescent light-up aptamer (FLAP) systems are promising biosensing platforms that can be genetically encoded. Here, we describe how a single FLAP that works with specific organic ligands can detect multiple, structurally unique, non-fluorogenic, and reactive inorganic targets. We developed 4--functionalized benzylidene imidazolinones as pre-ligands with suppressed fluorescent binding interactions with the RNA aptamer Baby Spinach.

Direct assessment of nitrative stress in lipid environments: Applications of a designer lipid-based biosensor for peroxynitrite.

Lipid membranes and lipid-rich organelles are targets of peroxynitrite (ONOO), a highly reactive species generated under nitrative stress. We report a membrane-localized phospholipid () that allows the detection of ONOO in diverse lipid environments: biomimetic vesicles, mammalian cell compartments, and within the lung lining. and POPC self-assemble to membrane vesicles that fluorogenically and selectively respond to ONOO.

The Saccharomyces cerevisiae Spo7 basic tail is required for Nem1-Spo7/Pah1 phosphatase cascade function in lipid synthesis.

The Saccharomyces cerevisiae Nem1-Spo7 protein phosphatase complex dephosphorylates and thereby activates Pah1 at the nuclear/endoplasmic reticulum membrane. Pah1, a phosphatidate phosphatase catalyzing the dephosphorylation of phosphatidate to produce diacylglycerol, is one of the most highly regulated enzymes in lipid metabolism. The diacylglycerol produced in the lipid phosphatase reaction is utilized for the synthesis of triacylglycerol that is stored in lipid droplets.

Catalytic core function of yeast Pah1 phosphatidate phosphatase reveals structural insight into its membrane localization and activity control.

The PAH1-encoded phosphatidate (PA) phosphatase is a major source of diacylglycerol for the production of the storage lipid triacylglycerol and a key regulator for the de novo phospholipid synthesis in Saccharomyces cerevisiae. The catalytic function of Pah1 depends on its membrane localization which is mediated through its phosphorylation by multiple protein kinases and dephosphorylation by the Nem1-Spo7 protein phosphatase complex. The full-length Pah1 is composed of a catalytic core (N-LIP and HAD-like domains, amphipathic helix, and the WRDPLVDID domain) and non-catalytic regulatory sequences (intrinsically disordered regions, RP domain, and acidic tail) for phosphorylation and interaction with Nem1-Spo7.

Healthy helpers: using culinary lessons to improve children's culinary literacy and self-efficacy to cook.

Background: Children do not eat the recommended amounts of vegetables, and school-based nutrition education has not been found to impact this behavior. Cooking education is associated with improved children's culinary literacy (CL) and eating behaviors. This study investigated the impact of a culinary literacy (CL) curriculum on children's acceptance of vegetable-added (mushrooms) recipes, CL, self-efficacy to cook (SE), and willingness to try vegetables (WV).

The Antihypertensive Guanabenz Exacerbates Integrated Stress Response and Disrupts the Brain Circadian Clock.

The circadian clock regulates a variety of biological processes that are normally synchronized with the solar day. Disruption of circadian rhythms is associated with health problems. Understanding the signaling mechanisms that couple cell physiology and metabolism to circadian timekeeping will help to develop novel therapeutic strategies.

Dynamic RNA Polymerase II Recruitment Drives Differentiation of the Intestine under the direction of HNF4.

Terminal differentiation requires a massive restructuring of the transcriptome. During intestinal differentiation, the expression patterns of nearly 4000 genes are altered as cells transition from progenitor cells in crypts to differentiated cells in villi. We identified dynamic recruitment of RNA Polymerase II (Pol II) to gene promoters as the primary driver of transcriptomic shifts during intestinal differentiation Changes in enhancer-promoter looping interactions accompany dynamic Pol II recruitment and are dependent upon HNF4, a pro-differentiation transcription factor.

TGFB1 induces fetal reprogramming and enhances intestinal regeneration.

The gut epithelium has a remarkable ability to recover from damage. We employed a combination of high-throughput sequencing approaches, mouse genetics, and murine and human organoids and identified a role for TGFB signaling during intestinal regeneration following injury. At 2 days following irradiation (IR)-induced damage of intestinal crypts, a surge in TGFB1 expression is mediated by monocyte/macrophage cells at the location of damage.

Microbial-host isozyme: A novel target in "drug the bug" strategies for diabetes.

The role of the gut microbiome in metabolic diseases, such as diabetes, has emerged as a pivotal area of medical research. Wang et al.'s recent work reported that a gut bacteria-derived microbial-host isozyme, mimicking a human enzyme responsible for blood glucose regulation, can significantly impact the efficacy of diabetes medications.

GCN2 is required to maintain core body temperature in mice during acute cold.

Nonshivering thermogenesis in rodents requires macronutrients to fuel the generation of heat during hypothermic conditions. In this study, we examined the role of the nutrient sensing kinase, general control nonderepressible 2 (GCN2) in directing adaptive thermogenesis during acute cold exposure in mice. We hypothesized that GCN2 is required for adaptation to acute cold stress via activation of the integrated stress response (ISR) resulting in liver production of FGF21 and increased amino acid transport to support nonshivering thermogenesis.

-Aminoisobutyric Acid Relates to Favorable Glucose Metabolism through Adiponectin in Adults with Obesity Independent of Prediabetes.

-Aminoisobutyric acid (BAIBA) is secreted by skeletal muscle and promotes insulin sensitivity, fat oxidation, and anti-inflammation. While BAIBA is purportedly lower in individuals with obesity, no work has examined if prediabetes (PD) differentially impacts BAIBA concentrations in people with obesity. .

Gut microbiota-derived tryptamine and phenethylamine impair insulin sensitivity in metabolic syndrome and irritable bowel syndrome.

The incidence of metabolic syndrome is significantly higher in patients with irritable bowel syndrome (IBS), but the mechanisms involved remain unclear. Gut microbiota is causatively linked with the development of both metabolic dysfunctions and gastrointestinal disorders, thus gut dysbiosis in IBS may contribute to the development of metabolic syndrome. Here, we show that human gut bacterium Ruminococcus gnavus-derived tryptamine and phenethylamine play a pathogenic role in gut dysbiosis-induced insulin resistance in type 2 diabetes (T2D) and IBS.