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Abstract Context Consuming calories later in the day is associated with obesity and metabolic syndrome. We hypothesized that eating a late dinner alters substrate metabolism during sleep in a manner that promotes obesity. Objective The objective of this work is to examine the impact of late dinner on nocturnal metabolism in healthy volunteers. Design and Setting This is a randomized crossover trial of late dinner (LD, 22:00) vs routine dinner (RD, 18:00), with a fixed sleep period (23:00-07:00) in a laboratory setting. Participants Participants comprised 20 healthy volunteers (10 male, 10 female), age 26.0 ± 0.6 years, body mass index 23.2 ± 0.7 kg/m2, accustomed to a bedtime between 22:00 and 01:00. Interventions An isocaloric macronutrient diet was administered on both visits. Dinner (35% daily kcal, 50% carbohydrate, 35% fat) with an oral lipid tracer ([2H31] palmitate, 15 mg/kg) was given at 18:00 with RD and 22:00 with LD. Main Outcome Measures Measurements included nocturnal and next-morning hourly plasma glucose, insulin, triglycerides, free fatty acids (FFAs), cortisol, dietary fatty acid oxidation, and overnight polysomnography. Results LD caused a 4-hour shift in the postprandial period, overlapping with the sleep phase. Independent of this shift, the postprandial period following LD was characterized by higher glucose, a triglyceride peak delay, and lower FFA and dietary fatty acid oxidation. LD did not affect sleep architecture, but increased plasma cortisol. These metabolic changes were most pronounced in habitual earlier sleepers determined by actigraphy monitoring. Conclusion LD induces nocturnal glucose intolerance, and reduces fatty acid oxidation and mobilization, particularly in earlier sleepers. These effects might promote obesity if they recur chronically.

Context:It is hypothesized that obesity adversely affects the ovarian environment, which can disrupt oocyte maturation and embryonic development.Objective:This study aimed to compare oocyte gene expression profiles and follicular fluid (FF) content from overweight/obese (OW) women and normal-weight (NW) women who were undergoing fertility treatments.Design:Using single-cell transcriptomic analyses, we investigated oocyte gene expression using RNA sequencing.Patients or Other Participants:Eleven OW women and 13 NW women undergoing fertility treatments were enrolled.Main Outcome Measures:Oocyte messenger RNA profiles as well as serum and FF hormone and lipid levels were assessed.Results:OW women had significantly higher body mass index, body fat percentage, and serum homeostatic model assessment−insulin resistance index compared with NW women (P < 0.01). Serum leptin and C-reactive protein (CRP) levels as well as FF leptin, CRP, and triglyceride levels were increased (P < 0.05) in OW compared with NW women. Oocytes from OW women had increased expression of proinflammatory (CXCL2; P = 0.071) and oxidative stress–related (DUSP1; P = 0.051) genes but had decreased expression of GAS7 (fat metabolism; P = 0.065), TXNIP (oxidative stress; P = 0.055), and transcription factors ID3 (P = 0.075) and TWIST1 (P = 0.099) compared with NW women.Conclusions:These findings provide evidence for the significant influence of body composition on oocyte transcript abundance in women undergoing hormonal induction to retrieve oocytes. They further identify the potential for maternal diet to influence oocyte gene expression. The preconception period is, therefore, an important window of opportunity to consider for lifestyle interventions.We studied oocyte mRNA profiles as well as serum and follicular fluid hormone and lipid levels in obese women compared with those in normal-weight women and found significant differences.

There is growing interest in leveraging real-world data to complement knowledge gained from randomized clinical trials and inform the design of prospective randomized studies in oncology. The present study compared clinical outcomes in women with metastatic breast cancer who received letrozole as first-line monotherapy in oncology practices across the United States versus patients in the letrozole-alone cohort of the PALOMA-2 phase 3 trial. The real-world cohort (N = 107) was derived from de-identified patient data from the Flatiron Health electronic health record database. The clinical trial cohort (N = 222) comprised postmenopausal women in the letrozole-alone arm of PALOMA-2. Patients in the real-world cohort received letrozole monotherapy per labeling and clinical judgment; patients in PALOMA-2 received letrozole 2.5 mg/d, continuous. Real-world survival and response rates were based on evidence of disease burden curated from clinician notes, radiologic reports, and pathology reports available in the electronic health record. Progression-free survival and objective response rate in PALOMA-2 were based on Response Evaluation Criteria in Solid Tumors v1.1. Concordance of survival and response rates were retrospectively assessed using inverse probability of treatment weighting-adjusted Cox regression analysis. Inverse probability of treatment weighting-adjusted Cox regression results showed similar median progression-free survival in the real-world and PALOMA-2 cohorts (18.4 and 16.6 months, respectively): the hazard ratio using real-world data as reference was 1.04 (95% CI, 0.69-1.56). No significant difference was observed in response rates: 41.8% in the real-world cohort vs 39.4% in the PALOMA-2 cohort (odds ratio using real-world data as reference: 0.91 [95% CI, 0.57-1.44]). These findings indicate that data abstracted from electronic health records with proper quality controls can yield meaningful information on clinical outcomes. These data increase confidence in the use of real-world assessments of progression and response as efficacy endpoints. Trial registration NCT01740427; Funding: Pfizer.

Circulating blood cells such as platelets represent a readily available sample type to determine mitochondrial function in humans. Here, we set out to determine the influence of sample preparation, assay buffer composition, and instrumental platform on the respiratory function of platelets isolated from human blood. Approximately 50 mL of whole blood was collected from healthy adults (n = 16) following an overnight (>12 h) fast. Platelets were immediately isolated from whole blood by centrifugation for respirometry. Respiratory function was assayed in intact and permeabilized platelets using an Oxygraph‐2K (O2K) high‐resolution respirometer in either RPMI or MIR05 (containing 5 mM glucose, 1 mM pyruvate, and 2 mM glutamine), or the participant's own plasma. In addition, respiratory function was determined in intact platelets using a Seahorse Extracellular Flux analyzer (XFe96) in RPMI buffer containing 1 mM pyruvate, 2 mM glutamine, and variable glucose concentrations (5, 10, and 10 mM). In assays performed in an O2K, routine and ATP‐linked respiration were greater in cells assayed in RPMI compared to MIR05 (p < 0.001). However, compared to cells assayed in RPMI or MIR05, routine and ATP‐linked respiration were higher in intact platelets assayed in their own plasma (p < 0.001). In digitonin‐permeabilized platelets, state 3 respiration was greater when assayed in MIR05 compared to RPMI (p < 0.05). Across instrumental platforms, routine and leak respiration were lower in intact platelets assayed on an O2K versus an XFe96 (p < 0.05), whereas respiration available for ADP phosphorylation was greater in cells assayed on an O2K versus an XFe96 (p < 0.001), due to a diminished coupling response to oligomycin in cells assayed on the XFe96 (p < 0.001). Platelet respiratory function is influenced by assay buffer composition and instrumental platform. Consideration of these factors should be made by investigators planning to use platelet respiratory function as a readout of cellular energetics.

Background Protein intake is essential to maximally stimulate muscle protein synthesis, and the amino acid leucine seems to possess a superior effect on muscle protein synthesis compared to other amino acids. Native whey has higher leucine content and thus a potentially greater anabolic effect on muscle than regular whey (WPC-80). This study compared the acute anabolic effects of ingesting 2 × 20 g of native whey protein, WPC-80 or milk protein after a resistance exercise session. Methods A total of 24 young resistance trained men and women took part in this double blind, randomized, partial crossover, controlled study. Participants received either WPC-80 and native whey ( n  = 10), in a crossover design, or milk ( n  = 12). Supplements were ingested immediately (20 g) and two hours after (20 g) a bout of heavy-load lower body resistance exercise. Blood samples and muscle biopsies were collected to measure plasma concentrations of amino acids by gas-chromatography mass spectrometry, muscle phosphorylation of p70S6K, 4E–BP1 and eEF-2 by immunoblotting, and mixed muscle protein synthesis by use of [ 2 H 5 ]phenylalanine-infusion, gas-chromatography mass spectrometry and isotope-ratio mass spectrometry. Being the main comparison, differences between native whey and WPC-80 were analysed by a one-way ANOVA and comparisons between the whey supplements and milk were analysed by a two-way ANOVA. Results Native whey increased blood leucine concentrations more than WPC-80 and milk ( P  < 0.05). Native whey ingestion induced a greater phosphorylation of p70S6K than milk 180 min after exercise ( P  = 0.03). Muscle protein synthesis rates increased 1–3 h hours after exercise with WPC-80 (0.119%), and 1–5 h after exercise with native whey (0.112%). Muscle protein synthesis rates were higher 1–5 h after exercise with native whey than with milk (0.112% vs. 0.064, P  = 0.023). Conclusions Despite higher-magnitude increases in blood leucine concentrations with native whey, it was not superior to WPC-80 concerning effect on muscle protein synthesis and phosphorylation of p70S6K during a 5-h post-exercise period. Native whey increased phosphorylation of p70S6K and muscle protein synthesis rates to a greater extent than milk during the 5-h post exercise period. Trial registration This study was retrospectively registered at clinicaltrials.gov as NCT02968888 .

Many individuals with psychotic symptoms have less complex language than healthy individuals. Word etymology is a lexical feature that has not yet been studied in clinical populations, but among healthy individuals, words of Old French origin are chosen over Germanic-origin words to convey formality (e.g. “inquire” vs. “ask”). Differences in language complexity among individuals with psychotic symptoms may relate to differences in etymological content in speech. Here, we determined the proportion of Germanic-origin word use and Old-French-origin word use in a large cohort of individuals with recent-onset psychosis or at clinically high risk for psychosis, hypothesizing that individuals with recent onset psychosis would have increased use of Germanic-origin words and decreased use of Old-French-origin words. This hypothesis was borne out, even after adjusting for sex, age, recruitment site, education, racial identity, and for a subset, IQ. Etymology proportions were associated with role but not social functioning in individuals with psychotic symptoms, consistent with the premise that they reflect speech formality. Understanding speech differences in the psychosis spectrum through the lens of etymology may lead to new interventions to improve role functioning. Lay Summary When people converse, there is a tendency to use more words of Old French origin (“inquire”, “intelligent”) as opposed to words of Proto-Germanic origin (“ask”, “smart”) when the conversation requires formality. In analyzing the speech etymology content of people experiencing psychotic symptoms, we found their speech to be less formal than healthy controls. We also found an association between less formal speech and reduced role functioning, implying that speech differences could impact academic and/or career success.

N-Acylethanolamines (NAEs) are bioactive acylamides that are present in a wide range of organisms. In plants, NAEs are generally elevated in desiccated seeds, suggesting that they may play a role in seed physiology. NAE and abscisic acid (ABA) levels were depleted during seed germination, and both metabolites inhibited the growth of Arabidopsis thaliana seedlings within a similar developmental window. Combined application of low levels of ABA and NAE produced a more dramatic reduction in germination and growth than either compound alone. Transcript profiling and gene expression studies in NAE-treated seedlings revealed elevated transcripts for a number of ABA-responsive genes and genes typically enriched in desiccated seeds. The levels of ABI3 transcripts were inversely associated with NAE-modulated growth. Overexpression of the Arabidopsis NAE degrading enzyme fatty acid amide hydrolase resulted in seedlings that were hypersensitive to ABA, whereas the ABA-insensitive mutants, abi1-1, abi2-1, and abi3-1, exhibited reduced sensitivity to NAE. Collectively, our data indicate that an intact ABA signaling pathway is required for NAE action and that NAE may intersect the ABA pathway downstream from ABA. We propose that NAE metabolism interacts with ABA in the negative regulation of seedling development and that normal seedling establishment depends on the reduction of the endogenous levels of both metabolites.

Background Neonatal diet impacts many physiological systems and can modify risk for developing metabolic disease and obesity later in life. Less well studied is the effect of postnatal diet (e.g., comparing human milk (HM) or milk formula (MF) feeding) on mitochondrial bioenergetics. Such effects may be most profound in splanchnic tissues that would have early exposure to diet-associated or gut microbe-derived factors. Methods To address this question, we measured ileal and liver mitochondrial bioenergetics phenotypes in male piglets fed with HM or MF from day 2 to day 21 age. Ileal and liver tissue were processed for mitochondrial respiration (substrate only [pyruvate, malate, glutamate], substrate + ADP, and proton “leak” post-oligomycin; measured by Oroboros methods), mitochondrial DNA (mtDNA) and metabolically-relevant gene expression analyses. Results No differences between the diet groups were observed in mitochondrial bioenergetics indices in ileal tissue. In contrast, ADP-dependent liver Complex I-linked OXPHOS capacity and Complex I + II-linked OXPHOS capacity were significantly higher in MF animals relative to HM fed piglets. Interestingly, p53, Trap1, and Pparβ transcript abundances were higher in MF-fed relative to HM-fed piglets in the liver. Mitochondrial DNA copy numbers (normalized to nuclear DNA) were similar within-tissue regardless of postnatal diet, and were ~ 2–3 times higher in liver vs. ileal tissue. Conclusion While mechanisms remain to be identified, the data indicate that neonatal diet can significantly impact liver mitochondrial bioenergetics phenotypes, even in the absence of a change in mtDNA abundance. Since permeabilized liver mitochondrial respiration was increased in MF piglets only in the presence of ADP, it suggests that formula feeding led to a higher ATP turnover. Specific mechanisms and signals involved with neonatal diet-associated differences in liver bioenergetics remain to be elucidated.