bluuebunny/crossref_metadata_2025_split huggingface dataset:
Myocardial Notch Signaling Reprograms Cardiomyoctes to a Conduction‐Like Phenotype
Authors: Rentschler Stacey , Yen Alberta , Lu Jia , Petrenko Nataliya , Patel Vickas V , Fishman Glenn I , Epstein Jonathan A 
Published: June 2021

Notch signaling has previously been shown to play an essential role in regulating cell fate decisions in many systems. We hypothesized that Notch may be involved in directing the progressive lineage restriction of cardiomyocytes into specialized conduction cells. In murine hearts where Notch signaling is activated within the myocardium from early development onwards, Notch promotes a conduction‐like phenotype as evidenced by ectopic expression of conduction system‐specific genes, as well as cell autonomous changes in cellular electrophysiology. Activation of Notch in newborn ventricular cardiomyocytes from Contactin2‐EGFP transgenic mice, which specifically labels conduction cells, demonstrates Notch‐induced changes in “chamber” ventricular cardiomyocytes consistent with a phenotypic switch to Purkinje‐like cells, including transcriptional changes, action potential prolongation and hyperpolarization of the resting membrane potential. Taken together, this suggests that Notch can instruct the differentiation of cardiac progenitors into specialized conduction‐like cells and that this plasticity remains in late‐stage cardiomyocytes, which has potential implications for engineering of specialized cardiovascular tissues.Grant Funding Source: Career Award for Medical Scientists Burroughs Wellcome Fund and K08 HL107449‐01 to SR, U01 HL100405‐1 to JAE
Using C. elegans to dissect fat and feeding regulatory pathways
Authors: Ashrafi Kaveh 
Published: June 2021

Fat regulation involves a complex interplay between feeding centers in the nervous system and the transport, storage and mobilization of fat in the periphery. Using mutagenesis and genome‐wide RNAi studies, we previously identified over 400 genes that regulate fat levels in C. elegans. These include components of neuroendocrine signaling, channels and transporters, transcription, metabolism and many genes with previously unassigned functions. Our findings highlight the shared ancestry of C. elegans and mammalian fat regulation. More importantly, this work identifies hundreds of new genes that participate in novel fat regulatory pathways. We have now undertaken the daunting task of understanding the modes of function of these fat regulatory genes within the context of intact organisms. These genes affect functions as diverse as metabolism and behavior.I will discuss our latest findings in dissecting the neural circuits that modulate feeding behavior and fat metabolism in C. elegans. These data will include roles for the C. elegans counterparts of human obesity genes as well as utility of C. elegans in identifying novel small molecule entities that modulate fat metabolism
Flavored milk is not associated with excess weight gain in children and adolescents
Authors: Egan Kara A , McCabe George P , Martin Berdine R , Hyner Gerald C , McCabe Linda D , Weaver Connie M 
Published: June 2021

In an effort to meet the dietary standards established in the HealthierUS School Challenge, numerous schools have eliminated flavored milk from cafeterias. We tested the hypothesis that intake of flavored milk would be associated with body weight and weight gain during a dairy intervention in 130 healthy and overweight 4th through 8th grade boys and girls. Using bi‐weekly dairy order records and self reported dairy consumption, we quantified milk consumption, flavored and white, over six months, and compared that with measured changes in height and weight from baseline. Both total (r = −0.17, p = 0.06) and flavored (r = −0.17, p = 0.05) milk consumption were negatively correlated with body weight at baseline. ANOVA showed no significant differences in weight gain during the follow‐up period between subjects who consumed less than 1 cup, 1 to 5 cups, or greater than 5 cups of flavored milk per week (0.50, 0.42, and 0.52 kg per month, respectively, p=0.704). Similar results were observed when assessing BMI. This study suggests that flavored milk should not be removed from school cafeterias because of the perception that it contributes to childhood obesity.Grant Funding Source: Dairy Management Inc.
Different analysis methods reveal different effect of national school lunch program on childhood obesity in the US
Authors: Xue Hong , Wang Youfa 
Published: June 2021

BackgroundThe impact of national school lunch program (NSLP) on the US childhood obesity epidemic is controversial, while NSLP is widely viewed critical to help school children improve dietary intake and develop lifelong healthy eating habits. Using national data, we studied the effects of NSLP on childhood obesity.MethodsNational Health and Nutrition Examination Survey (NHANES) 1999–2008 data of school‐age children (5–19 y) were used in a longitudinal‐type analysis framework accounting for unobserved effects with the application of difference‐in‐differences (DID) estimator. We calculated Healthy Eating Index (HEI, USDA 2005) scores using the 24‐hour recall data to evaluate the NSLP participants’ vs non‐participants’ dietary quality.ResultsOur analysis indicates significant influence of unobservables on the estimates of the effects of NSLP on BMI and obesity. NSLP participation was associated with increased BMI‐Z score by 0.1(SE=0.04, p<0.01), but the effect disappeared after corrected for unobservable effects. NSLP participation was positively associated with dietary quality (beta=1.04, SE=0.4, p<0.05) and total fruit consumption (beta=0.41, SE=0.07, p<0.01). Calories from solid fat, alcohol and added sugar were not higher for NSLP participants.ConclusionsOur analysis does not suggest an association between NSLP and childhood obesity. NSLP participants had a healthier diet.Grant Funding Source : NIH/NICHD (U54 HD070725‐01, 1R01HD064685‐01A1) and NIDDK (R01DK81335‐01A1)
Aging is a more significant determinant of hepatic DNA methylation patterns than a Western style diet
Authors: Park Lara Kristin , Saltzman Edward , Schnitzler Gavin , Yoon Byung Woo , Parnell Laurence D. , Lai Chao Qiang , Choi Sang-Woon 
Published: June 2021

We investigated how DNA methylation patterns change with aging and a Western style diet (WSD) in the liver. 2‐month old male C57BL/6 mice were randomized to control diet (CD) or WSD for either the following 6 (young) or 18 months (old). WSD is high in fat and low in fiber, vitamins and minerals. Methylation was investigated by the methylated DNA immunoprecipitation‐chip method on arrays covering all RefSeq genes and CpG islands. Modified t‐tests with the Benjamini‐Hochberg (BH) correction for multiple comparisons (α=0.05) were performed per probe for age and diet contrasts. Within n=713,168 probes, we found 17.0% and 8.7 % significant probes by age within CD and WSD, respectively. Ingenuity Pathway Analysis identified similar patterns by aging in WSD and CD with enrichment of genes in cancer, lipid metabolism, epigenetic regulation and neural function. Specifically, we observed hypermethylation of the Jumonji subunit Kdm6b and hypomethylation of Ras member Rap2a, cholesterol metabolism enzyme Hsd3b5, mitochondrial metabolism enzyme Suclg1 and multiple olfactory and vomeronasal receptors. No significant probes passed BH when comparing diets at the same age. Thus, aging has a greater effect than diet on hepatic DNA methylation patterns with enrichment of genes that may potentiate chronic disease development. Gene expression remains to be evaluated. Supported by NIH Grants R01 AG25834.Grant Funding Source: NIH
Identification of Human‐Flavonoid Targets Using an Innovative Approach Reveals New Mechanisms Involved in Their Anti‐Inflammatory Activities
Authors: Arango Daniel , Morohashi Kengo , Yilmaz Alper , Brahimaj Bledi , Kuramochi Kouji , Grotewold Erich , Doseff Andrea I. 
Published: June 2021

Flavonoids are dietary nutraceuticals with anti‐carcinogenic, chemopreventive, and anti‐inflammatory activities. We showed that apigenin, a flavone broadly found in fruits and vegetables, has anti‐inflammatory activity in vitro and in a mouse model of inflammation through the regulation of NF‐κB. However, its molecular mechanisms of action remain unknown. The goal of this study was to identify the human cellular targets of apigenin. We developed and implemented a novel approach coupling phage‐display with next‐generation sequencing (PD‐Seq) to identify human cellular targets of apigenin. Targets were validated using competition and pull down assays, with purified GST and GFP‐tagged proteins and cellular lysates. Development of a FRET‐nanosensor using a newly identified target provided insightful structure‐binding relationships of flavonoids. Molecular cell‐based studies showed that the apigenin target plays central roles in inflammation and reveals novel aspects on how nutraceuticals regulate immunity. Altogether, these results suggest that the innovative use of phage display in combination with next‐generation sequencing provides a robust method to identify novel targets of flavonoids. The findings reveal novel aspects on how nutraceuticals regulate biological activities providing better insights for the rational development of functional foods.Grant Funding Source : This work was supported by Grants RO1HL075040‐01 and NSF‐MCB‐0542244 to AID and by OSUPHPID fellowship to DA
Does changing the PUFA content of a high saturated fat meal influence postprandial lipid and lipoprotein expression in children with nonalcoholic fatty liver disease?
Authors: Mager Diana , Rodriguez-Dimitrescu Carla , Yap Jason , Mazurak Vera , Vine Donna , Jetha Mary , Ball Geoff 
Published: June 2021

BackgroundHyperinsulinemia leading to altered lipid metabolism induced by high saturated intakes may contribute to NAFLD. We hypothesized that consumption of a ↑saturated/↓PUFA meal would evoke a postprandial metabolic environment characterized by prolonged hyperinsulinemia, hypertriglyceridemia and hypercholesterolemia when compared to a ↑saturated/↓ PUFA meal in childhood NAFLD.MethodsWe studied 36 children (n=15 NAFLD; n=21 lean controls) following consumption of two meals: ↑saturated/↓ PUFA vs↑saturated/↓PUFA that were equivalent except for PUFA content (2.8% vs.4.9%). Blood for analysis of total‐HDL‐LDL‐cholesterol, triglycerides (TG), glucose, insulin, non‐esterifiedfatty‐ acids (NEFA), Apo‐B48, ApoB‐100, ApoC‐III and ALT (fasting) was collected at 0, 1, 3 and 6 hr. Data was analyzed using the trapezoidal method for area under the curve (AUC)/iAUC.Results: Mean age and BMI‐z (±SD) of participants was 13.4±2.8 and 2.3±0.4 (NAFLD); and 13.8±2.6 and 0.1±1.0 (lean). Mean insulin AUC (371 ±238 vs. 82±26) and iAUC (210 ± 179 vs. 41 ±20) for NAFLD was significantly higher than for controls (p<0.05). No significant differences in AUC/iAUC for insulin, TG, total‐and‐LDL cholesterol or ApoB48 was observed between meal types (p>0.05), although significant differences in iAUC NEFA (1.27±0.91 (↓PUFA) vs. 0.42±0.17 (↑PUFA), HDL‐cholesterol and ApoB‐100 by meal type in children with NAFLD and lean controls were observed (p<0.05).Conclusions: Children with NAFLD experience postprandial hyperinsulinemia and marked changes in lipid, cholesterol, and lipoprotein expression when compared to lean children when fed meals with high saturated fat with varying PUFA content.
Folic Acid Supplementation Alters Adipose Tissue Lipid Metabolism
Authors: Kelly Karen B , Proctor Spencer D , Field Catherine J , Jacobs Rene L 
Published: June 2021

Mandatory folate fortification polices in Canada and the United States has resulted in high levels of circulating folate in a large proportion of the population. At the same time, a trend toward increased energy intake and reduced energy expenditure has lead to an increased prevalence of obesity, characterized by an accumulation of TAG in adipose tissue. Folate plays an essential role in maintaining S‐adenosylmethionine (AdoMet), an important biological methyl‐donor. AdoMet functions in the formation of phosphatidylcholine from phosphatidylethanolamine catalyzed by the enzyme phosphatidylethanolamine N‐methyltransferase (PEMT). PEMT activity contributes to storage of triacylglycerol (TAG) in adipocytes.The objective of this study was to investigate the effect of dietary folic acid supplementation on adipose tissue lipid metabolism. Sprague Dawley rats were fed a high fat diet containing 0.75 mg or 7.5 mg folic acid for 12 weeks.Adipose tissue weight was significantly greater in rats fed excess folic acid. This was accompanied by an increased expression of genes involved in re‐esterification of fatty acids to glycerol, suggesting elevated TAG formation. Up‐regulation of genes involved in phospholipid biosynthesis supports increased storage of TAG in adipocytes upon folate supplementation.In summary, folate supplementation enhances TAG storage in adipose tissue of high fat diet‐fed rats.Grant Funding Source : CIHR, Food and Health Innovation Initiative
Dietary vitamin D3 at 50x the adequate intake increases apoptosis in the quadriceps of the female G93A mouse model of amyotrophic lateral sclerosis: a pilot study
Authors: Parkhomenko Egor , Milionis Angelica , Gianforcaro Alexandro , Solomon Jesse Adam , Hamadeh Mazen Jamal 
Published: June 2021

BackgroundWe previously showed that dietary vitamin D3 (D3) at 50x the adequate intake (AI) increased functional capacity in the transgenic G93A mouse model of amyotrophic lateral sclerosis (ALS), with females exhibiting signs of D3 toxicity. ALS is a fatal neuromuscular disease characterized by death of motor neurons in the CNS, muscle weakness and paralysis.ObjectiveIn this pilot study, we analyzed the quadriceps of G93A mice following dietary D3 supplementation at 50x the AI for contractile proteins (α‐actin; troponin C, trop C), inflammation (IL‐6), cell stress response (Hsp70), mitochondrial efficiency (UCP3) and apoptosis (CASP3 cleaved/pro ratio), mechanisms contributing to ALS pathology.MethodsStarting at age 25 d, 41 G93A mice were provided food ad libitum with either adequate (AI; 1 IU D3/g feed; 12 M, 11 F) or high (HiD; 50 IU D3/g feed; 10 M, 8 F) D3. At age 113 d, the quadriceps were analyzed for protein content. Differences were considered significant at P ≤ 0.10.ResultsIn females, HiD had 87% higher CASP3 vs AI (P = 0.084). Males had 59% higher α‐actin (P = 0.063), 21% lower trop C (P = 0.017), 42% lower IL‐6 (P = 0.099) and 58% higher Hsp70 vs females (P = 0.097).ConclusionDietary D3 at 50x the AI increases apoptosis in the quadriceps of female G93A mice, which could be due to D3 toxicity. (Supported by NSERC and Faculty of Health‐York U).Grant Funding Source : Supported by NSERC and Faculty of Health‐York U
Increased dietary saturated fat intake is negatively associated with compliance to exercise regimen and improvement in fitness parameters
Authors: Krishnan Sridevi , Gustafson Mary , Campbell Caitlin , Souza Elaine , Keim Nancy L 
Published: June 2021

ObjectiveTo determine if dietary intake of fat, sugar, and/or sodium affects improvement in aerobic fitness in response to a 6‐mo endurance and resistance training program in peri‐menopausal women.Methods18 women aged 42–52y underwent a 6 mo exercise intervention, working out 6 d/wk, 60 min/d. The program included daily aerobic activity at ≥ 50% of heart rate (HR) reserve and resistance exercises 3 d/wk. Monitors recorded heart rate during exercise, and compliance was calculated using the number of minutes above prescribed HR. Improvement in aerobic capacity was measured by VO2max at beginning and end of the study. Dietary intake was assessed by 24h recalls on 4 d in 1stmonth and 4 d in 6thmonth of intervention.ResultsTotal fat and saturated fat intake were negatively correlated to compliance (r = −0.501, p<0.05; r = −0.511, p<0.05), but added sugars, total sugars and sodium intake were not. Change in VO2max was positively correlated with compliance (r = 0.475 p<0.05), but negatively associated with saturated fat intake (r= −0.416, p<0.05).ConclusionOur observations on the association of fat intake, exercise compliance, and fitness improvement warrant further investigation to understand their underlying biological and behavioral significance. Funded by USDA CRIS 5306 51530 019 00DGrant Funding Source : USDA
Preventing excessive weight gain by encouraging healthy eating habits among adolescents in Brazil: a randomised community trial
Authors: Cunha Diana , Souza Bárbara , Pereira Rosangela , Sichieri Rosely 
Published: June 2021

ObjectiveEffect of an educational programme aimed to discouraging sweetened beverages and cookies, crackers and chips and encouraging fruits consumption, to prevent excessive weight gain.Methods20 classes were randomly assigned in to intervention or control. From 572 students enrolled, 399 students participated to the study (intervention: 10 classes with 207 individuals; control: 10 classes with 192 participants). There were nine sessions with nutrition education in the intervention group during the school year 2010. For all interventions, parents and teachers were included and received specific materials. The main outcome was the change in BMI. Intention‐to‐treat analysis was performed taking into account the cluster (classes) effect.ResultsBMI change was not significantly different between groups (p=0.22), however, consumption of sweetened beverages (mean difference= −0,20; 95% CI=−0,30; −0,11) and cookies (−1,35; 95% CI = −0,20; −0,75) showed a greater reduction and fruits consumption showed a greater incrase (0,17; 95% CI =0,01;0,34) in the intervention compared to control.ConclusionThe incentive to adopt healthy eating habits did not lead to changes in BMI, but changed dietary habits. Strategies based exclusively on the quality of diet is not enough to reduce weight gain.Trial Registration: clinicaltrials.gov. Identifier: NCT01046474.Funding: PAHEF, FAPERJ, CNPq.Grant Funding Source: Pan American Health and Education and Brazilian Research Council
Effects of flaxseed oil supplementation and FADS genotype on declarative memory abilities in toddlers
Authors: Cheatham Carol L 
Published: June 2021

ObjectiveDocosahexaenoic acid (DHA) is integral to neuronal function and subsequent cognition. Biosynthesis of DHA from its precursor alpha‐linolenic acid (LNA) is controlled by the FADS gene complex. Previously unobserved genetic differences may be a confound in studies of biosynthesis. This intervention was designed to determine the cognitive effects of providing substrate (flaxseed oil) to a system with little exogenous DHA intake (human toddlers).Methods16‐month‐olds (n=65) were enrolled in a 4‐month double‐blind intervention and randomized to flaxseed or corn oil. Parents squeezed 2400 mg of oil into their toddlers’ food daily for 180 days. Memory was assessed at 0, 7, 180, and 187 days using a non‐verbal declarative memory paradigm. Toddlers were exposed to 4 new imitation events and were tested for memory immediately, after 20 min, and after 7 days at baseline and end (total events = 8). Genotype at rs174575 on the FADS2 gene was determined.ResultsBaseline, 20‐min delay, and 7‐day delay results indicate no differences in memory performance when analyses are based on participant genotype. However, when analyses are completed with maternal genotype, children of homozygous recessive mothers earned lower scores on the memory tasks.ConclusionMaternal genotype needs to be considered instead of or in addition to the participants’ genotypes when assessing the effects of fatty acid supplementation.
Lactoferrin modulates lipopolysaccharide‐induced perturbations in gene expression in human fetal intestinal epithelial cells
Authors: Nonnecke Eric B , Lönnerdal Bo L 
Published: June 2021

Lactoferrin (Lf) functions in the orchestration of iron homeostasis, immune maturation, and proliferation of intestinal epithelial cells (IEC) in the breastfed infant. The exaggerated inflammatory response of enteropathogenic‐derived infantile diarrheas is potentiated, in part, by exposure to lipopolysaccharide (LPS). Lf sequesters the lipid A moiety of LPS with high affinity and may dampen the effects of overt TLR complex activation. In the present study, effects of Lf in the presence of LPS on the expression patterns of stress‐response genes were examined using a fetal IEC model. FHs74 cells were treated for 24 h with 400 μg/ml native (N)‐ and holo (H)‐ human (hLf), bovine (bLf), or commercially available bovine Lf (cbLf) with or without 1 μg/ml LPS. Cell viability was attenuated (> 30%) by LPS challenge, an effect that was ameliorated by the addition of Lf(s). Using PCR array profiling N‐hLf treatment was determined to differentially modulate LPS‐induced up‐regulation of numerous intermediates and products of the NFκB, MAPK, and Fas signaling pathways. Q‐PCR was employed to validate PCR array findings that Lf(s) mediates perturbations of multiple pro‐inflammatory cytokines due to LPS challenge including IL1, IL6, and IL8. Our findings suggest Lf may protect the neonatal intestinal epithelium against LPS by altering the expression of key regulatory genes associated with an LPS derived inflammatory response.Grant Funding Source: N/A
Recognition of Fungal β‐glucan by Human Neutrophil CR3 Results in Homotypic Aggregation and Neutrophil Extracellular Traps
Authors: Byrd Angel Shree’ , Yu Kebing , Johnson Courtney M. , Lavigne Liz M. , Salomon Arthur R. , Reichner Jonathan S. 
Published: June 2021

The armament of neutrophil‐mediated host defense against fungal and bacterial pathogens includes the formation of a lattice of DNA and microbicidal enzymes known as Neutrophil Extracellular Traps (NETs). The receptor mediated interactions and intracellular signaling events responsible for the elaboration of NETs in response to fungi are not known and were determined in this study. Recognition of the fungal cell wall component β‐glucan by human neutrophils resulted in rapid formation of cell aggregates and NET release. This response required fibronectin + β‐glucan demonstrating a role for CD11b/CD18. CD11b/CD18 blockade obviated this response which did not require production of oxidative metabolites. Downstream signaling events were determined using a global phosphoproteomic approach. Upon fibronectin + β‐glucan treatment, 46 phosphopeptides were upregulated and 15 were downregulated as compared to fibronectin alone. Validation revealed a functional role for ERK (Y204). NET formation to Candida albicans hyphae was also shown to be dependent on CD11b/CD18 recognition of hyphal β‐glucan, occur in the absence of reactive oxidant species, and depend on ERK. This study successfully identified a key receptor ligand interaction that induces NET formation and elucidates the global tyrosine phosphoproteome of human neutrophils to gain a better understanding of innate immune responses to fungal pathogens.NIH GM066194