bluuebunny/crossref_metadata_2025 huggingface dataset:
AMPK regulates contraction‐induced glucose uptake in situ but not ex vivo
Authors: Fentz Joachim , Pehmøller Christian , Treebak Jonas Thue , Kjoebsted Rasmus , Viollet Benoit , Wojtaszewski Jørgen
Published: June 2021

The use of transgenic models studying the role of 5′AMP‐activated protein kinase (AMPK) in contraction‐induced glucose uptake (CTGU) has led to inconclusive results. Drawbacks of using less appropriate models displaying incomplete abrogation of AMPKα catalytic activity may explain these differences. The purpose of this study was to determine whether a total lack of both AMPK α1 and α2 catalytic subunits abolishes CTGU in muscle under ex vivo and in situ conditions.

We generated a skeletal muscle specific AMPK‐α1 and‐α2 double knock‐out (dKO) mouse model. Electrical stimulation was applied directly to the muscle (ex vivo, 10 min (either 1 or 2 second trains/15 seconds)) or to the sciatic nerve (in situ, 15 min (1 train/second) +30 min recovery) to stimulate contraction. Muscle glucose uptake was measured using radioactively labeled isotopes. Ex vivo CTGU in AMPKα WT and dKO soleus and extensor digitorum longus (EDL) muscles was similar between genotypes. Equal force production was registered under all of the above conditions. Contrary to the ex vivo data, the CTGU in situ was impaired by ~50% in the tibialis anterior, soleus and EDL muscles of AMPKα dKO mice compared to WT mice (p<0.05). Basal non stimulated glucose uptake was similar between genotypes, both ex vivo and in situ.

The results suggest that AMPK's role in CTGU may be modulated by a factor(s) related to muscle perfusion and/or stimulation methodology.
Gravin Scaffolding Protein Mediates Signaling in High Fat Diet Model
Authors: Fan Qiying , Diaz Andrea C Diaz , Wijaya Cori S , Yin Xing , Singh Sonal , McConnell Bradley K
Published: June 2021

Atherosclerosis is an inflammatory response principally in the walls of arteries contributing to cardiovascular related mortality, which can be induced by diets rich in fats. Gravin (AKAP12), an A‐kinase anchoring protein (AKAP), is targeted to specific intracellular locations with protein kinase A (PKA) as well as other signaling molecules. It has been shown that gravin can regulate cholesterol efflux and LDL receptor expression via SREBPS activation. The purpose of this study was to determine whether the absence of gravin mediated signaling would prevent atherosclerosis induced by a high fat diet. Five week‐old wild‐type (WT) and gravin‐knockout (KO) mice were subjected to high fat diet (HFD) or normal diet (ND) for 16 weeks. Lipid profile was measured via HPLC and arterial blood pressure was measured via a Millar catheter. Cholesterol, triglyceride and VLDL levels as well as systolic and diastolic pressure were significantly decreased in KO compared to WT treated with HFD (p<0.0001); no differences were observed between KO and WT with ND. This data indicates that the absence of gravin mediated signaling is able to decrease lipid metabolism as well as to lower the blood pressure in response to HFD.
Upregulation of mitophagy in enterocytes during intestinal ischemia in rats
Authors: Kalogeris Theodore John , Wang Meifang , Korthuis Ronald J.
Published: June 2021

Intestinal ischemia reperfusion (I/R) elicits decreases in mitochondrial respiratory activity and membrane potential, as well as an increase in the mitochondrial‐dependent apoptotic pathway in intestinal enterocytes. However the precise roles of ischemia versus reperfusion in post‐ischemic mitochondrial dysfunction in the gut are unclear. In these studies we have begun to examine the kinetics of mitochondrial dysfunction during the ischemic period. Intestinal enterocytes were isolated from rats after graded periods (up to 40 min) of occlusion of the superior mesenteric artery, and mitochondrial membrane potential (Ψ) and markers of mitophagy and mitochondrial mass were measured. Mitochondrial Ψ (measured by TMRE fluorescence), showed a slight increase by 10 min, but was significantly decreased by 20–40 min ischemia. The autophagosome marker, LC3, showed a time‐dependent increase in the LC3‐II/LC3‐I ratio from 20–40 min ischemia, and there was a shift in the relative distribution of parkin from cytosol to mitochondria by 40 min. Ischemia also elicited cytosolic release of cytochrome c, and decreases in mitochondrial Mfn2 and porin by 40 min. These results indicate that post‐ischemic mitochondrial dysfunction in intestinal enterocytes is preceded by changes in mitochondrial function even prior to reperfusion. Supported by NIH AA‐014945 and HL‐095486.
Characterization of Different Modes of Ca2+ Uptake under Physiological Conditions in Heart Mitochondria
Authors: Tewari Shivendra , Pradhan Ranjan K , Bazil Jason N , Camara Amadou KS , Stowe David F , Beard Daniel A , Dash Ranjan K
Published: June 2021

Cardiac mitochondria can act as a significant Ca2+ sink and shape cytosolic Ca2+ signals that affect various cellular processes such as energy metabolism and excitation‐contraction coupling. However, mitochondrial Ca2+ uptake mechanisms under physiological conditions are not well understood. Characterization of these mechanisms is crucial in developing a quantitative understanding of Ca2+ transients in the heart. For this purpose, we performed Ca2+ uptake experiments in isolated guinea pig heart mitochondria at physiological concentrations of extra‐matrix Mg2+ (0–2 mM MgCl2) and Ca2+ (0–0.6 mM CaCl2) with 1 mM EGTA. Experimental data were quantified using an integrated model of mitochondrial bioenergetics and cation handling, including our recently developed models of mitochondrial Ca2+ uniporter and Ca2+ sequestration system. Our model analyses reveal the existence of two Ca2+ uniporters, a fast CU (fCU) and a slow CU (sCU), with contrasting differences in their Ca2+ and Mg2+ sensitivities. fCU is a high affinity low capacity Ca2+ uniporter, while sCU is a low affinity high capacity Ca2+ uniporter. Both uniporters are inhibited by extra‐matrix Mg2+. The Mg2+ binding affinity of fCU is higher as compared to that of sCU.
The genetic association of polymorphism rs2383207 in chromosomal locus 9p21, with coronary artery disease
Authors: Rizk Nasser , Arzemohmmed Fazeela Dadbakhsh , Ebrahim Samah Ebrahim , El‐Menyar Ayman Ahmed
Published: June 2021

Background

The 9p21.3 locus was associated with coronary artery disease (CAD). The aim of this study was to investigate the association between rs2383207 in chromosomal locus 9p21 with coronary artery disease based on positive angiographic findings [case group] compared with subjects without angiographic lesions [control group] in Arab subjects.

Methods

Blood was drawn from a total of 176 patients and 210 control subjects. Genotyping of rs2383207 was performed by the 5’ nuclease assay using TaqMan assay.

Results

The studied SNP was in Hardy–Weinberg equilibrium. CAD patients had significantly higher frequency of hypertension, higher glucose, CK‐MB and troponin level than controls. The frequency distribution of the genotype (rs2383207, G>;A) revealed that (64.4%), (54.3%), had GG and (32.1%), (37.9%) had GA, and (3.5%), (7.8%) had AA among CAD and control group, respectively with P value=0.137. The carriers of G allele of rs2383207 variant had a significant association with the risk of getting CAD, and the odds ratio “OR” and 95% confidence interval (95%CI) was 1.53 (1.16–2.24) times among CAD patients, with p value =0.04. To estimate the size of this association, the carriers of GG vs. GA+AA genotype of rs2383207 had the odds ratio and 95% CI of getting CAD with lesion (1.5, 1.1–2.9, p value=0.032).

Conclusion

Our finding confirmed a strong association of the rs2383207 in 9p21.3 locus with CAD in Arab populations.
Metabolic profile Assessment in offspring of wistar rats treated during pregnancy and lactation with sodium selenite
Authors: Kluck George Eduardo Gabriel , Melo Roberto Laureano , Império Güínever Eustáquio , Reis Luís Carlos , Cortes Wellington Silva
Published: June 2021

The essential micronutrient selenium has been linked to property exhibiting insulin‐mimetic effects in metabolism. On the other hand, some studies shows that selenium supplementation at high doses can increase the incidence risk of diabetes. Thereby, due to an inverse correlation between the serum selenium concentration and the progressing gestational period, the objective here was evaluating offspring metabolism of female Wistar rats treated during pregnancy and lactation with sodium selenite. For this purpose, two groups (n=6 each and ~ 250g) of female Wistar rats were underwent to the following treatments: isotonic saline or sodium selenite (1mg/kg, p.o). Our results indicate that treated group, after weaning, had higher expression of type 2 deiodinase in brown adipose tissue than control. Moreover, the programmed offspring had higher milk intake and had an increased lipid oxidation. Therefore, we conclude that selenium supplementation during pregnancy and lactation alters offspring metabolic profile. In this context, we conjecture that possible selenium induced insulin resistance in offspring can be caused by thyroid hormones genomic and non genomic actions.

Support: FAPERJ & CNPq.
Preconditioning of cardiac stem cells by electrical stimulation induces cytoprotection against oxidative stress through release of connective tissue growth factor by miR‐378 downregulation
Authors: Kim Sun Wook , Kim Ha Won , Huang Wei , Wang Yigang , Ashraf Muhammad
Published: June 2021

Survival of stem cells following transplantation in the infarcted myocardium is a critical issue for the cell‐based therapy and preconditioning (PC) of stem cells is a method for cytoprotection. In this study, we investigated the cytoprotective effect of PC with electrical stimulation (EleS) on cardiac stem cells (CSCs) survival. Sca‐1+ CSCs were isolated from male C57BL6 mice hearts. PC of CSCs with EleS (EleSCSCs) was carried out for 3 h at 1.5 V followed by exposure to H2O2. Cytoprotective effects and cell adhesion ability were significantly increased by EleS as evaluated by TUNEL, lactate dehyrogenase release assay and adhesion assay as well as Sry gene analysis in vivo. EleS increased phosphorylation of AKT, FAK and GSK3β, and decreased pro‐apoptotic protein caspase‐3 cleavage. Pretreatment with Wortmannin, a PI3K inhibitor, and FAK inhibitor‐14 abolished the pro‐survival effects of EleS. Importantly, we found that connective tissue growth factor (Ctgf) is a key determinant for EleS‐induced CSC survival and adhesion. Furthermore, we identified miR‐378 is a potential negative regulator for Ctgf expression in EleSCSCs.

In conclusion, EleS enhanced CSC survival in vitro and in vivo through AKT/FAK/CTGF/miR‐378 signaling cascade, being suggested as a novel preconditioining strategy.

This work was supported by National Institutes of Health grant, [HL087246 to M.A.].
The metabolic fate of anthocyanins in humans
Authors: de Ferrars Rachel Margaret , Cassidy Aedin , Curtis Peter , Raheem Kalowole Saki , Zhang Qingzhi , Kay Colin D.
Published: June 2021

High intakes of anthocyanins (ACN) have been linked to decreased cardiovascular disease risk. However, due to their apparent low bioavailability, it has been postulated that phenolic degradation products of ACNs may be responsible for their bioactivity. We examined the metabolic fate of ACNs following a single dose and short‐term (12 wk) exposure to an elderberry extract, to establish the differential effects of acute v short‐term exposure on metabolism. Biological samples from a 12 wk intervention study (n=15 postmenopausal women, 500 mg/day elderberry ACNs) were analysed for ACN metabolites using HPLC‐MS/MS. 29 metabolites were identified in urine (12 ACN and 17 phenolic metabolites) and 21 in plasma (4 ACN and 17 phenolic metabolites). ACNs reached concentrations of 0.55±0.05 μM/mM creatinine in urine after 3h and 0.034 μM in plasma after 2h. The phenolic degradation products and their metabolites reached concentrations of 31.15±2.37 μM/mM creatinine in urine after 3h and 1.24 μM in plasma after 2h. The profile of metabolites was not significantly different after 12 wks of intake. These results indicate that ACNs are extensively metabolised in vivo, with little suggestion of plasma accumulation following repeated exposure. The reported bioactivity of ACN most likely relates to the high concentrations of circulating phenolic metabolites. Research support: Norwich Medical School, University of East Anglia.

Grant Funding Source: Department of Nutrition, Norwich Medical School, University of East Anglia.
EPA promotes fatty acid storage and thermogenic capacity in primary differentiated mouse subcutaneous adipocytes
Authors: Zhao Ming , Chen Xiaoli
Published: June 2021

Adipose tissue dysfunction has been associated with lipid dysregulation and insulin resistance. Compared with visceral fat, subcutaneous adipose tissue has been recently emerged as a lipid storage and thermogenic depot, playing a beneficial role in lipid homeostasis and insulin resistance. N‐3 PUFAs are known to have a role against hyperlipidemia and insulin resistance. Herein, we determined if EPA promotes beneficial metabolic activities of subcutaneous adipocytes. Primary stromal‐vascular (SV) cells isolated from mouse inguinal adipose tissue were cultured and induced to differentiate into adipocytes. EPA was added to SV cell culture during differentiation. On day 8 of differentiation, glucose metabolism, fatty acid storage, and thermogenic capacity were assessed. When compared to controls, EPA‐treated subcutaneous adipocytes had increased levels of basal glucose uptake and GLUT4 mRNA expression, but decreased glucose and lactate levels in the cultured media, suggesting decreased glycolysis. To assess fatty acid storage capacity, lipolysis, fatty acid uptake, and TAG synthesis were determined. We observed that EPA‐treated adipocytes had significantly decreased glycerol release and downregulation of HSL and ATGL gene expression, while markedly increased expression of genes involved in fatty acid uptake, CD36 and TAG synthesis, GPAT1 and GPAT3. Moreover, EPA treatment led to a significant increase in the expression of thermogenic genes including PGC1α, COXiv, UCP1, UCP2 and UCP3 as well as adiponectin expression. We conclude that EPA enhances fatty acid storage and energy dissipation capacity in subcutaneous adipocytes, contributing in part to its metabolic benefits.

Grant Funding Source: NIH
Gut microbiota biofilm disruptions by Giardia: Pathology in human enterocytes and germ‐free mice
Authors: Beatty Jennifer , Akierman Sarah , Rioux Kevin , Beck Paul , McKnight Webb , Feener Troy , Wallace John , Buret Andre
Published: June 2021

Giardia duodenalis may cause post‐infectious Irritable Bowel Syndrome (PI‐IBS). Mechanisms underlying PI‐IBS are unknown, but disruptions in the intestinal microbiota of IBS patients are documented. The intestinal microflora exists as biofilms, and we hypothesized that disruptions in these communities may lead to PIIBS.

Aim

To study effects of Giardia on the species, and pathogenic profile of microflora biofilms.

Methods

Microbiota from human colonic mucosal biospies were cultivated as biofilms, and assessed in CaCo2 monolayers and germ‐free (GF) mice.

Results

Giardia alters species profiles in microflora biofilms, and promotes planktonic growth via exopolysaccharide breakdown. Monolayers exposed to Giardia‐treated biofilms showed altered occludin and TLR‐4 expression, and apoptosis. GF mice humanized with Giardia‐treated biofilms show mucosal granulomas and increased mast cell tryptase.

Conclusion

Giardia disrupts human microbiota biofilms, which disturb epithelial integrity and TLR‐4 expression, and cause intestinal pathophysiology in GF mice. The data illustrate novel pathways employed by pathogens that may lead to PI‐IBS. Supported by NSERC.
Developing the Nation's Human Capital in STEM for Tomorrow
Authors: Ferrini‐Mundy Joan
Published: June 2021

The National Science Foundation (NSF) sponsors basic research and the development of human capital across all disciplines of science, technology, engineering, and mathematics (STEM). The agency is committed to identifying and developing talent in all demographics through coordinated and sustained programmatic efforts and innovation in instruction, curriculum, and learning opportunities. As the content, nature, and practice of science are transformed by new global challenges, big data, and interdisciplinarity, the NSF seeks to transform the STEM learning of tomorrow's scientists and citizens. I will describe key investment strategies by the agency to achieve this objective, with examples from funded projects, and explore new opportunities that can be leveraged to build an innovative and supportive learning ecosystem that is aligned with technological and social changes.
Photo assisted 24‐hour dietary recalls in adults with intellectual and developmental disabilities
Authors: Ptomey Lauren Taylor , Herrmann Stephen , Lee Jaehoon , Sullivan Debra , Donnelly Joseph
Published: June 2021

OBJECTIVE

Dietary assessment of adults with intellectual and developmental disabilities (IDD) is challenging due to their limited cognitive abilities. The objective of this study was to determine if photo‐assisted 24‐hour dietary recalls improve the assessment of energy and macronutrient intake in adults with IDD.

METHODS

Participants used a tablet computer to take photos of all food and beverages consumed before a standard dietary recall. After a standard multiple‐pass 24‐hour diet recall was conducted the photos were reviewed with the participant and differences were recorded. The standard recall and the photo‐assisted recall were entered separately into Nutrition Data System for Research (NDSR) and compared using mixed modeling.

RESULTS

30 eating occasions were entered from 10 participants (50% female; mean age 31.0 ± 12.3 years). Participants captured photos for 62% ± 28% of all recorded eating occasions. The photo‐assisted recalls reported greater energy intake per eating occasion than the standard recalls (543.9 ± 227.7 kcals vs. 352.5 ± 277.7 kcals, p=0.005) and a greater intake of fat (0=0.021) protein (p=0.012) and carbohydrates (p=0.006).

CONCLUSION

Photo‐assisted 24‐ hour recalls provided a significant increase in total calories and macronutrient content compared to a standard 24‐hour recall and may improve the dietary assessment of adults with IDD.

Grant Funding Source: NIH: DK083539
Chemical analysis of omega‐3 (n‐3) fatty acid supplements for the Dietary Supplement Ingredient Database (DSID)
Authors: Andrews K W , Roseland J M , Middleton A , Solomon A , Palachuvattil J , Dang PT , Holden J M , Pehrsson P R , Dwyer J T , Bailey R L , Betz J M , Costello R B , Saldanha L G , Hardy C J , Gahche J J , Emenaker N J , Douglass L
Published: June 2021

A study of a national sample of n‐3 fatty acid dietary supplement products included multiple lots of 83 fish oil, flax oil and fish/plant oil blends purchased from retail and direct channels. Products were analyzed for six n‐3 fatty acids using validated methods and certified reference materials, and data were compared to label information. Preliminary results show mean % differences from label within 10% of label claims for the major n‐3 fatty acids: alpha‐linolenic acid (ALA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). The minor n‐3 fatty acids, docosapentaenoic acid (DPA) and stearodonic acid (SDA) each add about 7–8% to the EPA+DHA totals for fish oil products. Some lab methods have additional fatty acids included in the total. Product labels listed a total n‐3 fatty acid amount 65% (n=54) of the time, with a variety of calculations indicated. The optimum number of n‐3 fatty acids to include in the DSID totals for comparison to labels is being investigated. National estimates for n‐3 fatty acids will be included in the next release of the DSID, which currently reports estimates of ingredients in multivitamin dietary supplements (http://dsid.usda.nih.gov). Funding: ARS/USDA & ODS/NIH Y1CN501006
The role of C‐3 α epimer of 25‐hydroxyvitamin D on maintenance of bone mineral density
Authors: Bianchini Christina E. , Lavery Paula , Agellon Sherry , Weiler Hope A.
Published: June 2021

The function of C‐3 α epimer (C‐3 Epi) of 25‐hydroxyvitamin D (25(OH)D) in vivo is unknown. In in vitro studies, C‐3 Epi is less potent in stimulating calcium transport but equivalent in suppressing parathyroid hormone. The objective was to compare C‐3 Epi to 25(OH)D and cholecalciferol in maintaining bone mineral density (BMD). Adult Sprague Dawley rats (12 weeks, n=36 female n=36 male) were randomized to: control AIN93‐M diet (2 IU vitamin D3/g food) or experimental diets for 8 weeks: C‐3 Epi at 0.5 and 1 IU/g food and a 25(OH)D group (0.5 IU/g food) reference group. Body weights and food consumption were measured weekly. Blood samples were collected at week 0, 4 and 8 as well as whole body dual‐energy X‐ray absorptiometry (DXA; QDR 4500A, Hologic). Differences were tested using a mixed model ANOVA. There were no differences among groups for weight or dietary intake. In females, the 1 IU C‐3 Epi group had higher whole body BMD compared to the cholecalciferol and 25(OH)D groups (Table 1); similar differences were observed in males (data not shown). These preliminary data suggest that C‐3 Epi is not detrimental to growth or bone. Future analyses including regional DXA and micro computed tomography plus biomarkers of bone metabolism are required to clarify the physiological responses. Research supported by NSERC and Dairy Farmers of Canada.
1 The use of an ad libitum higher‐protein, low‐glycemic index diet in overweight children: the Diogenes Study
Authors: Astrup Arne , Damsgaard Camilla T , Papadaki Angeliki , Jensen Signe M , Dalskov Stine‐Mathilde , Hlavaty Petr , Saris Wim H.M. , Martinez J. Alfredo , Handjieva‐Darlenska Teodora , Rohr‐Andersen Malene , Stender Steen , Larsen Thomas M , Mølgaard Christian , Michaelsen Kim F
Published: June 2021

Effect of higher‐protein, low GI diet on body weight and cardiovascular risk factors was studied in 253 children (5–18 yrs) of overweight/obese parents. Families were randomized to 1 of 5 ad lib diets for 6 months: high protein (HP) or low protein (LP) with either high GI (HGI) or low GI (LGI); or control. In 6 centres children received dietetic instruction, in 2 centres diet adherence was ensured by free provision of all foods at study shops. Measurements conducted month 0, 1 and 6. Dietary protein content was slightly higher in HP than LP (20.7±0.7 vs 17.9±0.7E%, P=0.004), with greater difference at shop centres (25.1±1.2 and 17.0±1.1 E%, P<0.001). GI was reduced by 3.5 points in LGI vs HGI (P<0.001). HP produced 2.6 cm (P=0.007) greater reduction in waist circumference and 0.25 mmol/L (P=0.003) lower serum LDL cholesterol than LP. In the supermarket centres HP resulted in reduction in BMI z‐scores (P=0.01), waist circumference (3.5 cm, P=0.003), diastolic blood pressure (0.8 mmHg, P=0.007), MAP (0.7 mmHg, P=0.008), insulin (P=0.02), HOMA‐IR (P=0.02) and HDL cholesterol (P=0.04) vs LP. Increased protein intake improved cardiovascular markers in high‐risk children, particularly with most intensive intervention.

EU FOOD‐CT‐2005–513946/ www.diogenes‐eu.org
Triiodothyronine‐Induced Hepatocyte Proliferation Requires β‐Catenin
Authors: Fanti Maura , Singh Sucha , Stoops Jhon , Columbano Amedeo , Monga Satdarshan P.S.
Published: June 2021

Triiodothyronine (T3) exerts its action in inducing cell growth and differentiation by binding to their nuclear receptors. T3 is also a potent mitogen for differentiated hepatocytes that is distinct from growth factors. It was shown by immunohistochemistry that T3 administration induces cyclin D1 and expression of β‐catenin. Indeed, while T3 induced hepatocyte proliferation in wild‐type mice (WT), no proliferative response to T3 was observed in hepatocyte‐specific β‐catenin knockout mice (KO). T3 treatment of rat and mouse hepatocytes induced β‐catenin activity as assessed by TOPflash reporter assay. Furthermore, in vivo experiments demonstrate that T3 treatment does not activate the canonical Wnt signaling or disrupt E‐cadherin‐β‐catenin complex but leads to increased Ser675‐β‐catenin. As this phosphorylation is PKA‐mediated, we next treated T3‐fed mice with PKA inhibitor H89. Concomitant administration of T3 and H89 led to a significant decrease in cyclin‐D1 expression and in turn reduced T3‐mediated hepatocyte proliferation. Thus β‐catenin is essential for T3‐ mediated mitogenic response in hepatocytes and may have therapeutic implications in liver insufficiency.
Translational Nucleotide Excision Repair in Triple Negative Breast Cancer
Authors: Reed Eddie
Published: June 2021

Triple negative breast cancer (TNBC) is generally diagnosed by immunohistochemical methods that result in negative staining for the estrogen and progesterone receptors, and human epidermal growth factor receptor 2, which are targets for the most successful treatments for breast cancer. African American women are particularly affected by the disease, and among those in this ethnic group who develop breast cancer there is a 20 to 40 percent chance of it being triple‐negative. Although the use of DNA damaging agents is standard therapy in the treatment of multiple classes of cancers, growing studies suggest that pathways that seek to repair DNA damage might also be fruitful targets. This lecture will address modulation of DNA damage and DNA repair pathways in treating TNBC, with a particular focus on nucleotide excision repair.
Lysophospholipid GPCRs in medical therapeutics and disease mechanisms
Authors: Chun Jerold
Published: June 2021

Lysophospholipids that include lysophosphatidic acid (LPA) and sphingosine 1‐phosphate (S1P) influence a spectacular range of cellular processes that affect virtually every vertebrate cell type. Their effects are mediated by a family of cell‐surface GPCRs designated by their receptor names LPA1–6 and S1P1–5, and the gene names LPAR1–6, S1PR1–5. These receptors couple to all major G proteins and consequently activate a diverse range of downstream pathways. New ways of measuring the interaction of a lipid with its cognate receptor through the use of back‐scattering interferometry (BSI) will be presented. In addition, medically relevant consequences of modulating lysophospholipid receptors for both therapeutic benefit – as evidenced by the actions of an S1P receptor modulator called fingolimod (Gilenya), the first oral medicine for treating multiple sclerosis – and mechanistic understanding of diseases – as illustrated through studies on LPA receptors in the etiology of hydrocephalus – will be discussed.
Effect of web‐based self‐reporting of dietary intake on college students’ self‐efficacy
Authors: Leibowitz Joshua , Cunningham Britni , Dols Amanda , Dumm Emily , Eng Angelica , Franke Kate , Gross Alison , Helinek Jonathan , Indig Jonathan , O'Connor Alexander , Russell Timothy , Sharma Aroon , Sahyoun Nadine
Published: June 2021

The objective of the study was to determine the effect of an online diet‐tracking tool on college students’ self‐efficacy, specifically pertaining to their fruit and vegetable intake. A convenience sample of students was recruited and administered a self‐efficacy survey online before and after an 8 week intervention in which participants were asked to track their dietary intake online. Participants were assigned to a control group and 2 experimental groups. Experimental group 1 (n=41) had access to the website to track their intake without reminder emails and experimental group 2 (n=48) had access to the website with weekly reminder emails. A control group (n=62) was not given access to the intervention website. Within the control group, it was found that there was a significant decrease in the self‐efficacy of females (p= 0.020), but not for males (p= 0.069) However, within both experimental groups, the difference in pre‐ and post‐test self‐efficacy scores for females was not significant (p= 0.512). While the intervention did not show a general increase in participants’ self‐efficacy, it can be correlated with an increase in female self‐efficacy scores from a negative change to no change; therefore attenuating some of the observed sex differences.

Research was supported by the Gemstone Program at the University of Maryland, College Park, MD
Chronic immune activation in Zimbabwean infants mediates the influence of clinical morbidity on child growth
Authors: Jones Andrew David , Prendergast Andrew J , Rukobo Sandra , Chasekwa Bernard , Mutasa Kuda , Ntozini Robert , Mduduzi Mdu NN , Stoltzfus Rebecca J , Humphrey Jean H
Published: June 2021

This study aims to determine the extent to which chronic immune activation (IA) mediates the influence of clinical morbidity on child growth. We conducted a case‐control study of 202 Zimbabwean infants who were stunted (height‐for‐age Z‐score (HAZ) <‐2) or non‐stunted (HAZ>;‐0.5), respectively, at 18 months and for whom morbidity histories and cryopreserved plasma had been collected at 6 weeks, and 3, 6, 12, and 18 months of age. We measured biomarkers of immune activation (CRP, AGP, IL‐6) and growth hormone axis (IGF‐1) by ELISA. Using generalized estimating equations, report of recent diarrhea (P=0.09), cough (P=0.35), or fever (P=0.18) was not strongly associated with child HAZ. Diarrhea was, however, negatively associated with IGF‐1 (P<0.001) and positively associated with AGP (P=0.001); IGF‐1 suppression following diarrhea did not recover at subsequent visits. Report of cough and fever were similarly negatively associated with IGF‐1 (P<0.01) and positively associated with CRP, AGP and IL‐6 (all P<0.001) levels. Structural equation models further indicated that IA mediates the effect of morbidity on IGF‐1 levels and child growth. The influence of morbidity on growth deficits may function primarily through episodic contributions to the chronic IA that is observed in both stunted and non‐stunted children in this population. These findings provide evidence of an important role for chronic inflammation and the growth hormone axis in the pathogenesis of stunting.
Novel metabolic and non‐metabolic mechanisms influencing bioavailability of vitamin E
Authors: Bardowell Sabrina , Ding XinXing , Parker Robert
Published: June 2021

Bioavailability of the antioxidant vitamin E is vitamer‐dependent, and in part involves hepatic catabolism via side‐chain oxidation and urinary excretion. Here we report new insights into both enzymatic and non‐enzymatic elimination pathways, using mice with either global disruption in Cyp4f14 (a murine vitamin E hydroxylase) or liver‐specific disruption in cytochrome P450 reductase (L‐CPR). The substantial deficit in vitamin E metabolism observed in both models was counterbalanced by increased fecal elimination of unchanged tocopherols in supplemented mice, revealing a major mechanism limiting tissue vitamin E accumulation. This mechanism may account for the observed reduction in bioavailability of all forms of vitamin E at elevated intakes in humans. L‐CPR mice, devoid of all vitamin E oxidase activity in the liver, still excreted substantial amounts of ω‐oxidation metabolites in urine and feces. Analysis of microsomes from other mouse tissues revealed vitamin E hydroxylase activity in adipose tissue, brain, and kidney, but not lung. Appreciable activity was observed in the small intestine, the portal of entry. Microsomes from human liver, intestine and kidney, but not lung, all exhibited activity, illustrating both central (liver) and organ‐specific control over the types and amounts of tocopherols that accumulate in tissues. Funded by NIH DK‐007158 and DK‐067494.
Relationship of plasma levels of C‐reactive protein and adiponectin and change of lean body mass in obese postmenopausal women supplemented with safflower oil
Authors: Cole Rachel M , Andridge Rebecca , Belury Martha A
Published: June 2021

Postmenopausal obese women may lose up to 500 g of lean body mass each year after the onset of menopause. Supplementation with linoleic acid‐rich safflower oil (8 g tid) for 16 weeks decreased C‐reactive protein (CRP) while increasing lean body mass and adiponectin levels1. This study evaluated the relationship of baseline levels and magnitude of change of CRP and adiponectin with change of lean body mass in obese postmenopausal women with type 2 diabetes supplemented with safflower oil. After controlling for baseline levels of lean body mass, there was no relationship between baseline CRP and change of lean body mass. However, there was a significant inverse association between change in (log) CRP and the change in lean body mass meaning a 10% decrease in CRP was associated with a 181 g increase in lean body mass (95% CI: 12–351, p=0.04). There was a significant association between baseline adiponectin and the change in lean body mass: For every one unit increase in baseline adiponectin there was a 222 g increase in lean body mass (95% CI: 26–420, p=0.03). We found no association between the change of adiponectin and change of lean body mass. Next, we hope to determine the interactions between safflower oil, CRP, adiponectin on improved muscle function in postmenopausal women. Supported by an unrestricted gift (Cognis, Corp), the Ohio Agr. Res. Dev. Ctr. & the Kennedy Professorship.
DASH Accordance among Older Hispanics: Comparison of Three DASH Scores
Authors: Sarkar Divyani , Tangney Christy Clare , Staffileno Beth A , Foley Sharon , Bacon Cheryl A , Wilbur JoEllen
Published: June 2021

Hypertension prevalence is higher among non‐Hispanic whites compared to Hispanics, yet fewer Hispanics receive treatment. There are several approaches to assess accordance to the Dietary Approaches to Stop Hypertension (DASH) plan and these rarely include Hispanics. A food frequency questionnaire was used to score and compare three DASH scoring paradigms (Fung et al 2008 (FUDASH), Toledo et al 2007(TODASH) and Folsom et al 2007(FODASH). Using SPSS, Spearman correlations and kappa tests were performed between DASH scores. In this cross‐sectional study of Hispanics, 169 participants were 66±9 years, obese (BMI 30±5) and 73 % female;29% were hypertensive. There were 17% accordant (score, 29–38) based on FUDASH 13% were accordant (score, 3–6) based on TODASH and 55% were accordant (score, 6–10) based on FODASH. Correlations and kappas are as follows: FUDASH‐TODASH (rs=0.46, p<0.001; kappa=0.25, p <0.001), TODASH‐FODASH (rs=0.43, p<0.001; kappa =0.10 p<0.01) and FUDASH‐FODASH (rs=0.69, p<0.001; kappa=0.16; p<0.0001). Based on these analyses, choice of the scoring paradigm to assess DASH accordance is critical and warrants further study.

Grant Funding Source: Departmental
The environment of phytonutrients may contribute to their bioefficacy against cancer
Authors: Zhao Yi , Whelan Jay
Published: June 2021

The reductionist approach contributes greatly to our understanding of anticancer properties of phytonutrients, but in vitro studies demand concentrations that are 100–1000 times higher than achievable in humans, producing results with little physiologic relevance, resulting in disappointing outcomes in clinical trials. However, maintaining these bioactives in the presence of other compounds originally derived from the food/extract of origin may synergistically lower the bioactive dose so translatability becomes feasible. The objective of this study was to determine if bioefficacy of phytonutrients can be enhanced when used in combination at doses that are ineffective when used in isolation. Proliferation of CWR22Rv1 PCa cells was evaluated and synergy was assessed when treated with turmeric, Chinese goldthread and their bioactives (curcumin and ar‐turmerone, berberine and coptisine) in isolation or in combination. Combining bioactives or herbal extracts were highly synergistic at physiologic concentrations where the dose reduction index was up to 190 fold. Berberine and curcumin (in isolation) were not as potent as their extracts of origin. Combinations of herbal extracts and/or their isolated bioactives lowered concentrations that approached physiologic relevance and may account for why foods/plant extracts are more likely to be beneficial against cancer compared with isolated components.

Grant Funding Source: This research was supported in part by the Tennessee Agricultural Experiment Station, UTK
Potential novel role of the immune system in the pathogenesis of myxomatous mitral valve disease
Authors: Thalji Nassir M , Hagler Michael A , Suri Rakesh M , Miller Jordan D
Published: June 2021

Myxomatous mitral valve disease (MMVD), if untreated, progresses to valve prolapse, mitral regurgitation, and heart failure. Molecular mechanisms contributing to MMVD are poorly understood, and surgery remains the primary treatment for this disease. In the current study, we used whole‐genome expression microarrays in normal (n = 12) and myxomatous (n = 11) mitral valves as a nonbiased approach to identify novel pathways contributing to MMVD. In addition to identifying known contributors to fibrosis in MMVD (e.g. TGFβ signaling), we found robust evidence of immune cell infiltration and activation in myxomatous valves. Specifically, toll‐like receptors (TLRs) 3 and 7, which play a key role in antigen recognition, alongside cell surface receptors CD14 and CD83, characteristic of antigen presenting cells of monocytic lineage, were overexpressed in myxomatous tissue. Interleukin‐7 and the chemokine receptor CX3CR1, implicated in monocyte activation and recruitment, were also upregulated. Interestingly, immune localization appeared independent of “classic” inflammatory cytokines such as IL‐6. Differential expression of a subset of genes was confirmed with qRT‐PCR and immunohistochemistry. In conclusion, these data are the first to demonstrate infiltration of immune cells in MMVD, which may represent a critical process in the initiation and/or progression of this disease.

NHLBI
Detection of the endocannabinoid metabolome in human plasma and breast milk
Authors: Durham Holiday A , Wood JodiAnne T , Vadivel Subramanian K , Makriyannis Alexandros , Lammi‐Keefe Carol J
Published: June 2021

The endocannabinoid metabolome (ENDOMET), endogenous cannabinoids that are lipid messengers, is critical for early development, including fertilization, implantation and pre‐ and postpartum (PP). The regulation underlying these physiological effects remains to be completely elucidated. We evaluated the ENDOMET in plasma of i) non‐pregnant (n=6) and pregnant women (20–22weeks‐ delivery, n=68) and ii) breast milk (BM) at 2 and 10 weeks PP (n= 20). The plasma and BM ENDOMETs [arachidonoyl ethanolamide (ET) (AEA), palmitoyl ET (PEA), oleoyl ET (OEA), docosahexaenoyl ET (DHEA), 2‐arachidonol glycerol (GLY) (2‐AG), 2‐palmitoyl GLY (PEA), and 2‐oleoyl GLY (2‐OG)] were measured using liquid chromatography‐mass spectrometry. ANOVA determined differences in the ENDOMET across time.

Results

plasma ETs increase with pregnancy and peak at delivery (AEA, PEA, OEA, DHEA, p<0.01); GLYs decrease during pregnancy and are stable (2‐AG, p=0.14; 2‐PG, p=0.07, 2‐OG, p=0.02). While BM ETs are considerably lower than plasma ET in pregnancy, BM levels remain stable during PP. BM GLYs are higher than plasma GLYs in late pregnancy. 2‐OG and 2‐AG decrease during PP (p=0.02; 0.05). Plasma and BM ETs are much lower in concentrations than GLYs. Our data point to a reciprocal relationship between ETs and GLYs during pregnancy and PP. Work is needed to better understand how maternal plasma and BM ENDOs regulate pre‐and postnatal outcomes.
Toxic Metabolism and DNA Repair and Haematopoesis
Authors: Patel Ketan
Published: June 2021

Recent work from my lab has discovered that metabolism generates reactive aldehydes. These reactive molecules are potent at damaging DNA, and the consequences of this are revealed by the combined inactivation of enzymes that detoxify these aldehydes and the Fanconi anemia DNA repair pathway in mice and vertebrate cell lines. I shall discuss this work and recent unpublished work on how natural aldehydes damage blood stem cells. This work has consequences for understanding how metabolism and ethanol exposure can be genotoxic particularly in the vast population of southeast Asians carrying a genetic defect in aldehyde catabolism ( “pink flushers”) and also in the emergence of bone marrow failure and leukaemia in Fanconi Anaemia.
A socioscientific issues model for integration of the medical sciences, social sciences, and medical humanities
Authors: Eastwood Jennifer Lynne , Rodenbaugh David , Sabina Richard , Krug Ernest , Poznanski Ann , Mi Misa , Joyce Barbara
Published: June 2021

As medical education embraces a competency‐based model, educators are challenged to reach beyond content‐centered instruction to encompass the human aspects of patient care, including ethics, communication, and understanding of social factors that influence health and disease. Authorities in medical education (AAMC, IOM) call for new ways to integrate social and behavioral sciences into curricula and to help students apply scientific knowledge to complex, multifaceted problems. Thus, we advance a socioscientific issues (SSI) framework, in which real‐life issues with both scientific and social aspects serve as interdisciplinary contexts for learning and problem solving. SSI have been established as effective contexts for enhancing students’ science content learning, motivation, decision‐making, and epistemological development. In this presentation we offer a shareable model for leveraging SSI in medical education. We provide an exemplar Team‐Based Learning (TBL) module on sickle cell disease, detailing its core competencies, such as knowledge of science content and social determinants of health, cultural competence, data analysis, and reflection. We will discuss the process of interdisciplinary module development as well as outcomes from implementation with second year medical students. Finally, we will provide practical implications for using an SSI framework in medical education.
Some aspects of the state‐of‐the‐arts in biomedical science research: a guide for the aspiring African
Authors: John Theresa Adebola
Published: June 2021

To guide Africans to success in biomedical science (BS) research, the author presents some aspects of the state‐of‐the‐arts of BS research in advanced countries using the USA. Thirty three peer reviewed scientific research articles in the April 2012 issue of the FASEB Journal (Volume 26(4)) were studied using the following parameters: a) number of authors; b) number of academic departments; c) number of academic institutions; d) funding of research. Results showed the articles were written by 7.97±0.61 authors from 3.46±0.3 departments of 2.79±0.29 institutions. The contributors were classified into four categories: basic sciences, clinical sciences, institutions and centres, and programs and labs. Amongst the publications, 21.2% were single disciplinary. Two tier collaboration amongst any two of the four categories were observed in 16/33 (48.5%) of the articles. Three tier and four tier collaborations were observed amongst 7/33 (21.2%) and 3/33 (9%) respectively. Thus 26/33 (78.7%) of the articles were multidisciplinary. Collaborative efforts between basic science and clinical science departments were observed in 9/33 (27.3%). Public funding through government agencies provided 85 out of a total of 143 (59.5%) grants. The collaborative and multidisciplinary nature is characteristic of BS research in the USA, where research tends to result in solutions to problems and economic benefits.
Considering the constrained lever model: Feeding biomechanics of OH 5 assessed using finite element analysis
Authors: Smith Amanda L , Benazzi Stefano , Ledogar Justin A , Smith Leslie , Weber Gerhard W , Dechow Paul C , Grosse Ian R , Spencer Mark A , Wang Qian , Strait David S
Published: June 2021

The craniofacial morphology of Paranthropus boisei exhibits a number of highly derived characteristics that have been argued to be functionally related to feeding. These features are hypothesized to either decrease structural stress, increase the mechanical advantage of the masticatory muscles, or both. But complications arise when the constrained lever model is considered. This study uses finite element analysis to test the hypothesis that the P. boisei cranium is structurally stronger and configured to more efficiently generate bite force than the crania of Pan troglodytes and Australopithecus africanus. To assess our analyses within the context of the constrained lever model of chewing biomechanics, joint reaction forces are also examined.

A finite element model was created from a reconstruction of the OH 5 cranium. The model was assigned chimpanzee material properties, constrained at the TMJs and bite points, and subjected to scaled muscle forces derived from chimpanzees. Strains, bite forces and strain energy were recorded. The results were compared to those from FEA of other hominid crania. Results indicate the face of P. boisei is structurally strong and the extreme morphology of this species allows for the generation of high bite forces on posterior teeth without violating the constrained lever model.

(NSF BCS 0725219, 0725183, 0725147, 0725141, 0725136, 0725126, 0725122, 0725078) and the EU FP6 Marie Curie Actions MRTN‐CT‐2005–019564 “EVAN”.
Differential Replication Fork Progression during Drosophila Follicle Cell Gene Amplification
Authors: Alexander Jessica L , Orr‐Weaver Terry L
Published: June 2021

Progression of replication forks must be tightly monitored to ensure complete duplication of the genome. However, specific features of the chromatin that influence fork progression are still largely unknown. The Drosophila Amplicons in Follicle Cells (DAFCs) present an ideal model system to track fork movement in real‐time and delineate causes of differential fork progression. The DAFCs undergo gene amplification by repeated origin firing and rely on the same machinery that drives DNA replication during S‐phase. Each DAFC reaches a unique level of amplification that reflects the total number of origin firings. Bidirectional fork movement generates a gradient of amplification that spans 100kb at each amplicon. Comparative Genome Hybridization analysis reveals fork progression is not uniform throughout the amplified domain, suggesting local chromatin features affect fork movement. Additionally, ectopic DAFCs generated by P‐element transformation are subject to position effects influencing the level of amplification. We will present experiments testing whether these position effects also impact replication fork progression and the extent of the amplified domain.
Polarized release of TCR‐enriched microvesicles at the center of the T cell immunological synapse
Authors: Choudhuri K. , Llodrá J. , Roth E. W. , Tsai J. , Gordo S. , Wucherpfennig K. W. , Kam L. , Stokes D. L. , Dustin M. L.
Published: June 2021

Using high resolution optical and electron microscopy, we show that centrally accumulated T cell receptors (TCR) at in the center of the immunological synapse (IS) is located on the surface of extracellular microvesicles that bud at the IS center. An early endosomal‐sorting complex required for transport (ESCRT) sorts TCR for inclusion in microvesicles, while terminal ESCRT components mediate scission of microvesicles from the T cell plasma membrane. The HIV polyprotein GAG co‐opts this process for budding of virus‐like particles. B cells bearing cognate pMHC receive TCR from T cells and initiate intracellular signals in response to isolated synaptic microvesicles. These microvesicles deliver transcellular signals across antigen‐dependent synapses by engaging cognate pMHC on APC.