bluuebunny/crossref_metadata_2025 huggingface dataset:
Revamping anatomy education: student‐authored dissection manual significantly improves learning and academic performance
Authors: Tetzl Dustin , Neira Justin , Ramirez Jose , Grossmann Lily , Bernd Paulette
Published: June 2021

In an effort to improve the first‐year medical students’ anatomy lab experience, we as second‐year students created our own custom dissection manual. Working with the course director, we tailored this dissector to Columbia University's anatomy course with marked advantages over commercial dissectors.

Many factors make our dissector unique: step‐by‐step photographs of a cadaver dissection and supplementing diagrams, review checklists, concise instructions, dissection tips, and information only pertinent to structure identification. The dissector's efficacy was evaluated by comparison of student surveys, faculty assessments, and exam statistics from the 2010 and 2011 classes, who used the commercial or custom dissector, respectively.

Comparison of 2010 and 2011 surveys showed an overwhelming increase in satisfaction with the new dissector, increased learning ease, more efficient use of lab time, and decreased frustration. Faculty reported an overall “higher dissection quality” and “less dependence on faculty” in the lab. Exam means increased by at least one standard deviation (N = 236, p < 0.0001).

Due to its unique student‐developed nature, this project has closely addressed students’ needs, and has proven itself highly effective in its implementation at Columbia University. This student‐led model can serve as a template for other schools looking to customize and improve their anatomy curriculum.

Grant Funding Source: none
Quercetin Bioavailability And Biotransformation Are Inversely Related To Vitamin C Status In College‐Aged Adults
Authors: Guo Yi , Mah Eunice , Jalili Thunder , Bruno Richard S
Published: June 2021

Dietary quercetin (Q) may reduce the risk of cardiovascular disease (CVD), but little is known about its bioavailability. We conducted a pharmacokinetics study to define whether antioxidant status affects Q bioavailability in young adults. Participants (n = 8M/5F) ingested 1095 mg Q aglycone with a standardized meal. Then, plasma antioxidants [ascorbic acid (AA), tocopherols, uric acid, carotenoids], Q and its methylated metabolites isorhamnetin (I) and tamarixetin (T) were measured at timed intervals for 24 h. Q bioavailability (AUC0‐24 h 308–1738 μM x min) and maximum concentrations (Cmax 0.4–2.8 μM) exhibited high inter‐subject variability. AUC0‐24 h and Cmax of I and T were also highly variable (120–750 and 33–787 μM x min; 0.1–0.9 and 0.1–1.2 μM, respectively). AA, but no other antioxidants, was inversely related to Q AUC0‐24 h and Q Cmax (P<0.05; r = −0.63 to −0.49). AA was also negatively related to AUC0‐24 h of I + T (P<0.05, r = −0.58) and tended to inversely relate to Cmax of I + T (P=0.06; r = −0.46), suggesting that low AA status increases Q bioavailability and biotransformation. AA was also inversely related to myeloperoxidase (P<0.05, r = −0.56), a proinflammatory enzyme that increases CVD risk. These data suggest that low AA status increases Q bioavailability, possibly through a proinflammatory mechanism that increases its intestinal absorption.

Grant Funding Source : Donaghue Nutrition Research Program
Metabolism of black tea theaflavins by gut microbiota
Authors: Sang Shengmin , Chen Huadong , Hayek Said , Guzman Javier Rivera , Jobin Christian , Ibrahim Salam
Published: June 2021

As a popular beverage, tea (Camellia sinensis, Theaceae) has been associated with many beneficial health effects, including the prevention of cancer and heart disease, a phenomenon mostly attributed to the presence of polyphenolic compounds. The main bioactive polyphenols in black tea are theaflavins, which are formed by the oxidation and polymerization of catechins in green tea leaves during fermentation. Theaflavins including theaflavin (TF), theaflavin‐3‐gallate (TF3G), theaflavin‐3′‐gallate (TF3′G), and theaflavin‐3,3′‐digallate (TFDG). We and others have found that theaflavins have poor systematic bioavailability. Therefore, it is still unclear how these compounds could exert their biological functions. It has been reported that higher molecular weight polyphenols are metabolized by the microbiota and their metabolites may play an important role in chronic disease prevention. In the present study, we investigated the microbial bioconversion of theaflavins in specific pathogen free (SPF) mice, germ free (GF) mice, and in human fecal microbiota in vitro. Microbial bioconversion was monitored using liquid chromatography/electrospray ionization tandem mass spectrometry by analyzing the MSn (n = 1–3) spectra. Our results indicated that TFDG, TF3G and TF3′G can be metabolized by gut microbiota to generate gallic acid, pyrogallol, and TF. Glucuronidated and sulfated, instead of methylated metabolites of TF3G, TF3′G and TFDG were detected and identified as the minor mouse fecal metabolites of TFDG. To our knowledge, this is the first report on the microbial metabolism of theaflavins.
Dose response bioavailability of coffee chlorogenic acids in humans
Authors: Renouf Mathieu , Marmet Cynthia , Giuffrida Francesca , Williamson Gary , Dionisi Fabiola
Published: June 2021

Chlorogenic acids are coffee bioactives that are becoming of great interest for their health promoting effects. However, human bioavailability of these compounds is not fully understood. We investigated dose response plasma appearance of coffee chlorogenic (CGAs) and phenolic (PAs) acids after ingestion of increasing doses of soluble coffee by 10 healthy volunteers.

Two groups of metabolites appeared over 24h where plasma CGAs and PAs were measured after enzymatic treatment. The first group of metabolites appeared rapidly, less than 2 hours after ingestion, indicative of intestinal absorption. Dihydrocaffeic and dihydroferulic acids peaked around 10h, which suggest colonic metabolism and absorption. Regardless of the dose, colonic metabolites were the most present compounds, followed by phenolic acids and chlorogenic acids. Finally, all compounds quantified in plasma showed a positive dose response effect proportional to the ingested dose, indicating passive absorption mechanisms. It also highlights the importance of this beverage as a significant dietary source of bioavailable bioactive compounds.
Bioaccessibility of pistachio polyphenols, carotenoids and tocopherols in the upper gastrointestinal tract
Authors: Mandalari Giuseppina , Bisignano Carlo , Filocamo Angela , Chessa Simona , Saro’ Mariagiovanna , Torre Germana , Faulks Richard , Dugo Paola
Published: June 2021

A number of studies have demonstrated positive effects of pistachio consumption in modifying lipid risk factors for coronary heart disease. The aim of the present study was to characterize pistachio polyphenols, carotenoids and tocopherols and investigate their bioaccessibility during digestion. A dynamic gastric model of digestion which provides a realistic and predictive simulation of the physical and chemical processing and accurately mimics both the transit time and the luminal environment within the human stomach was used for the digestion studies. Raw, roasted salted pistachios and muffins made with raw pistachios were tested. Results showed that pistachio polyphenols (59–63 mg/100 g), carotenoids (lutein 11–16 mg/100 g) and tocopherols (227–236 mg/100 g) are bioaccessible during digestion and therefore available for absorption in the gastrointestinal tract. No significant differences in bioaccessibility were observed between raw and roasted pistachios in the stomach and small intestine.

However, the presence of muffin limited the release of protocatechuic acid and luteolin in the gastric and duodenal compartment. Polyphenols, carotenoid and tocopherol absorption would contribute to the beneficial relationship between pistachio consumption and health‐related outcomes.

This work has been funded by the American Pistachio Growers.
Increased Monocyte Toll‐like receptor Activity In Patients With Metabolic Syndrome
Authors: Kaur Harmeet , Adams-Huet Beverley , Devaraj Sridevi , Jialal Ishwarlal
Published: June 2021

The Metabolic Syndrome (MetS) is a pro‐inflammatory state and confers an increased risk for both diabetes and cardiovascular disease. There is a sparse data on cellular sources of inflammation in MetS, especially monocytes. Toll‐like receptors (TLRs) TLR2 and TLR4 have been incriminated in atherosclerosis and insulin resistance. The aim of present study was to examine any difference in monocyte activity in terms of expression of TLR2, TLR4 and downstream signaling cascades in MetS patients compared to controls. Surface expression of both TLR2 and TLR4 on monocytes were significantly increased in MetS subjects versus controls after adjustment for waist circumference along with further increase in NFkappa b and p38 MAPKinase activity (p<0.01). Also, priming of monocytes with lipopolysaccharide resulted in significant release of interleukin 1‐beta, 6 and 8 in MetS subjects. TLR4 correlated significantly with IL‐Ib, MCP‐I, NFKappa B and p38‐MAPKinase and TLR2 correlated significantly with IL‐6, NFKappa b and p38‐MAPKinase. Thus this study provides novel data of increased TLR2 and TLR4 activity in MetS serving as a cellular hub for the pro‐inflammatory state.

Grant Funding Source : AMERICAN DIABETES ASSOCIATION
Flaxseed lignan supplementation improves markers of obesity in C57BL6 mice
Authors: Ford Nikki A. , Hursting Stephen D.
Published: June 2021

Overweight breast cancer patients have a poorer prognosis than their lean counterparts which may be attributed to increased inflammation and higher levels of serum hormones. Due to the ineffectiveness of many weight loss regimens we utilized a commercially available flaxseed lignan supplement (Brevail®) to modulate the effects of body fatness on serum and tissue biomarkers. C57BL/6 mice, which are prone to obesity, were fed a 10% fat diet for 8 weeks prior to randomization onto one of two doses of Brevail (0.074 mg (B2) or 0.025 mg (B1) secoisolariresinol diglycoside/ kg diet) for another 8 weeks. Although flaxseed lignan supplementation did not alter final body weight, B2 significantly reduced the percentage of body fat (P=0.017) relative to control fed mice. Hepatic lipid droplets were also reduced in size and number by lignan consumption. Fasting glucose and insulin were reduced in a dose‐dependent manner (P=0.036 and P<0.0001, respectively) while the QUICKI index, which is a measure of insulin resistance, also significantly improved with lignan consumption (P=0.001) relative to control fed mice. B2 also reduced the adipokines resistin and leptin (P=0.001, P=0.032, respectively) which have been implicated in chronic inflammation. Together these data suggest that Brevail supplementation may improve breast cancer risk markers by altering body fatness, obesity‐related adipokines and markers of inflammation.

Grant Funding Source: Susan G. Komen
Cinnamon polyphenols regulate high‐fructose feeding and age‐induced decreases in sirtuins in rat intestinal enterocytes
Authors: Qin Bolin , Polansky Marilyn M , Anderson Richard A
Published: June 2021

Sirtuins (SIRTs) may play a role in aging, insulin sensitivity, lipid metabolism, stress responses, and inflammation. Cinnamon type A polyphenols (CPA) have also been shown to improve glucose, insulin, and lipid metabolism, and inflammation. However, little is known of the effects of CPA on the expression of SIRTs. In this study, Wistar rats were fed a fructose‐rich diet for 6 weeks to induce insulin resistance and freshly isolated intestinal enterocytes were used to investigate the effects of purified CPA in vitro on SIRTs genes by RT‐PCR and proteins by Western blot analyses. SIRT1, 2, 3, 5, and 7 gene expressions were increased by 20 and 100 μg/mL CPA after 2 and 4h treatment; SIRT1‐3 protein levels were higher in 100 μg/mL CPA‐treated enterocytes after 4h. Similar effects were observed in the small intestinal enterocytes isolated from older Wistar rats (65 wks) consuming a stock diet. These results suggest that cinnamon polyphenols may activate sirtuins in intestinal enterocytes functionally altered by diet and age (Funded by USDA CRADA No.58‐3K95‐7‐1184 with Integrity).
Cyanocobalamin treatment improves vitamin B12 status and peripheral neuroconduction in deficient Chilean elderly
Authors: Brito Alex , Allen Lindsay H. , Verdugo Renato , Sanchez Hugo , Hertrampf Eva , Albala Cecilia , Lera Lydia , Castillo Jose Luis , Lavados Manuel , Shahab-Ferdows Setareh , Uauy Ricardo
Published: June 2021

Few data are available on the effects of cyanocobalamin treatment on B12 status and neurological function in deficient but asymptomatic free‐living populations. The objective was to evaluate the effects of a single i.m. dose of 10,000 μg B12 on biomarkers and neurophysiology in Chilean elderly with B12 deficiency. The 34 subjects (70–79 y) were 52% female with serum B12 <148 pmol/L had been excluded for ethical reasons from a larger RCT of B12 supplementation. B12 intake was 2.4±1.0 μg/d (67% met the EAR). Change in serum B12, total homocysteine (tHcy), methylmalonic acid (MMA), holo‐transcobalamin (holo‐TC), and sensory peripheral neuroconduction were assessed 4 mo after treatment. Serum B12 increased (p<0.001) from 80 (44–121) to 231 (103–294) pmol/L after treatment and 78% exceed 148 pmol/L. Holo‐TC increased (p<0.001) from 35 (27–41) to 56 (40–85) pmol/L and MMA reduced (p<0.001) from 389 (263–654) to 220 (146–295) nmol/L. There were no significant changes in tHcy. At baseline, distal sensory latency of the right and left sural nerve was 3.4±0.3 msec and 3.3±0.3, respectively. The mean distal sensory latencies decreased (p<0.0001) to 3.0±0.3 msec on both sides. 9 subjects clasified as demyelinating neuropathy normalized their distal latency post‐treatment. B12 biomarkers and latencies of the sural nerves detected adverse effects of B12 deficiency on neural function and reversibility after treatment. Funded by FONDECYT #10700592
Vision Changes after Space Flight Are Related to Alterations in Folate‐Dependent One‐Carbon Metabolism
Authors: Smith Scott M , Gibson C Robert , Mader Thomas H , Ericson Karen , Ploutz-Snyder Robert , Heer Martina , Zwart Sara R
Published: June 2021

At least 20% of astronauts on International Space Station missions have developed measurable ophthalmic changes after flight. This study was conducted to determine whether the folate‐dependent 1‐carbon pathway is altered in these individuals. Data were modeled to evaluate differences between individuals with ophthalmic changes (n=5) and those without them (n=15). We also correlated mean preflight serum concentrations of the 1‐carbon metabolites with changes in measured refraction after flight. Serum homocysteine (HCy), cystathionine, 2‐methylcitric acid, and methylmalonic acid concentrations were 25%–45% higher (P<0.001) in astronauts with ophthalmic changes than in those without them. These differences existed before, during, and after flight. Preflight serum HCy and cystathionine, along with in‐flight serum folate, were significantly correlated (P<0.05) with postflight changes in refraction, and preflight serum concentrations of 2‐methylcitric acid tended to be associated (P=0.06) with ophthalmic changes. The biochemical differences observed in those with vision issues strongly suggests impairment of the folate‐dependent 1‐carbon transfer pathway. Impairment of this pathway, by polymorphisms, diet or other means, may interact with components of the microgravity environment to influence these pathophysiologic changes.
Increased mRNA expressions of atheroprotective proteins in the peripheral blood mononuclear cells of humans taking low‐dose methotrexate
Authors: Chiang En-Pei Isabel , Chih Hui-Min , Chen Der-Yuan , Lan Joung-Liang , Chang Hsin-Yueh , Chen Wei-Wen , Tang Feng-Yao
Published: June 2021

Methotrexate (MTX) is a commonly prescribed disease‐modifying antirheumatic drug (DMARD) in rheumatoid arthritis (RA). ATP‐binding cassette transporter‐A1 (ABCA1) and 27‐Hydroxylase (HY27) are known antiatherogenic proteins that promote cellular cholesterol efflux. MTX promotes the reversal of cholesterol transport in vitro. We examined whether clinical MTX use is associated with altered blood lipids and/or ABCA1/HY27 expressions. Plasma lipid profiles and PBMC HY27 and ABCA1 expressions were compared between subjects taking MTX and other DMARDs (MTX‐)(n=100). ABCA1 and HY27 expressions significantly elevated in MTX+ compared to MTX‐subjects. ABCA correlated with MTX doses (r=0.205, p=0.042). MTX+ subjects are more likely to have increased HY27 (OR=2.5, p=0.038). Although no differences were observed in the blood lipids, the potential impacts of MTX on cholesterol metabolism should not be overlooked and the atheroprotective effects from MTX induced HY27 and ABCA1 expressions may still be present in those persons with pre‐existing dyslipidemia.

CONCLUSIONS

We demonstrated novel findings on the increased gene expressions of atheroprotective protein HY27 and ABCA1 in human PBMCs with clinical use of low‐dose MTX.
n‐3 PUFAs reorganize B cell membrane rafts and molecular order accompanied by differential effects on B cell function
Authors: Rockett Benjamin Drew , Teague Heather , Harris Mitchel , Shaikh Saame Raza
Published: June 2021

n‐3 PUFAs manipulate lipid raft organization to suppress T cell and macrophage function; however, little is known about this relationship with B cells, especially at the animal level. We previously established a high n‐3 PUFA dose remodeled mouse B cell raft clustering. To establish relevance, we first tested a n‐3 PUFA dose modeling human intake on B cell raft organization, relative to a control, using biochemical and quantitative imaging methods. Biochemical analysis revealed incorporation of docosahexaenoic acid into phosphatidylcholines of raft‐like domains with no change in cholesterol distribution. TIRF and fluorescence polarization imaging showed n‐3 PUFAs manipulated B cell raft size, increased GM1 expression, and increased membrane order upon cross‐linking GM1 molecules. Finally, we tested the hypothesis that modifying rafts would suppress B cell responses ex vivo. Contrary to expectations, n‐3 PUFAs enhanced LPS‐induced B cell activation, yet suppressed B cell stimulation of naïve CD4+ T cells. Overall, the results demonstrated a relevant n‐3 PUFA dose remodeled rafts; furthermore, the data showed raft remodeling was accompanied by unique changes in B cell function.

Grant Funding Source: NIH R15AT006122
Energy Restriction Results in Phenotypic and Functional Alterations to NK Cells
Authors: Clinthorne Jonathan Frederick , Gardner Elizabeth
Published: June 2021

Energy restriction (ER) is a dietary intervention shown to increase lifespan and reduce the incidence of spontaneous tumors in rodents. Natural killer (NK) cells are innate lymphocytes responsible for tumor surveillance and their activity is altered by ER. We have previously shown NK cell function is reduced in influenza infected ER mice, prompting us to investigate whether ER influences NK cell homeostasis independent of influenza infection. Here, we show 40% ER of young mice results in phenotypic and functional changes to NK cells compared to AL mice. Splenic NK cells from ER mice were analyzed for various cell surface markers associated with NK cell maturation and development using flow cytometry. NK cells from ER mice were not only reduced in number and percentage compared to AL mice; but also expressed significantly less CD11b, CD43, and KLRG1, markers normally associated with mature NK cells. We observed no impairment in the ability of NK cells from ER mice to produce interferon‐γ, but found granzyme B production significantly reduced compared to NK cells from AL mice. Phenotypic and functional changes to NK cells observed in ER mice provide insight into how ER may compromise the innate immune response to intact pathogens. Supported by R01AG034949 (E.G.)

Grant Funding Source : NIA
Maternal blueberry diet suppresses Wnt1‐induced mammary tumor progression in offspring
Authors: Rahal Omar , Pabona John Mark P , Hennings Leah , Prior Ronald L , Kelly Thomas , Al-Dwairi Ahmed , Simmen Frank A , Simmen Rosalia CM
Published: June 2021

Despite the well‐accepted notion of peri‐natal origins of adult diseases, the factors and regulatory mechanisms underlying breast cancer development remain unclear. Diet is a highly modifiable determinant of breast cancer risk, and the effects of the in utero nutritional environment persist beyond fetal life. We investigated whether in utero/lactational exposure to blueberry (BB) via maternal diet alters the trajectory of Wnt1‐induced mammary tumorigenesis in offspring. Wnt1 transgenic mice were exposed to maternal diets of casein (CAS; n=33) or blueberry‐supplemented CAS (3% BB; n=28) from gestation day 4 until post‐natal day 21. Offspring were then weaned to CAS and mammary tumor development was followed until age 8 months. While tumor incidence and latency were similar for both groups, tumor weight (by 2‐fold, p=0.034) and growth rate (by 60%; p=0.008) were reduced in offspring of BB‐ versus CAS‐fed dams. Tumors from the BB group had higher expression of tumor suppressors PTEN and E‐cadherin and lower cyclin D1 and pro‐apoptotic Bcl2 levels. Transcript levels for DNA methylation enzymes DNMT1 and EZH2 were higher in BB tumors. Serum levels of insulin and serum leptin/adiponectin ratio were lower for tumor‐bearing BB than CAS offspring at sac. Our findings support a role for nutritional epigenetics in adult breast cancer outcome.

Grant Funding Source : USDA‐CRIS (RCMS), DOD‐BCRP (OR) and NIH‐NCI (FAS).
RNA‐seq Analysis of Placental Gene Expression: Effect of Maternal Obesity
Authors: Shankar Kartik , Zhong Ying , Kang Ping , Ronis Martin J , Gomez-Acevedo Horacio
Published: June 2021

The rat placentation site is organized into distinct zones, the labyrinth (L), junctional (J) and metrial gland (MG) compartments. We utilized massively parallel sequencing (RNA‐seq) to assess mRNA expression profiles for each zone of the late‐gestation rat placenta (dpc18.5). In addition, we elucidated gene expression changes in the L, J and MG placental compartments, and fetal liver from in lean and obese dams at dpc18.5. Maternal obesity was induced in rats by overfeeding via total enteral nutrition. Analysis of expression profiles revealed that transport and vasculature‐related processes predominated in the L, hormone secretion in the J and immune interactions in the MG. Using k‐means clustering of ~4000 differentially expressed genes, we identified transcription factors (TF) with highest expression in either L, J or MG. The site‐specific expression of 27 TF was ascertained via qPCR. Exposure to maternal obesity produced pronounced changes in gene expression (± 1.3‐fold) in the MG (630 transcripts), followed by the J and L zones (437 and 151, respectively). mRNA expression of 172 transcripts was altered in the fetal liver. Gene expression changes in each compartment due to maternal obesity were unique. Our results suggest that maternal obesity alters distinct gene sets and biological processes in the rat placenta that are likely to impact development of the offspring. Support ARS‐CRIS 6251‐51000‐ 005‐00D.
Alterations in hepatic gene expression and genome‐wide DNA methylation in rat offspring exposed to maternal obesity in utero
Authors: Borengasser Sarah , Zhong Ying , Gomez-Acevedo Horacio , Ronis Martin , Shankar Kartik
Published: June 2021

Adult offspring from obese (OB) rat dams gain greater body weight and fat mass than controls when fed HFD. At PND21, we examined energy expenditure (EE) (indirect calorimetry), hepatic gene expression (microarrays), and changes in genome‐wide and global DNA methylation (enrichment‐coupled DNA sequencing, Illumina), coupled with specific signaling pathway analysis. Microarray analyses revealed a reprogramming of lipogenic and lipid degradative pathways as shown by increased expression of SREBP‐1 and decreased PPAR‐α/AMPK signaling. Offspring from OB dams had decreased EE (p<0.05) and higher respiratory exchange ratio values (p<0.05) on AIN‐93G or HFD, indicating an impaired capacity to utilize fatty acids (FA). Mitochondrial (mito) protein content of electron transport chain complexes (II, III, and ATPase) was decreased (p<0.03) in OB dam offspring. Hepatic mRNA and mito protein expression of SIRT3, a regulator of mito oxidative capacity and FA oxidation were decreased (p<0.002) in OB dam offspring. Fasting‐induced increases in mRNA and protein expression of PGC‐1α and PPAR‐α were diminished in OB dam offspring. The 3′‐UTR region of PPAR‐α was hypermethylated in offspring of OB dams consistent with impaired FA mobilization. Maternal obesity influences early hepatic gene expression and DNA methylation. Further, it appears that mito dysfunction precedes the development of excessive weight gain in offspring from OB dams. Support NIHR01‐DK084225
DNA methylation in candidate genes as a biomarker for transgenerational risk of preeclampsia
Authors: Wright Michelle L. , Anderson Cindy M. , Uthus Eric O. , Ohm Joyce E.
Published: June 2021

Preeclampsia (PE), characterized by global fetal undernutrition due to placental insufficiency, affects over 100,000 women annually in the US. Gene‐environment interactions resulting from placental insufficiency during critical developmental windows may explain differential methylation of key genes associated with familial risk of PE. In this study, our goal was to validate methylation status of CpG dinucleotides in loci of genes identified via genome‐wide methylation array (Illumina Infinium) in women with and without PE (n=6/group). Differentially methylated loci were primarily located in non‐CpG island regions of genes. Bisulfite sequencing was performed on maternal peripheral blood samples and placental tissue of fetal origin to detect methylated cytosines in 7 candidate genes involved with vascular function, inflammation, and lipid metabolism. Pyrosequencing was performed to identify conversion of unmethylated cytosine to uracil in the altered sequence, providing single‐nucleotide resolution of the segment of DNA. This study provides novel evidence for the generation of epigenomic marks associated with an intrauterine environment of placental insufficiency, providing a putative explanation for the heritable risk of preeclampsia across generations.

Grant Funding Source: Robert Wood Johnson Foundation
Combining self‐report dietary assessment instruments to reduce the effects of measurement error
Authors: Midthune Douglas Neil , Carroll Raymond J , Subar Amy F , Freedman Laurence S , Thompson Frances E , Kipnis Victor
Published: June 2021

With the advent of a self‐administered automated 24 hour dietary recall instrument (24HR), developed at the National Cancer Institute (NCI), it is now possible to envision its use in cohort studies investigating the relationships between diet and disease. Understanding that all dietary assessment instruments are subject to measurement error, we compare 3 possible strategies for estimating intake: 1) administering 1–12 24HRs per subject; 2) administering a single food frequency questionnaire (FFQ); and 3) administering a combination of 24HRs and a single FFQ. We used data from the National Cancer Institute's Eating at America's Table Study, which collected 4 24HR, one per season, and an FFQ in a nationally representative sample of 965 U.S. adults. We compared the precision, power and required sample size for the different strategies under the assumption that the 24HR is unbiased for true usual intake. We found that the strategy of 4–6 administrations of the 24HR is sufficient for most nutrients and food groups, and that the combined use of multiple 24HR and FFQ data often provides estimates superior to either alone. In most cases, adding an FFQ to one or more 24HRs improved precision more than adding an additional 24HR. If self‐administered automated 24HRs are to be used in cohort studies, one should consider administering 4–6 24HRs and an FFQ.
Dyad Pedagogy: From the anatomy classroom to the workplace
Authors: Marquez Samuel
Published: June 2021

Health care practice is in a state of flux insisting that practitioners be clinically competent in the most complex workplace ever. ACGME cites: insightful clinical reasoning; teamwork; & culturally‐able behaviors ‐‐ as hallmarks of the clinically‐able physician. Workplace imperatives informed the choice of Dyad Pedagogy (DP) in order to integrate affective & psychomotor skills into the cognitive so as to develop workplace behaviors as the students learned anatomy. DP methodology ‐‐arranging students in pairs ‐‐expanded a traditional Anatomy course with interactive problem‐solving activities in a first‐year anatomical science course at the College of Health Related Professions in SUNY Downstate Med Center. Dyad activities were structured within anatomical themes focused on context‐relevant anatomy problem‐solving scenarios. Implementation of DP demonstrated effectiveness in advancing student mastery of anatomical content and its clinical relevancy; success in promoting interpersonal behavior and collaborative problem‐solving skills; and in honing oral presentation techniques. Use of DP energized the classroom as it did the creation of new metrics to assess these objectives. A rigorous assessment confirmed that students’ demonstrated mastery of anatomical knowledge integrated with workplace behaviors. DP optimized the reach of learning beyond the anatomy classroom and into the workplace.
Targeted messages delivered by nurses and radio improved infant and young child feeding in Mexico
Authors: Monterrosa Eva C , Frongillo Edward A , Gonzalez-Cossio Teresa , Bonvecchio Anabelle , Villanueva Maria Angeles , Thrasher James , Rivera Juan A
Published: June 2021

Scalable interventions are needed to improve infant and young child feeding (IYCF). We examined effectiveness of a theory‐based communication intervention to improve IYCF in Mexico. Women with children 6–24 mo were selected randomly from vaccination rosters from 6 semi‐urban low‐income communities in Morelos state (intervention, n=266) and 3 in Puebla state (control, n=201). For the intervention, nurses visited participants once at home to deliver 5 messages: breastfeeding, food consistency, flesh‐food and vegetable consumption, and responsive feeding; messages aired 7 times/d for 21 days on 3 radio stations. We used a pre‐post‐test design to evaluate changes in beliefs, attitudes, and intentions via 3‐point scales, and in practices with a 7‐d food frequency. Mixed models were used to examine intervention‐control differences in pre‐post changes. Coverage for the nurse component was 89%, and 34% for radio. Beliefs, attitudes, and intention about IYCF were significantly improved in the intervention communities compared to control. Intervention participants had significantly greater: breastfeeding frequency (2 times/d), vegetable (0.5 day) and beef consumption (0.2 day), and thicker consistency in soups (0.5 day). This study provides evidence that a targeted communication intervention using a scalable model significantly improved IYCF.

Funding by Alive & Thrive, Health Services Morelos

Grant Funding Source: Alive and Thrive
Feasibility of accelerometers for measuring children's daily physical activity
Authors: Schaefer Sara Elizabeth , Van Loan Marta , Allen Lindsay , German John Bruce
Published: June 2021

Understanding physical activity is essential in the fight against child obesity. Certain accelerometers may be more useful in assessing this variable in children; easier to wear devices may facilitate better compliance and measurement over longer time periods. The objectives of this study were to a) compare children's acceptability of various accelerometers and b) compare their research utility. Children 7–10 y (n=25) were recruited within Yolo County, CA to test each of three accelerometers; the Philips Actical™ (worn on hip), the SenseWear BodyMedia™ (upper arm) and the Polar Active™ (wrist). Each week children received a device to wear over 5 continuous days. Parents were asked to note device removals. After each use, children and parent each completed a structured interview with trained staff. Upon completion, children were asked to place the devices in order from most to least preferred. The Polar Active was most accepted by children and useful to researchers in providing data on activity intensity levels. This device also engaged children with real time feedback on activity achievements. These findings will aid researchers in choosing measurement tools for children's physical activity.

Grant Funding Source : Foods for Health Institute
Th17 lymphocyte adhesion to endothelium is highly dependent on E‐selectin and ICAM‐1 mediated interactions
Authors: Alcaide Pilar , Maganto-Garcia Elena , Newton Gail , Travers Richard , Croce Kevin J , Bu De-Xiu , Luscinskas Francis W , Lichtman Andrew H
Published: June 2021

T cell subset specific migration to inflammatory sites is tightly regulated involving interaction of the T cells with the endothelium. T helper 17 (Th17) cells often appear at the same sites of inflammation than T helper 1 (Th1) cells but not simultaneously, sometimes they appear at different sites and sometimes co‐existence does occur. However, Th17 cells adhesion to vascular endothelium and migration into tissues and organs has not been well studied. We examined the adhesion of mouse Th17 cells to endothelial adhesion molecules and endothelium under flow in vitro and to microvessels in vivo, and characterized their migratory phenotype by flow cytometry and qRT‐PCR. More Th17 than Th1 cells interacted with E‐selectin and fewer bound to TNF‐α activated E‐selectin deficient endothelial cells. Intravital microscopy demonstrated that Th17 cells engage in more rolling interactions with TNF‐α treated microvessels than Th1 cells in wild type mice but not in E‐selectin deficient mice. Th17 adhesion to ICAM‐1 was dependent on integrin activation by CCL20. In an air pouch model of inflammation, CCL20 triggered recruitment of Th17 but not Th1 cells. Our data provide evidence that Th17 cells adhesion with the endothelium is highly dependent on E‐selectin and ICAM‐1 and is quantitatively different from Th1 cells. Funded by NIH: K99‐HL097406 (PA); HL36028 (FWL, AHL); K08‐HL086672 (KJC); HL53993 (FWL).
The proteoglycan biglycan enhances antigen‐specific T cell activation potentially via MyD88 and TRIF pathways and triggers autoimmune perimyocarditis
Authors: Groene Hermann-Josef , Wang Shijun , Papatriantafyllou Maria , Kaya Ziya , Burgdorf Sven , Young Marian F. , Schaefer Liliana , Popovic Zoran V.
Published: June 2021

Biglycan is a proteoglycan present in extracellular matrix of a variety of organs and has been reported to be overexpressed in myocardial infarction. Myocardial infarction may be complicated by perimyocarditis through to date unclear mechanisms. Our aim was to investigate the capacity of TLR2/TLR4 ligand biglycan to enhance the presentation of specific cardiac Ags. In vitro, Ovapulsed DCs from WT, TLR2, TLR4, MyD88 or TRIF deficient mice were treated with LPS or biglycan and incubated with Ovarecognizing MHCI‐ or MHCII‐restricted T cells. Biglycan enhanced cross‐priming of MHCI‐restricted T cells in both TLR2‐ and TLR4‐ pathway dependent manner. Ova‐specific activation of MHCII‐restricted T cells was TLR4‐dependent. Our in vivo correlate was a model of autoimmune perimyocarditis triggered by injection of cardiac‐Ag pulsed DCs. Biglycan‐treated DCs triggered perimyocarditis in an intensity comparable to LPS‐treated DCs. Substitution with TLR4‐deficient DCs abolished this effect. In a second approach, WT and biglycan‐deficient mice were followed two weeks after induction of myocardial infarction. WT mice showed significantly higher T‐lymphocyte infiltration than biglycan‐deficient mice. We conclude that biglycan may enhance Ag‐specific T cell priming via MyD88 and TRIF and stimulate autoimmune perimyocarditis.
Interleukin 10 prevents apoptosis of brain endothelium during bacteremia
Authors: Londono Diana , Diego Cadavid
Published: June 2021

IL‐10 deficient mice infected with the relapsing fever bacterium Borrelia turicatae rapidly succumb to brain hemorrhage if they are unable to clear peak bacteremia. Here we investigated the protective role of IL‐10 during relapsing‐remitting bacterial infection and explored the molecular events involved in protection of brain endothelium by IL‐10. The results showed that severe endothelial cell injury leading to hemorrhage in the brain and other organs occurred in IL‐10 deficient mice during relapsing‐remitting infection. Human brain microvascular endothelial cells (HBMEC) upon exposure to whole bacteria or purified bacterial lipoprotein are rapidly killed by apoptosis and produced abundant pro‐inflammatory mediators but did not produce any IL‐10. HBMEC apoptosis during exposure to low number of bacteria was associated with down regulation of TNF and TNFAIP3 and upregulation of BAX. In contrast, exposure to high concentrations of purified outer membrane lipoprotein was associated with dramatic upregulation of FAS, FAS ligand, and the adaptor molecules RIPK1 and CFLAR. Exogenous IL‐10 reversed all the apoptotic signaling changes induced by whole bacteria or purified lipoprotein. The results indicate that IL‐10 prevent brain endothelial cell injury and point to a prominent role for bacterial lipoprotein mediated activation of different apoptosis pathways in this process.
Over Expression of Dimethylarginine Dimethylaminohydrolase‐1 (DDAH1) Slows Progression Fibrocalcific Aortic Valve Stenosis in Hypercholesterolemic Mice
Authors: Zhang Bin , Oehler Elise A. , Roos Carolyn M. , Arghami Arman , Miller Jordan D.
Published: June 2021

Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthases, is primarily degraded by DDAH1. We tested the hypotheses that over expression DDAH1 reduces endothelial dysfunction and slows progression of fibrocalcific aortic valve disease (FCAVD) in hypercholesterolemic mice. We used low density lipoprotein receptor‐deficient, apolipoprotein B100‐only (LA) mice that were either wild‐type (D0/0) or overexpressed human DDAH1 (DTg/0). Systolic blood pressure (SBP, tail cuff), vasomotor function (isolated organ bath), and aortic valve function (echocardiography), were measured at 3 and 6 month time points. Compared to LA‐D0/0 mice, SBP was reduced by ~15 mmHg in LA‐DTg/0 mice at both 3 and 6 months (p < 0.05). Although aortic endothelial function progressively declined with prolonged hypercholesterolemia, there were no differences between LA‐D0/0 and LA‐DTg/0 mice. While aortic valve function was similar between LA‐D0/0 and LA‐DTg/0 mice at 3 months (peak transvalvular velocity: 1.95±0.09 m/sec versus 2.03±0.07 m/sec), overexpression of DDAH1 slowed progression of valvular dysfunction at 6 months (2.07±0.10 m/sec versus 2.30±0.05 m/sec). In conclusion, our data suggest that increasing DDAH1 may be an effective therapeutic strategy to slow progression of FCAVD, and is likely to exert protective effects independent of changes in systemic endothelial function.
Muscle RING finger‐1 (MuRF1) inhibits thyroid receptorα transcriptional activity and thyroid hormone‐dependent cardiac hypertrophy
Authors: Wadosky Kristine M. , Zungu Makhosazane , Portman Michael , Willis Monte S.
Published: June 2021

We previously identified that MuRF1 regulates PPARα transcriptional activity in cardiomyocytes by post‐translationally modifying the protein with ubiquitin. To determine if MuRF1 has a broader role in regulating nuclear receptors, we determined MuRF1's effect on thyroid receptor‐α(TRα) activity, the predominant TR subtype in the heart. Using thyroid receptor response element (TRE)‐driven luciferase assays, we found that MuRF1 significantly inhibited triiodothyronine (T3)‐dependent increases in TRα activity. To explore the physiological significance of MuRF1's inhibition of TRα activity, we challenged MuRF1 −/− and MuRF1 transgenic (with cardiac‐specific overexpression) to daily T3 treatment (1 mg/kg/day) for 14 days and followed the heart by echocardiography at baseline, 7 days, and 14 days. After 14 days of T3 treatment, MuRF1−/− animals exhibited a 90.9% increase in LV mass over baseline, while wildtype littermates showed only a 58.9% increase in LV mass over baseline. Conversely, MuRF1 Tg mice showed a 44.4% increase in LV mass over baseline compared to the 73.0% increase in LV mass over baseline exhibited by wildtype littermates. These results suggest MuRF1 inhibits thyroid hormone‐dependent cardiac growth governed, at least in part, by MuRF1's ability to directly interact with TRα, inhibiting its transcriptional activity likely by post‐translational modification with ubiquitin.
STIM1 silencing prevents pressure‐overload induced cardiac hypertrophy in mice
Authors: Benard Ludovic Olivier , Jeong Dongtak , Matasic Daniel S , Kohlbrenner Erik , Hajjar Roger J , Hulot Jean-Sebastien
Published: June 2021

STromal Interaction Molecule 1 (STIM1), a membrane protein of the endoplasmic reticulum (ER), has recently been proposed as a positive regulator of cardiomyocyte growth by promoting calcium (Ca2+) entry through the plasma membrane and the activation of Ca2+‐mediated signaling pathways (Circulation, 2011).

To further extend this observation, we studied the impact of STIM1 silencing in pressure‐overload induced mouse model of cardiac hypertrophy using recombinant Associated Adenovirus 9 (AAV9)‐mediated gene silencing. C57/Bl6 Mice were injected with saline (noAAV) or with rAAV9 expressing shRNA against STIM1 (shSTIM1) or a control shRNA (shScr) at 1E+11 viral genome by tail vein injection. Three weeks later, Transverse Aortic Constriction (TAC) surgery was performed (4 experimental groups: sham, TAC‐noAAV, TAC‐shScr and TAC‐shSTIM1). In contrast to TAC‐noAAV or TAC‐shScr, the rAAV9‐shSTIM1 treated animals developed significantly reduced cardiac hypertrophy developed as assessed by echocardiogtaphy and hemodynamics three weeks after surgery. TAC‐ShSTIM1 however displayed left ventricular dilation and a non‐significant trend for depressed systolic function.

These results indicate STIM1 as a key regulator of cardiac hypertrophy.
Chinese Visible Human Project and its application
Authors: Zhang Shao-Xiang
Published: June 2021

“Visible Human Project (VHP)” was initiated by US National Library of Medicine in 1989. Afterwards, the library signed contract with Health Science Center of the University of Colorado to formally carry out the project in August 1991. Accordingly, research team at the University of Colorado collected a structural data set of human body after obtaining successive sectional images. A digital image data set of a complete human male cadaver was acquired and made available for public use in November 1994, which aroused worldwide enthusiasm in this field. And remarkable social and economic benefit has been gained. Thereafter, some countries initiated their visible human project one after another. Korea started 5‐year “Visible Korean Human (VKH)” project (Mar.2000—Feb.2005) in 2000 and first data set was derived from a patient with acquired cerebroma in 2001. China started its project in 1999 which the first data set of Chinese visible human was set up at The Third Military Medical University in October 2002. Before then, by utilizing data made public by US VHP, Chinese scientists in informatics had exerted themselves on preliminary work to pave the way for further achievement. Now VHP research is so promising a scientific field to meet the need of digital era and will be increasingly common in many areas relating with structure and function of human body, the deployment of Chinese Visible Human Project (CVHP) is of great strategic significance in science and technology.

Since it was build up nine years ago, CVH data set has been widely applicated in various fields including creating a human body model for radiation protection and for comparing images for B ultra sound diagnosis and making models for surgary simulation.
Estrogen Receptor‐Positive Breast Cancer Cells Drive CAFs to Secrete Leptin and Support Tumor Invasiveness
Authors: Barone Ines , Catalano Stefania , Gelsomino Luca , Panza Salvatore , Marsico Stefania , Giordano Cinzia , Bonofiglio Daniela , Casaburi Ivan , Covington Kyle R , Fuqua Suzanne , Andò Sebastiano
Published: June 2021

Background

Tumor phenotype is a result of the complex interactions between malignant cells and surrounding stroma. Leptin, a known cytokine involved in breast cancer development, is expressed by several cells as fibroblasts. K303R estrogen receptor (ERα) mutation, identified in 50% of invasive breast tumors, was associated with worst outcomes.

Methods

Wild type (WT) and K303R ERα stably transfected MCF‐7 cells for breast cancer. Human Cancer Associated Fibroblasts (CAFs) as stromal cells. Microarray and realtime PCR to evaluate changes in breast cancer‐secreted factors. MTT, Soft Agar and Scratch assays for growth and motility. Leptin release by RIA.

Results

CAFs secrete leptin when cocultured with WT ERα breast cancer cells and to a higher extent in cells expressing the K303R hyperactive ERα. Immunodepletion experiments show that CAFs‐derived leptin, in turn, supports cancer cell invasiveness. Moreover, K303R‐conditioned media (CM) dramatically alter CAFs shape, increase Fibroblast Activation Protein expression, and enhance CAFs viability and motility compared to WT‐CM. We identify Epidermal Growth Factor as a major determinant for K303R‐activated CAFs phenotype.

Conclusions

We uncover a bidirectional cross‐talk between breast cancer cells and ‘educated’ CAFs. Blockade of these intercellular communications represent an effective strategy for molecular targeted therapies in breast cancer.
Reprogramming the cancer epigenome by “metabolic transduction”
Authors: Byun Jung S , Gardner Kevin
Published: June 2021

C‐terminal binding protein (CtBP) is a dimeric nuclear corepressor complex that functions generally to target chromatin modifying complexes including histone de‐acetylases, histone de‐methlylases, histone methyl‐transferases and DNA methyl‐transferase complexes to chromatin. CtBP thus has the potential to mediate widespread changes in the epigenetic landscape and influence broad programs of cellular behavior. Recently, we showed genome‐wide profiling by ChIP‐seq that CtBP controls a network of genes linked to cellular programs that influence cellular re‐programing or “plasticity” including stem cell transcriptional programs, angiogenesis, and epithelial‐to‐mesenchymal transition. In human breast cancer samples, we find that CtBP protein expression profiling by immunohistochemistry followed by digital quantitation reveals a clear trend between CtBP expression and poor survival from breast cancer. Follow‐up studies show that CtBP RNA are significanlty higher in the endometrial cancer cell line HEC‐1A compared to MCF‐7 and that, similar to breast cancer, central targets of CtBP repression lead to increased signaling through the WNT pathway. This suggested that CtBP may be a common feature in tissues and cellular systems that undergo reprogramming of any type and this capacity to reprogram may be exploited in different epithelial cancer in processes linked to CtBP.