bluuebunny/crossref_metadata_2025 huggingface dataset:
From genes to milk: genomic organization of the mammary transcriptome
Authors: Lemay Danielle G , Rijnkels Monique , German J. Bruce , Pollard Katherine S
Published: June 2021

In a previous study, it was observed that a subset of non‐redundant expressed sequence tags derived from bovine mammary gland tissue were co‐located in the bovine genome statistically more frequently than expected by chance. On the basis of this finding, we hypothesized that genes expressed in mammary tissue, like those expressed in other tissues, are organized into gene neighborhoods. Novel methods were developed to characterize mammary gene neighborhoods using publically available microarray data. Gene neighborhood size, both in terms of the number of genes and the base pair length, is similar between genes expressed in the lactating mammary gland and in other tissues. As a trend, correlation of gene expression decreases with increasing genomic distance but the scatter of the data reflects strong correlations between a subset of distantly located genes. This observation is consistent with co‐expression of genes that are far apart in linear DNA but physically close in vivo due to folds in the three‐dimensional chromatin structure. Overall, these investigations confirm that milk production arose within mammalian ancestors without requiring major changes to eukaryotic genome architecture. Funded by the California Dairy Research Foundation.
Walnuts alter IGF‐1 signaling and lipogenesis genes and reduce TRAMP prostate tumor size and growth
Authors: Davis Paul Andrew , Vasu Vihas , Gohil Kishor , Kim Hyunsook , Yokoyama Wallace , Khan Imran , Cross Carroll
Published: June 2021

To assess walnut effects on prostate cancer, male TRAMP mice (age 8 wks,n=84; JAX) were fed ad lib either lowfat(LF), highfat(HF) or highfat walnut(WD) diets with equal αandγ tocopherol for 9,18, 24 wks. Prostate wts at 18 weeks were lower in LF(1.1±0.1g) and WD(1.3±.1g) vs HF(2.4±0.6g). WD plasma IGF1 was (59±11vs84±32ng/ml HF, p ≤ 0.03). Prostates(GUI) were probed using GeneChip Mouse Gene 1.0 ST Array and dChip. 11 and 78 genes were differentially expressed (≥ 1.2 fold Δ and p ≤ 0.05) in WD versus HF at 9 and 18 weeks respectively ‐FOXO3A (−1.4 fold at 18 weeks) controls IGF‐1/insulin sensitivity and StearoylCoA Desaturase‐1(−1.93 fold at 9 weeks) controls lipogenesis and tumor formation/growth. Walnuts reduce tumor size and growth via decreased plasma levels and genes associated with growth/IGF‐1 signaling.
The effect of physiological concentrations of six hormones on the growth of breast and prostate cell lines treated with human serum
Authors: Esfahani Amin , Bashyam Balachandran , Kendall Cyril WC , Srichaikul Korbua , Archer Michael C , Jenkins David JA
Published: June 2021

Background

The majority of cell culture studies assess the effect of hormones on cancer cell growth using media supplemented with charcoal treated serum (CTS). Our objective was to determine the effect of various hormones on the growth of breast and prostate cancer cells incubated in untreated whole human serum (PHS).

Methods

MCF‐7, MCF‐10A breast and LNCaP prostate cancer cell lines supplemented with PHS were treated with two physiological concentrations of six hormones (17β‐estradiol (E2), dehydroepiandosterone (DHEA), dihydrotestosterone (DHT), testosterone (T), insulin and glucagon). Cell viability was measured after 72 hours using the MTS assay.

Results

All hormones stimulated growth of MCF‐7 cells (p<0.05). MCF‐10A cell growth was inhibited by DHEA, DHT and T (p<0.05), unaffected by E2 and glucagon, and stimulated by insulin (p<0.05). LNCaP cell growth was stimulated by the highest concentration of DHEA and DHT (p<0.05) and inhibited by the highest concentration of E2 (p<0.05). Insulin and T did not alter LNCaP growth. PHS lowered the magnitude of the hormonal effect by comparison to CTS.

Conclusions

Unexpectedly, high concentrations of testosterone did not stimulate LNCaP cell growth and we observed for the first time that glucagon stimulates breast cancer cell growth. (Funding provided by Canada Research Chair discretionary funds)
Plasma hepcidin is a modest predictor of dietary iron bioavailability in humans, whereas oral iron loading, measured by stable‐isotope appearance curves, increases plasma hepcidin
Authors: Troesch Barbara , Biebinger Ralf , Egli Ines , Zeder Christophe , Hurrell Richard , Zimmermann Michael
Published: June 2021

Plasma hepcidin appears to be a major regulator of iron absorption and homeostasis, but there are few data in humans.

We aimed to see if circulating hepcidin predicted iron bioavailability and to measure the plasma hepcidin response to varying amounts of absorbed iron.

In study 1, women (n = 98) with serum ferritin concentrations < 25 or > 40 μg/L were given stable isotope–labeled meals with ferrous sulfate (FeSO4), ferrous fumarate (FeC4H2O4), or ferric pyrophosphate (FePPi). Then, plasma hepcidin and iron absorption were measured. In study 2, iron‐sufficient men (n = 4) were given oral doses of 3.8 mg and 60 mg iron as labeled FeSO4. The stable isotope appearance and the plasma hepcidin curve were measured over 6 h.

In study 1, plasma hepcidin and ferritin strongly correlated (r = 0.79, P < 0.001). Plasma hepcidin significantly, but modestly, predicted iron bioavailability from FeSO4 and FeC4H2O4 (r = 20.51 and 20.46, respectively; P < 0.0001) but not from FePPi (r = 20.30, P = 0.056). In study 2, the 3.8 mg dose increased circulating absorbed iron to 0.42 μmol/L but did not increase plasma hepcidin. The 60 mg dose increased mean circulating absorbed iron to 5.9 μmol/L and produced a ~30% increase in plasma hepcidin at 6 h (P < 0.01).

Plasma hepcidin is only a modest predictor of dietary iron bioavailability. Oral iron loading increases circulating hepcidin.

The ETHZ and DSM Nutritional Products financially supported this study.
Iron bioavailability from maize‐based diets fed to iron deficient broiler chickens
Authors: Tako Elad , Lung'aho Mercy , Kochian Leon V , Hoekenga Owen A , Glahn Raymond P
Published: June 2021

Iron biofortification is a strategy that alleviates Fe deficieny by improving staple crops, such as maize (Zea mays). Using a Caco2 cell model, two maize varieties were developed for high and low Fe bioavailability. In vitro observations should be tested in animals prior to human efficacy studies. We tested bioavailable Fe in our maize varieties using the broiler chicken as a model. Diets were made with 75% w/w maize of either the low (“Low”) or high (“High”) Fe bioavailability maize; Fe content was not different (both 24 μg/g). In vitro analysis showed lower ferritin formation (ie. Fe uptake, P<0.05) in cells exposed to the “Low” (20 ng/mg) vs. “High” (37 ng/mg) diets. Chicks (n=6) were fed the maize based diets for 4 weeks. Hemoglobin (Hb), body weight, feed consumption and gene expression were measured. Duodenal DMT1, Dcytb and ferroportin were higher (P<0.05) in the “Low” group vs. the “High” group, indicating adaptation to the “Low” diet. Hb concentrations, hemoglobin maintenance efficiency, Hb‐Fe and liver ferritin were higher in the “High“ group vs. the “Low” group (P<0.05), indicating greater Fe absorption from the diet and improved Fe status. We conclude that the in vivo results support the in vitro observations, ie. the “High” variety contains more bioavailable Fe than the ”Low” and that maize shows promise for Fe biofortification.
Folate intake post‐folic acid grain fortification and pancreatic cancer risk in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial
Authors: Oaks Brietta , Dodd Kevin W , Meinhold Cari L , Jiao Li , Church Timothy R , Stolzenberg‐Solomon Rachael Z
Published: June 2021

Folate plays a critical role in DNA methylation, synthesis, and repair. Several epidemiologic studies suggest that higher folate intake is associated with reduced pancreatic cancer risk. We investigated the association between dietary folate intake and pancreatic cancer in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO) cohort. Dietary data were collected using a food frequency questionnaire (1998–2005). Among the 51,988 male and 57,187 female participants, aged 55–74 years at enrollment, 162 men and 104 women developed pancreatic cancer during follow‐up (median 6.5 years). We used Cox proportional hazard regression to calculate hazard ratios (HR) and 95% confidence intervals (CI). The highest compared to the lowest quartile of food folate was associated with a significantly reduced pancreatic cancer risk among women, (≥ 253.3 vs. ≤ 179.1 μg/day, HR = 0.47, 95% CI 0.23, 0.94, ptrend = 0.09) but not among men (≥ 229.6 μg/day vs. ≤ 158.0 μg/day, HR = 1.20, 95% CI, 0.70, 2.04, ptrend = 0.67, p‐interaction by sex = 0.03). There was also a significant inverse trend in risk of pancreatic cancer across increasing quartiles of total folate in women (ptrend = 0.04) but not men (ptrend = 0.65). Folic acid supplements were not associated with pancreatic cancer. These findings support an association between higher food and total folate intakes and reduced risk of pancreatic cancer in women but not men.

Grant Funding Source: NIH Cancer Research Training Award
Low dietary vitamin D (VD) and high dietary calcium (Ca) increase prostate carcinogenesis in APT121 transgenic mice
Authors: Fleet James C. , Smolinski Justin B. , Rengel Robert C. , McCreedy Rebecca , Clinton Steven K.
Published: June 2021

Epidemiologic studies suggest that low serum 25 hydroxyvitamin D (25OHD) or reduced serum 1,25 dihydroxyvitamin D (1,25 D) caused by high Ca diets increases prostate cancer risk. We examined these hypothesis in APT121 mice with disrupted Rb function that model the early stages of prostate cancer (i.e. prostate intraepithelial neoplasia (PIN), adenocarcinoma, well differentiated and microinvasive carcinoma (microCa)). Mice were fed diets (n = 30 per diet) varying in dietary VD3 (25, 150, 1,000 IU/kg diet) or Ca (0.2%, 0.5% or 1.5% Ca) from 428 wks (3×3 factorial design). Diet VD increased serum 25OHD (53, 87, and 154 nmol/L for the 25, 150, and 1000 IU diets) and diet Ca suppressed serum 1,25D (285, 199, and 94 pmol/L for the 0.2, 0.5, and 1.5% Ca diets). High diet VD reduced the prostate cancer phenotype (microCa incidence = 95%, 86% and 69%; incidence of less severe PIN lesion = 5, 14, 31% for the 25, 150, and 1000 IU diets, respectively) while high diet Ca modestly worsened prostate pathology. In contrast, femur bone mineral density was most responsive to dietary Ca (+8.6% between 0.2 and 1.5% Ca) and not influenced by diet VD. Our study supports the hypothesis that high dietary VD prevents the early stages of prostate carcinogenesis in vivo and that high Ca diets modestly attenuate the anti‐carcinogenic effects of 1,25(OH)2D while having a beneficial impact upon bone density. Support from NCI award CA101113 to JCF and AICR to SKC
A method to estimate instantaneous rates of gas exchange in indirect calorimetry
Authors: Gribok Andrei V , Rumpler William V , Hoyt Reed , Buller Mark
Published: June 2021

Respiration chambers are the primary tools to study energy metabolism of humans and animals for periods of several minutes to several days. The chambers employ the method of indirect calorimetry, where the amount of oxygen consumed (VO2) and the amount of carbon dioxide produced (VCO2) are the two main measurement used to determine substrate utilization via the respiratory quotient (RQ) and energy expenditure. However, the large volume and inertia of the chambers, pose unique challenges in estimation of the short‐term dynamics of the gas exchange. To account for dynamic changes in the VO2 and VCO2, a correcting factor needs to be added to the equations used to estimate the gas exchange rate. This correction requires an estimate of a derivative of the fractional gas concentration. Being a high‐pass filter, differentiation amplifies measurement noise rendering the resulting instantaneous values useless. To rectify this situation, we applied a standard regularization technique to obtain accurate instantaneous values of VO2 and VCO2. The correctly estimated gas exchange rates allowed accurate estimation of the instantaneous RQ and its dynamic characteristics, such as frequency content, which provides a new tool for studying the substrate utilization in different populations. In contrast to the current practice of reporting substrate oxidation and energy expenditures as 4h to 24h averages, our approach allows the reporting of data over intervals of several minutes to fractions of hours.
Plasma Vitamin D Concentrations and Dietary Sources among Puerto Ricans Living In the Greater Boston Area
Authors: Jamal‐Allial Aziza , Tucker Katherine L.
Published: June 2021

Puerto Ricans are the second largest Hispanic sub‐group in the US; yet there are no available data on this population regarding plasma concentrations or dietary sources of vitamin D. We determined plasma 25‐hydroxy vitamin D concentrations (plasma 25(OH)D) and their associations with key variables, cross‐sectionally, among 1292 Puerto Rican adults, 379 men and 913 women aged 45–75 years. Dietary data from FFQ were used to rank food items by vitamin D intake contribution. The geometric means for plasma 25(OH)D concentrations were 15.8 ± 1.5 ng/ml for men and 16.0 ± 1.5 ng/ml for women. Our results showed that 68.6% of men and 65.5% of women were deficient, based on the cutoff of <20 ng/ml. Multiple linear regression analysis showed that plasma 25(OH)D was significantly lower in winter and spring and higher in summer, relative to the fall (each P<0.0001). Age and plasma albumin were positively associated, while BMI was inversely associated with plasma 25(OH)D (P<0.05). Smokers had significantly lower plasma 25(OH)D than past smokers (P=0.003) but not than never smokers. Plasma 25(OH)D did not differ by sex, serum creatinine, supplementation use, or physical activity. Milk products contributed 34% of total vitamin D intake, followed by supplements, 21.5%, and fish products, 18.3%. To our knowledge, this is the first report to document plasma 25(OH)D status in this growing segment of the US population.
Mediterranean‐Style Dietary Pattern and Incident Diabetes in the Framingham Heart Study Offspring
Authors: Hruby Adela , Jacques Paul F. , Rumawas Marcella E. , Fox Caroline S. , Meigs James B. , Troy Lisa M.
Published: June 2021

A Mediterranean‐style diet is considered a heart‐healthy dietary pattern and has been associated with decreased risk of cardiovascular disease (CVD). We developed the Mediterranean‐Style Dietary Pattern Score (MSDPS) to assess associations between diets conforming to the Mediterranean‐style diet and chronic disease risk. The MSDPS is unique among Mediterranean diet scores because it accounts for over‐consumption of Mediterranean pattern foods as well as consumption of non‐Mediterranean foods. We examined associations between MSDPS and incident type 2 diabetes (DM2) among 1326 men and 1588 women in the Framingham Offspring cohort (mean age 54 years at baseline) with MSDPS values of 4.0–49.6 (possible range 0–100). Incidence of DM2 (n=162) was assessed over 11 years (1991–2001). Logistic regression was used to obtain an OR (95% CI) of DM2 by MSDPS. After adjustment for age, sex, baseline BMI, smoking status, hypertension, and total energy intake, there was no significant association between MSDPS and incident DM2, OR=0.99 (0.96, 1.01). Further adjustment for physical activity did not materially change these results. Conformity to a Mediterranean‐style diet as measured by the MSDPS is not associated with lower risk of DM2 in this middle‐aged population of US men and women.
Postnatal growth following maternal gestational supplementation with docosahexanoic acid (DHA): randomized placebo‐controlled trial in Mexico
Authors: Stein Aryeh D , Wang Meng , Martorell Reynaldo , Neufeld Lynnette , Flores‐Ayala Rafael , Rivera Juan , Ramakrishnan Usha
Published: June 2021

Little is known about the long term benefits of ingesting DHA supplements during pregnancy. We have reported (Ramakrishnan et al., ICN 2009) that offspring of primiparous Mexican women who participated in a randomized double‐blind placebo‐controlled trial of 400 mg/day DHA from week 20 of gestation through delivery were heavier and had larger head circumferences (HC) at birth than children whose mothers received placebo; no effect was observed in offspring of multiparous women. We have followed these children through 18 mo of age (n= 739; 76% of the birth cohort), measuring length, weight and HC at 1, 3, 6, 9, 12, 18 mo. At 18 mo, intent‐to‐treat differences between the DHA and control groups were: length −0.22 cm (95% CI −0.58, 0.14); weight −0.03 kg (−0.19, 0.13); HC 0.01 cm (−0.18, 0.21) (all p>0.05 by t‐test). To assess the overall growth pattern through age 18 mo we used GEE; intent to treat analysis showed no association (p>0.4 for each test). For all 3 measures, the treatment by parity interaction had p<0.1. Among first‐borns, estimates were: weight 0.08 kg (−0.07, 0.23): length 0.55 cm (0.14, 0.96, p<0.05): HC 0.10 cm (−0.16, 0.35); among later‐borns, estimates were: weight −0.08 kg (−0.19, 0.03); length −0.19 cm (−0.50, 0.11); HC −0.20 cm (−0.40, −0.01, p<0.05). We conclude that growth patterns through age 18 mo following prenatal DHA supplementation in a study population with low intakes of DHA differ by maternal parity.
1. Maternal zinc supplementation during pregnancy: effects on offspring autonomic function at 4 ½ years of age
Authors: Caulfield Laura Elizabeth , Zavaleta Nelly , Chen Ping , Putnick Diane , Bornstein Marc H , DiPietro Janet
Published: June 2021

Objective

To evaluate the persistence of differences in autonomic function in Peruvian children at 4 ½ years of age, whose mothers had participated during pregnancy in a zinc supplementation trial.

Methods

We followed up 205 children from the original trial, and present data on 165 (80%) children, 79 who mothers took 25 mg/d zinc in addition to 60 mg iron and 250 ug folic acid (FA) during pregnancy, and 86 whose mothers took iron and FA only. We collected ECG data on the children at rest and while they undertook cognitive testing following a standardized protocol. Derived cardiac measures were heart period (HP), HP variability (HPV), respiratory sinus arrhythmia (RSA), mean standard deviation (MSD) and HP range.

Results

At baseline, children in the zinc supplementation group had greater HP, RSA, HPV, MSD and range (P < 0.05). When analyzed across the tasks, prenatal zinc supplementation was estimated to result in 21.602 (9.491) greater HP, 0.310 (0.130) greater HPV, 4.723 (1.946) greater MSD (all P < 0.05), 0.327 (0.182) greater RSA (P =0.075), and 14.298 (8.273) greater range (P=0.086).

Conclusions

Differences in autonomic function associated with maternal prenatal zinc supplementation were detectable in the offspring at 4 ½ years of age. Supported by NICHD.
Hepatic One Carbon Metabolism in Diet‐Induced Obesity
Authors: Glier Melissa B , Sulistyoningrum Dian C. , Ghosh Sanjoy , Devlin Angela M
Published: June 2021

Obesity is a major cause of fatty liver disease. We hypothesize that disturbances in liver one carbon metabolism contribute to the pathology of obesity‐related fatty liver disease. We studied the effect of diet‐induced obesity in mice heterozygous for targeted deletion of cystathionine‐β‐synthase (+/−) and C57BL/6J (+/+) mice fed a high fat (60% energy) diet (HF) or a control diet (C) from weaning for 12 weeks. HF+/− and HF+/+ mice had higher body weight (P<0.001), greater fat mass accumulation (P<0.001), higher liver triglycerides (P<0.05), and lower liver cholesterol ester (P<0.001) than C+/− and C+/+ mice, respectively. Independent of diet, C+/− mice had lower liver S‐adenosylmethionine (AdoMet) (P<0.05) levels, and higher liver S‐adenosylhomocysteine (AdoHcy) (P<0.001) levels. Both +/− and +/+ mice fed the HF diet had lower levels of liver AdoHcy (P=0.001) than mice fed the C diet. HF+/− mice had lower liver AdoMet levels (P=0.01) than C+/− mice, however this effect was not observed in +/+ mice. These findings suggest that disturbances in liver one carbon metabolism are associated with hepatic lipid accumulation in mice with diet‐induced obesity.
Meta‐analysis of cancer incidence in folic acid supplementation trials
Authors: Baggott Joseph E. , Oster Robert A. , Tamura T.
Published: June 2021

It has been suggested by several research groups that folate is procarcinogenic. Data in the 1940s of folate supplementation indicated that it enhanced the proliferation of cancer cells. Folate is a unique vitamin because its coenzymes are required for de novo adenine, guanine, and thymine nucleotide biosynthesis; therefore, it is essential for DNA synthesis and repair, and RNA synthesis, and structurally related folate analogs, such as methotrexate, are used as anticancer agents. Using a meta‐analysis weighted for the duration of folic acid (FA, pteroylglutamic acid) supplementation, we analyzed the cancer incidence of 5 published large prospective FA supplementation trials that lasted 1 year or more involving men and women. These articles were selected from over 1,100 identified by a PubMed search that was done in June 2009, and skin cancer was excluded by the original investigators or by us. Our data suggest that cancer incidence was higher in the FA supplemented groups than the non‐FA supplemented groups (relative risk = 1.26 [95% confidence interval: 1.05–1.51]). FA supplementation trials should be performed with careful monitoring of cancer incidence by investigators, and funding agencies should provide long‐term support. In the US, solid monitoring systems to detect side effects, such as increased cancer risk, should have been established before the food FA fortification mandate.
A single dose of quercetin lowers blood pressure in hypertensive but not prehypertensive males
Authors: Larson Abigail , Guo Yi , Black Kathryn S , Hayman Melissa A , Richardson Russell S , Bruno Richard S , Jalili Thunder , Symons J David
Published: June 2021

Previously we reported that 730 mg/d quercetin (Q) for 28 d reduces blood pressure (BP) in hypertensive subjects without affecting systemic markers of oxidative stress. Q supplementation in hypertensive rodents lowers BP by decreasing ACE activity. We hypothesized that a single dose of Q would lower BP and ACE activity in hypertensive males. A preliminary study conducted in normotensive males (n=6) indicated that maximal plasma Q concentrations (2.33 ± 0.72 μM) occurred 10 h after ingesting 1095 mg Q and levels returned to baseline (0.45 ± 0.06 μM) by 24 h. Based on these data hypertensive (n = 6, 40 ± 11 y, BMI < 35) and prehypertensive (n = 5, 48 ± 10 y, BMI < 35) males consumed a low Q diet for 7 days. Participants then ingested placebo (P) or 1095 mg Q, with each treatment separated by >48 h. BP (mmHg), heart rate (HR), and blood samples to assess ACE activity (U/L) were obtained 10 h later after an overnight fast. In hypertensive males systolic BP (139 ± 3 vs. 149 ± 3) and mean BP (105 ± 3 vs. 112 ± 3) were decreased (p<0.05) by Q vs. P treatment, respectively. ACE activity was not different between the Q (16 ± 4 U/L) and P (18 ± 4 U/L) treatments. BP, HR, and ACE activity were similar 10 h following Q and P in prehypertensive subjects. Thus, a single Q dose decreases BP in hypertensive but not prehypertensive males.

Grant Funding Source: PEAK Academy of the University of Utah
Soluble mediators from endotoxin‐stimulated stellate cells cause sustained JNK activation, ER stress and apoptosis of hepatocytes
Authors: Gandhi Chandrashekhar R , Huang Chao , Stolz Donna , Harvey Stephen AK , Wu Tong
Published: June 2021

Cells respond to various injurious stimuli by undergoing endoplasmic reticulum (ER) stress that is utilized as a survival or death mechanism. Bacterial lipopolysaccharide (LPS)‐stimulated hepatic stellate cells (HSCs) produce mediators that inhibit DNA synthesis and induce apoptosis of hepatocytes. Our objective was to investigate whether (a) LPS causes ER stress and apoptosis of hepatocytes in vivo, and (b) soluble mediators released by LPS‐stimulated HSCs cause ER stress leading to apoptosis of hepatocytes in vitro. LPS (10 mg/kg; ip) treatment of rats for 6h was found to cause ER stress/autophagy, activation of JNK MAPK and activation/expression of ER stress‐related molecules PERK, eIF2á and CHOP, and activation of caspase‐3 in hepatocytes. In vitro, soluble mediators released by LPS (10–1000ng/ml)‐stimulated HSCs in serum‐free condition caused cytosolic vacuolization associated with activation/increased expression of PERK, eIF2á and CHOP. LPS‐stimulated HSCs also caused activation of p38‐ and JNK‐MAPK in hepatocytes. However, blockage of JNK but not p38 activation ameliorated ER stress, inhibition of DNA synthesis and caspase‐3 activation caused by LPS‐stimulated HSCs. The results suggest that the ER stress induced by mediators released by LPS‐stimulated HSCs in hepatocytes may be an important mechanism that dictates their survival or death. Supported by an NIH grant (DK 54411).
Evaluation of a T cell growth factor (TcGF) in a model of liver injury induced immunologically
Authors: Osuna‐Martínez Ulises , García‐Solís Mario , Torres‐Aguilar Lorena , Reyes‐Esparza Jorge , Rodriguez‐Fragoso Lourdes
Published: June 2021

The aim of this study was to evaluate the effect of TcGF in a model of liver injury induced immunologically by chronic administration of porcine serum (PS). For the study 32 male Wistar rats (200 g) were used. Animals were divided into 4 groups of treatments (n=8): (1) Control (PBS 0.5 ml 3 times a week for 8 weeks), (2) TcGF (50 ng/kg 3 times a week for 4 weeks), (3) PS (373 mg/kg twice a week for 8 weeks), and (4) PS + TcGF. At the end of the 8th week of treatment animals were sacrificed using CO2 chamber. Liver morphology was evaluated by optic microscopy using H&E and Masson stain, liver functions (ALT, AST, PA, and bilirubins) and lymphocyte T population (CD3, CD4 and CD8) were evaluated in blood samples. Animals treated with PS developed alterations on portal structure, and liver fibrosis; there was an increase in the serum activity of ALT (2.9‐fold), TB (1.0‐fold) and DB (3.9‐fold) in comparison with the control (p< 0.05). There was an increase in CD3 (2.15‐fold) and CD8 cells (4.87‐fold) compared with control (p< 0.05). Rats with liver injury and treated with TcGF showed a reduction in portal alterations, showed less fibrosis, a reduction of ALT (47%) and an increase in CD3 and CD8 cells (1.93‐fold and 3.88‐fold) as compared with PS group (P < 0.05). TcGF induced by itself increases in CD3 and CD8 cells. In conclusion, the treatment with TcGF reduced the liver injury and improved the liver function in animals treated with PS.
Designing a First Year Integrated Course to Meet the Mission & Values of a New Medical School
Authors: Guttmann Geoffrey D.
Published: June 2021

It is exciting to design a new medical school curriculum because you have a table rasa or clean slate with which to work. The design of the curriculum has to fit within the culture that is being built in the medical school. In constructing the curriculum, it is important to evaluate the mission and values that will be the guiding principles. The Commonwealth Medical College's (TCMC) mission involves serving “society using a community‐based, patient‐centered, interprofessional and evidenced‐based model of education” and “utilizes innovative techniques.” Two of the three major first year courses integrate the basic sciences and particularly the anatomical sciences within the spiral curriculum. Gross anatomy, histology, embryology, radiological anatomy, clinical anatomy and physiology are components of the Human Structure and Function (HSF) course that runs 17 weeks. Pathology, microbiology and pharmacology play a role in HSF but are not studied to the same depth as in the second year. The other first year course is Brain, Mind and Behaviour (BMB), which follows a patient presentation approach, used by the University of Calgary. BMB will initiate students to applying clinical reasoning to their learning and integrating all basic sciences. Much enthusiasm and support for our curriculum comes from our community clinical faculty, who have volunteered to participate in the teaching and learning program at TCMC.
Dynamic Changes in Cell Surface Glycosylation Regulate Immune Cell Survival, Differentiation and Function
Authors: Baum Linda Gwen
Published: June 2021

Glycans decorate virtually every cell surface protein, and glycosylation of cell surface proteins changes dynamically during cellular development, differentiation and activation. The processes that regulate these dynamic changes are not well understood, but it is clear that regulation of cellular glycosylation is critical for these events. We will focus on the changes in cell surface glycosylation that occur during development and function of T cells in the thymus and in the periphery, and how regulated glycosylation controls the interaction of T cells with endogenous lectins that control positive and negative selection of immune competent thymocytes, as well as T cell adhesion and migration, polarization, and apoptosis. Using cellular and molecular approaches, as well as animal models, we will discuss how regulation of this type of post‐translational modification affects T cell function in autoimmunity, hypersensitivity, cancer, and organ transplant settings. Supported by NIH AI060694, CA139368 and GM63281.
Coordination of dorsoventral axis formation by multiple heparan sulfate proteoglycans
Authors: Kramer Kenneth L
Published: June 2021

Heparan sulfate proteoglycans are essential mediators of multiple cell‐cell signaling pathways during embryonic development. To better understand how glypicans (GPCs) ‐ a membrane anchored subfamily of heparan sulfate core proteins ‐ function in zebrafish development, we used antisense morpholinos to individually and specifically knock down the expression of all ten GPC genes in zebrafish. Knockdown of GPC2, GPC6a, or GPC6b uniquely resulted in strong dorsoventral phenotypes between gastrulation and 24hpf. To better understand the molecular pathways in which GPCs are involved, we used a candidate gene approach to study changes in transcription of BMP, Wnt and FGF target genes because these cell‐cell signaling pathways are known to regulate dorsoventral patterning. We identified gene expression patterns that were different between each GPC knockdown, with GPC2 having a distinct affect on FGF target genes. These results were confirmed using several complimentary approaches, suggesting that GPC2, GPC6a, and GPC6b regulate distinct steps in dorsoventral patterning, an observation that adds a new dimension to our understanding of how proteoglycans work together to mediate early development.
A clinician‐anatomist's view of surface anatomy
Authors: O'Donoghue Daniel L.
Published: June 2021

The heart of a clinical encounter relies on detailed knowledge and discussions that relate symptoms and presentations to an individual's anatomy. Patients have complaints that usually relate to some specific area of their body and the clinician is engaged to help elucidate or address the concerns of the patient. Regardless of the body location for the patients concern, the clinician should be able to provide authoritative and sensible explanation to the patient. Patients seek two important pieces of information, the diagnosis and the prognosis. The structured clinical encounter flows from a patient history through a sequence of physical maneuvers designed to discover the status of the various organ systems of the body. In the general physical exam, this process evaluates all body regions and be consistent so as to maximize the information gleaned from individual to individual. Significant finding must be interpreted in light of the individual's anatomy and how it relates to overall function. This presentation will highlight major techniques and salient abnormal finding that are indicative of the major organ systems. There are no disclosures to reveal.
How hybrid mass spectrometers with multiple analyzers and dissociation methods will transform protein sequence analysis
Authors: Coon Joshua J.
Published: June 2021

We describe the use of new mass spectrometry technology for the large‐scale characterization and quantification of proteomes. The new instrument allows for the implementation of multiple peptide dissociation methods and for the automated selection of each in a real‐time based on multiple precursor attributes. Protein quantification is readily accomplished through use of isotopic labels – either SILAC or iTRAQ. The instrument will propel top‐down proteomics by combining ETD and Orbitrap detection to achieve direct analysis of intact proteins on a sub‐second timescale with ~ 300 ppb mass accuracies. Such mass accuracies are used to directly annotate tandem mass spectral peaks with ion type and chemical composition. We demonstrate these and other aspects of the instrument on a variety of applications involving human embryonic stem (hES) cells. In particular we identified over 8,000 proteins and 13,000 phosphopeptides in an experiment investigating similarities and differences between hES and iPS cells that may affect the use of iPS cells for research and therapeutic purposes.
Antibodies to TNF‐α Soluble Receptors Exacerbate Airway Inflammation in a Mouse Model of Asthma
Authors: Kim Jiyoun , Vaickus Louis , Bouchard Jacqueline , Schuller Elizabeth , Remick Daniel G
Published: June 2021

We investigated TNF soluble receptor (TNF‐SR) regulation of airway TNF‐α expression to determine mediators responsible for exacerbation of pulmonary inflammation and airway hyperresponsiveness (AHR).

A house dust extract (HDE) containing cockroach allergens and endotoxin was used to immunize BALB/c mice on day 0 with 2 additional pulmonary challenges on d14 and d21. Groups of mice received a mixture of rat anti TNF‐α SR I and II antibodies (Abs), or rat IgG. Two hrs after the last HDE challenge AHR was measured and bronchoalveolar lavage (BAL) fluid collected.

Abs to TNF‐α SR essentially depleted pulmonary TNF‐α SR I and II while the airway concentration of TNF‐α was significantly increased compared to control Abs. Total inflammatory cells were reduced, primarily due to fewer neutrophils despite increases in the CXC chemokines KC and MIP‐2. Blockade of TNF‐SRs increased AHR.

IgG
Anti TNF SR Abs
P value

TNF‐α (pg/ml)
5371 ±641
14498 ± 2988
0.007

TNF‐sRI
143 ±9
16 ± 2
<0.0001

TNF‐sRII
2829 ±204
7 ± 1
<0.0001

Total cells (x1000)
657 ± 215
960 ± 334
0.049

Neutrophils (x1000)
557 ± 200
868 ± 331
0.039

KC (pg/ml)
1227 ±415
1997±247
0.021

MIP‐2 (pg/ml)
2081 ±647
3704±670
0.023

AHR (% increase of Penh)
180±21
285±45
0.04

These results demonstrate that blocking both TNF‐α SR I and II significantly increases AHR and exacerbates the asthma‐like pulmonary inflammation via increased expression of TNF and CXC chemokines in a mouse model of asthma.

This work was supported by NIH Grant R01 ES0135283‐03.
HOW CELLS SENSE AND SET THEIR CHOLESTEROL
Authors: Lange Yvonne , Ye Jin , Steck Theodore
Published: June 2021

While most of the cholesterol in cells is located in the plasma membrane (PM), its level is maintained at an optimum by diverse homeostatic proteins in intracellular organelles. We suggest a mechanistic link: increments in PM cholesterol above the complexing capacity of the PM phospholipids have a high escape potential (fugacity). This “active” excess of cholesterol circulates rapidly through the cytoplasm, thereby setting the sterol level in the cytoplasmic membranes which, in turn, regulates the activity of the homeostatic proteins. These include acyl CoA:cholesterol acyltransferase and Scap in the endoplasmic reticulum (ER) as well as sterol 27‐hydroxylase in the mitochondria. The mitochondrial product, 27‐hydroxycholesterol, binds to Insig, leading to down‐regulation of HMGCoA reductase; it also increases the expression of genes encoding several cholesterol‐lowering proteins by activating nuclear receptors. In this way, cholesterol exceeding the PM phospholipid complexing threshold feeds back upon sterol‐sensitive pathways in various cellular compartments on different time scales to null the cholesterol increment, thus maintaining the physiological level of cell cholesterol. Notably, many exogenous intercalating amphipaths displace PM cholesterol from phospholipid complexes, activating it and thereby eliciting the same homeostatic responses as excess cholesterol itself.
Avoiding Cardiovascular Complications in People Living With Systolic Hypertension, The ACCOMPLISH Trial
Authors: Jamerson Kenneth A
Published: June 2021

Background

ACCOMPLISH is the first trial to use combination therapy for the initial treatment of high‐risk hypertensive patients. The single hypothesis, the combination of amlodipine/benazapril will be superior to hydrochlorothiazide/benazapril in reducing CV morbidity and mortality challenges two standards of care in treating hypertensive patients (monotherapy and diuretic based therapy).

Methods

11,442 patients were recruited in the US and Scandinavia after meeting inclusion criteria for higher CV risk. Subjects began study medication after randomization without washout or run in periods. Randomization procedures were centralized and double blinded. The planned mean observation of 36 months had 90% power to detect a 15% reduction in the composite end point (CV mortality, stroke, MI, coronary revascularization, unstable angina, and resuscitation from death).

Results

The Data Safety and Monitoring Committee observed that with 60% of the expected information for the trial, that an efficacy boundary for the primary end point had been crossed and recommended termination of the trial.

Hypertension remains a leading cause of morbidity and mortality globally. While lowering blood pressure with any effective therapy reduces cardiovascular risk, the ACCOMPLISH trial found additional benefit attributable to a specific combination of antihypertensive medications. In particular, the combination of benazepril plus amlodipine was superior to the combination of benazepril plus hydrochlorothiazide in reducing cardiovascular disease events in high‐risk hypertensive subjects.

Conclusion

The results of the ACCOMPLISH trial provide evidence for a paradigm shift in the management of patients with hypertension.
Hypolipidemic medication use is associated with protective dietary behaviors against metabolic risk in Latinos with type 2 diabetes
Authors: Vega‐López Sonia , Chhabra Jyoti , D'Agostino Darrin , Samuel Grace K. , Calle Mariana C. , Segura‐Pérez Sofia , Fernandez Maria Luz , Damio Grace , Pérez‐Escamilla Rafael
Published: June 2021

HbA1c, fasting glucose (FPG) and lipids, and food frequency data were compared in 204 Latinos with type 2 diabetes (T2D), depending on hypolipidemic medication (HypoMed) use. As expected, total cholesterol (TC), LDL‐cholesterol (LDL‐C) and triglycerides (TG) were significantly higher among participants without HypoMed (46%, n=94) by 14% (p<0.0001), 21% (p<0.0001) and 22% (p<0.05), respectively. Participants without HypoMed reported greater consumption of fast food (29 ± 51 vs. 16 ± 30 times/y, p<0.05), commercially prepared meals (60 ± 72 vs. 34 ± 38 times/y, p<0.001), snack foods (10 ± 17 vs. 3 ± 4 times/mo, p<0.005) and pasta (5.4 ± 5.7 vs. 3.6 ± 3.0 times/mo, p<0.05). Among participants without HypoMed, frequency of consumption of fast food was correlated with HbA1c (r=0.254, p<0.05), TC (r=0.298, p<0.005), LDL‐C (r=0.237, p<0.05), TG (r=0.207, p<0.05) and Glu (r=0.288, p<0.005). Moreover, frequency of consumption of commercially prepared meals was correlated with HbA1c (r=0.237, p<0.05), TC (r=0.378, p<0.0001), LDL‐C (r=0.302, p<0.005), TG (r=0.300, p<0.005) and Glu (r=0.330, p<0.001). These associations were not observed among participants using HypoMed. Results suggest that Latinos with T2D who do not use HypoMed may follow dietary behaviors that further contribute to metabolic disease risk. Funding: CT Center for Eliminating Health Disparities among Latinos (NIH‐NCMHD grant # P20MD001765).
Dietary calcium affects neonatal bone development
Authors: Mahajan Avanika , Alexander Lindsey S. , Seabolt Brynn S. , Catrambone Daniel E. , McClung James P. , Odle Jack , Pfeiler T. Wayne , Loboa Elizabeth G. , Stahl Chad H.
Published: June 2021

Effects of dietary calcium (Ca) deficiency on skeletal integrity and endocrine parameters are well characterized in growing and mature mammals; however, little work has examined Ca nutrition during the neonatal period. In this study, we examined the effects of neonatal Ca nutrition on bone integrity, endocrine parameters, and in vivo mesenchymal stem cell (MSC) activity. Neonatal pigs (24 ± 6h post‐partum) were pair‐fed either a Ca adequate or a 30% Ca deficient liquid formula diet for 18 days. There were no differences in growth rate or feed conversion efficiency based on dietary Ca level and all pigs grew at a rate similar to sow‐reared pigs. As anticipated, dietary Ca deficiency reduced (P < 0.05) both BMD and bone flexural strength. The anticipated increase (P < 0.05) in plasma PTH levels in pigs fed the Ca deficeint diet was not evident until the end of the study. Surprisingly, dietary Ca level did not affect plasma Ca or 1,25(OH) 2 vitamin D concentrations throughout the study. Calcium deficiency reduced (P < 0.05) the in vivo proliferation of MSC isolated from bone marrow by approximately 50%. These results indicate that neonatal Ca nutrition is crucial for bone integrity and suggest that early life Ca restriction may have long‐term effects on bone integrity via its effects on MSC activity.
Variations in cord 25‐hydroxyvitamin D levels in Hispanic and Caucasian infants are not related to neonatal bone mineral status
Authors: Hicks Penni Davila , Hawthorne Keli M. , Rogers Stefanie P. , Carpenter Thomas O. , Abrams Steven A.
Published: June 2021

Background

At birth, an infant's vitamin D status, as assessed by 25‐hydroxyvitamin D level (25‐OHD) is dependent on the 25‐OHD status of the mother. There are few data regarding 25‐OHD in Hispanic infants and the relationship between 25‐OHD and bone mineral outcomes.

Objectives

To evaluate the range of 25‐OHD in Hispanic newborn infants (HNI) compared to Caucasian newborn infants (CNI) in a southern US setting and to determine if cord blood 25‐OHD is related to bone mineral status in the first week of life.

Methods

At birth, umbilical cord blood was analyzed using the Diasorin RIA (Diasorin Inc, Stillwater, MN) for 25‐OHD. Approximately 1 week after birth, infants' received a whole body dual‐energy x‐ray absorptiometry measurement to assess bone mineral content/density (BMC/BMD).

Results

Data are Mean ± SD. The 25‐OHD levels were significantly lower in HNI (n=20) versus CNI (n=18) (17.2 ± 5.7 ng/mL vs 24.1 ± 6.8 ng/mL, p = 0.002). There was no difference in whole body BMC or BMD between HNI and CNI (BMD: 0.197 ±0.013 g/cm2 vs 0.196 ± 0.011 g/cm2, p = 0.9). Using a value of 20 ng/mL to indicate possible vitamin D insufficiency there was no difference in BMC or BMD of 19 infants with 25‐OHD levels < 20 ng/mL vs 19 infants with 25‐OHD levels ≥ 20 ng/mL (BMD: 0.195 ± 0.015 g/cm2 vs 0.197 ± 0.011 g/cm2, p = 0.8).

Conclusion

Hispanic newborns in a southern US setting have lower 25‐OHD than Caucasians but this is not related to newborn bone mineral status.

Supported in part by the Marshall Klaus Award of the American Academy of Pediatrics
Impairment of maintenance and function of influenza‐specific T cell memory in diet‐induced obese mice
Authors: Karlsson Erik A , Sheridan Patricia A , Beck Melinda A
Published: June 2021

Memory T cells generated during a primary influenza infection are important for protection against subsequent influenza exposures. Previously, we have demonstrated that diet‐induced obese mice have increased morbidity and mortality following secondary influenza infection compared with lean mice. To determine if the problem resided in a failure to generate and/or maintain memory T cells and/or a failure in T cell memory function, obese and lean mice were infected with influenza X‐31. At day 31 post infection, obese memory T cells had a >50% decrease in response to stimulation by influenza PR8‐pulsed dendritic cells from lean mice. This defect was specific to memory T cells, as dendritic cells from obese mice present antigen normally to memory T cells from lean mice. At 80 days post infection, obese mice had a 10% reduction in memory T cell numbers. This reduction may be due to significantly reduced memory T cell expression of IL‐2Rβ (CD122), but not IL‐7Rα (CD127), which are both required for memory cell maintenance. Since leptin has been associated with both IL‐15 and CD122, peripheral leptin resistance in the obese mice may be a contributing factor to the impairment. It is imperative to understand how the obese state alters ability of memory T cells to function and be maintained. Moreover, impairment in maintenance of functional memory responses has significant implications for vaccine efficacy in an obese population.

Grant Funding Source: DK56350
Associations between eating patterns, dietary intakes and eating behaviours in premenopausal overweight women
Authors: Leblanc Vicky , Provencher Véronique , Bégin Catherine , Corneau Louise , Tremblay Angelo , Lemieux Simone
Published: June 2021

It has been suggested that consuming a large proportion of energy in the morning is associated with a lower daily energy intake. To our knowledge, no study has yet investigated how the distribution of energy consumed at different times of the day is associated with eating behaviours.

Objective

To examine associations between eating patterns, energy intakes and eating behaviours in 144 overweight premenopausal women.

Methods

Women completed a 3‐day food record. The Three‐Factor‐Eating‐Questionnaire was used to assess eating behaviours (dietary restraint, disinhibition, hunger).

Results

Proportion of energy consumed at breakfast was negatively associated with total daily energy intake (r= −0.22; p< 0.01) and energy density (r= −0.17; p< 0.05) while proportion of energy from snacks was associated with total daily energy intake (r= 0.27; p< 0.01). Proportion of energy consumed at breakfast was associated with flexible restraint (r= 0.24; p< 0.01) while it was negatively correlated with situational susceptibility to disinhibition (r= −0.21; p< 0.05). Finally, proportion of energy consumed in the evening was correlated with hunger (r= 0.23; p< 0.01).

Conclusion

These results suggest that eating behaviours could be important factors to further consider in order to explain the association observed between a higher proportion of energy consumed earlier in the day and lower total energy intake.

Supported by CIHR.
Effects of intracerebroventricular injection of fatty acids on food intake and body weight regulation
Authors: Mashek Douglas Gene , Schwinkendorf Darin Robert
Published: June 2021

Nutrient sensing within the hypothalamus plays a critical role in the complex network of signals controlling energy metabolism. We used intracerebroventricular (ICV) injections of the saturated palmitic acid (PA), monounsaturated oleic acid (OA), and polyunsaturated omega‐3 docosahexaenoic acid (DHA) to investigate the effects of various fatty acids on food intake, body weight, and the hypothalamic melanocortin system in rats. Both the OA and DHA groups experienced significant decreases in food intake and body weight when compared to controls. PA injections produced no changes in either food intake or body weight. Expression of POMC, a prominent anorectic neuropeptide, was found to be significantly increased in the OA and DHA groups, whereas POMC expression was essentially unaltered in the PA group. Central administration of a melanocortin receptor antagonist, SHU9119, blocked the effects of OA on food intake and body weight, thus implicating a central role for POMC in mediating the effects of fatty acids. Delineating the mechanisms and signaling pathways through which different fatty acids alter central control of energy metabolism may provide future opportunities for the prevention and treatment of metabolic diseases such as obesity and diabetes. This work was supported by the Minnesota Obesity Center.