bluuebunny/crossref_metadata_2025 huggingface dataset:
Plasma Zinc Correlations with Markers of Inflammation in Overweight and Obese Adults; a Cross Sectional Phenotyping Study
Authors: Woodhouse Leslie , Adams S. , Keim N. , Van Loan M. , Zunino S.
Published: June 2021

Obesity is associated with chronic low‐grade systemic inflammation which is characterized by increased levels of circulating pro‐inflammatory and cardiometabolic risk markers. Studies have reported lower circulating zinc (Zn) levels with obesity, and other studies have not. More research is needed to determine the mechanisms involved in the low Zn phenotype associated with obesity, and a cross sectional study looking at obesity, inflammatory markers and plasma Zn will determine potential correlations to aid in the understanding of how obesity affects Zn status. Adults (19‐60 years; BMI 25‐46 kg/m2) were recruited (n=228; 53 men, 175 women) for 6 nutritional intervention studies. Exclusion criteria included vegetarian diet, high blood pressure, high fasting glucose, and lipid or cholesterol lowering medications. Baseline measures included BMI, DEXA for fat mass (FM) and lean body mass (LM), fasting plasma Zn, & inflammatory (IL1‐β, IL‐6, IL‐8, TNF‐α, hsCRP) & metabolic (insulin, leptin, PAI‐1, & adiponectin) markers. Plasma Zn correlated positively with LM & PAI‐1, and negatively with leptin. Leptin correlated positively with BMI, FM, CRP, insulin, and negatively with LM and Zn. Insulin correlated positively with FM, BMI, IL‐1β, IL‐6, TNF‐α and leptin, and negatively with adiponectin. A stepwise multiple regression model showed that 28% of the variance in fasting plasma Zn can be explained by LBM, CRP, insulin and adiponectin. 32% of the subjects had lower Zn status based on iZiNCG criteria, and this group showed no difference in body composition, but had higher levels of inflammatory markers. With obesity studies it is important to determine body composition & inflammatory & cardiometabolic markers in order to further elucidate Zn status.
Quantity and Variety in Fruit and Vegetable Intake and Cardiovascular Disease (CVD) Risk: The Women's Health Initiative (WHI)
Authors: Bhupathiraju Shilpa , Tinker Lesley , Dubowitz Tamara , Johnson Karen , Seguin Rebecca , Manson JoAnn , Hu Frank
Published: June 2021

Epidemiological data have shown a protective effect of fruit and vegetable (FV) intake on CVD. Consequently, dietary guidelines recommend increasing FV intake and, most recently, have also suggested increasing variety. We examined the independent roles of quantity and variety in FV in relation to incident CVD among 88,249 women in the WHI. Diet was assessed at baseline using a validated FFQ. Variety was defined as the number of FV consumed in the past 3 months. Potatoes, starchy vegetables, and fruit juice were not included. During 18 years of follow‐up, we documented 5672 incident CVD cases. In multivariable analyses, after adjusting for dietary and non dietary covariates, those with the highest FV intake (median=3.9 servings/d) had a 12% lower CVD risk (95% CI 4%‐20%) compared to those with the least intake (median =1 serving/d). Higher fruit intake was associated with 34% (95% CI 19%‐48%) lower coronary heart disease risk while higher vegetable intake was associated with a 15% (95% CI 3%‐25%) lower stroke risk. Conversely, quantity‐adjusted variety was not associated with CVD (HR=0.97, 95% CI 0.86‐1.10). Our data suggest that quantity, rather than variety, in FV intake is associated with lower CVD risk. Policy efforts should continue to focus on increasing overall FV intake in the population.

Supported by NIH, NHLBI, HHS grants/contracts HL60712, K01HL10880705, HHSN268201100‐046C/‐001C/‐002C/‐003C/‐004C and AHA grant 13POST14370012.
Low sodium intake is associated with higher HDL cholesterol in premenopausal Filipino women
Authors: Lee Nanette , Duazo Paulita
Published: June 2021

Low sodium (Na) intake is known to reduce hypertension risk, but some studies suggest that it can have a deleterious effect on cardiovascular disease (CVD) risk due to adverse effects on blood lipids. We examined the association between Na intake and blood lipids [total, low density, and high density cholesterol (TC, LDL, HDL) and triglyceride (TG)] in 1,865 Filipino women (age 35‐69 y) and assessed whether the association differed by menopausal status using data from the 2005 Cebu Longitudinal Health and Nutrition Survey. In addition, to estimate possible long‐term effects, we examined the association between Na intake in 2005 and lipid levels (TC and HDL) in 2012. Na intake was on average about 2,900 mg/day and categorized into: low if <1,500mg/day (26%), moderate if 1,500 to <2,500 mg/day (28%) and high if >=2500 mg/day (46%). Salty condiments added during cooking or at the table accounted for 76% of Na intake. Regression analyses adjusting for age, BMI and other confounders showed that low Na intake had favorable effects on HDL levels but only among premenopausal women: compared to moderate Na intake (reference), those with low intake had 1.88 mg/dL (95% CI: 0.3, 3.46) higher HDL and 32% lower odds [OR 0.68 (0.49, 0.95)] of having low HDL (<40 mg/dL). Similar results are seen when estimating the effect of low Na intake in 2005 on HDL in 2012: low intake is associated with 2.79 mg/dL (0.5, 5.09) higher HDL and lower odds of low HDL [OR 0.61 (0.43, 0.87)]. No significant associations were observed for other lipids. Thus, no adverse effects of low Na intake on blood lipids but rather a potentially beneficial effect on HDL levels of premenopausal women were found among Filipino women. Results support efforts to reduce sodium consumption to lower CVD risk in the country. Funding: NIH 5R01AG039443
Artificial Sweetener Consumption and Microbiome Profiles in 31 Adults Living in the United States
Authors: Frankenfeld Cara , Lamb Evan , Sikaroodi Masoumeh , Shoemaker Sarah , Gillevet Patrick
Published: June 2021

The objective was to evaluate gut microbiome in relation to recent aspartame and Acesulfame‐K artificial sweetener consumption. Thirty‐one adults completed a four‐day food record and provided a fecal sample on the fifth day. Fecal samples were analyzed for bacterial DNA using Multitag Pyrosequencing. Median values for bacterial abundance across non‐consumers and consumers were compared. Overall bacterial abundance profiles across non‐consumers and consumers were compared using UniFrac analysis. Seven participants (23%) consumed aspartame. Seven participants (23%) consumed Acesulfame‐K. These were not the same seven individuals, and three individuals consumed both aspartame and Acesulfame‐K. No participants consumed saccharin. There were no differences in median bacterial abundance for any bacteria (class or order) across consumers and non‐consumers of either aspartame or Acesulfame‐K. The median Bacteriodetes:Firmcutes ratio also did not differ across aspartame non‐consumers (0.96, range: 0.15‐2.97) and consumers (1.08, range: 0.69‐1.87), (p‐value=0.60). Relative abundance of bacteria by class is illustrated for Acesulfame‐K non‐consumers vs. consumers. The median Bacteriodetes:Firmcutes ratio was non‐significantly higher in Acesulfame‐K non‐consumers (1.11, range: 0.14‐2.97) and consumers (0.79, range: 0.38‐2.97), (p‐value=0.74). These results suggest that recent intake of aspartame or Acesulfame‐K is not associated with overall gut microbiome profile in adults. Further studies with more individuals are warranted to evaluate lower abundance microbial taxa or interactions other factors. Support: Internal Funding
ATP7a Silencing Impairs Iron Transport in Fully‐Differentiated Rat Intestinal Epithelial (IEC‐6) Cells
Authors: Ha Jung‐Heun , Gulec Sukru , Doguer Caglar , Flores Shireen , Han Yi , Wang Xiaoyu , Collins James
Published: June 2021

Intestinal iron absorption is tightly regulated since no active excretory pathways for iron exist in mammals. Iron homeostasis isintertwined withthat of copper (Cu), but specific molecular interactions are yet to be defined. To further evaluate iron‐copper interplay in the mammalian intestine, low, control, or high‐iron diets (3, 50and 10,000 ppm, respectively) were fed to weanling rats ad libitum for 5 weeks. Rats fed the low‐iron diet developed iron‐deficiency anemia, and genes involved in duodenal Fe homeostasis increased significantly as compared to the other groups. Interestingly, genes encoding proteins involved in Cu homeostasis were also upregulated in the low Fe group, including copper‐transporting ATPase 1 (ATP7a) and metallothionein

Low iron
Control iron
High iron

Hemoglobin
2.8 (0.29)****
13.09 (0.64)
13.14 (0.64)

Hematocrit (%)
14.05 (2.58)****
50.61 (4.78)
50.47 (1.15)

Atp7a mRNA
6.34 (2.69)****
1.03 (0.28)
2.18 (1.31)

Metallothionein 1a
12.59 (15.81)*
1.85 (2.40)
1.30 (0.94)

Dmt1 mRNA
179.89 (84.5)****
1.07 (0.42)
1.67 (0.88)

Dcytb mRNA
6939.76 (4386.76)****
1.70 (1.88)
17.56 (21.17)

Ferroportin1 mRNA
3.95 (1.55)****
1.15 (0.62)
1.66 (1.13)

Transferrin receptor 1 mRNA
10.67 (2.83)****
1.09 (0.47)
0.71 (0.25)

We thus hypothesized that ATP7a function is important for intestinal iron metabolism. To test this postulate, we blocked ATP7a expression in rat IEC‐6 cells by shRNA‐mediated gene silencing. Notably, ATP7a knock down (KD) impaired Fe uptake and efflux in fully‐differentiated cells. Moreover, ATP7a KD decreased doudenal cytochrome b and ferroportin 1 mRNA expression, while conversely, hephaestin (Heph) gene expression increased significantly

image

Consistent with Heph induction, ferroxidase (FOX) activity in total cell lysates increased in the KD cells

image

These observations demonstrate that ATP7a activity is necessary for iron absorption in IEC‐6 cells. Altered expression of iron transport‐related genes in the KD cells could be the underlying molecular mechanism by which ATP7A alters iron flux. Furthermore, increased Heph expression and FOX activity may be a compensatory response to increase iron transport.
TNFα Post‐Translationally Targets ZnT2 to Lysosomes to Activate Lysosomal‐Mediated Cell Death and Mammary Gland Involution
Authors: Hennigar Stephen , Kelleher Shannon
Published: June 2021

Mammary epithelial cells undergo widespread lysosomal‐mediated cell death (LCD) during early mammary gland involution. Recently, we demonstrated that TNFα, a cytokine released during early involution, redistributes the zinc (Zn) transporter ZnT2 to accumulate Zn in lysosomes and activate LCD and involution. The current objective was to determine how TNFα retargets ZnT2 to lysosomes. We hypothesized that TNFα signaling dephosphorylates ZnT2 to uncover a highly conserved dileucine motif (L294L) in its C‐terminus, allowing adaptor protein complex‐3 (AP‐3) to bind and traffic ZnT2 to lysosomes. Confocal micrographs showed that TNFα redistributed wildtype (wt) ZnT2 from late endosomes (Pearson's coefficient=0.202±0.05 and 0.097±0.03; P<0.05) to lysosomes (0.292±0.03 and 0.649±0.03; P<0.0001), which increased lysosomal Zn (P<0.0001) and activated LCD (P<0.0001) compared to untreated cells. Mutation of the dileucine motif (L294V) eliminated the ability of TNFα to redistribute ZnT2 from late endosomes to lysosomes, increase lysosomal Zn, or activate LCD. Moreover, TNFα increased (P<0.05) AP‐3 binding to wt‐ZnT2 but not to L294V. Finally, using phospho‐ and dephospho‐mimetics of predicted phosphorylation sites (T281, T288, and S296), we found that dephosphorylated S296 was required to target ZnT2 to accumulate Zn in lysosomes and activate LCD. Our findings suggest that women with variation in ZnT2′s C‐terminus may be at risk for inadequate involution and breast disease due to the inability to target ZnT2 to lysosomes.

Supported in part by R01HD058614.
High‐Protein Diet during Gestation Promotes Adiposity and Food Intake in Female Rat Pups in the Longer Term
Authors: Desclée de Maredsous Caroline , Oosting Annemarie , Delteil Corine , Blachier François , Barbillon Pierre , Mary‐Huard Tristan , Tomé Daniel , Oozeer Raish , Davila Anne‐Marie
Published: June 2021

Dietary proteins during perinatal period are an important nutritional factor for later life metabolic health and disease risk (Michaelsen et al, 2012). The aim of this study is to determine the effect of maternal high‐protein (HP) diet during gestation or lactation on offspring metabolic response to a western diet challenge after weaning. Three groups of Wistar rat dams received either control diet (20% proteins) during gestation and lactation (C group), HP diet (55% proteins) during gestation (HPgest group), or HP diet during lactation (HPlact group). From weaning until the age of 10 weeks, female pups were fed either control or western (W) diet.

When compared to C and HPlact pups, HPgest pups have less visceral adipose tissue (AT) at weaning (p=0.02) but have at 10 weeks‐old a higher free fatty acids plasma concentration (p=0.04), more subcutaneous AT (p=0.02) and more adipocytes (p=0.007).

In addition, when compared to C pups and to HPlact pups, HPgest pups fed W diet have a higher weight gain (gestation diet*diet after weaning*time effect: p<0.0001), an increased food intake (gestation diet*diet after weaning effect: p=0.01) and a higher adiposity at 10 weeks (gestation diet*diet after weaning effect: p=0.006 in absolute weight and p=0.02 in % body weight).

These results show that maternal HP diet during gestation, but not lactation, leads to a higher sensitivity of female pups to obesity. The programming effect induced by HP diet during gestation promotes an enhanced differentiation and/or proliferation of adipocytes, thus increases the capacity of pups to store fat.
Higher protein intake during a mixed meal ingestion increases net protein accretion through a reduction in protein breakdown
Authors: Kim Il‐Young , Schutzler Scott , Spore Josh , Williams Rick , Ferrando Arny , Wolfe Robert
Published: June 2021

It has been reported that the maximal protein synthetic response to protein intake is achieved with an intake of 20 ‐ 35 g of protein. However, in these studies account was not taken of possible changes in protein breakdown. In the present study we determined whole body protein kinetics [protein synthesis (PS), breakdown (PB), and net balance (NB), mg/kg ffm/min] in the fasted state and after ingestion of 4 oz (LP, 30g protein) or 10 oz (HP, 75g protein) beef in isocaloric mixed meals. Eleven healthy young adults were studied on two occasions in a randomized crossover design with primed continuous tracer infusions of L‐[2H5]phenylalanine & L‐[2H2]tyrosine on day 4 following 3 days of diet habituation. Basal whole body protein kinetics was not different between HP and LP [PS, 3.5 ± 0.1 vs. 3.5 ± 0.1; PB, 4.2 ± 0.1 vs. 4.2 ± 0.1; NB, ‐0.7 ± 0.0 vs. –0.7 ± 0.0]. Feeding increased NB in both treatments but to a greater extent in HP vs. LP [3.4 ± 0.3 and 1.0 ± 0.1; for all, p<0.001]. PS was increased similarly in both treatments [HP, 4.2.0 ± 0.2 and LP, 4.1 ± 0.2; for all, p<0.001]. PB was decreased in both treatments (for all, p<0.005) but to a greater extent in HP vs. LP [0.8 ± 0.2 vs. 3.1 ± 0.1; p<0.001]. In conclusion, whole body net protein accretion was increased with a protein intake above “optimal” protein intake primarily through further reductions in protein breakdown.
The acute effects of protein quantity and distribution on appetite control, satiety, and food intake in overweight young women
Authors: Leidy Heather , Roenfeldt Connor , Alwattar Ammar , Shafer Rebecca
Published: June 2021

Purpose

To examine the acute effects of protein quantity and protein distribution on appetite control, satiety, and daily food intake in overweight young women who habitually eat breakfast.

Design

20 young women (age: 19±1y; BMI: 28.9±0.6kg/m2) completed 4 meal patterns in which the protein content of the breakfast and lunch meals varied.

Normal Protein Breakfast +Normal Protein Lunch(NPB‐NPL)
High Protein Breakfast + High Protein Lunch (HPB‐NPL)
Moderate Protein Breakfast + Moderate Protein Lunch (MPB‐MPL)
High Protein Breakfast + High Protein Lunch (HPB‐HPL)

Protein at Breakfast (g)
10
30
20
30

Protein at Lunch (g)
15
15
25
30

Sum of Protein at Breakfast and Lunch (g)
25
45
45
60

The women followed each pattern for 3 acclimation days. On the 4th day of each pattern, the respective 10‐h testing day was completed. Blood samples and assessments of perceived appetite and satiety were assessed at specific times throughout the day. Prior to dinner, a brain scan was completed using fMRI to identify brain activation in response to food stimuli. Ad libitum dinner and evening snacks were also provided.

Results

Only the HPB‐HPL pattern led to daily reductions in hunger, desire to eat, and prospective food consumption as well as daily increases in PYY concentrations vs. NPB‐NPL (all, P<0.05), whereas the HPB‐NPL and MPB‐MPL did not. In addition, the HPB‐HPL and MPB‐MPL patterns led to blunted pre‐dinner cortico‐limbic neural activation vs. NPB‐NPL (both, p<0.01). No other differences in appetite control and satiety were detected between patterns. Lastly, no differences in evening snack behavior or daily food intake were detected between patterns.

Conclusions

Although a high protein breakfast in combination with a high protein lunch led to improved appetite control and satiety, these responses did not translate into reductions in evening snacking or daily intake in women who habitually consume breakfast. Further, no protein‐related dose‐responses or protein distribution effects were detected.

Funding Egg Nutrition Center & The Beef Checkoff
Goji berry attenuates dextran sulfate sodium‐induced colitis
Authors: Kang Yifei , Xue Yansong , Du Min , Zhu Meijun
Published: June 2021

Inflammatory bowel diseases (IBD) including ulcerative colitis (UC) and Crohn's disease, are gastrointestinal disorders characterized by intestinal inflammation. Goji berry (Lycium barbarum), also known as wolfberry, is a traditional Chinese herbal medicine, which has long been recognized for its health beneficial effects such as antioxidative effects and diabetes prevention. Nonetheless, little is known regarding its effects in dextran sulfate sodium (DSS)‐induced colitis, a common colitis model of mice, which was investigated in this study. C57BL/6J male mice were first fed a standard rodent diet with or without 1% (w/w) goji berry for 4 weeks, then colitis was induced by supplementing 3% DSS in drinking water for 7 days, followed by a 7‐day recovery period to mimic symptoms of UC. Goji supplementation has no effects on body weight gain and feed intake in mice without DSS‐induced colitis. In DSS‐induced groups, Goji berry ameliorated body weight loss, diminished diarrhea and gross bleeding, resulting in a significantly decreased disease activity index associated with diminished DSS‐induced colon shortening. Histologically, Goji berry improved colonic edema, mucosal damage, and goblet cell depletion induced by DSS. In addition, Goji berry suppressed abnormal IL‐6 and COX2 mRNA expression, as well as apoptosis marker, active caspase‐3 content. In conclusion, for the first time, we demonstrate that dietary Goji berry supplementation confers protective effects against DSS‐induced colitis, suggesting a potential therapeutic value for IBD patients (NIH R15HD073864).
Protecting a woman's right to breastfeed: the extension of maternity leave in Vietnam
Authors: Hajeebhoy Nemat , Nguyen Tuan , Nguyen Phuong , Mannava Priya , Phan Linh , Vu Ha , Mathisen Roger , Do Phuong
Published: June 2021

Exclusive breastfeeding in the first six mo of life is critical to child development and health. Effective from May 1, 2013, Vietnam became one of the first lower‐ to middle‐income countries to offer 6‐month paid maternity leave (6mo‐PML). We analyzed data from different sources to 1) describe the process of adopting the 6mo‐PML policy, 2) examine perceptions of employed women about this policy, and 3) assess the association between maternity leave and the exclusive breastfeeding practice. Five key components leading to policy change were the establishment of partnerships, consensus building among various stakeholders, evidence‐based policy advocacy, development of messages and materials, and engaging the media. An online survey (n = 1,005) showed employed women believed that 6mo‐PML was beneficial for infant's health (72%), mother's health (59%), society (45%) and family (34%). To avail of 6mo‐PML, mothers needed support from employers to maintain positions (80%) and hire temporary staff (48%). Findings from an onsite survey (n = 6,240) show that the percent of mothers who returned to work when the infant was < 4 mo, 4 mo and 5 mo were 5%, 15% and 22%, respectively. Mothers who returned to work had a statistically lower prevalence of exclusive breastfeeding than those who did not in the overall sample (20% vs. 34%) and for all age groups (< 4 mo: 35% vs. 42%; 4 mo: 19% vs. 26%; and 5 mo: 9% vs. 15%). Adjusted OR for returning to work was 0.65 (95%CI 0.53, 0.80). With increasing numbers of women entering the labor force, adoption of maternity protection policies is critical to enabling working mothers to optimally breastfeed their children.

Funding: Bill & Melinda Gates Foundation, through Alive & Thrive, managed by FHI 360
EFFECT OF LOW GLYCEMIC INDEX DIET ON APOLIPOPROTEIN B AND LDL PARTICLE SIZE
Authors: Srichaikul Korbua , Ireland Chris , Kendall Cyril , Sievenpiper John , Lamarche Benoit , Jenkins David
Published: June 2021

Background

Apolipoprotein B (Apo B) and small LDL particles have been strongly associated with increased coronary artery disease while low glycemic index diets (GI) may reduce risk. We have therefore assessed the effect of consumption of a low GI diet on Apo B and LDL particle size.

Methods

155 type 2 diabetic subjects treated with antihyperglycemic agents were randomized and completed either 6 months of high fiber or low glycemic index dietary advice in a parallel design. Serum samples were obtained pre‐treatment and at the end of the 6 month study period.

Results

There was no significant treatment difference in Apo B but a significant reduction in estimated small dense LDL cholesterol (sdLDL‐C) on the low GI diet by ‐0.15 ± 0.08 mmol/L compared to the high fiber diet (p=0.048). No significant treatment differences were seen in LDL particle size distribution. Dietary glycemic load, not glycemic index, correlated positively to serum levels of sdLDL‐c (Rho=0.17, p=0.036), while correlated negatively with serum levels of medium LDL particles (Rho=‐0.17, p=0.042) and large LDL particles (Rho=‐0.18, p=0.026).

Conclusion

These findings suggest a benefit of low glycemic index diets in reduction of sdLDL‐c levels in type 2 diabetes.

Funding Canadian Institutes of Health Research, Canada Research Chair Endowment of the Federal Government of Canada, and Barilla (Italy).
Proteomic analysis of plasma in adult active pulmonary tuberculosis patients with diabetes mellitus
Authors: Zhang Xiulian , Ma Aiguo , Sun Shuangling , Sun Yongye
Published: June 2021

Abstract:

There is a high burden of both diabetes and tuberculosis in China. Althoug both diabetes and tuberculosis have been the objects of intensive study the association between the two diseases is not fully understood. The aim of this study was to determine whether thetqualitative and quantitative differences in expression of some protein expression in plasma could be related to active pulmonary tuberculosis complicated with diabetes. Using two‐dimensional gel electrophoresis and mass spectrometry we analyzed expression of the proteins associated with active pulmonary tuberculosis complicated with diabetes. Results showed that under the baseline condition, the levels of a‐1 antitrypsin precursor, vitamin D‐binding protein precursor, CD5 antigen like precursor, clusterin precursor, apolipoprotein A‐I precursor, haptoglobin and fibrinogen g‐chain differed between patients with active pulmonary tuberculosis and active pulmonary tuberculosis complicated with diabetes. Western blott results confirmed differential expression of clusterin. These results suggest that active pulmonary tuberculosis complicated with diabetes may be associated with specific protein expression pattern in plasma. C‐terminal haptoglobin is a possible candidate protein of interest, which might be a link between active pulmonary tuberculosis and diabetes. The dynamics of protein expression during disease progression may improve our understanding of the pathogenesis of active pulmonary tuberculosis complicated with diabetes.

Supported by NSFC‐81172662
p38MAPK Signaling but not Direct Inhibition of Desmoglein Binding is Crucial for Loss of Cell Cohesion in Pemphigus Vulgaris
Authors: Vielmuth Franziska , Waschke Jens , Spindler Volker
Published: June 2021

Pemphigus vulgaris (PV) is a severe autoimmune disease caused by autoantibodies against the desmosomal adhesion molecules desmoglein (Dsg) 1 and Dsg3. Both, direct inhibition of Dsg interaction by autoantibody binding and intracellular signaling events are discussed to be essential and sufficient for loss of cell cohesion finally leading to epidermal blister formation. Here we used atomic force microscopy (AFM) to perform Dsg3 adhesion measurements on the surface of living keratinocytes to determine the contribution of direct inhibition and p38MAPK‐ and lipid‐raft‐dependent signaling to loss of cell cohesion after treatment with Dsg3‐specific autoantibodies. Direct inhibition of Dsg3 binding was almost complete after 15 min antibody treatment and did not proceed further up to 120 min under conditions where no reduction of surface Dsg3 was detectable. However, loss of cell cohesion and keratin retraction progressed during this time course. Interestingly, direct inhibition of Dsg3 binding was still profound when loss of cell‐cell‐cohesion was completely abrogated by p38MAPK inhibition. This demonstrates that p38MAPK suppression prevents loss of cell cohesion despite Dsg3 binding still being blocked. Furthermore, signaling is lipid‐raft‐dependent because methyl‐ß‐cyclodextrin (ß‐MCD) also fully prevented loss of cell cohesion, but did not reduce direct inhibition of Dsg3 binding. Taken together, these results demonstrate that inhibition of Dsg3 binding alone is not sufficient to cause loss of cell cohesion but rather alters p38MAPK‐ and lipid‐raft‐dependent signaling events which in turn cause cell dissociation.
CLMP Expression is Increased in the Intestinal Epithelium Under Inflammatory Conditions and Regulates Intercellular Adhesion, Proliferation and Migration
Authors: Luissint Anny‐Claude , Xiaoming Liu , Bennett Ashley , Nishio Hikaru , Hilgarth Roland , McCall Ingrid , Nusrat Asma , Parkos Charles
Published: June 2021

The intestine is lined by epithelial cells that form a dynamic physical barrier against external substances. Maintenance of this mucosal barrier requires proliferation, migration and differentiation of epithelial progenitor cells along the crypt‐luminal axis while keeping strong cell‐cell cohesion. Epithelial barrier function is created by tight junctions (TJ) and increased intestinal permeability has been linked with the pathogenesis of inflammatory bowel disease. CAR‐Like Membrane Protein (CLMP) is structurally related to the TJ transmembrane protein, Coxsackie and Adenovirus Receptor, but CLMP role in controlling intestinal epithelial barrier function in homeostasis and inflammation is not known. We observed that CLMP is distributed in intercellular junctions of murine and human intestinal epithelial cells (IECs), and its expression is increased after inflammatory cytokine exposure. CLMP overexpression in IECs, unlike its depletion, resulted in strengthened cell‐cell adhesion and increased cell migration after injury indicating a positive role of CLMP in the maintenance of epithelial barrier function and wound repair. Interestingly, CLMP overexpression led to decreased epithelial cell proliferation and inhibited the growth of subcutaneous xenografts in Rag1null mice. Our results support a role of CLMP in controlling intestinal epithelial barrier function and homeostasis. These studies will help to better understand signaling pathways that influence the intestinal epithelial barrier function during chronic inflammation.
Endothelial CD99 Signals Through Soluble Adenylyl Cyclase and PKA to Regulate Leukocyte Transendothelial Migration
Authors: Watson Richard , Buck Jochen , Levin Lonny , Wang Jing , Arase Hisashi , Muller William
Published: June 2021

CD99 is a critical regulator of leukocyte transendothelial migration (TEM, diapedesis); however, it remains entirely unknown how CD99 signals during this process. In this study, we find that engagement of endothelial cell (EC) CD99 during TEM activates protein kinase A (PKA) via soluble adenylyl cyclase (sAC). Active PKA stimulates membrane trafficking from the lateral border recycling compartment (LBRC) to sites of leukocyte diapedesis, facilitating the passage of leukocytes across the EC junction. Pharmacologic or genetic inhibition of sAC, or PKA, recapitulates the phenotype of CD99 blockade on TEM, arresting leukocytes partway through EC junctions, both in vitro and in vivo. In contrast, inhibition of transmembrane adenylyl cyclases did not produce such effects. Furthermore, we show that a positively charged juxtamembrane region in the cytoplasmic tail of CD99 is critical for interacting with sAC and the A‐kinase anchoring protein, ezrin. Together, this signaling complex is responsible for the ability of CD99 to govern leukocyte extravasation. This is the first description of the CD99 signaling pathway in TEM as well as the first implication of sAC in leukocyte extravasation.
Novel Peptide‐Conjugated Maresins Stimulate Tissue Regeneration and Clearance of Infections in Planaria and Inflammatory Exudates
Authors: Dalli Jesmond , Chiang Nan , Serhan Charles
Published: June 2021

During the resolution of inflammation chemical mediators are produced in resolving exudates that regulate inflammation, stimulate resolution and tissue regeneration. Identification of novel signals that regulate these processes and their pathways is of interest. Here in regenerating planaria, infectious murine exudates, human milk and macrophages, we identified novel potent molecules that stimulated tissue regeneration in planaria and promoted tissue repair in mice. These molecules proved to be peptide‐conjugated maresins and are coined maresins conjugates in tissue regeneration (MCTR). They displayed potent anti‐inflammatory and proresolving actions i.e. limiting neutrophil infiltration and promoting the containment and clearance of infections in vivo. In addition, these novel molecules stimulated bacterial phagocytosis by macrophages and efferocytosis of apoptotic cells both with mice in vivo and human cells in vitro. MCTR1 and MCTR2 were biosynthesized from docosahexaneoic acid and both carried sulfido‐conjugated triene double bond systems. Together, these findings identify novel, conserved resolution moduli (in planaria, mice and humans) that regulate host responses to control infection, tissue regeneration and organ protection providing novel .
Regulatory Role of Endothelial CD47 during Leukocyte Transmigration
Authors: Leick Marion , Azcutia Veronica , Newton Gail , Luscinskas Francis
Published: June 2021

The vascular endothelium plays a critical role in inflammation and leukocyte recruitment by expression of adhesion molecules and leukocyte chemoattractants. Adhesion molecules bind leukocytes and transmit signals to the endothelial cells (EC) required for transendothelial migration (TEM). An important unanswered question is how ECs integrate the signals arising from leukocyte engagement of multiple adhesion molecules. CD47, also known as Integrin Associated Protein, is a broadly expressed glycoprotein and binds thrombospondin‐1 and leukocyte expressed Signal Regulatory Proteins (SIRPα and SIRPg). Besides these “in trans” interactions, CD47 also interacts “in cis” (in the same plasma membrane) with multiple integrins. We previously reported that endothelial CD47 plays a role in TEM and transmits intracellular signals upon engagement. Interestingly, CD47 signals phenocopy those occurring after engagement of ICAM‐1. We hypothesized CD47 interacts with ICAM‐1 to form a protein complex in EC plasma membrane and that this complex binds leukocytes and transmits intracellular signals during leukocyte TEM. Here we report CD47 associates with ICAM‐1 in EC by Fluorescence Lifetime Imaging Microscopy of Förster Resonance Energy Transfer (FLIM‐FRET). Furthermore, ICAM‐1 crosslinking‐induced signaling through pyk2 and src kinases was impaired in CD47‐/‐ mouse heart ECs (MHEC) as compared to WT MHEC. This was also demonstrated in HUVEC silenced for CD47. Understanding how CD47 interacts with different molecules will clarify its role in leukocyte recruitment and EC dependent mechanisms that regulate TEM.

Supported by grants from National Research Fund of Luxembourg (FNR, Award # 4800397) and NIH HL‐36028.
Measuring Child Length and Height: Assessing the Accuracy of a Portable Infrared‐based Digital Tool
Authors: Baxter Jo‐Anna , Roth Daniel , Zlotkin Stanley , Yin Shi , Milgram Paul , Mouzaki Marialena
Published: June 2021

Accurate measurement of growth in infants and children is important, as it reflects a child's nutritional status and overall health. Conventional methods of measuring length and height are challenging due to limited access to appropriate tools, poor tool quality, and lack of child cooperation. Pediatric Platform for Anthropometry (PePA) is a portable, computer‐assisted infrared‐based tool that measures length/height without direct child contact. This study investigated PePA's accuracy by comparing length/height measures to the gold standard (length board or stadiometer). The precision and acceptability of PePA and the gold standard were also assessed. In a preliminary analysis of 316 eligible children (0‐18 years), 278 participants' PePA and gold standard measures met the study criteria for inclusion in the analysis. For 6% of those eligible, no successful PePA measures were obtained. The overall intraclass correlation (ICC) [95% CI] between PePA and the gold standard was 0.9988 [0.9985, 0.9991]. The ICC for length only (n=16) and height only (n=262) was 0.9840 [0.9286, 0.9951] and 0.9981 [0.9976, 0.9985], respectively. The mean (±SD) time to obtain a PePA measure was less than the standard tool (8.4±3.2 versus 14.1±5.3 seconds, respectively; p<0.05). Preliminary results suggest that PePA has a very high concordance with the gold standard and is faster in obtaining a measure.

Research support was provided by a Hospital for Sick Children Innovation Grant.
Dietary Predictors of Growth in Vulnerable Young Children from Four Low‐Resource Countries: a Longitudinal Study
Authors: Lander R , Krebs N , Mazariegos M , Garces A , Westcott J , Goco N , Tshefu A , Pasha O , Chomba E , Hambidge M ,   First Bites Study Group
Published: June 2021

Longitudinal associations between dietary factors and growth patterns were examined in infants/toddlers from Zambia, DRC, Guatemala and Pakistan in a secondary analysis of a previously published large randomized efficacy trial of daily meat vs fortified cereal supplements as complementary foods. Growth (i.e. z‐scores for length (LAZ), weight (WLZ)), diet (i.e. infant/young child feeding practices (IYCFP), food groups consumed), and SES data were collected from 929 breastfed children aged 6‐18 mo (arms combined). Diet at 9 and 12 mo were correlated with growth measures at 12 and 18 mo, respectively, using adjusted IYCFP (terciles), multiple linear regression and logistic regression analyses. Significant findings (p<0.05) include: 1) no dietary meat/fish/insects (MFI) and no milk/dairy (MD) at 9 mo were associated with reduced LAZ at 12 mo; 2) increased risk (OR) of stunting (LAZ<‐2SD) at 12 mo was found in boys (1.9) and low SES (1.7) and associated with low dietary diversity (DD) (3.2), no MFI (1.9), and no MD (2.3) at 9 mo; 3) low DD and no MD at 12 mo were associated with decreased LAZ at 18 mo, while low food variety, low DD and no MFI with reduced WLZ; 4) increased risk of stunting at 18 mo was found in boys (1.8) and associated with no MD (1.7) at 12 mo. This longitudinal study emphasizes the critical role of the quality of complementary feeding on growth in the first 2 years of life in children from low‐resource settings

Funded by NIH/NICHD/ODS

Acknowledgement: LL Wright, NICHD, Rockville, MD
The Uptake of Vitamin A into the Neonatal Brain
Authors: Urbanek Joanna , Tan Libo , Ross A Catharine , Green Michael
Published: June 2021

The most rapid phase of brain development occurs during the neonatal period and vitamin A (VA, retinol) is critical for many aspects of this process, including neurogenesis, synaptic plasticity, learning and memory formation. However, the metabolism of VA in a neonatal brain is almost unexplored. The objective of this study was to examine the uptake of VA into the brains of neonatal rats and to assess the effect of VA supplementation on the amount of VA being taken up. On postnatal day 4, pups (n = 103) received an oral dose of either VA (6 μg of retinyl palmitate/g of body weight) or canola oil, both containing 2.5 μCi of [3H]retinol acting as the tracer. Subsequently, pups (n = 4/group/time) were euthanized at 13 time points from 30 min to 24 d after dose administration. The uptake of VA was estimated using the Windows version of the Simulation, Analysis and Modeling software. The results showed that the mass of retinol in the brain was closely dependent on its mass in plasma over time and that the uptake of VA into the brain involved both postprandial chylomicrons as well as the retinol‐binding protein (RBP). VA supplementation increased the uptake of chylomicron‐derived VA from 0.1 nmol/d in the control group to 4.8 nmol/d in the supplemented group. These results indicate that chylomicrons may be a primary mechanism of delivering the recently ingested, dietary VA into a neonatal brain. This project is supported by NIH grant no. HD066982.
Selective Carotenoid Growth Inhibition in Breast Cancer: Independence of Hormonal Sensitivity
Authors: Smith Joshua , Gong Xiaoming , Rubin Lewis
Published: June 2021

Background

Carotenoid intake has been associated with ↓ed cancer risk, including breast cancer. We tested if specific carotenoids inhibit cancer cell proliferation or induce apoptosis and interaction with chemotherapeutic agents.

Methods

Hormone sensitive and triple negative breast cancer lines and immortalized breast cells were treated with carotenoids (β‐carotene, lycopene [LYC], lutein [LUT] or astaxanthin; 0.5‐2.0 µM) singly or in combination with taxanes. Cell proliferation was analyzed by MTT and EdU assays; intracellular ROS, cell cycle and apoptosis were assayed by flow cytometry. RT‐PCR arrays were used to evaluate gene expression ± carotenoid exposure. Carotenoid‐drug combinatorial effects were determined using the Chou‐Talalay method.

Results

LUT and LYC significantly ↓ed cancer cell proliferation (threshold, < 0.5µM) with little dose‐dependency; β‐carotene and astaxanthin had no significant effects. LUT‐, LYC‐mediated growth inhibition was similar to that induced by taxanes. LUT + taxane synergistically inhibited cancer cell proliferation. LUT also ↑ed intracellular ROS and G1 arrest and expression of apoptosis‐related genes.

Conclusion

LUT and LYC inhibit breast cancer cell growth independent of cell hormone receptor status and additively‐synergistically with taxanes. These carotenoid‐mediated effects appear to involve inducing cell cycle arrest and increasing apoptosis. LUT (best known for effects on eye and brain health) and LYC may be important adjuncts to breast cancer chemotherapy.
Competencies 101: The knowledge, skills, behaviors and attitudes of a top notch anatomy educator
Authors: Lyons Virginia
Published: June 2021

The Liaison Committee on Medical Education (LCME) defines the standards of accreditation for medical schools in the United States and Canada. These standards are stated in an annual publication titled “Functions and Structure of a Medical School”, however recently this publication has undergone significant revision. In the current version of this document published in March 2014, the former 132 standards have been distilled down to 12. It is important for educators to become familiar with the new standards, as they govern the design and implementation of the components of the curriculum. Standard 6 discusses competencies, curricular objectives and curricular design. Anatomists can assist their institution in meeting this standard by: 1) writing learning objectives in outcome‐based terms and distributing them to all students and faculty; 2) creating self‐directed learning experiences in their courses; 3) developing electives in the anatomical sciences that allow students to explore their areas of interest in depth; 4) providing opportunities for anatomy‐based community service activities; and 5) developing interprofessional activities in the anatomical sciences.
The Hidden Learning Environment: Effect of informal student networks on team performance in a Gross Anatomy Course
Authors: Chawla Sagar , Pawlina Wojciech , Hafferty Frederic , Lachman Nirusha
Published: June 2021

Collaborative learning is recognized for its positive impact on student performance. Influence of social networking on evolution of student learning is rooted in construct of collaborative learning theory. Studies have alluded to benefits of informal learning (outside class) with little information evidenced in academic performance. Gross anatomy course at Mayo Clinic uses team based learning approach over 7 weeks. Teams are diversified (eg. cultural background, college attended, gender) while normalized (similar total average pre‐admission scores) to give each team equal footing from which to work. Teams are assigned at start of histology block 8 weeks prior and maintained through anatomy block. Based on premise of collaborative learning, we predicted students who spent more time interacting with classmates outside class contributed to collective knowledge of team and positively influenced team performance. Study aimed to determine if interaction of team members with classmates outside of assigned team impacted academic performance. Students voluntarily completed weekly surveys identifying classmates they had studied with after hours. Group size and duration of academic interaction were analyzed. Data were compared with final team performance for practical and written exams. Data were statistically analyzed and measured in terms of where teams ranked in overall class performance. Preliminarily, teams with 2 or more members who studied with non‐team members outside class showed improvement, with more overall members outside the bottom tertile. Students in bottom tertile studying with students in top tertile in a small group (< 5) > 1 hour outside class showed 5% improvement. Students in the top tertile are more likely to study alone or with students in the same tertile. Students who study with those in lowest tertile tend to have a positive effect on their performance. When students are allowed to choose their own networks, they tend to form mixed networks, in addition to formal teams.
Inflammation in Colorectal Cancer Inflammatory Bowel Disease, and Diabetes Mellitus: The Link
Authors: Jurjus Abdo , Zeenny Marie‐Noel , Eid Assaad , Chams Sana , Jurjus Rosalyn
Published: June 2021

Introduction

Various chronic diseases like Inflammatory bowel disease (IBD), colorectal cancer (CRC) and Type 2 diabetes mellitus (T2DM) are triggered by infection and or unregulated chronic inflammation. Where is the link?

Inflammation

Inflammation is basically a beneficial complex response which may involve a panel of bioactive pro‐and anti‐inflammatory molecules. However, a persistent or an inadequately resolved chronic inflammation may increase the risk of several pathologies such as IBD, CRC and T2DM, through toxic factors and bioactive molecules promoting epithelial‐mesenchymal transition (EMT) and facilitating carcinogenesis through the activation of JAK/STAT signaling pathway (IL‐6, TNF‐α), the differential phosphorylation of SMAD's which induce EMT (TGFB's), or mechanisms involving reduced oxygen species (ROS) and reactive nitrogen species (RNS).

CRC and IBD: It is widely accepted that IBD patients have a higher risk of CRC. The IBD's are multifactorial pathologies involving alterations in the microbiota which can induce chronic inflammation leading to a potential role in carcinogenesis through mediators relevant in EMT induction like TGFB, TNF‐α , IL‐6, ROS and others.

T2DM: Multiple inflammatory mechanisms provoke the pathogenesis of T2DM through mediators like (TNF‐α, IL‐6, IL‐8, and TGFB, which may alter the normal structure of the β‐cells by inducing pancreatic islet's apoptosis, thus the leading to the release of insulin‐like growth factor ‐1 (IGF‐1) which stimulates EMT, and carcinogenesis. In T2DM, Hyperglycemia contributes to the onset of inflammation, the increase of ROS, and triggering of inflammatory cytokines while hyperinsulinemia activates IGF‐1 over production which induces EMT and activates two mitogenic pathways that favor cancer growth: P13K/AKK and β‐catenin pathways

Conclusion

IBD, CRC and T2DM are commonly interrelated clinical problems. They share a common basis influenced by disease‐related inflammation enhanced by changes in the endocrine milieu.
New Insight in Inflammatory Bowel Disease Pathophysiology: Current and Future Therapeutic Applications
Authors: Reimund Jean Marie , Freund Jean‐Noël , Duclos Bernard
Published: June 2021

Inflammatory bowel diseases [IBD: Crohn's disease (CD) and ulcerative colitis (UC)] can be difficult to control with conventional treatments (5‐aminosalicylates, corticosteroids and/or immunosuppressors). The advent and the growing use of anti‐TNF‐alpha monoclonal antibodies in IBD represented a remarkable progress in IBD therapy. Nevertheless, not all patients respond to anti‐TNF‐alpha antibodies and others, either present secondary side effects or failure after initial response to these antibodies, and as a consequence the need to stop them. It is now demonstrated that a greater understanding of IBD pathophysiology may conduct to identify new targets for IBD treatment and remains a continuous challenge, potentially allowing the development of active therapeutic molecules. Some of them are currently in phase II or III trials or near to be launched. As an example, basic research led to the development of anti‐interleukin (IL)‐12/23 monoclonal antibodies (ustekinumab, Janssen) or of anti‐integrin monoclonal antibodies in particular anti‐a4b7 integrins antibodies (vedolizumab, Takeda) or anti‐axb7 monoclonal antibodies (etrolizumab, Roche Gentech) which block the interactions between leukocytes and the intestinal vascular endothelial cells. In addition, other drugs (small molecules or monoclonal antibodies) will enlarge the therapeutic armamentarium in IBD, blocking or interfering with targets such as Janus kinase (Jak) inhibitors (small molecules designed to block intracellular signaling of several pro‐inflammatory cytokines), stimulation of Toll‐like receptor (TLR)‐9, regulatory T cell therapy, etc. One other future direction will probably include the identification of potential therapeutic targets in intestinal microbiota, an important but difficult research field in IBD. Here, these new approaches will be discussed as well as their current or future place in IBD treatment strategy.