bluuebunny/crossref_metadata_2025 huggingface dataset:
Lipoxins control neutrophil superoxide anion production by regulation of polyisoprenyl diphosphate phosphatase 1 activity
Authors: Carlo Troy , Kalwa Hermann , Levy Bruce D
Published: June 2021

In health, pro‐resolving signals are produced to facilitate the successful termination of inflammatory responses. Lipoxins (LXs) are agonists of resolution that block the actions of neutrophils (PMNs). Located in PMN cell membranes, presqualene diphosphate (PSDP) acts as an intracellular signaling molecule that inhibits superoxide anion (O2−) production. Polyisoprenyl diphosphate phosphatase 1 (PDP1) is a lipid phosphate phosphatase that remodels cellular PSDP to its monophosphate form in response to agonists. Here, we present evidence, in human leukocytes, of an intracellular signal cascade with PDP1 that can respond to both pro‐inflammatory and counter‐regulatory signals as a molecular switch controlling the activation state of human PMNs. Exposure of human PMNs to 15‐epi‐LXA4 and transfection of PMN‐like HL60 cells with PDP1 siRNA led to decreased NADPH oxidase assembly and O2−. Of note, transfection of freshly isolated human PMNs with PDP1‐specific antibodies led to decreased O2− generation and potently blocked 15‐epi‐LXA4‐ mediated inhibition of PMN responses. PDP1 was phosphorylated in vitro by protein kinase C betaII (PKCbetaII) and inhibitors of PKCbetaII block PSDP remodeling and PMN O2− generation. Exposing PMNs to 15‐epi‐LXA4 inhibited agonist dependent PKCbetaII phosphorylation and its association with PDP1. Together, these findings suggest a critical role for PDP1 in PMN activation.
Vibrio parahaemolyticus VopA is a potent inhibitor of cell growth and cell migration in the intestinal epithelium
Authors: Jones Rheinallt , Luo Liping , Leoni Giovanna , Nusrat Asma
Published: June 2021

Vibrio parahemeolyticus is an enteric pathogen found in contaminated seafood that has recently been shown to invade nonphagocytic cells. During invasion, V. parahaemolyticus secretes effector proteins that usurp the host's signaling pathways. One secreted effector protein, VopA, has potent inhibitory effects on MAPK signaling. Here, we assess the pathological outcome of VopA activity in cultured mammalian cells, and in the Drosophila melanogaster animal model. VopA potently influenced Focal Adhesion Kinase (FAK) phosphorylation, where p‐FAK levels at Tyr residues 397, 576/577, and 925 were significantly increased, and the p‐FAK level at Ser 910 was significantly decreased. Cultured cells expressing VopA were impaired in their ability to migrate and reseal scratch wounds in vitro. In addition, VopA‐expressing cells were significantly smaller in diameter, and were resistant to apoptosis. Expression of VopA in the Drosophila midgut, thus modeling secretion of VopA by V. parahemeolyticus, reduced organismal lifespan, resulted in disarrangement of enterocytes, and inhibited enterocyte migration. Together, these data show that VopA subverts cell fate to facilitate opportunities for V. parahaemolyticus to establish a niche within the intestine.
Neutrophil Microparticles are heterogenous in content and function
Authors: Perretti Mauro , Dalli Jesmond , Norling Lucy V , Melendez Trini Montero‐ , Hinds Charles
Published: June 2021

Altered plasma neutrophil‐derived microparticle levels have recently been implicated in a number of vascular and inflammatory diseases, yet our understanding of their actions is very limited. Stimulation of neutrophils, either in suspension or adherent to an endothelial monolayer, led to the production of microparticles containing >;600 distinct proteins with 247 being shared by the two subsets. Assessing the expression profile of a number of validated proteins in three types of human samples (healthy volunteer and septic plasma along with blister‐derived exudates) confirmed that specific protein abundance in the microparticles might reflect the activation status/mode of the neutrophil. The two microparticle subsets responded to external stimuli showing that ‐ when appropriately stimulated ‐ they release reactive oxygen species, synthesise leukotriene B4 and chemotax. These findings demonstrate that neutrophil‐derived microparticles are heterogenous and can deliver packaged information propagating the parent cell's activation status, potentially playing a novel and fundamental role both under homeostatic and disease conditions.
Normalizing tumor vasculature and microenvironment: Insights from in vivo microscopy
Authors: Jain Rakesh K
Published: June 2021

A solid tumor is like an aberrant organ – comprised of cancer cells and host cells embedded in an extra‐cellular matrix – nourished by blood vessels and drained by lymphatic vessels. In its journey from the blood stream to cancer cells, a therapeutic agent must cross the vessel wall and the extra‐cellular matrix that cancer cells are ensconced in. Using intravital microscopy and a number of sophisticated animal models, our laboratory has shown that blood and lymphatic vessels as well as matrix associated with tumors are structurally and functionally abnormal. This abnormality can impair delivery of drugs and immune cells in tumors, compromise their efficacy after they accrue in tumors, and, independent of these, facilitate tumor progression. Our lab has dissected the molecular and cellular mechanisms underlying these abnormalities, and developed a number of strategies to “normalize” these barriers and thus, improve delivery and efficacy of treatments. Finally, we have translated some of these strategies from bench to bedside for treatment of cancer and other diseases characterized by abnormal blood vessels.
Evo‐Devo and an Expanding Evolutionary Synthesis
Authors: Carroll Sean B.
Published: June 2021

Biologists have long sought to understand which genes and what kinds of changes in their sequences are responsible for the evolution of anatomy and morphological diversity. Advances in molecular and evolutionary developmental biology over the past thirty years have led to a general understanding that animal form evolves largely by altering the expression of functionally conserved proteins, and that such changes largely occur through mutations in the cis‐regulatory sequences of pleiotropic developmental regulatory loci and of the target genes within the vast networks they control.
GTPase and ATPase tangos during intracellular protein targeting
Authors: Shan Shu‐ou
Published: June 2021

Rougly one third of the proteome are destined for the cellular membrane, whose proper localization is essential for the structure and function of all cells. The signal recognition particle (SRP) is a universally conserved cellular machinery that couples the synthesis of membrane and secretory proteins to their proper cellular localization, and has served as a paradigm to understand the molecular basis of protein localization. Using a combination of chemical, biophysical, structural and cellular approaches, our work has established a quantitative framework for how two highly homologous GTPases in the SRP and SRP receptor use a novel GTPase cycle to drive this fundamental cellular pathway, and elucidated how fidelity of protein localization by the SRP is achieved through a combination of binding, induced fit, and kinetic proofreading mechanisms. These findings also define a novel class of ‘dimerization‐activated’ GTPases, represented by the SRP and SRP receptor, whose regulatory principles may extend to a growing number of nucleotide hydrolases that drive diverse cellular processes.
Microanatomical maps: a CT and histological study of soft tissue‐bone interfaces in developing primates
Authors: Smith Timothy , DeLeon Valerie B.
Published: June 2021

The widespread availability of high resolution computed tomography (CT) provides an unprecedented ability to view skeletal material of minute size, including subadult specimens. Here, we describe a novel approach of coregistering microCT scans of late fetal nonhuman primates with serial histological sections. We use three primates (loris, tarsier, tamarin) that have absolutely or allometrically large eyes. After reslicing 3D volumes of skulls so that they match histological sections of the same specimen, CT slices are annotated according information only available via histology (e.g., osteoclasts and osteoblasts). The result is a three‐dimensional “growth map,” presenting as a skull with surfaces coded for resorption and deposition. After interfacing the bone with functional matrices of the head (eyes, mucosae, teeth), the influence of soft tissue growth can be inferred. For example, similar patterns of superomedial resorption of orbit are observed in all three species. On the other hand, the extent of bone deposition in the orbital floor, which separates the eye and dentition, differs among the three species. Our growth maps show that more than one soft tissue attribute (e.g., size or position) can produce the same pattern. Moreover, the overall growth patterns are directly associated with the spatial proximity of the eyes with other structures (e.g., teeth).
The remarkable pliability and promiscuity of specialized metabolism
Authors: Noel Joseph Patrick
Published: June 2021

Metabolic pathways are often considered “perfected” or at least predictable as substrates efficiently rearrange into products through the intervention of a catalytically and/or metabolically optimized enzyme. Moreover, these individual steps link up forming a myriad of metabolic circuits that are often modeled with a high degree of certainty. However, upon closer examination, most enzymes are not precise with respect to their activity, using not just one substrate but often a variety, and producing not just one product but a diversity. Hence, the metabolic systems assembled from enzymes possessing varying degrees of what can be termed catalytic promiscuity are not clear‐cut and restrictive; rather, they may at times operate somewhat stochastically in the intracellular milieu. This “messiness” complicates our understanding of normal and aberrant cellular behavior while paradoxically sowing the seeds for future advantageous metabolic adaptations for the host organisms.
The First Big Leap, College to Graduate School.
Authors: Kennelly Peter James
Published: June 2021

From kindergarten through college, the educational journey of a typical entering graduate student has been highly structured and largely predictable. Like a restaurant menu, the curriculum has been predetermined and advancement occurs on a well‐defined schedule. By simply following along with the pack, i.e. your classmates, you can expect to graduate on schedule. On the other hand, upon entering graduate school a student leaves behind the comfortable predictability of rigid structure and the safety of the pack. Each graduate student embarks on an individual journey of discovery, training, and growth under their own individual mentors. Moreover, discovery does not adhere to a schedule. The excitement and challenge of an original thesis research project thus carries with it inherent elements of risk and unpredictability. While many problems have more than one solution, they can be of disparate length and difficulty. Maximizing the benefits and rewards of graduate study therefore requires a willingness to grow beyond the safe passivity of former educational experiences; to initiate, engage, and ultimately take ownership of your education and training.
Scent of a parasite: isoprenoids in malaria
Authors: Odom Audrey Ragan
Published: June 2021

Severe malaria due to Plasmodium falciparum is responsible for nearly one million deaths per year. New drugs are urgently needed to treat malaria, due to widespread resistance to many antimalarial therapies and emerging resistance to artemisinin. P. falciparum parasites contain an essential metabolic pathway to produce a class of compounds known as isoprenoids. This pathway proceeds through the key metabolite methylerythritol phosphate (MEP). The MEP pathway is an enticing antimicrobial drug target, since it is essential in other important pathogens, including Gram negative bacteria and Mycobacterium tuberculosis, but is not found in humans. Isoprenoids comprise a large and complex set of metabolites that are used for diverse functions in other biological systems, particularly plants. We have begun to address which isoprenoids are made by malaria parasites, and why this class of compounds is essential in P. falciparum. We have initiated a variety of metabolomics methods to identify the isoprenoids produced by cultured intraerythrocytic P. falciparum. These studies have revealed a large number of organic compounds, including plant‐like terpenes, that are specific to P. falciparum and not present in cultured erythrocytes alone. Ongoing studies examine the biological roles of these compounds in intraerythrocytic parasite development and odorant reception by the malaria vector mosquito, Anopheles gambiae.
Gene‐Environment Interaction between Twist and Thyroid Hormone Results in Extreme Craniosynostotic Phenotypes in Mice
Authors: Parsons Trish Elizabeth , Weinberg Seth Michael , Elsalanty Mohammed , Khaksarfard Kameron , Yu Jack Chungkai , Cray James
Published: June 2021

Craniosynostosis (CS) is the premature fusion of one or more cranial sutures; it can both hinder the growth of the brain and result in severe craniofacial dysmorphology. Although several genes have been implicated with CS, it is unclear how these genotypes lead to widely variable phenotypes. One possibility is gene‐environment interaction. A CDC study found several environmental risk factors associated CS, including maternal hyperthyroidism. We hypothesize that predisposed genotypes will result in more extreme CS phenotypes when exposed to thyroid hormone. To test this we introduced thyroxine to the maternal environment of a genetic CS mouse model, Twist+/−. TWIST has been linked with CS and this model exhibits variable phenotypic expression of CS. Twist+/− and WT control pregnant dams were given thyroxine‐laced water at E13, before suture formation. We sacrificed neonates at P15 and scanned the skulls using μCT. We collected landmarks from the 3D reconstructions and analyzed them using geometric morphometrics. Our preliminary results show that thyroxine has a clear affect on the shape of both Twist+/− and WT skulls and it affects the two groups differently. Exposed Twist+/− mice have higher cranial vaults, wider calvaria, shorter maxilla lengths and wider midfaces compared to both WT and Twist+/− unexposed mice; these shape changes are similar to those associated with CS.

Grant Funding Source: Cleft Palate Foundation
High risk CNIs, race and early stage breast cancer
Authors: Thompson Patricia A , Brewster Abenaa , Do Kim‐Anh , Sahin Aysegul A , Mills Gordon , Bondy Melissa
Published: June 2021

We determined tumor copy number imbalances in 971 stage I/II breast tumors treated at MDACC from 1985–2000 that included 123 Hispanic and 125 African American cases. CNI were obtained using Affymetrix Oncoscan™. Models of relapse containing CNIs significantly outperformed models with clinical characteristics alone. For triple negative tumors, the combination of CNIs + clinical covariates yielded a significantly better prediction of relapse (C‐index; 0.79 ± 0.023) than the best clinical model (C‐Index = 0.64 ± 0.034). Race/ethnicity was not associated with relapse risk after accounting for clinical covariate but high risk CNIs were more frequent in AA and Hispanic cases in luminal and TNBC models. For example, a narrow region of 7q36.1 was more commonly lost in AA than NHW and Hispanic LUM cases (p=0.01). Furthermore, loss at Xq11–12 a risk factor for recurrence in TNBC was more common among AA and Hispanic women than NHWs (p=0.009). Measures of specific CNIs add significant additional predictive information for risk of recurrence and suggest additional opportunities to refine prognostication for early stage luminal and triple‐negative breast cancers. Further, specific CNIs differ in proportion by race/ethnicity, which perhaps reflects differential germline susceptibility or distinct etiologic risk factors that contribute to observed disparity among race/ethnic groups in breast cancer specific outcomes.
Specificity Factor 1 (Sp1) Mediates Transcriptional Induction of Atp7a During Hypoxia in Rat Intestinal Epithelial (IEC‐6) Cells
Authors: Xie Liwei , Collins James F.
Published: June 2021

Genes with GC‐rich promoters were preferentially induced in the rat intestinal epithelium during iron deficiency. Moreover, promoters of iron homeostasis‐related genes (e.g. Dmt1, Dcytb) contain evolutionarily conserved GC‐rich sequences. The Menkes Copper ATPase (Atp7a) gene was strongly induced during iron deficiency, and we previously demonstrated that Atp7a was coregulated with iron transport‐related genes by HIF2α. In this study, we sought to test the role of Sp1 in transcriptional regulation of Atp7a, as phylogenetic footprinting revealed conserved GC‐rich sequences in the Atp7a promoter. An Sp1 inhibitor (mithramycin) reduced Atp7a and iron transport‐related gene expression. Sitedirected mutagenesis of a basal −224 bp promoter construct showed that several GC‐rich sites participated in the HIF2α‐mediated induction of promoter activity in IEC‐6 cells. Moreover, mithramycin also blocked induction of Atp7a and iron transport genes by hypoxia. We also show that phosphorylation of Sp1 increased in IEC‐6 cells exposed to hypoxia; Sp1 is known to be regulated by phosphorylation, which increases DNA binding and trans‐activation properties. Further, chromatin immunoprecipitation (ChIP) assay indicated that Sp1 binds to the Atp7a promoter. Current data thus suggest that synergistic interactions between Sp1 and HIF2α mediate the induction of Atp7a expression during hypoxia/iron deficiency.

Grant Funding Source: NIH
Genome‐wide contribution of genotype by environment interaction to blood lipid variation
Authors: Lai Chao‐Qiang , Arnett Donna K , Richardson Kris , Parnell Laurence D. , Borecki Ingrid B. , Ordovas Jose M.
Published: June 2021

How important is genotype by environment interaction (GxE) in human disease risk? Using the tool for Genome‐wide Complex Trait Analysis, we have examined 16 major nutrients and lifestyles, designated as E factors, for their interactions with the genome influencing four blood lipids at the genome‐wide level among 406 men and 414 women in the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) study. Based on the estimated GxE variances, we identified several major E factors that contribute significant GxE variance to the total variance of lipid traits in this population: carbohydrates for total cholesterol, alcohol use and total fat intake for HDL‐C, and polyunsaturated fat intake for triglycerides. We then performed genome‐wide association study (GWAS) for the most significant E factor and one nonsignificant E factor and identified a set of SNPs showing GxE interactions for each lipid trait. GWAS results further support significant contribution of GxE interaction in blood lipid variation. In summary, we demonstrated a novel approach to determine to what extent GxE contributes to the variations of blood lipids and which specific factors are important for a given risk factor at the genome‐wide level. These findings provide basic evidence on how important genotypes by diet and lifestyle interaction contribute to CVD risk.
Improvement of the intestinal Caco‐2 cell model for iron absorption studies by the introduction of liver (HepG2) cells
Authors: Scheers Nathalie Maria , Almgren Annette , Sandberg Ann‐Sofie
Published: June 2021

The Caco‐2 cell system is a well‐established in vitro model for iron absorption studies. However, the model does not reflect the regulation of iron absorption by secreted effectors produced in the liver. In the present study we aimed to develop the Caco‐2 cell model by introducing human liver cells (HepG2) to the Caco‐2 cells. The Caco‐2 and HepG2 cell layers were separated by a liquid compartment, which allowed for interactions between the epithelia. We observed that iron status of the Caco‐2 cells in the Caco‐2/HepG2 cell model was affected by the presence of liver cells and that hepcidin levels correlated with the changes. We also compared ferritin formation (in Caco‐2) and hepcidin release (from HepG2) induced by two bread samples in the two models. We conclude that the Caco‐2/HepG2 model may provide an alternative approach for iron absorption studies where the effects of hepcidin are desired. This study was financially supported by the region of Västra Götaland, Sweden (grant no: RUN612–470‐10)
Correlation Network Analysis in Evaluating Dietary Milk Polar Lipids in A Mouse Model of Diet‐induced Obesity
Authors: Zhou Albert Lihong , Ward Robert , Lefevre Michael
Published: June 2021

Leaky gut, endotoxemia, inflammation and obesity are interrelated events during the development of diet‐induced obesity (DIO). To study the effects of dietary milk polar lipids on those relationships, 3 groups of B6 mice were fed for 15 weeks: (1) AIN‐93G based moderately high fat diet (CO); (2) CO with gangliosides; (3) CO with phospholipids. Gut integrity and body fat were measured 6 and 9 times. Plasma cytokines & lipids were tested 3 times. Final measurements included tissue lipids profiles, liver lipid gene expression, and tight junction proteins in gut mucosa. Correlation matrices of parameters were subjected to network analysis by Cytoscape. Forced‐directed layouts and community clusters were produced for networks, which revealed general patterns of the effects of dietary polar lipids. Higher connectivity among parameters in network layouts may indicate more integrative and cohesive connections among biological functions. A decrease in parameter connectivity was observed after initiation of the high fat feeding. Based on networks patterns, dietary polar lipids appear to have negative effect on parameters measured during early phase of DIO and positive effect on all parameters after DIO. In conclusion, correlation network analysis is a powerful tool in revealing general patterns of the effects of dietary treatments between multiple biological parameters.

Grant Funding Source: Western Dairy Center
Development and validation of the US Healthy Food Diversity (HFD) Index: a novel measure of dietary variety, quality, and proportionality
Authors: Vadiveloo Maya , Mijanovich Todor , Dixon L Beth , Parekh Niyati
Published: June 2021

Imprecise measurement of dietary variety may confound associations between variety and obesity. The intent of this study was to develop the novel US HFD index to measure total dietary variety while including measures of dietary quality and proportionality delineated in the 2010 Dietary Guidelines for Americans (DGA).

Two 24‐hour recalls from the 2003–2006 National Health and Nutrition Examination Survey were merged with the My Pyramid Equivalent databases to obtain food‐group level data. The US HFD was generated with the equation HFD=(1 − ∑s2i)* hv where s= share by volume of each food in the diet and hv=health value of the diet, per the 2010 DGA. The US HFD ranges from 0 and 1‐ 1/n; eating a variety of foods in proportions indicated by the DGA maximizes the score (~1). The NCI Method was used to estimate usual intake of the 26 US HFD food groups and sample‐weighted means, standard errors, and correlations were generated with SAS 9.3.

Reliable dietary data from 7,470 non‐pregnant adults ages 20+ were analyzed. US HFD scores ranged from 0.25–0.51. Mean scores were 0.38±0.002 in men vs. 0.40±0.001 in women and 0.38±0.002 in smokers vs. 0.39±0.001 in non‐smokers. Energy‐adjusted US HFD scores correlated with the mean probability of adequacy for 15 nutrients (ρ=0.50 in men and ρ=0.51 in women, p<0.001). The US HFD is a valid measure of dietary variety and may help clarify associations between variety and obesity in future research.

Grant Funding Source: American Heart Association Founders Affiliate Predoctoral Fellowship (12PRE9320023)
Teaching medical students how to walk the walk: Will improving student dietary habits change patient counseling perceptions?
Authors: Kay Danielle , Abu‐Shamat Layla , Leong Benjamin , Monlezun Dominique , Sarris Leah , Harlan Timothy
Published: June 2021

Howe et al. (2010) found that residents and physicians fail to meet dietary guidelines on fruit and vegetable (F/V) intake and that personal dietary habits had no effect on perceived efficacy of patient counseling. At Tulane University School of Medicine (TUSOM), a survey was sent out to assess students’ dietary habits, prior nutritional experience, and perceptions of nutritional counseling competency and counseling importance. Only 51.9% of respondents eat F/V on average at least once daily. Also, there is no significant difference in perceived competency in counseling overweight patients on weight loss strategies (p=0.36) and in perceived importance of nutritional counseling at each visit (p=0.17) between students with daily F/V consumption and students with less F/V intake. Overall, student F/V intake was less than dietary recommendations. There was also no correlation between F/V intake and perceived nutritional counseling competency and importance. We hope to assess the impact of novel medical nutrition curriculum on students’ dietary habits and whether this intervention will affect counseling efficacy and patient compliance. Research support: Tulane University Center for Culinary Medicine

Grant Funding Source: Tulane University Center for Culinary Medicine
The interaction between physical activity and obesity gene variants in association with BMI: Does the obesogenic environment matter?
Authors: Richardson Andrea S , North Kari E , Graff Mariaelisa , Young Kristin L , Mohlke Karen L , Lange Ethan M , Lange Leslie A , Harris Kathleen M , Gordon‐Larsen Penny
Published: June 2021

Background

Little is known about how obesity SNPs interact with moderate to vigorous physical activity (MVPA) in relation to BMI during adolescence, accounting for the obesogenic environment.

Methods

We tested 43 SNP by MVPA interactions with BMI (measured heights and weights) using stepwise addition of obesogenic neighborhood factors in 8,028 respondents from the National Longitudinal Study of Adolescent Health (1996; ages 12–21). Multi‐level models were stratified by race: European Americans (EA; N=5,022), African Americans (AA; N=1,726), and Hispanic (HA; N=1,280), controlling for age, sex, current smoking, region, and hours of TV/video, with addition of: 1) physical activity resources: physical activity facilities, parks; 2) neighborhood infrastructure: green space, street connectivity; and 3) neighborhood social factors: neighborhood poverty, and crime.

Results

Nine of 43 SNP × MVPA interactions were nominally significant (EA: 7, HA: 2), with larger estimated effects on BMI in adolescents with lower MVPA. For example, in EA, rs987237 was associated with a 1.02 unit higher BMI in adolescents with < 5 (b=1.02, CI: 0.6–1.5) versus ≥ 5 (b=0.271, CI: −0.001–0.6) bouts MVPA/week. Findings were robust after inclusion of neighborhood obesogenic covariates.

Conclusions

These findings suggest that MVPA may attenuate obesity susceptibility during adolescence independent of neighborhood context.

Grant Funding Source: R01HD057194
Alternate day fasting when combined with endurance exercise reduces leptin but not adiponectin and resistin
Authors: Bhutani Surabhi , Klempel Monica C , Kroeger Cynthia M , Varady Krista A
Published: June 2021

Background

Alternate day fasting (ADF), consisting of a feed day (24‐hour ad libitum food intake) alternated with a fast day (75% energy restriction), is effective in reducing body weight and modulating adipose tissue physiology. However, the ability of ADF in combination with endurance exercise to improve the above variables has never been tested.

Objective

Accordingly, this study examined whether the combination of ADF plus exercise produces superior changes in body weight and plasma adipokine levels, when compared to each treatment alone.

Methods

Obese subjects (n=64) were randomized to 1 of 4 groups for 12 weeks: 1) combination (ADF + endurance exercise), 2) ADF, 3) exercise, or 4) control.

Results

Body weight was reduced (P < 0.05) by 7 ± 1 kg, 5 ± 1 kg, and 1 ± 1 kg, and fat mass decreased (P < 0.001) by 6 ± 1 kg, 4 ± 1 kg and 1 ± 1kg in the combination, ADF and exercise group, respectively. Fat free mass was retained in all groups. Adiponectin and resistin values did not change in any group post‐treatment. Leptin levels significantly decreased (P < 0.05) by 38 ± 10 ng/ml, 15 ± 6 ng/ml and 15 ± 6 ng/ml in the combination, ADF, and exercise group, respectively.

Conclusion

These findings suggest that the combination of ADF plus exercise produces superior changes in body weight, body composition and leptin levels, when compared to each intervention alone.

Grant Funding Source: American Heart Association Predoctoral Fellowship
Parent and child use of dietary supplements are associated
Authors: Dwyer Johanna T , Jacques Paul F , Rogers Gail T , Sempos Christopher , Bailey Regan L
Published: June 2021

Background

Little is known about the interaction between parents and children in dietary supplement (DS) use.

Objective

Determine if parental use of dietary supplements predicted child use.

Methods

4556 parent‐child pairs who responded to questions about DS use over the past 30 days and participated in the CAM supplement of the 2007 National Health Interview Survey. DS were categorized as multivitamin mineral (MVM) (2 or more vitamins +/or minerals) only; single vitamin or mineral DS (SVM) with or without use of MVM; non‐vitamin non‐mineral DS with or without use of MVM or SVM (NVNM) and DS nonusers. Prevalence of use and standard errors were calculated using SUDAAN PROC DESCRIPT to account for the complex sampling design and standardized to the 2000 census.

Results

In the pairs, 46.4% of the parents and 36.6% of the children took DS, and use of MVM and SVM was much more common than NVNM. For parents who used any DS, fully 55% of their children used them as well. Among parents who used MVM, 50% of the children used MVM, for parents who used SVM, only 10% of the children used SVM and for parents who used NVNM, only 13% of the children used them.

Conclusion

Parents who use DS are more likely to give them to their children than those who do not. In most cases the children took micronutrient DS (MVM and SVM). Parents who used NVNM were more likely to have children who used NVNM.

Support: Office of Dietary Supplements, NIH, and Jean Mayer USDA HNRC on Aging at Tufts University
Effects of water‐based hand sanitizers and micronutrient powders along with nutrition and hygiene education to prevent infections and linear growth faltering among low birth weight infants in Bangladesh
Authors: Shafique Sohana , Jalal Chowdhury S.B. , Jolly Saira P. , Shikder Hasina , Sellen Daniel W. , Zlotkin Stanley
Published: June 2021

Objective

To measure the relative efficacy of Benzalkonium Chloride containing, water‐based hand sanitizers (HS) and multiple micronutrient powder (MNP) along with nutrition and hygiene education (NHE) to prevent infections and linear growth faltering among low birth weight (LBW) infants.

Methods

Prospective 2×2 factorial, cluster‐randomized trial, conducted among 467 full‐term LBW infants from 0–12 months (mo) in rural Bangladesh, using 48 clusters randomly assigned as follows: from 0–6 mo, i) NHE only or ii) NHE plus HS; from 6–12 mo, i) NHE only; ii) NHE plus HS; iii) NHE plus MNP (to be provided with complementary foods); and iv) NHE plus HS and MNP.

Results

During 0–6mo, the proportion of LBW infants with any infection was significantly lower in the ‘NHE plus HS’ group compared to the ‘NHE only’ group (P<0.001). Mean duration of diarrhea among LBW infants was significantly lower in the ‘NHE plus HS’ group compared to ‘NHE only’ (3.4±1.2 vs. 6.0±1.6 days, P<0.01). Upper respiratory tract infections and cough were also significantly lower in the ‘NHE plus HS’ group in comparison with ‘NHE only’ (29.8% vs. 33.0% and10.6% vs. 12.2%, P<0.05, for both).

Conclusions

Caregiver use of hand sanitizers might effectively reduce infections among term LBW infants in the first six months of life.

Grant Funding Source: Bill & Melinda Gates Foundation to FHI 360, through the Alive & Thrive Small Grants Program managed by UC Davis.
Insulin ameliorates skeletal muscle degradation during sepsis in neonatal pigs
Authors: Orellana Renan A , Koo Sue Jie , Nguyen Hanh V , Suryawan Agus , Desai Moreshwar , Coss‐Bu Jorge A , Davis Teresa Ann
Published: June 2021

Insulin decreases whole body protein breakdown during sepsis in adolescents, but not in adults. Neonates have higher rates of muscle deposition, protein turnover, and response to insulin than adults. To determine the effects of insulin on skeletal muscle protein degradation during sepsis, neonatal pigs (n=16) underwent cecal ligation and puncture (CLP) or sham surgery and were pair‐gavage fed for 5 days. Pancreatic‐substrate clamps were performed for 2 h providing insulin to attain fasting or fed (+Ins) insulin levels and to maintain glucose and amino acids (AA) in the fasting range. Protein synthesis (PS) and protein degradation signals were examined in longissimus dorsi. Circulating insulin and total AA did not differ between CLP and Shams, but CLP had reduced plasma BCAA and Leu than Shams. CLP+Ins had lower AA deposition rates and higher circulating 3‐methylhistidine than Shams+Ins. Compared to Shams, CLP had decreased PS and Fox03 phosphorylation and increased AMPK phosphorylation and MuRF abundance in muscle. Compared to CLP, CLP+Ins had higher PS, PKB and Fox01 phosphorylation and caspase‐3 abundance, and lower PCG‐1α mRNA expression, AMPK phosphorylation and MuRF abundance in muscle. The results suggest that insulin anatagonizes the CLP‐induced decrease in PS and suppresses proteosomal degradation signal activation in skeletal muscle of neonatal pigs. NIH AR44474, NIH AR51563, and USDA 58–6250‐6–001
Neonatal dietary calcium alters mesenchymal stem cell differentiation potential in pigs
Authors: Li Yihang , Seabolt Brynn , Stahl Chad
Published: June 2021

Neonatal Ca nutrition affects bone development and mesenchymal stem cell (MSC) activity; however, its effect on MSC differentiation potential has not been fully characterized. MSC were isolated from neonatal pigs fed either a Ca deficient, adequate, or excessive diet. After in vitro adipogenic induction, PPARG and AP2 expression was up‐regulated in MSC from Ca deficient (P<0.1) and Ca excess (P<0.05) groups. Under osteogenic induction, osteocalcin (OC) gene expression was depressed in MSC from Ca deficient pigs. To further evaluate the impact of Ca status on MSC activity, 20 individual colonies were obtained from each pig. From these colonies, we selected the most and least osteogenic (O+/O−) and the most and least adipogenic (A+/A−) clones based on functional staining. During osteogenesis, increased (P < 0.1) gene expression of Runx2 and OC was seen among O+ colonies. Increased expression of OC was seen among Ca adequate (P<0.01) and excess (P=0.07) colonies compared with the Ca deficient colonies. During adipogenesis, A+ colonies had greater expression (P < 0.1) of AP2 and LPL. No interaction between osteogenic or adipogenic capability and Ca status was seen. This suggests that the differences in adipocytic and osteogenic differentiation of MSC based on the Ca status of the pig is due to alterations in the number of highly osteogenic and adipogenic MSC in the heterogeneous population.

Grant Funding Source: NC Agricultural Research Service
Global DNA hypomethylation in peripheral blood mononuclear cells as a biomarker of cancer risk
Authors: Guarini Patrizia , Udali Silvia , Pattini Patrizia , Moruzzi Sara , Girelli Domenico , Pizzolo Francesca , Martinelli Nicola , Olivieri Oliviero , Choi Sang Woon , Friso Simonetta
Published: June 2021

DNA methylation is a reversible epigenetic phenomenon that can be modified by nutrients such as folate and influenced by the MTHFR677C>;T polymorphism in a gene‐nutrient interaction manner. In human cancer, global DNA hypomethylation is an almost universal finding.

Peripheral blood mononuclear cells (PBMCs) are easily accessible in humans and our aim was to test PBMCs DNA methylation according to the folate‐MTHFR677C>;T polymorphism interaction, as a potential biomarker for cancer risk.

Global DNA methylation was measured in PBMCs of 68 subjects with cancer history at enrollment and 62 with cancer after eight‐year follow‐up compared to age‐and sex‐matched controls (68 at enrollment, 58 at follow‐up).

Cancer subjects had lower plasma folate concentrations (P=0.003), higher frequency of MTHFR677TT (P=0.013) and lower PBMCs‐ DNA methylation than controls (P<0.0001). A DNA methylation threshold of 4.74% categorized cancer patients from controls. Subjects with cancer at follow‐up had at enrollment lower DNA methylation than controls (P<0.0001).

The association of MTHFR677TT and low plasma folate showed the lowest DNA methylation levels (4.39%). Cancer deaths had a lower DNA methylation compared with other cause deaths (P=0.015) and the survivors had an increased DNA methylation compared to cancer (P=0.004).

Low global DNA methylation in PBMCs may be a useful predictive biomarker of cancer.
Associations Between Biomarker‐Calibrated Protein Intake and Bone Health in the Women's Health Initiative
Authors: Beasley Jeannette M , Larson Joseph , LaCroix Andrea Z , Neuhouser Marian L , Tinker Lesley F , Jackson Rebecca , Huang Ying , Snetselaar Linda , Eaton Charles , Prentice Ross L
Published: June 2021

OBJECTIVE

The effects of dietary protein intake on bone health are controversial. This study examined the relation between protein intake with bone mineral density (BMD) and fracture within the Women's Health Initiative (WHI).

METHODS

The WHI recruited 161,806 women aged 65–79 into the WHI‐Observational Study (OS) and WHI‐Clinical Trial (CT) between 1993 and 1998. Fractures were collected annually (WHI‐OS) or semi‐annually (WHI‐CT) by questionnaire through 2011. BMD was measured at baseline and 6 years among 10,833 women using dual‐energy x‐ray absorptiometry. Protein and energy intake were assessed via the WHI Food Frequency Questionnaire and calibrated using regression equations established based on biomarkers of protein and energy intake. Cox (fracture) and linear (BMD) regression models were adjusted for confounders including age, race/ethnicity, and body mass index.

RESULTS

Median calibrated protein intake was 14% of energy. Women consuming 20% higher calibrated protein were 9% less likely to have a hip fracture (95% CI= 1%‐15%). Each 20% increase in calibrated protein was associated with higher BMD for total body (mean 6‐year change 0.004 g/cm2, 95% CI = 0.001–0.007 g/cm2) and hip (0.003 g/cm2, 95% CI= 0.001–0.005 g/cm2).

CONCLUSION

Higher protein intake was associated with reduced risk of hip fracture and better maintenance of BMD over time. These data suggest higher protein intake may be an intervention target for preserving bone health.

Funded by NHLBI (WHI) and NIA (4R00AG035002).
Pemphigus autoantibodies identify a desmoglein 3/p38MAPK adhesion complex regulating keratinocyte cohesion
Authors: Spindler Volker , Dehner Carina , Roetzer Vera , Waschke Jens
Published: June 2021

Loss of cell adhesion in the autoimmune blistering skin disease pemphigus vulgaris is mediated by autoantibodies targeting the desmosomal cadherins desmoglein (Dsg)3 and Dsg1. We recently demonstrated a Dsg‐cosslinking peptide (TP) to protect against autoantibody‐mediated cell dissociation in vitro and in vivo by promoting interaction of Dsg molecules and inhibiting the activation of p38MAPK. Here, we used TP to further characterize the mechanisms underlying loss of cell adhesion via desmoglein signaling. Interference with Dsg interaction by tryptophan or AK23, a Dsg3 antibody from a pemphigus mouse model, induced cell dissociation as well as p38MAPK activation, indicating loss of Dsg binding to be a trigger for intracellular signaling. Upon incubation with AK23, immunoprecipitation and proximity ligation assays revealed rapid phosphorylation of p38MAPK associated with Dsg3, which was blocked by TP incubation. Similar to inhibition of p38MAPK by SB202190, TP prevented AK23‐induced keratin filament retraction, a hallmark of pemphigus, and promoted oligomerization of Dsg3 within desmosomes. Taken together, these data indicate for the first time that a disease‐relevant adhesion‐dependent signaling complex consisting of Dsg3 and p38MAPK exists which regulates cell cohesion via keratin filament reorganization.
Molecular Chaperones in Cellular Protein Folding: Mechanisms and Pathways
Authors: Hartl Franz Ulrich
Published: June 2021

The past two decades have witnessed a paradigm shift in our understanding of protein folding in the cell. While the three‐dimensional structures of functional proteins are determined by their amino acid sequences, it has become clear that in the crowded cellular environment many proteins depend on molecular chaperones to fold efficiently and at a biologically relevant time scale. Assistance of protein folding is provided by different types of chaperone which act to prevent misfolding and aggregation, often in an ATP‐dependent mechanism. In the cytosol, nascent chain‐binding chaperones, including Trigger factor and Hsp70, stabilize elongating polypeptide chains on ribosomes in a non‐aggregated state. Folding is then achieved either on controlled chain release from these factors or following polypeptide transfer to downstream chaperones, such as the cylindrical chaperonins, GroEL and TRiC. The latter provide nano‐compartments for single protein molecules to fold in isolation, unimpaired by aggregation.

Once folded, many proteins continue to require chaperones to retain their functional state, particularly under conditions of cell stress. Failure of the chaperone network to maintain proteostasis, i.e. the conformational integrity of the cellular proteome, may facilitate the manifestation of pathological states, such as Parkinson's and Huntington's disease, in which proteins misfold and are deposited as aggregates. A decline in proteostasis capacity occurs during aging, presumably explaining why age is a major risk factor of neurodegeneration.

I will discuss recent findings from mechanistic and systems‐level studies to understand the organisation of the cellular chaperone network.
Chaperonin‐mediated protein folding
Authors: Horwich Arthur L.
Published: June 2021

Chaperonins provide essential kinetic assistance to protein folding to the native state. Early studies with Ulrich Hartl identified the double‐ring assembly Hsp60 as playing an essential role in mediating the folding of many proteins imported into the mitochondrial matrix. Further studies have involved structure and function studies of the mechanism of action of the homologous bacterial cytoplasmic chaperonin system, GroEL/GroES, in collaboration with Paul Sigler, Helen Saibil, and Kurt Wüthrich. These have revealed that GroEL mediates folding via the use of its central cavity, first capturing a non‐native protein via multivalent binding to a hydrophobic binding surface, forestalling aggregation, and then, following binding of GroES to the same ring, releasing the protein to fold in isolation in a GroES‐encapsulated chamber where aggregation cannot occur.
Science Outreach at Washington University in St. Louis: The Young Scientist Program
Authors: Bradley Michael John , Siebrasse Erica , Mosher Jennifer , Woolsey Thomas
Published: June 2021

The Young Scientist Program (YSP) is run by graduate and medical students and aims to improve science education in local schools, attract students to scientific careers, and increase the participation of underrepresented groups in science. YSP has developed several programs to reach St. Louis area students and teachers.

Teaching Teams

YSP develops and leads inquiry‐driven science modules in local science classes covering a variety of scientific topics. Modules are modified with teacher input to integrate classroom curricula and state standards. Teaching teams have impacted >;7000 students since 1993.

Summer Focus

YSP places local high school students in laboratory internships. Each participant completes an independent research project with a graduate or postdoctoral mentor, and writes a research paper during the eight‐week internship. More than 250 local students have participated in Summer Focus.

Teacher and Researcher Partnership

YSP provides summer research and curriculum enrichment experiences for public school teachers. Participants work with mentors on individual research projects and on development of modules for their classrooms.

Benefits and Outcomes

Volunteers gain a variety of skills not formally taught during graduate training. Student and teacher participants report increased interest in and understanding of scientific concepts.
Public engagement with scientists at the University of Missouri: Saturday Morning Science
Authors: McClure Bruce , Johnson Marc , Cornelison D , Kroll Melody , Scheiner Cynthia
Published: June 2021

Saturday Morning Science (SMS) is a free public lecture series held every Saturday at the University Of Missouri throughout the fall and winter semesters. Talks are geared toward the general public and include discussions of basic scientific concepts, demonstrations, and a question‐and‐answer session. Since 2003 we have presented over 220 talks with a total attendance of about 29,000. Weekly attendance averages ~150, with between 75% and 95% of the audience coming from the community. Most attendees are adults, but the audience includes K‐12 students and teachers, children, retirees, and others. About 30% have attended more than ten SMS presentations. The speakers, informal atmosphere, and volunteer support are keys to the success of SMS. We choose excellent speakers who can present science in a lively and engaging manner and convey science in a way that is entertaining and accessible. Topics vary widely: physics, computer vision, plant immunity, epidemiology, linguistics, planet formation, fuel cells, traditional medicine in Africa, and more. We seek to present exciting science to the public as well as foster a culture where engagement between scientists and the public is the norm. Support for SMS comes from the MU Office of Research, Monsanto, the Christopher S. Bond Life Sciences Center, the MU Bookstore, and volunteers.
Engagement of Middle School Students in Discovery Science: A strategy to Elevate Achievement and increase public awareness and appreciation of Science in Rural Communities
Authors: Fidler Aaron , Call Jaxen , Call Ricco , Jellison Lucien , Ward Braeden , Tate Rhonda , Hudson Julie , Hudson Billy
Published: June 2021

Science outreach encompasses many different forms, including science cafes, science festivals, public lectures. These activities afford scientific experts the opportunity to share their knowledge with the public. We have piloted an educational strategy involving rural middle school students with the dual purpose of elevating science achievement and increasing the rural public awareness and appreciation of science through the students. To this end, we have engaged four gifted and talented students in a search for the evolutionary origin of a newly discovered chemical bond. The sulfilimine chemical bond reinforces the collagenous network that underlies epithelial cells in all animal tissues. The students were tasked with searching for evidence for the bond in Cnidaria phylum by collecting and analyzing Hydractina, Ectopleura and Metridium from the Maine coast. Their investigation was hands‐on and guided by a team involving their classroom teacher and scientists within the classroom and by video conferencing between the classroom and the university. Their findings indicate that the bond exist in all these Cnidarian species, indicating that the bond arose during the Cambrian Explosion, representing an essential innovation for the genesis of animal tissues. The students took the initiative to report their finding to the school board, fellow students, parents, school board and other members of the community. This effort engaged the students with the scientific process, provided an opportunity to experience discovery, and lead to their sharing of their knowledge and experience with a rural community.