bluuebunny/crossref_metadata_2025 huggingface dataset:
Enemy Within ‐ Immune and Autoimmune Responses to Cytosolic DNA and RNA
Authors: Chen Zhijian James
Published: June 2021

The inappropriate presence of DNA in the cytosol is a danger signal that alerts the host of potential microbial invasion and triggers innate immune responses including the production of type‐I interferons. Under certain pathological conditions, self DNA, which normally reside in the nucleus or mitochondria, could also trigger autoimmune responses from the cytosol, resulting in human diseases such as lupus. Cytosolic DNA induces interferons through a signaling pathway that involves the adaptor protein STING, the kinases IKK and TBK1, and the transcription factors NF‐kappaB and IRF3. Through a biochemical approach, we have identified the cytosolic DNA sensor that activates STING and triggers type‐I interferon production. This sensor turns out to be a novel enzyme which we named cyclic GMP‐AMP synthase (cGAS). cGAS is activated by its binding to DNA and upon activation it catalyzes the synthesis of a unique cyclic GMP‐AMP (cGAMP) isomer containing both 2′‐5′ and 3′‐5′ phosphodiester linkages. This cGAMP isomer, termed 2′3′‐cGAMP, functions as a second messenger that binds to and activates STING, leading to the induction of interferons and other cytokines. Genetic experiments show that cGAS is essential for innate immune responses triggered by DNA viruses and retroviruses, including HIV. This work uncovers a cyclic dinucleotide signaling pathway that was previously not known to exist in metazoa, reveals a new signaling mechanism in innate immunity, provides cGAS as a new therapeutic target for the treatment of autoimmune diseases, and offers cGAMP as a new adjuvant for the development of new vaccines and immune therapeutics.
The Amyloid State of Proteins
Authors: Eisenberg David , Sawaya Michael , Nelson Rebecca , Soragni Alice , Rodriguez Jose , Jiang Lin , Sangwan Smriti , Johnson Lisa , Laganowsky Arthur , Liu Cong , Soriaga Angela , Landau Meytal , Cascio Duilio , Sievers Stuart , Saelices‐Gomez Lorena , Guenther Elizabeth , Hughes Michael
Published: June 2021

Amyloid diseases, including Alzheimer's, Parkinson's, and the prion conditions, are each associated with a particular protein in fibrillar form. At the morphological level, these fibers appear similar and are termed “amyloid.” From x‐ray and electron diffraction, we found that the adhesive segments of amyloid fibers are short protein sequences which form pairs of interdigitated, in‐register beta sheets. These amyloid fibrils were long suspected to be the disease agents, but evidence suggests that in at least some of the neurodegenerative diseases, smaller, often transient and polymorphic oligomers are the toxic entities. In attempts to determine structures for such oligomers, we have discovered segments of amyloid‐forming proteins that form toxic, antiparallel beta, out‐of‐register structures. In one case, the oligomer is a cylindrical barrel, formed from six anti‐parallel, out‐of‐register protein strands, which we term a cylindrin. In another case, the oligomer is an open, continuous cylindrin‐like structure that we term a corkscrew. Cylindrins offer models for the hitherto elusive structures of amyloid oligomers, and are distinct in structure from amyloid fibrils. From the known structure of the spine of an amyloid fibril, we find it is possible to design an inhibitor of fibril formation.
Understanding the Signaling Architecture of Calcium‐Dependent Protein Kinases in Apicomplexan Parasites
Authors: Lourido Sebastian , Tilley Lucas
Published: June 2021

Identifying the substrates of different protein kinases remains a major obstacle to understanding the signaling pathways that regulate eukaryotic cells. The complexity and plasticity of these pathways makes it difficult to distinguish the contribution of individual kinases in global studies, and yet in vitro assays frequently lack many of the cellular features that dictate kinase‐substrate specificity. By engineering kinases that accommodate bio‐orthogonal ATP analogues, others have previously demonstrated the feasibility of monitoring the activity of individual kinases in complex lysates. We have improved on these methods using pore‐forming toxins to semi‐permeabilize cells and quantitative phosphoproteomics to identify the substrates of two related kinases, CDPK1 and CDPK3, in the human parasite Toxoplasma gondii. We have previously demonstrated that both calcium‐dependent protein kinases (CDPKs) contribute to the regulation of parasite motility and are essential for the infectious cycle. By preserving cellular ultrastructure, we are able to determine the contribution of subcellular localization to kinase specificity. Furthermore, analysis of the substrates has extended our understanding of the cellular processes regulated by these kinases. Beyond its relevance to human health, T. gondii serves as a model for other apicomplexan parasites, including Plasmodium spp., the causative agents of malaria. We hope that our work will serve as the basis for comparing calcium‐regulated signaling within the phylum, and as a model for understanding the role of subcellular localization in the evolution of kinase families.
The Molecular Signals that Regulate Gamma Delta T Cells
Authors: Adams Erin
Published: June 2021

γδ T cells represent a significant proportion of T cells in humans yet the signals to which they respond have remained, for the most part, uncharacterized. Our laboratory is interested in identifying these signals and how they regulate γδ T cell activity in the tissues in which these cells reside. The majority of human γδ T cells express a T cell receptor (TCR) using a Vδ1, Vδ2 or Vδ3 domain. We have been examining the antigen‐recognition capabilities of Vδ1 and Vδ2 (specifically Vγ9Vδ2 T cells) expressing T cells; these two major T cell subsets differ extensively in how they are regulated by antigenic signals. Our work and that of others has demonstrated an association between members of the CD1 family of lipid‐presenting molecules and human Vδ1 TCR expressing γδ T cells, the major intestine‐resident γδ population. We have predominantly focused on Vδ1 recognition of CD1d presenting the self‐lipid sulfatide and have shown the biochemical and structural basis for this recognition and have further evidence that this is an important ligand for Vδ1 immune surveillance in the gut. Vγ9Vδ2 T cells, in contrast, predominate in human blood and are activated by target cells exposed to pyrophosphate containing small molecules called phosphoantigens. We have shown the critical role for the butyrophilin protein, BTN3A1, in this recognition process, demonstrating that phosphoantigens interact directly with BTN3A1′s intracellular B30.2 domain. How this translates into engagement of the Vγ9Vδ2 TCR is still unclear. Together, we provide functional, biochemical and structural insight into modulation of human γδ T cell activity by MHC‐like and non‐MHC molecules, demonstrating the diverse ways in which γδ T cells survey their environment for infection or dysregulation.
Engineering T Cell Receptors for Optimal Affinities and Desired Specificities
Authors: Kranz David , Harris Daniel , Stone Jennifer , Smith Sheena , Chervin Adam
Published: June 2021

T cells, via their T‐cell receptors (TCRs), evolved to target intracellular antigenic peptides, as cell‐surface complexes with MHC products. While the structural and biochemical characteristics of the TCR:pepMHC interaction have been well studied, there remains interest in understanding the molecular basis of peptide specificity exhibited by TCRs. Furthermore, understanding the binding properties of the TCR that can optimally mediate the activity of T cells is important, especially as adoptive T cell therapies have become more feasible. We have used various strategies to engineer the binding properties of TCRs for adoptive T‐cell therapies, either as full‐length heterodimeric TCRs or as CAR‐like signaling receptors. TCR engineering has been performed using yeast display of single‐chain TCRs in order to generate affinity‐matured variants. In addition, we recently used synthetic TCR libraries in key CDR residues to convert the specificity of a TCR from a virus peptide to a cancer peptide. This approach allows the de novo isolation of TCRs with desired specificities using completely in vitro, directed evolution approaches. Various aspects of the engineering, specificity, and activity mediated by these receptors will be presented.
Functional Interactions of Disease‐Linked Disordered Proteins: Alpha‐Synuclein, Tau and Complexin
Authors: Eliezer David
Published: June 2021

The proteins alpha‐synuclein and tau are linked to Parkinson's and Alzheimer's disease, respectively, yet little is known about their normal physiological functions, while complexin, a protein more loosely linked to neurological and psychiatric disorders, has several opposing functions whose mechanisms remain poorly understood. All three proteins are completely or highly disordered when free in solution. Structural characterization of different states of alpha‐synuclein has lead us to propose a model in which the protein can bridge between the synaptic vesicle and plasma membranes. This model also has implications for membrane‐induced synuclein aggregation. These topics will be discussed in the context of one of the most recent Parkinson's disease associated synuclein mutations. Tau is normally a microtubule binding protein, but can also bind to membrane surfaces, an interaction that may be either physiologically or pathologically relevant. Recent work in the lab has confirmed that tau‐membrane interactions are mediated by short amphipathic helices, which may also play a role in mediating membrane‐ or microtubule‐induced aggregation. Complexin contains a central helix motif that binds to assembled SNARE complexes, and this interaction is key to two opposing functions, enhancing synchronous exocytosis and inhibiting spontaneous vesicle fusion. Binding of the disordered C‐terminal domain of complexin to membranes is critical for its inhibitory function. We have shown that such binding is highly dependent on membrane curvature, and that a local structural transition to a helical conformation, again necessary for function, only occurs upon binding to highly curved membranes such as synaptic vesicles. Thus complexin's function is regulated by a membrane curvature dependent structural transition.
Membrane Lipids in Migrating Cells Illuminated by Molecular Sensors and Chemical Actuators
Authors: Inoue Takanari , Miao YuChuan , Devreotes Peter
Published: June 2021

Cell motility plays a vital role in both normal physiology and the pathogenesis of many diseases. We have recently shown that cell motility requires the signal transduction network serving as a pacemaker to drive cytoskeletal activities. This network features spontaneous firing that promotes the formation of sustained protrusions which govern random cell migration. However, a molecular identity of the signal excitability remains unknown. Phosphatidylinositol 4,5‐bisphosphate (PIP2) is one of the eight phosphoinositide species consisting of the cellular membrane structures, and well characterized as a substrate of PI3K that produces phosphatidylinositol 3,4,5‐trisphosphate (PIP3). PIP2 has long been viewed as a general source of negative charges, offering docking sites for cytosolic proteins through electrostatic interactions. Here, we examine the roles of PIP2 in this signal transduction network using a Dictyostelium cell as a model. To specifically manipulate PIP2 levels with high spatiotemporal precision, we rapidly recruited a yeast‐derived PIP2‐specific 5‐phosphotase, Inp54p, to the plasma membrane using the chemically‐induced dimerization (CID) system. Following the Inp54p recruitment, the cells went into a heterogeneous oscillation between a spreading and a crunching morphology. While a PIP3 phosphatase PTEN fell off the membrane when cells spread, it rebounded to the membrane as cells crunched. Other signaling events such as Ras activation, PIP3 production, and actin polymerization are largely induced along the periphery as cells spread. Together with a series of pharmacological experiments, our results indicate that PIP2 impedes protrusion events through multiple redundant pathways, providing a driving force for the excitable signaling network.
Compartmentalized PI3K/Akt/mTOR Signaling in Living Cells
Authors: Zhang Jin
Published: June 2021

The complexity and specificity of many forms of signal transduction are widely suspected to require spatial microcompartmentation and dynamic modulation of the activities of signaling molecules, such as protein kinases, phosphatases and second messengers. We have developed a series of fluorescent biosensors to probe the compartmentalized signaling activities. In this talk I will present studies where we combined genetically encoded fluorescent biosensors, targeted biochemical perturbations, and superresolution imaging to investigate the molecular mechanisms and functional roles of spatiotemporal regulation of the PI3K/Akt/mTOR signaling pathway.
Specificity and Promiscuity in Enzyme Superfamilies
Authors: Allen Karen , Dunaway‐Mariano Debra
Published: June 2021

In order to identify and assess sequence markers that support enzyme structure and specificity, we have undertaken the study of enzyme superfamilies, namely the enzymes from the Haloalkanoate Dehalogenase (HAD) superfamily and the thioesterases of the hotdog‐fold superfamily. Because of the number of homologues within each organism in these families the members provide numerous examples of iso‐functional orthologues to study determinants of specificity and paralogues to study function diversification. Although specificity is often considered the hallmark of enzymes, the occurrence of enzymes displaying substrates promiscuity or substrate ambiguity can offer advantages to the cell. Indeed there may be selective pressures that favor the occurrence of promiscuous enzymes. Examples from the HADSF and thioesterases show that promiscuity can provide the cell ways to perform housekeeping functions and a means of bypassing blocked steps in metabolic pathways. In order to obtain a “panoramic view of promiscuity”, we have employed large‐scale substrate screening on a diverse set of HADSF enzymes and hotdog‐fold thioesterases from a sampling of bacteria across phyla. The screens have uncovered orthologs of known enzymes and revealed some new pathways and activities. The results highlight that promiscuity is much more prevalent than one might imagine. The HADSF and thioesterases exemplify two different ways that enzyme structure can act to promote substrate promiscuity.
Piceatannol Inhibits Lipolysis in Adipocytes by promoting autophagy‐lysosome‐induced degradation of Lipolytic Proteins
Authors: Kim Kee‐Hong , Kwon Jung Yeon , Chen Chih‐yu , Komanetsky Susan , Zhu Yuyan , Kershaw Jonathan
Published: June 2021

Obesity is closely linked to the development of insulin resistance. This is largely through overly activated lipolysis in adipose tissue for providing excess fatty acids to peripheral tissues for developing hyperglycemia. Adipose triglyceride lipase (ATGL)/desnutrin, catalyzes the initial and rate‐limiting step of triglyceride hydrolysis for the release of free fatty acids to circulation. Thus, inhibiting lipolysis by lowering ATGL activity and/or expression has been proposed to be a therapeutic approach to improve glucose tolerance and insulin sensitivity in obesity. The objective of this study was to determine the role of piceatannol, a resveratrol analogue found in various fruits and red wine, in adipose lipolysis. Unlike resveratrol, acute treatment of piceatannol inhibited the release of glycerol and fatty acids from 3T3‐L1 adipocytes and isolated mouse adipose tissue both in basal and stimulated conditions. Piceatannol‐inhibited lipolysis was resulted from marked decrease in ATGL and its cofactor CGI‐58 protein levels with little effect on the mRNA levels. Consistently, intraperitoneal administration of piceatannol to obese mice lowered plasma levels of lipolysis markers and insulin, with reduced ATGL level in adipose tissue. Mechanistically, we elucidated that the anti‐lipolytic effect of piceatannol was through piceatannol‐induced lysosomal degradation of ATGL and CGI‐58 via activation of autophagy in adipocytes. Overall, our results identified piceatannol as a natural anti‐lipolytic small molecule that could uncouple obesity from its related metabolic diseases. Moreover, our study provides new insights into autophagy‐lysosome‐dependent regulation of adipose lipolysis.
Biochemical Profiling of Human Plasma and Urine From Cranberry Juice Consumption Identifies Potential Biomarkers of Consumption and Gut Flora Metabolites
Authors: Khoo Christina , Baer David , Novotny Janet
Published: June 2021

The purpose of this study was to investigate the influence of polyphenol‐rich low calorie cranberry juice (LCCJ) consumption on cardiovascular health and consumption biomarkers. In a double blind, placebo controlled randomized clinical trial, volunteers (n=26 men, n=30 women), with BMI of 28.4+4.3 (mean+SD) consumed LCCJ or a color/flavor/calorie‐matched placebo beverage (PB) as part of a controlled diet for 8 wks. Baseline urine and plasma showed few differences between groups, but significant metabolic changes were detected after 8 weeks. The Metabolon platform detected 616 biochemicals in plasma and 996 in urine, linked to alterations in gut microflora metabolism, redox balance, fatty acid degradation, and glycerolipid metabolism. Statistically significant changes were seen in gut microflora metabolites of families of amino acids (phenylalanine, tyrosine, tryptophan), bile acids, and benzoate‐containing molecules. LCCJ increased levels/maintenance of plasma cysteine, an essential amino acid required for synthesis of glutathione, which may be beneficial when required. Also, 2,4,6‐trihydroxybenzoate, not found in the beverage or plasma, was detected in urine, significantly increased by 1.75‐fold in the LCCJ group and decreased to 0.34‐fold of starting levels in the PB group, suggesting that this may be a potential biomarker of consumption for cranberry juice. These changes may be linked to potential beneficial actions of cranberry polyphenols on health, consistent with improved clinical cardiometabolic parameters reported previously. Supported by Ocean Spray Cranberries.
A 1H NMR‐Based Approach to Investigate Metabolomic Differences in the Plasma and Urine of Young Women after Cranberry Juice or Apple Juice
Authors: Liu Haiyan , Tayyari Fariba , Khoo Christina , Gu Liwei
Published: June 2021

The present study aimed to investigate overall metabolic changes caused by cranberry juice or apple juice consumption using a global 1H NMR‐based metabolomics approach. Eighteen female college students, between 21‐29 years old, were given either cranberry juice or apple juice for three days using a cross‐over design. Plasma and urine samples were collected before and after juice consumption. Metabolome in urine and plasma were analyzed using 1H NMR‐based metabolomics followed by multivariate analyses. No metabolic difference was observed in human plasma before and after juice consumption for either cranberry or apple juices. However, metabolome in plasma and urine after cranberry juice consumption were different from those after apple juice consumption. Cranberry juice consumption caused a greater increase in urinary excretion of hippuric acid and a higher level of citric acid in the plasma. On the other hand, cranberry juice decreased the plasma level of lactate, D‐glucose, and two unidentified metabolites compared to apple juice consumption. The metabolomic changes caused by cranberry juice consumption may help to explain its reported health benefits.

This research is supported in part by Ocean Spray Cranberries, Inc.
Biomarkers of Fruit and Vegetable Intake in Men and Women
Authors: Couillard Charles , Vohl Marie‐Claude , Couture Patrick , Lemieux Simone , Lamarche Benoît
Published: June 2021

A high fruit and vegetable (FAV) intake is associated with a lower prevalence of chronic diseases but identifying the optimal number of daily FAV servings (DFAVS) needed to reduce chronic disease risk is difficult due to the biases of common self‐report dietary assessment tools. In this regard, plasma carotenoid levels have been suggested to be more accurate markers of FAV consumption than self‐reported intakes. The aim of the present study was to examine the associations between DFAVS and plasma carotenoid levels in a group of 155 men and 110 women enrolled in 6 full‐feeding dietary interventions we previously conducted. We measured and compared fasting plasma carotenoids (α‐carotene, β‐carotene, β‐cryptoxanthin, lutein, lycopene, zeaxanthin) and retinol levels with regards to the number of DFAVS provided and consumed by participants. Plasma β‐cryptoxanthin, lutein and zeaxanthin levels were positively associated with consumed DFAVS (p<0.005). However, consumed DFAVS were negatively associated with plasma α‐carotene (p<0.0005) and lycopene (p<0.0001) levels while no association was noted with plasma β‐carotene and retinol. When men and women were analyzed separately, we found that for any given number of DFAVS that were consumed, women had higher circulating lutein levels compared to men (p=0.0110). Significant sex*DFAVS (p=0.0001) and sex*dietary β‐cryptoxanthin (p=0.0001) interactions were also noted favoring higher plasma β‐cryptoxanthin levels in women than in men. Results for these feeding trials reinforce the use of plasma β‐cryptoxanthin and lutein levels as biomarkers of FAV consumption but suggest the existence of potential sex differences influencing circulating β‐cryptoxanthin and lutein levels following FAV consumption.
Dietary Supplement Type is Associated with Either Positive or Negative Self‐Reported Mental Health Status in Armed Forces Personnel
Authors: Austin Krista , McGraw Susan , Farina Emily , Knapik Joseph , Lieberman Harris
Published: June 2021

Most (~70%) Armed Forces personnel consume dietary supplements (DS). We investigated associations between multiple classes of DS and mental health status using the 2011 DoD Survey of Health Related Behaviors (N = 39,887). The survey assessed self‐reported depression, anxiety, anger, stress, post‐traumatic stress, risk taking, resilience and overall affect. Associations between DS type and mental health measures were examined with logistic regression (P < 0.01). Weight loss DS use was associated with higher depression (OR: 1.33, 95% CI: 1.15,1.54), anxiety (OR: 1.46, 95% CI: 1.30,1.63), anger (OR: 1.58, 95% CI: 1.34,1.86), stress (OR: 1.32, 95% CI: 1.21,1.45), post‐traumatic stress (OR: 1.61, 95% CI: 1.34,1.95), risk taking (OR: 1.50, 95% CI: 1.30,1.74) and lower overall affect (OR: 0.69, 95% CI: 0.59,0.82). Herbal DS use was associated with higher anxiety (OR: 1.22, 95% CI: 1.09,1.37), stress (OR: 1.22, 95% CI: 1.12,1.33), post‐traumatic stress (OR: 1.35, 95% CI: 1.11,1.65) and risk taking (OR: 1.42, 95% CI: 1.23,1.65). Bodybuilding DS use was associated with greater risk taking (OR: 1.34, 95% CI: 1.18,1.52) and resilience (OR: 1.36, 95% CI: 1.10,1.68). Users of individual vitamins/minerals reported lower anxiety (OR: 0.87, 95% CI: 0.79,0.95) and stress (OR: 0.88, 95% CI: 0.82,0.94). DS use may be associated with either positive or negative mental health status, depending on the class of DS used. Views expressed are those of the authors and do not reflect official policy of the Department of Army, Defense, or US Government. Support: US MRMC/DoD Center Alliance for DS Research.
A Novel Combination of Sulforaphane and Maitake Extract Induces Phase II Enzymes
Authors: Slider Laxmi , Erwin Sharis , Ownby Stacy , Cornblatt Grace
Published: June 2021

Environmental threats including chemical pollutants found in air, water, and food supplies are eliminated from the body by the action of cytoprotective Phase II detoxifying enzymes. Cruciferous vegetables, including broccoli, contain glucoraphanin, which is converted to the isothiocyanate, sulforaphane. Sulforaphane is a potent inducer of Phase II enzymes including UGT and HMOX. It induces these enzymes by activating Nrf2, a master switch in the antioxidant response element pathway. Furthermore, extracts of maitake mushrooms contain glucans which offer immunomodulating potential. We have demonstrated that maitake extract works with sulforaphane to further induce Phase II enzymes. Here, we show that cultured human hepatocytes treated for 24 hours with a combination of sulforaphane and maitake extract induces gene expression and increased protein expression of Phase II enzymes including UGT and HMOX. Further, in a study carried out in 10‐week‐old Sprague Dawley rats given a control (PBS) or the combination of 10mM sulforaphane and 1.54 mg/kg maitake mushroom extract by daily oral gavage for two weeks, quantitative real‐time PCR analysis of mammary tissue showed an increase in expression of UGT and HMOX. Overall, we demonstrate that a blend of sulforaphane and maitake extract induces Phase II enzymes, which provide a powerful, natural defense against everyday exposures to environmental threats.

Funding: Nutramax Laboratories, Consumer Care, Inc.
Association of Demographic, Lifestyle, Physiologic, and Intake Variables With Urine Caffeine and Caffeine Metabolites in the US Population
Authors: Rybak Michael , Pao Ching‐I , Sternberg Maya , Ahluwalia Namanjeet , Pfeiffer Christine
Published: June 2021

The NHANES 2009–2010 provides the first nationally representative data on urine caffeine and 14 caffeine metabolite concentrations in the US population 蠅6 y. In our previous work, caffeine analytes fell in 2 groups in relation to their association with caffeine intake. Group 1 analytes (caffeine, 3 of its metabolites [paraxanthine, theophylline, 1,3,7‐trimethyluric acid]) and 5 subsequent metabolites of paraxanthine and/or theophylline) were moderately correlated with 24‐h caffeine intake (diet and supplements), supporting their possible use as intake biomarkers. Group 2 analytes were weakly correlated with caffeine intake. We examined the association of caffeine and its 14 metabolites (Groups 1 and 2) in urine with demographic (age, sex, race‐ethnicity), lifestyle (smoking, alcohol intake, BMI), physiologic (GFR, CRP, AST, ALT, creatinine) and 24‐h intake (caffeine, theobromine) variables in persons 蠅20 y (n=1428) using multiple regression. Using b coefficients to estimate significant (P <0.05) effects, a 5% increase in caffeine intake was associated with a 1.7–2.4% increase in Group 1 analytes; a 5% increase in theobromine intake with a 0.9–1.0% increase in Group 2 analytes; and a 5% increase in creatinine with a 1.2–5.2% increase in both groups. Associations with other variables were not always significant. Using backwards elimination to generate parsimonious models, age, sex, race, caffeine and theobromine intakes, and creatinine were retained for all Group 1 and 2 analytes whereas other variables showed mixed patterns.
Comparison of Labeled Composition and Strength of Prenatal Multivitamin/Mineral (MVM) Prescription (P) and Non‐Prescription (N‐P) Supplements
Authors: Saldanha L , Dwyer J , Andrews K , Bailen R , Bailey R , Betz J , Costello R , Dang P , Gahche J , Gusev P , Han F , Palachuvattil J , Savarala S , Pehrsson P
Published: June 2021

Many prenatal MVM supplements sold in the US are available by prescription only. Our objective is to determine if P prenatal MVMs differ in labeled composition and strength from N‐P products. Publically‐available databases, e.g., NHANES, Dietary Supplement Label Database (DSLD), DailyMed, and Monthly Prescribing Reference were used to compile composition data for P and N‐P products. The mean number ±SE of vitamins and minerals in P prenatals was 8±0.4 and 4±0.2 and in N‐P was 11±0.4 and 8±0.5, respectively. The table shows the percentage (%) of products containing 5 select nutrients of interest recommended for pregnant women, mean labeled amounts, and difference (P < 0.05) in means between P and N‐P products. The only observed difference is in levels of folic acid.

#
Folic Acid
Iodine
DHA
Calcium
Vit D

Mean±SE (%)§
Mean±SE (%)
Mean±SE (%)
Mean±SE (%)
Mean±SE (%)

P
42
882±41¶ (98)
161±5 (50)
270±10 (60)
178±13 (33)
459±35 (88)

N‐P
59
782±24 (90)
151±9 (66)
210±23 (49)
289±29 (81)
526±44 (86)

This preliminary survey suggests that P and N‐P prenatal MVMs may differ in ingredient composition and strength. The degree of difference may be ingredient dependent. Analytically‐derived data on the composition of N‐P prenatal MVMs have been published in the Dietary Supplement Ingredient Database (DSID‐3), and a pilot study analyzing the content of P prenatals is planned.
FUNDING: Office of Dietary Supplements, NIH.
Early Childhood Malnutrition Increases Metabolic Syndrome in Adulthood
Authors: Fischer Laura , Galler Janina
Published: June 2021

The effects of childhood malnutrition on adult metabolic health are poorly understood. In the past decade, the prevalence of cardio‐metabolic diseases has risen in developing countries, suggesting a correlation between early malnutrition and adult metabolic health. To address this relationship we assessed the prevalence of metabolic syndrome and related risk factors in previously malnourished and healthy control adult participants (age 33‐47) in the Barbados Nutrition Study (BNS) The BNS is a 47‐year longitudinal study, following individuals with histories of malnutrition limited to the first year of life– who were enrolled in an intervention program through 12 years of age– and healthy controls from the same classrooms and neighborhoods. This study examined the prevalence of diabetes, hypertension, dyslipidemia and metabolic syndrome, defined by the International Diabetes Federation, in previously malnourished (n=80) and controls (n=68). Multiple regression analysis, controlling for gender, age and childhood socioeconomic status was applied. Results demonstrated a significant effect of malnutrition on diabetes and metabolic syndrome (adjusted OR=4.8 and 3.8, respectively; p<0.05). Additionally, there was a significant effect of the nutrition x gender interaction on metabolic syndrome. The interaction was the result of a significant effect of gender on metabolic syndrome in controls (adjusted OR=8.6 p<0.05) but no effect of gender in the malnourished group. We have confirmed malnutrition in childhood contributes to higher risk of metabolic syndrome in adulthood. Further investigation into the metabolic programming following childhood malnutrition is warranted to identify underlying mechanisms, which can result in better prevention and treatment strategies.

Acknowledgements: This research was supported by NIH grant HD060986.
Higher Total Protein Intake During Exercise Training Improves Body Composition But Not Indices of Metabolic Syndrome
Authors: Amankwaah Akua , Kim Jung Eun , Weinheimer‐Haus Eileen , Janle Elsa , Campbell Wayne
Published: June 2021

We retrospectively assessed the effect of total protein intake (TPro) during exercise training on body composition (BC) and indices of metabolic syndrome (MS) in overweight/obese middle‐aged adults. 100 men/women performed aerobic/resistance exercise training 3x/wk and consumed unrestricted diets along with 200 kcal supplements (0, 10, 20 or 30 g whey protein) 2x/d for 36 wk. Subjects were clustered into 3 TPro groups: < 1.0 (n=36 low protein, LP), 蠅1.0 ‐ <1.2 (n=25 moderate protein, MP), and 蠅 1.2 (n=39 high protein, HP) g•kg‐1•d‐1. TPro was inversely associated with changes in body mass (BM), BMI, fat mass (FM), % FM, and lean mass (LM), and positively associated with change in % LM (multiple regression). Similar results were observed for regional (android and gynoid) BC changes. TPro was not associated with changes in MS indices: waist circumference, blood pressure, and serum glucose, triacylglycerol, and HDL. Based on cluster analyses, TPro influenced changes in BC. The responses in the LP, MP, and HP groups were as follows: (means with superscripts without a common letter differ, p<0.05) BM (1.9±0.6a, 0.1±0.7ab, ‐0.3±0.5b kg), FM (0.7±0.5a, ‐1.3±0.6b, ‐1.1±0.4b kg), % FM (‐0.2±0.3a, ‐1.7±0.4b, ‐1.2±0.3ab %), and % LM (0.2±0.3a, 1.7±0.4b, 1.2±0.3ab %). Comparable results were observed in the android region, but TPro did not influence responses in the gynoid region. Intake of LP, MP, or HP did not influence the responses of MS indices. These results suggest that the beneficial impact of higher TPro on weight control and adiposity do not extend to indices of metabolic health in middle‐aged overweight /obese adults.

Support: US Whey Protein Res Consort; NIH T32AG025671; NIH UL1TR001108; Purdue Ingest Behav Res Ctr
Strawberry Polyphenols and Insulin Resistance: a dose‐response study in Obese Individuals with Insulin Resistance
Authors: Park Eunyoung , Edirisinghe Indika , Wei Hequn , Prabha Vijayakumar Lakshmi , Burton‐Freeman Britt
Published: June 2021

Insulin resistance is a major risk factor for developing type 2 diabetes mellitus (T2DM). Epidemiological data suggest that dietary anthocyanins (ACN) are associated with lower insulin resistance (IR) and T2DM risk. The present study assessed the effects of strawberries, a major dietary source of ACN, on acute insulin and glucose responses in individuals with IR. In a randomized 4‐arm crossover study, 23 obese adults consumed beverages containing freeze‐dried strawberry powder (FDS) at 4 levels [0, 10, 20, or 40 g corresponding to ~0 to 368 umol ACN]. The FDS beverages were fiber controlled and served with a standard meal with blood collected before and for 6 h after meal consumption on 4 occasions. Mean 6 h insulin was significantly lowered after consuming the 40 g FDS beverage/meal compared to all other beverages (p<0.05). No differences were observed in 6 h glucose responses, although the magnitude of increase from baseline was significantly lower (~29%) after the 40 g FDS beverage compared to other beverages (p<0.05). In adults with higher fasting insulin and greater IR, significant reductions in peak post meal insulin was apparent with 20 g and 40 g FDS beverages (p<0.05), whereas in those with a lesser degree of IR the 40 g FDS reduced peak post meal insulin. Oxidative stress was not different between groups, whereas IL‐6 was lowest after the 10 g FDS beverage. FDS ACN increased in plasma dose‐dependently reaching peak concentrations between 130 and 189 ± 45 min. These data support the view that strawberries have a role in improving insulin sensitivity in people with insulin resistance. Supported by CA Strawberry Commission, CA Dept of Food and Ag, Sacramento, CA. USA
The consumption of acai beverage (Euterpe oleracea Mart.) improves biomarkers for inflammation in individuals with the metabolic syndrome
Authors: Kim Hyemee , Simbo Sunday , Chown Justin , McAlister Lilly , Roque Andrea , Banerjee Nivedita , Talcott Steve , Kreider Richard , Mertens‐Talcott Susanne
Published: June 2021

Acai polyphenolics (Euterpe oleracea Mart.) have been reported to have anti‐inflammatory properties both in vitro and in short‐term clinical studies. However, the longer‐term effects of acai consumption have not yet been investigated. The objective of this study was to determine the anti‐inflammatory activities of acai consumption on levels of inflammatory risk markers in individuals with metabolic syndrome. A total of 37 metabolically challenged individuals was randomized to either placebo‐control or the acai beverage group. Study subjects consumed 2 x 10.5 oz/day for 12 weeks. Measurements of body composition, dietary intake, and blood and urine samples were collected every 4 weeks. Overall, MANOVA analysis revealed a significant beverage x time effect (p=0.004) for pro‐inflammatory markers. Participants in the acai beverage group experienced changes after 12 weeks in TNF‐α (Control 16.87 ± 31.78 pg/ml; Acai ‐3.83 ± 22.00, p=0.0651) and IFN‐γ (Control ‐1.61 ± 5.03; Acai ‐6.68 ± 6.03, p=0.0308). ANCOVA analysis revealed changes in hs‐CRP (‐3.08 ± 0.85 mg/L, p=0.002) and IL‐6 (‐28.5178 ± 9.072 pg/mL, p=0.0807) by acai beverage intake compared to the control group. Results indicate that acai beverage improved the levels of pro‐inflammatory markers compared to the control group. These results suggest that the consumption of acai beverage may be beneficial in the mitigation of risk factors relevant to the metabolic syndrome.
Low Vitamin D Status Increases the Risk of Periodontal Disease in Puerto Rican Adults
Authors: Palacios Cristina , Abreu Orlando , Tatakis Dimistris , Elias‐Boneta Augusto
Published: June 2021

Objective

To evaluate the association between vitamin D status and periodontal disease in Puerto Rican adults.

Methods

This was a case‐control study in subjects 35‐64y with cases as moderate/severe periodontitis (defined by CDC and AAP) and periodontally healthy adults (controls), matched by BMI and gender. Participants completed questionnaires with demographic information, vitamin D consumption and sun exposure, underwent full‐mouth periodontal examination and provided a venipuncture blood sample for the measurement of serum 25(OH)D levels. Results were analyzed using conditional logistic regression analysis for matched pairs.

Results

A total of 19 pairs completed the study. Mean serum 25(OH)D levels were lower in cases (18.5±4.6 ng/ml) compared to controls (24.2±7.1 ng/ml; p<0.05). A lower risk of periodontal disease risk was observed in those with 25(OH)D levels >25 ng/ml (OR 0.250; 95% CI 0.053, 1.177; p=0.08). When adjusting for potential confounders, such as age, vitamin D intake and sun exposure, a significantly lower risk of moderate to severe periodontal disease was found in those with levels >25 ng/ml compared with those with lower levels (OR 0.135; 95% CI 0.019, 0.970; p<0.05).

Conclusions

Serum 25(OH)D levels >25 ng/ml were associated with 87% lower risk of moderate to severe periodontal disease in this sample. These finding suggest that there is a need to screen Puerto Rican adults for assessment of vitamin D levels.
Combined Glucagon‐like Peptide‐2 and Epidermal Growth Factor Therapy Maximally Stimulates Adaptation in Neonatal Intestinal Failure without Ileum
Authors: Lim David , Lévesque Crystal , Wales Paul , Vine Donna , Brubaker Patricia , Nation Patrick , Wizzard Pamela , Sigalet David , Li Julang , Bigam David , Turner Justine
Published: June 2021

Purpose

Most infants with intestinal failure (IF) suffer from loss of distal intestine, and ileum. We studied the effect of glucagon‐like peptide‐2 (GLP2) and epidermal growth factor (EGF) therapy in a novel preclinical IF model with distal resection.

Methods

Neonatal piglets received one of 4 treatments (saline, GLP2, EGF, or GLP2/EGF in combination; n=6 in all groups) for 7 days after a 75% distal intestinal resection or no resection (sham). Adaptation was assessed by gut morphology, histology and permeability to mannitol. qRT‐PCR was performed for insulin‐like growth factor‐1 (Igf1), its receptor (Igf1r) and Egfr. Data are analyzed by two‐way ANOVA.

Results

Combination therapy increased intestinal length and mucosal weight over GLP2 or EGF alone and saline (p<0.01). Villus height increased with GLP2 but increased most with combination therapy compared to saline (p<0.01). Combination therapy decreased intestinal permeability to mannitol over GLP2 or EGF alone and saline (p<0.01). Igf1r expression increased with EGF and decreased with GLP2, with no effect on Igf1 or Egfr (p=0.03).

Conclusions

The adaptive changes present a role for combined GLP2 and EGF therapy in neonatal IF without ileum. Unlike mid‐intestinal resection, the effects of GLP2 or EGF alone are not as pronounced, nor is Igf1 upregulated, highlighting remnant anatomy as an important determinant of treatment effects.
Breakfasts Higher in Protein Increase Postprandial Energy Metabolism in Overweight, Breakfast Skipping Women
Authors: Dunn Amy , Neumann Brianna , Johnson Dallas , Adams J , Baum Jamie
Published: June 2021

Early adulthood is a vulnerable time for weight gain among women. The average weight gain for women between the ages of 20 and 30 is 12‐25 lbs. A primary contributor to obesity is an increase in unhealthy eating habits, such as skipping breakfast, which is strongly associated with obesity. The objective of this pilot study was to determine if breakfast consumption and breakfast composition improve energy metabolism in overweight/obese women (ages 18‐36) who skip breakfast. Subjects were placed into one of three groups: breakfast skipping (SKP; n=4), carbohydrate (CHO; n=3) or protein (PRO; n=5) and were instructed to either continue skipping breakfast or consume a CHO or PRO breakfast for 7 days. All food was provided. On days 1 and 7 energy expenditure (EE), glucose and satiety were measured at 0, 15, 30, 60, 90 and 120 min postprandial (pp). Consuming breakfast decreased (P < 0.01) hunger and the desire to eat and increased fullness compared to SKP. There was a trend for PRO to be more satiating than CHO. Consumption of PRO decreased (P < 0.01) the desire for sweet. There was no difference in pp glucose response between PRO and CHO. Consuming breakfast for one week increased (P < 0.05) pp energy metabolism and PRO had higher (P < 0.05) pp energy metabolism compared to CHO and SKP. There was no change in REE. Taken together, this preliminary data suggests that eating breakfast decreases pp hunger and increases pp energy metabolism compared to breakfast skipping, however the effects seem to be greater when a PRO versus a CHO breakfast is consumed. Funded by Arkansas SURF grant.
The Effects of Consuming Eggs on the Physical Development of Students Participating in a School Feeding Program in Uganda: A Pilot study
Authors: Baum Jamie , Milller Jefferson
Published: June 2021

Protein‐energy malnutrition is an issue in sub‐Saharan Africa. Increasing protein intake among children is a challenge. Eggs are an inexpensive source of high quality protein, and consumption of eggs could play a role reducing malnutrition. This study was designed as a pilot study to determine if supplementation with eggs (hard‐boiled) has the potential to improve growth and development in rural Ugandan school children (ages 6‐9). Subjects were enrolled in 3 different schools in the Kitgum District of Uganda (60‐100 subjects per school). Schools were randomly assigned 1 of 3 dietary interventions: control (no eggs), 1 egg, or 2 egg supplementation. Subjects received eggs at school 5 days per week for 4 months. Height, weight, mid‐upper‐arm circumference (MUAC) and tricep skinfold (TSF) thickness were measured each month. Mid‐upper‐arm muscle area (MUAMA) was calculated from MUAC and TSF. Compared to the control group, subjects supplemented with 1 and 2 eggs had significant weight gain over 4 months (P < 0.05). Subjects consuming 2 eggs had a significant increase in height (P < 0.05). Over the 4‐month period, the MUAC of students receiving 2 eggs per day significantly increased (P < 0.05) compared to the 1 egg and control groups, while the MUAC of students receiving 1 egg increased compared to the control group (P = 0.09). These pilot data suggest that supplementing school meals with eggs may contribute positively to physical development in children in rural Uganda.
Higher Total Protein Intake and Change in Total Protein Intake Impact Body Composition Changes in Adults Who Performed Exercise Training For 36 Weeks
Authors: Kim Jung Eun , Conley Travis , Weinheimer‐Haus Eileen , Campbell Wayne
Published: June 2021

This retrospective study assessed the impact of total protein intake (TPro) during intervention and change in TPro (CTPro, during‐pre intervention) on changes in body composition (BC) in middle‐aged overweight/obese adults. 117 men and women performed aerobic and resistance exercise training 3x/wk and consumed an unrestricted diet along with 200 kcal supplements (0, 10, 20 or 30 g whey protein) 2x/d for 36 wk. Using a multiple regression model, TPro and CTPro were inversely associated with changes of whole body mass, fat mass (FM), % FM, lean mass (LM) and BMI, and positively associated with a change in % LM. Comparable results were observed for regional (arm, leg, and trunk) BC changes. Using a cluster analysis approach, changes in whole BC were different among groups that consumed TPro <1.0 (n=43) vs. 1.0‐1.2 (n=29) vs. 蠅1.2 g•kg‐1•d‐1 (n=45) (means with superscripts without a common letter differ, p<0.05): body mass (1.7±0.4a, ‐0.1±0.7b, ‐0.1±0.5b kg), FM (0.5±0.4a, ‐1.4±0.6b, ‐1.0±0.4b kg), % FM (‐0.2±0.2a, ‐1.7±0.4b, ‐1.1±0.3b %), and % LM (0.3±0.2a, 1.7±0.4b, 1.1±0.3b %). The gain in LM was not different among groups (1.1±0.2, 1.3±0.3, 0.9±0.2 kg). These results suggest that TPro 蠅1.0 g•kg‐1•d‐1 improve BC responses (compared to TPro <1.0 g•kg‐1•d‐1) and above 1.2 g•kg‐1•d‐1 do not augment these responses. The protein intake related improvement in BC was attributable to differential changes in FM in conjunction with exercise‐induced LM accretion. CTPro might also influence BC responses and should be considered in future research when different TPro are achieved via diet or supplements.

Support: US Whey Protein Res Consort; NIH T32AG025671; NIH UL1TR001108; Purdue Ingest Behav Res Ctr
cAMP Signaling Strengthens Cardiomyocyte Cohesion
Authors: Schinner Camilla , Schlipp Angela , Vielmuth Franziska , Rötzer Vera , Hartlieb Eva , Spindler Volker , Waschke Jens
Published: June 2021

Cardiomyocytes are electrically and mechanically coupled via intercalated discs (ICDs) composed of desmosomes, adherens junctions and gap junctions. The desmosomal cadherins desmoglein 2 (Dsg2) and desmocollin 2 and the classical cadherin N‐cadherin are the transmembrane adhesion molecules of the ICD and provide intercellular adhesive strength. Gap junctions dynamically remodel to adapt to cyclic adenosine 5′‐monophosphate (cAMP) signaling. It is unknown whether such rapid adaption also is evident for the adhesive function of the ICD. Atomic force microscopy revealed that cAMP signaling enhanced the number of Dsg2‐specific interactions along cell junctions and elevated their binding forces. This was accompanied by increased cell cohesion in cardiomyocyte cultures and murine heart slices. Enhanced Dsg2 staining along cell borders and increased junction length reflected cAMP‐induced reorganization of ICDs. cAMP signaling induced PKA‐dependent phosphorylation of the ICD plaque protein plakoglobin (Pg). In line with this, Pg deficiency abrogated cAMP‐mediated junctional remodeling and prevented increased cohesion in cardiac slices. Here we provide evidence that cAMP signaling strengthens cardiomyocyte cohesion in a Pg‐dependent manner. This mechanism may be of high medical relevance because reduced Pg levels at intercalated discs were shown to be a consistent feature of arrythmogenic cardiomyopathy.