bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Metabolomic Analysis of the Hispanic Paradox
Authors: Patterson Jeffrey , Bresette William , Liu Jingping , Eghlimi Ryan , Atlas Sarah , Gu Haiwei 
Published: April 2020

INTRODUCTIONObesity has increased in prevalence among Latinos in the United States over the last several decades and continues to trend upward. The current obesity rate for this population is 34.4%, which is significantly higher than that of the general American population (28.7%). However, increased body fat and excessive weight are not necessarily associated with an increase in premature mortality.METHODSIn this cross‐sectional analysis, we used a metabolomic analysis to look at the mechanisms behind the Hispanic Paradox. To do this, we examined the role dietary intake, body mass index (BMI; kg/m2), and generational level (GL) played on serum metabolomic fingerprints in 70 Mexican Americans (26 male, 44 female). Metabolomic phenotypes of plasma were measured using liquid chromatography tandem‐mass spectrometry (LC‐MS).RESULTSThere was no significant metabolic separation among BMI groups (normal weight = BMI < 25; overweight = 25 £ BMI < 30; obese = BMI ³ 30), suggesting that the metabolome remains unchanged despite an increase in BMI. When stratified for caloric intake (< 2200 kcal/d vs > 2200 kcal/d), a log‐transformed OPLS‐DA model showed clear separation in men, while females remained relatively unchanged. Only one metabolite, pipecolinic acid (P = .009; fold change = 3.43), was significantly greater among obese women relative to their non‐obese counterparts, whereas no metabolites were significantly different among men with different BMI status. A log‐transformed PLS‐DA model found similar results between GLs 1, 2, and 3–5 Mexican Americans, potentially signifying the resistance to alteration of the female metabolome. A significant metabolite between the female generation levels was N‐acetylethanolamine, an anti‐inflammatory, analgesic, and satiety producing compound. Additionally, a pathway analysis of significant metabolites between men and women revealed significant alterations in branched‐chain amino acid (BCAA) and aromatic amino acid (AAA) profiles and mechanisms, both prevalent in obesity and type 2 diabetes (T2DM).CONCLUSIONWhile Mexican American males demonstrated variance in metabolic profiles when examined for caloric intake and generational level, the metabolome of female participants showed resilience and largely remained unaffected. Further research is needed to better understand how significant pathways associated with comorbidities may not affect the relatively consistent metabolome of Mexican Americans.
Developing New Dopamine D2 Receptor Agonists and Partial Agonists for Parkinson’s Disease and Schizophrenia
Authors: Keck Thomas M. , Nguyen Catherine , Kurtyan Emily , Stephanie Bohn , Crowthers Raymond , Tharakan Jaslin , Briaguez Wendy , Ricchezza Joseph , Pino Michael , Brunt Dylan , Sullivan Holli-Joi , Wu Chun 
Published: April 2020

Parkinson’s disease (PD) and schizophrenia are neuropsychiatric disorders that affect millions worldwide. Current medications target the dopamine D2 receptor (D2R). However, adverse side effects associated with these medications significantly reduce quality of life and drug compliance. Thus, new therapeutic strategies are clearly needed. D2R activation by agonists can activate cAMP and ß‐arrestin signaling pathways in neurons. Current evidence suggests that new biased D2R agonists—which preferentially activate one pathway over the other—and new D2R partial agonists could provide greater treatment specificity and avoid side effects. In order to develop new D2R‐selective agonists and partial agonists with potential biased signaling properties, new structural templates are needed. The objective of this project is to identify and investigate new D2R ligands with novel chemical scaffolds, with the long‐term goal of producing more effective medications for neuropsychiatric disorders. An initial virtual screen of a ZINC lead‐like library with >3.6 million molecular structures was performed using models of the D2R crystal structure refined into unbiased agonist and G protein‐biased agonist biding modes via molecular dynamics simulations. Following this in silico screen, 8 potentially novel D2R ligands were purchased and tested in radioligand competition binding screens using [3H]N‐methylspiperone and [3H]7‐OH‐DPAT. 6 of 8 purchased compounds (A01, A02, A03, A08, B03, B06) have detectable affinity for D2R (Ki = 0.75–51 μM), demonstrating the feasibility of our approach. New molecular dynamics simulations have been completed to expand in silico screens to include partial agonist and β‐arrestin‐biased agonist binding modes, and to evaluate a larger ZINC library (>17.9 million structures). Studies are ongoing to determine Ki values at D3R and D4R, and to characterize compound efficacy in cAMP and β‐arrestin signaling pathways for each hit compound. Collaborations are in development to build initial analogue libraries of each compound. Each hit compound is a new structural entity with no previously known dopaminergic activity. The identification of new chemical entities with D2R activity will build the foundation for future research to optimize pharmacological parameters for preclinical medications development.Support or Funding InformationThis research is supported by the Rowan University College of Science & Mathematics SEED Fund and the New Jersey Health Foundation. Travel support is provided by the Dean of the College of Science & Mathematics and the Rowan University Provost’s Office.
Rapid Diagnosis of Bacterial Pneumonia Using Volatile Organic Compounds (VOCs)
Authors: Dailey Allyson , Couch Robin 
Published: April 2020

Timely diagnosis and treatment is essential for reducing morbidity, mortality, and inappropriate antibiotic usage often associated with bacterial pneumonia. Volatile organic compounds (VOCs) are a large and chemically diverse group of carbon‐based molecules, generally related by their volatility at ambient temperature. We have demonstrated the diagnostic potential of VOCs derived from biological samples
1–
4, and have established uniquely identifying microbial VOC fingerprints of several bacterial agents of pneumonia, including Francisella tularensis (Rabbit Fever) and Yersinia pestis (Plague). Additionally, we have created VOC fingerprints that distinguish wildtype from genetically engineered kanamycin‐resistant strains of select biothreat agents. We illustrate here the use of our rapid non‐invasive approach to the diagnosis of BALB/c mice infected with either Yersinia pestis CO92 or Francisella tularensis SCHU S4.Support or Funding InformationFunding is provided by DTRA (Grant Number: HDTRA 1‐16‐1‐0040).
Activation of PACAP expression in mouse RTN neurons at birth protects postnatal breathing
Authors: Shi Yingtang , Stornetta Daniel , Reklow Robert , Sahu Alisha , Wabara Yvonne , Nguyen Ashley , Li Keyong , Zhang Yong , Perez-Reyes Edward , Ross Rachel , Lowell Bradford , Stornetta Ruth , Funk Gregory , Guyenet Patrice , Bayliss Douglas 
Published: April 2020

The brainstem systems that regulate breathing are established prenatally but they remain immature and vulnerable to failure at the time of birth; this reflects, in part, underdevelopment of the respiratory chemosensory systems that typically monitor blood gases (O2, CO2) to regulate breathing. In the mouse retrotrapezoid nucleus (RTN), Phox2b‐expressing respiratory chemoreceptor neurons are a nexus for integration of multiple respiratory‐related inputs, homeostatically regulating blood gases by providing CO2‐modulated drive to brainstem respiratory rhythm generator and pre‐motor circuits. In this work, we demonstrate that postnatal expression of a neuropeptide in chemosensitive RTN neurons is precisely tuned to influence breathing at the time of birth. First, by using single cell qRT‐PCR and multiplex in situ hybridization, we define a striking postnatal burst of pituitary adenylate cyclase‐activating peptide (PACAP) expression in RTN neurons that is activated in neonates within minutes of exposure to the external environment. Further, by using whole body plethysmography, we show that mouse pups (P2‐P12) lacking PACAP in Phox2b neurons (Phox2b::Cre;PACAPfl/fl) have severely blunted CO2‐stimulated ventilation (reduced by >50%) and a striking ~3‐fold greater incidence of apneic episodes. PACAP expression in RTN neurons persists into adulthood, albeit at apparently lower levels. PACAP deletion/depletion in adult RTN neurons (in Phox2b::Cre;PACAPfl/fl mice or by shRNA‐mediated knockdown) also depresses CO2‐regulated breathing (by ~30–40%) and increases apneas (~3‐fold), while viral‐mediated re‐expression of PACAP in RTN neurons corrects these deficits. After PACAP knockdown in RTN, CO2‐dependent Fos expression was retained in RTN neurons but decreased in cells of the preBötzinger complex (preBötC), which contains respiratory rhythm‐generating neurons targeted by the RTN. Consistent with the preBötC as a site of action for RTN‐derived PACAP, we show that: 1) the PACAP receptor, PAC1, is expressed in preBötC; 2) PACAP injection directly into the preBötC stimulated central respiratory output, both in vitro and in vivo; and 3) shRNA‐mediated depletion of PAC1 in the preBötC phenocopied breathing deficits observed with RTN deletion of PACAP. Notably, PACAP variants are associated with sudden infant death syndrome (SIDS), and with a SIDS‐like phenotype in PACAP‐null mice. Collectively, these data demonstrate that well‐timed PACAP expression by RTN neurons protects the developmentally immature respiratory control system from hypoventilation and potentially dangerous apneas at birth, and identifies key molecular components of a circuit that supports breathing at this particularly vulnerable period in life.Support or Funding InformationR01 HL108609; R01 HL074011
Integrating Pathophysiology to Enhance Learning and Information Literacy in Undergraduate Anatomy and Physiology
Authors: Brundage Cord M. , Khanbabaian Alina 
Published: April 2020

Practical understanding of physiologic principals can be aided by exploring the process by which they become dysfunctional. This strategy is used in clinical education, but can also provide context to retain and reinforce abstract concepts for undergraduate anatomy and physiology students. Weekly assignments were added to a junior anatomy and physiology class that challenged students to identify a disease associated with the previous week’s physiologic principals. Students were asked to explain what physiologic process are disrupted and how normal physiologic function changed (with reference to a peer reviewed article) and include proper in‐text and bibliographic citations. Student performance on embedded course questions increased significantly in students completing pathophysiology assignments compared to previous semester (n = 48 for each; p < 0.05). Appropriate use of in‐text citations, reference formatting and the selection of primary literature were assessed using a 4‐point rubric for weekly assignments. Student performance improved in all categories over the course of the semester. Summative indirect assessment suggested that students felt more comfortable searching and referencing research. The majority of students also felt that the pathophysiology assignment helped to increase their overall understanding of course material. Collectively the integration of pathophysiology and primary literature may offer instructors an alternative means of enhancing student learning and information literacy in undergraduate anatomy and physiology courses.Support or Funding InformationSupport for this project provided by Cal Poly Pomona. Don B. Huntley College of Agriculture and a Cal Poly Pomona Special Projects for Intellectual Community Environment (SPICE) Grant for innovative approaches to instruction.
Protocol Development for the Production of Purified Matrix Metalloproteinase 1
Authors: DeMarco Angela Mary , Grove Laurie 
Published: April 2020

Matrix metalloproteinase 1 (MMP1) is an enzyme involved in the degradation of the extracellular matrix of cells. In human MMPs, an active site containing three histidine amino acids uses zinc to catalyze peptide bond cleavage. Higher expression of this protein is associated with cancer and arthritis, so there is interest in using MMP1 to target drug delivery for these patients. Because there are twenty‐six MMPs, inhibiting the activity of one may influence the others causing unforeseen downstream affects. This is largely due to poor selectivity of the inhibitors, so more specificity is required to ensure only MMP1 is targeted.The simple multicellular organism Volvox uses proteinases that are more active with copper than zinc. Zinc and copper have similar acid/base properties, so they should function in a similar way but don’t within these two systems. Volvox has two histidines and one glutamine in its active site. Exploring the functionality of the two proteinases with different metals may reveal the importance of the three histidines in its preference to zinc. Before experimentation can occur on MMP1, a method to produce large amounts of purified protein needs to be established.Plasmids containing the gene for human full‐length proenzyme MMP1 with His tags was purchased and the identity was confirmed using restriction digest. These plasmids were then used to transform E. coli which was cultured to allow for protein expression. Sonication was used to lyse the cells. The lysate was then purified using Ni 2+ magnetic beads. SDS‐PAGE and kinetic assays were done on the MMP1 to ensure that it was an active enzyme sample. It was found that the E. coli was properly producing the protein, but further work is being done to ensure it is fully active. When this production method is perfected, the MMP1 collected here will be used in metal replacement assays and work with Crispr to generate multiple active site single point mutations.Support or Funding InformationWentworth Institute of Technology
Generation and characterization of a serum albumin‐humanized mouse model for biomarker discovery
Authors: Han Weiguo , Yin Lei , Sheng Jonathan , Fan Xiaoyu , Yang Weizhu , Zhang Qing-Yu , Turesky Robert , Ding Xinxin 
Published: April 2020

The aim of this study is to develop a serum albumin‐humanized mouse model, for identifying human protein biomarkers of exposure to hazardous xenobiotics. The albumin‐humanized mouse was generated via cross‐breeding between a human albumin‐transgenic mouse and an albumin‐null mouse. The ability of human and mouse albumins to react with metabolites of the lung carcinogen 4‐(methylnitrosamino)‐l‐(3‐pyridyl)‐1‐butanone (NNK) was compared. Adult albumin‐humanized mice and wild‐type mice were treated with NNK (100 mg/kg body weight, IP). Blood, liver, and lung were analyzed 6 hours after NNK treatment. The NNK metabolite 4‐hydroxy‐l‐(3‐pyridyl)‐1‐butanone (HPB), free or as albumin‐HPB adduct, was detected in the plasma, whereas the O6‐methyl‐deoxyguanosine (O6‐mdG) DNA adduct, formed via NNK bioactivation, was detected in lung and liver. Results of quantitative analyses revealed lower levels of O6‐mdG in tissues of the humanized mice (10.4 and 85.5 pmol/μmol guanine, for lung and liver, respectively) than in wild‐type mice (18.4 and 240 pmol/μmol guanine, for lung and liver, respectively), a difference possibly explained by differing pharmacokinetic profiles of NNK. Interestingly, although a substantial genotype‐related difference was not observed in free HPB levels in the plasma (0.31 and 0.39 ng/ml, for wild‐type and humanized, respectively), human albumin‐HPB adduct levels in the humanized mouse were 6X higher than mouse albumin‐HPB adduct levels in the wild‐type mouse (per mg albumin). These data suggest that human and mouse albumins have different reactivities with reactive NNK metabolites and they illustrate the utility of the albumin‐humanized mouse model for biomarker discovery.Support or Funding InformationSupported in part by NIH grant CA092596
Endothelial Ca2+ signals in Penetrating Arterioles Control Local Blood Flow in the Brain.
Authors: Mughal Amreen , Longden Thomas , Hennig Grant W. , Nelson Mark T. 
Published: April 2020

Cerebral blood flow is exquisitely regulated to meet the fluctuating demands of active neurons. This activity‐dependent increase in blood flow (functional hyperemia) is managed by a number of molecular mechanisms collectively referred to as ‘neurovascular coupling’. Penetrating arterioles—the bridge between pial arteries and deep capillaries—serve as a high‐level control system to regulate local perfusion into the cortex. Here we show that dynamic Ca2+ signals in arteriolar endothelium, consisting of unitary and compound events with distinct spatiotemporal patterning, are dramatically increased by sensory stimulation and are followed by dilation of upstream arterioles and increased RBC flux in downstream capillaries. These arteriolar endothelial Ca2+ signals in the cortical vasculature are dependent on Gq‐protein coupled receptor signaling likely involving prostaglandin E2 (PGE2). PGE2‐dependent activation of EP1 receptors, results in IP3 receptor‐dependent Ca2+ release from the endoplasmic reticulum and Ca2+ entry via TRPV4 channels. Our data highlight the pivotal role of endothelial Ca2+ signals in the regulation of cerebral blood flow.Support or Funding InformationSupported by the National Institutes of Health, Totman Medical Research Trust, Fondation Leducq, EC Horizon 2020.
Reliability of a Novel Ultrasound Transducer Holder for Flow‐Mediated Dilation
Authors: Rodriguez Lisa A. , Morales-Acuna Francisco , Aguilera Juan , Gurovich Alvaro N. 
Published: April 2020

BackgroundFlow‐mediated dilation (FMD) is the most common test to evaluate endothelial function. Although efforts have been made to incorporate FMD in clinical settings, guidelines still do not advocate for its use because the wide variability on results among testers. Strategies to overcome this problematic scenario include the use of transducer holders to increase the reproducibility on image acquisition. Therefore, the purpose of this study was to test the reliability of a novel ultrasound (US) transducer holder for brachial FMD.MethodsUsing 3D printing technology, an arm US transducer holder was created to assist the assessment of the vasculature via US imaging during FMD. A total of 15 young healthy subjects were evaluated for Intrarater and Interrater FMD reliability. Statistical analysis included Coefficient of Variation (CV) and Intraclass Correlation Coefficient (ICC). Based on the CV, reproducibility was categorized as excellent (0–10%), good (10–20%), moderate (20–30%), or poor (>30%). Regarding ICC, reproducibility was catalogued as poor (>0.5), moderate (0.5–0.75), good (0.75–0.9), and excellent (>0.90).ResultsThe baseline and peak after deflation artery diameter images were analyzed using an automatic edge detection software. The following data was collected:The results in table
1 show that the degree of reliability for an arm US transducer holder during FMD, between and within raters using artery diameter, %FMD, and delta‐FMD as markers, is excellent. The CV for all categories within the inter‐ and intrarater were under 7%, which supports achieving inter‐ and intrarater reliability. The ICC for all categories, with the exception of one, was 90% or better, this shows that the reproducibility of the holder was catalogued as excellent. The Interrater ICC for one category, delta‐FMD, was rated good at 0.89.ConclusionExcellent reliability was achieved with interrater and intrarater FMD using the arm US transducer holder device. This holder has the ability to improve the results of this type of noninvasive endothelial function testing.
Analyzed data collected during FMD

Reliability Test

Baseline Artery Diameter

Peak Artery Diameter

%FMD

Delta‐FMD

Intrarater CV (%)

0.26 (0.39)

0.40 (0.42)

6.44 (6.1)

6.27 (6.09)

Interrater CV (%)

0.23 (0.16)

0.52 (0.38)

5.75 (5.29)

5.82 (5.39)

Intrarater ICC

0.99

0.99

0.97

0.95

Interrater ICC

0.97

0.96

0.97

0.89
Dietary Fat and Sugar Differentially Affect Beta‐Adrenergic Stimulation of Cardiac ERK and AKT Pathways in Mice Subjected to High‐Calorie Feeding
Authors: Ashraf Sadia , Yilmaz Gizem , Chen Xu , Harmancey Romain 
Published: April 2020

Introduction. High dietary fat and sugar promote cardiac hypertrophy independently from an increase in blood pressure. The respective contribution that each macronutrient exerts on cardiac growth signaling pathways remains unclear. The goal of this study was to investigate the mechanisms by which high dietary fat and sugar levels affect cardiac growth regulatory pathways in the mouse heart.Methods. Nine‐week‐old male C57BL/6 mice (n = 20/group) were fed a standard rodent diet (STD; 3.0 kcal/g), a high‐fat diet (HFD; 5.24 kcal/g), a high‐fat and high‐sugar Western diet (WD; 4.73 kcal/g), a high‐sugar diet with mixed carbohydrates (HCD; 3.85 kcal/g), or a high‐sucrose diet (HSD; 3.85 kcal/g). Body composition was assessed weekly by EchoMRI. Whole‐body glucose utilization was assessed with an intraperitoneal glucose tolerance test. After six weeks on diets, mice were treated with saline or 20 mg/kg isoproterenol (ISO) and the activity of cardiac growth regulatory pathways was analyzed by immunoblotting. One‐ or two‐way ANOVA was used for statistical comparisons.Results. Compared with STD, HFD increased body fat mass 4.5‐fold (P < 0.0001), induced glucose intolerance (P < 0.0001), and increased insulin levels 3.6‐fold (P < 0.0001), thereby enhancing basal and ISO‐stimulated AKT phosphorylation at both threonine 308 and serine 473 residues (+37–100%; P < 0.05). Both HCD and HSD potentiated ISO‐mediated stimulation of the glucose‐sensitive kinases PYK2 (>50%; P < 0.05) and ERK (>30%; P < 0.05), thereby leading to increased phosphorylation of protein synthesis regulator S6K1 at threonine 389 residue (≥70%; P < 0.05). All these anthropometric, metabolic and cardiac growth signaling alterations occurred simultaneously in WD‐fed mice.Conclusions. The results indicate that dietary fat and sugar affect cardiac cell growth signaling pathways in C57BL/6 mice through distinct and additive mechanisms. The findings may provide new insights into the role of overnutrition in pathological remodeling of the heart.Support or Funding InformationThis work was supported by grants R01HL136438, P20GM104357 and P01HL051971 from the National Institutes of Health.