bluuebunny/crossref_metadata_2025_split huggingface dataset:
DOES CARDIOPLEGIA PROVIDE CARDIAC PROTECTION BY INDUCING Nr‐E2 RELATED FACTOR‐2(Nrf2)
Authors: Diao Hongting 
Published: April 2020

BackgroundOpen heart surgery is often an unavoidable procedure for treatment of cardiovascular disease. Myocardial ischemia‐reperfusion injury (MIRI) can occur as a result of cardiopulmonary bypass. The multifaceted mechanisms of MIRI involve the generation of proinflammatory mediators and increases in reactive oxygen species (ROS), resulting in damage to proteins, lipids, and DNA, ultimately impacting postoperative cardiac function and outcomes. Nf‐E2 related factor‐2 (Nrf2), a basic leucine zipper transcription factor, is regarded as one of the most important regulators in antioxidant pathways. Nrf2 binds to and activates the Antioxidant Response Element (ARE) in the promoters of many antioxidant and detoxification genes.PurposeWe addressed whether or not cardioplegic solutions induce the activation of Nrf2, therefore serving to protect the myocardium from MIRI. Methods. We used adult cardiomyocytes in culture to test whether or not four different types of cardioplegic solutions induce Nrf2. The conditions tested include routine laboratory cell culture at 37°C and hypothermic temperatures of 10–20°C.ResultsOur data show that certain cardioplegic solutions caused increases in Nrf2 protein levels under both cell culture and hypothermic conditions. ARE luciferase reporter assay confirmed Nrf2 activation by the cardioplegic solutions. Both High K and Del Nido showed reliable activation of Nrf2.ConclusionsOur data supports our hypothesis that cardioplegic solutions can be cardiac protective via the activation of Nrf2.Support or Funding InformationThis work is supported by research grants of NIH R01 GM125212 (QMC), NIH R01 GM126165 (QMC), Holsclaw Endowment (QMC)
Development and Application of a New Platform for Measuring Phospholipase A2 Activity in Cells Using Mass Spectrometry
Authors: Argus Joseph P. , Dennis Edward A. 
Published: April 2020

Members of the phospholipase A2 (PLA2) superfamily hydrolyze fatty acids from the sn‐2 position of membrane phospholipids. PLA2‐mediated release of n‐3 and n‐6 polyunsaturated fatty acids (PUFAs) is a highly regulated and critical step in producing eicosanoids and docosanoids. These signaling molecules play key roles in a variety of important processes including inflammation, onset of premature labor, and neural degenerative diseases. Thus, a better understanding of how PLA2 functions in cells may uncover new therapeutic avenues and lead to potent pharmacological agents. Though a rapid in vitro assay of PLA2 function has been recently published, one barrier to progress in this field is the lack of methods for determining PLA2 activity in cells. To address this issue, we have developed a new platform for measuring PLA2 activity ex vivo. Enriching cells with natural or deuterated PUFAs followed by mass spectrometry allows for tracking of hydrolysis at the sn‐2 position by both the disappearance of substrate phospholipids and the appearance of product PUFAs. An optimized cell culture procedure and lipid analysis workflow allow for significantly improved throughput. We anticipate that this platform will not only lead to a better understanding of PLA2 regulation and function in cells, but also allow for rapid screening of inhibitor candidates.Support or Funding InformationSupported by NIH grant GM20501
Chronic Fatigue in a Mouse Model of Gulf War Illness
Authors: Bishay Anthony , Kozlova Elena , Chinthirla Bhuvaneswari , Tran Jasmin , Curras-Collazo Margarita 
Published: April 2020

The Gulf War, a war fought in the deserts of Saudi Arabia, left a quarter of US troops debilitated with a set of symptoms known as Gulf War Illness (GWI). These include neurological impairments, gastrointestinal disturbances and chronic fatigue suggesting that gut‐brain interactions may be provoking metabolic dysfunction leading to chronic fatigue. This study was focused on establishing a mouse model of GWI to better understand the etiology and pathophysiology of chronic fatigue in GWI. This study tested the hypothesis that GWI mice exposed to GW agents (acetylcholinesterase inhibitor, pyridostigmine bromide (PB), the insecticide permethrin, and the insect repellant, N,N‐Diethyl‐meta‐toluomide (DEET), and restraint stress, would produce exercise intolerance and resting and post‐exercise metabolic dysfunction. To simulate the route/duration in troop exposure, adult male C57B16/N mice were given PB (13 mg/kg, oral gavage), permethrin (0.3 mg/kg, 70% ethanol, top) and DEET (40 mg/kg; 70% ethanol, top) daily for 5d/wk X 4 wk. Mice were also exposed to 5min restraint stress. Sham controls received saline gavage, topical alcohol and restraint stress. Testing was conducted 1wk after exposure (PT) and at 90d PT. Fasted mice were subjected to an insulin tolerance test (0.5U/kg Humulin N i.p.) and blood glucose measured subsequently. One week later, mice were subjected to a 5‐day exercise endurance (EE) test to test for fatigue. Specific criteria were established to confirm the determination of exhaustion. During optimization of the EE test (3d training, 2d testing), we found that motivating mice to run for over 20min was feasible without electric shock. On exercise endurance, GW exposure produced a decreased latency to fatigue relative to sham (p<.05). GW mice showed exercise exhaustion relative to the sham controls immediately following post‐treatment (PT) (15.4 +/− 2.6 min), and at 90PT (8.7 +/− 1.3 min). Corresponding values for sham were (23.5 +/− 2.5 min), and (26.8 +/− 5.1 min), respectively. These mean values show a significantly lesser latency to exhaustion that persisted in for GW relative to sham. Metabolic measures taken immediately after EE showed incremental elevations in post‐exercise lactate levels in GW mice relative to their pre‐treatment control (p<0.001 n=6–7/per group). In contrast, shams showed similar post‐exercise lactate elevations at pre‐treatment, PT and PT90. Mean (+/− sem) values were 6.1 +/− 0.38 mmol/dL pre‐treatment, 6.1 +/− 0.4 mmol/dL at PT and 6.8 +/− 1.8 mmol/dL at PT90. Insulin injection reduced average glycemia to a greater peak in sham than in GW, i.e., 64.1% vs 78% baseline (p<.05, n=3–6/group) but the latter normalized at PT90. In combination, our results show that GW agents reduce time to exercise exhaustion, and produce abnormal post‐exercise metabolism and insulin insensitivity that may explain, in part, chronic fatigue in GWI.Support or Funding InformationAmerican Physiological Society (A.B.) and UC Minigrant (A.B. and J.T.)
The Personalized Precise Exercise Training with Holistic Integrative Protocol (PPET‐HIP) for Effective Management in Patient with Chronic Diseases (CDs)
Authors: Sun Xingguo 
Published: April 2020

BACKGROUNDThe patients with chronic diseases (CDs, i.e. hypertension, hyperglycemia, hyperlipidemia, hyperuricemia and obesity etc. with or without MI or Stoke) were uncured, according to the guidelines of all each one group of exports. However, based on our new Holistic Integrative Physiology and Medicine (HIPM), we might be able to use the core personalized precise exercise training and continuous functional monitoring with holistic integrative protocol (PPET‐HIP) for effective management of CDs patients.METHODSTen CDs patients, who has more than 10–30year history and four of them had MI or Stoke, were recruited from 2014–2018.Before and after 12‐week intervention, general evaluations(blood pressure, glucose, and lipid profiles), cardiopulmonary exercise testing (CPET), echocardiogram, and the adjustment of drugs treated CDs patients were recorded respectively. Based on HIPM for CPET interpretation, we gave each patient an PPET‐HIP for adjusting of all life styles.RESULTSAll patients exercised safely with any problem. After 12w HIPM‐PPT management, the all abnormal parameters of hypertensive, hyperglycemia, hyperlipidemia, hyperuricemia and obesity were become normal; CPET parameters, left ventricular function, and QoL were improved significantly than those before (P<0.05). Then we decreased drugs dosages and totally stopped drugs, the levels of blood pressure, glucose and lipid were still maintained stable. Surprisingly, the curable condition was achieved in CDs patients.CONCLUSIONSHIPM guiding CPET for the PPET‐HIP could safely and effectively control the conditions of patients with CDs.Support or Funding InformationNational Natural Science Foundation of China (81470204);Fuwai Hospital, National Cardiovascular Institute of Chinese Academy of Medical Sciences (2012‐YJR02);Research on Clinical Characteristics of the Capital (Z141107002514084);Research and Outcome Promotion of Clinical Characteristics in the Capital (Project No. Z161100000516127)
Identifying Neural Correlates of Nicotine Withdrawal in Mice: The Neuregulin Signaling Pathway
Authors: Fisher Miranda , O'Donovan Bernadette , Adeluyi Adewale , Ortinski Pavel , Turner Jill 
Published: April 2020

Addiction to nicotine and the ability to quit smoking are influenced by genetic factors. Therefore, it is important to understand how genes and drugs of abuse mechanistically impact each other. One well‐characterized protein responsible for regulating both response to drugs and gene expression is the transcription factor cAMP response element‐binding protein (CREB). Work from our lab indicates that hippocampal specific alterations in CREB signaling and synaptic plasticity underlie certain nicotine withdrawal (WD) phenotypes in a region‐specific manner. We found that CREB deletion in the ventral hippocampus (VH), a region known for regulation of mood and emotion, results in amelioration of nicotine WD‐induced anxiety‐like behaviors. High throughput chromatin immunoprecipitation sequencing (ChIP‐seq) studies determined that WD from nicotine differentially modulates CREB binding to the gene Neuregulin‐3 (Nrg3), a neural‐enriched epidermal growth‐like factor that plays a role in the formation and maintenance of mature synapses. Interestingly, genome wide association studies (GWAS) in humans have found that single nucleotide polymorphisms within the NRG3 gene and that of its cognate receptor, ERBB4, are associated with smoking cessation outcomes. In mice, qPCR and Western blotting experiments established that NRG3 and ErbB4 are upregulated at the 24h WD time point in the VH, with expression returning to baseline by 1‐week post WD. Conditional VH deletion of Erbb4 blocked WD‐induced anxiety‐like behaviors. This phenotype was accompanied by decreased levels of inhibitory GABAergic release and altered network clustering of excitatory pyramidal cells within the ventral CA1, an area enriched in Nrg3 and Erbb4 mRNAs and sensitive to nicotine WD. This data suggests that disruption of VH NRG3‐ErbB4 signaling attenuates WD‐induced anxiety‐like phenotypes through altering GABAergic modulation of CA1 pyramidal cell activity. Further examination of downstream signals of ErbB4 activation may lead to the identification of potential targets for treating nicotine withdrawal symptomology.Support or Funding InformationThis study was supported by•NIH/NIDA grant DA032681, the PhRMA Foundation, and the USC ASPIRE Grant program (JRT).•SPARC Grant, University of South Carolina (MLF)
The Deaf Culture Panel: Introducing Culture into Anatomy Education
Authors: Greene Sarah , Scott Jessica Armytage 
Published: April 2020

The anatomy laboratory is a place where one can integrate education in basic science and professionalism in medicine. Cultural competence is one component of professionalism that has received less attention in the anatomical sciences as opposed to other competencies. Yet cultural competence is imperative in providing appropriate and effective communication and care across multiple patient populations. A lack of such competence has contributed to heath care disparities between hearing and d/Deaf and hard of hearing (DHH) patients. Therefore, this study sought out to introduce and evaluate a Deaf Culture panel presentation, which was provided as one of five Applied Anatomy sessions during the first‐year integrated medical student curriculum at Morehouse School of Medicine. This 90‐minute session was scheduled during the Head and Neck section of the course, soon after the ear and auditory system had been studied. Three panelists were invited to share their experiences in medicine during this panel; two were culturally Deaf and communicated in American Sign Language, and one utilized a cochlear implant and communicated in spoken English. Panelists shared their experiences and challenges in communication with the medical community about health care. This included incorrect assumptions made by health care professionals, challenges with access to appropriate communication, and the effect of this poor communication on their ultimate care. Although this panel was considered a lecture and therefore optional, a large majority of the class of 100 students were in attendance. This panel was evaluated in several ways. First, students were invited to complete optional pre‐ and post‐assessments to measure how this session impacted their knowledge and awareness of Deaf culture and working with DHH patients. Assessments demonstrated a significant increase in knowledge and awareness from pre‐ (n=33) to post‐assessment (n=13; P < 0.001). Next, students were asked to evaluate the session using a Likert scale of 1–5. The average rating of the session was 4.8, indicating that the session was quite well received. Next, students were given the option to write open‐ended comments on their experiences with the session. One such response included, “I learned several things that I will carry into my career and life in general.” Finally, informal observations by the authors during and after the panel suggested that students were highly engaged during the session, with several staying afterwards to ask questions of the participants one on one. These findings are promising in terms of incorporating this type of experience into medical education more broadly. This was a successful integration of a session to promote cultural competence and communication within the anatomy curriculum, which has the potential to directly impact future patient care.Support or Funding InformationNIH, Grant number P03‐G12MD007602U.S. Department of Education, Grant Number P03‐1B141018
Dynamic expression profiles during development of placodes in the embryonic chicken eye
Authors: Franz-Odendaal Tamara Anne , Giffin Jennifer 
Published: April 2020

The conjunctival epithelium of the chicken eye develops a series of placodes beginning at embryonic day 6.5. These placodes develop into conjunctival papillae over the course of 1.5 days before disappearing. These transient structures are responsible for inducing the underlying mesenchyme to develop into a ring of scleral ossicles. Here we assess the gene expression patterns of five major signaling pathways known to be involved in the development of other epithelial appendages, namely the WNT/β‐catenin, bone morphogenetic protein (BMP), ectodysplasin (EDA), fibroblast growth factor (FGF) and hedgehog (HH) pathways. Our comprehensive qPCR analyses of distinct regions of the eye, at different time points, enabled us to assess multiple gene expression patterns. Our data show that FGF1, FGF20, sonic hedgehog (SHH), ectodysplasin receptor (EDAR) and BMP4 are amongst the most highly upregulated genes identified in the system. EDAR, FGF20 and SHH were also significantly different across different regions of the eye and over developmental time within specific regions. Correlation analyses among relative normalized gene expression values revealed the strongest correlation between EDA and lymphoid enhancer factor‐1 (LEF1) and between FGF2 and FGF10. The enhanced sensitivity of qPCR reveals a more detailed signaling pattern than previously known. The dynamic expression patterns uncovered here are consistent with a conserved patterning signaling network observed in a diverse range of other placodes, including hair follicles and feather buds.Support or Funding InformationThis study was funded by the Natural Sciences and Engineering Research Council of Canada
Cocaine‐induced locomotor stimulation is mediated by autophagic degradation of the dopamine transporter
Authors: Harraz Maged M. , Guha Prasun , Kang In Guk , Malla Adarsha P. , Semenza Evan R. , Song Young Jun , Treisman Isaac , Cortés Pedro , Coggiano Mark A. , Tanda Gianluigi , Snyder Solomon H. 
Published: April 2020

Cocaine exerts its stimulant effect by inhibiting dopamine reuptake leading to increased dopamine signaling. This action is thought to reflect binding of cocaine to the dopamine transporter (DAT) to inhibit its function. However, cocaine is a relatively weak inhibitor of DAT, and many DAT inhibitors do not share the behavioral actions of cocaine. Here we show that sub‐nanomolar concentrations of cocaine elicit neural autophagy in vitro and in vivo. Pharmacologic inhibition of autophagy significantly reduces the locomotor stimulant effect of cocaine in mice. Autophagy depletes transporters for dopamine but not serotonin in the nucleus accumbens following cocaine injection. The dopamine transporter is enriched in the ventral midbrain lysosomal fraction following intraperitoneal injection of cocaine, which is reversed by inhibition of autophagy. Furthermore, autophagy inhibitors significantly reduce dopamine levels in the nucleus accumbens following cocaine injection. Taken together, these findings suggest that the behavioral stimulant effect of cocaine is mediated at least in part by autophagic degradation of DAT.Support or Funding InformationFunding: this work was supported by U.S. Public Health Service Grants DA00266 and DA044123 to SHS and a NARSAD Young Investigator Grant (grant # 25360) from the Brain & Behavior Foundation to MMH. Support for this research was provided in part by the National Institute on Drug Abuse ‐ Intramural Research Program, NIH/DHHS (Z1A DA000611).
The Regulation of Fibroblast to Myofibroblast Activation by Zinc Finger E‐Box Binding Homeobox 1 and 2
Authors: Meikle Zach , Yu Liping , Netticandan Thomas , Wigle Jeffrey 
Published: April 2020

After a myocardial infarction (MI), a dense collagen scar is formed that initially prevents the heart from rupturing. However, after the scar is formed, collagen deposits accumulate and the extracellular matrix (ECM) is remodeled in the viable areas of the heart, distal from the site of injury, which causes the entire organ to vstiffen in a process called cardiac fibrosis (CF). CF often contributes to the development of heart failure (HF) which is a major clinical problem in Canada. Cardiac fibroblasts (FBs) provide structural support and remodel the ECM in the healthy heart, but after an MI, FBs become activated, proliferate, and adopt a myofibroblast (MF) phenotype. MFs can continue to produce ECM long after they become activated which leads to CF and ultimately HF. Two transcription factors that have been identified as potential contributors to CF are zinc finger E‐box binding homeobox 1 and 2 (ZEB1/2). ZEB1 and ZEB2 are essential for epithelial‐mesenchymal transition (EMT) and, previous studies in our lab have shown that ZEB2 is also directly involved with FB activation. Based on other research we hypothesize that ZEB1 may also regulate FB activation and be functionally redundant with ZEB2. Our initial results show that ZEB1 protein and RNA levels both increase as FBs convert to MFs. By comparing samples at varying time points we have increased our understanding of the FB to MF activation process. This study show that ZEB1 may be involved in the fibrotic process and further analysis will determine the extent of its involvement.Support or Funding InformationSupported by a grant from NSERC and from the St. Boniface Hospital Foundation Research without Borders initiative.
Response to Epigenetic Disruption in Tumor Suppressor of Hepatocellular Carcinoma (HCC)
Authors: Luna Aesis , Wu Qunfeng , Hlady Ryan , Sathyanarayan Aishwarya , Rustgi Vinod , Guarrera James , Robertson Keith , Liu Chen 
Published: April 2020

Hepatocellular Carcinoma (HCC) is a highly fatal liver cancer with no effective treatments. HCC tumors, formed after long‐term viral or alcohol related inflammation and cirrhosis, have a surprisingly low number of genetic mutations. Prior research has found that epigenetic patterns, such as DNA methylation at gene promoter sites, are common in HCC patients. Recent improvements in genetic sequencing and online genetic databases, have allowed us to identify a set of gene targets, including FMO3, for HCC detection or treatment. The hypothesis is that FMO3 is reduced by epigenetic dysregulation, leading to tumor formation.To find the connection between FMO3, epigenetic events and HCC tumor pathways, our lab created novel HCV‐stable and non‐infected HCC cell lines. We also used Huh7 and Huh7.5 cells to show the epigenetic changes in stressed cells and methylation inhibited cells. To mimic inflammation and stress leading to epigenetic changes, Huh7 cells were exposed to heat shock at 40°C for 40 min. Huh7.5 cells were treated with epigenetic inhibitor 5‐Aza‐2 deoxycytidine. RT‐qPCR and Western Blot show that FMO3 is significantly reduced in stressed cells and upregulated when treated with the methylation inhibitor. These results indicate that FMO3 may be used for early cancer risk detection and/or to improve treatment options by identifying the relationship between epigenetic regulation and tumorigenesis.Support or Funding InformationNIH NIDDK 1R01DK110024‐01A1
Antibody mediated targeting of autoimmune cells in multiple sclerosis
Authors: Rustad Karin , Ripplinger Alexandra , Kisheev Anastasye , Buttigieg Josef 
Published: April 2020

Multiple Sclerosis (MS) is a debilitating autoimmune disorder of the central nervous system (CNS) affecting over 77,000 Canadians, with a prevalence rate of almost one out of 300 Canadians, with the highest rates in Saskatchewan. Myelination of neuronal axons is essential for the normal and rapid electrical conduction along an axon. Currently there are few feasible options to treat MS. Here, we propose a novel therapy that specifically targets aberrant immune cells.We created a trimolecular peptide (TPC) that combines and antigen sequence (myelin oligodendrocyte glycoprotein; MOG 35‐55), a modified type IV secretatory system (TIVSS) peptide, and an apoptotic protein. As the TPC displays MOG, the TPC is hypothesized to only bind to immune cells that are actively seeking MOG (e.g. in MS). Since the TPC contains TIVSS, the cell that bound the antigen (e.g. MOG 35‐55) is forced to take up the TPC. Lastly, the apoptotic protein, which is now inside the cell, causes the cell to undergo apoptosis. Thus eliminating the aberrant cell.In order to test this TPC compound, we induced experimental autoimmune encephalopathy (EAE) using MOG 35‐55. Test compound was administered 15 days post EAE induction. Administration of the TPC resulted in the suppression of autoimmune cells, as determined via flocytometry. We also found significant improvements in motor function as well as a reduction in MS plaque formation in the cerebellum. By targeting the pathogenic immune response whilst leaving the patient’s normal immune response intact, we believe this strategy will lead to improved clinical outcomes without the side effects seen in current MS therapies.Support or Funding InformationSaskatchewan Health Research Foundation