bluuebunny/crossref_metadata_2025_split huggingface dataset:
Hypercapnia Attenuates Ventricular Ectopy during Wakefulness in a Young Man with Heart Failure
Authors: Keir Daniel A. , Duffin James , Floras John S. 
Published: April 2020

Ventricular premature beats (VPBs) are common in heart failure (HF). Patients with HF often exhibit oscillations in breathing pattern (or Cheyne‐Stokes Respiration, CSR) that lead to increased VPBs during the hyperpneic phase. In such patients, CO2 inhalation during sleep eliminates CSR and reduces VPB prevalence. Whether this VPB‐lowering effect of CO2 occurs in awake HF patients without CSR remains unexplored. In a young CSR‐free HF patient (26 years; LVEF=20%; BMI=30 kg·m−2) with mild obstructive sleep apnea (AHI=17 events/h) and frequent ectopy, we compared the incidence of VPBs during: 1) resting breathing; 2) volitional hyperventilation; 3) and at standardized intervals (quartiles) during two CO2 rebreathing tests with end‐tidal O2 tension (PETO2) maintained at either 50 mmHg (hypercapnic‐hypoxia) or 150 mmHg (hypercapnic‐hyperoxia). Breath‐by‐breath ventilation, PETO2, and PETCO2 were measured by flowmeter and rapid gas analyzer and ECG and O2 saturation were monitored continuously. At rest (PETCO2=39 mmHg) and during hyperventilation (PETCO2=28 mmHg), VPBs occurred with 15% and 12% of all heart beats, respectively. With hyperoxic CO2 rebreathing (PETO2=148mmHg), as PETCO2 increased from 40, 46, 52, 57 mmHg in the first through fourth quartile, VPB incidence decreased from 11% to 6%, 3%, and 0%, respectively. Hypoxic rebreathing (PETO2=51mmHg) showed a similar trend: VPB incidence fell from 9% at a PETCO2 of 40 mmHg to 0% at 46 mmHg and remained at 0% thereafter. The hypercapnia‐induced reduction in VPB frequency was not dependent on heightened ventilation: VPBs were evident during volitional hyperventilation (12%) but not during the CO2 rebreathing quartiles with matched ventilation (0% for both hypoxia and hyperoxia). Furthermore, blood O2 also did not appear to modulate this response: VPB incidence at rest (15%) was similar to both hypoxic (11%; O2 saturation=86%) and hyperoxic (13%; O2 saturation=99%) CO2 rebreathing quartiles with matched ventilation (~9 L·min−1) and PETCO2 (~39 mmHg). These observations suggest that in HF, acute hypercapnia attenuates ventricular ectopy. The mechanism appears to be unrelated to increased respiratory or sympathetic drive, myocardial stretch accompanying large tidal volumes, or altered O2 availability. How hypercapnia exerts anti‐arrhythmic effects remain uncertain; we hypothesize that CO2 mediated increases in coronary flow may be involved.Support or Funding InformationExperiments were funded by a Project Grant from the Canadian Institutes of Health Research (PJT 159491).
Maternal Exposure to Electronic Cigarettes Causes Body Composition Alterations in Pups
Authors: Coblentz Tyler , Reppert Sarah , Cheuvront Tristen , Chantler Paul D , Olfert I. Mark , Bryner Randy 
Published: April 2020

Electronic cigarette (E‐cig) usage is promoted as a safe alternative to traditional smoking, even during pregnancy, but long‐term effects of vaping are still unknown. Maternal smoking during pregnancy has been well studied and shown to increase both body mass index and obesity within children later in life. However, the effects of vaping on the offspring of maternal E‐cig users remains poorly studied. We hypothesized that maternal vaping during pregnancy will also increase body mass and obesity in the mature offspring with E‐cig exposed rat dams.Pregnant Sprague Dawley dams were exposed to nicotine‐free E‐cig aerosol (E‐cig0), E‐cig aerosol containing 18 mg/ml of nicotine (E‐cig18), or ambient air (control). Maternal E‐cig exposure (Joyetech eGrip OLED using 5‐sec puff @ 17.5 W) consisted of 60 puffs over 1‐hour each day, 5 days/week, starting on gestational day 2 and continued until pups were weaned. Progeny themselves were never directly exposed to E‐cig aerosol. Dual energy X‐ray absorptiometry (DXA) was used for body composition analysis in male and female rat offspring at 31±1 weeks of age (Air n=16, E‐cig0 n=21, E‐cig18 n=19).In females, total body mass and lean body mass (LBM) was not different between the exposure groups, however fat mass (FM) was greater in E‐cig0 compared to air and E‐cig18 exposed groups (125±9 vs. 103±12 and 100±5 g, respectively, ANOVA p<0.05). Percentage BF (%BF) was also greater in E‐cig0 compared to air and E‐cig18 (33±2 vs. 28±2 and 29±1 %, respectively, ANOVA p<0.05). As expected, total body mass, LBM, and FM values were significantly lower in females than males (ANOVA p<0.001), but no differences in body composition was observed within the males across the exposure groups.In conclusion, maternal vaping without nicotine may increase risk for elevated body fat in adult life and the development of obesity in female progeny with fetal exposure in utero.Support or Funding InformationWVU Cancer Institute Philip R Dino Innovative Research Grant (IMO), NIHGMS 5U54GM104942‐03 (PDC)
Exploring the Mechanisms of Drug Resistance with a 3D Molecular Model of HIV Protease
Authors: Gilmore Keviyanah , Craft Alexis , Lauderdale Tra’Mya , Jernigan Joy , Billings Ryan , Jones Candace , Van Stry Melanie 
Published: April 2020

Human immunodeficiency virus (HIV) affects 37 million people worldwide. HIV causes Acquired Immunodeficiency Syndrome (AIDS) by impairing the immune functions in the human body and is transmitted through contact of body fluid. HIV attacks the body’s immune system, specifically CD4 T cells which help the immune system fight off infection. Antiretroviral therapy (ART) has prolonged the life expectancy of those under the treatment process. ART is a combination of antiretroviral drugs that keep the virus from replicating. The drug combination “cocktail” combines the power of multiple drugs to block multiple targets in HIV replication. HIV‐1 protease is an essential enzyme for the life cycle of HIV. Therefore, HIV‐1 protease is an important target used in antiretroviral therapy. However, under the selective pressure of protease inhibitors, mutations may occur at the active site, crippling inhibitor binding and leading to drug resistance. Umass6 is an analog of the HIV protease inhibitor, duranovir, with a bulky P1′ moiety that allows enhanced overall van der Waals interactions at the active site. Here, we design a 3D model of the drug resistant HIV protease mutant I50V bound to UMass6 using Jmol based on the crystal structure described by Gordon J. Lockbaum and colleagues
(1). HIV protease is a homodimer with the active site located in the interface between the subunits. Our model highlights the location of the I50V mutation within the active site and the resulting structural changes that cause the loss of inhibitor potency. Our 3D model also highlights the critical residues involved in inhibitor binding and the catalytic residue, D25, within the active site. Designing 3D model exposes students to protein structure, mutations, and tools for understanding drug resistance.Support or Funding InformationThis work is supported by NSF‐DUE1725940 and NSF‐HRD1623340.
Sex Differences in an Fmr1 Knock‐out Mouse Model of Fragile X Syndrome
Authors: Armstrong Jessica L. , Chen Yiming , Saraf Tanishka S. , Canal Clinton E. 
Published: April 2020

Fragile X Syndrome (FXS) is the leading inherited, monogenetic cause of intellectual disabilities and autism spectrum disorder (ASD). Epilepsy, sensory hypersensitivities, and several other neuropsychiatric symptoms are also common in FXS and ASD. FXS is caused by a >200 CGG‐repeat on the FMR1 gene, located on the X‐chromosome, that silences its transcription, preventing expression of the protein, FMRP. Possessing a single X‐chromosome, FXS occurs more frequently in males than females. Males with FXS typically have more severe clinical symptoms than females with FXS. For example, males are more than twice as likely to have epilepsy. Genetic mosaicism (X‐inactivation) in females with FXS is the presumed, exclusive reason for the lower symptom severity. Our results presented here challenge this presumption. During preclinical testing of Fmr1 knock‐out mice, we observed a statistically significant, higher prevalence of audiogenic seizures in juvenile (P23–P25), male Fmr1 knock‐out mice (89%) compared to juvenile, female Fmr1 knock‐out mice (50%) (P=0.01, N=19 males and N=18 females), closely paralleling the sex difference in epilepsy prevalence in FXS. Importantly, however, female Fmr1 knock‐out mice are homozygous for the mutated Fmr1 gene, and therefore, like male Fmr1 knock‐out mice, do not express FMRP. We also found that expression of the serotonin receptor, 5‐HT1AR, was significantly elevated in whole brains of adult, male Fmr1 knock‐out mice, compared to wild‐type mice (P=0.04, N=8 each); we did not observe this difference in female mice (P=0.24, N=7 each). We are currently investigating whether 5‐HT1ARs contribute to the sex difference in audiogenic seizure susceptibility. In conclusion, our preclinical data suggest that the reduced symptom severity in females with FXS may not be solely attributed to X‐inactivation of the mutated FMR1 allele.Support or Funding InformationFunded by: FRAXA Fellowship and DOD W81XWH‐17‐1‐0329
Evaluation of Antimicrobial Activity & Phytochemical Analysis of Leaf Extracts of Acacia rigidula and Acacia berlandieri
Authors: Cavazos Peter Daniel , Lanorio Jocelyn , Ynalvez Ruby A. 
Published: April 2020

The emergence and spread of antibiotic resistance, as well as the evolution of new strains are of great concern to the global health community. The search for novel agents to combat the rapid evolution of bacterial pathogens becomes ever more important as current methods are proving ineffective. Plant species within the Fabacae family have been reported to exhibit antimicrobial activity; therefore, we hypothesize that these two species will display antibacterial properties. The objectives of this study were to (1) determine the presence of antimicrobial activities, (2) qualitatively determine secondary metabolites of plant extracts from Acacia berlandieri (Guajillo) and Acacia rigidula (Blackbrush), (3) analyze extracts using Nuclear Magnetic Resonance spectroscopy (NMR), infrared spectroscopy (IR), and ultraviolet‐visible spectroscopy (UV‐Vis) to identify different secondary metabolites within a test sample, and (4) determine antioxidant activities within both plant species.Plant leaves were sequentially extracted using acetone, methanol, and acetic acid that were then subjected to susceptibility testing against nine microorganisms. Results provided evidence of antimicrobial activity from the crude extracts of both species. The activity was significantly higher (p<0.001) from the leaves of species A. rigidula. Among the nine microorganisms, two gram‐negative and two gram‐positive bacteria were susceptible. Qualitative phytochemical testing revealed important secondary metabolites: phenols, flavonoids, saponins, terpenoids, and tannins. Each of which have been shown to possess antimicrobial properties and exert different modes of action. NMR, IR, and UV‐Vis spectroscopy revealed the basic structures within our unknown samples that are commonly found in flavonoids, saponins, and tannins, reinforcing the results of phytochemical testing. Preliminary results revealed some antioxidant activity within selected A. rigidula extracts. Analysis of the leaves extracts of A. berlandieri and A. rigidula have revealed the presence of medicinally valued bioactive components. This study confirms the efficacy of selected plant extracts as natural antimicrobials and suggests the possibility of employing them in drugs for the treatment of infectious diseases caused by the test organisms.
Using the CLASS‐Bio Survey to Assess Engagement through Forensic Science in General Biology
Authors: Jones Candace 
Published: April 2020

Lane College is a historically black college committed to educating underserved minority students. My objective was to give students different pedagogical strategies to meet students where they are and moving away from the lecture based format to improve student success. In General Biology I chose to engage students through forensic sciences. I implemented forensic science in the laboratory in one of my two sections of General Biology I in the Fall 2018 semester. Students determined the items that needed to be analyzed from a mock crime scene after being presented with some basic forensic science techniques in the first week of laboratory. Each additional week the students participated in analysis of hair, fiber, soil, synthetic blood tests, chromatography, and DNA fingerprinting. To assess the intervention, I used the CLASS‐Bio Survey which measures student attitudes and beliefs about learning science (n=32) that was given pre and post to both sections as a way to compare the effect of the intervention. In the section that I gave the Forensic Science intervention the CLASS‐Bio Survey perceptions were higher in all categories Enjoyment, Real World, Problem Solving Synthesis and Application, Problem Solving Effort, Conceptual, Problem Solving Strategies, and Reasoning in the pre survey. The class that received the forensic science intervention had a 19.1% increase in Enjoyment, 18.4 % increase in Problem Solving Strategies and a 15.9 % increase in Problem Solving Effort than compared with the class that did not receive the intervention in the post survey.Support or Funding InformationNational Science Foundation Award HRD # 1623340 to MVS
Myoblast Mitochondrial Adaptation to Chronic Alcohol Administration
Authors: Levitt Danielle E. , Simon Liz , Molina Patricia E. 
Published: April 2020

Skeletal muscle adaptation to chronic alcohol consumption involves disruption of anabolic, catabolic, and oxidative metabolism pathways and is associated with decreased muscle mass and impaired metabolic function. These maladaptive responses may contribute to increased risk of metabolic disorders, particularly in people living with human immunodeficiency virus (PLWH) on combination antiretroviral therapy (ART). Aging, increased survival of PLWH on ART, and lifestyle choices including unhealthy alcohol use are complicated by metabolic comorbidities. We tested the hypothesis that mitochondrial homeostasis is critically impacted by chronic binge alcohol (CBA) administration. Specifically, we hypothesized that CBA impairs skeletal muscle expression of genes underlying mitochondrial metabolic function and alters myoblast function in SIV‐infected, ART‐treated rhesus macaques. Female rhesus macaques (n=10) were assigned to receive either CBA (50–60 mM peak blood alcohol/day, 5 days/week) or isovolumetric water (VEH) for 3 months before SIVmac251 infection. After 2.5 months, ART was initiated, and skeletal muscle samples were collected from all animals at study endpoint (~12 months post‐SIV infection). mRNA was extracted and analyzed for genes related to mitochondrial biogenesis and metabolic function [peroxisome proliferator‐activated receptor‐gamma coactivator (PGC)‐1α, PGC‐1β, mitochondrial transcription factor A (TFAM), estrogen related receptor (ERR)α, nuclear respiratory factor (NRF)1 and 2]. Naïve (no alcohol or SIV) primary myoblasts were isolated from skeletal muscle and incubated with alcohol (50 mM) or control (media only) for three days. To assess mitochondrial metabolic function, oxygen consumption rate was determined at baseline in alcohol‐treated and control myoblasts after the addition of oligomycin, carbonyl cyanide‐4 (trifluoromethoxy) phenylhydrazone (FCCP), and rotenone and antimycin A using Agilent Seahorse technology. CBA reduced expression of PGC‐1β, TFAM, ERRα, NRF1, and NRF2, but not PGC‐1α mRNA in skeletal muscle from SIV‐infected, ART‐treated female rhesus macaques. In vitro, alcohol treatment reduced basal and maximal oxygen consumption rate of naïve myoblasts. Together, our findings demonstrate maladaptive changes in myoblast mitochondrial gene expression and function. These results identified potential therapeutic targets to improve skeletal muscle metabolic health in PLWH. Specifically, the role of PGC‐1β as a potential mechanism by which alcohol impairs skeletal muscle mitochondrial function warrants further investigation on its responsiveness to pharmacotherapeutic intervention to restore its levels and improve mitochondrial metabolic health in PLWH with unhealthy alcohol use.Support or Funding InformationThis research was supported by grants from the National Institute on Alcohol Abuse and Alcoholism, 1F32AA027982‐01A1, 5P60AA009803‐25, K01AA024494‐03, and 5T32AA007577‐20.
HRH1 in Human and Mouse Pancreatic Cancer
Authors: Salmerón Cristina , Sriram Krishna , Baird Alyssa , Insel Paul 
Published: April 2020

Pancreatic cancer, in particular pancreatic ductal adenocarcinoma (PDAC), is a highly lethal cancer (5‐year survival rate <10%). New, effective therapies are thus an important, unmet need. We recently found that many G protein‐coupled receptors (GPCRs), the largest and most diverse group of membrane receptors in eukaryotes and targets of a third of FDA‐approved drugs, are overexpressed in PDAC compared to normal pancreatic tissue. One such receptor, histamine receptor H1 (HRH1; ~32‐fold increase in PDAC), is targeted by many FDA‐approved antihistamines and high HRH1 expression is an unfavorable prognostic marker for PDAC. Moreover, increased mast cell (histamine‐secreting cells) in PDAC correlates with angiogenesis and tumor progression and a recent epidemiologic study showed that atopic allergic conditions and antihistamines protect subjects with age >70 from developing PDAC. We hypothesize that HRH1 enhances the malignant phenotype of PDAC and that antihistamines might be repurposed as a therapy for PDAC.We found that HRH1 mRNA is highly expressed in multiple human PDAC cell lines and is the highest expressed among the 4 HRH subtypes. Histamine via HRH1 increases Ca2+ levels in PDAC cancer cell lines, an effect blocked by multiple antihistamines (clemastine, fexofenadine, loratadine and diphenhydramine). We also observed that histamine can promote PDAC cell proliferation and migration via HRH1. Using the KPfC mouse (KrasLSLG12D/; p53fl/fl; Ptf1a‐Cre/), a genetically engineered mouse model of PDAC that spontaneously develops PDAC tumors after 6 weeks of age, we isolated PDAC tumors and generated five separate PDAC cancer cell lines. We found that KPfC mice PDAC tumors have higher HRH1 mRNA expression than does the normal pancreas of p53fl/fl littermate controls. As in human PDAC, KPfC PDAC cancer cell lines expressed higher HRH1 mRNA levels than the other HRH subtypes. Moreover, histamine increases intracellular Ca2+ in KPfC cancer cells, an effect blocked by antihistamines (clemastine and loratadine).Taken together, these data strongly suggest that HRH1 regulates Ca2+ signaling and functions associated with the malignancy of PDAC cancer cells and tumors. HRH1 is thus a potential therapeutic target for PDAC, perhaps by the repurposing of FDA‐approved HRH1 antihistamines.Support or Funding InformationSupported by an HHMI post‐bac fellowship and an ASPET David Lehr Award
Addition of retinoic acid‐inducible gene 1 to enhance Ebola virus‐like particle vaccine
Authors: Heath Arden , Fogarty Julia , Shrestha Ramila , Martinez Osvaldo 
Published: April 2020

Ebola virus (EBOV), a filovirus family member, is a highly pathogenic virus that causes Ebola hemorrhagic fever (EHF) resulting in documented mortality rates in humans as high as 50%. Currently, the basic EBOV virus‐like particle (VLP) vaccine contains the Ebola virus (EBOV) matrix VP40 and attachment glycoprotein (GP). VLPs are morphologically and biochemically similar to parental virus, yet because they lack a genome and cannot replicate, are safe enough to be used as vaccines. We hypothesize that addition of a constitutionally active retinoic acid‐inducible gene 1 (RIG‐I) would enhance the ability of the vaccine to induce interferon‐dependent immune functions yielding an improved vaccine. Expression of EBOV VP40 in 293T cells induces the spontaneous production of VLPs into the media supernatant and if expressed with EBOV GP, will produce VLPs studded with the attachment GP. Recombinant chimeric constitutively active (ca)RIG‐I‐VP40 matrix and a nonfunctional mutant L58A (mu)RIG‐I‐VP40 matrix genes were constructed to produce VLPs containing constitutively active and nonfunctional RIG‐I. Supernatant from 293Ts transfected with caRIG‐I‐VP40, muRIG‐I‐VP40 or VP40 along with GP expression plasmids were tested for the presence of VLPs. Western blotting of purified VLPs confirmed the presence of RIG‐I in caRIG‐I‐VP40 and muRIG‐I‐VP40, but not VP40 containing VLPs. Monocyte‐like and PMA‐differentiated macrophage‐like THP‐1 Dual cells were treated with nothing, VP40+GP, caRIG‐I‐VP40+GP, muRIG‐I‐VP40+GP VLPs as well as LPS and a Vaccinia virus (VACV‐70) positive controls and tested for induction of interferon (IFN) signaling. CaRIG‐I containing, but not muRIG‐I containing VLPs induced interferon signaling from both macrophages and monocytes. In Future studies we will also test whether addition of RIG‐I to EBOV VLPs can activate human peripheral blood monocytes.Support or Funding InformationWinona State University student research and travel grantsWinona State University Foundation Special Projects