bluuebunny/crossref_metadata_2025_split huggingface dataset:
Peripheral Adipose Arteriole Dilator Response to Amyloid Proteins and Palmitic Acid Recapitulates Central Leptomeningeal Arteriole Response: Validation of a Novel Human Tissue Model
Authors: Truran Seth , Karamanova Nina , Serrano Geidy , Madine Jillian , Davies Hannah , Beach Thomas , Migrino Raymond Q. 
Published: June 2021

BackgroundCerebrovascular dysfunction is critical in the pathophysiology of Alzheimer's disease and related dementia disorders (ADRD). The relationship between cardiovascular risk factors (e.g. saturated fatty acid palmitic acid PA) and amyloid proteins (Aβ or medin) in ADRD is unknown. Treatments that worked on animal models have failed to work in humans, pointing to the need to develop human tissue‐based models that recapitulate human condition. We showed feasibility of using cadaver leptomeningeal arterioles (LMA) following rapid autopsy to study central arteriole physiology but availability is extremely limited to few centers. Abdominal adipose arterioles (AA), on the other hand, are relatively easy/safe to obtain but require validation to confirm whether physiologic responses parallel cerebrovascular responses.AimTest the hypothesis that AA endothelium‐dependent dilator responses to Aβ, amyloidogenic medin and PA (agents that impair cerebrovascular function)parallel the responses of LMA.MethodsAA were isolated fromsubcutaneous fat from living volunteers undergoing routine abdominalsurgery. In brain and body donorsundergoing rapid autopsy, LMA ± abdominal AA were isolated. Arterioles were cannulated, pressurized and preconstricted with endothelin‐1. Baseline (control) dilator response to acetylcholine (10−9–10−4M)was obtained. Following washout, arterioles were exposed for 1 hour to physiologic doses of Aβ 2 μM, medin 5 μMor PA 150 μM and post‐treatment dilator response was measured and compared tobaseline; responses between AA and LMA were also compared.ResultsSee fig. Responses were not significantly different between AA and LMA.ConclusionsAβ, medin and PA caused endothelial dysfunction to a similar degree in both LMA and AA. The findings suggest that peripheral AA areacceptable surrogates to study functional response of central cerebrovasculararterioles and may be a valuable novel human tissue model.Support or Funding InformationNIH (NIAR21AG044723/NINDSU24NS072026/NIAP30AG19610/NIARO1AG019795), VAMerit (BX‐003767/BX007080), British Heart Foundation (FS/12/61/29877), Arizona Department of Health Services, Arizona Biomedical Research Commission(4001/0011/05‐901/1001), Fox Foundation for Parkinson's Research and US Department of Defense (AZ160056).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Cardioprotective Effects by a Novel Opioid Peptide in Myocardial Ischemia/Reperfusion Injury
Authors: Kim Hanna , McIntyre Anahi , Woodley John , Lopez Alexandra , Dittakavi Tejaswi , Finnegan Matthew , Amuquandoh Kevin , Ambrosino Maxwell , Walker Kiana , Patel Harsh , Chen Qian , Barsotti Robert , Young Lindon H. 
Published: June 2021

Preliminary studies in mice have shown that a novel tri‐peptide (Phe‐D‐Arg‐Phe‐Amide, MW=468 g/mol) attenuates ventilation induced diaphragm dysfunction when given as a pretreatment. Tri‐peptide is structurally similar to the SS‐20 peptide (Phe‐D‐Arg‐Phe‐Lys‐Amide), which has been shown to be cardioprotective when given before ischemia, but thought not to have opioid properties (Cho et al., 2007). Our study aims to determine whether pre‐ or posttreatment with tri‐peptide is more efficacious in attenuating the deleterious effects of myocardial ischemia/reperfusion (I/R) injury and whether this cardioprotection is mediated by opioid receptor activation. This was tested by observing whether tri‐peptide‐induced cardioprotection was abolished when administered in conjunction with naloxone, a nonselective opioid receptor antagonist. Tri‐peptide (50μM) was administered prior to I (pretreatment, n=8) or during R (posttreatment, n=8) in isolated perfused rat hearts subjected to I(30 min)/R(45 min) and compared to untreated control hearts (n=7) and hearts pre‐treated with tri‐peptide (50 μM) + naloxone (Nlx, 10μM, n=8). Tri‐peptide pretreatment hearts significantly recovered post‐reperfused left ventricular developed pressure (LVDP) to 59±6% of initial baseline values compared to untreated control, posttreatment tri‐peptide, and pretreatment tri‐peptide + Nlx hearts in which LVDP recovered to only 33±7%, 34±8%, and 26±4% of initial baseline values respectively (p<0.01). Furthermore, tri‐peptide pretreatment hearts exhibited significantly reduced infarct sizes of 26±1% compared to untreated control and posttreatment tri‐peptide hearts, in which infarct sizes were 38±4% and 37±2% respectively (p<0.05) assessed using 1% triphenyltetrazolium chloride staining. Pretreated tripeptide + Nlx hearts showed infarct sizes of 32±3% which was not significantly different from untreated controls. These data suggest that pretreatment and not posttreatment with this novel tri‐peptide was cardioprotective and that this protection was mediated via opioid receptor activation. Future studies will attempt to determine the specific opioid receptor subtype involved in tri‐peptide cardioprotection by testing whether delta or kappa opioid receptor antagonists block the cardioprotective effects of tri‐peptide pretreatment.Support or Funding InformationThis study was supported by the Center for Chronic Disorders of Aging, the Division of Research and the Department of Bio‐Medical Sciences at Philadelphia College of Osteopathic Medicine.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Comparing the Efficacy of Pharmacological Preconditioning with Myristic Acid‐conjugated, TAT‐ conjugated and Native Protein Kinase C Epsilon Peptide Activator in Myocardial Ischemia/Reperfusion (MI/R) Models
Authors: McIntyre Anahi , Kim Hanna , Finnegan Matthew , Amuquandoh Kevin , Chen Qian , Barsotti Robert , Young Lindon 
Published: June 2021

Protein kinase C epsilon (PKCɛ) activation is thought to be central in mediating cardioprotection conferred by myocardial ischemic preconditioning. PKCɛ activation via PKCɛ activator peptide (PKCɛ+, HDAPIGYD, MW= 887 g/mol) as pretreatment (PT) is a pharmacological means to mimic preconditioning. However, unconjugated or native PKCɛ+ requires the use of cell permeabilization methods for efficacious intracellular targeting to improve cardiac function and reduce necrotic cell death. Therefore, conjugating PKCɛ+ to known intracellular delivery moieties may be a method to effectively activate PKCɛ for cardioprotection. To test this hypothesis, we subjected isolated perfused rat hearts to PT with PKCɛ+ conjugated to either myristic acid (Myr‐HDAPIGYD, MW= 1097 g/mol, 10mM, n=5) or transactivating (TAT) carrier peptide (YGRKKRRQRRR‐CC‐HDAPIGYD, MW= 2632 g/mol, 10mM, n=6) to evaluate the efficacy of these intracellularly targeted peptide analogs in attenuating contractile dysfunction and infarct size after MI (30 min)/R (90 min) in comparison with native PKCɛ+ PT (10mM, n=5) and untreated control hearts (n=6). We found that compared to control hearts, PT with Myr‐PKCɛ+ and TAT‐PKCɛ+ significantly reduced infarct size from 41±3% to 29 ±1% and 28±2% (p<0.05) respectively compared to control hearts assessed by 1% triphenyltetrazolium chloride staining of heart tissue. By contrast, hearts PT with native PKCɛ+ showed almost no change in infarct size compared to controls, 41±3% versus 35±2%. Both myristic acid‐ and TAT‐conjugated PKCɛ+ PT hearts restored post‐reperfused left ventricular developed pressure (LVDP) to 52±5% and 50±10% compared to both native PKCɛ+ PT and control hearts which only recovered to 33±9% and 38±4% of initial baseline values respectively, but this improvement was not statistically significant. These preliminary results indicate that increasing cellular permeability of PKCɛ+ via conjugation to either myristic acid or TAT significantly improved its efficaciousness in attenuating infarct size when given before ischemia as a pharmacologic mimic of ischemic preconditioning. These results suggest that Myr‐ or TAT‐conjugated PKCɛ+ may be an effective treatment to attenuate cell death in coronary bypass or organ transplantation settings.Support or Funding InformationThis study was supported by the Center for Chronic Disorders of Aging, the Division of Research and the Department of Bio‐Medical Sciences at Philadelphia College of Osteopathic Medicine.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
The Effects of Metformin on Methylglyoxal‐induced cardiomyocytes cell damage
Authors: Sandhu Robinderpal , Lefkovitz Dylan , Kim Alisa , Wieczorek Peter , Barsotti Robert , Young Lindon , Chen Qian 
Published: June 2021

Methylglyoxal is a precursor of advanced glycation end products which is closely related to vascular complication in diabetes. However, the direct effects of methylglyoxal on cardiac myocytes still need to be elucidated. This study investigated the dose‐dependent effects of methylglyoxal on H9C2 myoblastic cell. Furthermore, we determined if metformin would reduce methylglyoxal caused cell damage. Cell viability was evaluated by a cell counting kit‐8 assay and intracellular reactive oxygen species (ROS) was evaluated via a dichlorofluorescin diacetate (DCFDA) assay. After incubation of different doses of methylglyoxal (5 μM‐1400 μM, n=12–18) for 24 hours, lower dose range of methylglyoxal (5 μM‐800 μM) slightly increased the cell viability by 15±4% compared to the control (n=12). By contrast, higher dose methylglyoxal (1000 μM, 1200 μM, 1400 μM) significantly reduced cell viability to 74 ± 6%, 63 ± 5%, and 56 ± 7%, respectively (all p<0.05) compared to control cells. Meanwhile, higher dose of methylglyoxal (1000 μM, 1200 μM, 1400 μM) also increased intracellular ROS by 42 ± 27% (n=4), 89 ± 23% (n=4, p<0.05), and 109 ± 11% (n=3, p<0.05), respectively. By contrast, administration of metformin (1–40 mM) with methylglyoxal (1200 μM) (n=4) dose‐dependently increased cell viability. Metformin (40 mM) increased cell viability by 123± 41% (p<0.05) and reduced intracellular ROS by 70% (n=1) when compared to methylglyoxal treated cells. The preliminary data suggests that higher dose of methylglyoxal causes cardiac cells damage possibly by increased oxidative stress. Metformin can reduce oxidative stress and protect cardiac cells under higher methylglyoxal concentration and may reduce vascular complications in diabetic patients.Support or Funding InformationThis study was supported by the Center for Chronic Disorders of Aging, the Division of Research and the Department of Bio‐Medical Sciences at Philadelphia College of Osteopathic Medicine.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Does Treadmill Walking affect Neurovascular Coupling during Cognitive Activation in Healthy Individuals?
Authors: Favre Michelle E. , Douglas Samantha B. , Wood Scott J. , Serrador Jorge M. 
Published: June 2021

Treadmill desks have become increasingly popular in the workplace to improve physical health. However, it is unknown whether treadmill walking affects neurovascular coupling, which is the increase in cerebral blood flow during cognitive tasks. Additionally, it is unknown whether the speed of treadmill walking affects neurovascular coupling or if there is a sex difference in the response. A total of 49 subjects (22 male, 27 female) walked on a treadmill at four different walking speeds (0.5 mph, 1.5 mph, 2.5 mph and 3.5 mph) in addition to a standing condition (0 mph). While standing or walking at each speed, participants also performed the Stroop color‐word test. Continuous cerebral flow velocity in the right middle cerebral artery (MCAv), blood pressure, heart rate, and end‐tidal CO2 were measured throughout testing. The percent increase in MCAv from the no tasking condition (standing or walking at each speed) to the Stroop tasking condition (Stroop + standing or walking at each speed) was analyzed to measure neurovascular coupling. Results showed a significant effect of walking speed (p=0.003) as well as a significant interaction between walking speed and sex (p=0.012) on the percent increase in MCAv during the Stroop tasking condition (0 mph: Men = 2.6 ± 5.8%, Women = 1.8 ± 3.7%; 0.5 mph: Men = 2.3 ± 4.2%, Women = 3.6 ± 5.2%; 1.5 mph: Men = 4.1 ± 6.2%, Women = 4.2 ± 4.9%; 2.5 mph: Men = 3.4 ± 7.4%, Women = 4.0 ± 4.3%; 3.5 mph: Men = −1.7 ± 7.8%, Women = 3.4 ± 7.0%). There was also a small, but significant effect of walking speed on the difference in end‐tidal CO2 between the Stroop tasking condition and the no tasking condition within each speed (p=0.005; 0 mph: Men = 0.0 ± 1.1 mmHg, Women = −0.1 ± 1.4 mmHg; 0.5 mph: Men = −0.1 ± 0.8 mmHg, Women = 0.0 ± 0.7 mmHg; 1.5 mph: Men = 0.0 ± 1.3 mmHg, Women = 0.2 ± 0.9 mmHg; 2.5 mph: Men = 0.4 ± 1.7 mmHg, Women = 0.1 ± 0.9 mmHg; 3.5 mph: Men = −1.0 ± 2.0 mmHg, Women = −0.2 ± 1.1 mmHg). There was no interaction between speed and sex in end‐tidal CO2. This data suggests that there is a small, but significant reduction in neurovascular coupling in men during the Stroop test at 3.5 mph, but this reduction may be partially explained by the reduction in end‐tidal CO2. This study highlights that neurovascular coupling is preserved during treadmill walking across the slower walking speeds. However, neurovascular coupling at 3.5 mph needs to be further examined with controlled levels of end‐tidal CO2 to support whether neurovascular coupling is reduced at this faster walking speed in men.Support or Funding InformationThe study was supported by the Department of Defense through CDMRP W81XWH‐14‐1‐0598 and CDMRP W81XWH‐14‐2‐0012.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Isolation Stress During the Adolescence Exacerbates the Locomotor Activity Effects of Cocaine in Rats
Authors: Perez‐Cardona Enrique U. , Rivero Carlos , Freire Jaime , Ortiz Natalia , Sacarello Gabriel , Santiago Ivan , Torres Ricardo , Mendez Andrea , Diaz Abdias , Rodriguez Efrain , Segarra Annabell 
Published: June 2021

Adolescence is a complex developmental period characterized by sexual and brain maturation. Stress during adolescence, as abandonment and social isolation, interferes with maturation of higher brain functions such as decision making, learning and memory. Since rats are social animals, we investigate the consequences of housing rats individually during adolescence on the development of addictive behaviors. From postnatal day 23 (weaning), male and female rats were either housed in groups of the same sex or single housed throughout the experiments. At day 35 they were tested for their locomotor response to cocaine (15 mg/kg). Our results indicate that isolation during adolescence increases the locomotor response to cocaine in drug‐naive female rats. Unlike females rats, isolation during the adolescence does not affect the initial locomotor response to cocaine in males. However, these prepubertal males that normally do not show cocaine sensitization at this age, sensitized to cocaine when reared in isolation during adolescence. These results show that rearing rats in isolation exacerbates the behavioral effects of cocaine, and that the effect varies according to the sex of the animal. They also advocate for closer monitoring of neglected and solitary adolescents since they may be at a higher risk to develop drug dependency.Support or Funding InformationThis work supported by NSF under grant #OISE1545803.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Malabsorption of copper and other nutrients as well as intestinal parasite infections cause health problems and lower birthrates in the American Bison
Authors: Rhodes Ryon Sun , Topliff Christina L. , Kelling Clayton L. , Coon Steven 
Published: June 2021

BackgroundHerds of American Bison have been raised on pastures of different Indian Reservations in Montana. It has been discovered that many of these Bison have serious health problems related to malnutrition causing lower birth rates. Plants on these reservations absorb unusually high levels of selenium and molybdenum which the animals feed on. Previous studies indicate metals such as copper are necessary for proper health and birthrates. Copper is necessary for normal conception rates and will cause retarded growth of the offspring. In addition, poor calving rates in apparently healthy bison with adequate protein and energy in diets might simply be from copper deficiency.HypothesisDecreased copper absorption is due to increased absorption of selenium and molybdenum and parasitic infections.MethodsWhen the animals are euthanized liver samples and fecal samples are removed for analysis. Body scores were taken to access the states of malnutrition and number of offspring were counted to access birthrates.ResultsIncreased toxic levels of selenium (3.7ppm) and Molybdenum (4.2ppm) and low levels of copper (10ppm) have been detected in tissue samples from the livers of the bison. However increased levels of Zinc have also been detected in these animals (125ppm). In addition, the presence or increased levels of intestinal parasites have also been detected in the fecal matter taken these animals. These parasites which include Coccidia and various worm infestations may also be also interfering with the normal absorption of copper and other nutrients in the animals.ConclusionsMalabsorption of nutrients such as copper may be caused by increased absorption of selenium, molybdenum or zinc as well as infections from parasites in the Bison digestive tract.Support or Funding InformationUSDA 2016‐38424‐25559This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Mass Spectrometry‐Based Proteomics Reveals a Regulatory Role for DYRK1A in DNA Damage Repair
Authors: Guard Steven E. , Poss Zach , Ebmeier Chris , Old William 
Published: June 2021

Down syndrome, the most common genetic cause of intellectual disability, results from trisomic chromosome 21. A section of chromosome 21 containing 33 genes, known as the Down syndrome critical region, plays a crucial role in producing the cognitive defects characteristic of Down syndrome. The dual‐specificity tyrosine phosphorylation regulated kinase 1A (DYRK1A), located within the Down syndrome critical region, is necessary for normal brain development from flies to humans. Neurological defects in mice arise from an additional DYRK1A gene copy, while heterozygous loss of function causes microcephaly, facial dysmorphia, impaired motor function and behavioral problems in humans, demonstrating the sensitivity of DYRK1A function to gene dosage. However, the molecular mechanisms underlying these phenotypic changes are not fully understood. Defining the protein interacting partners of DYRK1A and subsequent function of these relationships is crucial for understanding the implication of trisomic chromosome 21 on human health.Most known functions and substrates of this kinase are cytoplasmic, leaving the smaller subpopulation of DYRK1A in the nucleus relatively unstudied. To systematically investigate the nuclear interacting partners of DYRK1A, immunoprecipitation of the endogenous protein in conjunction with mass‐spectrometry based proteomics was used to generate a deep interactome. This nuclear interactome reveals interactions between DYRK1A and several E3 ubiquitin ligases that act as negative regulators of DNA double stranded break repair. Efficient repair of these lesions is necessary for maintaining genome stability and is dependent on a ubiquitin signaling cascade. CRISPR knockout of DYRK1A and inhibition of this kinase with the selective inhibitor harmine decreases the efficiency of DNA double strand break repair following ionizing radiation. The persistence of DNA double strand break markers increased in DYRK1A knock out cells and in a dose dependent manner with harmine at late time points following the initial damage.Maintaining genomic stability during expansion of neural progenitors is crucial for brain development. The rapid expansion of progenitors during typical neurogenesis is of particular risk, as early‐born cortical progenitors are hypersensitive to replication‐associated DNA damage. Inaccurate repair of genomic lesions at such a time can result in severe and ill effects on the developing organism. The results from this study strongly implicate DYRK1A gene dosage in the efficient repair of DNA double strand breaks, and in a neural context could contribute to the neurodevelopment defects associated with DYRK1A.Support or Funding InformationBlumenthal Fund Fellowship; Linda Crnic Institute; DARPAThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Biophysical characterization of interactions between a uridylated histone mRNA degradation intermediate and SLBP
Authors: Harris Sarah Elizabeth , Mihailescu Mihaela‐Rita , Lackey Patrick 
Published: June 2021

Histone mRNAs are a tightly cell‐cycled regulated group of mRNAs that are strongly expressed at the beginning of S‐phase and rapidly degraded when DNA replication ends. This cell cycle regulation is controlled by histone mRNA's unique 3′ end; instead of the traditional poly(A) tail, histone mRNA instead ends with a 3′ stem‐loop. This stem‐loop is an important factor in controlling the expression and degradation of histone mRNA during S‐phase, along with two key protein binding partners: the stem‐loop binding protein (SLBP) and the human 3′ exonuclease (3′hEXO). At the beginning of degradation, 3′hEXO trims 2–7 nucleotides from the 3′ end. These nucleotides are then often replaced by a short uridylation that preserves the length of the stem‐loop. The exact function of these uridylated intermediates and whether they affect histone mRNA metabolism is currently unknown. We characterized the structure of a stem‐loop with seven nucleotides trimmed from the 3′ end and replaced with seven uridines using nuclear magnetic resonance (NMR) to show that a stem‐loop still forms, despite this trimming‐and‐replacement mechanism that turns the six‐membered stem into a nine‐membered stem. We also characterized interactions between SLBP, 3′hEXO, and the trimmed and uridylated RNA using electrophoretic shift mobility assays (EMSA) and found that the RNA does, in fact, interact with both proteins. This raises new questions about the nature of the uridylated stem‐loop and its function in the translation and degradation of histone mRNA.Support or Funding InformationThe National Science Foundation CHE‐1659821 (REU)This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.