bluuebunny/crossref_metadata_2025_split huggingface dataset:
Adipose tissue expression of HuR modulates cardiac pathology via adipose tissue‐derived extracellular vesicles
Authors: Anthony Sarah R. , Guarnieri Adrienne R. , Green Lisa C. , Slone Sam , Nieman Michelle L. , Owens A. P. , Kanisicak Onur , Tranter Michael 
Published: May 2022

Obesity is widely associated with increased cardiovascular disease (CVD) extending beyond common co‐morbidities such as dyslipidemia and diabetes, as evidenced by increased CVD risk in ‘metabolically healthy obese’ individuals. Adipose tissue serves a broad role as an endocrine organ and has been shown to have a multitude of effects on cardiac physiology depending on metabolic state, adipose depot location, and primary cell type. We have previously shown that adipose tissue‐specific deletion of HuR (Adipo‐HuR‐/‐) reduces BAT‐mediated adaptive thermogenesis, accompanied by the spontaneous development of cardiac hypertrophy and fibrosis in mice. We and others have also shown that expression of HuR in subcutaneous white adipose tissue (scWAT) is decreased in obesity, suggesting a potential mechanistic link between obesity, HuR expression in scWAT, and CVD.To identify underlying mechanisms, we applied both RNA‐seq and weighted gene co‐expression network analysis (WGCNA) across both cardiac and adipose tissue (BAT, scWAT, and perigonadal WAT) to correlate adipose tissue gene expression with the phenotype of cardiac fibrosis. Our results suggest HuR‐dependent adipose tissue‐derived extracellular vesicles (Ad‐EVs) as the mediator of cardiac pathology. To provide functional evidence for the role of Ad‐EVs in driving cardiac pathology in Adipo‐HuR‐/‐ mice, we demonstrate that plasma‐isolated vesicles from Adipo‐HuR‐/‐ mice, but not wild‐type littermate controls, induced a significant increase in hypertrophic signaling in primary isolated mouse cardiomyocytes.In conclusion, our results demonstrate that loss of HuR expression in adipose tissue, as observed in the setting of obesity, is sufficient to induce cardiac hypertrophy and fibrosis, in part through endocrine‐mediated Ad‐EV signaling.
Studying Quantitative Relationships Between the Indicators of Physical Development at Birth and the Functional State of the External Respiratory System
Authors: Filippova Irina , Saperova Elena V. 
Published: May 2022

The external respiration system is studied in various areas of human physiology and ecology in order to both identify the patterns of functioning of this system and to assess the nature and extent of the influence of environmental factors on respiratory function.Indicators of the external respiration system are considered as individual indicators of the body's adaptation to the environment. The result of the influence of unfavorable environmental factors is most pronounced in the period of intrauterine development and largely determines the functional capabilities of the organism in the later periods of ontogenesis.The aim of our work was to study the relationship between birth weight and expiratory flow rates. 500 children aged 4 to 7 years were examined. With age, there is an increase in the volumetric expiratory flow rate, which is associated with the processes of general development and growth of the body. The results of the analysis of variance also indicate that this relationship is statistically significant. The value of the Fisher coefficient (F) is 6.73 at a significance level of 0.00021. The greatest increase in expiratory volume flow rates is observed between four and five years (0.54 l/s or 54%), between six and seven years (0.36 l/s or 36%), and the increase between five and six years is insignificant (p>0.05).In the course of our research, the dependence of the indicators of the volumetric expiratory velocity on the floor was also established. In boys, this figure was 1.34 l/s, in girls ‐ 1.19 l/s. This difference was also significant after taking into account age (p<0.05).To identify the nature of the influence of anthropometric parameters at birth on the value of the volumetric expiratory flow rate, a multiple regression analysis was carried out, taking into account birth weight, birth length and age. To clarify the nature of the relationship under study, partial correlation coefficients were calculated, which showed that age and birth weight have the greatest influence on expiratory PTM. Body length at birth does not have a significant effect on external respiration. The partial correlation coefficients are as follows: body weight at birth – 0.244451; age – 0.569063; body length at birth – ‐0.156432.Since we found that there are certain differences in the expiratory flow rate between boys and girls, we performed a regression analysis for each group. Thus, we can conclude that the indicators of external respiration increase with age due to the processes of growth and general development of the body. The results of the regression analysis of the influence of anthropometric parameters on the volumetric expiratory flow rate indicate the greatest influence on PTM of age and body weight at birth, both in boys and girls.
A New Method for Undruggable Targets: Amino Acids as Fragments of Inhibitors
Authors: Castillo Abdul , Fuglestad Brian 
Published: May 2022

Over the last decade, protein‐protein interactions (PPIs) have emerged as promising targets in the precise treatment of serious diseases. Many essential cellular pathways that are implicated in human diseases are controlled by intracellular PPIs. Such PPIs could be potential drug targets, and thus the ability of molecules to inhibit specific PPIs has remarkable therapeutic value. Unfortunately, PPI interfaces are generally large and present great difficulty for small molecule inhibitor design. Alternate strategies are being developed towards drug design and discovery for this type of target. For example, the synthesis of unnatural amino acids allows production of extremely large libraries of highly modified peptides, which may be screened against a PPI target. Peptide hits are a potential source of lead compounds in the search for new pharmaceutical agents and are promising for PPI inhibition. It is in this context that selection of the right unnatural amino acid becomes crucial.For this reason, developing new strategies to solve this problem is a key factor to find more efficient and specific inhibitors to PPI’s.In this study, we introduce a simple, Nuclear Magnetic Resonance (NMR) based methodology that screens natural and unnatural amino acids as “fragments” for development of new peptide‐based inhibitors for specific PPI’s. We validate this new method against MDM2, a well‐characterized and important negative regulator of the p53 tumor suppressor with known small peptides that inhibit its interaction with p53. A central tryptophan is the largest contributor to binding in this interface, and the corresponding MDM2 binding pocket is where we focused our efforts. Using this methodology, we screened non‐natural tryptophan derivatives, and several displayed a better binding affinity compared with the natural counterpart. Our simplified method allows priority ranking of amino acids according to their affinity to the protein. The highest‐ranking amino acids will be incorporated into peptides synthetically to confirm that improved free amino acid affinity translates to enhanced peptide binding and inhibition. In addition, this serves as a convenient and robust method to ‘pre‐screen’ amino acids for incorporation into in vitro peptide selection via mRNA display.
Chronic Unpredictable Stress impairs Relaxation Responses to Acetylcholine in Resistance Arteries from Mice
Authors: Arishe Olufunke O. , Wilczynski Stephanie , Crockett Alexia , Priviero Fernanda , Hollis Fiona , Webb Clinton 
Published: May 2022

BackgroundExposure to chronic stress is considered a major environmental factor that causes vascular aging, giving rise to the development of cardiovascular diseases. The chronic unpredictable stress (CUS) protocol has emerged as a translationally relevant model for studying the pathophysiology of stress exposure in rodents. The CUS protocol relies on heterotypic, unpredictable, and uncontrollable stressors that prevent adaptation and lead to disrupted stress response systems, mimicking the real‐life situation. CUS induces changes in cardiovascular function that are accompanied by the release of inflammatory cytokines. Indeed, previous studies have reported endothelial dysfunction in humans exposed to chronic stress and experimental animal models of chronic unpredictable stress. However, the mechanisms through which CUS induces cardiovascular injury are still unknown and require investigation.HypothesisThis study tests the hypothesis that mice exposed to CUS will have impaired endothelial function.MethodsVascular function using wire myographs was performed on isolated mesenteric resistance arteries (MRAs) from male and female C57BL/6 mice subjected to CUS for 28 days. The arterial rings were kept in physiological salt solution at 37°C, constantly aerated with 95%O2/5%CO2. Concentration‐response curves to phenylephrine (PE; 10‐9‐3x10‐5M) were performed in some arterial rings, whereas concentration‐response curves to acetylcholine (ACh; 10‐9 – 3x10‐5M) were performed in arterial rings precontracted with phenylephrine (PE 3x10‐6M). Concentration‐response curves were analyzed using non‐linear regression analysis. Data are presented as mean ± S.E.M. Statistical significance set at p<0.05. Data were analyzed with GraphPad Prism 9.2.0.ResultsIn the MRA of both males and females, relaxation responses to ACh were impaired in the animals exposed to CUS when compared to their controls. There were no differences in the contractile responses to PE between controls and mice exposed to CUS.ConclusionOur results show that relaxation responses to acetylcholine are impaired in mesenteric resistance arteries from mice exposed to chronic unpredictable stress. This suggests that exposure to chronic unpredictable stress causes endothelial dysfunction and may have important implications for the role of stress on the development of cardiovascular diseases, particularly, hypertension.
Effects of the Rho Kinase Inhibitor Fasudil on Adrenergic Contractions of Rat Aorta and Mouse Spleen
Authors: Docherty James R. , Alsufyani Hadeel A. 
Published: May 2022

G‐protein coupled receptors such as α1‐adrenergic receptors (AR) are linked via the G‐protein Gq/G11 to both Ca2+ entry and release of Ca2+ from stores, but can also activate the small GTP binding protein RhoA and Rho kinase to produce contractions involving Ca2+ sensitization. In rat portal vein, tonic but not phasic components of contractions to the α1‐AR agonist phenylephrine involve predominantly the α1B‐AR subtype, and are at least partly mediated by mechanisms involving Rho kinase sensitive to fasudil (Alsufyani & Docherty, 2021). In this study we examined the involvement of Rho Kinase in contractions involving α1‐AR in two further tissues to investigate the predominant α1‐AR subtype involved. We have examined the Rho kinase inhibitor fasudil in rat aorta and mouse spleen, tissues containing multiple α1‐AR subtypes. Male Wistar rats (250‐300g) and C57 mice were killed by CO2 overdose and cervical dislocation, and rat aortic rings and mouse spleens were mounted in organ baths under 0.5 g tension, and bathed with Krebs‐Henseleit solution at 37oC. Tissues were contracted with cumulative additions of norepinephrine (NE) in 0.5 log unit increments, over the concentration range 10‐8‐10‐3M. Both α2‐ and α1‐ARs mediate contractions of mouse spleen and the major α1‐AR involved is the α1B‐adrenoceptor, and this receptor interacts with an α1D‐AR at low, and an α1A‐AR at high, NE concentrations (Alsufyani et al., 2021). In mouse spleen, fasudil (3 μM) reduced contractions to both low and high concentrations of NE. In rat aorta, contractions to NE are reported to be mediated by two subtypes of α1‐AR: α1B‐ and α1D‐ARs, with responses to low but not high concentrations of NE being sensitive to the antagonist BMY7378. Responses to high concentrations of NE in rat aorta are sensitive to the non‐selective α1‐AR antagonist prazosin and the putative α1B‐AR antagonist cyclazosin. Fasudil (3 and 10 μM) significantly reduced contractions to both low and high concentrations of NE in rat aorta in a dose dependent manner in terms of maximum response. It is concluded that α1‐AR mediated contractions to NE in both rat aorta and mouse spleen are sensitive to non‐competitive block by the Rho kinase inhibitor fasudil in concentrations of 3‐10 μM. Although multiple subtypes of α1‐adrenoceptor are involved in contractions of both rat aorta and mouse spleen, the evidence suggests that, as previously reported in rat portal vein, α1B‐adrenoceptors are most likely linked to the Rho kinase pathwayAlsufyani HA & Docherty, J.R. Can J Physiol Pharmacol. 2021 Jun;99(6):654‐659. Alsufyani HA, et al. Basic Clin Pharmacol Toxicol. 2021 Dec;129(6):416‐426.
Generation and characterization of Elovl4bknockout zebrafish as a model for Juvenile‐Onset Macular Degeneration
Authors: Nwagbo Uzoamaka , Bernstein Paul S. 
Published: May 2022

PurposeVery long‐chain polyunsaturated fatty acids (VLC‐PUFAs) are a distinct class of lipids with chain lengths greater than 24 carbons. ELOVL4 is a protein responsible for VLC‐PUFA biosynthesis. However, in patients with autosomal dominant Stargardt 3 disease, the gene encoding ELOVL4 is mutated, and as a result, a dysfunctional, truncated protein is produced instead. It is unclear whether the disease phenotype is caused by truncated protein aggregates, the absence of VLC‐PUFAs, or a combination of these factors. Moreover, homozygous elovl4 ablation is neonatal lethal in mice. This study aimed to delineate the effect of VLC‐PUFA loss on photoreceptor function.MethodsElovl4b knockout zebrafish were generated by creating a deletion mutation in exon 2 of the elovl4b gene using CRISPR‐Cas9. Mutant zebrafish were screened for non‐specific mutations by outcrossing mutant adults with wild‐type fish. Their eyes were isolated, total fatty acids extracted, and the quantity of VLC‐PUFAs determined through gas chromatography and mass spectrometry.ResultsWe found that homozygous Elovl4b mutant zebrafish eyes had altered lipid profiles and a significantly lower abundance of C30 to C34 VLC‐PUFAs compared to age‐matched wild‐type controls. We also predict diminished a‐ and b‐wave amplitudes from ERG recordings – indicative of a loss of photoreceptor function and a thinner outer nuclear layer than controls.ConclusionOur data indicate that the loss of Elovl4b in zebrafish can cause an ocular phenotype comparable to juvenile‐onset macular degeneration. The availability of a homozygous animal model of ELOVL4 deficiency will also allow for further studies on other ELOVL4‐related diseases.
Anatomy‐Focused Exercise Videos to Combine Studying with Wellness
Authors: Knox Michael , Brackmann Megan , Mehta Sejal , Schaefer Maureen , Tubbs Ryan 
Published: May 2022

Study Objective and HypothesisThe link between exercise and mental wellness is well appreciated. Yet, many medical students struggle to find the time to incorporate physical activity into their daily lives. A new and innovative teaching style that incorporates movement with Anatomy was developed at Michigan State University. Students are provided a series of supplemental videos that utilize exercise and choreography to reinforce difficult anatomical concepts. Previously published research by Guzzardo et al. demonstrated a link between movement, anatomy learning, and enjoyment. This current study deepens that understanding by gathering student feedback that qualifies the effects of the videos on their wellness.MethodsFirst and second year medical students at Michigan State University were provided links to videos housed on the Knockout AnatomyYouTube channel during their Anatomy or Neuromuscular courses. All students within those two cohorts were invited to participate in our IRB‐approved qualitative study. Nineteen students completed virtual interviews that asked questions pertaining to their current level of activity, the importance of movement in their life, their motivation behind watching the videos, how the videos made them feel afterward, and if the videos helped them learn the material.ResultsStudent responses were broken into four major themes. 1) All interviewees stated they view exercising as important for mental health and academic performance, and nearly all reported their time spent exercising has decreased since starting medical school. 2) After participating in the movement‐based videos, most interviewees reported a positive increase in mood and energy levels. 3) Several interviewees reported that participating in the videos reminded them of the positive benefit of routine exercise, and they were more motivated to achieve their weekly exercise goals on a more consistent basis. 4) Academically, most interviewees reported that the videos helped them retain anatomy information, particularly with challenging anatomy topics such as brachial plexus, dermatomes, and myotomes.ConclusionMany medical students feel they are unable to reach their exercise goals due to time constraints. Professors in all disciplines can better understand the positive effects of exercise on student wellness and challenge themselves to explore new and innovative ways to bring movement into the learning environment.ReferencesGuzzardo, G., Gilbert, M., Schaefer, M. and Nazaroff, C. (2021). Exercise Anatomy: A Flexible Approach. The FASEB Journal, 35:S1.
The Antiarrhythmic Effect of Inhibition of the Mitochondrial Calcium Uniporter under Catecholamine Overload is Partly Dependent on Mitochondrial Function Preservation
Authors: de Jesús Salazar Ramírez Felipe , Bernal‐Ramírez Judith , Luévano‐Martínez Luis , García‐Rivas Gerardo 
Published: May 2022

IntroductionVentricular arrhythmias are a major cause of mortality in cardiovascular patients. Catecholamines have been associated with the development of ventricular arrhythmias and no new intervention has demonstrated efficacy in reducing mortality since the use of β‐blockers. Mitochondrial calcium transport has been deemed necessary for an adequate adrenergic response and constant adrenergic stimulation leads to mitochondrial calcium overload with subsequent mitochondrial dysfunction. Inhibition of the mitochondrial calcium uniporter (MCU) have been described to reduce asynchronized contraction in cellular and animal models. In this study, we assessed the effects that MCU inhibition by administration of Ru360, a MCU inhibitor, has on ventricular arrhythmia incidence in a model of catecholamine toxicity and characterize cellular and mitochondrial function to describe the subcellular mechanisms involved.MethodsThe study followed the national guidelines for laboratory animal use and care and was approved by the Animal Care and Use Committee. 12‐15‐week‐old C57bl/6 male mice received Ru360 or normal saline via IV, and a baseline ECG was recorded. Afterwards, Isoproterenol (400mg/kg) was administrated subcutaneously, and ECG recording was kept for another 20 minutes. Finally, hearts were excised, and cardiomyocytes and mitochondria isolated for further characterization. Data is presented as mean ± SEM. Fisher exact test was performed to evaluate arrhythmia incidence and one‐way ANOVA followed by Holm‐Sidak method for mitochondrial experiments and heart rate measurements.ResultsRu360 completely prevented the development of ventricular arrhythmias at a dose of 50nmol/kg. Mitochondrial Ca2+ transport inhibition preserved mitochondrial function and membrane integrity demonstrated by a preserved respiratory control and calcium retention capacity and a partially preserved mitochondrial membrane potential. MCU inhibition also prevented mitochondrial membrane potential loss upon the addition of a Ca2+ insult. The effects shown appear to be caused by a reduced oxidative stress, shown by a higher cytochrome c oxidase activity, that helps preserve cellular Ca2+ homeostasis as seen in confocal microscopy.ConclusionRu360 prevents arrhythmias possibly by reducing mitochondrial Ca2+ overload, preserving mitochondrial function, preventing mitochondrial ROS formation and oxidative damage, and conserving cellular Ca2+ homeostasis.
Mesenteric Artery Reactivity in Young APOE3 and APOE4 Mice
Authors: Wagner Katherine L. , Dunlap Jazmin N. , Gusek Brikena , Jones Carleton (. , Eckman Delrae M. 
Published: May 2022

IntroductionVariant isoforms of apolipoprotein E (APOE) are risk factors for both Alzheimer’s disease (AD) and cardiovascular disease (CVD), with the APOE4 isoform increasing risk compared to the most common isoform, APOE3. Allelotype alters cerebral artery reactivity and cardiac indices in aged animals (ongoing studies in our lab), yet little is known about how allelotype affects systemic circulation. Thus, we hypothesized that APOE allelotype alters mesenteric arteries (MA) in mice. We determined the mechanical characteristics and vascular reactivity of 3rd‐order MA isolated from young (Y, 3 to 4 mo), male and female mice expressing human‐ApoE targeted replacement of APOE3 (B6.129P2‐Apoetm2(APOE*3)Mae N8) and APOE4 (B6.129P2‐Apoetm3(APOE*4)Mae N8) (Taconic Labs).MethodsMAs were isolated, cleaned of connective tissue, cut into 8mm segments, and cannulated in an arteriograph chamber to assess vascular reactivity via myogenic tone (MT) and phenylephrine (PE)‐induced constriction (1µM). Passive mechanical properties assessed at intraluminal pressures of 10mm Hg to 140mm Hg included lumen diameter, wall thickness, wall tension, stress vs pressure, distensibility and arterial stress/strain. Data were analyzed using two‐way ANOVA and Students t‐test.ResultsMT was greater in E3 mice compared to E4 mice (P<0.001). K+‐ and PE‐induced constriction were similar between E3 mice and E4 mice. Subtle, yet significant changes were observed in passive mechanical properties. Lumen diameter and wall tension was greater in E4 mice compared E3 mice (P<0.01). Wall thickness was greater in E3 mice vs E4 mice (P<0.05). Stress vs pressure was greater in E4 mice vs E3 mice (P<0.05). E4 mice tended to have greater stress vs pressure and distensibility values than E3 mice, but they did not reach statistical significance. Finally, stress vs strain values in MA from E3 mice and E4 mice were similar.Summary/ConclusionsThese data indicate allelotype alters MA vascular reactivity and structural properties. Additional studies are warranted to determine whether these changes in systemic circulation persist with ageing and contribute to altered cerebral and cardiac structure/function observed in ongoing studies in our lab.