bluuebunny/crossref_metadata_2025_split huggingface dataset:
Higher Susceptibility to Skeletal Muscle TA (Tibialis Anterior) Injury with Increased Inflammation in Aged Mice.
Authors: Tipparaju Srinivas M. , Virzi Jazmie M. , Puig Viviana M. , Brotto Marco 
Published: April 2020

BackgroundSkeletal muscle contributes to a major portion of normal human body weight and plays a key role for physiological functions including growth, development and a host of metabolic regulating roles. Therefore, skeletal muscle injury is a major concern, particularly in pediatric and older populations.ObjectiveTo evaluate the differences in skeletal muscle injury, we utilized male Wild type C57BL6 young (5‐month old; n=4), and mature‐aged (12‐month old; n=4) aging mouse models.MethodsWe utilized Barium Chloride injection to induce inflammatory damage to the tibialis anterior muscle (TA), and monitored early skeletal muscle changes during 72 hours. Immunohistochemistry and morphometric analysis was conducted to identify changes between saline treated vs. barium chloride treated TA muscle.ResultsH&E staining from injured TA muscle identified an area of damage of ~52% in the young compared to a significantly larger area of damage of ~78% in mature mice. We also performed histomorphometric analyses to identify additional morphological changes. We found changes consistent with an increased cross sectional area post injury along with increased inflammation in the injured TA muscle.ConclusionsThe barium chloride TA muscle injury model allows for evaluation of TA muscle injury as early as 72‐hour post injection. Barium chloride injured muscles show significantly increased inflammation compared with saline injected muscle. The mature‐aged 12‐month old mice demonstrated greater injured area and enhanced inflammatory response, suggesting that even in mature mice, there is an increased susceptibility to muscle damage. These findings might have previously unforeseen consequences for older adults reaching middle age.Support or Funding InformationNIH R01 DK119066 and William N. Saunders Endowment in geriatric pharmacotherapy to (SMT). MB was partially supported by NIH‐National Institutes of Aging PO1 AG039355 (M.B.), and R01AG056504 and R01 AG060341 (M.B.), and the George W. and Hazel M. Jay and Evanston Research Endowments (MB).
Valproic Acid Upregulates The Expression of The Neurotrophin Receptor TrkC in Human Neuroblastoma Cells
Authors: Dedoni Simona , Marras Luisa , Olianas Maria C. , Ingianni Angela , Onali Pierluigi 
Published: April 2020

Preclinical and clinical studies have shown that the Trk receptors of neurotrophic factors play an important role in regulating the biological properties and the clinical evolution of neuroblastoma, the most frequent extracranial solid tumor in childhood. We have recently reported that treatment of retinoic acid (RA)‐differentiated human neuroblastoma cells with valproic acid (VPA) and other histone deacetylase (HDAC) inhibitors downregulates the expression and signaling of the BDNF receptor TrkB, a marker of unfavorable and aggressive neuroblastoma. In the present study we report that VPA, at therapeutically relevant concentrations, upregulates the expression of the neurotrophin 3 receptor TrkC in undifferentiated and RA‐differentiated SH‐SY5Y neuroblastoma cells. The exposure to VPA markedly increased the TrkC mRNA and the levels of the full length and truncated forms of TrkC protein. This change was associated with enhanced expression of TrkC at the plasma membrane, as indicated by cell surface biotinylation experiments and immunofluorescence assays in non permeabilized cells. The upregulation of TrkC was time‐dependent, being evident after 24 h of drug addition, and was accompanied by the emergence of apoptotic cell death. VPA increased the levels of the transcription factor RUNX3, a positive regulator of the NTRK3 gene encoding TrkC, and inhibition of this response by siRNA treatment attenuated the upregulation of TrkC. Moreover, pharmacological blockade of either ERK1/2 or JNK, but not p38MAPK, signaling pathways reduced VPA‐induced TrkC expression. VPA was found to induce TrkC also in MYCN‐amplified BE(2)C, NB‐1 and Kelly neuroblastoma cells and its effect was mimicked by other HDAC inhibitors, such as romidepsin and entinostat. These data indicate that VPA upregulates TrkC by activating a transcriptional programme involving epigenetic changes and MAPK signaling. As the expression of TrkC has been associated with a favorable outcome in neuroblastoma, the upregulation of this neurotrophin receptor may constitute an important component of the antineuroblastoma activity of VPA.Support or Funding InformationSardegna Ricerche‐Progetto IBERNAT‐NBL P.O.R. Sardegna 2014–2020, CUP F21B17000730005.
The effects of probiotic supplementation and eating a high fat diet on sensitivity of rats to the behavioral effects of methamphetamine
Authors: Sandoval Oscar , Alfsen Amanda , Beltran Nina , Serafine Katherine 
Published: April 2020

Eating a high fat diet can lead to obesity, insulin resistance, and can cause dysfunction to dopamine systems. For example, rats eating high fat laboratory chow are more sensitive than rats eating standard chow to the behavioral effects of drugs that act on dopamine systems (i.e., methamphetamine). Dietary supplementation with probiotics (including a combination of lactobacillus and bifidobacterium) has been shown to aid in digestion and decrease depressive‐like behavior among rats eating high fat chow. It is not known if probiotic supplementation can similarly decrease the effects of eating high fat chow on sensitivity of rats to the behavioral effects of dopaminergic drugs. To test the hypothesis that dietary supplementation with probiotics prevents high fat diet‐induced enhanced sensitivity to methamphetamine, rats eating standard chow (17% kcal from fat), high fat chow (60% kcal from fat), or eating standard or high fat chow with daily probiotic (1 billion CFU) supplementation were tested once weekly using cumulative doses of methamphetamine (0.1–3.2 mg/kg; i.p.) Dose‐response curves were analyzed using two‐way repeated measures ANOVAs using Tukey’s multiple post‐hoc comparisons tests where appropriate. After 5 weeks of testing, there were no significant differences in drug sensitivity to methamphetamine among rats eating different diets. Although the experiment is ongoing, previous literature suggests that sensitivity to methamphetamine will increase with continued testing (e.g., sensitization) and that rats eating high fat chow will be more sensitive to this effect than rats eating standard chow to drugs that act on dopamine systems.Support or Funding InformationO.S. is supported by the National Institute of General Medical Sciences of the National Institutes of Health (NIH) under R25GM069621. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.
Impact of Ampakine CX‐717 on Diaphragm EMG Activity and Breathing in Non‐anesthetized Freely Behaving Rats
Authors: Rana Sabhya , Sunshine Michael D. , Fuller David D. 
Published: April 2020

Glutamatergic neurotransmission is partly mediated by ionotropic AMPA receptors, and these receptors play an important role in the neural control of breathing. Ampakines are positive allosteric modulators of AMPA receptors. These drugs can stimulate breathing during hypo‐ventilated states, such as following an opioid overdose. Our laboratory has recently shown that acute exposure to an ampakine, CX717 (15 mg/kg), can acutely stimulate neural drive to the diaphragm in anesthetized but otherwise healthy rats. The goal of the current work is to evaluate the impact of ampakine on diaphragm muscle activation in freely moving non‐anesthetized rats. Ventilation and metabolic rate (VCO2) were measured using whole body plethysmography and diaphragm EMG was assessed using intramuscular electrodes. Spinally intact rats (n=2) were given a single intravenous bolus of CX717 at four months after implantation of diaphragm EMG electrodes. Delivering CX717 at 15 mg/kg had no detectable impact on VCO2, inspiratory tidal volume or diaphragm EMG burst amplitude. In addition, at 30 minutes following IV ampakine, both animals showed a robust increase in diaphragm EMG activity, tidal volume, and the ratio of ventilation VCO2 (VE/VCO2) during an acute hypoxic challenge (5 min, 10.5% inspired O2). Qualitatively, we observed a possible sedative effect as shown of lack of movement and exploratory behavior following ampakine exposure. Our preliminary conclusion is that ampakine CX717 at a dose of 15 mg/kg has little impact on breathing in the otherwise healthy rat. Ongoing studies are evaluating impact of the vehicle (2‐hydroxypropyl‐beta‐cyclodextrin) versus ampakine using a cross‐over study design in spinally intact rats and in rats with spinal cord injury.Support or Funding Information5 R01 HL139708 02 (DDF)F31 HL145831‐01 (MDS)
Detection of mRNA Encoding Organic Anion Transporters in Zebrafish Eyes
Authors: Coles-Ruiz Melanie , McIntosh Roxanne , García Dana M. 
Published: April 2020

The solute carrier 22 (slc22) family is a group of transmembrane proteins that specialize in the transport of organic ions. A sub‐category of slc22 consists of organic anion transporters (OAT) that transport cyclic nucleotides such as cyclic adenosine monophosphate (cAMP). In the process of light to dark adaptation of fish eyes, cAMP is hypothesized to be a regulatory signal between the photoreceptors and retinal pigment epithelium (RPE) that drives pigment granule aggregation in the latter. We hypothesize that cAMP is exported from the photoreceptors into the sub‐retinal space, and one of the slc22 OAT proteins imports cAMP into the RPE. To test this hypothesis, reverse transcription polymerase chain reaction (RT‐PCR) was used to test for the presence of mRNA encoding seven different OAT proteins (1, 2a, 2b, 2c, 2d, 2e and 3) in whole eyes from zebrafish. Messenger RNA encoding each of the OAT proteins was detected, corroborating results of earlier studies. Experiments are underway to test which of the OAT genes are expressed in isolated RPE. Identification of the OAT proteins in RPE is an important step in illuminating a novel signaling pathway.Support or Funding InformationThis project was supported by Texas State University in the form of an undergraduate research fellowship to MCR and funds from the Office of the Provost awarded to DMG in recognition of her service as Presidential Fellow.
Upregulation of G protein‐couple receptor 68 (GPCR68) in pulmonary artery smooth muscle cells from animals and humans with pulmonary hypertension
Authors: Rahimi Shamin , Babicheva Aleksandra , Rodriguez Marisela , Jain Pritesh , Rahimi Shayan , Yuan Jason X.-J. 
Published: April 2020

IntroductionPulmonary arterial hypertension (PAH) is a progressive and fatal disease with no cure. It is characterized by elevated pulmonary vascular resistance (PVR) and pulmonary arterial pressure (PAP) in part due to pulmonary vascular remodeling and sustained pulmonary vasoconstriction. The increased pulmonary arterial smooth muscle cell (PASMC) proliferation contributes to excessive pulmonary vascular remodeling while a rise in cytosolic free Ca2+concentration ([Ca2+]cyt) in PASMC is a major trigger for pulmonary vasoconstriction and a key stimulus for PASMC proliferation. G‐protein coupled receptors (GPCR), which are attractive pharmacological targets, are important regulators of pulmonary vascular tone and PASMC phenotype. Stimulation of GPCR leads to Ca2+ influx and increased [Ca2+]cytdue to store‐operated Ca2+ entry (SOCE) via inositol 1,4,5‐trisphosphate (IP3) production and receptor‐operated Ca2+entry (ROCE) via diacylglycerol (DAG) production. GPCR68 (or OGR1) is a proton‐sensing GPCR that responds to extracellular acidity and regulates a variety of cellular functions. As a Gq/11‐coupled receptor, GPR68 activation is known to lead to Ca2+ release from the intracellular stores in IP3‐dependent manner but the role of GPCR68 in the development of PAH is still unknown.MethodsLung, heart, brain, liver, and kidney tissues were isolated from control rats. Pulmonary hypertension model was induced by a single dose of monocrotaline (MCT) in rats. PASMC isolated from control or MCT rats and healthy subjects or patients with idiopathic pulmonary arterial hypertension (IPAH) were cultured in 5% fetal bovine serum (FBS) smooth muscle growth media and incubated in a humidified 5% CO2 atmosphere at 37°C. Total RNA was isolated from tissue or cells using TRIZOL method. mRNA expression of GPCR68 was quantified by RT‐PCR and qRT‐PCR. The data was analyzed using ImageJ and statistical analysis was performed using paired or unpaired Student’s t‐test.ResultsRT‐PCR analysis revealed that GPCR68 is expressed in brain, lung, heart, liver, and kidney in normal rat tissues (n=5). GPCR68 mRNA level was significantly higher in lung tissue and PASMC isolated from MCT‐treated rats compared with controls. Moreover, our data shows that GPCR68 is expressed in both human PASMC and pulmonary arterial endothelial cells. qRT‐PCR showed that GPCR68 was upregulated in PASMC isolated from IPAH patients compared with cells isolated from healthy subjects.ConclusionOur finding suggest that GPR68 is involved in the development and progression of PAH and may play an important role in Ca2+ signaling and enhanced [Ca2+]cyt in PASMC from animals and humans with PAH.Support or Funding InformationThis work was supported, in part, by grants from the National Heart, Lung, and Blood Institute of the National Institutes of Health (HL125208, HL135807, and HL126609).
Effects of Glyphosate on Locomotion and Anxiety‐like Behavior in Rats
Authors: Reyes-Sepúlveda Carlos Javier , Cáceres-Chacón Mauricio , Alvelo-Fernández Paola , Haddock-Martínez Hector , Ramos-Sánchez Raúl , Martínez-Guzmán Osmarie , Rivera-López Melissa , Sierra-Mercado Demetrio 
Published: April 2020

Glyphosate is the active ingredient in several commercial herbicides. The development of glyphosate‐resistant seeds has led to an increase in the use of glyphosate in agriculture. This has resulted in the exposure of non‐agricultural lands and bodies of water to glyphosate. Though initially considered safe for mammals, recent studies in rats have shown that administration of glyphosate leads to alterations in locomotion and anxiety‐like behavior. These studies generally used unrealistically high concentrations of glyphosate. Therefore, the effects of a dose of glyphosate considered safe by the Environmental Protection Agency through drinking water remain unclear. To determine if these levels affect locomotion and anxiety‐like behavior, we provided rats with access ad libitum to glyphosate‐contaminated drinking water or filtered water for four weeks. Glyphosate‐contaminated water was prepared for a target dose of 1.75mg/kg of glyphosate daily. We hypothesize that intake of glyphosate‐contaminated drinking water will decrease locomotion and increase anxiety‐like behavior. Locomotion was assessed in an open field. We observed that glyphosate did not decrease the overall distance travelled (control: 30.67m, glyphosate: 23.70m; p=0.058) nor did it affect average speed (control: 0.102m/s, glyphosate: 0.079; p=0.058). Anxiety‐like behaviors were also measured in the open field. Here, glyphosate did not increase the amount of entries to the center (control: 25.5, glyphosate: 27.5; p=0.726) nor time spent in the center (control: 74.22s, glyphosate: 87.9; p=0.572). In conclusion, this dose and exposure time of glyphosate did not affect locomotion or anxiety‐like behavior. Future directions include performing immunohistochemistry to assess neuronal activity in brain regions involved in locomotion and anxiety‐like behaviors.Support or Funding InformationYoung Investigator grant (NARSAD) of the Brain & Behavior Research Foundation, PRCTRC Pilot, NIGMS COBRE and RCMI8G12MD00760 to DS‐M; NSF PRCEN fellowships to CJR‐S, MC‐C, HH‐M, RR‐S and MR‐L, UPR Med Sci Campus Chancellor’s Office and School of Medicine Deanship.
Dietary salt and endothelin A receptor activation regulates T cell responses in a tissue‐dependent manner
Authors: Molina Patrick , Pollock Jennifer 
Published: April 2020

Numerous studies have investigated the role of high salt diet (HSD) by utilizing salt‐sensitive animal models or co‐administration with pro‐hypertensive insult. HSD is implicated in altering tissue‐dependent immunologic responses. Endothelin (ET‐1) is a major vasoconstrictor peptide synthesized in response to HSD. The ET‐1/endothelin A (ETA) receptor pathway has been implicated in regulating inflammatory responses, and to blunt the immunologic response with pro‐hypertensive conditions. However, the singular role of HSD on renal, colonic and splenic T cells is not fully understood. Therefore, we hypothesized that ETA receptor activation blunts T cell responses with HSD. Utilizing flow cytometry, we immunophenotyped renal, colonic, and splenic T cells in 12‐wk old male C57BL6/J mice provided normal salt diet (NSD, 0.4% NaCl food), ETA blockade (atrasentan, 10mg/kg/day) with NSD, HSD (4% NaCl food plus 1% NaCl drinking water), or co‐administration of atrasentan and HSD for 5 weeks. Kidneys, colons and spleens were collected for single cell suspensions. Isolated cells were stimulated followed by fluorescent antibody staining for flow cytometric analysis. Data are expressed as cell number means SEM (n=4/group) with statistical differences calculated by two‐way ANOVA with Tukey’s correction for multiple comparisons. HSD significantly blunted the total number of renal CD4+T cells mice compared to NSD as well as atrasentan treatment without further suppression of CD4+T cells under co‐administration of both HSD and atrasentan (NSD: 5217 619; Atrasentan: 1.8 0.15*; HSD: 2.4 0.32*; Atrasentan/HSD: 1.8 0.15*, x103, *p<0.001). Colonic CD4+T cells were similarly blunted under Atrasentan‐only and HSD‐only administration, without further reduction under co‐administration. However, splenic CD4+T cells were significantly expanded under chronic atrasentan administration (NSD: 2.66 1.45; Atrasentan: 7.63 0.61#; HSD: 6.63 0.69#; Atrasentan/HSD: 6.46 0.96#, x106, #p<0.05). We next examined IL‐17A production by CD4+T cells, which allows us to determine TH17 cells. Compared to NSD, HSD or atrasentan significantly blunted the total number of renal TH17 cells (NSD: 65 9; Atrasentan: 22 5*; HSD: 26 4*; Atrasentan/HSD: 20 3*, *p<0.001). Colonic TH17cells were similarly blunted. However, splenicTH17cells were seemingly unaffected under chronic atrasentan administration with similar results under HSD and combination of HSD/Atrasentan (NSD: 2.9 1.4; Atrasentan: 8.6 1.6; HSD: 7.6 2.8; Atrasentan/HSD: 5.5 1.6, x104, p>0.05). These findings suggest that HSD or ETA receptor activation may regulate T cell responsiveness in a tissue‐dependent manner.Support or Funding InformationU01HL117684, P01HL69999, AHA SFRN 24450002, P01HL136267, 1 F31 HL151264‐01
Disturbed blood flow acutely increases endothelial microparticles and decreases flow mediated dilation in patients with heart failure with reduced ejection fraction
Authors: Sales Allan Kluser , Oliveira Thiago O. , Mendonca Gustavo S. M. , Fonseca Guilherme , Braga Pedro G. S. , Rocha Helena N. M. , Rocha Natalia G. , Lima Marta F. , Negrao Carlos E. , Nunes Alves Maria Janieire N. 
Published: April 2020

IntroductionDisturbed blood flow, characterized by high retrograde and oscillatory shear rate (SR), is associated with a proatherogenic phenotype. The impact of disturbed blood flow in patients with heart failure with reduced ejection fraction (HFrEF) remains unknown. We tested the hypothesis that acute elevation to retrograde and oscillatory SR provoked by local circulatory occlusion would increase endothelial microparticles (EMPs) and decrease brachial artery flow‐mediated dilation (FMD) in patients with HFrEF.MethodsEighteen patients with HFrEF aged 55±2 years, with left ventricular ejection fraction (LVEF) 26±1%, and 14 healthy subjects aged 49±2 years with LVEF 65±1 randomly underwent experimental and control sessions. Brachial artery FMD (Doppler) was evaluated before and after 30 min of disturbed forearm blood flow provoked by pneumatic cuff (Hokanson) inflation to 75 mm Hg. Venous blood samples were collected at rest, after 15 and 30 min of disturbed blood flow to assess circulating EMP levels (CD42b−/CD31+;flow cytometry).ResultsAt rest, FMD was lower in patients with HFrEF compared with healthy subjects (p<0.001), but blood flow patterns and EMPs had no differences (p>0.05). The cuff inflation provoked a greater retrograde SR both groups (p<0.0001). EMPs responses to disturbed blood flow significantly increased in patients with HFrEF (p=0.03). No changes in EMPs were found in healthy subjects (p>0.05). Disturbed blood flow decreased FMD both groups. No changes occurred in control condition.ConclusionDisturbed blood flow acutely decreases FMD and increases EMP levels in patients with HFrEF. These findings suggest that patients with HFrEF are vulnerable to blood flow disturbances.Support or Funding InformationFAPESP Grants (2014/11671‐6 and
2017/25613‐6)
Impact of Premedical Anatomy Experience, its Perceived Benefit, and Study Effort on Student Performance in Medical Gross Anatomy
Authors: Goldenstein Allison J. , Howell Megan M. , Pazdernik Vanessa K. , Houser Jeremy J. 
Published: April 2020

Predicting medical student success in Gross Anatomy could be beneficial for implementing early interventions for those who may struggle. In our earlier studies, previous anatomy experience did not clearly explain differences in performance in Gross Anatomy. These previous studies failed to assess student perception of previous courses and how this may affect study habits. This current study investigated the effect of study effort in conjunction with premedical anatomy experience and the student‐perceived benefit of that course on their success in the medical Gross Anatomy course.Two surveys were administered to students. The first survey was distributed during orientation week prior to semester one inception. This survey covered the number, type, and level of anatomy courses taken prior to matriculation into medical school. Additionally, students were asked to rate the perceived benefit of the course for mastery of anatomical concepts and the potential benefit for success in medical Gross Anatomy. The second survey was administered during the first week of second semester, asking their average study efforts dedicated to lecture‐based and laboratory‐based examinations. These responses were matched with each student’s semester, lecture, and laboratory grades from the first semester of Gross Anatomy. Model selection methods determined final predictors for overall semester grade and grade on the first lecture exam. Tests for linear trends across increasing degrees of perceived benefit of their previous anatomy experience on their success in the Gross Anatomy course were performed.The best predictors were lecture effort and the perceived benefit of their previous anatomy experience on their success in the Gross Anatomy course. Given the same amount of effort, the more beneficial the student believed their previous anatomy courses were toward future success in the medical Gross Anatomy course, the better the Gross Anatomy course grade. This was true for those who responded that the course was ‘slightly beneficial’ (mean=0.81, SE=0.009) up to ‘very beneficial’ (mean=0.86, SE=0.007; P<.001). Likewise, controlling for the overall semester grade, among students who responded that the course was at least ‘slightly beneficial’ up to ‘very beneficial’, the lower the average study effort given on lecture examination study (‘slightly beneficial’ mean effort=0.87; ‘very beneficial’ mean effort=0.82; P=.002). These results were similar for the first lecture examination grade.Prior anatomy experience alone does not predict success in medical Gross Anatomy. However, a student who perceives more benefit from a previous anatomy course will generally put in less effort to attain a particular grade in Gross Anatomy. As this model of prediction is the same for the first lecture exam, early interventions may be implemented to minimize poor performance.