bluuebunny/crossref_metadata_2025_split huggingface dataset:
Renin‐angiotensin‐aldosterone system blockade ameliorates myocardial and ventricular function of rats with diabetes mellitus
Authors: Pagan Luana , Gimenes Rodrigo , Damatto Ricardo , Cezar Marcelo , Rosa Camila , Nunes Marcela , Damatto Felipe , Campos Dijon , Gomes Mariana , Bonomo Camila , Okoshi Marina , Okoshi Katashi 
Published: June 2021

The objective of this study was to evaluate the influence of renin‐angiotensin‐aldosterone system (RAAS) blockade with losartan (LOS) on cardiac structure and function of rats with diabetes mellitus (DM).MethodsMale Wistar rats with 300 g body weight were divided into four groups: control (CTL, n=20), CTL+LOS (n=22), diabetic (DM, n=24), and DM+LOS (n=18). DM was induced by streptozotocin; LOS was diluted in drinking water and administered for 8 weeks. Arterial pressure (AP) was measured by tail‐cuff method. Echocardiogram (Echo) was performed to evaluate in vivo cardiac structures and left ventricular (LV) function. In vitro myocardial function was analyzed in LV papillary muscle. Statistics: Variables were compared by ANOVA (p<0.05).ResultsAP was lower in DM+LOS compared to the DM group (103±15 vs 120±15 mmHg). The in vitro functional study showed better myocardial performance in DM+LOS vs. DM group (developed tension ‐ DT: 7.32±2.00 vs. 5.90±1.29 g/mm2;p<0.05). Echo showed greater LV diastolic diameter (CTL: 8.05±0.54; CTL+LOS: 8.11±0.46; DM: 8.42±0.31; DM+LOS: 8.14±0.42 mm) and left atrial (LA) diameter (LA/aorta ‐ CTL: 1.34±0.09; CTL+LOS: 1.33±0.11; DM: 1.50±0.11; DM+LOS:1.51±0.13) in DM groups, and lower LV diastolic diameter in DM+LOS vs. DM group. LV systolic (mitral annular velocity by tissue Doppler) and diastolic function (isovolumic relaxation time and tissue Doppler Em/Am ratio) was impaired in DM group and improved by LOS.ConclusionThe RAAS blockade improves myocardial and ventricular function in diabetes mellitus rats. Support: CNPq and CAPES.
Day‐to‐day Variability in Arterial Diameter and Brachial Artery Flow‐Mediated Dilation in Sedentary Young Men and Women
Authors: Shenouda Ninette , Skelly Lauren , Gibala Martin , MacDonald Maureen 
Published: June 2021

Brachial artery flow‐mediated dilation (FMD), an index of endothelial function, is predictive of cardiovascular disease risk. A wide range of FMD day‐to‐day variability has been reported, but whether this variability differs between men and women is unknown. We examined potential sex‐based differences in FMD and its day‐to‐day variability. Sedentary but otherwise healthy men (N=10, age: 22±3 years) and women (N=7, age: 21±2 years) completed two brachial FMD tests 24 hours apart. Women were tested during the mid‐follicular phase of their menstrual cycle (days 7‐12). Baseline arterial diameter (ADBL) and maximum reactive hyperemia diameter (ADRH) were determined, and relative FMD was calculated as FMD% = (ADRH–ADBL)/ADBL. Day 1 measures and between‐day differences were assessed with independent t‐tests. Day‐to‐day variability was assessed with the coefficient of variation (CV) and intraclass correlation coefficient (ICC). Compared to men, women had smaller arterial diameters (p<0.05), but a similar FMD response (p=0.828). No sex‐differences were observed in between‐day differences for any measures (p>0.05). Day‐to‐day variability was low for AD in both sexes (CV of 3‐5%), but high for FMD (men: 43%, women: 55%). Similarly, ICCs were substantial to almost perfect for AD in both sexes (ICC of 0.77‐0.92), but poor for FMD (men: 0.01, women: 0.07). These findings suggest that arterial diameter exhibits better day‐to‐day repeatability than relative FMD in both men and women. Despite women having greater FMD variability than men, between‐day differences were not statistically significant. A larger sample size may be required to detect potential sex‐differences.Funded by NSERC, OGS and GSSI.
Dietary Sodium Loading Increases Central Systolic Blood Pressure More in Middle‐Aged Compared to Young Salt Resistant Adults
Authors: Muth Bryce , Brian Michael , Matthews Evan , Ramick Meghan , Lennon‐Edwards Shannon , Farquhar William , Edwards David 
Published: June 2021

Excess dietary sodium intake has been linked to increased incidence of cardiovascular disease and the development of hypertension. We sought to determine the effect of short‐term dietary sodium loading on central blood pressure in young (YG; n=46, 26±1 yrs) and middle‐aged (MA; n=27, 51±1 yrs) normotensive, salt resistant adults. Subjects were randomized to 7 days of low sodium (LS: 20 mmol/d) and 7 days of high sodium (HS: 300 mmol/d). Salt‐resistance was defined as mean 24‐hour MAP change 蠄5 mmHg between diets (LS: 87±1 vs. HS: 86±1 mmHg, p > 0.05). On the last day of each diet, carotid‐femoral pulse wave velocity (PWV) and the synthesis of a central aortic pressure waveform (by radial artery applanation tonometry and generalized transfer function) and wave separation analysis were performed. When compared to the LS diet, the HS diet elicited an increase in central systolic blood pressure (cSBP) in both YG (LS: 95±1 vs. HS: 98±1 mmHg, p < 0.05) and MA (LS: 107±2 vs. HS: 116±3 mmHg, p < 0.05), with a larger increase seen in MA (YG: 3±1 vs. MA: 9±2, p < 0.05). In MA, HS elicited greater central forward wave amplitude (LS: 26±1 vs. HS: 30±1 mmHg, p < 0.05) and central reflected wave amplitude (LS: 18±1 vs. HS: 22±1 mmHg, p < 0.05) but no difference was seen in YG. PWV was not altered by 7 days of HS in either group (p>0.05). These data suggest that higher sodium intake is associated with a greater increase in cSBP in MA compared to YG adults that may be due to increases in forward and reflected wave amplitudes.Supported by NIH Grant R01 HL104106
Schild Analysis of In Vivo Theophylline Antagonism of Adenosine in Fetal Sheep Coronary Arteries
Authors: Jonker Sonnet , Giraud George , Louey Samantha 
Published: June 2021

Adenosine causes near‐maximal vasorelaxation of fetal coronary arteries but adenosine receptor antagonism in this bed has not been characterized. We performed Schild analysis of theophylline (adenosine antagonist with similar affinity for receptors A1, A2a and A2b) in near‐term fetal sheep coronaries. Fetuses (n=4) were instrumented with vascular catheters and a circumflex transit‐time flow probe. Vascular pressures (corrected to amniotic pressure) and coronary flow (corrected to driving force) were recorded continuously. Heart rate was controlled with propranolol and atropine. Theophylline (bolus then continuous infusion) was given into the right atrium. Graded infusions of adenosine into the left atrium stimulated increased coronary flow. Theoretical adenosine concentrations were calculated from infusion rates and assumed left ventricular output; theophylline concentrations were measured in arterial blood. The plateau was constrained at 100% of adenosine‐stimulated coronary flow, while the floor was unconstrained, allowing for theophylline suppression of baseline flow due to endogenously produced adenosine. Log(EC50), pA2, Schild and Hill slopes were constrained to share values within one fetal experiment. Schild analysis yielded a mean global R2=0.98, EC50=0.88±0.41uM(sd), Hill slope=2.5±0.4, Schild slope=0.94±0.63 and pA2=4.8±0.4. A Schild slope close to 1 indicates theophylline acts as a competitive antagonist of adenosine in the fetal coronaries in this dose range, thus pA2=pKb. These data suggest that maternal methylxanthine consumption may alter fetal coronary perfusion.Supported by NICHD R01HD071068 and P01HD034430.
Protective effects of melatonin against ischemic neuronal damage in rats with transient focal cerebral ischemia
Authors: Won Jinyoung , Lee Seunghoon , Park Sookyoung , Hong Yonggeun 
Published: June 2021

BackgroundThe neurohormone melatonin may prevent neuronal cell death caused by neurodegenerative diseases. Purpose: Using a transient cerebral ischemic model (MCAO), we assessed the neuroprotective effect of melatonin in an ischemic region. Results: In this study of efficacy, experimental animals were subjected to MCAO for 60 min, and then given melatonin (injected at 5 mg/kg). The following three groups were formed: (1) control group (MCAO vehicle); (2) melatonin pre‐treatment group (injected intraperitoneally 5 min prior to MCAO and again 1 h post‐occlusion); and, (3) melatonin post‐treatment group (injected subcutaneously [twice daily] post‐MCAO onset for 3 days). In melatonin‐treated ischemic rats, brain infarction was reduced 3 days post‐MCAO surgery compared with controls, and physiological and neurological features differed, including molecular changes associated with cell death. Significant decreases in p53, Bax, caspase‐6, and LC3 expression levels were observed in the melatonin pre‐ and post‐treatment groups (P < 0.05). Suggestion: The brain morphological and molecular changes indicate that melatonin is associated with neurogenesis and confers protection against neuronal cell death.Funding: 2012R1A1A2005089, 2013R1A2A2A01067169, KGM4611512, 2014R1A1A3051724
Variant Specific Cleavage of the Na+‐Ca2+ Exchanger NCX3 During Excitotoxicity
Authors: Michel Lauriane , Hoenderop Joost , Bindels René 
Published: June 2021

Recent studies highlighted the crucial role of the Na+‐Ca2+ exchanger isoform 3, NCX3, during stress exposure, allowing for a significant Ca2+ entry in neuronal cells. Consequently, the hyperfunctionality of NCX3 triggered via its cleavage by the calpain protease, is considered to play a neuroprotective effect in numerous pathologies such as Alzheimer's disease and ischemia.NCX3 family contains three variants hypothesized to carry diverse capacity of exchange.We aimed in dissecting the molecular mechanisms responsible for NCX3 cleavage during excitotoxicity.The capacity of exchange of each variant expressed in HEK293T cells was measured by recording single cell [Ca2+]i in response to Na+ removal. Additionally, the influence of calpain on NCX3 was investigated using overexpression of the endogeneous inhibitor, Calpastatin, and silencing of the calpain family.We observed that the variants containing the exon B, NCX3‐B and NCX3‐BC, are predominantly expressed in the brain. Measurements of NCX3 revealed a significant decrease in the capacity of exchange of NCX3‐AC and NCX3‐BC during overexpression of Calpastatin. A similar effect was observed by silencing calpain‐1. Site‐directed mutagenesis was performed on a hypothesized cleavage site for calpain located in the exon C of NCX3. The mutation of L600 and L601, at the cleavage site, caused a loss of hyperfunctionality, as observed during the silencing of calpain‐1.Calpain activity triggers an increase in the capacity of exchange of NCX3. However only the variants containing the exon C, NCX3‐AC and NCX3‐BC, are sensitive to calpain cleavage. The predominant expression of NCX3‐BC observed in the brain together with the identification of the cleavage site in NCX3 allows for potential drug design targeting these specific residues.
Effects of Melatonin on Neural Reconstruction and Motor Recovery through Regulation of Endoplasmic Reticulum Stress Response and Autophagy in Spinal Cord Injured Animal
Authors: Jin Yunho , Park Sookyoung , Hong Yonggeun 
Published: June 2021

Autophagy and endoplasmic reticulum (ER) stress response are known to cause improved motor function and reduced damage of axons after spinal cord injury. This study aims to elucidate the effects of melatonin treatment on neural reconstruction and motor recovery through regulation of ER stress response and autophagy. Expression of neural and autophagic markers at mRNA level increased in injured experimental animals. And much higher increase of those markers was observed when treated with melatonin. Especially, at day 3, 28 after SCI, NG2 expression was increased at the injured site when treated with melatonin (p<.05). With melatonin treatment, LC3 expression was also increased at day 28 after surgery (p<.05). There was a tendency for spinal cord injured groups and melatonin‐treated groups to show increased ER stress response markers, when compared with the expression of non‐injured groups and non‐melatonin‐treated groups, respectively. Furthermore, more axonal sprouting and relatively intact morphology were observed in melatonin‐treated groups. Locomotor function was also improved when treated with melatonin. In conclusion, melatonin treatment promoted the neural reconstruction of both neuronal and glial cells. It also reduced autophagic cell death and, consequently brought improved locomotor function.Funding : 2012R1A1A2005089, 2013R1A2A2A01067169, KGM4611512, 2014R1A1A3051724
Exercise increases stem cell retention and exercise capacity post‐MI
Authors: Chirico Erica , Muthukumaran Geetha , Ding Dennis , Houser Steven , Starosta Tim , Mu Anbin , Margulies Kenneth , Libonati Joseph 
Published: June 2021

Stem cell therapy for myocardial infarction (MI) has been shown to improve cardiac function and reduce infarct size. Exercise training, in the form of cardiac rehabilitation, is an essential part of patient care post‐MI. Hence, we tested the effects of acute and chronic aerobic exercise training on stem cell retention and cardiac remodeling post‐MI.Small epicardial MIs were induced in 12 month old C57BL/6 mice via cryoinjury. 2‐weeks post MI, GFP+ bone marrow derived cells (BMC) were injected (tail vein) immediately after acute exercise (N=14) or sedentary conditions (N=14). A subset of mice continued a 5 week intervention of chronic treadmill exercise (10‐13 m/min; 45 mins/d; 4 d/wk; N=7) or remained sedentary (N=6). Exercise tolerance was assessed with a graded exercise test and cardiac function with echocardiography.One bout of acute aerobic exercise increased GFP+ BMC retention in the infarcted zone of the heart by over 30% relative to sedentary conditions (P<0.05). This effect was not recapitulated with dobutamine infusions in resting animals. Chronic exercise training increased exercise capacity (95% vs sedentary, P<0.05) and cardiac mass (P<0.05), but did not alter LVEF or infarct size (P=NS). There was a significant inverse correlation between exercise tolerance and wet:dry lung weight (r=‐0.55, p = 0.02).We conclude that acute aerobic exercise increases BMC retention in infarcted hearts. While chronic exercise training following stem cell therapy increased cardiac remodeling and exercise capacity, training did not alter the effects of BMC on resting cardiac function or infarct size.
Hemodynamic Responses to Mild Warming during Simulated Hemorrhage
Authors: Poh Paula , Gagnon Daniel , Romero Steven , Petruzzello Steven , Convertino Victor , Crandall Craig 
Published: June 2021

Warming a hemorrhaging victim is the standard of care. However, heating can be detrimental to the maintenance of arterial pressure and cerebral perfusion.PurposeTo test the hypothesis that moderately warming a normothermic individual can be detrimental to the maintenance of arterial pressure and cerebral perfusion during a hemorrhagic insult.MethodsFive men (age, 33 ± 9 y) underwent the following repeated measures design: following 15 min of supine rest, 10 min of 30 mmHg of lower body negative pressure (LBNP) was applied to simulate a moderate hemorrhagic challenge while subjects were normothermic. With LBNP continuing, subjects were exposed to warming (mean skin temperature (Tsk): 36.8 ± 0.4°C), skin surface cooling (Tsk: 29.7 ± 1.2°C), or thermoneutral (Tsk: 33.4 ± 0.4°C) for 40 min via water perfused suit.ResultsInteraction between the thermal perturbation and LBNP time did not reveal statistically distinguishable changes in blood pressure (P = 0.15), cardiac output (P = 0.14), stroke volume (P = 0.74) or cerebral perfusion (P = 0.13). However, the elevation in heart rate was greater (P = 0.01) during warming (22 ± 6 bpm) relative to cooling (7 ± 10 bpm) and thermoneutral (10 ± 6 bpm) conditions.ConclusionsThese preliminary data suggest that mild warming during the applied level of simulated hemorrhage does not compromise arterial blood pressure or cerebral perfusion. It remains unknown whether mild warming would be detrimental during a more profound hemorrhagic challenge.
Genomic Editing of Stem Cells for Modeling and Therapy of Genetic Diseases
Authors: Menon Tushar , Firth Amy , Scripture‐Adams Deirdre , Parker Greg , Gilmore William , Lewis Benjamin , Qualls Susan , Zack Jerome , Verma Inder 
Published: June 2021

The application of advanced genome editing technologies, when combined with induced pluripotent stem cells (iPSC), presents a unique opportunity to develop unprecedented patient‐specific in vitro models of disease‐in‐a‐dish that can be used for the development of more effective and universal stem cell therapies. Towards this aim, we have corrected SCID‐X1 patient‐derived iPSC using TALENs, resulting in the rescue of defective IL2RG expression and in the recovered generation of lymphoid cells derived from these iPSC. We have also corrected the common ΔF508 mutation of CFTR in cystic fibrosis patient‐derived iPSC using a novel, efficient, footprint‐free CRISPR‐mediated approach, and shown the subsequent functional recovery of CFTR function in airway epithelium derived from the corrected iPSC.However, the inability to derive truly transplantable cell types from iPSC limits the long‐term clinical and therapeutic potential of this approach. To address this we have carried out direct CRISPR‐mediated gene correction of CD34+ hematopoietic stem cells (HSC) from the FoxP3 mutant scurfy (sf) NOD mouse, which is defective for the development of regulatory T‐cells. These directly gene‐edited FoxP3sf HSC can then be evaluated for their potential for long‐term engraftment and regeneration of regulatory T‐cells by transplantation into lethally irradiated recipient mice. The ultimate goal is to establish novel pre‐clinical models for stem cell‐based therapy for a variety of genetic disorders.
Poly‐amido‐saccharides (PASs): Characterization of the Secondary Structure and Protein Interactions
Authors: Blessing William , Chin Stacy , Dane Eric , Grinstaff Mark 
Published: June 2021

Natural polysaccharides are of significant interest in chemistry and biochemical research because of their structural diversity and essential roles in physiological processes. Many proteins are known to interact with natural carbohydrates to illicit a physiological or metabolic response. Challenges of studying these responses stem from obtaining the carbohydrate polymers, especially of high molecular weights. Currently, they must be extracted, which can introduce variation between samples and require extensive purification. We have developed a method using anionic ring‐opening polymerization to synthesize high‐yields of enantiopure carbohydrate‐based polymers: poly‐amido‐saccharides (PASs). PASs can be synthesized with consistency, defined molecular weights, low polydispersity, and high functionalization.PASs contain the distinct chiral, cyclic main‐chain structure and pyranose backbone and are joined by an unnatural α‐(1,2)‐amide linkage, which affords PASs with unique chemical properties and structures. The helical structure of PASs elucidated through circular dichroism equips PASs with a multitude of potential functionalities including protein stabilization. This is crucial to investigate protein‐carbohydrate interactions that are necessary for protein stability. Here, we will describe how the structure of PASs contributes to its capability to stabilize proteins by comparing PASs derived from glucose and galactose based monomeric units and a mixture of both monomeric units. Furthermore, we will use PASs as a novel synthetic tool to mimic and probe carbohydrate‐protein‐mediated processes such as binding with lectin concanavalin A and galactose receptor‐mediated endocytosis.
Gene expression and coexpression alterations marking evolution of bladder cancer
Authors: Stroggilos Rafael , Frantzi Maria , Zoidakis Jerome , Mavrogeorgis Emmanouil , Mokou Marika , Roubelakis Maria G , Mischak Harald , Vlahou Antonia 
Published: June 2021

ABSTRACTDespite advancements in therapeutics, Bladder Cancer (BLCA) constitutes a major clinical burden, with locally advanced and metastatic cases facing poor survival rates. Aiming at expanding our knowledge of BLCA molecular pathophysiology, we integrated 1,508 publicly available, primary, well-characterized BLCA transcriptomes and investigated alterations in gene expression with stage (T0-Ta-T1-T2-T3-T4). We identified 157 genes and several pathways related prominently with cell cycle, showing a monotonically up- or down-regulated trend with higher disease stage. Genome wide coexpression across stages further revealed intrinsic and microenvironmental gene rewiring programs that shape BLCA evolution. Novel associations between epigenetic factors (CBX7, ZFP2) and BLCA survival were validated in external data. T0 together with advanced stages were heavily infiltrated with immune cells, but of distinct populations. We found AIF1 to be a novel driver of macrophage-based immunosuppression in T4 tumors. Our results suggest a continuum of alterations with increasing malignancy.
Tachycardia evoked from insular stroke in rats is dependent on glutamatergic neurotransmission in the dorsomedial hypothalamus
Authors: Marins Fernanda Ribeiro , Limborço‐Filho Marcelo , Iddings Jennifer A. , Xavier Carlos Henrique , Biancardi Vinicia C. , Stern Javier E. , Ramiro Diaz Juan , Oppenheimer Stephen M. , Filosa Jessica A. , Peliky Fontes Marco Antônio 
Published: June 2021

AbstractBackground and purposeDamage to the insula results in cardiovascular complications. In rats, activation of N‐methyl‐d‐aspartate receptors (NMDARs) in the intermediate region of the posterior insular cortex (iIC) results in sympathoexcitation, tachycardia and arterial pressure increases. Similarly, focal experimental hemorrhage at the iIC results in a marked sympathetic‐mediated increase in baseline heart rate. The dorsomedial hypothalamic region (DMH) is critical for the integration of sympathetic‐mediated tachycardic responses. Here, whether responses evoked from the iIC are dependent on a synaptic relay in the DMH was evaluated.MethodsWistar rats were prepared for injections into the iIC and DMH. Anatomical (tracing combined with immunofluorescence) and functional experiments (cardiovascular and sympathetic recordings) were performed.ResultsThe iIC sends dense projections to the DMH. Approximately 50% of iIC neurons projecting to the DMH express NMDARs, NR1 subunit. Blockade of glutamatergic receptors in the DMH abolishes the cardiovascular and autonomic responses evoked by the activation of NMDARs in the iIC (change in mean arterial pressure 7 ± 1 vs. 1 ± 1 mmHg after DMH blockade; change in heart rate 28 ± 3 vs. 0 ± 3 bpm after DMH blockade; change in renal sympathetic nerve activity 23% ± 1% vs. −1% ± 4% after DMH blockade). Experimental hemorrhage at the iIC resulted in a marked tachycardia (change 89 ± 14 bpm) that was attenuated by 65% ± 5% (p = 0.0009) after glutamatergic blockade at the DMH.ConclusionsThe iIC‐induced tachycardia is largely dependent upon a glutamatergic relay in the DMH. Our study reveals the presence of an excitatory glutamatergic pathway from the iIC to the DMH that may be involved in the cardiovascular alterations observed after insular stroke.