bluuebunny/crossref_metadata_2025_split huggingface dataset:
Vacuolar proton pump a4 subunit is critical for inner ear development and renal function
Authors: Picard Nicolas , Hennings Jean‐Christopher , Huebner Antje , Stauber Tobias , Maier Hannes , Brown Dennis , Jentsch Thomas , Vargas‐Poussou Rosa , Eladari Dominique , Huebner Christian 
Published: June 2021

Renal distal tubular acidosis (dRTA) has been associated with human ATP6V0A4 (a4 subunit of the proton pump) gene mutations. This disease is characterised by acidic blood pH, low blood bicarbonate and potassium concentrations, and often, hypercalciuria leading to nephrocalcinosis. Some patients with ATP6V0A4 mutations also develop late onset senso‐neurinal deafness.We generated a mouse model deficient for the a4 subunit. Survival rate of KO mice was dramatically reduced and did not exceed 7–8 weeks of age. Mouse deficient for the Atp6v0a4 gene (a4−/−) recapitulated most of the renal impairment seen in patients with dRTA since they exhibited life‐threatening metabolic acidosis consecutive to a marked reduction in renal acidification capacity. This was associated with complete hearing loss associated with a strong enlargment of the endolymphatic sac of the inner ear. In the kidney, a4 subunit has been localised in the proximal tubule and in the intercalated cells of the collecting duct which are two renal segments involved in acid‐base balance. Histo‐morphological analysis of a4−/− mouse kidneys revealed a profound lysosomal remodelling in the proximal tubule associated with an abnormal trafficking of the proton pump in both proximal tubule and intercalated cells. Their low molecular weight proteinuria was explained by a general proximal tubule dysfunction. We conclude that A4 subunit is a mandatory component for the assembly of the vacuolar proton pump ATPase complex and is critical for inner development, distal acidification and proximal tubule absorptive capacity.
Testosterone increases muscle sympathetic nerve activity in young healthy males
Authors: Miner Jonathon Cory , Miner Jennifer Ann , Kaplan Paul F. , Minson Christopher Todd 
Published: June 2021

A positive correlation between levels of testosterone and muscle sympathetic nerve activity (MSNA) has been found in women with polycystic ovarian syndrome, and is associated with cardiovascular risk factors. However, testosterone has been shown to be cardio‐protective in male rats. To date, we are unaware of any studies that have tested the direct impact of testosterone administration on MSNA in young, healthy males. The purpose of the current study was to examine the acute effects of short‐term testosterone administration on MSNA on this demographic.MethodsMSNA (via microneurography), heart rate, and beat‐by‐beat blood pressure were recorded following a venous blood draw for baseline testosterone levels in four young, healthy male subjects. After assessing resting measures, each subject self‐administered 120 mg/day of transdermal testosterone for seven days and were then retested. We analyzed MSNA frequency (bursts min−1) and incidence (bursts 100 heartbeats−1).ResultsTestosterone level increased in all subjects (676±47 ng/dl to 774±16 ng/dl). Increased levels of total testosterone tended to increase MSNA frequency, (11±3 to 15±1, p=0.10) and incidence (22±4 to 27±3, p=0.18).ConclusionShort‐term, transdermal testosterone administration tends to increase MSNA frequency and incidence in young, healthy males. Supported by NIH Grant HL081671.
Impaired hypoxic vasodilation in healthy older adults: role for altered sympatho‐adrenal control of vascular tone
Authors: Richards Jennifer Clarke , Crecelius Anne R. , Kirby Brett S. , Garcia Leora J. , Luckasen Gary J. , Larson Dennis G. , Dinenno Frank A. 
Published: June 2021

We tested the hypothesis that peripheral vasodilation to graded systemic hypoxia (90, 85, 80% SaO2) is impaired in older healthy adults due to attenuated β‐adrenergic mediated vasodilation and elevated α‐adrenergic vasoconstriction. Forearm blood flow was measured (Doppler ultrasound) and vascular conductance (FVC) was calculated in 12 young and 8 older adults to determine the dilatory response to hypoxia in control, local (brachial artery catheter) β‐blockade (propranolol), and combined α+β blockade (phentolamine+propranolol) conditions. Compared to young, older individuals exhibited impaired vasodilation to hypoxia (peak Δ+35±8% vs. +9±6 %ΔFVC P<0.05). Following β‐blockade, older adults actively constricted (−14±5%ΔFVC) whereas the young response was not significantly impacted. α+β blockade increased the dilatory response to hypoxia in both groups, however the dilatory response remained significantly greater in young compared with the old (+58±11% vs.+17±11%ΔFVC P<0.05). Our findings indicate that hypoxic vasodilation is significantly impaired in older adults and this can be attributed to lower β‐receptor mediated dilation, elevated α‐adrenergic constriction and lower local vasodilatory signaling. These findings may have implications for understanding regional blood flow control in aging patient populations that exhibit systemic and/or local hypoxia.Supported by HL102720
Role of NOS in early‐stage BBB disruption following transient focal cerebral ischemia
Authors: Jiang Zheng , Li Chun , Arrick Denise M. , Yang Shu , Sun Hong 
Published: June 2021

BackgroundEarly‐stage BBB disruption following ischemic stroke is an antecedent event to infarction and hemorrhagic transformation. We determined the role of NOS in early‐stage BBB disruption using a new model of transient focal cerebral ischemia.MethodsA cranial window was prepared over the left parietal and temporal cortex of C57BL/6J mice. To induce ischemia, the MCA was ligated at M2 segment just proximal to its bifurcation for 2 hours. Reperfusion was induced by releasing the ligation. L‐NAME, L‐NPA, 7‐NI and aminoguanidine alone or with papaverine were topically perfused to the cranial window during the reperfusion. The cerebral vasculature was imaged at 5, 10, 30, 60, 90, 120, 150 and 180 minutes of reperfusion and diameter change in all branches of the MCA, anastomosis and terminal branches of the collateral arteries were calculated. BBB disruption was assessed by measuring extravasation of Evans Blue (EB) and sodium fluorescein (Na‐F) at 3 hours of reperfusion.ResultsL‐NAME abolished reperfusion‐induced vasodilation in all branches of the MCA, anastomosis and terminal branches of the collateral arteries, whereas L‐NPA, 7‐NI and aminoguanidine only inhibited the vasodilation in large size branches of the MCA and anastomosis. On the other hand, L‐NAME, L‐NPA, 7‐NI and aminoguanidine all reduced extravasation of EB and Na‐F. In addition, papaverine abolished L‐NAME‐induced reduction in extravasation of Na‐F.ConclusionsAll three types of NOS may contribute to early‐stage BBB disruption directly and indirectly via NOS‐mediated hyperemia following transient focal cerebral ischemia.
Role of Fibrinogen in Traumatic Brain Injury
Authors: Muradashvili Nino , Tyagi Reeta , Benton Richard L. , Lominadze David 
Published: June 2021

Elevated level of fibrinogen (Fg) ‐ hyperfibrinogenemia (HFg) exacerbates circulatory complications during inflammatory diseases such as stroke, hypertension, traumatic brain injury (TBI). We already showed that HFg alters vascular reactivity and compromises endothelial cell layer integrity causing a leakage of plasma substances into the interstitium. We tested the hypothesis that TBI increases Fg deposition and cerebrovascular permeability in injury penumbra through activation of matrix metalloproteinase‐ 9 (MMP‐9).Permeability of pial venules and Fg deposition in injury penumbra formed after a mild cortical contusion injury (CCI) were studied in wild type (WT, C57BL/6J) and MMP‐9 gene knockout (MMP9−/−) mice. Fg deposition and formation of caveolae, examined by the extent of co‐localization of caveolin‐1 and plasmalemma vesicle‐associate protein‐1 were assessed in brain cryo‐sections. In each group, BSA leakage, caveolae formation, and Fg deposition were increased after CCI compared to those in respective sham‐operated mice. However, they were greater in WT than in MMP9−/− mice.These data suggest that blood level of Fg is elevated after TBI and its increased deposition intensifies cerebrovascular protein leakage mainly through caveolar transcytosis via activation of MMP‐9. The results of our study point to a new therapeutic targets that can be used to assist the post‐TBI healing process.
Control of feeding behavior by CRH 2 receptors in the paraventricular nucleus of the hypothalamus of adrenalectomized rats
Authors: Rito‐Domingo Melisa , Alonso Verónica Elsa López , Santos Karla Araceli Reyes , Segundo Gabriela Ambrocio , García Karina Cruz , Díaz Juan Manuel Mancilla 
Published: June 2021

The Corticotropin releasing hormone (CRH), play an important role in the normal maintenance of food intake, body weight and energy metabolism. CRH is a powerful inhibitor of feeding. Urocortin 2 (Ucn 2) a CRH like peptide mediate this effect through CRH 2 receptors expressed in the paraventricular nucleus of the hypothalamus (PVN), but it is not yet know the behavior mechanism and effect on glucose and triglycerides, that acts in the presence of agonist Ucn 2 and antagonist Antisauvagine 30 (Asv 30). The aim of the present study was determinate the role of CRH 2 receptors in food intake feeding behavior and in concentration of glucose and triglycerides of adrenalectomized Wistar rats. 34 male rats of Wistar strain of 250–300 g were accustomed to a diet of separate sources of protein, carbohydrate and fat, then were implanted a cannula on right PVN and a second surgery to remove the adrenal glands bilaterally (ADX) or sham surgery (sham). After the post‐surgery recovery period of 5 days, the rats were assigned to a group and a treatment, sham (vh+vh), ADX (vh+vh), ADX Agonist (vh+Ucn 2), ADX antagonist (Asv 30+vh) and ADX pretreatment (Asv 30+Ucn 2). A record of continuous duration of 60 min was made for the analysis of the behavioral satiety sequence (BSS). The results showed that administration of Ucn 2 reduced carbohydrates intake and promotes the transition of feeding and resting in the BSS, The pretreatment with Asv‐30 delayed the transition of feeding and resting. The glucose and triglycerides concentration decrease with the administration of Ucn‐2 and the antagonist reverse this effect. In conclusion the results of this study suggest that CRH 2 receptors of the PVN are important for the regulation of feeding, glucose and triglycerides in adrenalectomized rats.Research support: DGAPA IN306711
Heat production per unit mass determines the core temperature response to exercise in compensable conditions
Authors: Cramer Matthew N. , Jay Ollie 
Published: June 2021

We hypothesized that the change in core temperature during exercise in compensable conditions is determined by heat production per unit mass (W/kg), and not absolute heat production (W) or the percentage of peak oxygen uptake (%VO2peak). Nine heat‐acclimated males of high (HI: 89.1±6.3 kg, n=6) or low (LO: 67.2±5.7 kg, n=3) body mass cycled at 500 W, 6.5 W/kg, and 9.0 W/kg in 25°C, as well as 9.0 W/kg in 35°C. Heat production was estimated using indirect calorimetry, and rectal temperature (Tre) was measured throughout. At 500 W (HI: 5.7±0.1 W/kg, LO: 7.3±0.2 W/kg; p<0.001), the change in Tre (ΔTre) was greater in LO (HI: 0.51±0.06°C, LO: 0.96±0.10°C; p=0.007) despite similar %VO2peak (HI: 45±3%, LO: 47±1%; p=0.573). At all W/kg, ΔTre was not different between groups, yet %VO2peak was greater in HI at 6.5 W/kg (HI: 50±3%, LO: 42±1%) and 9.0 W/kg (HI: 67±2%, LO: 57±3%). A similar ΔTre was observed within each group at 9.0 W/kg in 25°C and 35°C (p>;0.05). In summary, our data suggest core temperature responses between participants in compensable conditions should be compared by administering exercise intensity based on heat production per unit mass, not absolute heat production or %VO2peak.Supported by a NSERC Discovery Grant (O. Jay)
Autonomic Function Assessed with Heart Rate Variability in Everest Climbers
Authors: Marck Jan Willem , Issa Amine , Taylor Brian , Summerfield Doug , Kasak Alex , Johnson Bruce 
Published: June 2021

BACKGROUNDExposure to high altitude (HA) results in sympathetic nervous system (SNS) activation. This might interact with HA related illness. HRV is a technique to quantify SNS and parasympathetic nervous system (PNS) interactions and thus offers a noninvasive index in extreme environments.OBJECTIVETo quantify the changes in HRV in elite athletes (AT), acclimatized for 2 mo. at Everest base camp (BC) prior to summiting, relative to a control group (CT) (climbing and acclimatizing to BC in 3 wks).METHODSAT (N=4, Age=35±10 y, BMI=22±2, M/F ratio 2/2) and CT (N=8, Age=35±10 y, BMI=26±2, M/F ratio 8/0) performed autonomic tests consisting of quiet breathing, paced breathing prior to, mid‐way at BC and at 2 wks post expedition.RESULTSAt BC, AT had (compared to CT) higher HR (p=0.07) and reduced HRV (SDNN, p=0.09). For AT and CT combined: measures of HRV were reduced at BC (SDNN, p=0.05, Poincare length, p=0.05) and remained below baseline 2 wks post climb (SDNN, p=0.01; PCL, p=0.01).CONCULSIONHRV is reduced with HA exposure in both AT and CT and remains reduced 2 wks post exposure, suggesting either SNS activation and/or PNS withdrawal.FUNDING: Mayo Clinic & The North Face.
Motor unit number estimates in world‐class masters athletes: is 80 the new 60?
Authors: Allen Matti Douglas , Power Geoff A , Filion Maire Eve , Doherty Timothy J , Rice Charles L , Taivassalo Tanja , Hepple Russell T 
Published: June 2021

Despite age‐related loss of functioning motor units (MU), masters athletes (MA) in their 7th decade of life retained more MUs than recreationally active controls in the tibialis anterior (TA). It is unknown whether MAs beyond the 7th decade would show similar results. The purpose was to estimate the number of functioning MUs (MUNE) in world‐class, older male (n=4; 80 ± 5 y) and female (n=4; 80 ± 8 y) MAs ranging from 75 to 93 y. A maximal compound muscle action potential (CMAP) was recorded from the TA. Decomposition‐enhanced spike‐triggered averaging was used to analyze surface and intramuscular EMG from the TA during voluntary dorsiflexion contractions in order to derive a MUNE. For both sexes, CMAP was ~43% greater than previously reported in age‐matched normative data in males (6.7 ± 0.9 vs 4.7 ± 1.0 mV) (McNeil et al 2005), which may suggest a maintenance of excitable muscle mass in MAs. Mean surface MU potential (SMUP) size was similar between female MAs (64.3 ± 8.1 μV ) and normative data (78.2 ± 19.3 μV ), whereas male MAs had greater SMUP size than either group (138.0 ± 58.5 μV ). The resultant MUNE for female and male MAs was 100 ± 9 and 55 ± 24 MUs, respectively (p<0.05), with females but not males being higher than age norms. These preliminary results may indicate a sex‐specific protection of MUs in elite MAs >; 75 y of age, where MAs of both sexes may better maintain excitable muscle mass with aging.Supported by: CIHR (MOP 84408 to T.T.)
The influence of satellite cell‐depletion on glycosaminoglycan accumulation in aged skeletal muscle
Authors: Hardyniec Zakkary James , Lee Jonah D , Peterson Charlotte A. 
Published: June 2021

We utilized the Pax7‐DTA mouse model to directly test the role of satellite cells in aged muscle fibrosis. The Pax7‐DTA mouse allows for the conditional depletion of satellite cells in adult muscle with tamoxifen treatment. Four month old mice were treated with tamoxifen or vehicle and sacrificed at 24 months of age. Pax7 immunohistochemistry of the gastrocnemius muscle demonstrated a reduction of 78% of the satellite cell pool in tamoxifen‐compared to vehicle‐treated aged mice. Thus, early‐adulthood tamoxifen treatment successfully reduces the satellite cell pool, which does not effectively recover during the course of the lifespan. Alpha‐wheat germ agglutinin immunostaining demonstrated a 40% increase in glycosaminoglycan expression from muscle depleted of satellite cells, with no differences in muscle cross‐sectional area compared to muscle from vehicle‐treated muscle. The robust increase in glycosaminoglycan expression in satellite cell depleted muscle provides strong evidence that satellite cells participate in the regulation of muscle extracellular matrix remodeling with age, however do not influence overall muscle size.Funding: NIH R01AR060701 and R21AG34453 (CAP); Ellison Foundation/American Federation of Aging Research EPD12102 (JDL); American Physiological Society undergraduate research fellowship (ZJH); University of Kentucky Center for Muscle Biology.
Abnormal fiber type specification in dystroglycanopathy skeletal muscle
Authors: Beedle Aaron M , Melick Garrett A 
Published: June 2021

FKTN is one of eight causative genes for secondary dystroglycanopathy‐type muscular dystrophies. In these disorders, alpha‐dystroglycan lacks sugar structures essential for its binding to extracellular matrix proteins, leading to progressive muscle weakness and wasting, with variable involvement of the brain, eyes, and heart. There is evidence of abnormal muscle development or regeneration/differentiation in both FKTN‐deficient patients and conditional Fktn knockout mice. Therefore, the objective of our study is to determine muscle fiber differentiation patterns in conditional Fktn knockout versus littermate mice. With histological analyses in naïve and regenerating muscle, we find that the nature and timing of fiber type specification is different in young Fktn knockouts compared to littermates. Our data suggest that dystroglycan deficiency in skeletal muscle alters muscle specification of myosin heavy chain isoforms. Future studies are necessary to determine whether fiber type switching is pathogenic or compensatory, and the extent to which altered fiber types redirect the metabolic profile of dystroglycanopathy muscle.Research supported by the University of Georgia, College of Pharmacy.
The G Protein‐coupled bile acid receptor, TGR5, is expressed on colonic epithelial cells and regulates ion transport
Authors: Ward Joseph Bernard Jude , Mróz Magdalena Slawa , Keely Stephen J 
Published: June 2021

TGR5 has been implicated in the regulation of intestinal motility and has also been identified as a regulator of Cl− secretion across gallbladder epithelium. However, there is a paucity of information regarding the role of TGR5 in colonic epithelial cells (CECs). Here we sought to investigate a potential role for TGR5 in regulation of CEC ion transport.6α‐ethyl‐23(S)‐methylcholic acid (INT‐777) was used to activate TGR5. Ion transport was measured by short‐circuit current (Isc) across muscle‐stripped segments of rat colon. mRNA expression was measured by RT‐PCR. TGR5 localisation was measured by confocal microscopy.TGR5 mRNA and protein were highly expressed in CECs. TGR5 was localised bilaterally in rat colonic crypts. INT‐777 addition to rat colonic mucosa caused a rapid and transient decrease in Isc. This decrease was dependent on the presence of Cl− in the bathing solution. INT‐777 was effective from the basolateral side only. Furthermore, treatment with INT‐777 reduced subsequent Clsecretory responses to carbachol.These studies reveal a novel role for TGR5 in regulating colonic epithelial ion transport. TGR5 activation rapidly reduces basal Isc and inhibits subsequent Cl− secretory responses. Our data suggest that TGR5 may provide a new target for development of drugs to treat intestinal transport disorders.INT‐777 was supplied by Intercept Pharmaceuticals.Funded by Science Foundation Ireland.
Effects of a (pro)renin receptor blocker on weight gain in obese mice
Authors: Tan Paul , Shamansurova Zulaykho , Michel Catherine , Nguyen Thi , Schiller Peter , Gutkowska Jolanta , Lavoie Julie 
Published: June 2021

ObjectiveElucidate the role of the (pro)renin receptor [(P)RR] in obesity using a mouse model.MethodsMice were fed with a normal (N) or high‐fat/high carbohydrate (HF/HC) diet and treated with saline or a (P)RR blocker [(P)RRB] for 10 weeks. At sacrifice, white adipose tissue (WAT) [subcutaneous fat (SCF), perirenal fat (PRF), perigonadal fat (PGF)] were collected. mRNA was assessed by real‐time PCR, proteins by Western Blot and circulating proteins by array.Results(P)RRB decreased weight gain only in mice receiving a HF/HC diet compared to the saline group. (P)RR and renin mRNA in all WAT were increased with obesity compared to N diet without any effect of the (P)RRB with the exception of the SCF where (P)RR was decreased. (P)RR protein increased similarly to mRNA expression with obesity in PRF and SCF but was unaffected by the (P)RRB. Leptin and mesoderm‐specific transcript/paternally expressed gene 1 (MEST/PEG1), a marker of adipocyte cell size, mRNA increased with obesity in all WAT and decreased with (P)RRB on both diets. A similar effect was observed for resistin mRNA in SCF. Circulating leptin was modified similarly as its mRNA while circulating resistin was increased with obesity with no effect of the (P)RRB.ConclusionObesity modulates (P)RR in WAT. (P)RRB seems to decrease weight gain, leptin mRNA and circulating level as well as adipocyte size.
Adiponectin Restores Diabetic Heart Sensitivity to Ischemic Posctconditioning: Role of STAT3 Activation
Authors: Li Haobo , Wang Tingting , Lei Shaoqing , Ng Kwok‐fu , Irwin Michael , Xu Aimin , Xia Zhengyuan 
Published: June 2021

Diabetic hearts are prone to ischemia reperfusion (IR) injury and not sensitivity to ischemic postconditioning (IPostC) cardioprotection, and the mechanism is unclear. Adiponectin (APN) confers cardioprotection in non‐diabetes by activating STAT3 (pSTAT3), a key protein in mediating IPostC protection. In diabetic heart, APN is decreased, together with reduced pSTAT3. We hypothesized APN may activate STAT3 in diabetic heart and restore its sensitivity to IPostC. Control (C) and Streptozotocin induced diabetic (D) rats were subjected to 30 min coronary artery ligation followed by 2 hours of reperfusion, without or with IPostC achieved by 3 episodes of 10s reperfusion and 10s re‐occlusion at the onset of reperfusion. Rat was injected with APN (1×109pfu) 7 days before inducing IR. Cardiac functions were assessed by pressure volume (PV) conductance system. Post‐ischemic myocardial infarct size was higher in D relative to C, together with significant reduction of cardiac pSTAT3 and reduction of end systolic PV relation,a reliable measure of ventricular systolic function, in D rats. All these changes in D were reverted by IPostC in the presence but not in the absence of APN (P<0.05 vs. D+APN+IPostC vs. D or D+APN), and abolished by AG490 (which inhibits STAT3 activation). It is concluded that APN restores diabetic heart sensitivity to IPostC by activating STAT3.Supported by RGC/GRF (784011, 768211), NSFC (81270899)