bluuebunny/crossref_metadata_2025_split huggingface dataset:
Interaction of nitric oxide and reactive oxygen species in the development of hypoxic pulmonary hypertension
Authors: Chovanec Milan , Hnilickova Olga , Smolkova Pavlina , Herget Jan 
Published: June 2021

Chronic hypoxia damages peripheral pulmonary vessels and causes hypoxic pulmonary hypertension (HPH). According to our hypothesis, the release of reactive oxygen species (ROS), nitric oxide (NO) and products of their interaction contribute to the pathogenesis of HPH. Experimenting with chronic hypoxic adult male rats, we tested the effect of NO and ROS interaction. Hypoxic rats were treated solely with SOD mimetic Tempol (group T, n=6) and NO donor Molsidomine (group M, n=9) or in combination (group MT, n=6) during first 7 days of exposure to 3 weeks hypoxia (FiO2=0.1). Seven untreated hypoxic rats (group H) and seven normoxic controls (group C) were used.Pulmonary artery blood pressure (PAP), and the weight of RV, LV+S were measured. PAP was significantly decreased in group M (P<0.05) and group T (P<0.05) but not in group MT compared with group H. In all hypoxic groups the right‐to‐left heart weight ratio was significantly increased compared to group C, and groups receiving Tempol (T, MT) had significantly (P<0.01 and P<0.01 respectively) less increase in weight of RV or whole heart compared with group H.Molsidomine or Tempol added alone (but not in combination) at the beginning of exposure to chronic hypoxia reduces HPH. Tempol alone or in a combination reduces of hypoxia‐induced right heart hypertrophy.Supported by Cardiovascular Research Center MSMT 1M 0510, Grants: GACR 305/05/0672 and GAUK 7780/2007
Venous compliance and wall distensibility in the venous compartments of the lower limb in men
Authors: Lindenberger Marcus , Zachrisson Helene , Neider Daniel , Länne Toste 
Published: June 2021

Objectives: Lower limb venous compliance is of hemodynamic importance for orthostatic challenge. The qualities of different venous compartments is however unknown. The aim was to study venous buffering compliance (vBC) as well as venous wall distensibility (vWD) in deep (femoral vein, FV) and superficial large veins (great saphenous vein, GSV), as well as to assess calf venous compliance (vC).Methods: Strain‐gauge plethysmography was used to assess vC. Diameter (D), vBC and vWD of the FV and GSV were examined with ultrasound in 15 young (YM, 25±1 yr) and 14 old (OM, 70±2 yr) males. D was measured at rest and after venous stasis (6 min, 60 mmHg), and vein area (A) calculated. Pressure‐Area curves (absolute, mm2, and relative, %) during a linear pressure decrease were produced, and vC, vBC and vWD calculated using a quadratic regression equation.Results: vC was greater in YM, P < 0.05. vBC was greater in GSV in YM than OM, P < 0.01. D was larger in FV than GSV in YM and OM, P < 0.0001, and vBC was greater in FV than in GSV irrespective of age, P < 0.01. However, when correcting for venous size (vWD), greater vWD was found in GSV than in FV in YM as well as OM, P < 0.05.Conclusions: Calf venous compliance was greater in young as compared to old men. Femoral vein had higher venous buffering compliance than great saphenous vein, due to its greater size. When correcting for size, great saphenous vein showed greater wall distensibility than femoral vein.
An Aldosterone‐sensitive Basolateral P2X4 Receptor Stimulates the Renal Epithelial Sodium Channel
Authors: Bao Hui Fang , Yu Ling , Helms My , Eaton Douglas C 
Published: June 2021

Our results suggest that one way aldosterone can stimulate ENaC is via elevation of P2X4 receptor expression and trafficking to the basolateral membrane of A6 cells. We found that application of either ATP or 2‐methylthio‐ATP (2‐meSATP, a selective P2X receptor agonist) to the basolateral bath significantly elevated ENaC activity in cell‐attached patches formed on the apical membrane of aldosterone‐conditioned A6 cells. In contrast, no effect was observed when 2‐meSATP was applied to the apical bath, or when aldosterone was deprived from the culture medium for 72 h. Furthermore, a P2X4‐like channel was recorded in cell‐attached patches formed on the basolateral membrane of the flipped A6 cell monolayer. The effect of basolateral 2‐meSATP on ENaC activity was blocked by either chelation of extracellular Ca2+or inhibition of PI 3‐kinase. Western blot experiments showed that deprivation of aldosterone for 72 h strongly reduced the P2X4 receptor expression. Furthermore, confocal microscopy data showed that the P2X4 receptor is likely to be located in the basolateral membrane, which is confirmed by basolateral surface biotinylation of ENaC.This work was supported by NIH grants HL071621‐01 and DK37963‐16 awarded to DCE.
AVP causes transient formation of cAMP and activation of phosphodiesterase activity in MDCK cells
Authors: Froehlich Otto , Blount Mitsi A. , Yang Yuan , Klein Janet D. , Sands Jeff M. 
Published: June 2021

Exposure of MDCK cells to forskolin (FSK) and vasopressin (AVP) raises intracellular cAMP levels by activating adenylate cyclase (AC). FSK (5 μM) raised, over 10 min, the cellular cAMP approximately ten‐fold to a constant new level. The response to AVP (10−8M) was transient, with cAMP reaching a maximum (5‐fold) after about 5 min and then decaying. The transient cAMP response contrasts with the slow activation (30–40 min) urea flux in MDCK cells. In the presence of the phosphodiesterase (PDE) inhibitor, IBMX, the AVP‐induced cAMP spike was amplified and lasted longer. IBMX also enhanced the AVP‐stimulated urea flux. This enhancement was also achieved with the PDE4 inhibitor rolipram (2–20 μM) but not the PDE1 inhibitor vinpocetine (10–200 μM).We observed an approximately 2‐fold increase of PDE activity when assaying lysates of AVP‐treated MDCK cells. It appears that protein kinase A is involved in activating PDE, as H89 lengthened the AVP‐induced cAMP transient. Furthermore, AVP and FSK combined caused a very large cAMP transient (10× larger than AVP alone) that returned to levels slightly above those found for FSK alone. Overall, these data suggest a negative feedback mechanism in MDCK cells in which AVP not only activates AC but also, with a delay, PDE to reduce cAMP to a lower steady‐state level. Activation of PDE involves protein kinase A, which is known to be activated by the AVP‐stimulated cAMP
SAPHIR: a collaborative multi‐scale, multi‐resolution Core Model Environment for the Physiome—with a prototype core model of blood pressure regulation and fluid homeostasis
Authors: Thomas S. Randall , Hannaert Patrick , Baconnier Pierre , Fontecave Julie , Guillaud François , Le Rolle Virginie , Maziere Pierre , Tahi Fariza , Zehraoui Farida , Abchiche Nadia , Hernandez Alfredo 
Published: June 2021

We present the current state of the SAPHIR project, a multi‐resolution core modeling environment (CME) in the spirit of the IUPS Physiome, with application to a prototype core model based on a modular implementation of the classic systems model by Guyton et al. (1972 Ann. Rev. Physiol. 34:13–44) and its extension by Ikeda et al. (1979 Annals Biomed. Engin. 7:135–166). This core model targets short‐ and long‐term regulation of blood pressure and homeostasis of body fluids and major solutes. The aim is to provide a collaborative modeling environment enabling plug‐and‐play construction of integrated systems models with lumped‐parameter sub‐models at the organ/tissue level yet also allowing focus on cell‐ or molecular‐level detailed models embedded in the larger core model. Thus, in silico exploration of gene‐to‐organ‐to‐organism scenarios is possible while keeping computation time manageable. The CME is built on the M2SL toolbox, a multi‐scale, multi‐resolution, multi‐mode open source package developed in C++ by one of us (AH). Associated with the CME is an ontology‐based database allowing exploration of the modules, parameter values, and equations.In parallel with the CME implementation of the core model, we also present stand‐alone implementations in Berkeley Madonna (Ikeda model) and Simulink (Guyton model).
The effect of denervation on the molecular clock in skeletal muscle
Authors: McCarthy John Joseph , Miyazaki Mitsunori , Wolff Gretchen , Esser Karyn Ann 
Published: June 2021

We recently identified the circadian transcriptome in mouse skeletal muscle. The primary objective of this study was to test the hypothesis that innervation is required to maintain oscillation of the circadian molecular clock in muscle. A second objective was to determine if the phase of the molecular clock is the same in different muscles. Using the Period‐2:Luciferase mouse, the tibialas anterior was denervated (d‐TA) by sectioning the common peroneal nerve on one leg with the contralateral leg serving as a sham operated control. Following two weeks of denervation, various muscles and liver were collected from three animals every four hours for 24 hr. RT‐PCR analysis revealed that the expression pattern of components of the molecular clock (Bmal1, Per2 and Clock) as well as Myod1, a clock‐controlled gene, was altered in the d‐TA compared to i‐TA. Luciferase activity, reflecting Per2 protein expression, of the d‐TA was significantly elevated at each time point in comparison to inneravted‐TA (i‐TA), though the time of peak expression remained unchanged. In the heart, diaphragm and liver, peak luciferase activity peaked four hours later than what was observed in hindlimb muscles suggesting the phase of the clock is slightly different in these tissues. Collectively, these results indicate loss of neural input causes alterations in the molecular clock in adult skeletal muscle.KAE (AR045617) and JJM (AR053641)
Blue light phase advances entrained rhythms of brain temperature and sleep in rhesus monkeys
Authors: Robinson Edward L , Fuller Charles A 
Published: June 2021

Blue light sensitive retinal ganglion cells and their neural projections appear to be the main pathway for the effects of light on circadian entrainment and alerting. The effects of blue light on rhythms and sleep in a 24 hour light‐dark cycle were studied in a rhesus monkey model. Six individually housed and unrestrained animals were entrained in cool‐white fluorescent light (WH) for 12 hours daily (LD 12:12), then exposed to 4 days of LD12:12 with blue LED lamps (BL). Both sources averaged 6.1 x 1013 quanta cm−2s−1 at eye level. Performance was measured using the Psychomotor Test System (Georgia State Univ.). Brain temperature (Tbr) and sleep were recorded via biotelemetry. Sleep stages from the last two days of WH and BL were scored in 30‐second epochs. The average fraction of time in sleep over 24‐hours, as well as during L or D, did not differ between WH and BL. Shallow slow‐wave sleep (stages 1 and 2) and deep slow‐wave sleep (stages 3 and 4) also showed no significant differences. The fraction of time in REM sleep over 24‐h was significantly elevated as was REM during D. Acrophases from sine fits showed a statistically significant advance of the phase angle of entrainment in Tbr, in the first two days of BL. Acrophases and average waveforms of sleep stages from the subsequent two days show apparent phase advances and a slight increase in daytime sleep, but did not differ significantly.(Supported by NASA Grant NNJ04HF44G)
Effects of underwater breathing apparatus on ventilatory parameters at rest
Authors: Alain Duvallet , Emilie Duvallet , Michele Beaudry , Annick Bouchez‐Buvry 
Published: June 2021

The aim of the study was to determine the effect of breathing through a self contained underwater breathing apparatus (SCUBA) on the ventilatory parameters at rest. SCUBA imposed separated inspiratory and expiratory external resistances and increased the dead space. Volumes and maximal flow‐volume loops were randomly performed with and without SCUBA in 160 men and 125 women aged of 30.9 ± 15.1 years. Data were compared by t paired test, ANOVA and ANCOVA.SCUBA did not influence maximal vital capacity (4,15 ± 1,02 vs 4,15 ±1,04 l; p = 0,95), increased the expiratory reserve volume (1,24 ± 0,53 vs 2,36 ± 0,78 l; p<0,0001) and decreased inspiratory capacity (2,91 ± 0,83 vs 2,36 ± 0,78 l; p<0,0001). Scuba decreased significantly all parameters of flow‐volume loops. The results were independent of age, sex, and height.Breathing through a scuba lead to an airway obstruction and shifted the expiratory resting volume in the inspiratory capacity. At high volume, the pulmonary elastic recoil strengths are increased that allowed the expiration easy and inexpensive despite the applied external resistances. Although reduced dynamic lung compliance, the weak external inspiratory resistances and inspired air pressure made the inspiration easy. The available surface area of the valves in the scuba was greater than 50mm2 which was shown to be a threshold to compromise alveolar ventilation (Wasserman, 1995). However, the effect of these modifications on alveolar ventilation and gas exchanges must be study.
The effects of antioxidants on insulin signaling in spontaneously hypertensive rat vascular smooth muscle cells
Authors: Gardner Carla , Motley Evangeline , Washington Benny 
Published: June 2021

The objective of this study was to investigate the possible role of reactive oxygen species on insulin signaling in a hypertensive rat model. Because Protein kinase B/Akt serves as a link between upstream insulin signals, such as insulin receptor substrate‐1 and their cellular consequences, we sought to determine the phosphorylative characteristics of Akt in the insulin signaling pathway. To elucidate the effects of reactive oxygen species, spontaneously hypertensive vascular smooth muscle cells were treated with 6.25–50 μM hydrogen peroxide (H2O2). Our results indicated that 6.25 μM H2O2 enhanced Akt phosphorylation, while 25 μM decreased insulin‐induced Akt phosphorylation. We also demonstrated that H2O2 decreased insulin receptor substrate‐1 phosphorylation. Further, H2O2‐induced inhibition of insulin signaling was inhibited by the antioxidant, pyrrolidine dithiocarbamate. These studies provide more evidence that reactive oxygen species inhibit insulin signal transduction thereby causing insulin resistance leading to cardiovascular disease.This work was supported by a grant from the Faculty Research Award program of the Division of Research and Sponsored Programs, Tennessee State University.
Reduced cytokine production by glycogen‐elicited peritoneal cells from diabetic rats.
Authors: Alba‐Loureiro Tatiana Carolina , Pithon‐Curi Tânia Cristina , Curi Rui 
Published: June 2021

Studies with diabetic rats and mice showed important alterations in neutrophil function such as decreased cell migration, phagocytosis capacity and release of TNF‐α, IL‐1β and PGE2 upon exposure to LPS. Elicited peritoneal cells (mainly neutrophils) obtained from STZ‐induced diabetic male Wistar rats (65mg/Kg b.w, 2 and 6 weeks) were investigated. Diabetic (D) and control (C) rats received an intraperitoneal injection of glycogen solution (1%). Four hours afterwards, the peritoneal lavage was performed and the following parameters were: total cell counts in peritoneal lavage and the measurement of the cytokines (IL‐1β, CINC‐2α/β, TNF‐α and IL‐10) was performed in samples of the peritoneal cavity fluid by ELISA. A similar number of cells migrated to the peritoneal cavity in all groups. The diabetic state caused a significant decrease of IL‐1β (45%), TNF‐α (47%), IL‐10 (50%) and CINC‐2α/β (55%) levels in the intraperitoneal cavity fluid. However, the amount of cytokine produced by elicited peritoneal cells from insulin treated diabetic rats was the same observed in control rats. Therefore, the impairment in the production/liberation of cytokines by elicited peritoneal cells might contribute to an impaired inflammatory response and high susceptibilityto infections observed in diabetic state.Research supported by: FAPESP and CNPq
Endothelial‐specific BH4 expression accelerates refractory wound healing by enhancing eNOS activity and suppressing oxidative stress in type 1 diabetes
Authors: Tie Lu , Marrotte Eric J. , Channon Keith M. , Chen Alex F. 
Published: June 2021

Background: Refractory wound is a severe complication in diabetes that leads to limb amputation, but the mechanisms are poorly understood. eNOS plays a key role in normal wound repair, but is uncoupled in streptozotocin (STZ)‐induced type 1 diabetes due to reduced cofactor BH4. We tested the hypothesis that GTP cyclohydrolase I (GTPCH), the rate‐limiting enzyme of BH4 synthesis, retards eNOS uncoupling with accelerated wound healing in STZ mice.Methods and Results: Blood glucose levels were significantly increased in both male GTPCH transgenic mice (Tg‐GCH) and the wild‐type (WT) littermates 5 days after STZ regimen. A full‐thickness excisional wound was created on mouse dorsal skin by a 4‐mm punch biopsy. The rate of wound closure in STZ mice was delayed by 18.48% compared to normal WT mice, which was rescued in STZ Tg‐GCH mice by an average of 8.48% (n=3–5, p<0.05). HPLC analysis showed that cutaneous BH4 level was significantly reduced in STZ mice vs. WT mice (n=4–5, p<0.05), which was maintained in STZ Tg‐GCH mice. In STZ mice, cutaneous eNOS activity and nitrite level were decreased compared to WT mice, paralleled by increased superoxide (O2−) level. In STZ Tg‐GCH mice, nitrite level was potentiated and O2− level was suppressed compared to STZ mice.Conclusion: Endothelial‐specific BH4 overexpression accelerates wound healing in STZ type 1 diabetes mice by enhancing eNOS activity and suppressing oxidative stress.
Exercise‐induced muscle damage and oxidative stress in untrained and moderately trained subjects
Authors: Park Kyung‐Shin , Sedlock Darlene A. , Navalta James W. 
Published: June 2021

Muscle damage, which is greater following an unaccustomed downhill run (eccentrically‐biased exercise) compared to a level grade run or a second downhill run, increases intracellular free radicals which reduce oxygen radical absorbance capacity (ORAC).PURPOSEto investigate differences in markers of muscle damage and oxidative stress between moderately trained (MT) and untrained (UT) college students.METHODS:Nine MT and nine UT [VO2max (ml.kg−1.min−1) = 54.9±1.1(SE) vs. 45.7±1.8] performed three 40 min treadmill runs at ~70% VO2max: a level run (L) and two downhill (−10%) runs (DH1 and DH2). Blood was sampled before and immediately (POST), 2h, 24h, and 48h postexercise, and analyzed for creatine kinase activity (CK) and ORAC.RESULTSRunning speed was faster for MT than UT in L (p<.05) and DH (p<.01). Following DH1, CK activity was significantly elevated at 24h in both groups (p<.01), and significantly higher at 2h in MT than UT (p<.01). ORAC of MT was significantly lower at 24h in DH1 vs L and DH2 (p<.01). ORAC did not significantly change in UT.CONCLUSIONSMuscle damage and oxidative stress were greater in MT than UT following unaccustomed downhill running at the same relative metabolic intensity. Therefore, factors other than relative metabolic rate, e.g., muscle activation (running speed, stride length), or other exercise training‐related mechanisms, may be mediating this response.
Genetics of progression of pleomorphic xanthoastrocytoma (PXA) in the pediatric population
Authors: Hazrati Lili‐Naz , Solomon Lauren , Lee Eric , Monsalves Eric , Ma Jing , Tabori Uri , Hawkins Cynthia 
Published: June 2021

Recent publications suggest that with time, PXAs, rare low grade astrocytomas of children and young adults, may acquire anaplastic features and progress to malignancy with a prognosis similar to high grade astrocytomas. As malignant progression of low grade astrocytomas is rare in children, we sought to uncover the genetic changes that underlie this transformation.A search of the databases at our institution (1985–2007) identified 7 patients with a primary diagnosis of PXA. Most had multiple recurrences, with two fatalities. Extracted DNA was hybridized onto 500K SNP mapping gene arrays (Affymetrix) and gene copy‐number changes identified (dCHIP).Analysis of copy‐number changes at first presentation showed few alterations, mainly corresponding to genes within the Wnt/Cadherin pathways. However, with recurrences, the number of genes with copy‐number changes increased and other pathways implicated in cell proliferation, motility and invasiveness became modified, with prominent involvement of the integrin, Ras, and EGFR pathways. These data show that recurring PXAs acquire cumulative and progressive genetic changes that contribute to their rapid growth and increasing invasiveness and thus their less favorable outcome. Further, our experience supports the idea that in the pediatric population, PXAs are prone to recurrences and do not behave as typical low grade astrocytomas. Funding: CIHR.
A multi‐method, formative assessment process aided the development an effective, but shortened, clinical anatomy course
Authors: Rizzolo Lawrence J. , Rando William , O’Brien Michael , Stewart William B. 
Published: June 2021

Essential concepts of clinical anatomy have to be conveyed to medical, physician assistant (PA) and nurse‐practitioner (NP) students in courses that are reduced in hours. We employed five assessment methods to guide the design and implementation of new anatomy courses for these career paths. 1) Focus groups produced qualitative data on students’ experience and learning behaviors; 2) Written surveys produced data on how students used course resources to achieve course objectives; 3) User logs kept data on students’ use of course‐specific web sites; 4) Faculty observations reported on students’ participation in lab and discussion; and 5) Traditional exams tested students’ mastery of course content. Among our core findings: Surveys and focus groups revealed how the course created unanticipated pressures for students and faculty. Web log, survey and focus group results showed that websites were used heavily, but inefficiently. Focus groups and faculty observations confirmed high levels of preparation by students. In response to our assessments we: 1) instituted programs for faculty development and new course materials to help faculty and students cope with new demands; and 2) provided greater guidance to students about how to make use of course resources. Aside from preliminary results of summative assessments, unanticipated events provided early indications of the course's success: increased clinical faculty participation; the NP program converted anatomy from an elective to a required course; the PA program requested we develop a version for them; and residency programs use elements of it.FIPSE grant P116B031017, US Dept of Education
Phenotypic and functional characterization of proangiogenic monocytes
Authors: Duda Dan G , Jones Rosemary , Dawson Michelle , Capen Diane , Tyrrell Alex , Fukumura Dai , Jain Rakesh K 
Published: June 2021

The function of proangiogenic monocytes in blood vessel assembly is currently unclear. We characterized myeloid progenitors among bone marrow‐derived cells (BMDCs) from 3 mouse strains by flow cytometry, and established their function in tumors by intravital and confocal microscopy. These cells expanded ex vivo, expressed PDGFRβ, c‐Kit and Sca1, and were distinct from mesenchymal and endothelial BMDCs. Implanted with tumor cells, they persisted and integrated into stroma but not tumor vessel walls, although they significantly promoted tumor growth and metastasis. We also studied myeloid progenitors in a model of capillary repair after hyperoxic acute lung injury. By immunogold labeling and flow cytometry, we detected a population of CD11b+CD45+ cells positive for VEGFR2 and PDGFRβ. We used high‐resolution imaging to capture sequential changes in these cells as they formed capillary walls. By transition to an endothelial or pericytic phenotype, these myeloid progenitor cells contributed to capillary repair, engrafting into the endothelial surface and aligning as perivascular cells. In summary, we show that a previously unrecognized population of myeloid cells can both promote tumor growth and function as common endothelial and perivascular cell precursors.Supported by R01‐HL070866, R01‐CA115767 and AACR.