bluuebunny/crossref_metadata_2025_split huggingface dataset:
Nominal Carbonic Anhydrase Activity Mitigates Airway‐Surface Liquid pH Changes During the Respiratory Cycle
Authors: Thornell Ian M , Li Xiaopeng , Tang Xiao Xiao , Zabner Joseph L , Welsh Michael J 
Published: November 2023

The airway‐surface liquid pH (pHASL) is slightly acidic relative to the plasma pH and becomes more acidic in airway disease (e.g., cystic fibrosis, asthma, and COPD). Pathological pHASL may dysregulate ASL viscosity, mucociliary transport, and bacterial killing. Under constant 5% CO2, porcine large airways are more acidic (~7.0) than small airways (~7.4). However, the small airways are exposed to a constant 5% CO2, whereas the large airways are exposed to wide swings in pCO2 during respiration. Therefore, pHASL in the large airway may oscillate and be more alkaline during respiration. In this study, we investigated how oscillating CO2 affects the large airway pHASL for differentiated porcine tracheal epithelia cultured at the airway‐liquid interface. The apical surface of epithelia was initially exposed to 5% CO2. Apical CO2 was then rapidly switched to 0.04% CO2, allowed to equilibrate, and was then returned to 5% CO2. The pH was monitored by SNARF‐1 dextran fluorescence. Relative to a breath (~4 s), the time constant for pH changes were unexpectedly slow (τ = 51.9 ± 5.8 s, n = 12). We hypothesize that this slow time constant might be due to low carbonic anhydrase activity, which catalyzes the carbonic buffering reaction. Consistent with this hypothesis, the carbonic anhydrase inhibitor acetazolamide did not appreciably change the time constant (τ = 64.1 ± 6.1 s, n = 10; p = 0.21 vs. non‐treated). In contrast, adding exogenous carbonic anhydrase strikingly decreased the mean time constant (τ = 17.3 ± 3.1 s, n = 16; p < 0.01 vs. non‐treated). Curated mRNA microarray data indicated nominal expression for all extracellular and secreted carbonic anhydrase isoforms in large airway epithelia. To further understand how CO2 affects pHASL in the large airway, we modeled the pHASL during respiration using the pH‐dependent rates (dph/dt) obtained from our functional experiments. There were three major findings from our simulations. First, under physiological conditions (inspiratory:expiratory ratio = 1:2; respiration rate = 15 breathes per minute), the pHASL oscillations were small (peak‐to‐peak pHASL = 0.09 ± 0.02 pH units). In contrast, adding carbonic anhydrase increased the pHASL oscillations (peak‐to‐peak pHASL = 0.56 ± 0.16 pH units). Second, correcting the large airway steady‐state pHASL for the respiratory cycle still yields an acidic pHASL relative to the small airway (pHlarge 7.05 vs. pHsmall 7.45). Third, the inspiratory:expiratory ratio affected the average pHASL, whereas the respiration rate affected the magnitude of pHASL oscillations. Thus, minimal carbonic anhydrase activity in large airways prevents sizeable shifts in pHASL during respiration. Maintaining relatively constant pHASL may optimize airway host defense by antimicrobials and mucociliary transport.Support or Funding InformationNIH HL091842, NIH HL5167, CF Foundation LI1410
Fungus‐Derived Zearalenone as an Inhibitor of cAMP‐Dependent Chloride Secretion in Human Colonic Epithelial T84 Cells
Authors: Muangnil Paradorn , Tadpetch Kwanruthai , Rukachaisirikul Vatcharin , Chatsudthipong Varanuj , Muanprasat Chatchai 
Published: November 2023

Secretory diarrhea remains a major health problem caused by either intestinal infection or side‐effect of many drugs. An elevation in intracellular cAMP activates transepithelial Cl− secretion, which provides the driving force for secretory diarrhea. Therefore, inhibition of cAMP‐activated transepithelial Cl− secretion in intestinal mucosa is regarded as a potential therapeutic strategy for secretory diarrhea. This study aimed to identify fungus‐derived compounds that inhibit cAMP‐activated transepithelial Cl− secretion and investigate its underlying mechanism(s). From the screening of compounds derived from fungi, zearalenone (β‐resorcyclic acid lactone produced by Fusarium fungi) was found to inhibit cAMP‐activated Cl− secretion across human intestinal epithelial (T84) cell monolayers as measured by short‐circuit current (Isc) analysis with half maximal inhibitory concentration (IC50) of ~ 0.5 μM. This effect was observed only when zearalenone was added into apical side, but not basolateral side, suggesting that zearalenone affects mainly apical transport processes. We further demonstrated that zearalenone reversibly inhibited cystic fibrosis transmembrane conductance regulator (CFTR)‐mediated apical Cl− transport with IC50 ~ 0.8 μM, indicating that zearalenone inhibits cAMP‐acivated Cl− secretion in T84 cell, at least in part, by inhibiting CFTR Cl− channel activity. The mechanisms of zearalenone‐induced CFTR inhibition involved neither phosphodiesterase‐mediated cAMP degradation, multi‐drug resistance protein 4‐mediated cAMP efflux nor protein phosphatase‐mediated CFTR dephosphorylation. In addition, the CFTR inhibitory effect of zearalenone was not affected by co‐treatment with β‐estradiol, indicating that the CFTR inhibition by this compound did not result from its binding to estrogen binding site on the CFTR. Zearalenone at concentrations up to 50 μM did not produce the cytotoxic effect on T84 cells. This study revealed that zearalenone represents the first class of CFTR inhibitors derived from fungi, which may be useful in the treatment of secretory diarrhea resulting from overactivation of cAMP‐dependent chloride secretion.Support or Funding InformationThis work was supported by the NSTDA Chair Professor grant (the Fourth Grant) of the Crown Property Bureau Foundation and the National Science and Technology Development Agency and BRG5890008 grant from the Thailand Research Fund and Mahidol University
Curation of Renal Inner Medullary Collecting Duct Proteome Database with Sequence‐Based Searching Using K‐BLAST
Authors: Medvar Barbara , Pisitkun Trairak , Sarkar Abhijit , Knepper Mark 
Published: November 2023

The renal collecting duct regulates water excretion through the action of vasopressin to regulate the water channels aquaporin‐2 (AQP2) and AQP3. A long‐term goal is to understand the mechanisms involved in collecting duct function and regulation at a cellular and molecular level. Ancillary to laboratory‐based investigations, mathematical modeling of the cellular mechanisms can provide a guide to experimentation and curation of information. The first step in modeling is the generation of a list of model components. For collecting duct modeling we have now curated a list of proteins expressed in the rat renal inner medullary collecting duct from proteomic data from 18 different publications. The database has been posted as a public resource at https://hpcwebapps.cit.nih.gov/ESBL/Database/IMCD_Proteome_Database/. It includes proteins corresponding to 8,959 different genes. To search the IMCD Proteomic Database efficiently we have created a Java‐based program called K‐BLAST, which uses the NCBI BLAST kernel to search for specific amino acid sequences corresponding to proteins in the database. K‐BLAST reports information on the matched protein and identifies proteins in the database that have similar sequences. We have also adapted K‐BLAST to interrogate our previously published IMCD Transcriptome Database. We have made the K‐BLAST program available for use either as a web application or a downloadable .jar file at https://hpcwebapps.cit.nih.gov/ESBL/Database/K‐BLAST/. Database searching based on protein sequence removes ambiguities arising from the standard search method based on official gene symbols and allows the user efficient identification of related proteins that may fulfill the same functional roles.Support or Funding InformationNIH ZIA‐HL006129
Blast Exposure with mTBI is associated with Impaired Cerebral Blood Flow in US Veterans
Authors: Serrador Jorge Manuel , Haber Yaa , Brewer Kelly , De La Cruz Leslie , Falvo Michael 
Published: November 2023

Blast exposure is a significant problem for the current and recent military conflicts, however, data remains limited on the effects of a pressure wave on autonomic and cerebral blood flow regulation. The goal of this work was to determine if veterans with a blast exposure and/or mild traumatic brain injury (mTBI) demonstrate impaired cerebral blood flow regulation.Thirty veterans (2 females, 44.8 ± 13.7 years) participated. Nine were controls with no history of blast or mTBI, four had blast exposure with mTBI, five had blast with mTBI and 11 had history of mTBI without blast exposure. One subject was excluded because they had a moderate TBI. To assess cerebral blood flow regulation we monitored TCD in both the anterior (ACA) and middle cerebral arteries (MCA) during three sit to stand maneuvers. We also measured beat by beat blood pressure and end tidal CO2 via nasal cannula. Veterans with a history of Blast+mTBI had significantly higher mean arterial pressure (100±13 mmHg) than either mTBI (87±13 mmHg), Blast only (84±13 mmHg) or controls (84±13 mmHg). Cerebral flow velocity while standing was significantly reduced in the Blast+mTBI group (MCA: 87±9%; ACA: 87±9% of seated baseline) compared to mTBI group (MCA: 94±9%; ACA: 98±10%) or Blast only group (MCA: 103±9%; ACA: 99±9%) or Controls (MCA: 99±9%; ACA: 101±10%). In contrast, autoregulatory index was not significantly different between groups in the MCA or ACA. End tidal CO2 was also not different between the groups when standing.These data indicate that veterans who had a blast exposure and a head injury had higher blood pressures and lower cerebral flow velocity when standing, even when compared to those with a head injury not due to blast, or those that were exposed to a blast but did not receive a head injury. These data suggest that blast waves that have sufficient energy to cause a head injury result in more significant impairment of cerebral blood flow when standing than those with an impact mTBI not associated with a blast wave. This may contribute to some of the persistent symptoms these Veterans report after returning. Future work needs to verify these findings in a larger group of Veterans.Support or Funding InformationSupported by the War Related Illness & Injury Study Center, Veterans Administration and NIH grant R21DC009900 (Serrador).
Effects of Resting Muscle Carnosine Content on the Intramuscular Antioxidant Response to a Bout of Resistance Exercise
Authors: Varanoske Alyssa N , Hoffman Jay R , Church David D , Jajtner Adam R , Townsend Jeremy R , Beyer Kyle S , Oliveira Leonardo P , Fukuda David H , Stout Jeffrey R 
Published: November 2023

INTRODUCTIONAcute bouts of resistance exercise can result in elevations in oxidative stress. Carnosine (CARN) is a histidine dipeptide that has been suggested to have antioxidant properties, and as a result may enhance the recovery processes following exercise. However, there appears to be only limited data that has examined the effect of resting muscle CARN content on its role as an antioxidant or reducing oxidative stress following an acute bout of resistance exercise. The purpose of this study was to compare the effects of high (HI) and low (LO) resting muscle CARN on antioxidant status. A secondary purpose was to compare the intramuscular oxidative stress response following an acute bout of resistance exercise between individuals with HI and LO CARN values.METHODSFifteen recreationally‐active men volunteered for this study. Muscle biopsies were sampled from the vastus lateralis of the left leg at baseline (BL). A subset of these participants (n=12) then completed an acute muscle‐damaging protocol consisting of the squat (6 sets × 10 repetitions), leg press (4 sets × 10 repetitions) and leg extension (4 sets × 10 repetitions) exercises at 70% of their 1‐repetition maximum. Additional muscle biopsies were sampled at one (1H), five (5H), and 24 (24H) hours post‐exercise. Intramuscular CARN content from biopsy samples was determined via high‐performance liquid chromatography, whereas glutathione (GSH), catalase (CAT), peroxiredoxin 2 (PRX2), superoxide dismutase 1 (SOD1), superoxide dismutase 2 (SOD2), and thioredoxin 1 (TRX1) were quantified via enzyme‐linked immunosorbent assays. Participants were categorized into HI (n=7; 21.7±2.9 y; CARN: 14.8±4.2 mmol·kg−1 ww) and LO (n=8; 21.8±2.5 y; CARN: 6.4±2.3 mmol·kg−1 ww) groups by their BL CARN levels. Magnitude‐based inferences were used to analyze group differences and change scores in antioxidant concentrations at BL and after exercise.RESULTSSubjects with HI CARN had “Likely” greater GSH at BL compared to those with LO CARN (11.50±2.71 μM vs. 8.75±3.75 μM, respectively). In individuals who completed the resistance exercise protocol, GSH values at 1H were “Likely” greater in individuals with HI CARN compared to those with LO CARN. Decreases in CAT, PRX2, SOD1, and TRX1 from BL to 24H were all “Likely” greater in individuals with HI CARN compared to those with LO CARN. Furthermore, changes in SOD2 from BL to 1H, BL to 5H, and BL to 24H were “Very Likely”, “Likely”, and “Very Likely” lower in individuals with HI CARN compared to those with LO CARN, respectively.DISCUSSIONIn conclusion, individuals with HI CARN at BL appear to exhibit a differential antioxidant recovery response to resistance exercise compared to individuals with LO CARN.
Effects of the Different Acute Exercise on Serum Cortisol of Undergraduate
Authors: He Jing , Sun Ping You , Qiu Li Lin 
Published: November 2023

OBJECTIVETo compare the effects of different acute exercise on Serum Cortisol of undergraduate.METHODSSubjects (n=160)were randomized into endurance training(E, n=40), strength training (S, n=40), combined strength and endurance training(SE, n=40), or control group(C, n=40)for 45min, and take 4ml venous blood at before and after training.RESULTS1、 The Serum Cortisol of female significantly increased in E (438.90±60.48 651.10±138.45; P < 0.01). Serum Cortisol significantly increased in S (436.52±72.68; 690.64±92.06; P < 0.01), Serum Cortisol significantly increased in SE (416.09±8.49; 752.90±135.79; P < 0.01). and it increased significantly in C also (427.90±56.72; 679.37±177.95; P < 0.05). 2、 The Serum Cortisol of male significantly increased in E (394.31±685.73; 733.23±97.82; P < 0.01). Serum Cortisol significantly increased in S (353.04±131.08; 698.18±103.07; P < 0.05), Serum Cortisol significantly increased in SE (440.14±65.60; 761.18±108.29; P < 0.01), but it increased no significantly in C (424.95±98.24; 552.01±208.12; P > 0.05). 3、 The change of the Serum Cortisol of E、 S、 SE and C exist significant difference (female: P < 0.01; male: P < 0.05).CONCLUSIONEndurance training and Strength training and their combination all led to increase in Serum Cortisol. The different acute exercises have difference influence on Serum Cortisol, and the influence of combined training on serum cortisol is the largest.Support or Funding InformationThe key lab of adolescent health intervention and exercise assessment, Ministry of China,
Inter‐individual Variability in Muscle Sympathetic Nerve Activity during Static Handgrip in Healthy Young Men
Authors: Incognito Anthony V. , Doherty Connor J. , Lee Jordon B. , Burns Matthew J. , Millar Philip J. 
Published: November 2023

Cardiovascular responses at the onset of static handgrip are thought to be governed primarily by activation of higher brain regions (central command) and stretch‐sensitive group III/IV skeletal muscle afferents (muscle mechanoreflex), whereas responses during more prolonged contractions also involve activation of chemically‐sensitive group III/IV afferents (muscle metaboreflex). However, the contribution of central command to the muscle sympathetic nerve activity (MSNA) response at exercise onset is unclear. Existing evidence suggests that central stressors (e.g. mental stress) can either increase or decrease MSNA, identifying two populations of responders. We hypothesized that considerable inter‐individual variability may exist also at the onset of static handgrip, when the net contribution of central command is greatest. Continuous supine measurements of multi‐unit MSNA (microneurography) and blood pressure (Finometer) were recorded in 28 healthy men (24±5 years) during 2 minutes of static handgrip (30% maximal voluntary contraction) and 3 minutes of post‐exercise circulatory occlusion (PECO). Participants were divided into high (n=14) and low (n=14) MSNA responders based on the median MSNA burst frequency response during the first minute of static handgrip. High responders demonstrated greater MSNA responses during the first (Δ6±5 vs. −3±3 bursts/min, p<0.001) and second (Δ13±5 vs. 5±6 bursts/min, p<0.001) minute of handgrip and during the last minute of PECO (Δ9±7 vs. 4±6 bursts/min, p<0.05) compared to low responders. However, the change in MSNA between the first and second minute of handgrip was similar between high and low responders (Δ6±7 vs. 7±4 bursts/min, p>0.05). The increases in mean arterial pressure during handgrip (minute one: Δ9±6 vs. 7±4 mmHg; minute two: Δ20±9 vs. 16±9 mmHg) and PECO (Δ15±9 vs. 12±8 mmHg) were similar between high and low responders (All p>0.05), as were changes in heart rate, stroke volume, cardiac output, and total vascular conductance (All p>0.05). Examining the individual data as a continuous variable, the changes in MSNA and mean arterial pressure were unrelated during the first minute of handgrip (r=0.04, p>0.05), but related positively during the second minute of handgrip (r=0.50, p<0.01) and last minute of PECO (r=0.50, p<0.01). In summary, MSNA responses at the onset of static handgrip in young healthy men are highly variable and exhibit a dissociation with the pressor response.Support or Funding InformationThis research was supported by a Natural Science and Engineering Research Council (NSERC) of Canada Discovery Grant (P.J.M), the Canada Foundation for Innovation (P.J.M.), University of Guelph‐Humber Research Grant (P.J.M), and a Canadian Institutes of Health Research Fredrick Banting and Charles Best Canada Graduate Scholarship (A.V.I.).
Hypoxic response in skeletal muscle contributes to the adaptation of muscle fibers in mice
Authors: Nunomiya Aki , Shin Junchul , Kitajima Yasuo , Dan Takashi , Miyata Toshio , Suzuki Naoki , Aoki Masashi , Nagatomi Ryoichi 
Published: November 2023

BackgroundPreviously, we reported that activation of the hypoxia‐inducible factor pathway induced by prolyl hydroxylase domain 2 (PHD2) deficiency enhances the effect of running training in mice (Nunomiya et al., 2016). We also reported that muscle cross sectional area (CSA) of Phd2‐deficient mice was significantly smaller compared to that of control mice (Shin et al., 2016). Decreased cross sectional area of muscle fibers may favor oxygen delivery during training. It is unknown, whether the observed adaptations in skeletal muscle is due to the systemic‐ or local hypoxic response within the skeletal muscle fibers. We hypothesized that the hypoxic adaptation of skeletal muscle is independent of systemic hypoxic adaptation. The aim of this study is to determine whether systemic‐or local hypoxic response affected the muscle fiber size.MethodsTwo independent lines of Phd2‐floxed mice were used in this study; global Phd2 knockout mice (conditional knockout: cKO) and skeletal muscle specific Phd2 knockout mice (muscle specific knockout: MuKO). Because global Phd2 knockout is embryonic lethal, estrogen receptor (ER) agonist‐induced Phd2 conditional KO mouse using Cre‐loxP system was generated. To delete floxed Phd2 exon 2, tamoxifen was administrated to Phd2 cKO mice by i.p. injection.ResultsAs we reported previously, we detected the reduced CSA in the gastrocnemius muscle of Phd2 cKO mice. Additionally, soleus CSA in Phd2 cKO mice was also reduced in Phd2 cKO. These results suggest that the reduction of CSA was induced not only in type 2b fiber, but also in type 2a and type 1 fiber. Moreover, soleus CSA was decreased in Phd2 MuKO mice compared with control mice. These data suggest that the reduction of muscle CSA may depend on local hypoxic response in skeletal muscle fiber rather than systemic hypoxic response.ConclusionsOur data suggest that hypoxic response in skeletal muscle fiber induced by Phd2 deficiency resulted in smaller skeletal muscle fiber size in all fiber types.Support or Funding InformationThis work was supported by a JSPS Grant‐in‐Aid for JSPS fellows (26‐3209).
Nitrite Infusion Does Not Alter Isolated Canine Muscle Oxidative Metabolism In Situ During Hypoxia With Normal Convective O2 Delivery
Authors: Porcelli Simone , Rasica Letizia , Ferguson Brian S. , Kavazis Andreas N. , McDonald James R. , Mowry Francesca , Hogan Michael C. , Grassi Bruno , Gladden Bruce L. 
Published: November 2023

IntroductionPrevious studies have shown a decreased muscle oxygen consumption (V′O2) during moderate intensity exercise in hypoxia after augmented nitric oxide (NO) bioavailability, which suggests an increased efficiency of oxidative metabolism. It is not clear if these effects are related to an NO‐induced increase in convective O2 delivery and/or to an enhanced mitochondrial coupling efficiency. The aim of this study was to examine skeletal muscle contraction economy during hypoxic exercise following nitrite infusion with unchanged convective O2 delivery.MethodsCanine gastrocnemius muscles (n=8) were surgically isolated and electrically stimulated via the sciatic nerve, eliciting 1 contraction every 3 seconds (≈35% V′O2peak) for 3 minutes in hypoxic conditions (PaO2=42±3 mmHg). During contractions, sodium nitrite (NITR) or sodium chloride (SAL) was infused into the popliteal artery. Muscle blood flow was kept constant by a perfusion pump. Muscle force was measured and muscle V′O2 was calculated from the Fick principle. Muscle biopsies were obtained before and after NITR and were used to isolate mitochondria. Mitochondrial respiration rates were recorded by high‐resolution respirometry.ResultsMuscle V′O2 was not significantly different between NITR (60.6±18.0 ml/kg/min) and SAL (61.7±18.3ml/kg/min). After normalizing V′O2 per unit of developed force, the values were slightly but not significantly higher in NITR vs. SAL (p=0.10). No differences were found for ADP‐stimulated mitochondrial respiration (both for complex I and complex II), leak respiration and oxidative phosphorylation coupling.ConclusionIn hypoxic conditions, but in the presence of constant and normal convective O2 delivery, nitrite infusion did not affect canine skeletal muscle oxidative metabolism. These results suggest that the effects of increased NO availability on muscle contraction efficiency in hypoxia, if present, are likely not attributable to changes in mitochondrial respiratory function.