bluuebunny/crossref_metadata_2025_split huggingface dataset:
Blood Pressure is Positively Associated with Glycosylated Hemoglobin but not the Hypoxic Ventilatory Response in Obstructive Sleep Apnea Patients
Authors: Puri Shipra , Panza Gino , Rimar Caroline , Lin Ho-Sheng , Mateika Jason 
Published: April 2020

Study ObjectiveThe hypoxic ventilatory response (HVR) is considered an index of peripheral chemoreflex sensitivity. Previous work has suggested that an increase in the HVR is responsible for acute nocturnal blood pressure surges that ultimately lead to chronic elevations in blood pressure. Previous results have also indicated that glycosylation of hemoglobin (HbA1C) impairs nitric oxide (NO) relaxation of vascular smooth muscle leading to chronic elevations in blood pressure. Given these findings, we hypothesized that the HVR and HbA1C would be positively associated with blood pressure during sleep before and 3 weeks after treatment with mild intermittent hypoxia (MIH) in humans with obstructive sleep apnea (OSA).MethodsEight hypertensive participants with OSA were exposed to twelve 2‐minute episodes of hypoxia (PETO2 ≈ 50 mmHg) separated by 2‐minute normoxic intervals during wakefulness for 15 days over 3 weeks. PETCO2 was sustained at 2 mmHg above baseline during MIH administration. HbA1C was measured prior to completion of the protocol on Day 1 and 15. Moreover, blood pressure was measured over a period of 24 hours, before and after completion of the MIH protocol.ResultsOn Day 1, the HVR was negatively associated with HbA1C (−0.74, p < 0.04) and systolic (SBP) (R = −0.73, p < 0.05), diastolic (DBP) (R = −0.69, p < 0.05) and mean arterial blood pressure (MAP) (R = −0.71, p < 0.05) recorded during the sleep period of a 24 hour cycle. In contrast, HbA1C was positively associated with measures of SBP (R = 0.82, p < 0.01), DBP (R = 0.81, p < 0.01) and MAP (R = 0.86, p < 0.01) during sleep. Following treatment with MIH, blood pressure during sleep decreased (Before vs. After MIH: SBP 131.9 ± 4.1 vs. 122.9 ± 3.1, DBP 77.8 ± 3.9 vs. 72.8 ± 3.9, MAP 95.8 ± 3.8 vs. 89.5 ± 3.4, P < 0.02). The change (Δ) in SBP during sleep following MIH was correlated to the Δ HbA1C (R = 0.85, p ≤ 0.01). Moreover, the degree to which SBP dipped before vs. after MIH was also correlated to Δ HbA1C (R = 0.87, p ≤ 0.01). In contrast, Δ HVR was not correlated to the Δ in blood pressure parameters.ConclusionAlthough peripheral chemoreflex sensitivity may be responsible for acute surges in blood pressure, this factor does not appear to be a strong predictor of chronic changes in blood pressure. In contrast, modifications in local signaling molecules may ultimately have the greatest impact on chronic modifications in blood pressure. Indeed, our findings lend support to previous results which suggest that increases in blood pressure may be coupled to the impairment of nitric oxide in response to glycosylated hemoglobin. This relationship may exist in the presence of a blunted HVR.Support or Funding InformationDepartment of Veterans Affairs (I01CX000125 & 15SRCS003 JHM, 1IK1RX002945 GSP), and NIH (R56HL142757 & R01HL142757 JHM).
Identification of the Hsp90 Isoforms and Co‐Chaperones that Repress Opioid Anti‐Nociception in the Spinal Cord
Authors: Bejarano Paul , Duron David , Mishra Sanket , Blagg Brian S. J. , Streicher John M. 
Published: April 2020

The various isoforms of the chaperone protein heat shock protein 90 (Hsp90) in conjunction with specific co‐chaperones are key regulators of signal transduction. We have recently identified a novel role for Hsp90 within downstream mu opioid receptor (MOR) signaling both within the brain and spinal cord. Within the brain, we found that Hsp90α and the co‐chaperones Cdc37 and p23 promote MOR‐induced ERK phosphorylation and subsequent anti‐nociception. However, in the spinal cord Hsp90 represses MOR‐induced ERK phosphorylation and subsequent anti‐nociception, so that Hsp90 inhibitor treatment in the spinal cord results in enhanced opioid pain relief. This study aimed to identify the Hsp90 isoforms and co‐chaperones necessary for this mechanism within the spinal cord, and whether they differ from the brain. We used novel isoform and co‐chaperone selective small molecule inhibitors and in vivo gene knockdown using CRISPR/Cas9 to selectively block each of the Hsp90 isoforms and co‐chaperones in the spinal cords of male and female CD‐1 mice. We then used opioid‐induced anti‐nociception in the tail flick assay as a readout, combined with immunohistochemistry to validate CRISPR/Cas9 knockdown in the spinal cord. In contrast to our earlier brain studies, we found that the isoforms Hsp90α, Hsp90β, and Grp94 all acted to repress opioid anti‐nociception in the spinal cord, in that inhibiting these isoforms resulted in increased opioid anti‐nociception. We similarly found that the co‐chaperones Cdc37, p23, and Aha1 all similarly repressed opioid anti‐nociception in the spinal cord. These findings suggest that Hsp90β, Grp94, and Aha1 all act within the spinal cord but not the brain to regulate opioid anti‐nociception. These findings also suggest, in line with our earlier studies, that blocking these isoforms with systemic selective inhibitors could represent a novel therapeutic approach to enhance opioid therapy, increasing analgesic efficacy while reducing side effects like tolerance and reward/addiction.Support or Funding InformationThese studies were supported by an Arizona Biomedical Research Commission New Investigator Award (#ADHS18‐198875) and institutional funds from the University of Arizona to JMS, and NIH R01CA213566 to BB. BB is a founder with an equity stake in Grannus Therapeutics, a virtual startup for developing novel Hsp90 inhibitors. No other author has any relevant conflicts to declare.
Peri‐renal Adipose Tissue Inflammation Possibly Underlies Mild Renal Dysfunction in Early Metabolic Challenge
Authors: Hammoud Safaa H. , Koubar Sahar , Mougharbil Nahed Hisham , Eid Assaad Hisham , El-Yazbi Ahmed F. 
Published: April 2020

Cardiovascular disease remains a primary cause of morbidity and mortality in patients with diabetes. Cardiovascular complications in those patients are independent of glycemic control; intensive antihyperglycemic therapy was found to be ineffective in improving the prognosis of these complications. Evidence of vascular function deterioration in prediabetic patients implicates the involvement of mechanisms other than hyperglycemia in the development of cardiovascular dysfunction. Adipose inflammation constitutes a possible mechanism that is involved in the pathogenesis of diabetes and metabolic syndrome. We developed a rat model of mild hypercaloric (HC) stress with a delayed development of hyperglycemia to investigate the mechanism of cadiovascular dysfunction in early stages of metabolic challenge. We previously reported that prior to the development of hyperglycemia, perivascular adipose tissue inflammation was associated with cardiovascular structural and functional anomalies. No changes in blood glucose, body weight or blood pressure levels were observed in this rat model. Systemic inflammation was not detected in this rat model, however following 12 weeks of HC feeding, peri‐renal adipose tissue showed increased oxidative stress and inflammatory cytokine expression (IL‐1b). Moreover, proteinuria and hyperfiltration indicated an early stage of renovascular dysfunction. This renovascular dysfunction manifested as (1) loss of proper endothelial feedback, (2) loss of prostaglandin and nitric oxide activity, and (3) an uncontrolled vasodilation induced by upregulation of epoxyeicosatrienoic acid effect. Moreover, the renovascular dysfunction was associated with significant increases in renal oxidative stress, inflammatory mediators (IL‐1b and TGF‐b1) and culminated in renal structural damage. Glomerulosclerosis was increased following HC feeding as well as significant increases in the expression of a‐smooth muscle actin in proximal tubular cells suggesting possible epithelial to mesenchymal transformation. Ameliorating adipose inflammation by a two‐week treatment with non‐hypoglycemic doses of metformin (100 mg/Kg/day) or pioglitazone (2.5 mg/Kg/day), improved renovascular function and structural nephrotoxicity. These results provide evidence of an early progressive renal damage induced by localized perirenal adipose tissue inflammation in prediabetes.Support or Funding InformationResearch support: AUB‐FM grant #320186
Acute Fatiguing Exercise Alters Sarco‐endoplasmic Reticulum Stress‐related Signaling in Equine Skeletal Muscle
Authors: Klein Dylan Joseph , McKeever Kenneth , Anthony Tracy 
Published: April 2020

Sarco‐endoplasmic reticulum (S‐ER) stress results from physiological and pathological disturbances that alter S‐ER function. In turn, the unfolded protein response (UPR) and ubiquitin proteasome pathway (UPP) are activated in order to re‐establish S‐ER homeostasis and promote cellular resilience in the face of future cellular stressors. Unaccustomed, vigorous exercise (e.g. aerobic or resistance exercise) has been shown in the comparative mammalian literature to activate the UPR in skeletal muscle. As such, the S‐ER may play a crucial role in the adaptations of skeletal muscle to exercise. The horse represents a highly athletic and muscular mammal, yet no such research has been conducted in the horse. Eight (n=4 males, n=4 females; 3–8 yrs) unconditioned Standardbred horses completed a bout of high‐intensity fatiguing exercise in the form of a graded exercise test to determine the effects of exercise on UPR and UPP‐related markers in skeletal muscle. Biopsies were taken from the M. gluteus medius before, and at 3 h and 24 h post‐exercise, alongside time‐matched standing controls. Results showed that acute fatiguing exercise significantly increased phosphorylated eukaryotic initiation factor 2‐alpha (p<0.05) and tended to increase activating transcription factor 4 gene expression (p=0.096), but had no effect on additional UPR (e.g. Xbp‐1, Chop, Bip) or UPP (e.g. Fbxo32, Trim63)‐related mRNA transcripts. These results suggest that high‐intensity fatiguing exercise can alter UPR‐related signaling but does not induce a full transcriptional UPR or UPP in equine skeletal muscle at the time points measured.Support or Funding InformationUSDA NIFA NC1184, NIH DK109714
Kir4.1 is Critical for Regulation of ENaC and ROMK Activity in the Late Distal Nephron
Authors: Mutig Kerim , Wang Ming-Xiao , Zhang Dan-Dan , Lin Dao-Hong , Ellison David H. , Thomson Martin N. , Bachmann Sebastian , Wang Wen-Hui 
Published: April 2020

The extent of NaCl reabsorption in the early distal convoluted tubule (DCT1) via the apical Na+‐Cl− cotransporter (NCC) defines the sodium load of the ensuing late DCT (DCT2) and connecting tubule (CNT). DCT2 and CNT express the epithelial sodium channel (ENaC) and potassium Kir1.1 channel (ROMK) to perform electrogenic sodium‐dependent potassium secretion into the urine. Kidney‐specific deletion of Kir4.1 (Ks‐Kir4.1−/−) causes profound hypokalemia in mice, which may result from reduced DCT function and increased sodium load of DCT2/CNT, because potassium sensing via Kir4.1 is a critical step for NCC activation. Since Kir4.1 expression extends throughout DCT2 and CNT, we hypothesized that the deletion of Kir4.1 may also affect the expression and activity of ENaC and ROMK. To address this hypothesis we examined ENaC and ROMK functions by measuring the amiloride‐sensitive Na+ currents and TPNQ‐sensitive K+ currents in the DCT2/CNT of wild‐type (WT) and Ks‐Kir4.1−/− mice fed regular or K+‐deficient diets for three days. Cellular distribution of ENaC and ROMK was studied by immunofluorescence. K+‐deficient diet decreased amiloride‐sensitive Na currents from 205 pA to 120 pA at −60 mV and decreased TPNQ‐sensitive K currents from 1100 pA to 600 pA at −40 mV in WT animals. Ks‐Kir4.1−/− mice showed increased baseline Na+ (520 pA at −60 mV) and K+ currents (1600 pA at −40 mV). Feeding Ks‐Kir4.1−/− mice with K+‐deficient diet failed to inhibit ENaC and ROMK. Localization experiments revealed substantially increased ROMK signal intensities along DCT2 and CNT, which were identified by double immunostaining for parvalbumin, calbindin, or aquaporin 2. Moreover, DCT2 exhibited significant elongation in Ks‐Kir4.1−/− mice indicating nephron remodeling. We conclude that Kir4.1 regulates ENaC and ROMK functions in the DCT2 and CNT. Their upregulation in Ks‐Kir4.1−/− mice likely contributes to renal K wasting.Support or Funding InformationDeutsche Forschungsgemeinschaft grants MU2924/2‐2, BA700/22‐2, SFB 1365; National Institute of Health grants DK 54983 and DK 115366; Fondation LeDucq and NIDDK R0151496; Russian Academic Excellence project “5–100”.
ET‐1 Receptor Function in Women with Advancing Reproductive Age
Authors: McGinty Shane J. , Welti Laura M. , Kuczmarski Andrew V. , Shoemaker Leena N. , Moreau Kerrie L. , Wenner Megan M. 
Published: April 2020

Endothelin‐1 (ET‐1) contributes to endothelial dysfunction, a primary driver of hypertension and cardiovascular disease. Our lab has previously shown that the ETB receptor mediates vasodilation in premenopausal women (PRE), but this effect is lost in postmenopausal women (POST). Noticeable declines in endothelial function are evident early in the menopausal transition, but the function of the ETB receptor in perimenopausal women (PERI) is unclear.PURPOSEThe purpose of this study was to test the hypothesis that ETB‐mediated vasodilation progressively declines with advancing reproductive age in women.METHODSWe used the STRAW+10 staging criteria to classify women as PRE (n=12, 26±2 yrs, 23±1 kg/m2, 83±2 mmHg), PERI (n=9, 50±1 yrs, 24±1 kg/m2, 84±3 mmHg), or POST (n=11, 56±1 yrs, 24±1 kg/m2, 87±2 mmHg). Cutaneous vasodilatory responses to local heating were measured using laser doppler flowmetry during microdialysis perfusions of lactated Ringer’s (Control), ETB receptor blockade (BQ‐788, 300nM), and ETA receptor blockade (BQ‐123, 500nM). Cutaneous vascular conductance (CVC) was calculated during the plateau phase of local heating (42°C), and normalized to maximal vasodilation achieved by perfusion of sodium nitroprusside (28mM) and heating to 43°C.RESULTSPRE showed the greatest cutaneous vasodilation in response to local heating (PRE: 93±2; PERI: 84±2; POST: 88±2 %CVC max, P<0.05 vs PERI and POST). There was a trend for increased vasodilatory responses to ETB receptor blockade with advancing reproductive age (PRE: 85±3; PERI: 91±2; POST: 92±3 %CVC max, P=0.13). However, there were no differences in vasodilatory responses during ETA receptor blockade (PRE: 90±2; PERI: 91±3; POST: 92±3 %CVC max, P=0.84). Finally, brachial artery flow‐mediated dilation tended to decline (PRE: 7±1; PERI: 6±1; POST: 5±1 %Δ, P=0.09) while pulse wave velocity increased with advancing reproductive age (PRE: 6±0; PERI: 7±0; POST: 7±0 m/s, P<0.05 vs PERI and POST).CONCLUSIONSThese preliminary data suggest that adverse changes in vascular function, and potentially ETB receptor function, are evident early in PERI. Therefore, future research examining the role of the ET‐1 pathway in progressive vascular dysfunction throughout the menopausal transition is warranted.Support or Funding InformationNIH R01 HL 146558, P20 GM 113125
Signal Processing and Machine‐learning Algorithm to classify anesthesia depth
Authors: Reyes-Cruz Dario , Mosquera Oscar Leonardo , Botero-Rosas Daniel Alfonso , Gallego-Correa John Jairo , Leon-Ariza Henry H. , Duarte-Tamara Santiago , Botero-Machado Juan David , Rozo-Cespedes Laura , Garcia-Ramos Andres Felipe , Padron-Ayala Antonietta 
Published: April 2020

BackgroundAn algorithm with complexity measures, nonlinear dynamics, and neural networks were developed to detect and classify the anesthetic deep (AD). It has been shown that extreme anesthetic depth has been correlated with an increased risk of mortality. Likewise, intraoperative awareness has been reported in the anesthetic drugs under dosage.MethodsOur artificial intelligence classifier algorithm was developed using a Complexity Brainwave Index (CBI) and a heart rate variability parameter (HRVP). Data from 60 patients (25 men and 35 women), adults between 18 and 65 years of age undergoing surgical procedures (ASA I–II) were collected. The classifier was designed using multi‐layer feedforward neural networks with a hyperbolic activation function using the patient data set and their anesthesia records.ResultsThe CBI by itself showed a better prediction probability with Pk of 0.935 when compared with Datex‐Ohmeda index in which State Entropy and Response Entropy had a Pk of 0.884 and 0.899 respectively; also, our CBI showed a performance of 99% of the awake state and 93.3% for deep anesthesia state. Additionally, when combining the CBI and the HRVP, the C‐Statistic was 99% for the awake state, 87.41% for light anesthesia, 82,46% for general anesthesia, and 93.33% for deep anesthesia.ConclusionsOur results demonstrate that special biological signal filtering and a machine learning algorithm may be used to classify AD during a surgical procedure on ASA I–II patients, assisting anesthesiologists and clinicians in decision making.Support or Funding InformationUniversity of La Sabana
Effect of Streptozotocin (STZ) Concentration on Chemoreflex Function and Morphology of the Nucleus Tractus Solitarii in STZ‐Induced Alzheimer’s Disease
Authors: Humphrey Chuma M. , Hooker John W. , Thapa Mahima , Wilcox Mason J. , Ostrowski Daniela , Ostrowski Tim D. 
Published: April 2020

Alzheimer’s disease (AD) is associated with deterioration of memory and cognition due to changes in brain areas important for these functions. The majority of AD patients also suffer multiple episodes of breathing cessations (apneas) during sleep. AD‐related sleep apnea may be associated with the decline of brainstem centers that control breathing and chemoreflex function. The nucleus tractus solitarii (nTS) is a key region for respiratory control and any AD‐related deterioration of this nucleus critically impacts its function.In this study, we used the streptozotocin (STZ) ‐induced rat model for sporadic AD (6‐week old rats, N = 6–8 rats/group) and compared chemoreflex dysfunction to indices of morphological alterations in the nTS. Particularly, we compared data obtained two weeks following injections of either 2 mg/kg or 2× 1.5 mg/kg STZ. Peripheral chemoreflex function was tested with 10% O2 in a plethysmography chamber. While increased respiratory rate thirty minutes into hypoxia was significantly blunted with both STZ dosages, animals receiving 2 mg/kg STZ partially compensated with larger tidal volumes. Hence, minute ventilation (rate x volume) was only significantly decreased in animals that received 2× 1.5 mg/kg STZ. Consistent with previously published data analyzing memory dysfunction in this model, there was a trend for reduced overall hippocampal size for both STZ concentrations. Immunohistochemical analysis of neuronal density (Anti‐NeuN antibody) in the CA1 region showed no difference between both STZ concentrations and control. However, synaptic density (Anti‐Synaptophysin antibody) was significantly reduced in both STZ concentrations. The overall size of the caudal nTS (4 sections each 180 μm apart) in the brainstem exhibited a greater reduction in 2× 1.5 mg/kg STZ. NeuN density was not altered between STZ concentrations and control. Interestingly, despite the stronger decline of chemoreflex function and nTS size with 2× 1.5 mg/kg STZ, synaptic density in the nTS (calamus scriptorius area) yielded a significant reduction for 2 mg/kg STZ only.Our study shows that reduced nTS size and synaptic density may be underlying the early changes of chemoreflex dysfunction in this model of sporadic AD. 2× 1.5 mg/kg STZ seemed to have a greater impact on respiratory function and nTS size. However, the varying change in synaptic density of each STZ concentration may be due to regional differences, since nTS size at calamus scriptorius did not differ between groups. Future studies will incorporate analysis of more caudal and rostral sections.Support or Funding InformationTruScholar and MoLSAMP grant from Truman State University (TSU) to CMH, GIASR from TSU to MW, seed money from A.T. Still University to TDO
Exosomal Signaling by Skeletal Muscle: Role in Neuromuscular Ageing
Authors: Hemmings Kay , Pollock Natalie , Owen Euan , Mora Silvia , Brooks Susan , McArdle Anne 
Published: April 2020

Muscle mass and function are reduced with age in mammals and this is associated with disrupted neuromuscular interactions. Skeletal muscle mounts a robust stress response to contractions by an increased expression of Heat Shock Proteins (HSPs) that facilitate muscle remodeling, promote protein folding and clearance of damaged proteins. In contrast, other cell types including neuronal cells, are unable to mount a stress response. It has been proposed that HSPs may be transferred from one cell type to another in exosomes to maintain proteostasis in the recipient cells. Thus, speculation that the robust HSP response by muscle provides support to peripheral neuronal cells via exosomal transfer of HSPs is tempting. However, HSP generation by muscle following contractions is attenuated in old mice and humans. We hypothesise that inability of muscles of old mice to produce HSPs in response to contraction results in altered exosomal HSP transfer, and therefore a failure to maintain proteostasis in motor neurons, resulting in neuronal and muscle degeneration
(1).Muscle fibres were isolated from flexor digitorum bravis (FDB) muscles of adult (6–8 month) and old (24–26 month) mice, and initiated to contract using a non‐damaging electrical stimulation protocol
(2). Media was collected from quiescent fibres, and fibres immediately following contraction, and Extracellular Vesicles (EVs) purified using a Total Exosome Isolation kit (Thermo). NanoSight analysis was used to characterise the size and number of the EVs. Total protein content was determined and HSP levels were analysed by western blotting.Data demonstrated no significant difference in the total number of EVs released from quiescent fibres from adult and old mice, along with a similar increase in EVs released by muscle fibres of adult (2.7 fold) and old mice (3.1 fold) immediately following contraction compared with quiescent fibres. In contrast, the size distribution of the EVs from fibres of old mice was altered compared with EVs from adult fibres, and the total protein content of EVs was significantly less (40% decrease) in those released by quiescent old fibres compared with EVs of quiescent adult fibres. The lower protein content for EVs from old compared with adult fibres was maintained following stimulation.A 2.5 fold increase in HSP25 and a substantial increase in HSP60 content (from undetectable levels) was seen in EVs from fibres of adult mice immediately following contraction. In contrast, preliminary data suggested that the HSP60 content of EVs produced by quiescent muscle fibres from old mice is already elevated, with little further increase following contraction in a similar manner to muscles in vivo
(3). Additional data will examine the uptake of EVs by neuronal cells and the effect of age of donor on their uptake ability.Support or Funding InformationWith thanks to National Institute of Ageing (AG051442) and the University of Liverpool for their generous support.