bluuebunny/crossref_metadata_2025_split huggingface dataset:
Racial Differences in Serum Cystatin‐C Following Antenatal Corticosteroid Exposure
Authors: Zerihun Lillian M. , Nixon Patricia A. , Washburn Lisa K. , Gwathmey TanYa M. 
Published: November 2023

Antenatal corticosteroid (ANCS) administration to mothers at risk of pre‐term delivery has been linked to both transient and long‐term renal and cardiovascular damage in the exposed offspring. Previously, we reported that exposure to ANCS was associated with elevated levels of renal angiotensin II, which may contribute to renal inflammation and fibrosis over time. Cystatin‐C, a protease inhibitor excreted by glomerular filtration, is used as a biomarker for early‐stage renal damage, as its concentration is inversely correlated with glomerular filtration rate and it is thought to be less influenced by gender, age, and muscle mass than other biomarkers. The purpose of this study was to compare serum levels of Cystatin‐C in a cohort of young adults (~ 19 years of age) born prematurely (<37 weeks gestation) with very low birth weight (< 1500 g), who were exposed or not to ANCS. Potential race and gender‐specific effects were also examined. ANCS‐exposed Caucasians showed a trend for higher Cystatin‐C levels [1.00 ±0.05 mg/L; N=52] compared with unexposed Caucasians [0.89 ± 0.05 mg/L; N=34; P=0.091], while no differences were observed between ANCS‐exposed and unexposed African Americans. Importantly, ANCS‐exposed Caucasian males had significantly elevated serum Cystatin‐C [1.04 ± 0.06 mg/L; N=26] compared with ANCS‐exposed African American males [0.80 ± 0.05 mg/L; N=15; P=0.003]. Similarly, a trend was observed for higher serum Cystatin‐C in ANCS‐exposed Caucasian females [1.00 ± 0.08 mg/L; N=26] compared with ANCS‐exposed African American females [0.80 ± 0.05 mg/L; N=10; P=0.055]. However, no significant difference was observed between Caucasians and African Americans for unexposed males or females. These data suggest exposure to ANCS may have a greater impact towards increasing risk for early renal injury in Caucasian individuals than in African Americans at this age. These observations align with recent reports in the literature revealing racial differences in Cystatin‐C levels, and remain consistent with our previous findings of race and gender‐specific programming effects of ANCS on health outcomes in persons born with very low birth weight. These findings provide an important perspective for the alleviation of renal health disparities following ANCS exposure.Support or Funding InformationAHA 12CRP9390000 and HD047584
Chloroquine Is a Potent Pulmonary Vasodilator that Attenuates Hypoxia‐Induced Pulmonary Hypertension
Authors: Wu Kang 
Published: November 2023

Sustained pulmonary vasoconstriction and excessive pulmonary vascular wall thickening are two major causes for elevated pulmonary vascular resistance and pulmonary arterial pressure in patients with pulmonary arterial hypertension. Chloroquine, as an anti‐malaria agent, is found to have inhibitory effects on autophagy and a relaxant effect on airway smooth muscle cells. In this study, we observed that chloroquine (100–200 μM) significantly attenuates agonist‐ and high K+‐induced contraction in isolated rat pulmonary artery (PA). Pretreatment with L‐NAME or indomethacin and functional removal of endothelium failed to inhibit chloroquine‐induced relaxation in isolated PA rings pre‐constricted with phenylephrine or 40 mM K+. In pulmonary arterial smooth muscle cells (PASMCs), extracellular application of chloroquine significantly attenuated store‐operated Ca2+ entry induced by passive depletion of intracellularly stored Ca2+ in the sarcoplasmic reticulum using cyclopiazonic acid and partially inhibited ATP‐induced Ca2+ entry. Furthermore, chloroquine was shown to effectively attenuate Ca2+ entry via voltage‐dependent Ca2+ channels (VDCC). In vivo experiments showed that 50mg/kg chloroquine treatment (ip injections) significantly attenuated the development of pulmonary hypertension in rats exposed to chronic hypoxia (10% O2 for 3 weeks). These data indicate that chloroquine is a potent vasodilator of PA and a potential blocker of VDCC, store‐operated Ca2+ channels and receptor‐operated Ca2+ channels in PASMCs. The therapeutic potential of chloroquine on pulmonary hypertension is likely due to the combination of its vasodilative, anti‐proliferative and anti‐autophagic effects.Support or Funding InformationThis work was supported in part by the grants from the National Natural Science Foundation of China (81630004, 81470246, 81220108001, 81520108001), Guangzhou Department of Education Yangcheng Scholarship (12A001S), and Guangdong Province Universities, Colleges Pearl River Scholar Funded Scheme of China and China Scholarship Council (201608440324), as well as from the National Heart, Lung and Blood Institute of the National Institutes of Health (HL115014, HL066012).
P2X3 Receptor Antagonism Reduces the Occurrence of Apnoeas in Newborn Rats
Authors: Katayama Pedro Lourenço , Charles Ian , Pijacka Wioletta , Abdala Ana Paula , Salgado Helio Cesar , Ford Anthony P. , Paton Julian F. R. 
Published: November 2023

Apnoeas of prematurity (AoP) are a common problem in neonates. The mechanisms underlying this condition are not understood. We hypothesised hyperreflexia of afferent systems regulating breathing as a potential cause. Since P2X3 receptors are present on afferents controlling respiration and can mediated hyperreflexia (e.g. carotid body; Pijacka et al. 2016. Nat Med, 22, 1151–1159), we tested whether their antagonism would reduce AoP in new born rats. Rats were subjected to whole‐body plethysmography to record respiratory frequency (fR) and tidal volume (VT); minute ventilation (VE) was calculated (fR × VT). The frequency of apnoeas, which included both AoP and post‐sigh apnoeas, was counted over 10 min epochs at 5 and 15 min following administration of either a non‐brain penetrant P2X3 antagonist ‐ AF‐454 (15 mg/kg s.c.) or vehicle in separate rats. In 7 rats, basal apnoea frequency was 6.42 ± 1.32 per 10 min; AF‐454 reduced significantly the occurrence of these apnoeas at both 5 (2.42 ± 0.61; P>0.01) and 15 min post‐drug injection (3.4 ± 0.67; P>0.05). There was neither a change in fR, VT or MV after AF‐454 nor an effect from injection of vehicle (n=4). These data suggest that P2X3 receptor antagonism is a novel approach to reduce the occurrence of apnoeas in new born rats. We propose P2X3 receptor mediated afferent hyperreflexia as a mechanism triggering breathing dysfunction at birth.Support or Funding InformationBritish Heart Foundation, FAPESP and Afferent Pharmaceuticals
Behaviorally Inhibited Individuals Exhibit Greater Minute Ventilation and Breathing Frequency Than Non‐Inhibited Individuals When Breathing 4.5% CO2
Authors: Patschorke Emma , Evenhouse Annika , Grove Amanda , Kathryn McAuliffe , Santos Nick , Masini Marissa , Harris Morgan , Robinson Kyle , Williams Jordyn , Ferdman Leonard , Buchholz Kirstyn , Nicosia Tim , Miller Justin R , Miller Daniel P , Martino Paul F , Servatius Richard J 
Published: November 2023

Behavioral inhibition (BI) is a temperament in which an individual tends to avoid unfamiliar situations or environments. Individuals with high BI are more vulnerable to developing an anxiety disorder, such as Post‐Traumatic Stress Disorder (PTSD), when placed under stressful conditions. Behaviorally inhibited individuals learn faster and are slower to stop the response to a stimulus (Sheynin, 2005; Servatius, 2008). Our lab over the past several years has been investigating the relationship between a respiratory stress response to 4.5% CO2 and BI. BI is characterized by avoidance behavior, which is an active response aimed to reduce fear of a certain stimulus. In this study, a computer game was used as an aversive stimulus to detect BI. 4.5% CO2 was applied as a mild respiratory stimulant to detect any differences in those with BI compared to those without. One indication of PTSD is avoidance behaviors. 4.5% CO2 decreases the pH of the blood, hence causing an increase in frequency of breathing (fbr), tidal volume (VT), and inspired minute ventilation (VI). We hypothesize that individuals with high BI will exhibit greater increases in all parameters of breathing compared to individuals with low BI. The 4.5% CO2 was obtained by mixing room air with pure CO2 in a Tissot Spirometer and was validated using an Oxygraph O2 and CO2 analyzer. The mixed gas was then delivered from a 100 liter gas bag attached to a breathing tube attached to a Hans Rudolph two‐way nonrebreathing valve. The subjects placed the two‐way valve attached to a mouthpiece into their mouths and then had a nose clip placed over their noses to created a tight seal between the breathing gas bags and the participants. BI and non‐BI individuals were separated based on Adult Measure of Behavioral Inhibition (AMBI) and Retrospective Measure of Behavioral Inhibition (RMBI). Heart rate and respiratory data were collected using a BioPac computer data collection system while breathing room air and 4.5% CO2. In BI individuals, we observed a 35.9% (+/−33.3) increase in minute ventilation and a 32.4% (+/−32.1) increase in breathing frequency (n=4). In non‐BI individuals, we observed a −6.4% (+/−18.3) decrease in minute ventilation and a −15.1% (+/−2.9) decrease in breathing frequency (n=2). We observed no difference in tidal volume or heart rate for either group. In conclusion, individuals who scored high on the BI test have a greater response to a respiratory stimuli. Our future studies will include cortisol measurements by analyzing saliva samples taken before and after the test.Support or Funding InformationCarthage College Research and Development Grants
Expiratory Muscle Activation via High Frequency Spinal Cord Stimulation
Authors: Kowalski Krzysztof E , Romaniuk J Richard , Brose Steven W , Richmond Mary Ann , Kowalski Tomasz , DiMarco Anthony F 
Published: November 2023

BackgroundLack of an effective cough may result in the frequent aspiration of airway secretions and foreign material and the development of recurrent respiratory tract infections. In persons with spinal cord injury, lower thoracic low frequency spinal cord stimulation (conventional LF‐SCS, 50Hz, 15mA) results in large positive airway pressure generation (P), and is a useful method to restore an effective cough mechanism. Unfortunately, activation of the expiratory muscles via LF‐SCS requires high stimulus amplitudes, which may also cause unwanted side effects including stimulation of sensory fibers and therefore cannot be applied in patients with intact sensation.ObjectiveTo evaluate the effectiveness a novel method of expiratory muscle activation, which involves the application of high frequency spinal cord stimulation with low stimulus amplitudes (HF‐SCS; 500Hz, 1mA).MethodsStudies were performed on 13 anesthetized dogs. Multi contact stimulating electrodes were positioned over the dorsal surface of the lower thoracic and upper lumbar spinal cord. In one group of animals the effects of HF‐SCS and LF‐SCS on P were evaluated. SCS was applied at functional residual capacity (FRC) and also over a wide range of lung volumes. Given our previous success with LF‐SCS, these values were used as our gold standard to which all comparisons were made. In a second group of animals, the mechanism of expiratory muscle activation during HF‐SCS was evaluated. P and EMG recordings from the external oblique (EO) before and after spinal cord section at the T12 level were evaluated. Internal intercostal muscle (II) activation at the level of the stimulating electrode was also assessed via II EMG recordings, before and after T9 root section.ResultsFor both HF‐SCS and LF‐SCS, the optimum site for pressure generation was in the region of T9 spinal level (62±5 and 66±8cmH2O). P declined progressively at more rostral and caudal levels. In response to increasing lung volume, P increased in linear fashion during both HF‐SCS and LF‐SCS over the entire vital capacity range. For both HF‐SCS and LF‐SCS, bilateral dorsal column section significantly reduced EO EMG activity recorded below the level of spinal section and also resulted in a substantial fall in P (from 56±6 to 28±1cmH2O, p<0.05). Subsequent lateral funiculi section completely abolished those activities and resulted in further reductions in P. However, onset time of II EMG activity during HF‐SCS was significantly longer than obtained during direct T9 motor root activation (p<0.05).ConclusionThese results suggest that HF‐SCS produces a comparable level of expiratory muscle activation to that achieved with conventional stimulus parameters, but with much lower stimulus amplitudes and is more dependent upon synaptic pathways rather than direct motor root activation.Support or Funding InformationSupport: VA RR&D A1488‐R and NIH‐NINDS R01NS064157
Ventilatory Chemoreflexes and HMOX2 Variation in Individuals of Himalayan and Han Chinese Ancestry Residing at Sea Level
Authors: Heinrich Erica C , Djokic Matea , Powell Frank L , Simonson Tatum S 
Published: November 2023

Humans have lived on the Tibetan Plateau (>4,000 m) for thousands of years and exhibit distinct patterns of adaptation to high altitude. Individuals with Tibetan ancestry living at high altitude for their entire life have a greater hypoxic ventilatory response (HVR) than Han Chinese and Andeans resident at comparable altitudes. Tibetan highlanders also exhibit lower average hemoglobin concentration, a trait associated with SNP variants in the heme oxygenase 2 gene (HMOX2). The genomic region containing HMOX2 displays a strong signal of selection in several independent studies in Tibetans and HMOX2 has been linked to hypoxic chemosensitivity via carbon monoxide‐sensitive hydrogen sulfide signaling in the carotid body. The goals of our study were (1) to determine if HVR remains elevated in ancestral Tibetans residing at sea level and (2) to determine if putatively adaptive HMOX2 variants are associated with HVR in populations at sea level. We measured isocapnic HVR, hypercapnic ventilatory response (HCVR), and hematocrits in individuals of Himalayan ancestry (HA, Tibetan or Nepalese, female = 4; male = 3) or Han Chinese (HC, male = 7; female = 17) ancestry residing at sea level. We found no difference in the HVR across HA and HC men or women at sea level (men: HA=0.17±0.25, HC: 0.14±0.13 L min−1 %SaO2−1, NS; women: HA: 0.13±0.08, HC: 0.27±0.22, NS). However, HA women show decreased HCVR (HA: 0.14±0.14, HC: 0.59±0.28 L min−1 torr−1, p<0.01) and HA men show increased resting ventilation (HA: 10.85±1.86, HC: 7.58±1.66 L min−1, p<0.02) compared to HC women and men, respectively. Both HA men and women exhibit a higher resting oxygen saturation compared to HC (HA: 99.02±1.02, HC: 97.93±1.07%, p<0.02). Similar to previous observations, hematocrits tend to be lower on average in both HA men (HA: 43.1 ± 1.99; HC: 45.6 ± 2.34, p<0.14) and women (HA: 37.4±3.9; HC: 40.2±2.4, p<0.07). Our data show that the HVR in sea level residents of HA and HC ancestry are not different, suggesting that increases in the HVR with ventilatory acclimatization or decreases hypoxic desensitization (i.e. “blunting”) differs between these populations. We are completing SNP genotyping of HMOX2 in these populations based on Tibetan‐specific adaptive signals to determine if the HVR is associated with those adaptive variants.Support or Funding InformationThis work was supported by an NIH Ruth L. Kirschstein National Research Service Award (NRSA).
Gender Differences on Heart Rate Variability of Subjects Exposed to Regular Resistance Training Routine
Authors: Ramalho Ellen Sonnaly Villar , Souza‐Junior Estevam Luiz , Magnani Marciane , Braga Valdir A 
Published: November 2023

Heart rate variability (HRV) using frequency‐domain method is a tool for evaluating autonomic balance. In this cross‐sectional study, we investigated the low frequency (LF), high frequency (HF) and the LF/HF ratio components of the spectral analysis in men (n= 22) and women (n = 27) exposed to resistance training using the nerve express system analyzed by Student's t test. The study was approved by Ethics Committee of the Center for Health Sciences of the Federal University of Paraiba and was in accordance with the Helsinki Declaration of 1975, as revised in 2008. Our hypothesis was that there is a gender difference on HRV when subjects were exposed to resistance training. In men, the LF component was increased during supine (1171 ± 192 vs. 545 ± 74 ms2, P = 0.0067) and upright position after the orthostatic test (1824 ± 260 vs. 738 ± 133 v, P = 0.0011). In addition, LF/HF ratio, an index for sympathovagal balance, was increased in male subjects compared to females. These data suggest a possible gender difference on HRV of individuals exposed to resistance training.Support or Funding InformationSupported by Capes and CNPq
Acute Spinal Cord Injury Alters the Acquisition Phase of Learning in Long Evans Rats
Authors: Klein Evan , Cole Andrew , Tran Cindy , Workman Madeline , Zimmer M. Beth 
Published: November 2023

It is well known that spinal cord injury (SCI) affects regions of the body below the site of injury by damaging sensory and motor neural pathways. A few studies have also shown that SCI affects regions above the site of injury and affects higher cognitive processes such as learning and memory similar to traumatic brain injuries (concussions for example). Previous studies in our lab have shown that the acquisition phase of learning was altered two weeks after injury in young male rats. In addition, several studies have shown possible sex and/or age differences in neural responses after SCI. The current study was designed to determine if there are any differences between males and females on the effect of SCI on learning and memory. Young male and female Long Evans rats were anesthetized with ketamine and xylazine, and a C2 hemisection (=4), or a sham surgery (n=4) was performed. Male and female rats were given two weeks to recover, before using the Morris Water maze to examine learning and memory performance. Rats completed four trials a day for 5 days followed by a probe trial. This study will provide data to help our understanding of the impacts of SCI on higher brain function.Support or Funding InformationFerris Faculty Foundation, Ferris Faculty Research Grant, Ferris Dean's Grant (awarded to EK, AC, CT, MW).
Cerebral Edema and Blood Brain Barrier Dysfunction in the Dahl S Rat Model of Superimposed Preeclampsia
Authors: Maeda Kenji John , Warrington Junie P , Duncan Jeremy , Granger Joey P , Garrett Michael R , Ryan Michael J , Sasser Jennifer M 
Published: November 2023

Preeclampsia, characterized by hypertension and renal dysfunction in pregnancy, is associated with placental ischemia, which has been linked to increased blood‐brain barrier permeability and cerebral edema. We recently demonstrated that pregnant Dahl salt sensitive rats (Dahl S) closely mimic the maternal syndrome of preeclampsia. In this study, we tested the hypothesis that pregnant Dahl S rats develop cerebral vascular dysfunction associated with encephalopathies commonly observed in preeclamptic women. To test this, pregnant Dahl S and Sprague Dawley (SD, healthy pregnancy control) rats were studied during late pregnancy (gestational day 20, n=4–6). Mean arterial pressure (MAP) was significantly greater on day 20 of pregnancy in the Dahl S rat compared to SD (153±11 vs. 107±3 mmHg, p<0.05), and there was no drop in MAP during pregnancy in the Dahl S compared to virgin littermates (141±12, p=0.48). To assess blood‐brain barrier function, Evan's Blue extravasation into the brain was measured. Evan's Blue concentration was increased in both posterior (0.04±0.012 vs. 0.018±0.001 ng/g tissue/plasma concentration, p=0.07) and anterior (0.021±0.001 vs. 0.034±0.006, p=0.06) brain in pregnant Dahl S rats compared to virgin littermates, respectively. No difference was observed in either brain region in SD rats. In a separate group of Dahl S pregnant and virgin rats (n=5), brains were harvested and weighed on day 20, heated at 50°C for 72 hours, and weighed again to determine the dry:wet weight ratio as a measure of brain water content (edema). Greater water content was found in the posterior brain of the pregnant Dahl S compared to virgin littermates (78.0±0.1 vs. 77.4±0.2, p<0.05) with no significant difference in the anterior brain (79.2±0.2 vs. 78.8±0.3, p=0.33). These results suggest that the Dahl S rat model of superimposed preeclampsia exhibits blood brain barrier dysfunction and cerebral edema. Therefore, pregnant Dahl S rats may be a useful model to investigate mechanisms leading to cerebral vascular abnormalities that occur during preeclampsia.Support or Funding InformationNational Institutes of Health, American Society of Nephrology, UMMCIRSP
Nuclear transport of fungal transcription factors mediated by Importin‐α and specificities of this interaction
Authors: Bernardes Natália Elisa , Litvac Daniel , Bertolini Maria Célia , Panté Nelly , de Matos Fontes Marcos Roberto 
Published: November 2023

Importin‐α (Impα) is a protein that mediates nuclear import of macromolecules via recognition of nuclear localization sequences in the macromolecule that will be transported. Some proteins and transcription factors related with nitrogen and glycogen metabolism in fungus possess putative NLSs, suggesting that they can be transported into the nucleus via the classical nuclear import pathway, which is mediated by Impα and Importin‐β. This work presents biophysical and functional experiments that confirms the interaction between Impα from Neurospora crassa (NcImpα) and Mus musculus (MmImpα) complexed with potential NLSs of transcription factors NIT2; NCU1629 and PACC. Calorimetric analyses showed a high affinity of the NIT2_NLS, PACC_NLS and 1629_NLS peptides at the binding sites of NcImpα and a lower affinity with MmImpα. NcImpα/NIT2_NLS and MmImpα/NIT2_NLS complexes were cocrystallized and X‐ray diffraction data were collected with resolution of 2.5 and 1.5 Å, respectively. The final NcImpα/NIT2_NLS structure allowed unambiguously to observe that the NIT2_NLS peptide binds at major and minor binding sites of NcImpα. However, the final MmImpα/NIT2_NLS structure, showed the binding of the peptide just at the minor binding site. Nuclear import assays were performed with the potential NLS peptides conjugated with bovine serum albumin. Dextran was used to confirm the permeabilization of the cytoplasmatic membrane of cells by digitonin, without damaging the nuclear envelope. The nuclear import assays with NIT2‐NLS‐BSA‐Cy3 and 1629‐NLS‐BSA‐Cy3 indicated that a significant amount of these complexes were imported into the nucleus in digitonin‐permeabilized cells, incubated with cytosol from rabbit and an energy regenerating system. However the nuclear import was more efficient when a mammalian peptide was used, as confirmed by the quantification performed with Image J. The experiments confirmed that the peptides are functional NLSs, with high affinity to Impα and evidenced specificities of the interaction between NLS peptides with Impα from different organisms.Support or Funding InformationFAPESP ‐ São Paulo State Foundation