bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sleep Disturbance and Sympathetic Reactivity in Menopausal Women
Authors: Tahsin Chowdhury Tasnova , Panigrahy Nisha , Stokes William , Anselmo Miguel , Glazos Aline , Lee Emma , Reilly Cavan , Vanden Noven Marnie L. , Carter Jason R. , Keller‐Ross Manda L. 
Published: May 2022

IntroductionCardiovascular disease (CVD) is the leading cause of death in women. Sleep disturbances (DS), such as insomnia or frequent nocturnal awakenings, may increase the risk of CVD. Prior work suggests that autonomic blood pressure (BP) dysregulation in postmenopausal women may exaggerate risk of hypertension (HTN) and CVD. In addition, individuals with greater BP and sympathetic neural responses to stressors, such as a cold pressor test (CPT), demonstrate future risk for HTN development. Further, when exposed to 24‐hour sleep deprivation, older women, but not older men, demonstrate greater sympathetic activity. It is unknown, however, if women who experience DS demonstrate a greater sympathetic reactivity to a CPT. The purpose of this study was to determine if postmenopausal women with DS exhibit sympathetic reactivity to a CPT compared to women without DS.MethodsEighteen women (62±1yrs old; mean±SE) participated in two study visits. Visit 1: Informed consent and medical and health questionnaires. Visit 2: DS was assessed by the Menopause‐Specific Quality of Life questionnaire. Participants were classified as having disturbed sleep (DS; n=10) or non‐disturbed sleep (NDS; n=8) based on a scale of 1 indicating ‘none’ and 2‐8 being how bothersome it is. The study was conducted in the morning after overnight fast and abstinence of alcohol, caffeine, and exercise. Muscle sympathetic nerve activity (MSNA) was measured from the peroneal nerve using microneurography. Heart rate (HR) via 3‐lead electrocardiography, MSNA, and beat‐to‐beat BP using a non‐invasive finger cuff were measured during a 10‐min quiet rest and a two‐min CPT of the left hand.ResultsMenopause onset ranged from 40‐57yrs (50±1yrs). Body mass index was similar between groups (DS=25±1kg/m2, NDS=24±2kg/m2, p=0.53). MSNA burst incidence (bursts/100 heart beats, hb) increased throughout the CPT (time effect, p<0.01), but increases were not significantly different between DS (Δ19±6b/100hb; 95% CI [7,31]) and NDS (Δ11±6b/100hb; 95% CI [‐2,24]) (time*group, p=0.36) groups. Systolic BP, Diastolic BP and HR increased similarly (p>0.05) during the CPT for both groups. Sleep difficulty score was correlated with resting diastolic BP (r=0.43, p=0.03) and trended to correlate with the age of menopause (r= ‐0.37, p=0.05).ConclusionThese findings suggest that women with DS do not demonstrate greater sympathetic reactivity to a CPT, however, we did observe that DS was linked to greater diastolic BP at rest and appeared to be more bothersome for women who completed menopause at an earlier age. These findings suggest a pathway by which disrupted sleep may contribute to the future development of HTN and CVD in postmenopausal women.
Brain morphology and underlying genetic correlates in schizophrenia
Authors: Martínez Abadías Neus , Hostalet Noemí , Herrero Elena , Canales‐Rodríguez Erick J , Salvador Raymond , Pomarol‐Clotet Edith , Sevillano Xavier , Salgado‐Pineda Pilar , Fatjó‐Vilas Mar 
Published: May 2022

Schizophrenia (SZ) is a psychiatric disorder associated with brain and neurodevelopmental alterations that affects nearly 1% of the worldwide population. SZ is a complex disorder, polygenic and multifactorial, and despite large research efforts, its etiopathophysiology is still largely unknown. In this study, we assessed whether polymorphic variation in genes of the Sonic Hedgehog signaling pathway were associated with brain shape variation and contributed to differences between individuals diagnosed with SZ and healthy controls (HC). We genotyped three SNPs in SUFU, SHH and GLI3 genes (SUFU‐rs10786679, SHH‐rs10949808, GLI3‐rs3735361) in a sample of 308 subjects (113 patients with SZ and 195 HC), and quantified brain shape differences in a subsample of 100 subjects using the cartesian coordinates of brain landmarks recorded on head magnetic resonance scans.The genetic association analyses revealed that the T allele of the SHH‐rs10949808 was significantly associated with the risk for SZ, in both allelic (P=0.02586) and recessive (p=0.0312) models. Geometric Morphometric analyses showed that brain shape was significantly different between individuals diagnosed with SZ and HC. Discriminant functions correctly classified 72% of HC and 60% of patients based on brain morphology. Procrustes‐ANOVA analysis detected that diagnosis was a significant factor (P=0.001) and explained 5.11% of brain morphological variance; whereas any SNP presented significant effects in brain shape variance when analysed separately. However, when the three SNPs were combined into a single variable quantifying the number of risk variants (0 to 3) carried by each person, the analyses showed that patients with 3 risk variants presented a significantly different brain morphology as compared those carrying 2 (P=0.0297) or none risk variants (P=0.0487). These findings underscore the role of neurodevelopment‐related genes and Sonic Hedgehog pathway in SZ and the need to account for the polygenic nature of this disorder to further understand its etiology. Combining brain and genetic data, along with other morphological biomarkers, may open new lines of research in psychotic disorders.
KS‐WNK1 is Required to Translate the Response to Extreme Changes in Potassium Ingestion to NCC Activity and Expression
Authors: Bahena‐Lopez Jessica P. , Chavez‐Canales Maria , De‐la‐Peña Valeria , Murillo‐de‐Ozores Adrian R. , Vazquez Norma , Castañeda‐Bueno Maria , Ellison David H. , Ganba Gerado 
Published: May 2022

HypothesisKS‐WNK1 a shorter isoform of WNK1 that is exclusively expressed in the kidney, with abundance in the distal convoluted tubule (DCT), but its physiological role remains elusive. KS‐WNK1 stimulates NCC activity via WNK4‐SPAK pathway. Under low potassium diet, a known stimuli for NCC activity, WNK bodies are formed in DCT cells, and this requires the presence of KS‐WNK1. We recently shown that KS‐WNNK1 is highly sensitive to the CUL3‐KLHL3 complex (JCI 2020) and its expression under control conditions is negligible, but it is increased under low potassium diet (AJP Renal 2021). Thus, studies that have analyzed the role of KS‐WNK1 in mice exposed to normal K+ diet may not be the adequate approach. In wildlife, carnivorous mammals are exposed to cycles of no food and thus, zero K+ ingestion, followed by a vast meal in a few hours and thus, acute and high K+ ingestion. Due to the high sensitivity of KS‐WNK1 expression to K+ intake, we assessed NCC and KS‐WNK1 using a model from low K+ to high K+ diet to imitate what occurs in wildlife.MethodsWe exposed C57bl/6 (WT) and KS‐WNK1‐KO (KS‐KO) mice to 10 days of zero K+ diet (0KD) or normal K+ diet (NKD), followed by high K+ ingestion (HKD) (5%). Groups of mice were sacrificed before HKD and at 12 or 24 hours after HKD. We evaluated plasma K+ and by western blot we assessed NCC, phospho‐NCC, SPAK, phospho‐SPAK and KS‐WNK1 expression in kidney proteins.ResultsIn mice fed with NKD, there was no difference in plasma K+ or NCC phophorylation or expression between WT and KS‐KO mice. After 10 days of 0KD plasma K+ was significantly lower in KS‐KO mice than in WT mice (p<0.05) and NCC phosphorylation was higher in WT mice (p<0.05), consistently, KS‐WNK1 expression in WT mice was only observed in 0KD, but not in NKD and it is not present in KS‐KO mice. In WT mice pNCC/NCC dephosphorylation ratio at 12 hours after HKD was significantly higher in mice feed with 10 days of 0KD, than in mice fed with NKD, and accordingly, changes in plasma K+ were only observed in mice fed with 0KD and not in mice coming from NKD. The decrease in pNCC/tNCC dephosphorylation ratio after HKD, when mice were fed with 0KD was even lower in KS‐KO than in WT mice. Additionally, KS‐KO mice had higher plasma K+ after HKD coming from 0KD.ConclusionNo differences were observed between WT and KS‐KO in groups fed with NKD before the exposure to HKD. KS‐WNK1 was not expressed during NKD. In contrast, in mice fed with 0KD, our data show that activation of NCC was higher in WT that KS‐KO. Then, after HKD, down‐regulation of pNCC was more effective in WT than in KS‐KO mice. Therefore, our data suggest that KS‐WNK1 is not present and has no role when mice were fed with NKD, but is up‐regulated in 0KD and therefore, required to properly respond to extreme changes in potassium diet, as those that occurs in wildlife mammals.
Desmosome Dysregulation and MLC Phosphorylation Contribute to Loss of Barrier Integrity in DRA KO mice
Authors: Kumar Anoop , Anarwala Shawana , Abdul Qadeer Abdul , Kaur Jasleen , Jayawardena Dulari , Natarajan Anbazhagan Arivarasu , Priyamvada Shubha , Majumder Apurba , Saksena Seema , Alrefai Waddah A. , Gill Ravinder K. , Dudeja Pradeep K. 
Published: May 2022

DRA or SLC26A3 is the key transporter for chloride absorption in the mammalian intestine. Our recent studies demonstrated that DRA deficiency increased paracellular permeability and altered tight and adherens junction protein expression in mouse colon. However, the mechanisms underlying increased paracellular permeability and the role of intercellular junctional proteins (desmosomes) that play a critical role in the maintenance of intestinal barrier integrity in DRA KO mice are not well understood. Aim The current studies were undertaken to examine the role of desmosomes and Rho‐ROCK‐MLC phosphorylation pathway in colonic barrier integrity in DRA KO mice.MethodDRA KO and WT mice (M/F, 8‐10 weeks old) were used as an in‐vivo model. Protein expression was measured by immunoblotting and immunofluorescence, whereas mRNA expression was measured by QRT‐PCR and Rho A activity was examined utilizing the G‐LISA kit.ResultsOur results showed that the mRNA expression of desmosome proteins, desmoglein‐2 (DSG2) and desmocollin‐2 (DSC2) was significantly reduced (50‐70%, p<0.05) in DRA KO colons compared to wild‐type mice. Similarly, DSG2 protein expression was also significantly downregulated in DRA KO mice colon (~ 50%, p<0.05) as assessed by immunoblotting and immunostaining. We also examined the role of Rho‐ROCK‐MLC2 phosphorylation pathway in DRA KO mice. Interestingly, DRA KO mice colon showed a significant increase in Rho A protein expression (~5‐fold, p<0.01) and Rho A activity (~ 3.5‐fold, p<0.05) compared to WT. Furthermore, DRA KO mice also exhibited a significant decrease in ezrin phosphorylation (a downstream target of Rho A signaling) (~ 2‐fold, p<0.05) compared to WT mice. In addition, another downstream target of the Rho A pathway, MYPT‐1 (Myosin Phosphatase Target Subunit 1), also showed a significant decrease (~ 60%, p<0.05) in its protein expression in DRA KO mice. MYPT‐1 downregulation in DRA KO mice was associated with a significant increase in MLC‐2 phosphorylation (~ 2‐fold, p<0.05), which may have contributed to barrier dysfunction in colon of DRA KO mice. Since, our recent studies showed microbial dysbiosis in DRA KO mice, it was of interest to examine the role of gut microbiome by co‐housing WT and KO mice for 4 weeks for microbial exchange. Interestingly, co‐housed DRA KO mice also showed a significant but lower increase in Rho A expression (~ 3‐fold, p<0.05) and downregulation of MYPT‐1 expression (~ 60%, p<0.05) compared to co‐housed WT mice indicating that the regulation of Rho A and MYPT‐1 expression was only partly dependent on microbial dysbiosis observed in DRA KO mice.ConclusionOur studies highlight the novel role of desmosome dysregulation and increased MLC phosphorylation in compromised colonic barrier integrity in DRA KO mice.
Normalization of Oxygen‐Induced Retinopathy in the Mouse Supplementation with Myo/Nog Cells
Authors: Sutera Christopher K. , Wilgucki Grace , Weyback Edgar , Tsai E‐Jine , Brahmbhatt Rushil , Martin Mark , Adams Sarah , Lecker Paul , Johal Karanveer , Spikes John , Gorski Grzegorz , Gerhart Jacquelyn , Philp Nancy , George‐Weinstein Mindy , Bravo‐Nuevo Arturo 
Published: May 2022

IntroductionRetinopathy of Prematurity (ROP) is the leading cause of blindness in children, affecting 50% of infants born prior to gestational week 32. ROP is the result of postpartum supplemental oxygen administered to compensate for underdeveloped lungs. However, hyperoxia inhibits proper development supplying the retina. When the infants are returned to ambient air, an imbalance is present between the oxygen concentration and metabolic demands of retinal neurons. This leads to a rapid induction of angiogenesis, leaky blood vessels, neovascular tuft formation, and cell death. Myo/Nog cells that express MyoD, Noggin, and brain‐specific angiogenesis inhibitor 1 (BAI1) exhibit neuroprotective properties in the eye and brain and are proposed to play a role in regulating angiogenesis in ROP.MethodsAn Oxygen‐induced retinopathy (OIR) protocol was implemented in neonatal C57BL/6J mice by exposing them on postnatal days 7‐12 (P7‐P12) to hyperoxia (75% oxygen) and then returning them to normal air (21% oxygen) from P12 until P21. On P15, groups receiving treatments were intravitreally injected with 1 µL of phosphate‐buffered saline (PBS) containing 2000 Myo/Nog cells isolated from the brain with the BAI1 antibody (BAI1+ group), 2000 unsorted brain cells (BAI1‐ group), or PBS alone (PBS group). Electroretinography (ERG) was conducted on P21 to assess retinal function. Eyes were extracted and either dissected for flat‐mount observation of vasculature and tufts, or processed for histology. The thickness of the retina and number of TUNEL+ apoptotic cells were quantified in tissue sections of eyes processed for histology. Adobe Photoshop (Adobe, San Jose, CA) was used to splice together 9 images that made up each whole retina from flat‐mounted eyes. The blood vessels were selected using the “Lasso tool” on photoshop, quantified by number of pixels, and then compared to the total number of pixels in the whole retina.ResultsOIR induced neovascular tuft formation. Exogenously added Myo/Nog cells normalized the retinopathy induced by the OIR model, reducing the number of tufts and improving the quality of the vasculature. The vasculature was most developed in retinas injected with brain derived Myo/Nog cells. ERG data shows a trend towards improvement of visual function with Myo/Nog cell injection.ConclusionMyo/Nog cell regulation of retinal vascularization may be related to the production of BAI1. Improved visual function seen with injection of Myo/Nog cells may be related to both a reduction of neovascular tufts and direct effects on retinal neurons. Therefore Myo/Nog cells have therapeutic potential in the prevention of ROP by normalizing the vasculature and preventing neuronal cell death.
USP Potency Adjusted Bovine Mucosal Heparins are Comparable to Porcine Mucosal Heparin and May be Interchangeable for Anticoagulation
Authors: Olson Guy , Kouta Ahmed , Baig Nausheen , Jeske Walter , Hoppensteadt Debra , Iacobelli Massimo , Iqbal Omer , Bakhos Mamdouh , Cera Lee , Bansal Vinod , Fareed Jawed 
Published: May 2022

IntroductionMost of the heparins used clinically are derived from porcine intestinal mucosa. In contrast to the porcine mucosal heparin (PMH), the active pharmaceutical ingredient (API) of bovine mucosal heparin (BMH) exhibit a somewhat weaker USP potency as cross‐referenced against PMH. We hypothesized that at equivalent potencies as adjusted by using the USP reference, the BMH may exhibit comparable effects.Materials & MethodsMolecular weight profile and in vitro anticoagulant and antiprotease assays were used to compare the BMH with PMH. USP potency was measured in the amidolytic assays. Potency adjustments in reference to USP standard were made by weight basis. Potency adjusted BMH and PMH were injected at identical dosages (50 U/kg and 100 U/kg) to groups of human primates (n=4) via intravenous route and blood samples were collected for a 6 hour period of time.ResultsBMH exhibited higher molecular weight profiles compared to PMH as determined by size exclusion chromatography {BMH (Mw) 18.6 ± 0.5 kDa and PMH 15.4 ± 0.4 kDa}. BMH showed a potency of 130 U/mg whereas PMH showed a potency of 190 U/mg. When the BMH was compared at a potency adjusted concentration with PMH, it showed identical calibration curves in the aPTT and anti‐protease assays. Mean t1/2 ranged from 54 ± 11 min & to 71 ± 18 min for PMH & BMH respectively (p=>0.05). Mean AUC values based on anti‐Xa or anti‐IIa activities were comparable for both heparins. Mean Vd (~60 ml/kg) and Cl (~0.75 ml/kg/min) were also comparable for both heparins.ConclusionPotency adjusted based dosing results in comparable anticoagulants and pharmacokinetic profiles for BMH and PMH. Therefore, such dosing may provide uniform levels of anticoagulation for the parenteral indications for heparins. These observations suggest that potency equated BMH and PMH produced comparable anticoagulant effects and may be interchangeable.
Analysis of Academic Performance of Students Taking Physiology Reveals an Achievement Gap Relative to Student GPA
Authors: Wu Steven C. , Anderson Lisa C. 
Published: May 2022

We previously reported that the use of small stakes assessments in an undergraduate/graduate physiology class (PHSL3061/5061, Principles of Physiology) contributed to improved average test scores for physiology and biomedical engineering majors and reduced the number of non‐passing physiology majors (EB 2021). Our overall hypothesis is that using small stakes assessments could improve outcomes for all students.In this current study, we examined physiology majors from 2018‐2021 by race, gender, first generation status, class (sophomore, junior, senior), and indicated financial need. A typical physiology major taking PHSL3061/5061 tended to be white (60%), female (67%), non‐first generation student (75%), and in their senior year (60%).When small stakes assessments were given, the number of students achieving below 70% was reduced as previously reported. However, those students that achieved a final score below 70% tended to be black, indigenous, person of color (BIPOC) (60%), female (80%), first generation student (75%), in their senior year (60%), and indicated some financial need (60%). Moreover, when term GPAs versus final scores were plotted, this group tended to have a term GPA between 3.0‐3.5/4.0, revealing an achievement gap in PHSL3061 relative to their predicted performance based on GPA.We also compared academic performance (final score and term GPA at the end of the course) by race, gender, first generation, and class. The most significant differences in final score and term GPA were found between first generation and non‐first generation students.Overall, our data revealed a group of students that are not achieving scores relative to their GPAs. We believe that these analyses can identify achievement gaps sooner. Taken together, the use of small stakes assessments can still lead to improved outcomes for physiology students. Further analyses of physiology students by category could reveal other potential areas where there are achievement gaps.
Mice with Brain‐Specific Deletion of Hsd11b2 have an impaired renal vascular and tubular response to high salt intake
Authors: Bailey Matthew A. , Krilis Georgios , Stewart Kevin , Grenier Celine 
Published: May 2022

Loss‐of‐function mutations in Hsd11b2, the gene encoding the cortisol‐metabolising enzyme 11βHSD2, causes the hypertensive syndrome of Apparent Mineralocorticoid Excess. In affected individuals, overactivation of the mineralocorticoid receptor by cortisol is causative. Hypertension is salt‐sensitive, attributed to enhanced sodium reabsorption in the distal nephron and renal sodium retention. However, in the brain, 11βHSD2‐expressing neurons regulate salt appetite. We previously generated mice with conditional knockout of Hsd11b2 in the brain (Hsd11b2.BKO), which displayed enhanced salt preference and salt‐sensitive hypertension (DOI: 10.1161/CIRCULATIONAHA.115.019341). The mechanisms of salt‐sensitivity are unknown. In the current study we examined renal artery vasoreactivity and the in vivo acute pressure natriuresis response in male Hsd11b2.BKO mice and control littermates.Mice (n=10 per genotype/diet) were fed either high salt (3% Na) or 0.3% Na diet for 7 days. Animals were humanely killed, the renal arteries were isolated and mounted on a wire‐myograph to generate cumulative concentration‐response curves to phenylephrine and the nitric oxide donor, sodium nitroprusside. High salt diet significantly increased the sensitivity of the renal artery to phenylephrine‐induced vasoconstriction in Hsd11b2.BKO mice (LogEC50 0.3% diet ‐6.41±0.07 vs high salt ‐6.91±0.11; p=0.0013) but not in control mice. Sodium nitroprusside induced concentration‐dependent relaxation of renal arteries: the maximum relaxation was significantly reduced from 88±3% to 65±4% in Hsd11b2.BKO after high salt feeding (p<0.01); this was not seen in control mice. In other experiments, mice (n=5‐7 per genotype/diet) were anesthetised (thiobutabarbital sodium, 120mg/kg IP) and fractional renal sodium excretion was measured at baseline and following acutely increased blood pressure, achieved by sequential arterial ligation. In all mice, sodium excretion increased with blood pressure. In the high salt group, the pressure natriuresis response was significantly attenuated in Hsd11b2.BKO mice, compared to control animals.We find that genetic amplification of mineralocorticoid signalling in the brain attenuates the normal renal vascular and tubular adaptation to high salt intake. This regulation of renal salt excretion by the central nervous system may have implications for salt‐sensitive hypertension in humans.