bluuebunny/crossref_metadata_2025_split huggingface dataset:
Codeine Asymmetrically Inhibits The Laryngeal Adductor Reflex
Authors: Musselwhite M. Nicholas , Shen Tabitha Y. , Rose Melanie J. , Olsen Wendy L. , Pitts Teresa G. , Bolser Donald C. 
Published: April 2020

The laryngeal adductor reflex (LAR) is a fundamental airway protective behavior that prevents penetration of material from the upper airway into the trachea. Aspiration risk increases in humans after a single dose of an opioid and pneumonia is a common occurrence in opioid users. The LAR consists of a short latency (~10 ms), short duration (~10 ms) burst (R1) and a longer latency (~40ms) burst (R2) in laryngeal electromyogram (EMG) activity. The R1 LAR is thought to be primarily a brainstem reflex. We hypothesized that systemic administration of codeine, one of the most commonly prescribed opioids, would suppress the R1 LAR in an animal model that robustly expresses airway protective behaviors. The LAR was elicited in anesthetized, spontaneously breathing cats (n=13) by electrical stimulation (2 Hz, 0.1 ms pulse duration) of the superior laryngeal nerve (SLN) or mechanical stimulation of the vocal folds with a von Frey filament. Bilateral thyroarytenoid (TA) and midline posterior cricoarytenoid (PCA) muscle electromyograms (EMGs) were recorded. The R1 LAR manifested as a short latency (approx. 10 ms) evoked response consisting of peaks and troughs in both the TA and the PCA EMGs. Codeine (0.1–10 mg/kg, iv) dose dependently inhibited the magnitude of the contralateral TA and PCA LAR by approximately 60% but had no significant effect on the LAR in the ispilateral TA EMG. Similar lateralization of the effect of codeine was observed in animals in which the LAR was elicited by mechanical stimulation of the vocal folds. These effects were similar in animals whether only one or both SLNs were sectioned. In separate animals, the codeine dose response was conducted after pretreatment with the NMDA antagonist, MK‐801 (10 μg/kg) via the vertebral artery. MK‐801 enabled depression of the TA LAR on the ipsilateral side by iv codeine, but did not enhance the reduction in the contralateral TA or PCA LAR relative to animals that only received this opioid. These findings support lateralized suppression of the LAR by opioids that is mediated by central NMDA receptors. The differing effects of codeine on the LAR in the PCA and ipsilateral TA EMGs suggest that opioids may disrupt laryngeal protective actions through asymmetric positioning of the vocal folds.Support or Funding InformationSupported by NIH HL131716 and 3OT2OD023854
X‐ray crystal structure of MonCI, an epoxidase from the monensin biosynthesis pathway
Authors: Wang Qian , Nitka Tadeusz , Gao Qin , Lee Wen-Yee , Chen Xi , Irimpan Mathews , Vukovic Lela , Kim Chu-Young 
Published: April 2020

Polycyclic polyether natural products have gathered much attention due to their useful therapeutic properties including antimicrobial, antifungal, and anticancer activities. All polyether natural products contain multiple cyclic ether groups but they vary in the number, size, and arrangement of the cyclic ether groups. The ether rings found in natural polyethers are formed via enzymatic epoxidation and epoxide ring‐opening reactions. We have determined the 1.9 Å resolution crystal structure of MonCI, the flavin‐dependent epoxidase responsible for biosynthesis of the ionophore polyether antibiotic monensin. Our structural and molecular dynamics simulation studies indicate that the shape of the substrate‐binding pocket in MonCI dictates the stereoselectivity of epoxidation.Support or Funding InformationThe University of Texas System STARs Award
Investigating Sex Hormone Influence on Nesfatin‐1 Signaling through qPCR
Authors: Schnell Abigayle Lyn , Samson Willis K. , Yosten Gina L.C. 
Published: April 2020

Nesfatin‐1 is a potent anorectic peptide that participates in the hypothalamo‐pituitary‐adrenal (HPA) axis, and previous research indicates that the expression and function of nesfatin‐1 is influenced by female sex hormones. While nesfatin‐1 signaling in the HPA axis of male animals is well‐studied, nesfatin‐1 signaling in the HPA axis of female animals remains to be investigated. Changes in nesfatin‐1 action and expression in dispersed rat pituitaries as well as hypothalamus, pituitary, and adrenal gland tissues harvested across the estrus cycle was determined through use of qPCR. However, housekeeping genes used for normalization of qPCR data have not been validated for use in studies examining the role of female sex hormones. Therefore, tissues were collected from cycling female rats to perform qPCR experiments measuring expression of the most commonly used housekeeping genes in order to determine which housekeeping genes are stable across the estrus cycle. These studies suggest that nesfatin‐1 expression and signaling in the HPA is influenced by female sex hormones. Furthermore, our data indicate which housekeeping genes are most appropriate for research on sex differences.Support or Funding InformationNational Institute of Health
Regulation of glioblastoma tumor growth and stem cell properties through Gα12: an upstream player in YAP signaling
Authors: Chaim Olga M. , Miki Shunichiro , Ma Jianhui , Flores Anabel , Miyamoto Shigeki , Furnari Frank , Brown Joan Heller 
Published: April 2020

Glioblastoma multiforme (GBM), the most common and aggressive form of brain tumor, has been associated with the dysregulation of G‐protein coupled receptor signaling. Data from the Cancer Genome Atlas demonstrate remarkable upregulation of mRNA for the Gα12 protein, which is elevated in 26% of GBM patient tumors (the highest rate for all tumor samples surveyed). The Gα12 protein couples GPCRs to guanine nucleotide exchange factors (GEFs) for RhoA and was originally isolated as an oncogene. Furthermore, the subset of GPCRs that couples to Gα12 to activate RhoA includes S1P, LPA, and thrombin, inflammatory mediators that would be generated in the tumor cell environment. GPCR signaling to RhoA leads to activation of the transcriptional co‐activator YAP (Yes‐associated protein 1 gene). The role of YAP in growth of glioblastoma cells and in vivo GBM tumor development was explored in our previous studies (Yu et al. Oncogene 7(41): 5492–5507, 2018) using human glioblastoma cell lines and glioma stem cells (GSCs) derived from patient derived xenografts (PDX). We showed that shRNA mediated knockdown of YAP in GSC‐23 PDX cells significantly attenuated in vitro self‐renewal capability assessed by limiting dilution, oncogene expression, neurosphere formation, and stem cell gene expression. Orthotopic xenografts of the YAP knockdown PDX cells formed significantly smaller tumors and were of lower morbidity than wild‐type cells. Our current work examines the effects of Gα12, which would transduce effects of known and orphan GPCRs upstream that might be activated in the tumor environment to RhoA. We knocked down Gα12 using shRNA in two GBM cancer stem cell lines, GSC‐23 and HK‐281, decreasing Gα12 mRNA levels by 80% without compensatory upregulation in the expression of the homologous Gα13 protein. Loss of Gα12 attenuated GSC‐23 stemness as determined by limiting dilution assay and reduced mRNA levels for canonical stem cells genes (CCND1, NANONG, OCT4, SOX2 and NESTIN) by 35% to 60%. We are currently examining growth of GSC‐23 control and Gα12 knockdown cells following orthotopic injection into mouse brain. Histopathological findings revealed that the deletion of Gα12 reduced tumor‐derived cell migration and invasiveness. Gα12 knockdown tumors also presented with increased areas of necrosis. In vitro transwell assays confirmed that Gα12 knockdown reduced agonist‐stimulated GSC‐23 cell migration. We are exploring the role of YAP‐dependent genes (e.g. Thbs‐1, Dusp‐1, and CCN1) which were selectively decreased in tumors from PDX cells lacking Gα12 to determine their role in tumor cell migration and survival.Support or Funding InformationNIH grant CA218859
Tibetans resident at intermediate altitude (1300 m, 4327 ft) show similar hypoxic ventilatory responses but blunted heart rate responses to poikilocapnic hypoxia
Authors: Moya Esteban A. , Yu James J. , Brown Spencer , Gu Wanjun A. , Lawrence Elijah A. , Carlson Ryan , Brandes Anna , Wegeng William A. , Amann Kassaundra , McIntosh Scott , Powell Frank L. , Simonson Tatum S. 
Published: April 2020

Population living at high altitudes for hundreds of generations exhibit distinct respiratory and cardiovascular responses to hypoxia relative to other populations. The extent of these differences at intermediate altitude is less understood and could provide important insight into ancestry specific physiological responses in the absence of hypoxia. We hypothesized that Tibetans living at intermediate altitude (1300 m, 4327 ft) exhibit an increased hypoxic ventilatory response (HVR) and an elevated hypoxic heart rate response (HHR) compared to Han Chinese examined at the same altitude. To estimate O2 sensitivity, we measured ventilation (VI), heart rate (HR) and O2 saturation (Sat) under hyperoxic conditions (30% O2) and then during a hypoxic stimulus (10% minimum desaturation) keeping end‐tidal CO2 (EtCO2) levels constant (isocapnia) or allowing changes in the EtCO2 (poikilocapnia). We quantified HVR and HHR as change in VI and HR between hyperoxia and hypoxia standardized per the change in O2 Sat (ΔVI/ΔSat and ΔHR/ΔSat respectively). To estimate CO2 sensitivity, we measured changes in VI and HR responses between poikilocapnic and isocapnic hypoxia and standardized these changes per change in EtCO2 (ΔVI/ΔEtCO2 and ΔHR/ΔEtCO2 respectively). We did not find significant differences in ΔVI/ΔSat and ΔVI/ΔEtCO2 between Tibetan and Han Chinese during isocapnic and poikilocapnic hypoxia. The ΔHR/ΔSat between populations during isocapnic hypoxia was also not significantly different. However, Tibetans exhibited a blunted ΔHR/ΔSat during poikilocapnic hypoxia compared to Han Chinese (35.8% decrease, p < 0.02) with a significant ancestry effect in women (37.6% decrease, p < 0.009). The mean value of ΔHR/ΔEtCO2 was positive in the Han Chinese group but negative in Tibetan (169% difference, p < 0.02), indicating that Tibetans had a blunted HR response when CO2 is not controlled. Our results show that HVR responses in Tibetan individuals with high‐altitude ancestry is not different than Han Chinese residents at comparable intermediate altitude, but the HHR to hypoxia during poikilocapnia is blunted in individuals with Tibetan ancestry. These results suggest that, at intermediate altitude, individuals with Tibetan ancestry exhibit an attenuated heart rate response to hypoxia due to an increased contribution of the CO2 chemosensory response.Support or Funding InformationSupported by NIH 1RO1HL145470 and R01 HL‐081823.
The Big Q: Is Q‐methodology valid for evaluating a large‐scale, cross‐disciplinary anatomy and physiology course?
Authors: Saraco Anthony N. , Brewer-Deluce Danielle , Akhtar-Danesh Noori , Wainman Bruce C. 
Published: April 2020

IntroductionCourse evaluations are an important tool to gather feedback on the structure of a course, instructor effectiveness, and the overall learning experience. Critically, the Likert scale approach used by most institutions lacks course specificity and the difference between responses cannot be assumed equal (eg. “strongly agree – agree” vs. “agree – neutral”). This makes evaluating the effectiveness of a course and identifying areas that need improvement difficult. Q‐methodology is a technique that mitigates these issues by polling students for qualitative feedback statements that represent prevalent opinions of the course, then asking them to rank the statements relative to each other. Students are then clustered by shared opinions, values, and preferences.MethodsThis study uses Q‐methodology to assess student opinions on an undergraduate anatomy and physiology course (850 students). Specifically, students across five disciplines (midwifery, bachelor of health sciences, engineering, nursing, and integrated biomedical sciences) enrolled in the same second‐year undergraduate anatomy and physiology course were recruited into the study. All students experienced the same lecture and laboratory components as well as discipline‐specific tutorials. Students were asked to rank 37 statements relative to each other using an online platform. A by‐person factor analysis was completed using the qfactor program in Stata. Overall, the goal of this study was to validate Q‐methodology as an assessment modality across different populations experiencing the same course.Results143 students participated in the study (70.6% female, 25.2% male, 4.2% rather not specify; median age: 19, range: 18 – 38). The by‐person factor analysis classified students into three significantly different groups (22 students unassigned) representing 1) students who greatly appreciated the use of cadaveric specimens (n = 55), 2) students who were extremely dissatisfied by the means of evaluation (n = 40), and finally 3) students who despised the virtual reality (VR) supplementary resource (n = 26). Group 1 expected a significantly higher grade than the other two groups (p<0.05). No demographic data correlated with the groups, nor did discipline. All three groups agreed upon six consensus statements.ConclusionCritically, this study uncovered three distinct opinion patterns spanning all five academic disciplines within the course. The study provided guidance for course reform and suggested that discipline does not predict course evaluations. The study supports the use of Q‐methodology analyses for assessing student opinions on a large scale. Future work looks to re‐assess student course evaluations in the same course to determine how Q‐methodology outcomes change in response to “Q”‐directed course reform.
Concerted diurnal rhythms of gut microbiota with salt‐sensitive hypertension and renal inflammation
Authors: Mandal Juthika , Chakraborty Saroj , Cheng Xi , Galla Sarah , Hindupur Anay , Saha Piu , Yeoh Beng San , Mell Blair , Yeo Ji-Youn , Kumar Matam Vijay , Yang Tao , Joe Bina 
Published: April 2020

Aberrant diurnal rhythms of Blood Pressure (BP) are well known to be associated with hypertension, however, whether rhythmicity of microbiotal composition is associated with salt sensitive hypertension remains unknown. We hypothesized that BP and gut microbiotal composition follow synchronous rhythms in high salt fed Dahl Salt Salt‐Sensitive (S) rats and contribute to the progression of hypertension. To test this hypothesis, we examined groups of Dahl S rats for their diurnal rhythms of both the gut microbiota and blood pressure in low salt (0.3%) and high salt (2%) conditions. In high salt fed animals, Firmicutes/Bacteroidetes (F/B) ratio significantly changed between the dark (active) and light (rest) phases, which correlated with the diurnal rhythmicity of BP suggesting salt mediated rhythmic regulation of microbiota. Diurnal rhythms of Firmicutes, Bacteroidetes and Actinobacteria were independently associated with BP and significant in high salt fed animals. Discrete genera were observed to correlate independently or interactively with one or more of the following 3 factors‐1) BP rhythm, 2) dietary salt, 3) amplitude of BP. Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUST) analysis revealed diurnal rhythmicity of microbiotal pathways. During the active phase of the host, microbiota upregulated biosynthetic processes whereas during the resting phase of the host, microbiota upregulated degradation pathways of metabolites. These diurnal changes in microbiota, their functional pathways and BP response were prominently associated with a concerted rhythmicity of renal Lipocalin 2 and Endothelin1. Collectively, these data demonstrated the existence of synchronous diurnal rhythms of BP and renal inflammation with diurnal reshaping of gut microbiota in salt‐sensitive hypertension. Such a concerted rhythmicity with peaks observed at the mid‐active phase suggests that targeting this timepoint to reshape microbiota and/or intervene with medication could benefit hypertensives.Support or Funding InformationNational Institutes of Health (R01HL143082)
Targeting white matter microgliosis using minocycline in a co‐morbid preclinical rat model of Alzheimer’s disease and stroke
Authors: Agapova Victoria , Blanchet Victoria Helene , Allman Brian , Whitehead Shawn 
Published: April 2020

Current literature indicates a potential synergistic interaction between stroke and Alzheimer’s disease (AD). White matter (WM) inflammation, which is commonly triggered by cerebrovascular disease and AD, disrupts the normal function of white matter; and can trigger and exacerbate dementia‐type symptoms such as memory loss and executive dysfunction. Recent work in our lab demonstrated, for the first time, a link between stroke, AD‐related pathology, and WM inflammation. A unilateral lacunar stroke induction in a comorbid rat model of AD and stroke resulted in microglial activation within the WM tracts and subsequent impairment in behavioural flexibility, an important component of executive function. As such, the aim of the current study was to evaluate the effect of microglia targeting on WM pathology, executive function, learning, and memory in the co‐morbid rat model of AD (TgAPP21) and stroke. Minocycline, a tetracycline‐class antibiotic and an anti‐inflammatory drug, has been shown to decrease apoptosis, inflammation, and microglial activation following cerebrovascular injury. To study the behavioural outcomes of minocycline treatment, TgAPP21 rats received an endothelin‐1‐induced subcortical stroke at the age of 8 months. Following stroke, animals received intraperitoneal injections of minocycline or saline twice daily for four days to supress microglial activation. Cognitive behavioural flexibility post‐stroke was analyzed using set‐shifting operant conditioning test, while spatial learning and memory were assessed using Morris water maze. Immunohistochemistry was performed to evaluate the extent of microglial activation by detection of OX‐6 positive microglia in corpus callosum, internal capsule, and hippocampus. Minocycline treatment significantly decreased the number of errors committed by TgAPP21 rats on the visual cue component of the set‐shifting test, suggesting improved learning of the original visual cue task. However, minocycline also impaired animals’ ability to undergo an extra‐dimensional strategy shift from the original visual cue to a new spatial cue task, suggesting impaired behavioural flexibility. Further, minocycline treatment showed no significant effect on learning and memory of the Morris water maze task in TgAPP21 rats. Collectively, the data indicate that minocycline has distinct effects on the learning component of set‐shifting and Morris water maze tests, though further histological evaluation of OX‐6 positive microglia within WM tracts and hippocampus will contextualize current findings.Support or Funding InformationNatural Sciences and Engineering Research Council (NSERC), Canadian Institutes of Health Research (CIHR), Canadian Foundation for Innovation (CFI), Canadian Consortium for Neurodegeneration and Aging (CCNA)
The Powerhouse of Depression: The Impact of MTCH‐1 Deficiency on Reward Signaling in C. Elegans
Authors: Fong Megan J. , Langner Grace J. , Jazari Malianna Bahar , Sakiyama Matthew S. 
Published: April 2020

Major Depressive Disorder (MDD) is the leading cause of disability worldwide. One of MDD’s most troubling symptoms is the loss of reward firing, or anhedonia. Current publications indicate that MTCH‐2, a gene involved with mitochondrial transport, is related to a decrease in firing rates in the hippocampus of mice. Additionally, a GWAS reported an association between MTCH‐2 and neuroticism in humans. Consequently, we hypothesize that a MTCH‐2 related decrease in firing rates in the nucleus accumbens could potentially play a role in the development of depressive symptoms.The C. elegans MTCH‐1 protein shows an 87% homology to the human MTCH‐2 protein. Here, we examine the relationship between the MTCH‐1 gene, a previously unexamined gene, and C. Elegans reward firing. Because C. elegans reward firing levels have been associated with varying speed change fluidity in past studies, we measure C. elegans motility as a proxy for reward firing.In this study, we compare motility and gene expression between MTCH‐1 deficient worms and wildtype worms. We are using WormTracker to quantify motility based upon turn count in videos of worms recorded on ToupCam. Post all motility tests, a PCR and GFP assay on worms serve to verify their phenotypes. After our assays are concluded, we plan to use ANOVA for statistical analysis of our results. Thus, together, these data may demonstrate the influence of MTCH‐2 on reward firing, providing new insights into indicators and treatments of depression.Support or Funding InformationThis work was supported and funded by the Nueva School. The Shen Lab at Stanford University provided lab equipment and N2 worms. Worms and technical support were provided by Caenorhabditis Genetics Center (CGC) ‐ College of Biological Sciences.
Dysregulation of Skeletal Muscle Mitochondrial Function following Critical Illness: a Translational Approach
Authors: Gill Luther , Simon Liz , Molina Patricia 
Published: April 2020

Bioenergetic failure is a significant clinical consequence of sepsis‐induced critical illness and is characterized by reduced skeletal muscle mitochondrial density, and mitochondrial dysfunction. Early activation of mitochondrial biogenesis is associated with survival and improved physical function in critically ill patients. Therefore, investigating mechanisms associated with early activation of mitochondrial biogenesis may improve targeting of future rehabilitative strategies. A rodent cecal‐ligation and puncture (CLP) model was used to mimic sepsis‐induced critical illness. The objective of the study was to determine whether CLP impaired genes implicated in mitochondrial function in the diaphragm. The CLP model involved ligation of 50% of the cecum below the ileocecal valve in adult C57BL6 mice, followed by needle puncture of the cecum resulting in mid‐grade sepsis. Mice survived for 48 hours or more, following injury. Diaphragm and limb muscles were harvested 24 hours following CLP (N=6) and following a sham CLP procedure (N=6). Gene expression of mef2c, myh1, and pgc1‐α, were significantly decreased in the diaphragm of CLP injured animals when compared to controls. In addition, ubiquitin ligases, murf1 and atrogin were increased in the diaphragm 24 hours after injury (p< 0.01). Our results indicate that sepsis‐induced critical illness significantly impacts the expression of genes implicated in mitochondrial homeostasis and atrophy. Ongoing studies will identify whether CLP injury decreases skeletal muscle mitochondrial function.Support or Funding InformationNIH grants U54 GM104940 and Department of Physiology Funds.