bluuebunny/crossref_metadata_2025_split huggingface dataset:
Determining the role for Nuclear receptor SHP in liver and kidney metabolism
Authors: Shaw Ryan P.H. 
Published: April 2020

Nuclear receptors are a unique family of ligand‐activated transcription factors that can modulate gene expression across various cellular functions. Nuclear receptor SHP (Small Heterodimer Partner), is atypical such that it lacks the DNA binding domain and its endogenous ligand is currently unknown. SHP is well known for regulating hepatic bile acid synthesis as a downstream target of nuclear receptor FXR. But previously published reports suggest that SHP may control heart function, germ cell differentiation, and cellular transport. Therefore, we set to investigate SHP function in both liver and extra‐hepatic tissues using mouse models. Since SHP can regulate nuclear receptor Constitutive Androstane Receptor (CAR) that is primarily responsible for drug metabolism, we examined a role for SHP in coordinating detoxification pathways. In the liver, absence of SHP resulted in robust increases in cyclins in response to CAR activation despite no liver growth. Detoxification is largely controlled by a trifecta of organs consisting of the liver, gut, and kidney, where SHP expression is noticeable. In fact, some of the detoxifying phase I, II and III genes also control bile acid homeostasis. We have found under cholestatic conditions liver expression of phase I metabolic pathway genes (CYP1A2 and CYP2E10) were significantly repressed whereas phase II metabolic genes (GSTM1 and GSTA2) are upregulated in the absence of SHP. We also found that the deletion of FXR and SHP altered organic solute transporters and GSTA1/2 mRNA levels in kidneys. This data suggests that murine SHP may regulate phase I and II metabolic processes distinctly in the liver and potentially contribute towards glutathione conjugation in the kidney.Support or Funding InformationNIDDK(R01 DK113080 AE433)
Trait Anxiety and Blood Pressure Reactivity to Mental Stress
Authors: Bigalke Jeremy A. , Fonkoue Ida T. , Greenlund Ian M. , Carter Jason R. 
Published: April 2020

Chronic stress is a prevalent issue among the general population, and has been associated with other comorbid pathologies. Despite its widespread impact, the effects of chronic stress on cardiovascular outcomes are not well understood. The purpose of this study was to assess the role trait anxiety might play in blood pressure reactivity at the onset of psychological stress, namely mental arithmetic. We hypothesized that increased trait anxiety levels would be correlated with an augmented blood pressure response at the onset of mental stress, indicating a higher cardiovascular reactivity to stress. Twenty‐four adults (10 men, 14 women; 22±1 years) were assessed during a three‐minute supine baseline followed by five minutes of psychological stress (mental arithmetic). Physiological variables measured included heart rate (HR; electrocardiogram) and blood pressure (sphygmomanometer and finger plethysmography). Trait anxiety was measured prior to the experiment (Spielberger Trait Anxiety Inventory). Average raw and standardized trait anxiety levels were 32±2 and 42±2, respectively. Due to low representation of severe anxiety, a tertile analysis was performed on both raw (n=8 per tertile) and standardized trait (T1: n=8, T2: n=7, T3: n=9) anxiety levels to assess blood pressure reactivity between the different severities represented in our sample population. Mental stress significantly (p<0.001) increased mean arterial pressure (MAP; Δ10±1 mmHg), systolic pressure (SAP; Δ10±2 mmHg), diastolic pressure (DAP; Δ9±1 mmHg), and heart rate (HR; Δ14±1 beats/min), but these increases were not significantly different between tertiles (p>0.05). However, during the first minute following the onset of mental stress, ANOVA analysis revealed a significant difference in the increase of MAP between tertiles (p=0.05). Following post hoc analysis, the first raw trait anxiety tertile exhibited a greater increase (p<0.05) in MAP (Δ8 ±2 mmHg) when compared to tertiles two (Δ2±2 mmHg) and three (Δ2±2 mmHg). Similarly, the first standard trait anxiety tertile showed a significantly greater increase (p<0.05) in MAP (Δ8±2 mmHg) when compared to both tertile two (Δ2±2 mmHg) and three (Δ2±2 mmHg). Contrary to our hypothesis, the results of this study indicate a decreased cardiovascular stress response and potential autonomic dysregulation in individuals with heightened stress levels. These results suggest the use of subjective anxiety questionnaires may be helpful during autonomic function testing to better account for the potential role of anxiety in cardiovascular reactivity.Support or Funding InformationNIH R01 AA‐024892 and NIH R21 HL098676
Microbiota‐derived Purines Support Intestinal Proliferation and Mucus Barrier Integrity
Authors: Lee J. Scott , Wang Ruth , Goldberg Matthew , Kao Daniel , Colgan Sean 
Published: April 2020

The gastrointestinal mucosa forms a dynamic physical and biochemical barrier to isolate the host immune system from potentially pathogenic microorganisms. A dysfunctional barrier allows bacterial contact with and translocation across the epithelium. Recent studies have appreciated that epithelial barrier formation and maintenance is energetically demanding, yet the colonic epithelium exists in a rather energetically‐depleted state of physiological hypoxia. Moreover, the intestinal mucosa is short lived, undergoing turnover every 3 – 5 days, incurring a substantial need for nucleotide genesis to preserve the epithelial cell population and provide ATP for energy balance. In the present work, we demonstrate that large quantities of purines are made and released by the gut microbiota and that such microbiota‐derived purines (MDP) are available to the intestinal mucosa. Through a series of experiments in which MDP production was depleted by antibiotic treatment, and purines reconstituted by supplementation and colonization with purine‐producing bacteria, the contribution of MDP to colonic proliferation and energetics during DSS‐induced colitis was delineated. Through HPLC‐based metabolite analyses, exogenously supplied purines showed incorporation into the murine colonic purine metabolite pool, were utilized for nucleotide genesis, and promoted energy balance. Immunofluorescent and metabolite analyses revealed that DSS‐insulted colon tissue lacking MDP substrates were proliferatively stunted, with notable energetic and endoplasmic reticulum (ER) stress, to the detriment of mucus barrier integrity. Upon purine reconstitution, the energetic state of the tissue was improved and ER stress alleviated, with concomitant reclamation of proliferative capacity and mucus barrier sterility. Together, this work establishes MDP as a critical substrate for colonic tissue metabolism and facilitates mucosal homeostasis and inflammatory resolution.Support or Funding InformationThis work was supported by NIH grants F32DK122741, DK1047893, DK50189, DK095491, DK103712 and by the Veterans Administration Merit Award BX002182.
Control of Instant Membrane Resealing by Lysosomal Acid Ceramidase in Endothelial Cells
Authors: Huang Dandan , Li Guangbi , Yuan Xinxu , Zou Yao , Li Pin-Lan 
Published: April 2020

Previous studies have shown that lysosome exocytosis and ceramide platform formation in the outer leaflet of the lipid bilayer are essential for plasma membrane repair. As a lysosomal enzyme catalyzing ceramide hydrolysis, the role of acid ceramidase (AC) in the control of cell membrane repair remains unknown. In the present study, we tested a hypothesis that lysosomal AC‐mediating signaling plays a crucial role in instant membrane resealing of endothelial cells (ECs), which help maintain the integrity of EC membrane and related functional activity. By Western blot analysis, it was found that carmofur, an AC inhibitor, decreased the AC expression in murine ECs. On the contrary, Genistein, an AC activator, elevated the level of AC in these cells. Using wavelength‐switching fluorescent microscopy with propidium iodide (PI), a fluorescent membrane‐impermeant dye as membrane resealing marker and fura‐2 as intracellular Ca2+ indicator, we monitored instant membrane resealing following saponin‐induced membrane disruption simultaneously with Ca2+ influx recording in murine ECs. The speed of PI fluorescence increase (df/dt) within ECs and time to a peak of PI fluorescence elevation were used to reflect the instant membrane resealing. Under Ca2+‐free condition, we found that membrane resealing in ECs was enhanced by carmofur as shown by df/dt reduction, but inhibited by genistein (increase in df/dt). In Hanks’ buffer containing Ca2+, however, carmofur and genistein failed to alter membrane resealing of murine ECs when Ca2+ influx was increased. In isolated coronary ECs from WT/WT and Asah1fl/fl/Endocre mice, we demonstrated that AC gene knockout specifically in ECs remarkably enhanced membrane resealing following saponin‐induced membrane interruption, which also mainly occurred under Ca2+‐free condition. These results suggest that lysosomal AC expression and activity are critical for the regulation of instant membrane resealing in ECs after acute injury, which represents a Ca2+‐independent membrane repairing mechanism.Support or Funding InformationThis study was supported by NIH grants DK54927 and DK102539.
The Vascular Supply to Human Brown Adipose Tissue
Authors: Coolbaugh Crystal L. , George Mark K. , Hooijmans Melissa T. , Damon Bruce M. 
Published: April 2020

Brown adipose tissue (BAT) engages in non‐shivering thermogenesis in response to cold exposure. Several aspects of its function require significant arterial and venous supplies. For example, the arterial system delivers endocrine signaling molecules and metabolic substrates including glucose and non‐esterified fatty acids to both stimulate and fuel BAT thermogenesis. Heat produced from BAT is then presumed to transfer to the blood passing through the tissue to protect core body temperature in response to the initiating cold stimulus. However, whether human BAT contains such a vascular system is unknown. The purpose of this study was to characterize the arterial and venous supply to supraclavicular BAT. Six healthy subjects [4 men; age: 30.7 ± 5.8 yrs.; body mass index: 21.7 ± 3.5 kg/m2; total body fat % (dual‐energy x‐ray absorptiometry scan): 23.5 ± 6.2 %] underwent time‐of‐flight magnetic resonance angiography (MRA) of the arterial and venous systems and quantitative fat/water MR imaging (FWMRI) to identify BAT. Angiography images were reconstructed at 0.5×0.5×2.0 mm resolution. FWMRI was performed using a 21‐echo spoiled gradient‐echo sequence, with computation of the fat signal fraction using the manufacturer’s algorithms. FWMRI images were reconstructed at 1.0×1.0×4.0 mm resolution and then resized to match the resolution of the MRA data. The supraclavicular BAT depot was hand‐defined from the apex of the lung to its superior margin in the FWMRI images. Coronal, axial, and sagittal maximum intensity projections (MIPs) of the BAT regions were overlaid onto co‐registered MIPs of the arterial and venous angiograms. In five subjects, there was a single, tortuous branch of the second part of the subclavian artery that supplied the BAT depot; in the sixth subject there was insufficient conspicuity to trace this artery back to the subclavian artery. The arterial diameters ranged from 1.5–2.5 mm. In no case was the artery observed to pass completely through the supraclavicular BAT depot. In two subjects, there was a single 3.5 mm diameter vein returning from the head and passing through the medial portion of the BAT. In the other four subjects, there were 3–4 veins with 2–4 mm diameters that returned from the head and that passed through both the medial and lateral portions of the BAT depot. Individuals with the largest diameter arteries also tended to have the most extensive venous systems. These preliminary data suggest that MRA and FWMRI may be used to quantify the arterial and venous supplies of the human supraclavicular BAT depot. The extensive venous supply to BAT, coupled with the absence of arteries passing fully through this BAT depot, together suggest that the primary thermogenic role of the supraclavicular BAT depot is in rewarming blood returning from the head to the central circulation.Support or Funding InformationNIDDK/NIH R01‐DK‐105371, NCATS/NIH UL1‐TR000445
A First Report of altered bone microarchitecture in a commonly used mouse model of Alzheimer Disease (5XFAD Tg+)
Authors: Suryadevara Vidyani , Krehbiel Connor J. , Walker Chandler L. , Willis Monte 
Published: April 2020

Alzheimer’s disease (AD) is prevalent among 44 million people worldwide and is characterized by dementia and deterioration of cognitive capabilities. An accelerated bone loss (osteoporosis) is found in the early stages of the AD and correlates to the common morbidities observed in AD patients (e.g., hip fractures). We hypothesize that primary AD disease alters the bone structure and biomedical properties through direct and indirect (e.g., systemic crosstalk) mechanisms that are currently unknown. The 5XFAD Tg+ mice are a common preclinical AD model with five human AD‐related mutations, including three mutations in human APP (KM670/671NL, I716V, APP V717I) and 2 in human PSEN1 (M146L (A>C), L286V). These mice express high levels of Aβ42 and develop amyloid pathology and cognitive deficits by around four months. In the present study, we investigated the bone microarchitecture in 10‐month‐old hemizygous 5X FADTg+ compare to age‐ and strain‐matched wildtype controls. Specifically, left femurs were assessed by using mCT (SkyScan 1172, 9 mm resolution) for cortical and trabecular properties in the distal femur metaphysis (1 mm) and mid‐diaphysis regions for trabecular and cortical regions, respectively. Analysis of the 5X FAD Tg+ MALE femur microarchitecture revealed distinct changes in the cortical regions, including a significant reduction in total cross‐sectional area, bone marrow area, cortical thickness, periosteal and endocortical surface compared to wildtype controls. In contrast, the 5X FAD Tg+ FEMALE femur cortical properties were not different from wildtype controls. No change in trabecular microarchitecture was identified in MALE or FEMALE 5X FAD Tg+ mice. The alterations in the male cortical bone marrow area potentially indicate alterations through direct crosstalk with the brain, possibly through Aβ deposition, which is present outside of the brain at ten months, which we are presently investigating. The sex‐dependent effects on bone may be due to altered gender‐related transcription factors, possibly mimicking gender‐dependent changes in Aβ deposition and impaired memory levels.Support or Funding InformationLilly Foundation/Indiana Center for Musculoskeletal Health/ IU School of Medicine, Physician Scientist Initiative, Scientific Research Initiative
Documenting Donor Anatomical Variation and Pathology in the Anatomy Lab
Authors: Nesbitt Allison , Johnson Laura E. 
Published: April 2020

Anatomy donors are health professions students’ first patients and once‐in‐a‐lifetime teachers. Several institutions have introduced “first patient” humanistic exercises to connect human anatomy with clinical observation skills and for student reflection, including providing deidentified medical history of the donor to the students. For the past several years at the University of Missouri, students have been given personal and medical history provided by the donor at the time of enrollment. However, during the course of dissection, students frequently found anatomical variations and medical pathologies not previously documented by the donor to the program. These medical history discrepancies are partially due to the donor population of the University of Missouri Gift of Body Program, where some donors enroll as early as decades before death. To focus student attention on normal anatomical variation and the donor as a first patient with life history, a donor findings sheet was introduced in the summer of 2019 for a physical therapy anatomy course. On the first day of lab, students were introduced to their donors and were asked to observe and record visible markings, scars, and medical devices, and reason about equipment or procedures. The students briefly discussed the implications of their findings on the daily lives of their donors. Throughout the course, students continued to record anatomical variations, medical devices, and surgical procedures. After each of four units, students rotated anatomy laboratory tables to work with new donors and different classmates. A hand‐off from one table of students to the next was facilitated by the donor findings sheet. When comparing the donor findings sheet with the provided donor medical history, students recorded additional surface anatomy, anatomical variations or medical procedures that had not been reported in donor medical histories for thirteen of the sixteen donors (81%). Medical pathologies and procedures were documented more than anatomical variations. Pacemakers, hysterectomies, mastectomies, and spine conditions were most frequently recorded. Of the three donors with no previous medical history, students recorded medical conditions, surgeries or anatomical variations for two of the three donors. The documentation and discussion of the donor findings help students to see all patients as teachers, encourage exploration of human variation, practice documenting, and apply clinical observation and reasoning skills. Future analyses will incorporate student feedback of their perception of humanism in the anatomy lab, and their role in the documentation of variation and pathology in their donors.Support or Funding InformationNA
Variation in the Jaws and Teeth of the Amphisbaenian Zygaspis from Southern Africa
Authors: Meza Antonio , Akunne Nnamelu , Bell Christopher J. , Lewis Patrick J. 
Published: April 2020

Amphisbaenians are an understudied family of worm‐like reptiles consisting of over 150 extant species in 23 genera. Relatively little is known about the cranial anatomy of the group because most members of the clade are small and poorly represented in collections. With skulls of some species only a few millimeters long, traditional anatomical methods are difficult to use. Collection curators are also hesitant to allow destructive analysis of specimens, because few specimens are generally available. Most modern studies of cranial anatomy of amphisbaenians are based upon high‐resolution X‐ray CT scans. CT scanning is nondestructive and allows for detailed examination of even small elements. Most of those studies remain focused on a single specimen and therefore do not account for variation beyond potential asymmetry in a single specimen. We focus on a collection of specimens from a single genus, Zygaspis, and examine their upper and lower jaws and teeth to better estimate morphological variation within a tightly circumscribed clade of Amphisbaenans. The cranial anatomy of Z. quadrifrons is well described, although the description is based on a single specimen. That baseline description now allows for both inter‐ and intraspecific variation to be estimated by expanding the previous work to include other specimens of Z. quadrifrons and other species in the genus. Here, we examined Z. quadrifrons, Z. vandami, Z. niger, Z. ferox, Z. violacea, Z. dolichomenta, and Z. kafuensis, whose collective distribution spans most of southern Africa from the southern reaches of the Democratic Republic of the Congo and the Tanzania/Mozambique border to southern South Africa. One adult specimen from each species was CT scanned and analyzed with Amira software. We examined over 20 dental and mandibular characters, including tooth count, size, and orientation, the presence or absence of specific teeth and processes, and the morphology of the coronoid articulation with other elements of the mandible. We found significant variation in several features, including apparent variation in replacement teeth. Our preliminary results suggest that inter‐ and intraspecific variation does exist and should be accounted for in functional and phylogenetic studies. Further analysis of the genus, with an increased sample size and broadening to incorporate other cranial variables, would allow enhanced exploration of the morphological variation that occurs within Zygaspis.Support or Funding InformationSam Houston State University
Improving Understanding of Immunology for First Year Medical Students
Authors: Morrow Rebekah , Carter Ronda , Brown Jonathan R. , Hamilton Caleb 
Published: April 2020

BackgroundImmunology is a complex field of basic science. Understanding numerous concepts and details is necessary for pre‐clinical medical students to be able to apply immunological concepts to clinical cases and patient care. Faculty in the Hematology and Lymphatics course collaborated to change the way primary immunodeficiencies were taught in an effort to increase comprehension and integration of basic and clinical sciences.MethodsIn previous years, all immunology in the course was taught by basic sciences faculty. To change this approach, we added a lecture by a clinical faculty member which covered important/notable manifestations of primary immunodeficiencies. The basic sciences faculty member continued to emphasize underlying cellular defects that give rise to clinical presentations. We also included a new integrated event (a TBL session) taught by both clinical and basic sciences faculty, in which students were presented with clinical cases and asked to come up with differential diagnoses, explain their rationale and defend their choices, and explain the causes of patient symptoms.ResultsThe average score on immunology exam items increased by more than 10 percentage points. Average scores on the exam which included this material increased, while number of exam failures decreased. Student feedback also indicated that this approach was helpful for understanding the material.ConclusionsEmphasizing clinical correlations in teaching immunology to pre‐clinical medical students resulted in course improvements indicated by both quantitative and qualitative measures.