bluuebunny/crossref_metadata_2025_split huggingface dataset:
Assessing Gender Disparities in Total Joint Arthroplasty from the National Inpatient Sample Database
Authors: Cheah Cheryl , Hussein Inaya Hajj , Sayeed Zain , El-Othmani Mouhanad M. 
Published: April 2020

INTRODUCTIONDisparities in the health care system signify potential risks for vulnerable groups whose needs are not appropriately met. Several studies established basic inequalities between men and women with respect to health services available, including total joint arthroplasty (TJA) procedures‐. TJA has been successful in treating end‐stage arthritis, resulting in a steady increase in demand for the procedure over the last decades. This project aimed to assess and compare the differences in preoperative risk factors and postoperative outcomes between male and female patients undergoing TJA.METHODSOur study utilized de‐identified patient data from the National Inpatient Sample (NIS) database from 2006–2011. The NIS records ICD‐9‐CM codes to identify granular data involved in a patient’s in‐hospital stay. The data was stratified to create two cohorts of male and female patients that underwent primary TJA. We further stratified each cohort by matching for additional comorbidities using the Elixhauser Comorbidity Index. Postoperative and economic outcomes were measured for matched cohorts, respectively. Descriptive statistics were obtained, and univariate analyses using t‐tests and chi‐squared statistics were conducted for continuous and categorical data, respectively. Odds ratios with respective confidence intervals were calculated to assess the association of gender and post‐TJA complications.RESULTSFemale TJA patients present at a later age for TJA procedures, and present with comorbidities that result in them having greater odds of experiencing in‐hospital complications compared to male TJA patients. Furthermore, female TJA patients have a longer average inpatient stay than male TJA patients, incurring more than average total charges. Male TJA patients are more likely to be discharged home as compared to female TJA patients.CONCLUSIONUnderstanding these factors will help address the unmet needs and concerns of both genders regarding TJA, ensuring that qualified patients are able to access the necessary procedures for pain relief and functional improvementSupport or Funding InformationNone
Knowing Real Cardiac Anatomy Enhances Understanding of Virtual Anatomy
Authors: Spicer Diane E. , Bolender David , Mori Shumpei 
Published: April 2020

Present day advances in cardiac imaging, both clinically and with embryonic development, demonstrate the need for promoting attitudinally appropriate positioning of the heart in the dissection lab and with respect to the nomenclature of the cardiac structures. One of the first rules of anatomy is that all structures within the body should be described as viewed in the so‐called anatomical position. The true details of cardiac development are now being confirmed through the use of three dimensional imaging technology and can be directly correlated with the fully developed heart. In order to correlate the anatomic features depicted by actual dissection with the ever advancing imaging techniques, the anatomic details of the heart itself must be accurate. In the dissection lab, the heart is initially viewed within the thoracic cavity, but once removed it is typically assessed in the so‐called Valentine position. This no longer correlates with the clinical images or the actual position of the cardiac structures when viewed in their appropriate anatomic positon. The many nuances of cardiac anatomy can now be effectively taught using direct comparison between virtual and real dissection with both techniques allowing for adequate examination of the cardiac segments. Each of the cardiac segments and their junctions can then be assessed in their own right for their intrinsic anatomic features.The long axis of the heart lies roughly at a 45 degree angle to the long axis of the spine. The position of the ventricles extends from right posterior to left anterior with the so‐called right‐sided structures actually lying anterior to those described as being left‐sided. The aortic root forms the center piece of the heart and this is demonstrated well with virtual dissection. Of necessity, demonstrating this by physical dissection requires the removal of those structures located anterior to the aortic root, namely, portions of the inner heart curvature, subpulmonary infundibulm and pulmonary trunk. Once removed, the structures cannot be replaced as they can with virtual dissection. The three segments of the heart are the atriums, the ventricles and the arterial trunks, with valvar structures guarding the junctions between the segments. Developmentally it has now been demonstrated that there are two ‘true’ components making up the atrial septum. These septal structures are largely surrounded by folds that are now easily appreciated with the use virtual dissection techniques. Learning the component parts of the atriums, their appendages, true septums and interatrial folds is of high clinical significance with the development of new interventional procedures. The relationships at the atrioventricular and ventriculo‐arterial junctions are easily documented and compared between the two dissection techniques. Analysis of the cardiac segments is now performed via virtual dissection just as well, if not better than in the dissection lab.
Nucleic‐Acid Mediated Expression of Cardiopoietic Markers in Human Umbilical Cord‐Derived Mesenchymal Stem Cells
Authors: Arocha Sinibaldo Rafael Romero , Li Mark , Singh Raman Deep , Terzic Andre , Behfar Atta 
Published: April 2020

The management of patients with heart failure focuses on halting the progression of disease. To date, no therapeutic approach has been able to restore cardiac function to its original baseline state. Cell therapies, such as cardiopoietic (CP) stem cells, have shown to be promising platforms to restore cardiac function. The CP platform enhances the cardioregenerative potency of mesenchymal stem cells (MSCs). CP cells are characterized by the robust expression and nuclear translocation of cardiac transcription factors such Mesoderm Posterior Basic Helix‐Loop‐Helix Transcription Factor 1 (MESP1), early cardiac transcription factor Nkx2.5, myocyte enhancer factor 2C (Mef2C), and zinc finger‐containing transcription factor GATA4. Clinical trials using CP cells showed signs of safety and efficacy in improving cardiac function in patients with heart failure. However, the costs, time, and complexities associated with the manufacturing process have precluded the adoption of the therapy as a large‐scale clinical practice. In response, we adopted a microencapsulated‐modified‐messenger RNA (M3RNA) platform as a cost‐effective and time‐saving alternative to induce high expression of cardiopoietic markers. We hypothesized that the transfection of human umbilical cord‐derived mesenchymal stem cells (hUC‐MSCs) with M3RNA encoding mesodermal and/or cardiac transcription factor(s) will induce the expression of cardiopoietic markers (MESP1, Nkx2.5, Mef2C, and GATA4). hUC‐MSCs were transfected with M3RNA encoding Brachyury (this protein plays a key role in cardiomyocyte differentiation) and MESP1, Nkx2.5, Mef2C, and GATA4 using the transfection reagent Lipofectamine STEM. Protein expression was measured and quantified using fluorescence microscopy and flow cytometry. hUC‐MSCs transfected with M3RNA encoding mesodermal and/or cardiac transcription factor(s) demonstrated rapid protein expression at 4 hours post‐transfection that reached peak levels between 24 hours and 48 hours post‐transfection. Immunocytochemistry demonstrated similar morphology between transfected and non‐transfected cells. Thus, hUC‐MSCs can be transfected with M3RNA with high efficiency to produce rapid and predictable protein expression in vitro. We here demonstrate a simple, cost‐effective, and time‐saving approach to induce the expression of cardiopoietic markers in UC‐MSCs using M3RNA, which can serve as a highly translatable platform to circumvent many burdens associated with current strategies and development of cell‐based therapies for future clinical trials and practice.Support or Funding InformationMayo Clinic Center for Regenerative Medicine, Van Cleve Cardiac Regenerative Medicine Program, Marriott Foundation, Michael S. and Mary Sue Shannon Family, NIH NHLBI HL134664, Mayo Clinic Regenerative Sciences Post‐Baccalaureate Training Program
Ripk2 dictates blood insulin and glucose responses to cancer drug and microbial xenobiotics
Authors: Schertzer Jonathan , Duggan Brittany , Cavallari Joseph , Foley Kevin , Barra Nicole 
Published: April 2020

Xenobiotics, including therapeutic drugs, and components of microbes can promote inflammation that contributes to insulin resistance and dysglycemia. Tyrosine kinase inhibitors (TKIs) used in cancer have been considered as a therapy in diabetes and its complications. It is not clear which molecular target of TKIs impact blood glucose or insulin during obesity.One objective here was to define the role of the innate immune adapter protein, Ripk2 in TKI‐mediated changes in blood glucose and insulin during obesity. We tested gefitinib, which inhibits Ripk2 and imatinib, which does not inhibit Ripk2 as TKI interventions in diet‐induced obese mice. We also tested whether Ripk2 and these TKIs prevented the insulin sensitizing properties of bacterial components that we already know lower glucose and insulin resistance via Nod2‐Ripk2. We previously found specific bacterial cell components that lower blood glucose and insulin resistance. Now we found that crude bacterial extracts from the upper gut also lower blood glucose. Hence, the other objective was to determine if Ripk2 propagated insulin sensitizing properties of extracts from commensal bacteria.We found gefitinib lowered blood glucose during a glucose tolerance test (GTT) in WT, Nod1‐null, Nod2‐null and Ripk2‐null mice that were obese. Gefitinib lowered glucose stimulated blood insulin levels only in obese Ripk2‐null mice. Hence, deletion of Ripk2 in mice promoted the insulin sensitizing potential of gefitinib. Gefitinib, but not imatinib, prevented improvements in glucose control caused by a bacterial postbiotic that improves insulin sensitivity. Further, Ripk2 was required for improvements in glucose control when mice were injected bacterial extracts from the upper gut of obese or lean mice.We conclude that multiple TKIs, including gefitinib and imatinib lower blood glucose in obese mice, independent of Ripk2. However, Ripk2 participated in TKI‐induced lowering of blood insulin in response to an oral glucose load. The effects of TKIs on Ripk2‐mediated metabolism should be measured if this drug class is considered in treatment of diabetes or its complications. Also, the role of Ripk2 in propagating bacterial‐induced changes in blood glucose and insulin warrants further investigation.Support or Funding InformationSupported by a Natural Sciences and Engineering Research Council of Canada (NSERC) discovery grant. BD was supported by Ontario Graduate Scholarships. JC was supported by a Frederick Banting and Charles Best Canada Graduate Scholarship. KF was supported by a NSERC fellowship. JS holds a Canada Research Chair in Metabolic Inflammation.
Sex Differences in Baseline and Reactive Cerebrovascular Compliance
Authors: Moir M. Erin , Klassen Stephen A. , Zamir Mair , Shoemaker J. Kevin 
Published: April 2020

Adjustments in cerebrovascular resistance represent the primary characterization of cerebral autoregulation to date. However, recent studies have demonstrated that cerebrovascular compliance contributes to the relationship between BP and cerebral blood velocity (BV) during dynamic changes in BP. Therefore, the present study tested the hypotheses that i) hypotension‐induced autoregulatory processes involve increases in cerebrovascular compliance and ii) sex differences exist in cerebrovascular compliance. Twenty young healthy adults (24 ± 3 years, 10 females) completed a sit‐to‐stand protocol involving three minutes of sitting and three minutes of standing while brachial artery BP (Finapres Finometer) and middle cerebral artery BV (Multigon Neurovision) were collected. Individual BP (with temporal shift) and corresponding BV waveforms were input into a four‐element lumped parameter Windkessel model to calculate indices of cerebrovascular compliance (Ci) and resistance (Ri). Beginning 20 beats prior to standing and continuing 40 beats following the stand, every other heartbeat was extracted so that a total of 30 beats were analyzed (i.e., 10 beats during sitting, 20 beats during standing). Seated baseline Ci was calculated as the average of the 10 beats of sitting. Peak Ci minus seated baseline Ci determined the change in (Δ) Ci. Females demonstrated higher Ci than males during seated baseline (1.1e−3 ± 4.4e−4 vs. 7.1e−4 ± 2.1e−4 cm·s−1·mmHg−1; P = 0.04, d = 1.3). Upon standing, large and rapid increases in Ci were observed in both groups but females exhibited a lesser increase when compared with males (114 ± 48 vs. 202 ± 50 %; P < 0.01, d = 1.8). No differences were observed in peak Ci with standing (females: 2.1e−3 ± 6.7e−4, males: 2.1e−3 ± 5.5e−4 cm·s−1·mmHg−1; P = 0.89). While the drop in mean BP with standing was attenuated in females compared with males (−14 ± 5 vs. −25 ± 9 mmHg; P < 0.01, d = 1.5), no relationship existed between Δ Ci and Δ mean BP (b = −7.0e−7 cm·s−1·mmHg−2; r2 = 3.0e−4; b P = 0.94). Importantly, the increase in Ci preceded reductions in Ri (2 ± 2 vs. 11 ± 4 beats following standing; P < 0.01, d = 2.8). Therefore, large and rapid increases in Ci occur with standing‐induced hypotension that contribute to dynamic cerebral autoregulation. Further, females demonstrate attenuated Ci responses to standing despite exhibiting higher seated baseline Ci compared with males.Support or Funding InformationSupported by the Natural Sciences and Engineering Research Council of Canada.
The Impact of Spatial Ability on Learning with a 3D Stereoscopic Model of the Mediastinum
Authors: Labranche Leah , Terrell Mark , Wilson Tim D. , Carty Nancy , Kulesza Randy J. 
Published: April 2020

Three‐dimensional (3D) stereoscopic anatomy models have shown success in demonstrating complex spatial anatomical relationships. However, there is conflicting evidence as to whether or not such models are beneficial for students with low spatial visualization ability (Vz). A previous study suggests that students with low Vz may be hindered by the complex spatial cues provided by a 3D stereoscopic resource compared to students with high Vz. This study aimed to investigate the educational effectiveness of a digital 3D stereoscopic model of the human mediastinum, compared to a cadaveric specimen, for novice students in a biomedical masters‐level graduate program. In addition, this study aimed to further examine the effect of Vz on learning with a 3D stereoscopic anatomy model. We hypothesized that participants learning with the 3D stereoscopic model of the mediastinum would improve performance overall on an anatomy knowledge post‐test more than participants learning with a cadaveric specimen, and that high Vz participants would benefit more from the use of the 3D stereoscopic model compared to their low Vz counterparts. In addition, we hypothesized that participants learning with the 3D model of the mediastinum would rate the model more favorably on a post‐session survey compared to those learning with a cadaveric specimen. Participants were recruited from the Master of Medical Science (MMS) program at Lake Erie College of Osteopathic Medicine (LECOM), prior to the start of their Gross Anatomy course.Participants completed a demographic survey and Mental Rotations Test (MRT) pretest to determine their level of Vz. Participants were then assigned to either a 3D Group or a Cadaver Group, normalized for MRT score and sex. Each group was invited to a brief learning session using either a 3D stereoscopic model or cadaveric specimen of the mediastinum respectively. The 3D model was developed at LECOM using Amira® software, and projected stereoscopically using a dual projection system. All participants completed a pre‐ and post‐test in each session, consisting of spatially‐oriented multiple choice questions pertaining to anatomy of the mediastinum. Student satisfaction with either resource was also examined using a qualitative survey. Data collection and analysis will be completed in Spring 2020. Results of this study should be considered when developing and implementing anatomical resources for health professional education, to maximize learning for students of varying Vz.Support or Funding InformationFunded by the Lake Erie Consortium for Osteopathic Medical Training and the LECOM Internal Seed Grant
Caffeine Abolishes TrkB Receptor‐Dependent Respiratory‐Related Spinal Motor Facilitation in Isolated Neonatal Rat Brainstem‐Spinal Cords In Vitro
Authors: Johnson Stephen M. , Vasdev Ranveer M.S. , Miller Mckayla M. , Baker Tracy L. , Watters Jyoti J. 
Published: April 2020

Caffeine is the main treatment for apnea of prematurity because it stimulates breathing, reduces duration of respiratory support, and increases infant survival. Caffeine has multiple neuronal effects, but it is a well‐established adenosine A2a receptor (A2aR) antagonist. In adult rats, A2aR blockade increases the magnitude of intermittent hypoxia‐induced, TrkB receptor‐dependent, long‐term facilitation of phrenic motor output. In neonates, it is not known whether caffeine blocks A2aRs and enhances TrkB receptor‐induced facilitation of respiratory motor output. To test this question, neonatal (P0‐P3) rat brainstem‐spinal cords were isolated and respiratory‐related motor output recorded from C4‐C5 ventral spinal roots. Bath‐applied dihydroxyflavone (DHF, TrkB receptor agonist, 5–10 μM, 9‐min, n=22) increased respiratory motor burst amplitude by 13 ± 3% relative to baseline at 75 min following drug application, whereas vehicle dimethylsulfoxide‐treated time controls decreased burst amplitude by 11 ± 4% relative to baseline (n=15; p<0.001). A background caffeine application (50–250 μM; 15 min) that overlapped a DHF application (5–10 μM, 9 min) abolished DHF‐induced spinal motor facilitation (burst amplitude was decreased by 7 ± 4% relative to baseline at 75 min). The lack of DHF‐induced spinal motor facilitation with caffeine pretreatment could be due to decreased endogenous signaling in neonatal rat A2aRs (i.e., little or no crosstalk inhibition), or other caffeine effects, such as phosphodiesterase inhibition. If TrkB‐dependent spinal motor facilitation is beneficial in neonates, then caffeine administration may compromise one compensatory mechanism during apnea of prematurity.Support or Funding InformationSupported by: NS085226 (JJW), HL105511 (TLB)
HIV‐1 Capsid Binding Host Factor CPSF6 is Post Transcriptionally Regulated by the Cellular MicroRNA miR‐125b
Authors: Chaudhuri Evan , Dash Sabyasachi , Balasubramaniam Muthukumar , Holland Ocey L , Sowd Gregory , Villalta Fernando , Engelman Alan , Pandhare Jui , Dash Chandravanu 
Published: April 2020

The cleavage and polyadenylation specificity factor 6 (CPSF6) is a cellular protein involved in RNA cleavage and polyadenylation. Emerging evidence also suggest that CPSF6 plays a key role during HIV‐1 infection by guiding integration of the viral DNA into gene‐dense regions of the host genome. Since viral DNA integration is a critical step of HIV‐1 infection, the role of CPSF6 in the virus lifecycle is being intensely investigated. Surprisingly, the cellular mechanisms that regulate CPSF6 expression are largely unknown. In this study, we report a post‐transcriptional mechanism of regulation of CPSF6. Our initial bioinformatics analysis revealed that the 3′ untranslated region (3′UTR) of Cpsf6 contains a binding site for the cellular miRNA miR‐125b that is strikingly conserved across different mammalian species. Since miRNAs negatively regulate protein expression, we carried out knock‐down and over‐expression studies of miR‐125b. Results from these experiments revealed that miR‐125b expression is negatively associated with CPSF6 protein levels. Interestingly, HIV‐1 infection resulted in the down‐regulation of miR‐125b concurrent with induction of CPSF6. To probe that CPSF6 expression is post‐transcriptionally regulated by miR‐125b, we cloned the 3′UTR regions of Cpsf6 mRNA into a luciferase reporter. Results from luciferase assay provide evidence that miR‐125b expression negatively regulates Cpsf6 3′UTR activity. Accordingly, mutations in the miR‐125b seed sequences abrogated the regulatory effect of the miRNA on Cpsf6 3′UTR. Pull‐down studies demonstrated that miR‐125b physically interacts with the Cpsf6 mRNA. Continuing studies probe the necessity of productive HIV‐1 infection for negatively regulating miR‐125b expression as well as to elucidate the pathway through which HIV‐1 infection can knockdown miR‐125b expression. Collectively, these findings establish a post‐transcriptional mechanism of CPSF6 expression and describe a novel function of miR‐125b in virus‐host interaction.Support or Funding InformationThis work is partly supported by grants DA024558, DA30896, DA033892 and DA021471 from NIDA/NIH to CD. We also acknowledge the RCMI Grant G12MD007586, the Vanderbilt CTSA grant UL1RR024975, the Meharry Translational Research Center (MeTRC) CTSA grant (U54 RR026140 from NCRR/NIH, the U54 grant MD007593 from NIMHD/NIH, and Tennessee CFAR grant (P30 AI110527).
The F‐box Protein FBXL16 Upregulates the Stability of c‐myc Oncoprotein by Antagonizing FBW7 Function
Authors: Morel Marion , Shah Krushangi , Long Weiwen 
Published: April 2020

F‐box proteins are essential components of the SCF (SKP1‐CUL1‐F‐box) E3 ubiquitin ligases as they are responsible for substrate recognition. F‐box proteins bind to SKP1 through the F‐box motif and bring the substrate to the E3 ligase complex for ubiquitination. So far, 69 F‐box proteins have been identified in humans, and they fall into 3 families depending on their substrate recognition domains: FBXLs (Leucine‐Rich Repeats or LRR), FBXWs (WD repeats) and FBXOs (Other domains). FBXL16 is a poorly studied F‐box protein, which was shown to be a transcriptional target of E2F1 (Sato et al, 2010). As it doesn’t interact with the scaffold protein Cul1, FBXL16 might not form a functional SCF‐E3 ligase complex (Honarpour et al, 2014). In our present study, we found by data mining that FBXL16 is highly upregulated in many cancers, and its upregulation is often associated with poor patient survival, indicating that FBXL16 may play important roles in cancers. To decipher the role of FBXL16 in oncogenesis, we first analyzed its biochemical function in regulating protein levels of different SCF‐E3 substrates. Unexpectedly, we found that FBXL16 upregulates oncogenic proteins targeted by SCF‐E3 ligases, such as Steroid Receptor Coactivator 3 (SRC‐3) and c‐myc. Here, we have focused on c‐myc, a well‐known oncoprotein overexpressed in most human cancers, and found that FBXL16 interacts with and stabilizes c‐myc protein. This stabilization is dependent on c‐myc phosphorylation on both Threonine 58 and Serine 62, the phosphodegron recognized by FBW7 for its subsequent ubiquitination. Further, we found that FBXL16 antagonizes FBW7‐E3 ligase activity, leading to reduced c‐myc ubiquitination. In line with its role in upregulating the levels of oncoproteins, we found that FBXL16 promotes cancer cell growth and migration. Taken together, our findings reveal FBXL16 as a unique F‐Box protein antagonizing the activity of another F‐box protein FBW7 and as a new positive regulator of c‐myc. Further investigation is being carried out to determine the oncogenic roles of FBXL16 in vivo and may unravel FBXL16 as a new therapeutic target of cancers.Support or Funding InformationThis research was supported by NCI of the National Institutes of Health under award number R01CA193264.