bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Role of PVN MC4R Neural Pathway in Autonomic Control of Metabolic Homeostasis and Cardiovascular Function
Authors: Singh Uday , Saito Kenji , Cui Huxing 
Published: April 2020

Central melanocortin pathways, mainly via acting on melanocortin‐4 receptor (MC4R), play an important role in both energy balance and sympathetic traffics affecting cardiovascular function. MC4R deficiency in both humans and rodents causes obesity, insulin resistance and diabetes while maintaining low to normal sympathetic tone and blood pressure, suggesting a critical role of MC4R signaling in metabolic homeostasis and obesity‐associated sympathetic overdrive and hypertension. MC4R is widely expressed in the brain including hypothalamic paraventricular nucleus (PVN) which functions as an integrative center for energy metabolism and autonomic regulation. However, whether and how PVNMC4R pathways contribute to the sympathetic control of cardiovascular function and metabolic homeostasis remain incompletely understood. In present study, we first comprehensively mapped afferent projections of PVNMC4R neurons by stereotaxically delivering Cre‐dependent AAV driving expression of eYFP into the PVN of MC4R‐Cre knock‐in mice, which allow targeted anterograde tract‐tracing of PVNMC4R neurons throughout the brain. In addition to known brain region for feeding behavior (i.e. parabrachial nucleus), we found broad innervations of PVNMC4R neurons to various brain regions important for autonomic‐cardiovascular control and energy metabolism, including but not limited to nucleus of solitary tractus , dorsal motor nucleus of vagus, rostral ventrolateral medulla (RVLM) and spinal cord. Using a combination of sophisticated viral tools, we further reveal that thoracic spinal cord‐projecting PVNMC4R neurons are exclusively located in the posterolateral PVN and send collateral projections to RVLM. Functionally, microinjection of synthetic MC4R agonist (MTII) into the PVN evokes renal sympathetic nerve activity in anesthetized mice and chemogenetic activation of PVNMC4R neurons elevates blood pressure and decreases food intake in freely moving animals. Additionally, genetic ablation of PVNMC4R neurons in adult mice using Cre‐dependent AAV expressing Casp3 causes hyperphagia and massive weight gain (over 80% increase within 6 weeks). These results provide an important insight into the role of PVNMCR neural circuits in regulating metabolic homeostasis and cardiovascular function. Optogenetic and chemogenetic studies are ongoing to functionally dissect the neural circuits downstream of PVNMC4R neurons.Support or Funding InformationNational Institute of Health (R01), AHA Postdoctoral Grant Award (19POST34450083)
Instructional Hematology for Pre‐Health Undergraduates
Authors: Ogrodzinski Yvonne , Zubek John 
Published: April 2020

At Michigan State University (MSU), the physiology department’s lab course for pre‐health professionals places an emphasis on laboratory exercises relevant to healthcare and the development of data analysis, professional development, and problem solving skills. As such, the goal of the hematology laboratory experience is to help students understand the ripple effect of hematology and how it can be extended to other fields of medicine. This is done by exposing students to the collection of blood samples and related laboratory tests that can be a typical part of a health screening or onsite wellness visit. Even for those students who do not become hematologists, it is important to maintain current knowledge of the best practices regarding the treatment and testing required for the best patient service and understand how various blood disorders affect certain populations.We promote hematology learning through five blood testing stations in addition to microscope analysis. The five blood tests performed are hematocrit, blood typing, total lipid panel, prothrombin time and international normalized ratio (PT‐INR), and hemoglobin. Students will perform each of these blood tests with their own samples and are guided to the interpretation of each measurement with provided clinical standards. We also include the microscopic analysis of five live patient samples of blood with conditions including, sickle cell anemia, eosinophilia, acute myelogenous leukemia, and lymphoma. In analyzing each of these tests, students are tasked with relating their own data to overall health and clinical relevance. The learning objectives associated with these tests include the demonstration of safe handling of blood using Universal Precautions, among the ability to describe and recognize typical and pathologic values found in common blood tests. They are also required to explore the supporting physiology, such as the phases of hemostasis and consequences of incompatible blood transfusions. Students are able to practice their professional skills by teaching each other how to perform these tests after they have watched and performed their own, modeling the “see one, do one, teach one” pedagogy often found in clinical settings. Additionally, with the results and permission of our students, we are able to gather baseline blood data for this healthy age group and seek to compile and share these values as a composite look at typical data for this specific group.
A role for Angiotensin‐(1‐7) and its receptors in sprouting angiogenesis and vascular homeostasis
Authors: Grant Gary , Bernadoni Juliana Lech , Soh Hong Jie , Walther Thomas 
Published: April 2020

BackgroundAngiotensin converting enzyme 2 converts angiotensin (Ang) II into the biologically active heptapeptide Ang‐(1‐7). We have previously shown that Ang‐(1‐7) is involved in the stimulation and homeostasis of circulating endothelial progenitor cells, and that Ang‐(1‐7) is an endogenous ligand for the G protein‐coupled receptors Mas and MrgD. To better understand the role of the peptide in endothelial cell biology and homeostasis and the receptors involved, we aimed to investigate the effect of Ang‐(1‐7) on various functional parameters of endothelial cells.Methods and ResultsAng‐(1‐7) was just as effective as vascular endothelial growth factor (VEGF) at stimulating endothelial tube formation in an in‐vitro Matrigel based assay in HUVEC. To investigate the effects in a more physiological model, we isolated aortas from Mas, MrgD, and Mas/MrgD deficient animals together with age and gender matched controls in an ex‐vivo model of sprouting. While aortas with a deficiency in either Mas or MrgD still showed normal number and length of sprouts as wild type mice, aortic rings deficient for Mas/MrgD showed a reduction in sprout length by 87% and no of sprouts by 77% when compared with wild type controls. We were also able to show that Mas deficient mice had a reduction in circulating CD34+ cells, a marker for heamopoeitic stem cells. Finally, we were able to show that after shunting blood flow to the hind limb of mice in an in‐vivo hind limb ischemia assay, Ang‐(1‐7) was able to restore 62.2% of blood flow in comparison with 17.1% in solvent‐treated mice.ConclusionAll together, our data suggest a key role for Ang‐(1‐7) and its receptors in sprouting angiogenesis, vascular homeostasis, and thus might be a promising new option for the treatment of peripheral vascular disease.
Investigating the Function of Co‐activator‐associated Arginine Methyltransferase 1 (CARM1) During Denervation‐induced Skeletal Muscle Atrophy
Authors: Stouth Derek William , vanLieshout Tiffany , Ljubicic Vladimir 
Published: April 2020

CARM1 is a type I protein arginine methyltransferase (PRMT) that forms asymmetric dimethylarginines (ADMA) by transferring monomethyl groups to arginine residues on target proteins. We previously observed elevated CARM1 expression and methyltransferase activity in response to neurogenic muscle disuse. Transient knockdown of CARM1 in muscle also represses the progression of muscle wasting and the expression of atrophy‐related genes following denervation. Notably, CARM1 regulates intracellular signaling molecules that are important for atrophy such as AMP‐activated protein kinase (AMPK) and downstream unc‐51 like autophagy activating kinase 1 (ULK1), forkhead box class O (FOXO), and transcription factor EB (TFEB) in non‐muscle tissues. The purpose of this study was to more comprehensively elucidate the function of CARM1 during neurogenic muscle disuse. We employed the Cre/loxP system to generate skeletal muscle‐specific CARM1 knockout (mKO) mice. Following unilateral sectioning of the sciatic nerve, mKO and wild type (WT) mice were subjected to 3 and 7 days of denervation. The contralateral limb served as an internal control. Hematoxylin and eosin staining analyses were performed to assess cross‐sectional area (CSA) in the extensor digitorum longus (EDL) muscle. We also employed Western blot and immunoprecipitation analyses to evaluate protein expression and protein interaction levels, respectively, in the non‐denervated and denervated tibialis anterior muscles. Our CSA analyses revealed that the absence of CARM1 mitigated denervation‐induced atrophy in the EDL muscle after 7 days of disuse (p < 0.05). Compared to WT animals, phosphorylation levels of AMPK and ULK1 were lower (p < 0.05) in mKO mice following 3 days of neurogenic muscle disuse. We also report that CARM1 interacts with AMPK, FOXO1, and TFEB in skeletal muscle. Relative to the contralateral, non‐denervated control (CON) limb, the interactions between CARM1‐AMPK and CARM1‐FOXO1 increased (p < 0.05) after 3 days of denervation in WT mice. When compared to the CON limb, the CARM1‐TFEB interaction was lower (p < 0.05) in WT mice following 7 days of neurogenic muscle disuse. In comparison to WT animals, the methylation of AMPK was significantly blunted in mKO mice after 3 days of denervation, suggesting that CARM1 methyltransferase activity regulates AMPK signaling. Collectively, these results suggest that CARM1 interacts with intracellular signaling molecules that are integral for muscle wasting. Importantly, targeting the interplay between CARM1‐AMPK, CARM1‐FOXO1, and CARM1‐TFEB may provide a novel therapeutic strategy for mitigating neurogenic skeletal muscle atrophy.Support or Funding InformationNatural Sciences and Engineering Research Council of CanadaCanada Research Chairs
Dissect or not to dissect? Easy solution
Authors: Stashenko Vetaley 
Published: April 2020

Throughout the recorded past (from Edwin Smith Surgical Papyrus) anatomy education did not experience dramatic changes. Practically until the last 5–10 years we were using only a text and a cadaver. Only did generation Z start to experience an intervention of AI and VR in our dissection rooms and lecture halls. Literature research exhibits convincing evidence of the positive impact of these new pedagogical tools on student’s success and overall performance (Freeman et al. 2014; Michael 2006). Some new methods of active learning, however, have been proven to be more effective than others. Lombardi et al. (2014) observed that students who used plastic models, rather than prosected specimens or virtual dissections, scored considerably higher on both initial and follow‐up exams despite student perceptions that the different forms of actual dissections were of more value. Fancovicova et al. (2014) observed that students who had admittance to multiple forms of active learning performed at a higher level than students who had access to only one form (including dissection). Herur et al. (2011) reported that students who utilized multiple forms of active learning had significantly higher levels of retention at 15 and 30 days after the class than those who learned by passive means.There is a perception that dissection continues to be recommended as the golden standard of anatomical education. Our presentation will present our experience of exploration of the possibilities to improve student’s success through the creation of a technologically advanced anatomy classroom that allows the learning anatomy of living human beings, not only cadavers. First‐time students are able to hold their own 3D printed organs during lab exercises. We can observe anatomical variations and their effects on living specimens in real time. At the same time, traditional cadaver dissections allow us to appreciate the complexity of the human body.
Meta‐Analysis Reveals Gut Microbial Signatures in Colorectal Adenoma and A Link with Secondary Bile Acid Conversion
Authors: Wu Yuanqi , Jiao Na , Wu Dingfeng , Fang Sa , Gao Wenxing , He Xiaosheng , Zhu Lixin , Zhu Ruixin 
Published: April 2020

BackgroundColorectal adenoma is a common stage during the colorectal cancer (CRC) development. The early diagnosis during adenoma stage could be a key to effectively reduce CRC. Here, we examined the microbial biomarkers of adenoma aiming to identify non‐invasive early diagnosis markers for the prevention of CRC.DesignWe performed a meta‐analysis of four publicly available 16S rDNA datasets with 307 colorectal adenomas, 217 CRC and 252 control samples. Microbial compositions and functions were identified with DADA2 and PICRUSt2 in QIIME2. After adjusting confounding factors, differential analysis was conducted to determine the unbiased significant differential microbes and then Random Forest model was constructed to identify biomarkers. Finally, we applied internal and external validation to assess the diagnostic capabilities with these biomarkers.Results43 differential microbes between adenoma and control were observed. After adjusting the potential confounding factors, 11 of these microbes were identified as biomarkers that could distinguish adenoma from healthy status, with a robust diagnostic accuracy (AUC=0.80). Internal and external validation confirmed the robustness and consistent diagnostic capabilities of these biomarkers with an average AUC of 0.72. Meanwhile, we identified 117 differential microbes between adenoma and CRC. Among them, 26 microbes may serve as biomarkers to separate adenoma from CRC (AUC=0.8), with an average validation AUC of 0.77. Eubacterium ruminantium group was the only one species that appeared in both sets of biomarkers. In addition, multiple microbial functions were altered in microbiome, including secondary bile acid conversion as well as lipopolysaccharide metabolism.ConclusionMeta‐analysis strongly supports that microbial markers can distinguish among CRC, colorectal adenoma and healthy controls and therefore serve as non‐invasive screening tools for the early diagnosis and treatment of CRC. CRC and adenoma specific alterations in the microbial composition and microbial metabolic pathways provide potential targets for the prevention and intervention of CRC.Support or Funding InformationThis work was supported by National Natural Science Foundation of China 81774152 (to RZ) and 81770571 (to LZ).
Comprehensive analysis of policies of whole body donor programs within the United States
Authors: Elzie Carrie , Cruz Bianca 
Published: April 2020

Many schools around the United States use cadavers in their instruction; however, the acquisition of these bodies vary immensely from school to school. Previous studies have shown that many schools around the United States lack detail in their consent process. Therefore, we looked at all US whole body bequeathal programs (state and school specific) to assess the donor programs’ processes of selecting and receiving donors. Criteria reviewed included consent for education, consent for research, bequeathal policies, weight limit, reasons for refusal, time limit after death, and other policies. Programs of interest included all full body donation programs within the United States that were affiliated with or donated to colleges/universities. A total of 114 programs were analyzed.Programs that were no longer accepting donations were omitted. Information was gathered from published brochures and donation forms, as well as, direct inquiry with programs. Any information that could not be found through the consent forms or on the website was obtained by placing a call to the office. This was repeated for each donation program and the results were analyzed to compare the process, extent, and development of cadaver lab donation programs.All programs provided consent forms that specifically included the use for education. Consent for research was documented in 102 (89%) of the programs. For statewide programs, donors could request a specific school, although their desire was not guaranteed. In every program, donors were able to fill out donation forms in advance. In addition to individual bequeathal, many programs also allow donation by the next of kin. The majority of programs (55%) had a weight and or a BMI limit with the average of 240 pounds. Forty‐four (39%) programs had no weight limit but denied donors based on a BMI above 30. 5. Only 4% programs had no weight requirement and would evaluate the donors’ eligibility once the body was received. The most commonly cited reasons for refusal were autopsy, infectious disease, recent surgery, trauma, and malnourishment/obesity. Costs incurred to donate ranged from being free of cost to $750. At time of death, most facilities had a regimen of when they needed to receive the donation. All facilities requested to be notified as soon as possible and preferred receipt of the body anywhere between two and 168 hours from the time of death.A review of the donor programs within the US revealed mostly consistencies across policies. However, the biggest variable was related to cost. Future studies should look at the amount of donations each program receives and determine correlations between the aforementioned policies. Looking into ways to streamline the donation process and procedures would make it easier for potential donors to maximize their options and for all involved to be informed.
Metabolic responses to intermittent hypoxia are regulated by sex and gonadal hormones in mice.
Authors: Marcouiller François , Jochmans-Lemoine Alexandra , Ganouna Gauthier , Mouchiroud Mathilde , Laplante Mathieu , Marette André , Joseph Vincent 
Published: April 2020

Sleep apnea is a respiratory disease characterized by intermittent hypoxia (IH) due to repeated obstructions of the airways during sleep. Men and women after menopause are more likely to develop sleep apnea than women before menopause. In addition to disrupting sleep quality, sleep apnea is strongly associated with metabolic syndrome and type 2 diabetes, and the metabolic consequences of sleep apnea may vary according to sex or the hormonal status. We therefore used intact males, intact females, and ovariectomized (OVX) female mice to ask if IH induces sex‐specific metabolic responses and if endogenous female hormones prevent these effects. Within each group, mice were exposed to room air (RA) or IH (nadir 6% O2, 10 cycles/hour, 12 hours/day) during 2 weeks. Body weights were measured before and after the exposures to IH. At the end of the IH exposures, mice were fasted for 6 hours, a blood sample was drawn from the saphenous vein to measure fasting plasma glucose and insulin levels. We then performed intraperitoneal insulin or glucose tolerance tests to further assess glucose homeostasis. In distinct groups, we assessed liver levels of glycogen, triglycerides (TG), and expression levels of selected genes involved in glucose metabolism. In intact males, IH reduced weight gain, lowered the fasting levels of glucose and insulin in plasma, and slightly increased glucose tolerance. In intact females, the only effect of IH was a modest decrease of glucose tolerance. In OVX females, IH exposures reduced fasting glucose and insulin levels, induced insulin resistance, and led to a major glucose intolerance. In the liver, IH exposures slightly increased glycogen levels in males and OVX females and had a profound effect to decrease TG levels only in males. The expression levels of key liver glycolytic (LDH) and mitochondrial (Citrate synthase, PDH, PDK) genes were reduced by IH in males or in OVX females. We conclude that the metabolic consequences of IH exposures are sex specific. In females, endogenous ovarian hormones appear to prevent the development of a major glucose intolerance during IH exposure and help maintaining a normal expression pattern of hepatic genes involved in glucose metabolism. Surprisingly, the effects of IH are different in males and OVX females, suggesting that endogenous testosterone might also have a role in males.Support or Funding InformationSupported by CIHR.
Longitudinal analyses of epigenetic pathways in deployed active duty Service Members
Authors: Gautam Aarti , Yang Ruoting , Chakraborty Nabarun , Abu-Amara Duna , Hammamieh Rasha , Marmar Charles , Jett Marti 
Published: April 2020

BackgroundPre‐deployment identification of risk/ resilience factors is crucial in developing strategies to reduce or prevent post‐traumatic stress (PTSD) symptoms in military personnel. Management of PTSD is complicated because of the overlapping symptoms with the comorbid conditions and the diagnostic reliance on self‐report and time consuming psychological evaluation. A more comprehensive understanding of molecular pathophysiology of PTSD could facilitate an unbiased biomarker‐driven next‐generation intervention strategy. Herein, we study the epigenomic consequences of combat elicited PTSD in a longitudinal manner using blood methylation analysis.MethodsBlood samples were collected pre‐deployment, immediately post‐deployment, and at a three month follow‐up. This study assessed participants prior to stressor exposure during the index deployment and included comprehensive whole blood analysis. We collected self‐reports such as PTSD Checklist for DSM‐5 (PCL‐5) along with clinical tests. DNA methylation assays were carried out using Illumina 450K , followed by repeated‐measures ANOVA, correlation analysis, and PTSD differential analysis to characterize methylation status alterations associated with significant PTSD Check List (PCL) changes (PCL difference >10).ResultsWe identified 64 subjects with changes in PCL scores of 10 across the three phases of the sample collection. The correlation analysis between DNA methylation and the PCL5 trend identified genes from T cell pathways, dopamine receptor signaling and fatty acid activation pathways. We observed shifts in DNA methylation that distinguish PTSD from controls and also that tracks PTSD as measured by PCL5.ConclusionsWe observed shifts in DNA methylation related to deployment related adverse health outcomes. Active Duty cohort represented a real‐world scenario measured stress before and a short time after combat‐related trauma. Future work will integrate these epigenetic data with other molecular and clinical findings to better understand PTSD co‐morbidities, as well as susceptibility and resiliency.Support or Funding InformationResearch was conducted in compliance with all Federal requirements. The views expressed are those of the authors and do not constitute endorsement by the U.S. Army.