bluuebunny/crossref_metadata_2025_split huggingface dataset:
The ghrelin/leptin imbalance during cholestasis is driven by peripheral S1P2R‐dependent bile acid signaling
Authors: DeMorrow Sharon , Zigman Jeffrey , McMillin Matthew 
Published: November 2023

During the course of chronic cholestatic liver diseases cholangiocytes exhibit marked proliferative capacity followed by cholangiocyte loss. Dysregulation in the hormones controlling energy expenditure and food intake have been demonstrated as a consequence of cholestatic liver diseases. Specifically, in patients with primary biliary cirrhosis, circulating leptin levels are increased whereas, ghrelin, its counterpart, is decreased, although the cause of this imbalance is largely unknown. Increased serum bile acids are a key feature of cholestasis and are blamed for some of the extrahepatic consequences of these diseases. Bile acids are capable of signaling via a number of receptors including the sphingosine‐1 phosphate 2 receptor (S1P2R). The aims of this study were to assess the role of bile acid signaling in the imbalance between ghrelin and leptin. In a rat model of cholestasis (bile duct ligation; BDL) circulating levels of leptin was increased and ghrelin levels were suppressed. Ghrelin and leptin are weakly expressed in the liver and expression levels are unchanged during cholestasis, suggesting that ghrelin and leptin are originating from extrahepatic sources. Total ghrelin protein in the stomach was decreased after BDL surgery, as was the protein required for bioactivation of ghrelin (ghrelin O‐acyltransferase; GOAT). Furthermore, treatment with recombinant ghrelin decreased cholangiocyte proliferation (as assessed by cytokeratin‐19 expression) and markers of biliary fibrosis (a‐smooth muscle actin, collagen 1a1, and fibronectin 1) after BDL. Conversely, leptin expression in adipose tissue was increased after BDL and contributed to cholangiocyte proliferation and fibrosis. The imbalance between ghrelin and leptin after BDL could be attenuated in rats fed a diet enriched in the bile acid sequestrant cholestyramine. In vitro, treatment of mouse gastric ghrelin‐expressing cells with the conjugated bile acids taurocholic acid (TCA) and glycochenodeoxycholic acid (GCDA) inhibited ghrelin mRNA expression and could be prevented by pretreatment with the S1P2R antagonist JTE013. Similarly, the S1P2R antagonist prevented TCA‐induced upregulation of leptin in differentiated adipocytes. Taken together our data supports the observation that an imbalance between ghrelin and leptin exists during cholestasis that contributes to the resulting liver pathology. Furthermore our data suggests that this imbalance is as a consequence of S1P2R‐mediated bile acid signaling in the periphery.Support or Funding InformationThe following study was funded by an NIH R01 award (DK082435), and a VA Merit award (BX002638‐01) from the United States Department of Veterans Affairs Biomedical Laboratory Research and Development Service (BLR&D) to Dr. DeMorrow
Regulation of mesenchymal phenotypes by microRNA‐21 during alcohol‐induced liver injury
Authors: Meng Fanyin , Francis Heather , McDaniel Kelly , Alpini Gianfranco 
Published: November 2023

BackgroundMicroRNAs belong to the heterogeneous class of non‐coding RNAs (ncRNAs) that regulate gene expression in a sequence specific manner. The activation of miR‐21 and mesenchymal signaling is recognized as the key event of alcoholic liver injury and hepatic fibrosis. The current study was aimed to characterize the functional role of microRNA‐21 regulated mesenchymal phenotypes in mice liver with chronic and binge ethanol feeding (the NIAAA model) in vivo and activated human hepatic stellate cells (HSCs) in vitro.MethodsmiRNA expression in TGF‐β treated HSCs, as well as in 5 weeks chronic and binge ethanol feeding mouse liver specimen (with or without anti‐miR‐21 Vivo‐Morpholino treatment) and control HSCs and liver tissue, was assessed using a hybridization based microarray and by real‐time PCR, respectively. The mesenchymal phenotypes and the activation of HSCs were monitored by Western blot and real‐time PCR analysis through specific markers such as vimentin, S100A4, α‐SMA, laminin, fibronectin and MMPs.ResultsThe total liver histopathology score increased in chronic ethanol feeding group relative to control mice, whereas Sirius red staining revealed increased liver fibrosis with hepatic stellate activation after 5 weeks ethanol feeding. We identified that ethanol feeding significantly up‐regulated miR‐21 by 5.3±0.8 fold, which was further verified by Taqman real‐time PCR assay. The expression of miR‐21 was also significantly increased during human hepatic stellate cell activation when cultured in uncoated plastic culture dishes for 5 weeks. Treatment of HSCs with TGF‐β (10 ng/ml) for 24 hours induced a significant increase of miR‐21 expression in both activated and control state. Transfection of anti‐miR‐21 inhibitor markedly attenuated the expression of S100A4, laminin and fibronectin mRNAs and additionally blunted the increased expression of α‐SMA, MMP‐2 and MMP‐9, which are key genes involved in the activation of HSCs. Furthermore, the expressions of TGF‐β, as well as mesenchymal and fibrosis markers, including vimentin, S100A4, α‐SMA, laminin, fibronectin, MMP‐2, MMP‐9 and LIN28, were significantly reduced after miR‐21 Morpholino/AS treatment in chronic ethanol feeding mouse liver specimens compared to controls.ConclusionOur results show that miRNAs are critical regulators of mesenchymal transition, human hepatic stellate activation and transdifferentiation during alcoholic liver injury. The findings provide new insight into the function of specific miRNAs and the mechanisms of alcohol induced liver injury and fibrosis.
Paradoxical Role of Yes‐Associated Protein (YAP) in Liver Injury and Regeneration following Acetaminophen Overdose
Authors: Poudel Samikshya , Manley Michael W. , Bhushan Bharat , McGill Mitchell R. , Jaeschke Hartmut , Apte Udayan 
Published: November 2023

Acetaminophen (APAP) overdose is the major cause of Acute Liver Failure (ALF) in the Western world. Treatment options for APAP‐induced ALF are limited. Studies have shown that stimulating liver regeneration could be a potential treatment for ALF after APAP overdose. However, the mechanisms of liver regeneration after APAP overdose are not completely understood, which is the focus of research in our laboratory. We investigated the role of Yes associated protein (YAP), the downstream co‐activator of Hippo Signaling Pathway, in liver injury and regeneration following APAP overdose. Previous studies have shown that YAP is involved in stimulation of hepatocyte proliferation. Treatment of two‐three months old C57BL/6 male mice with 300 mg/kg APAP (APAP 300) resulted in significant liver injury and regeneration over a time course of 0 to 96 hr. Increased activation of YAP was observed during initial time points (3, 6 and 12 hr) after APAP administration which coincided with both injury and regeneration. To determine whether YAP activation plays a role in injury or regeneration, we generated hepatocyte specific YAP knockout mice (hYAP‐KO) using YAP‐floxed mice treated with AAV8.TGB.Cre. Hepatocyte specific deletion of YAP did not change hepatic CYP2E1, the enzyme involved in APAP bioactivation, and hepatic glutathione (GSH) levels. Consistent with these data, no difference in APAP‐protein adducts was observed between control and hYAP‐KO mice after APAP treatment. Liver injury measured by serum ALT and histopathology showed extensive and similar liver injury up to 12 hr after APAP treatment in both control and hYAP‐KO mice. However, the progression of the liver injury beyond 12 hr after APAP administration was significantly lower in hYAP‐KO mice as compared with control mice. The decrease in progression of liver injury was accompanied with an earlier decrease in JNK activation and faster GSH recovery in hYAP‐KO mice. Additionally, the hYAP‐KO mice showed an early induction of proliferative markers demonstrating early liver regeneration as compared to the control mice. These data indicate that hepatocyte specific activation of YAP may be involved in progression of liver injury and may inhibit liver regeneration after APAP overdose. These findings indicate a novel paradoxical role of YAP in APAP overdose and highlight YAP as a potential therapeutic target for the treatment of APAP‐induced ALF.Support or Funding InformationNIH (5P20RR021940‐07, T32ES007079‐32, R01DK098414) And the Liver Scholar Award by AASLD/American Liver Foundation
Role of post‐translational modifications in prion strain diversity
Authors: Aguilar‐Calvo Patricia , Bett Cyrus , Eraña Hasier , Castilla Joaquin , Nilsson Peter , Sigurdson Christina 
Published: November 2023

Prion diseases are caused by the post‐translational conversion of the cellular prion protein (PrPC) into a pathogenic β‐sheet rich misfolded isoform (PrPSc) that accumulates mainly in the brain. Prions can misfold into a wide variety of PrPSc conformations, known as strains, that correlate to diverse biochemical properties and result in distinctive disease phenotypes, including differences in incubation times, clinical signs, histopathological lesion profiles, and PrPSc deposition patterns in the brain within the same host genotype. Post‐translational modifications in PrPC include two N‐linked glycans and a glycophosphatidylinositol (GPI) anchor that may increase the conformational spectrum of PrPSc. Previous studies have shown that passage of GPI‐anchored prion oligomers into mice expressing GPI‐anchorless PrPC switches the prion morphology from diffuse aggregates to dense, fibrillar plaques, yet it is unclear whether the original prion conformation is maintained within the anchorless PrPSc fibrils.Here we aim 1) to determine the impact of the GPI‐anchorless state on the properties of the prion strain and 2) to identify the properties of the original GPI‐anchored prions that are maintained within the GPI‐anchorless fibril. We compared the biological, histological, and biochemical properties of four prion strains before and after three serial passages through mice expressing GPI‐anchorless PrPC. We found that the four GPI‐anchorless prion strains seemed to converge into a similar strain, as mice showed equivalent incubation periods and morphologically‐identical vasotropic fibrillar plaques in the brain. However, remarkable biochemical differences reminiscent of their respective original GPI‐anchored strains were also identified among anchorless prions. Interestingly, when passaged back into wild type mice expressing GPI‐anchored PrPC, some GPI‐anchorless prions recovered the properties from their original GPI‐anchored strain, indicating prion conformational fidelity. In contrast, other anchorless prions changed their properties markedly, consistent with the emergence of a new strain. Considering that GPI‐anchorless PrPC is normally present at low levels in the brain, these data suggest that alternate post‐translationally modified PrPC states may be a source of prion strain diversity within an individual.Support or Funding InformationNIH grant R01NS069566
The Use of High Fidelity Patient Simulations to Improve Critical Thinking Skills in First Year Medical Students
Authors: Harris David M , Schuster Amanda , Kay Denise , Kibble Jonathan D 
Published: November 2023

Many businesses and universities have stated that current Millennial students are lacking in critical thinking and analytical skill development compared to previous generations. Some attribute this to the ability to “google” information quickly and interact with social networks to make daily decisions. Millennials also comprise most of the medical students enrolled in the US and many instructors have noted that this generation seems to lack critical thinking skills. However, medical educators may be missing an opportunity to leverage the Millennials’ strength of team work. High fidelity patient simulations (HFPS) may provide a place to harness the strength of the team in a controlled learning environment in order to engage students and facilitate critical skill development. However, many factors may play a role in this experience and a “best practices” approach needs to be developed. For example, lack of foundational knowledge could negatively affect their HFPS performance. Likewise, their emotional feelings or engagement in a situation could affect the learning project. The goal of this study is to evaluate the effects of baseline knowledge and core effect on the development of critical thinking skills in first year medical students in physiology based HFPS.MethodsStudents are placed in groups of 6 and participate in 3 HFPS and observe 1. Before each simulation, a pre‐quiz is given to determine a base‐line knowledge for all the teams. After participation in a HFPS activity, students are given a card with feelings based upon activation and pleasure (core effect). Videos of the HFPS will be evaluated by faculty with a validated test instrument based on principles from Insight Assessment and Critical Thinking: What it is and why it counts.ResultsFaculty scores from the test instrument will be correlated with core affect and baseline pre‐quiz scores for each of the teams.DiscussionHFPS may provide a platform to engage first year medical students as well as facilitate development of critical thinking skills. Factors such as lack of basic knowledge or misconceptions, especially of physiology, could affect critical skill development. Discovering factors that play a role in critical skill development through a best practices approach could help HFPS become more effective in teaching and learning the Millennial generation.
Combining Physiology and Health Care Professions Education in High School‐aged students: High Tech PhUn!
Authors: Gurovich Alvaro N , Coovert Daniel , Storms Brittney Millspaugh , Terry Kim 
Published: November 2023

According to the Area Health Education Center (AHEC), there is a shortage of health care professionals in the country, especially in rural and underserved areas. In addition, and according to the National Science Foundation (NSF), there is a shortage of students choosing science careers as their professional path. To tackle these problems, the American Physiological Society (APS) and AHEC have created programs to increase the likelihood of high school students to choose science and health care professions paths, respectively. APS has a K‐12 outreach program that helps increasing awareness about STEM education called Physiology Understanding (PhUn) week, while AHEC has competitive grants to outreach students in high school science classes. Here, we combined PhUn week, health education, and high technology to show 3 physiological systems: musculoskeletal (MS), neuromuscular (NM), and central nervous system (CNS). Three hands‐on activities, one per system, were designed using a Biopac MP40 system and Biopac Science Lab software. These activities were performed by students attending a rural high school and guided by undergraduate and graduate students from health care professional curriculums. The activity was divided in 6 different sessions, three per senior science class, in three different days. Eleven undergraduate and 16 graduate students worked as facilitators, reaching 49 science students. Each class was divided in 6 small 4‐student groups with the following general activity set‐up: First day, short presentation about PhUn week and hand‐on activity focused on reaction time on dominant and non‐dominant forearm (NM); second day, hand‐on activities focused on brain activity during 4 different activities (CNS) and muscle recruitment at different forearm workloads (MS); and third day, analysis of collected data and overall final discussion including translation to health care education. By the end of PhUn week, students collected data from all 49 class mates in all three activities and the science teacher had enough physiological data to enhance their science curriculum. Motivating students from rural areas to choose STEM or health care professions path is not an easy task. Here, we developed a program that used three key components: 1) science curriculum, 2) PhUn week, and 3) applied high tech activities. Based on the level of engagement of all students, especially from the rural high school, we strongly suggest using applied high tech activities, such as this PhUn week activity, to improve likelihood of STEM and health care professions path in rural high school students.Support or Funding InformationSupported by IU AHEC 15/16 #PIU081 and APS PhUn week program
The Starling Actuator – the Implementation of Starling's Law of the Heart within a Mechanical Model of the Cardiovascular System
Authors: Strauss Graham L. , Sweeney Terrence Edward 
Published: November 2023

We recently developed the Scranton Cardiovascular Model1 (SCM), a computer‐driven, fluid pumping mechanical model of the cardiovascular system. The visual and tactile approach of the model, coupled with quantitative, multi‐parameter data collection and powerful analytical capabilities, greatly facilitate the teaching of cardiovascular physiology. However, a shortcoming of the SCM has been its inability to faithfully reproduce Starling's Law of the Heart2, a critical determinant of cardiac performance. This limitation of the SCM was due to the lack of coupling between the SCM's end‐diastolic ventricular volume (EDV) and the computer generated signal that controls cardiac contraction strength. Starling's Law behavior in the SCM has now been accomplished through construction of a device that we have coined the Starling Actuator. Visual approximation of EDV by the SCM user has always been possible, as the model's latex balloon heart operates within a clear acrylic chamber. The Starling Actuator exploits the user's visual estimation of EDV to enable volume‐dependent modulation of cardiac contraction strength without affecting heart rate or systolic duration. Employing the Starling Actuator, the user adjusts a dial to reflect the perceived degree of ventricular filling, which was determined to be within 10% of actual EDV. The Actuator dial, linked to a potentiometer, alters the baseline of the computer‐generated square wave signal controlling cardiac contraction strength, thereby modulating ejection force in an EDV‐dependent manner. Coupling visual approximation of ventricular volume with use of the Starling Actuator, we generated data that replicates the characteristic EDV‐stroke volume Starling curve3. The Starling Actuator thus enables the SCM to more faithfully model cardiovascular function under conditions that alter ventricular filling. The electronic signal from the Starling Actuator also shows promise in enabling the generation of ventricular pressure‐volume loops from SCM data.Support or Funding InformationSupported by the University of Scranton
A Mathematical Model of the Cardiovascular System Based on the Scranton Cardiovascular Model
Authors: Frederick Norman E , Jimenez Joshua Ray N. , Graham Jason M. , Sweeney Terrence Edward 
Published: November 2023

The complexity of the cardiovascular system has led to the development of mathematical models to understand and predict physiological function and dysfunction. The unique model that we describe here is designed to match the Scranton Cardiovascular Model (SCM), a mechanical model that we recently developed1 to be used as a teaching tool. The mathematical model, a lumped parameter model run in MATLAB, consists of 24 ordinary differential equations that represent the left ventricular, aortic, arterial, arteriolar, capillary, venular, peripheral venous, and central venous segments of the SCM. Resistance, compliance, and volume parameters dictate the function of each segment, and we have fine‐tuned these parameters to produce numerical simulations that match the data output of the SCM. Specific alteration of the parameters allows for mathematical modeling of disease states. The similarity between the results of the mathematical model and the SCM data should allow us to engineer new components for the SCM. Dysfunctional aortic valves, which have already been employed in the SCM, will be further engineered with the aid of the predictive mathematical model. The SCM, with increased functional diversity, becomes a better teaching tool due to improvements generated by the mathematical model. Further, the mathematical model itself aids in the understanding of cardiovascular function and dysfunction.Support or Funding InformationSupported by The University of Scranton
Animating the Kidney: Temporal and Spatial Integration of Complex Renal Mechanisms
Authors: Guttmann Geoffrey D , Guttmann David R , Mallet Robert T 
Published: November 2023

The kidneys are the body's central homeostatic organs and are essential for maintaining arterial blood pressure, body fluid osmolality, electrolyte concentrations and acid‐base balance, as well as eliminating metabolic waste products. Within the basic sciences healthcare professional curriculum, it has been necessary to isolate the physiological processes that the kidney performs. But the healthcare professional student has to apply these concepts within the context of the whole organism, i.e. the human body, and in a time integrative fashion as none of these processes operate in isolation. The traditional educational approach has been to present these concepts in a stepwise manner, which implies they occur sequentially, yet in fact, they occur simultaneously. Presentation and mastery of renal physiology are challenged by, a) structural complexity of the glomerular filtration membrane, nephron tubular epithelium, renal microcirculation, and interstitial fluid; b) the integrated function of these components; and c) their responses to numerous neuro‐hormonal factors. To illustrate these dynamic concepts, we have developed and will present sophisticated animations depicting three of the most conceptually challenging mechanisms of renal physiology: a) the impact of glomerular filtration, tubular reabsorption and secretion on renal solute handling and clearance; b) the generation and maintenance of the solute concentration gradient within the medullary interstitium and its essential role in achieving water balance; and c) the micturition reflex, including its initiation by tension in the bladder wall and its modulation by autonomic function and higher centers of the brainstem and cerebral cortex. We have created animations and artwork, utilizing Inkscape™ to make the new images, Gimp™ to import frames to make a .gif, and Anime Studio™ software to create animations. By depicting the integrated function of the component processes, these animations are intended to foster comprehension of complex renal physiology. These animations are suitable for inclusion in lectures, small group study sessions, or individual study. Individual and small group sessions can use podcasts, which include the animations. These podcasts enable students to replay the animations at their leisure and, thus, facilitate mastery of renal physiology.Support or Funding InformationUNTHSC Innovations in Teaching Using Technology Grant