bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pharmacological activation of AMPK prevents aircraft noise induced oxidative stress, endothelial dysfunction and vascular inflammation
Authors: Kvandová Miroslava , Kalinovic Sanela , Schmal Isabella , Stamm Paul , Frenis Katie , Daiber Andreas , Oelze Mathias Matthias , Schulz Eberhard , Steven Sebastian , Jansen Thomas , Münzel Thomas , Kröller-Schön Swenja 
Published: April 2020

BackgroundAircraft noise exposure is responsible for the emergence of oxidative stress, endothelial dysfunction and induction of vascular inflammatory response leading to cardiovascular complications like heart attacks and strokes. The AMP‐dependent‐Kinase (AMPK) has important protective roles in the vasculature especially in situations of oxidative stress and vascular inflammation. In the present study, we investigated the activation of AMPK using daily AICAR injections as a preventive strategy against noise induced destructive effects.Methods and ResultsAICAR (5‐Aminoimidazole‐4‐carboxamide‐1‐β‐D‐ribofuranoside; =AMP analog) was used for stimulation of AMPK activity and administered daily by intraperitoneal injections (200 mg/kg/day) for 7 days. After 3 days AICAR pre‐treatment, the C57BL/6j mice were exposed to aircraft noise (maximum sound level of 85 dB(A), average sound pressure level of 72 dB(A)), which does not impair hearing significantly.We could show that aircraft noise exposure lead to a significant endothelial dysfunction, which was significantly improved by AMPK activation by AICAR. In addition, we observed that AICAR administration was able to normalize the aircraft noise induced blood pressure increment. Similarly, noise exposure induced oxidative stress as well as in whole blood samples was reduced by AICAR administration. Endothelial dysfunction and oxidative stress is often correlated with vascular inflammation processes. Induction of an inflammation (MCP‐1, PAI‐1, IL‐6) by aircraft noise exposure was abrogated using AICAR injection in the vasculature and brain. Furthermore, we could show that aircraft noise exposure induces circadian rhythm dysregulation, which can be reduced by AICAR administration.ConclusionWe here present novel data of AMPK activation with AICAR as a protective strategy against negative effects of aircraft noise exposure. Our data suggest that activation of AMPK might be a future therapeutic strategy to prevent traffic noise‐induced cardiovascular complications.Support or Funding InformationGerman Research Foundation ‐
Deutsche Forschungsgemeinschaft (DFG).
Characterization of HIV‐1 Unmyrostolated Gag Polyprotein Interactions with the MAL HIV‐1 Genome
Authors: Arefeayne Nahum Fekadu , Swanson Canessa , Getachew Noel , Lafaver Brittany , Gilchrist Darin , Chioma Kennedy , Summers Michael 
Published: April 2020

Human Immunodeficiency Virus (HIV‐1) is a retrovirus that targets CD4 T‐cells within the immune system which leads to compromising the immune system and effectively resulting in the development of Acquired Immune Deficiency Syndrome, AIDS. Current antiretroviral gene therapies target areas of the HIV‐1 replication cycle that are susceptible to mutations, resulting in reduced efficiency of these treatments. Also, the cocktail of drugs that are typically prescribed to patients can result in adverse effects such as drug toxicity after long‐term use. There is a need for a new drug target that targets a highly conserved region of the viral replication cycle to allow for more effectivity in treatment. One region of the replication cycle known to be highly conserved is genomic recognition where the viral genome is recognized and bound by the viral Gag polyprotein. This highly conserved step stems from the minimal packaging region of the genome termed the Core Encapsidation Signal (CES) which is a portion of the viral genome located in the 5′‐Leader (5′‐L). It is proposed that the CES selectively recognizes and promotes the formation of Gag hexamers which become form the viral particle core. This research aims to understand the interactions of the CES and Gag polyprotein through the use of electrophoretic mobility shift assays (EMSAs) as well as isothermal titration calorimetry (ITC). These experiments allow for the identification of binding sites that may be occurring between the viral genome and the Gag proteins. Initial ITC data has shown CES to have seven binding sites however, this was only done with the Nucleocapsid (NC) domain of the Gag polyprotein, which is only a small domain of the Gag that only plays a role in RNA binding. Whereas the other structural domains play a role in packaging, assembly, and Using the full viral protein allows for a more biologically relevant evaluation for understanding the viral packaging cycle. In addition to EMSAs and ITC experiments, the future goal is to obtain a structure of the nucleation complex through the use of x‐ray crystallography and cryogenic electron microscopy. By understanding the protein‐RNA interaction that occurs during the formation of the nucleation complex of the virus and eventually elucidating the structure of this complex, antiretroviral therapies can begin to target this highly conserved region of the replication cycle.Support or Funding InformationThis research was funded by NIH/NIGMS grants RO1OM042561, 8RO1AI50498 and NIH/NIGMS MARC U*STAR T34 HHS 00026 National Research Service Award to UMBC. This research was supported in part by a grant to UMBC from the Howard Hughes Medical Institute through the HHMI Adaptation Project. We would like to thank the MARC U*STAR program and UMBC Summer Biomedical Training Program for the strong support.
Cervix Pathology For Medical Students: Morphing‐Based Animation
Authors: King Thomas Scott , Nelson Erin , Sharma Ramaswamy 
Published: April 2020

Cervical cancer is the third most common cancer in US women, resulting in approximately 4,000 deaths per year. Preventative screening of women will be part of the future clinical practices of many of our medical students. Therefore, microscopic examination of cervical pathology is an important component of histopathology teaching laboratories. Traditionally, students examine the normal cervical structure, including the transformation zone within which most cervical squamous cell carcinomas arise. Presentation of these topics may be typically incongruous in that normal and abnormal are taught sequentially but as separate topics and in two‐dimensional formats (i.e., histopathology micrographs). It is all too often incumbent on the student to “connect the dots”, and conceptualize the progress from the normal exocervix to metaplasia, dysplasia and ultimately neoplasia, within the “transformation zone”. Visualization of this process is not always well‐understood by all students. We hypothesized that students will assimilate pathological processes more quickly and effectively when these are viewed in transition, that is, by “morphing” from one stage of development to the next.We utilized morphing software to animate a series of drawings of preadolescent to post‐adolescent cervix with eversion and development of the transformation zone (squamous metaplasia). The three‐dimensional animations continued through dysplastic and neoplastic development. The video included colposcopic images of the transformation zone, and demonstrated findings of ectropion, dysplasia and neoplasia in the cervical surface. Morphing sequences were created using software that calculated multiple transitions by the processes of warping and cross‐dissolving between corresponding frames and generated an output movie by using a single intermediate morph from each pair along the sequence. Images were processed as three‐dimensional signals with third‐dimension being time. The resultant animated and morphing video was disseminated as AVI movie format for Windows applications, as animated GIF and Flash animation for WEB pages and PowerPoint presentations or to QuickTime format for Mac computers. The video is currently an integral component of the curriculum for second year students at our university and has been very well‐received by these students in each of the last two years.Analysis of the effectiveness of the video in facilitating learning is ongoing over a two‐year period. We are currently comparing two study groups of students using a self‐paced, formative assessment quiz to evaluate the student’s understanding of the cervical transformation zone and its clinical significance. Participating students are also asked to complete a brief survey addressing the overall usefulness of the video and perceived effectiveness of the video in gaining understanding of cervical transformation zone and its clinical importance.
Investigating the Role of Myo/Nog Cells in Tissue Injury in the Liver and Stellate Cell Cultures
Authors: Delancy Matthew M. , Milton LaBraya , Gerhart Jacquelyn , Abdalla Fathma , George-Weinstein Mindy , Bhave Vishakha , Behling Kathryn C. 
Published: April 2020

Myo/Nog cells, named for their expression of the skeletal muscle specific transcription factor Myo D, and the bone morphogenic protein inhibitor noggin, are critical regulators of normal development, progenitors of myofibroblasts in the ocular lens and neuroprotective in the retina. They also rapidly respond to wounding of the skin. The role of Myo/Nog cells in the modulation of tissue injury and fibrosis in the liver has not been studied. We examined the response of Myo/Nog cells to acetaminophen induced acute liver toxicity and their relationship to human hepatic stellate cells already known to play a role in acute and chronic liver injury responses. Liver tissue was obtained from mice following acetaminophen overdose over a time course of 0 to 96 hours. Additionally, LX‐2 human hepatic stellate cells were grown to confluence and subjected to a mechanical injury (scratch assay) and examined at several time points 0–24 hours after wounding. Immunofluorescent staining with the G8 monoclonal antibody was used to identify Myo/Nog cells in tissue sections of liver and stellate cell cultures. Preliminary analyses showed that in the mouse model of acetaminophen toxicity, there is a resident population of Myo/Nog cells in the liver that decline in number during the first 24 hours after the acetaminophen overdose and then increase, particularly in the region near the central vein (zone 3) where hepatocyte necrosis was greatest. The highest number of Myo/Nog cells was seen at 48 hours post acetaminophen administration, the time of maximal liver injury as previously documented by serum biomarkers. With the in vitro human stellate cell scratch assay, we found that a subset of these cells express the Myo/Nog marker G8, and the proportion of cells that express this marker increases after wounding, peaking at 24 hours after the scratch. G8 positive cells consistently clustered in proximity to the margins of the wound, with the greatest densities counted within the first high‐power field of the scratch. These studies suggest that Myo/Nog cells respond to acute liver injury by increasing in number and/or migrating toward the site of injury. Whether these cells play a role in mediating progression of liver injury or promote recovery via liver regeneration needs to be further evaluated in the model. The in vitro studies show that Myo/Nog cells may represent a subpopulation of human stellate cells in the liver, and this relationship should be further explored as a potential target for future therapeutics for acute and chronic liver injury.Support or Funding InformationAnonymous donation from a private funder.
NON‐PSYCHOACTIVE CANNABINOIDS (CBD/CBG) ACT VIA CANNABINOID CB2/CB1 RECEPTORS TO REGULATE INTESTINAL MYOFIBROBLAST METABOLIC ACTIVITY AND TO INHIBIT FORSKOLIN‐MEDIATED ELEVATION OF CYCLIC‐AMP
Authors: Venu Vivek Krishna Pulakazhi , Saifeddine Mahmoud , Mihara Koichiro , Kamal Brishna , Lantela Daniel , Hollenberg Morley D. 
Published: April 2020

Intestinal fibrosis, a common complication of inflammatory bowel disease (IBD), comprises an excessive accumulation of scar tissue in the intestinal wall. Fibrosis is thought to result from an aberrant response to injury resulting in excessive extracellular matrix (ECM) deposition, which can lead to tissue stiffening and intestinal stricture formation. Activation of the cannabinoid‐receptor‐CB2 has been reported to regulate mesenchymal cell function and to dampen fibrogenic signaling. More recently, non‐psychoactive cannabinoids, Cannabdiol (CBD) and Cannabigerol (CBG), have been found to be associated with anti‐inflammatory signalling that dampens inflammation. Here, we tested the hypothesis that CBD and CBG, via cannabinoid CB1/CB2 receptors, could function as potentially negative regulators of intestinal inflammation‐associated fibrosis through modulating intestinal myofibroblast function and triggering CB2/CB2 signalling. The effects of CBD and CBG on TGF‐β induced cell metabolic activity (MTT assay) were examined using cultured myofibroblast cells isolated from mouse and human intestine. Cannabinoid‐regulated signal transduction pathways were assessed using HEK‐293 cells transfected to express human CB2 and CB2 – red‐fluorescent‐protein‐tagged receptors. We found that at 48h and 72h TGF‐β induced cell metabolic activity was attenuated by 5% and 12% compared to TGF‐β‐treatment alone by increasing concentrations of CBG (10μM). Further, CBD (500nM) was able to inhibit TGF‐β induced cell metabolic activity by 12% and 25%, compared to TGF‐β alone at 48h and 72h. In CB1/CB2‐expressing HEK cells, preliminary data showed that both CBD and CBG, acting via CB2, were able to diminish forskolin (0.5 μM)‐increased cyclic‐AMP production, without affecting changes in intracellular calcium, indicating activation of Gi. In cells co‐expressing CB1/CB2 receptors, both CBG (100 nM) and CBD (20 nM) inhibited high forskolin concentration(5–10 μM)‐stimulated cAMP production. Nontransfected HEK cells showed no responses to either CBD or CBG. We conclude that the non‐psychoactive cannabinoids, CBD/CBG can regulate non‐neuronal cells, including intestinal myofibroblasts and kidney HEK cells via both CB2 and CB1 receptors.Support or Funding InformationSupported by grants from the Canadian Institutes of Health Research for MDH and Mitacs postdoctoral fellowships for VKPV
Sex Differences in Renal T cells in DOCA‐salt Hypertension are not Blood Pressure Dependent.
Authors: Belanger Kasey , Sullivan Jennifer 
Published: April 2020

BackgroundThere is increasing evidence implicating T cells in the development and maintenance of hypertension. Our lab has previously shown that there is a sex difference in renal T cells in deoxycorticosterone acetate salt (DOCA) hypertension, with females having greater T regulatory cells than males. Moreover, Tregs attenuate DOCA‐induced increases in blood pressure (BP) only in female rats. Therefore, the goal of the current study was to test the hypothesis that the sex difference in renal Tregs in DOCA‐salt rats is BP dependent.MethodsAt 10 wks of age, male and female Sprague‐Dawley rats were anesthetized, a right uni‐nephrectomy was performed, and all rats were implanted with telemetry devices for the continuous measurement of BP. After one week of recovery, all rats received a subcutaneous 21‐day slow‐release DOCA pellet (200 mg) with 0.9% saline water to drink. To prevent DOCA‐salt induced increases in BP, a subset of rats (N=9–12/group) were randomized to receive hydrochlorothiazide (HCTZ; 55 mg/kg/day) and reserpine (4.5 mg/kg/day) combined with 0.9% saline in the drinking water for 3 weeks. Rats were individually housed throughout the study. Water intake and body weights were measured every two days and the dose of drugs were altered, as needed, to maintain baseline BP levels. After 3 wks of treatment, the remaining kidney was isolated for flow cytometric analysis of T cells.ResultsAfter 3 wks of DOCA‐treatment, males had a higher BP than females (179 ± 3 mmHg vs. 157 ± 4 mmHg; n=6–7; Psex=0.0001). Treatment with HCTZ and reserpine prevented DOCA‐induced increases in BP in both males (110 ± 5 mmHg) and females (101 ± 5 mmHg; Ptreatment<0.0001; Pinteraction=0.307). With DOCA‐salt induced hypertension, males had more renal CD4+ T cells (expressed as %CD3+ T cells: 63 ± 2 vs 60 ± 1) and Th17 (expressed as %CD3+CD4+ cells: 14 ± 1 vs 11 ±1) than females (Psex=0.04). HCTZ and reserpine decreased both CD4+ cells (expressed as %CD3+ T cells: 61 ± 3.9 vs 60 ±2.9; Ptreatment<0.0001) and Th17 cells (expressed as %CD3+CD4+ cells: 5.15 ±0.93 vs 5.1 ± 1.3; Ptreatment<0.0001) and the decrease was comparable between sexes (CD4+: Pinteraction=0.86; Th17: Pinteraction=0.55). With DOCA alone, females had a higher number of Tregs than males (expressed as %CD3+CD4+ cells: 3.9 ±0.21 vs 2.6 ±0.2; Psex<0.0001). Preventing DOCA‐salt induced increases in BP with HCTZ and reserpine did not significantly change renal Tregs in either sex (Ptreatment=0.11; Pinteraction=0.38).DiscussionOur data suggests that while preventing DOCA‐salt induced increases in BP attenuates the increase in renal pro‐inflammatory T cells, sex differences in renal T cells is not dependent on hypertension.
Muscle Function During Feeding Through Infancy
Authors: Mayerl Christopher James , Tobin Hieronymus L. , Chava Almasi M. , Edmonds Chloe E. , Gould Francois D. H. , Stricklen Bethany M. , Bond Laura E. , German Rebecca Z. 
Published: April 2020

Infant mammalian feeding is a complex process that requires the integration of different behaviors and over twenty‐five muscles controlled by multiple cranial nerves. Despite extensive characterization of muscle activity during a feeding sequence, from suckling to swallowing, specific biomechanics of muscle function are unknown. The function of a muscle is determined by both when the muscle is active and the line of action of the muscle, as well as the change in length during activity. In mammals, there is potential for the line of action of the muscles involved in swallowing to change through ontogeny, as infants have a compressed oropharyngeal anatomy relative to adults. Additionally, while we understand when muscles are active during infant feeding, little has been done to understand whether those activity patterns correspond to concentric, eccentric, or isometric contractions. Here, we used contrast‐based microCT scanning coupled with electromyography (EMG) and fluoromicrometry to test the possibility that muscle function changes through infancy using our validated infant pig model. We collected anatomical data from pigs at infancy and just prior to weaning (21 days old), and isolated muscles of interest in Avizo. We collected EMG and fluoromicrometry data from five muscles involved in feeding (Geniohyoid, Digastric, Stylohyoid, Thyrohyoid, and Omohyoid) at the same ages. We found substantive changes in muscle anatomy through infancy and found extensive variation in muscle firing patterns and function within muscles. Some muscles (eg thyrohyoid) exhibited concentric contractions, whereas other muscles were eccentric (eg omohyoid). Still others exhibited multiple functions, and were eccentric during sucking EMG bursts, but isometric during swallowing EMG bursts (eg geniohyoid). Additionally, we found regional heterogeneity in muscle firing patterns in some muscles (eg stylohyoid), whereby electrodes placed in the middle of the muscle showed activity during swallows, but electrodes placed closer to the hyoid (more ventrally) recorded activity during sucking and swallowing. These results highlight the complexity of infant mammal feeding and demonstrate that muscle activity does not necessarily indicate muscle function. Instead, many muscles that are traditionally thought to function to pull the hyoid along their line of action may actually be functioning to stabilize the hyoid during swallowing. This suggests that control and coordination of the oropharyngeal structures is likely to be more important for successful feeding function than strength or the velocity of moving those structures.Support or Funding InformationAAA Postdoctoral Fellowship
Role of Mechanical Force on the Growth Plate
Authors: Serra Rosa 
Published: April 2020

The shape and size of the limb is determined by genetic, biochemical, and mechanical factors resulting from weight bearing activity or muscle contraction. Changes in bone shape in response to mechanical forces was first reported by Wolf, 1892. Observations by Hueter‐Volkman indicated that supraphysiological forces lead to reduced skeletal growth. More recently, Frost (1990) proposed the concept of chondral modeling to describe physiological loading. In this case, both tension and compression lead to increased skeletal growth up to a peak then compression beyond that peak leads to inhibition of growth. Recent experiments using zebra fish, chick, and muscle‐less Spd mice indicated a specific connection between mechanical load and endochondral bone formation in embryonic skeleton. A role for mechanical forces on postnatal skeletal development is apparent in clinical manifestations of children with hemiplegia resulting in unequal loading of developing limbs. A large proportion of children with hemiplegia demonstrated significant limb length discrepancy with the paralyzed limb being shorter than the other limb. An age dependent effect of force on limb development in mice during spaceflight and tail suspended rats indicated a critical developmental window where loading regulates growth plate function. Longitudinal growth of limbs occurs through cartilaginous structures called the growth plate in a process called endochondral bone formation. One important feature of the growth plate is that the cells align into columns that represent a continuum of differentiation. It was suggested that the magnitude of bone growth is dependent on chondrocyte proliferation, matrix deposition, and hypertrophy; however, without the columnar structure, growth would not be longitudinal and the proper length and shape of skeletal elements would be disrupted. Recent experimental data indicate that mechanical load is required to regulate growth plate function including proliferation of chondrocytes and column formation. The molecular mechanism governing proliferation and column formation in response to load are not known but may involve chondrocytes sensing mechanical changes in the environment thought their actin cytoskeleton. Unloading mouse hind limb results in disorganization of the actin structure in chondrocytes, loss of columnar structure in the growth plate, and reduced limb length. Mice with conditional deletion of genes associated with regulation of the actin cytoskeleton demonstrate similar alterations in their growth plates. These observations highlight the importance of mechanical loading on growth plate function but there is still limited understanding of the molecular mechanisms of how limb length is regulated in response to mechanical loads.Support or Funding InformationNIH/NIAMS R21 AR070097 and the US‐Israel Bi‐national Science Foundation