bluuebunny/crossref_metadata_2025_split huggingface dataset:
Preconditioning Effects of Forced and Voluntary Running on Stress– and Indomethacin–induced Gastric Injury in Rats
Authors: Filaretova Ludmila , Komkova Olga , Punin Yuriy , Yarushkina Natalia 
Published: April 2020

Physical activity and, especially, running, is natural stressor which is increasingly recommended as preconditioning for prevention of the number of diseases. Although regular physical activity can be beneficial in the prevention and the management of several diseases, the intensive exercise may promote or exacerbate the gastrointestinal injury. The aim of the study was to investigate preconditioning effects of forced and voluntary running on a vulnerability of the gastric mucosa to ulcerogenic action of cold‐restraint stress (3 h, 10°C) or indomethacin (IM, 35 mg/kg, sc). For forced treadmill (0 incline) running two protocols were used: high‐intensity (25 sm/s, 30 min) and moderate‐intensity (15 sm/s, 15 min) running. For voluntary running the rats were placed in the cages with wheels (2 h/day) during 4 days before experiment. On a Day of experiment preliminary fasted (24 h) rats were subjected forced running in treadmill or voluntary running in the wheel (2 h), then, they were given back in their cages and resting at room temperature for 1 h before the onset of ulcerogenic stimulus. Control animals were in their rcages, but they were also given ulcerogenic stimulus. Stress‐induced and IM‐induced gastric erosions were examined 3 h after the onset of cold‐restraint or 4 h after IM administration, respectively. A single high‐intensity treadmill session attenuated IM‐induced gastric erosions but aggravated stress‐induced gastric erosions. A single moderate‐intensity treadmill session didn’t influence IM or stress‐induced gastric injury, but moderate‐intensity treadmill in training regime (during 4 days before experiment) attenuated stress‐induced gastric erosions. Voluntary wheel running resulted in a decrease of IM‐induced erosions but an increase of stress‐induced gastric injury. The results obtained suggest that moderate‐intensity treadmill running in training regime exerts gastroprotective effect on stress‐induced gastric injury whereas by high‐intensity treadmill running as well as voluntary wheel running has proulcerogenic action in this model. At the same time high‐intensity treadmill as well as voluntary wheel running produced gastroprotective effect on IM‐induced gastric erosions. Thus, preconditioning effect of forced or voluntary running on the gastric injury is dependent on an intensity of treadmill running as well as a nature of ulcerogenic stimulus. We suppose that a significance of the compensatory gastroprotective action of glucocorticoids during IM‐induced prostaglandin deficiency which was demonstrated in our previous studies may explain the gastroprotective effects of the preconditioning in the IM ulcerogenic model.Support or Funding InformationThe study was supported by grant of Russian Science Foundation (RSF) N 19‐15‐00430.
Dopamine D1 Agonists, Working Memory, and the Prefrontal Cortex: Effect of Receptor Functional Selectivity/Signaling Bias
Authors: Yang Yang , Mailman Richard B. 
Published: April 2020

Dopamine D1 agonists produce an ‘inverted‐U’ dose‐response on working memory‐related behavioral tasks (i.e., low doses improve but high doses have no effect or tend to impair performance). This dose‐dependency has been observed at the single neuron level in the prefrontal cortex, where the cellular basis of working memory is represented. Few studies, however, have examined this process at the neuron population level and its signaling mechanism(s) is still unclear. In the current study, two D1 agonists, 2‐methyldihydrexidine (2MDHX) and CY208,243 (CY208), were examined and compared in rats performing a spatial working memory‐related T‐maze task. 2MDHX is a full agonist at adenylate cyclase and a super‐agonist at β‐arrestin recruitment, whereas CY208 has relatively high intrinsic activity at adenylate cyclase, but much lower at β‐arrestin recruitment. Both compounds had inverted U‐dose response curves at both the behavioral and prefrontal neuron population level, albeit with distinct differences. At behavioral level, they both caused similar improvement with high potency (10 nmol/kg). Conversely, the right‐hand (descending) part of the inverted U dose‐response curve had a great slope for 2MDHX than for CY208, suggesting an extended effective range for a compound with lower β‐arrestin activity. At the neuron population level, both drugs affected the percentage, uniformity, and ensemble strength of sensitivity in a dose‐dependent manner, but 2MDHX influenced neuron activity more before the choice in the T‐maze task whereas CY208 influenced it more after the choice. As the off‐target effects were not likely engaged at the very low doses (i.e., nmol/kg range) utilized in the current study, the differences between 2MDHX and CY208 most likely are related to their specific D1 functional selectivity profiles. The ‘inverted‐U’ dose‐response of D1 agonists on cognitive performance has been observed in many of animal models and confirmed in humans. Although the cognitive improvement at the optimal dose is impressive, the biphasic effect complicates potential clinical use of D1 drugs. Our data indicate that differential signaling may play a role in D1‐related dose‐dependent regulation of cognition, and suggest that D1‐related dose‐dependent regulation of working memory could be modified by functionally selective/biased ligands. This may help guide the discovery of novel D1 compounds that may yield a more monotonic response and therefore translate to the clinic more readily.Support or Funding InformationBrain & Behavior Research Foundation Young Investigator Grant # 19469 to YY, the 2017 Children’s Miracle Network Research Grant #10 to YY and RBM, the Penn State Translational Brain Research Center, and R01 NS105471 to RBM. Conflict of interest: Dr. Mailman is an inventor on patents related to D1 ligand discovery, and this conflict is disclosed and managed by the Penn State College of Medicine.
3‐hydroxy fatty acids Induce Placental Trophoblast Necroptosis during Acute Fatty Liver of Pregnancy
Authors: Sahoo Prakash Kumar , Natarajan Sathish Kumar 
Published: April 2020

Acute fatty liver of pregnancy (AFLP) is a rare catastrophic metabolic dysfunction developing in the third trimester of pregancy with significant maternal and perinatal mortality. AFLP develops as a result of a fetal homozygous mutation (1528G>C) in the gene encoding mitochondrial long‐chain 3‐hydroxy acyl Co‐A dehydrogenase (LCHAD) replacing glutamic acid with glutamine (E474Q) at position 474 in the catalytic domain of LCHAD. As a result of loss of activity in LCHAD, there is drastic decrease in fatty acid beta‐oxidation in mitochondria promoting accumulation of toxic metabolites including long‐chain free fatty acids, 3‐hydroxy fatty acids and acyl carnitines. Later the toxic metabolites get shunted to the maternal circulation leading to liver injury observed in patients with AFLP. While many studies has focused solely on liver, we wanted to understand AFLP pathology in placenta. In order to understand the underlying pathologies in placenta, we took advantage of established placental trophoblast cells (immortalized and choriocarcinoma derived). Upon treatment with 3‐hydroxy fatty acids (3‐HFAs) at different concentration we observed cell death and our results showed that the cell death is non‐apoptotic. Using necroptosis inhibitor we confimed that the cells are undergoing necroptotic cell death, while immunoblot analysis revealed increased phosphorylation of RIPK1. We also obsered mitochondrial damage upon treatment with 3‐hydroxy fatty acids. Together, these results suggest 3‐HFAs are highly toxic to cells and induce non‐apoptotic cell death in the form of necroptosis, while damagaing mitochondria.Support or Funding InformationThis study is supported by funding from NIH P20GM104320 grant.
Transcriptional Activation of Tumor Suppressor p73 is Modulated by MCL1 Through a Novel Protein Interaction
Authors: Widden Hayley , Kacmarczyk Aneta , Whitaker Robert H. , Placzek William J. 
Published: April 2020

Precise regulation of apoptosis and cellular response to DNA damage are central to the development of multi‐cellular organisms. In eukaryotes, the BCL2 family of pro‐ and anti‐apoptotic proteins mediate multiple pro‐survival and stress signals to regulate mitochondrial membrane integrity and ultimately apoptosis. Likewise, the p53 family of transcription factors activate multiple pro‐death and cellular senescence pathways in response to DNA damage. Recent studies to develop anti‐cancer agents targeting the BCL2 family have demonstrated that one of the anti‐apoptotic proteins, MCL1, is a critical therapeutic target as it has been shown to inhibit apoptosis in response to a variety of chemotherapeutic agents. MCL1 activity centers around the availability of its BH3 binding cleft to form heterodimers with other pro‐apoptotic BCL2 family proteins. In our search for novel agents that could inhibit these interactions, we identified a novel peptide motif, that we call the reverse BH3 (rBH3) motif, that can interact with the BH3 cleft of MCL1. Here, we show that the p53 homolog, p73, contains a rBH3 motif in its tetramerization domain and that this motif mediates a direct protein‐protein interaction between MCL1 and p73. Furthermore, we show that this interaction allows MCL1 to regulate p73 target gene activation. With MCL1 inhibitors now in clinical trials, we are interrogating the impact that pharmacological inhibition of MCL1 has on DNA damage response signaling in cancer cells who rely on p73 for induction of cell cycle arrest and apoptosis.Support or Funding InformationNIH grant R01GM117391 to WJP
Anatomy‐based Community Education Using Plastinated Organs
Authors: Hillmer Ryan , Patitucci Teresa 
Published: April 2020

Community outreach is an institutional mission at the Medical College of Wisconsin (MCW); which has three campuses spread throughout Wisconsin. There are numerous outreach programs established at each location run by medical students. These outreach programs are largely targeted at middle and high school‐aged students, focusing on promoting physical wellness and fostering an interest in healthcare‐related careers. Extension of these programs to underserved students who may not be able to travel to an MCW site is of particular interest. Although each MCW campus has plastic anatomical models and fixed anatomical specimens set aside for these programs, both have hindrances for use in community education. Plastic anatomical models are a step removed from actual specimens, and do not fully represent the potential for anatomical variations. Although most engaging, wet formalin‐fixed specimens can be irritating to the eyes and respiratory system and must be handled in a well‐ventilated environment. Using funding from the Medical College of Wisconsin and the American Association for Anatomy (AAA), we created a small library of plastinated organs to use during community outreach programs. The plastination process consists of initial organ fixation followed by dehydration of the organ in acetone. Following dehydration, polymer is infused into the organ via vacuum‐pressure and the organ is ultimately cured using gas or UV‐light. These organs are odorless, non‐toxic hardened tissue specimens that do not decay and can be easily transported and handled freely at both on and off‐campus environments. For this project, 3 hearts, 3 kidneys, and 3 brains were harvested from body donors enrolled in MCW’s Anatomical Gift Registry program. These organs were plastinated and sectioned to highlight internal and external anatomical features. Plastination kits consisting of a heart, kidney, and brain (along with educational pamphlets describing relevant anatomy of each organ) were distributed to each campus. Following interaction with plastinated organs, program participants are asked to complete a survey about their learning and interactions with these specimens. All research involving human subjects undergoes strict review by MCW’s IRB. Since their recent implementation, these programs have reached 201 community students and are ongoing throughout the year at all campus locations. We are currently collecting and analyzing user perception surveys, evaluating what students learned during their interactions with the plastinated organs and their preferences for using plastinated vs. wet‐fixed specimens. Preliminary feedback has been positive, where MCW medical students have expressed these plastinates provide a beneficial resource for community outreach programs.Support or Funding InformationFunding for this project was obtained through the following sources: AAA ‐ Education Outreach Grant and MCW Dean’s Programmatic Dollars.
Chronic hindbrain administration of oxytocin elicits weight loss in high fat diet‐induced obese mice
Authors: Blevins James Ernest , Edwards Mélise Marie , Nguyen Ha Khanh , Herbertson Adam Jay , Dodson Andrew Dale , Wietecha Tomasz Adam , Wolden-Hanson Tami , Graham James Lawrence , Havel Peter Joseph 
Published: April 2020

Previous studies indicate that oxytocin (OXT) reduces body weight (BW) in high fat diet (HFD)‐induced obese (DIO) rodents through mechanisms that may involve an enhanced ability of OXT to reduce food intake as well as increase energy expenditure. We have previously demonstrated that chronic fourth ventricular (4V) infusions of OXT (as a strategy to target hindbrain OXT receptors) evokes weight loss in DIO rats. Based on these findings, we hypothesized that increased hindbrain OXT signaling would elicit BW loss in DIO mice maintained on a HFD (60% kcal from fat). To test this hypothesis, age‐matched mice were fed HFD or chow for 4 months prior to implantation of 4V cannulas and 28‐day minipumps that infused OXT (16 nmol/day) or vehicle (VEH; saline). Food intake and BW were tracked for 28 days. Body composition was assessed immediately prior to VEH or OXT treatment and near treatment completion using Quantitative Magnetic Resonance (QMR; EchoMRI 4‐in‐1). OXT preferentially reduced BW by approximately 4.5±1.4% in DIO mice relative to chow‐fed mice (P<0.05; N=9–11/group). OXT‐elicited BW loss was associated with reductions in body adiposity, adipocyte size [inguinal white adipose tissue (IWAT)] and serum leptin (P<0.05). These effects were attributed, in part, to an enhanced effect of OXT to reduce energy intake in DIO mice (P<0.05) at a dose that was not associated with increased kaolin intake (pica behavior; P=NS). While reductions in energy intake contribute to OXT’s effects on BW, chronic 4V OXT appeared to increase uncoupling protein‐1 (UCP‐1) expression in IWAT (0.05<P<0.1; N=9–10/group) suggesting that OXT may also stimulate beiging of WAT. To assess OXT‐elicited changes in brown adipose tissue (BAT) thermogenesis, we examined the effects of acute 4V injections of OXT on interscapular BAT temperature (TIBAT) in mice. Consistent with our previous findings in rats, preliminary data in mice indicate that acute 4V injections of a lower dose (1 μg) appeared to elevate TIBAT at 0.5‐ (P=0.1) and 1.25‐h post‐injection (P=0.15) while a higher dose (5 μg) appeared to elevate TIBAT at 1.5‐ (P<0.05) and 4‐h (0.05<P<0.1) post‐injection (N=4/group). Together, these findings support the hypothesis that chronic hindbrain OXT treatment evokes sustained weight loss in DIO mice by reducing energy intake and increasing BAT thermogenesis and beiging of WAT at a dose that is not associated with visceral illness.Support or Funding InformationNational Institutes of Health R01 DK115976 and VA Merit Review Award BX004102
Serum deprivation primes cancer cells to adapt and survive oxidative stress
Authors: White Elshaddai , Pennant Nakea , Carter Jada , Nash Erica , Hawsawi Ohuod , Oderah-Marah Valerie , Hinton Cimona 
Published: April 2020

Inadequate nutrient intake, a survival benchmark in cancer cells, leads to oxidative stress (OS) disrupting homeostasis, activating signaling, and altering metabolism. As reactive oxygen species (ROS) increase, oxidative stressors activate mechanisms allowing cancer cells to adapt and survive. Our data suggests that nutrient‐deprived cancer cells tolerate OS. Moreover, a quiescent phenotype along with nuclear factor‐kappaB (NF‐κB) signaling may synergistically protect tumor cells from OS induced by nutrient deprivation. In DU145 prostate cancer cell line, we observed that serum‐deprived cells maintained viability after exposure to H2O2 and transitioned to a quiescent phenotype via up‐regulated quiescent markers. Additionally, we transiently silenced NF‐κB (RelA/p65) via siRNA, and demonstrated the percentage of total apoptosis in DU145 cells significantly increased in serum‐deprived cells exposed to H2O2. Furthermore, we observed that inhibition of quiescence significantly reduced NF‐κB‐mediated cell survival in response to OS using two quiescence inhibitors targeting Mirk/Dyrk1b kinase (quiescence inducer), AZ191 and NCGC00185981‐05/ML195; concomitantly, a distinct NF‐κB nuclear localization was not observed. It is unclear how prostate cancer cells adapt and survive oxidative stress; however, we hypothesize nutrient deprivation primes cancer cells for OS cell survival, concurrent with a transition to a quiescent phenotype and NF‐κB signaling.Support or Funding InformationThese studies were supported by the NIH/NIGMS/RISE #5R25GM060414‐15 and NIH/NIHMD/RCMI #5G12MD007590.
Environmental noise is a cardiovascular risk factor – mechanistic insights on oxidative stress, inflammatory pathways and endothelial dysfunction and preliminary data from diabetic mice.
Authors: Jimenez Maria Teresa Bayo , Frenis Katie , Kalinovic Sanela , Kvandová Miroslava , Helmstädter Johanna , Mirski Ksenija Vujacic , Oelze Matthias , Steven Sebastian , Daiber Andreas , Münzel Thomas , Kröller-Schön Swenja 
Published: April 2020

Most traditional cardiovascular risk factors (diabetes, smoking or hyperlipidemia) are associated with vascular complications such as endothelial dysfunction, oxidative stress and inflammation. During the last two decades, large epidemiological studies have shown that the physical environment such as noise from road, aircraft or railway may facilitate the development of cardiovascular and metabolic diseases. These studies have demonstrated a link between the incidence of ischemic heart diseases or metabolic disease such as diabetes and exposure to noise, supporting its role as an independent cardiovascular risk factor (reviewed in the WHO Noise Guidelines for the European Region).We investigated the influence of aircraft noise exposure on molecular mechanisms identifying oxidative stress and inflammation as central players in mediating vascular dysfunction (Münzel et al. Eur. Heart J. 2017; Kröller‐Schön et al. Eur Heart J. 2018). Peak sound levels of 85 and mean sound level of 72 dB(A) applied for 1, 2 and 4 days caused an increase in systolic blood pressure, stress hormones and induced endothelial dysfunction, oxidative stress and inflammation. Control exposures to white noise for 4 days did not induce these changes.The potential additive effects of noise exposure and preexisting diabetes as well as the underlying molecular mechanisms are currently being investigated in a mouse model since the characteristics of noise induced vascular dysfunction considerably resemble the mechanisms of vascular dysfunction observed in diabetes.Support or Funding InformationOur experimental studies on noise effects in mice were supported by vascular biology research grants from the Foundation Heart of Mainz and the Boehringer Ingelheim Foundation for the collaborative research group „Novel and neglected cardiovascular risk factors: molecular mechanisms and therapeutic implications”.
The Physiological Function of Sigmar1 in the Skeletal Muscle in Mice
Authors: Aishwarya Richa , Abdullah Chowdhury S. , Alam Shafiul , Morshed Mahboob , Remex Naznin Sultana , Orr A. Wayne , Hartman Brandon , King Judy A. , Bhuiyan Md. Shenuarin 
Published: April 2020

RationaleSigmar1 is an abundantly expressed molecular chaperone protein encoded by the SIGMAR1 gene. Mutations in SIGMAR1 have been associated with distal hereditary motor neuropathy, amyotrophic lateral sclerosis, silver‐like syndrome, and frontotemporal lobar degeneration. All these human mutation associated pathologies show skeletal muscle phenotypes like muscle wasting and atrophy. However, the physiological function of Sigmar1 in skeletal muscle has not been explored yet.ObjectivesWe aim to determine the expression and physiological function of Sigmar1 in skeletal muscle structure and function in mice.Methods and ResultsWe first confirmed the Sigmar1 mRNA and protein expression in different types of skeletal muscles (gastrocnemius, quadriceps, soleus, extensor digitorum longus (EDL), and tibialis anterior (TA)) isolated from mice. Immunostaining with the Sigmar1 antibody demonstrated Sigmar1’s localization predominantly in type 1 muscle. We used Sigmar1 global knockout (Sigmar1−/−) mice to determine the physiological function of Sigmar1 in skeletal muscle. Morphometric analysis showed normal muscle weight‐to‐tibia length ratio in all these muscles across the group. The cross‐sectional area of the muscles determined by WGA staining showed that quadriceps and gastrocnemius muscles isolated from Sigmar1−/− mice have bigger muscle fibers compared to wildtype (Wt) mice. Interestingly, absence of Sigmar1 in gastrocnemius and quadriceps muscle of Sigmar1−/− mice results in slow‐to‐fast fiber‐type switch. Interestingly, absence of Sigmar1 in different types of skeletal muscle isolated from Sigmar1−/− mice showed an increased number of central nuclei (H&E staining), increased collagen deposition (Picro‐Sirius red staining) and fibrosis (Masson’s trichrome staining) compared to Wt mice.ConclusionsOur findings suggested an abundant expression of Sigmar1 in different types of skeletal muscle and possess an essential physiological function in these muscles. Sigmar1 absence results in alterations in muscle fiber size, increased number of central nuclei, fiber‐type switch, and fibrotic remodeling suggesting Sigmar1’s function in maintaining healthy skeletal muscle.Support or Funding InformationThis work was supported by NIH/NHLBI grants R00 HL122354, R01HL145753, R01HL145753‐01S1 and PGM121307A to Dr. Bhuiyan. American Heart Association postdoctoral fellowship to Dr. Alam; Malcolm Fiest post‐ and pre‐doctoral fellowships to Dr. Abdullah and Aishwarya by CCDS, LSUHSC‐S.
Preimplantation Genetic Testing for Aneuploidy Versus Morphology as Selection Criteria for Single Frozen-Thawed Embryo Transfer in Good-Prognosis Patients: A Multicenter Randomized Clinical Trial
Authors: Munné Santiago , Kaplan Brian , Frattarelli John L. , Child Tim , Nakhuda Gary , Shamma F. Nicholas , Silverberg Kaylen , Kalista Tasha , Handyside Alan H. , Katz-Jaffe Mandy , Wells Dagan , Gordon Tony , Stock-Myer Sharyn , Willman Susan 
Published: April 2020

(Abstracted from Fertil Steril 2019;112:1071–1079.e7)
The rate of embryonic aneuploidy increases exponentially in women over the age of 35 years, coinciding with a dramatic decrease in the success of in vitro fertilization (IVF) in women of advanced maternal age. Despite advancements in preimplantation genetic testing for aneuploidy (PGT-A) including the introduction of next generation sequencing (NGS), morphologic assessment remains the primary method of embryo selection in IVF.