bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparative Mathematical Radiotherapy of Some Dog and Human Cancers
Authors: Saganuwan Saganuwan Alhaji
Published: April 2020

Cancer is a serious disease in canine species and can be managed using surgical, chemotherapeutic, immunotherapeutic and radiotherapeutic interventions. But for radiotherapy, determination of radiotherapeutic doses for specific cancer treatment is a serious problem both in medical and veterinary oncology. In view of this, a number of formulas used in medical oncology has been adopted and applied for determination of effective radiotherapeutic doses especially for dogs. Findings revealed that the formulas could be used to estimate radiotherapeutic doses for a number of cancer diseases in dogs. More so, factors such as age, sex, type of cancer, location of cancer and biological effective dose should be considered. The most relevant formula is BED = nd where BED = biologically equivalent dose; d = dose per fraction; α/β = ratio for tumor (10) and n = number of fractions. Metronomic radiotherapy which may be defined as repetitive exposure of cytotoxic radio‐active rays of < 2 Gy at regular and frequent intervals of 10–25 fractions of total 45 Gy may be safer for the treatment of malignancies in dog and human. But BED of 45 60 Gy has cancer control rate of 48 – 67%, and 50% probabilities of complications was caused by radiation rays of 54 Gy. Whereas a dose of > 2Gy in 2 fractions may improve quality of life and reduce chronic pain associated with terminal malignancies.

Support or Funding Information

No financial support was gotten
Hepatocyte Ploidy in Cats with and without Hepatocellular Carcinoma
Authors: Post Jacqueline , Langohr Ingeborg , Liu Chin-Chi , Mottram Peter , Webster Cynthia R. L. , Johnston Andrea
Published: April 2020

Hepatocellular carcinoma (HCC) is one of the most common causes of cancer related death in humans, yet it is an uncommon neoplasm in the domestic cat. The difference in prevalence and etiology between these two species is unexplained. Recent work in mice has shown that hepatocyte polyploidy (> 2n) is protective against the development of hepatocellular carcinoma. Further, human hepatocarcinogenesis is associated with a reduction in hepatocyte ploidy. Hepatocyte ploidy in the domestic cat has not been previously evaluated. Our research objective is to establish a baseline for hepatocellular chromosome number in normal cats and cats with HCC. We hypothesize that hepatocyte ploidy is significantly different in cats with or without HCC. Samples were selected from archival cases at both Cummings School of Veterinary Medicine, Tufts University (Tufts SVM) and Louisiana State University, Louisiana Animal Disease and Diagnostic Laboratory (LSU LADDL). Seven confirmed feline HCC cases and seven age and sex matched normal control cases were selected following review by a veterinary anatomical pathologists (IL). Using Hoechst H33342, a nuclear stain that stoichiometrically binds to the minor groove of DNA, fluorescence intensity was measured to determine hepatocellular ploidy. Neoplastic, peri‐tumoral, and normal hepatocytes were analyzed. There was statistical differences between the distribution of intensities between normal to peri‐tumoral, normal to neoplastic, and neoplastic to peri‐tumoral hepatocytes (p<0.0001). In addition, there is a significant difference between the number of 2N vs. 4N cells in normal and peri‐tumoral (p<0.0001) and neoplastic (p<0.0001) cells, and peri‐tumoral to neoplastic (p=0.002). There is no statistical difference in the number of multinucleated cells between groups. Normal feline liver has a greater number of 4N cells than neoplastic samples. This difference may contribute to development or be a cellular response to HCC development.

Support or Funding Information

Louisiana State University, School of Veterinary Medicine Summer Scholars Program; Kenneth F. Burns Trust
Dose‐Dependent Anti‐Inflammatory and Metabolic Effects of Eicosapentaenoic Acid in Diet‐Induced Obese Mice
Authors: Pahlavani Mandana , Davis Hanna , Miller Emily , Ramalingam Latha , Scoggin Shane , Moustaid-Moussa Naima
Published: April 2020

Obesity is a widespread epidemic that increases the risk for several metabolic diseases such as diabetes and cardiovascular diseases. Long‐chain omega‐3 polyunsaturated fatty acids such as eicosapentaenoic acid (EPA) possess anti‐inflammatory and potent triglyceride‐lowering properties at high doses (4–6 g/day). However, whether lower doses are effective in reducing metabolic alterations associated with obesity has not been investigated. The objective of this study is to determine dose‐dependent effects of EPA in diet‐induced obese mice. We used B6 male mice fed for 14 weeks a high‐fat diet (HF, 45% kcal fat) or HF diet supplemented with 36, 18, or 9 g/kg of AlaskOmega EPA‐enriched fish oil (800mg EPA/g fish oil), kindly provided by Organic Technologies. We conducted metabolic phenotyping during the feeding period, and harvested tissues and blood at termination. There were no differences in food intake across the four treatment groups. Only 36 g/kg of EPA significantly lowered body weight, fat content and epididymal fat pad weight (P<0.05), compared to HF. However, EPA at both 18 and 36 g/kg doses significantly increased glucose clearance and insulin sensitivity (P<0.05), compared to mice fed HF or 9 g/kg of EPA. Locomotor activity was significantly increased (P<0.05) in mice fed EPA 36 and 18 g/kg compared to other groups. Interestingly, compared to HF with all doses of EPA, energy expenditure and oxygen consumption were significantly increased (P<0.05); while serum insulin and leptin levels were significantly decreased (p<0.05). These results validate weight‐ and adiposity‐ independent metabolic benefits of EPA in obesity and demonstrate that doses of EPA comparable to those currently used to treat hypertriglyceridemia (18g/kg mouse diet, ~5g/d human diet) confer several metabolic benefits.

Support or Funding Information

USDA NIFA Postdoctoral Fellowship Grant # 2017‐07139
Lef‐1 is Required for Proper Cell Cycle Progression in Airway Basal Cells
Authors: Jensen-Cody Chandler Walker , Crooke Adrianne , Lynch Thomas , Engelhardt John
Published: April 2020

The surface airway epithelium (SAE) is a pseudostratified layer of cells found within the mammalian airway, and serves as a barrier between the environment and the rest of the body. Its function is crucial for proper respiration and innate immunity. At homeostasis the SAE has very low cellular turnover, yet has the capacity to regenerate itself after injury or infection at an astonishingly fast rate. This is due primarily to the population of resident stem cells found within the SAE called basal cells. Though much work has been done to identify the molecular mechanisms that govern basal cell proliferation, migration, and differentiation, many questions still remain.

The transcription factor Lymphoid Enhancer Binding Factor 1 (Lef‐1) is a Wnt effector protein expressed in stem cell populations in various epithelial tissues, including the developing lung. Our lab has shown that overexpression of Lef‐1 in primary airway stem cell cultures leads to increased proliferation and migration. Additionally, Lef‐1 is required for the development of airway submucosal glands (SMGs), epithelial structures that are continuous with the SAE. However, it is not known if Lef‐1 plays a role in basal cell function. Therefore, we sought to determine the effects of Lef‐1 deletion in basal cells. Though its expression in basal cells is almost undetectable on a population‐wide scale, deletion of Lef‐1 from primary mouse basal cells severely decreases their ability to proliferate in culture, and skews them more toward a secretory club cell fate. Lef‐1 deletion leads to a loss in DNA damage response (DDR) gene expression, including Tp73, Rad51, and Chek1. Lef‐1 knockout basal cells tend to stall in the cell cycle at the G1/S transition. Together these studies indicate an important role for Lef‐1 in basal cell replication and proliferation.

Support or Funding Information

University of Iowa Molecular Medicine ProgramUniversity of Iowa Department of Anatomy & Cell Biology Funding: 2R01 DK047967
Blood Metabolism and Oxidative Stress in Zika Mosquitoes
Authors: Eilerts Diane , Mendias Miguel Leis , Lazzari Claudio , Vinauger Clément
Published: April 2020

Aedes aegypti mosquitoes are the primary vector of disease‐causing viruses such as yellow fever, Zika, dengue fever, and chikungunya. With increasing insecticide resistance, novel control approaches informed by an improved understanding of mosquito biology are urgently needed to reduce vector‐borne disease transmission. Our research aims to further understand the molecular and physiological mechanisms that underlie mosquito‐host interactions. Female mosquitoes feed on warm‐blooded vertebrate hosts to obtain blood nutrients required for egg development, but are subjected to extreme thermal stress when feeding and, upon digestion of the blood, must cope with high levels of oxidative stress. Increased knowledge of the biological mechanisms mosquitoes use to cope with these stressors may have important epidemiological consequences for humans. Using next‐generation sequencing methods, we have characterized rhythmic daily variations in the global transcriptome of female Ae. aegypti heads, which encompass the visual and olfactory sensory appendages mosquitoes rely on to sense host‐seeking cues, the mouthparts, and tissues immediately exposed to blood stressors when feeding. Here we describe daily rhythms in mosquito host‐seeking and blood‐feeding stress tolerance. We also investigated daily rhythms in the metabolism of blood digestion, as these mechanisms represent targets of opportunity for mosquito control. Using state‐of‐the‐art respirometry methods to quantify rhythms in the metabolism of blood digestion in female Ae. aegypti mosquitoes, we were able to observe individual ventilatory patterns and compare the metabolic rates at rest and during digestion. These are the first measurements reported on carbon dioxide release from individual Ae. aegypti female mosquitoes and, thus, these results provide new insights regarding mosquito respiratory and metabolic physiology. Analysis of the metabolic rate following the ingestion of various diets additionally allows us to evaluate the effects of diet composition, oxidative stress exposure, and blood protein digestion on mosquito metabolism. Since this work can be used to identify novel vector control approaches targeting mosquito blood meal processing, our results will inform future efforts to decrease mosquito‐borne disease.

Support or Funding Information

USDA National Institute of Food and Agriculture, Hatch project 1017860. The Company of Biologists Journal of Experimental Biology Travelling Fellowship.
Localization of UT‐B Urea Transporter in the Developing Bovine Rumen
Authors: Zhong Chongliang , Stewart Gavin
Published: April 2020

The rumen ecosystem represents a classic example of a symbiotic relationship between host animals and microbial populations. Urea nitrogen secreted from the blood to the rumen is a crucial factor shaping this relationship. The transport of urea across rumen epithelium is facilitated by urea transport proteins namely urea transporter B (UT‐B) and possibly aquaporin‐3 (AQP3). However, how ruminants regulate nitrogen availability to microbes through these transport proteins remain unclear. Given that calves are the stage at which rumen microbial colonization begins, the developing rumen is an excellent model to observe this regulation. Using rumen epithelium samples of calves aged from birth (Day0, n = 4) to three months old (Day7, Day14, Day21, Day28 and Day96; n = 4–6 each age), immunolocalization was performed to locate UT‐B protein. Results showed that, although varied between the individual animals within each age group, signals were detected at all six stages by a previously characterized UT‐B antibody (n = 25/26). The strongest staining was found in stratum basale cells (or innermost layer for undeveloped papillae), especially those surrounding capillaries (n = 16/26). The staining in stratum spinosum was mainly present in well‐developed papillae at Day96 and was weak (n = 5/6), while stratum granulosum and stratum corneum were mainly negative throughout the six stages. The subcellular staining was clearly seen in the cells of stratum basale at Day96, with the strongest density at the basolateral side of plasma membranes facing large blood vessels (n = 5/6). Given these data, it is reasonable to speculate that UT‐B protein expression started from cells of stratum basale and progressively extended to adjacent cell layers toward the rumen lumen as rumen papillae developed. This localization pattern fits in the functional organization of transporting urea nitrogen from blood to rumen. Further semi‐quantification of staining strength by expression score suggested that UT‐B protein expression differed across ages (p < 0.01, n= 4–6, ANOVA), with the lowest at Day0 and highest at Day96. No difference was found among the stages of Day7, Day14, Day21 and Day28, but as a whole the abundance was higher than Day0 (p < 0.05, ANOVA) and lower than Day96 (p < 0.01, ANOVA). Overall, this study characterized the location pattern of UT‐B protein in calves’ rumen epithelium and confirmed age‐dependent change of UT‐B protein abundance. Its alteration might be associated with interactions with rumen microbial populations and reflect the nitrogen need for both microbes and host animals. These results give insights of how ruminant host animals regulate nitrogen availability to commensal microbial populations and in return benefit from it, through altering the permeability of the rumen wall to the supposed “waste” urea.

Support or Funding Information

This project is supported by China Scholarship Council (China) and University College Dublin (Ireland).
Histological Characterizations of the Brain Vascular Hyalinosis in Patients with Systemic Hypertension‐Induced Ischemic Stroke
Authors: Gychka Sergiy G. , Shults Nataliia V. , Sariipek Nurefsan E. , Rybka Vladyslava , Malysheva Tatiana , Dibrova Vyacheslav A. , Gavrish Alexander S. , Suzuki Yuichiro J.
Published: April 2020

Background

Ischemic stroke is a major cause of death among patients with systemic hypertension. The narrowing of the brain vascular lumen increases the incidence of stroke and the formation of hyalinosis lesion is an irreversible process that occurs in the late stage of the disease and contributes to the vascular narrowing and stroke. Understanding pathologic mechanisms of brain vascular hyalinosis, thus, should contribute to the development of new therapeutic agents that inhibits and/or reverse the formation of hyalinosis, thereby reducing the incidence of ischemic stroke. Despite the clinical importance of this lesion, properties of brain vascular hyalinosis have not been well investigated. Thus, the present study performed detailed histological examinations of the hyalinosis lesions of postmortem brain vascular tissues of human patients who died of ischemic stroke due to systemic hypertension.

Methods & Results

Hematoxylin and eosin staining, as well as periodic acid‐Schiff staining, showed the presence of vascular hyalinosis in patient brain tissues. In these lesions, the protein organization of the extracellular matrix was changed, the number and size of smooth muscle cells were altered, and plasma proteins, such as apolipoprotein E and fibrin, infiltrated into the vessel wall. Signs of oxidative stress and lipid peroxidation were also found. These changes are pronounced at the loci of the infiltration of the vessel walls by ApoE. We found increased number of vasa vasorum in adventitia of the small arteries. The formation and deposition of hyaline occur both from the side of the lumen of the artery and from the side of the vase vasorum. Transmission electron microscopy showed that with the development of hyalinosis, the number of smooth muscle cells that undergo atrophy. The deposition of proteins in the arterial wall is also associated with the degree of damage to endothelial cells in the lumen of the vessel and in the vasa vasorum.

Conclusions

These results demonstrate that, at the beginning of the development of hyalinosis, smooth muscle cells and vasa vasorum are increased. This process seem to involve oxidative stress, which damages endothelial cells both in the lumen of the arteries and in the vasorum vase and contributes to the infiltration of blood plasma proteins into the vascular wall. The resulting hyalinosis decreases the lumen of the arteries and increases the incidence of stroke.

Support or Funding Information

Supported by NIH
Mechanisms Involved in Angiotensin Receptor Blockade Superiority over ACE‐inhibition in Attenuating Neuropathic Pain Induced in Rats
Authors: Hegazy Nora , rezq samar , fahmy ahmed
Published: April 2020

Although, the beneficial role of angiotensin‐converting enzyme inhibitors (ACEi) or AT1 receptor blockers (ARBs) in attenuating Neuropathic pain (NP) was previously reported, the exact underlying mechanisms as well as superiority of using central versus peripheral acting Renin angiotensin aldosterone system (RAAS) drugs in NP is not yet explored. We investigated the effect of 14 days treatment of centrally (telmisartan and ramipril) or peripherally (losartan and enalapril) ARBs and ACEi, respectively in attenuating peripheral NP induced by sciatic nerve chronic constriction injury (CCI) in rats compared to pregabalin, the standard treatment for NP. Behavioral changes, inflammatory markers (nuclear factor‐kappa B (NFкβ), tumor necrosis factor (TNF)‐α release, Cyclooxygenase‐2 (COX‐2), prostaglandin E2 (PGE2) and bradykinin), oxidative stress markers (NADPH oxidase and catalase), signal transducer and activator of transcription 3 (STAT‐3) activation, levels of phosphorylated P38 mitogen activated protein kinase (P38 MAPK), angiotensin converting enzyme (ACE), AT1 receptor (AT1R) and AT2 receptor (AT2R) as well as histopathological picture were assessed in brain stem and sciatic nerve. CCI resulted in an obvious painful behavior along with increased levels of inflammatory and oxidative stress markers, STAT3 activity as well as the levels of phosphorylated P38 MAPK, ACE, AT1R and AT2R and worsened histopathological picture in both the brainstem and sciatic nerve. Treatment of CCI rats with ARBs resulted in improving in animal behavior and all measured parameters and were more effective compared to ACE inhibitors. Centrally acting ARBs or ACEi were not superior compared to their peripherally acting drugs of the same category. These findings suggest ARBs (central or peripheral) as an effective treatment modality for NP.
Low‐dose Lithium is Associated with Left Ventricular Ejection Fraction in Healthy Young Men but not Women
Authors: Dempster Kylie S. , Fajardo Val A. , Baranowski Ryan W. , Hamstra Sophie I. , Wade Terrance J. , O'Leary Deborah D.
Published: April 2020

The impact of lithium (Li) exposure on the cardiovascular system is perplexing, as beneficial, negative, and null effects have been identified. Li is an inhibitor of glycogen‐synthase kinase 3β (GSK3‐β) which has been identified as a possible therapeutic target for cardiovascular disease (CVD) and mental health disorders. While earlier ecological studies suggest that trace amounts of Li may protect against CVD, no study to date has investigated the effects of low‐dose Li exposure on cardiac structure and function in healthy young adults without CVD and whether these associations are sex dependent. The purpose of the present investigation was to examine the association between Li exposure and left ventricular mass (LVM) and function in healthy young adults. This investigation represents a cross‐sectional analysis of the Niagara Longitudinal Heart Study (NLHS) at the midpoint of data collection for 156 participants aged 19 – 25 years. A final sample size of 117 had both valid Li and left ventricular data upon analyses. LVM was indexed to height2.7 (LVMi), ejection fraction (EF), fractional shortening (FS), and stroke volume (SV) were assessed following echocardiography in the parasternal long‐axis view of the left ventricle. Serum Li levels were measured using inductively‐coupled plasma mass spectrometry. Li concentration was significantly associated with EF (r = −0.183, p = 0.05) and ESV (r = 0.197, p = 0.03) among the total sample. Li concentration did not differ when examined by sex (p > 0.05), however LVMi, ESV, EDV, SV, and EF were all significantly higher in males than females (p < 0.05). Li was only significantly correlated with EF in men (r = −0.320, p = 0.02) however no correlation was observed among women (p > 0.05). The novel result of our investigation was naturally occurring concentration of Li is associated with decreased EF in men, but not women, although, there was no significant difference in SV. Further, there was no effect of low‐dose Li on LVMi. This is in contrast to some animal studies which demonstrate long‐term exposure to Li has potent hypertrophic effect on the left ventricle, although, Li concentrations in our sample were considerably lower and fall within a normal physiological range. These findings may result from differential sensitivities of the GSK‐3β receptor to Li in the left ventricle in men and women, although further investigation is required.

Support or Funding Information

This research project is funded by the Canadian Institutes of Health Research (CIHR #s 363774, 399332). KSD is funded by a CIHR Doctoral Research Award – Frederick Banting and Charles Best Canada Graduate Scholarship (RFN#167014). VAF is supported by a Brock Explore Grant and an NSERC Discovery Grant (2019‐05833).
Autonomic Dysfunction in Women with Androgen Excess PCOS
Authors: Stone Tori , Leone Cheryl , Ayers Thomas , Stachenfeld Nina
Published: April 2020

Polycystic ovary syndrome (PCOS) is the most common reproductive endocrinopathy, affecting approximately 10% of reproductive age women. Further, 75% of women with PCOS have the more severe phenotype, Androgen Excess‐PCOS (AE‐PCOS), that is dominated by clinical and biochemical manifestations of hyperandrogenism. AE‐PCOS is also associated with elevated blood pressure (BP), which we hypothesized is the result of androgen‐associated impairments in autonomic function. Thus, we tested the hypothesis that androgen excess is associated with impaired baroreflex sensitivity (BRS) in women with AE‐PCOS. We tested four obese women with AE‐PCOS (age 30±3 y; BMI 39±11 kg/m2) at 0, HDT, ‐20, ‐30 lower body negative pressure (LBNP) under three conditions: Baseline (BL), during hormone suppression with a GnRH antagonist (GnRH ant, 7 days, 250 μg/day), and with GnRH ant+testosterone (T, 4 days, 5 mg/day). Women were mildly hypertensive at rest at BL, but BP increased following hormone suppression with the GnRH ant and remained elevated with T (93±7, 105±5, 105±9 mm Hg for BL, GnRH ant, and T, respectively, P=0.02). Blood pressure was well maintained during LBNP under the three hormone conditions. Forearm vascular resistance (FVR) increased during LBNP under each condition, but the increase was greatest during GnRH ant and T (Δ54±19, Δ235±145, Δ104±64 units for BL, GnRH ant, and T, respectively, P=0.04). The resulting BRS slopes were greater in GnRH ant (−5.2 units/mm Hg) compared to BL (−1.6 units/mm Hg), demonstrating concomitant testosterone and estrogen suppression improved BRS in women with AE‐PCOS. When we restored androgens, the BRS slope was again attenuated (T= −1.7 units/mm Hg), suggesting an important role for androgens in autonomic function in AE‐PCOS. GnRH ant increased resting BP independent of T in AE‐PCOS, which is likely a function of the continued estrogen suppression. Thus, hypertension associated with AE‐PCOS appears closely associated with estrogen suppression and independent of testosterone‐induced changes in BRS. In summary, both estrogens and androgens contribute to BP regulation in women with AE‐PCOS. Women with AE‐PCOS frequently present with mild hypertension that is driven by altered estrogen and testosterone exposures. Treating hypertension is crucial for preventing cardiovascular disease in this vulnerable population.

Support or Funding Information

R01 HL135089
Androgen‐Dependent Provocation by Tacrolimus of Nephrotoxic and Inflammatory Consequences of Endotoxemia in Rats
Authors: Elzokm Shrouk S. , Fouda Mohamed A. , Abdel Moneim Rahab A. , El-Mas Mahmoud M.
Published: April 2020

Reported data on the interaction of immunosuppressants and endotoxic insult on end organ damage have been conflicting. In this report, we assessed the (i) renal profile in rats treated individually or concurrently with tacrolimus and lipopolysaccharide (LPS), and (ii) role of androgens and their receptors in the interaction. The data showed that a single exposure of male rats to LPS (3 mg/kg i.p.) for 6 hr caused significant elevations in serum urea and creatinine together with evidence of cellular vacuolation and degeneration in proximal and distal tubules. Moreover, quantitative morphometric analysis revealed significant increases in the width of renal tubules in endotoxic rats. Except for tubular dilation, tacrolimus (2 mg/kg i.p.) exhibited no signs of renal damage on its own, but it aggravated the rises in serum biomarkers of renal function and histopathological derangements when administered to endotoxic rats. Similarly, ELISA determinations demonstrated that tacrolimus potentiated the LPS‐evoked increases in serum levels of the inflammatory cytokines tumor necrosis factor alpha and myeloperoxidase. We also report that the detrimental biochemical and histopathological renal outcomes caused by tacrolimus in endotoxic rats were virtually eliminated after surgical (castration) or pharmacologic (androgen receptor blockade by flutamide) interruption of androgenic activity. Overall, the data highlight a pivotal role for male gonadal hormones in worsened renal profile evoked by tacrolimus in endotoxic rats. If necessary, immunosuppressants other than tacrolimus are advised in humans with endotoxemia.
The Role of Mental and Motor Processes in Conceiving, Developing and Validating 3D Interactive Human Anatomy Learning Tools
Authors: Hoyek Nady , Rienzo Franck Di , Guillot Aymeric , Collet Christian
Published: April 2020

Understanding human anatomy requires several mental and motor processes: i) mental imagery: the ability to mentally represent a physical object, a concept or a situation; ii) mental rotation: the ability to mentally turn the image of an object in the three space planes; iii) motor imagery: the ability to imagine a human movement without any real movement execution. These mental and motor processes have been used in Lyon 1 university to conceive and develop hundreds of 3D animations that are used to teach anatomy for undergraduate allied health sciences students, especially kinesiology students. All our animations are available in our YouTube Chanel “Anatomie 3D Lyon”. Our approach is experimentally validated through several paradigms. For instance, we found a significant correlation between anatomy examination results and visuo‐spatial ability tests (Guillot et al., 2007). We also showed that mental rotation training enhanced the acquisition of anatomical information requiring visuo‐spatial ability (Hoyek et al., 2009). Our 3D animations, when used in real learning condition, enhance the acquisition of anatomy knowledge requiring spatial ability as compared to 2D images (Hoyek et al., 2014). We further showed the efficiency of 3D animations compared to static 3D images in the mental representation and description of the scapula (Berney et al. 2015). In sum, 3D animations are efficient in teaching and learning anatomy, however their passive visualization lacks interaction, which is essential for anatomy learning. In our actual funded projects (Antepulsio and An@tomy 2020) we are developing new interactive tools that allow both personal body experience and good spatial representation of anatomical structures. This approach is based on evidences that body movements could improve learning of different knowledge by augmenting or enriching traces in long‐term memory. This embodied perspective is particularly relevant for functional anatomy learning as the knowledge to acquire could be specifically related to the learner’s body in motion. Our new prototypes as well as our related preliminary results will be presented during the conference. All our experiments were approved by our local ethic board. They were conducted on our kinesiology students with their understanding and consent.

Support or Funding Information

1) Agence Nationale de la Recherche: project An@tomy20202) Fond Unique Interministériel: project ANTEPULSIO
Luminal bile acids region‐specifically strengthen intestinal epithelial barrier integrity after RYGB through FXR signaling
Authors: Hankir Mohammed , Langseder Theresa , Ghoreishi Yalda , Koenigsrainer Malina , Dischinger Ulrich , Otto Christoph , Arora Tulika , Seyfried Florian , Schlegel Nicolas
Published: April 2020

Roux‐en‐Y gastric bypass surgery (RYGB) provides superior long‐term glycaemic control in severely obese and insulin resistant individuals. The improved peripheral insulin sensitivity at later stages after RYGB has been attributed in part to a reduction in intestinal permeability and associated endotoxemia, but the underlying mechanisms remain unclear. Here, we used diet‐induced obese rat and Caco2 cell monolayer models to show that RYGB region‐specifically strengthens intestinal epithelial barrier (IEB) integrity. This was partly farnesoid X receptor (FXR)‐dependent for the bile‐exposed duodenum and colon but not for the bile‐excluded jejunum. Transfer experiments performed on recipient germ‐free mice additionally demonstrated that jejunal and colonic but duodenal content of RYGB‐operated rats contain microbiota‐produced factors which improve oral glucose tolerance in proportion to suppression in endotoxemia. Collectively, these findings suggest that luminal primary and secondary bile acids acting through FXR in duodenal and colonic epithelial cells respectively, contribute to overall strengthening of IEB integrity and improved glucose homeostasis after RYGB and further support the use of bile acid mimetics for the treatment of metabolic disease.
Testing Inhibitory Drugs of the Human UPR Sensor IRE1 on Aspergillus fumigatus
Authors: Deck Katherine , Abad Jose Guirao , Askew David
Published: April 2020

Aspergillus fumigatus is a fungus that is associated with life‐threatening pulmonary infections. Unfortunately, current antifungal drugs to treat this infection are limited, making the search for novel molecular targets a high priority. A. fumigatus has an intracellular stress response pathway known as the unfolded protein response (UPR), which is key to its ability to cause infection. Inhibitors of the human UPR pathway have been developed, but are untested on A. fumigatus. Here, the ability of STF 083010 and toyocamycin, human UPR inhibitors, to inhibit the corresponding fungal UPR pathway and reduce the fitness of A. fumigatus was tested. Culturing of A. fumigatus in the presence or absence of the compound under conditions that require UPR intervention demonstrated that toyocamycin did not affect the fungus, whereas STF 083010 inhibits colony growth and is fungistatic. Additionally, STF 083010 increases the toxicity of ER stress agents and cell wall damaging agents, and it also prevents the fungus from utilizing polymeric substrates. Finally, the ability of STF 083010 to inhibit the induction of UPR target genes by a strong stimulus was examined by qPCR. The results demonstrate that STF 083010 blocks the ability of DTT to induce the expression of hacAi and bipA, indicating suppression of the fungal UPR. These results provide the first evidence that pharmacologic inhibition of the UPR pathway is feasible in A. fumigatus, and that the loss of fitness by STF 083010 could be a novel approach to antifungal therapy.
Colonic mucosae is affected by experimental gastric restriction
Authors: Akamatsu Flávia Emi , Fontes Luiz Gustavo , Itezerote Ana , Saleh Samir , Hojaij Flávio , Andrade Mauro , Pereira José Aires , Martinez Carlos , Jacomo Alfredo Luiz
Published: April 2020

Background

Obesity‐related comorbidity is defined as a condition caused by overweight/obesity or known to contribute to the presence or severity of the condition. These comorbid conditions are expected to improve or go into remission in the presence of effective and sustained weight loss. World Health Organization reports obesity as a rising chronic condition with many devastating health consequences. Gastric reduction procedures are currently employed to treat morbid obesity and there are few reports concerning the consequent effects in large intestine.

Methods

Experimental model of gastric restriction was devised using rats. The animals were submitted to surgical gastrostomy and a cylindrical loofah was inserted into the stomach. We studied 30 adult male Wistar rats divided in three groups: the stomach reduction group (R20), the sham group (SH20), which underwent the same procedure except for the loofah insertion and the control group (C20). Animals were fed and kept in separate cages. Sections of the colon were obtained and stained with hematoxylin‐eosin and analyzed for the length of the crypts, mucous cells and inflammatory cells.

Goblet cells and inflammatory cells were obtained in all groups as mean, median, minimum and maximum and were compared between groups using generalized estimation equations (GEE) with normal distribution and identity link function supposing exchangeable correlation matrix between fields. Bonferroni’s multiple comparison was applied to identify differences between groups. The results are described by the mean value with respective standard deviation.

Results

The analysis of Goblet cells count on R20 group indicated a statistically significant reduction and shallower crypts as compared to the C20. There was a significant difference regarding inflammatory cells on R20 compared to C20 and SH20. Polymorphonuclear inflammatory cells were increased in all groups when compared to lymphomononuclear cell but with no significant difference among groups.

Conclusion

These findings might be a result of colonic mucosae atrophy secondary to the effects of gastric restriction in this model. The increase in neutrophil infiltrate may be related to the presence of bezoar, as well as the greater aggression to the colic epithelium due to lack of short chain fatty acids (CCFA), oxidative stress epithelial damage due to lack of CCFA.
Natural Saponin Formosanin C‐induced Ferroptosis in Human Hepatocellular Carcinoma Cells Involved Ferritinophagy
Authors: Su Chun-Li , Lin Pin-Lun
Published: April 2020

Formosanin C (FC) is an anti‐tumor diosgenin saponin isolated from Paris formosana Hayata (Liliaceae) which is a perennial herb grown in the humid and dark forests of Taiwan at about the level of 1000 m. The plat has been used as a folk remedy for snake‐bite inflammation and tumors. FC is also a component of “Yunnan Bai Yao”, a traditional Chinese hemostatic medicine. Ferroptosis is a new form of iron‐dependent cell death, which occurs via an increased labile iron pool and lipid reactive oxygen species (ROS). Ferritinophagy is a ferritin (an iron storage protein) degradation pathway, depending on a selective autophagic cargo receptor nuclear coactivator 4 (NCOA4). Increased labile iron pool by ferritinophagy has been recognized as an upstream regulator of ferroptosis. Thus, ferroptosis has been reported to be a form of autophagic cell death. Although iron is an essential nutrient that facilitates cell proliferation and growth, overexpression of ferritin and down‐regulation of ferroportin (an iron export protein) has recently been observed in human hepatocellular carcinoma (HCC), indicating the increased dependence of iron in the cancer cells. In the present study, FC caused a significant dosage‐related population growth inhibition in HCC HepG2 and Hep3B cells using SRB assay, which can be partially blocked by co‐administration of ferroptosis inhibitor ferrostatin‐1 (a scavenger of lipid ROS). FC induced elevation in lipid ROS formation can also be partially reversed by addition of either ferrostatin‐1, or the presence of antioxidant vitamin C and/or vitamin E using flow cytometry, confirming FC‐induced ferroptosis. Flow cytometric analysis also revealed that FC elevated the percentage of acidic vesicular organelles‐positive cells, representing the formation of autolysosomes and induction of autophagic flux in both cell lines. The FC‐induced autophagy was confirmed using Western blotting, characterized by the production of LC3‐II and a further elevation of LC3‐II expression by addition of autophagy inhibitor bafilomycin A1 to prevent the fusion of autophagosomes and lysosomes for cargo degradation. In the present of bafilomycin A1, accumulation of NCOA4 and ferritin was observed in both FC‐treated cell lines using Western blotting. Concurrently, increase in co‐localization of LC3 puncta with NCOA4 or ferritin was exhibited using confocal microscopy, suggesting FC‐induced ferritinophagy. It is noteworthy that HepG2 cells with a higher NCOA4 expression were more sensitive to FC‐induced ferroptosis and autophagy compared to Hep3B cells with a higher ferritin expression. Overall, our data suggest chemotherapeutic potential of phytochemical FC for treatment of HCC with higher expression of NCOA4 via ferritinophagy and ferroptosis.

Support or Funding Information

Supported in part by the Ministry of Science and Technology, Taiwan, No. MOST 106‐2320‐B‐003‐006‐MY3 and 107‐2320‐B‐003‐002‐MY2
Sympathetic Activation to Limb Venous Distension is Preserved during Muscle Metaboreceptor Stimulation
Authors: Cui Jian , Blaha Cheryl , Leuenberger Urs A. , Sinoway Lawrence I.
Published: April 2020

Venous saline infusions in an arterially occluded forearm evokes reflex increases in muscle sympathetic nerve activity (MSNA) and blood pressure (BP) in humans (venous distension reflex). Animal studies suggest that venous distension increases the discharge of Group III and IV afferent nerve endings in peripheral veins. Exercise also activates the Group III and IV afferent nerves in exercising muscles. It is unclear if the venous distension reflex contributes to BP regulation during exercise. We hypothesized that muscle metaboreceptor stimulation might alter the venous distension reflex response. BP (Finapres), heart rate (ECG), and MSNA (microneurography) were assessed in 18 young healthy subjects (13 M, 5 F, 26 ± 1 yrs). In trial 1, saline (5% forearm volume) was infused into veins of an arterially occluded arm (non‐handgrip trial). In the second experiment, subjects performed 2 min static handgrip followed by post exercise circulatory occlusion (PECO) of the arm. During PECO, saline was infused into veins of the arm (handgrip trial). In trial 1, infusion increased MSNA (18.5 ± 1.6 to 29.1 ± 2.4 bursts/min, P < 0.001) and BP (P <0.001) as expected. Handgrip significantly raised MSNA (19.8 ± 1.6 to 28.0 ± 1.8 bursts/min, P < 0.001), BP (P < 0.001) and venous lactic acid (1.0 ± 0.1 to 3.1 ± 0.4, mmol/L, P < 0.001). Venous saline infusion during PECO further raised MSNA (prior infusion vs. end of infusion, 29.0 ± 2.4 to 37.7±2.7 bursts/min, P= 0.001) and BP (P < 0.001). The changes in MSNA evoked by infusion during PECO were not significantly different from the rises in the non‐handgrip trial (delta 8.6 ± 1.5 to delta 10.6 ± 1.8 bursts/min, P = 0.258). The BP responses to the infusion were not different in the two trials. These observations indicate that venous distension reflex responses are preserved during the sympathetic activation mediated by the muscle metaboreceptor stimulation. These data may suggest that venous distension reflex contributes to the BP regulation during exercise.

Support or Funding Information

Supported by NIH R01 HL144781 (Cui and Sinoway) and UL1 TR002014 (Sinoway), and Pennsylvania Department of Health Tobacco CURE Funds SAP#4100079742 (Cui).
Assessment of Pulsatile Load During Lower Body Aerobic Exercise in Young and Older Adults
Authors: Stock Joseph Michael , Chouraminis Nicholas V. , Shenouda Ninette , Patik Jordan C. , Martens Christopher R. , Farquhar William B. , Chirinos Julio A. , Edwards David
Published: April 2020

Increased wave reflection magnitude (RM) and early return of reflected pressure waves augment pulsatile load, waste left ventricular effort, and are associated with cardiovascular events. Acute lower body aerobic exercise (AE) decreases RM and reflected wave transit time (RWTT) in young adults (YA). Due to age‐related changes in arterial structure and function, older adults (OA) experience an elevated RM and earlier RWTT at rest compared to YA. However, it is unknown how AE influences RM and RWTT in OA, and whether OA respond differently than YA.

PURPOSE

The purpose of this study was to test the hypotheses that 1) RM and RWTT would be reduced during AE and 2) the reduction in RM would be attenuated in OA while the reduction in RWTT would be augmented in OA compared to YA.

METHODS

Radial artery pressure waveforms and aortic blood flow velocities were acquired at baseline and during light, moderate, and vigorous intensity AE on a supine cycle via applanation tonometry and echocardiography, respectively, in 20 YA (25±5 yrs) and 20 OA (66±4 yrs). Central pressure waveforms were synthesized from radial waves using a generalized transfer function. Pressure‐flow relations were analyzed offline to perform wave separation analysis. This provided a comprehensive assessment of ventricular‐arterial interactions for the determination of the relative amplitude and timing of forward (Pf) and backward (Pb) pressure waves, yielding RM (Pb/Pf) and RWTT.

RESULTS

As expected, baseline RM was greater in OA (YA: 40±6 vs. OA: 49±6%, p<0.05) and RWTT was shorter in OA compared to YA (YA: 191±20 vs. OA: 140±18 ms, p<0.05). RM was decreased during all intensities of AE. However, the reduction in RM from baseline was different between YA and OA during light intensity AE (ΔYA: −12±8 vs. ΔOA: −17±7, p<0.05), trended toward being different during moderate AE (ΔYA: −12±10 vs. ΔOA: −18±7%, p=0.06), and was not different during vigorous AE (ΔYA: −15±6 vs. ΔOA: −18±6%, p>0.05). RWTT decreased during all intensities of AE. The reduction in RWTT from baseline was attenuated in OA compared to YA during light (ΔYA: −39±18 vs. ΔOA: −9±13ms, p<0.05), moderate (ΔYA: −51±18 vs. ΔOA: −11±17ms, p<0.05), and vigorous intensity AE (ΔYA: −57±25 vs. ΔOA: −19±17ms, p<0.05).

CONCLUSION

RM decreased during AE, however, differences in ΔRM between YA and OA were exercise intensity dependent. Our results suggest a greater decrease in RM in OA compared to YA during light‐moderate intensity AE. Contrary to our hypothesis, there was an attenuated reduction in RWTT in OA compared to YA during all intensities of AE, which may be due to the OA reaching the floor in RWTT.

Support or Funding Information

ACSM Foundation Doctoral Student Research Grant and NIH grant P20 GM 113125
Influence of Obesity on Vascular Dysfunction Following Hemorrhagic Shock
Authors: Walker Ashley E. , Cole Jazmin , Kumaran Sahana Krishna , Zhuang Xinhao , Wolf Julia R. , Henson Grant D. , McCully Belinda H.
Published: April 2020

Obesity is associated with higher rates for complications after traumatic hemorrhage, including higher incidence of multiple organ failure, thrombosis, and mortality. These adverse events are associated with prolonged tissue hypoperfusion, hypercoagulability, and edema that reflect profound vascular damage. However, the combined impact of obesity and traumatic hemorrhage on vascular function is not well understood. Therefore, we sought to determine the impact of diet‐induced obesity on vasoconstrictor and vasodilator properties of arteries before and after hemorrhagic shock.

Male Sprague‐Dawley rats were fed a control (CON; 13.5% kcal fat, n=10), moderate fat (MF, 33% kcal fat n=9) or high fat (HF, 60% kcal fat, n=10) diet for 6–8 weeks. Hemorrhagic shock was induced by laceration of a mesentery artery and a Grade V splenic injury under anesthesia, and a period of hypotension (mean arterial pressure = 30–40 mm Hg) was maintained for 30 minutes. We assessed vasoconstrictor and vasodilator properties in isolated mesenteric arteries harvested before and after hemorrhagic shock. Before hemorrhage, peak norepinephrine (NE) vasoconstriction was higher in CON rats (78±4%) versus HF (62±5%, p=0.01), while MF rats exhibited a peak NE vasoconstriction not different from either groups (71±3%, p>0.05 vs CON and HF). Baseline endothelium‐dependent dilation, assessed as the maximal response to acetylcholine, was not different between groups (CON: 97±1%, MF: 88±4%, HF: 92±3%, p=0.08). Hemorrhage lowered the peak NE vasoconstriction (post: 61±8%, p=0.05) and endothelium‐dependent dilation in CON rats (post: 90±2%, p<0.001), but had no effect on NE vasoconstriction and endothelium‐dependent dilation in MF and HF rats (p>0.05 vs pre‐hemorrhage). Endothelium‐independent dilation, assessed as the response to sodium nitroprusside, was similar pre‐ and post‐hemorrhage in all groups (p>0.05).

In conclusion, we find traumatic hemorrhage induces vascular dysfunction characterized by a reduced vasoconstrictor response and impaired endothelial function, but only in rats fed a normal chow diet. While obesity results in vascular dysfunction at baseline, it does not contribute to a further worsening of function after traumatic hemorrhage.

Support or Funding Information

Funded by a UO‐OHSU Collaborative Seed Grant
miR‐3074‐3p promotes myoblast differentiation by targeting Cav1
Authors: Lee Bora
Published: April 2020

Muscle fibers are generally formed as multinucleated fibers that are differentiated from myoblasts. Several reports have identified transcription factors and proteins involved in the process of muscle differentiation to date, but the role of microRNAs (miRNAs) in myogenesis is still unclear. Here, comparative analysis of the miRNA expression profiles in mouse myoblasts and gastrocnemius (GA) muscle uncovered miR‐3074‐3p as a novel miRNA showing markedly reduced expression in fully differentiated adult skeletal muscle. Interestingly, elevating miR‐3074‐3p promoted myogenesis in C2C12 cells, primary myoblasts, and HSMMs, resulting in increased mRNA expression of myogenic makers such as Myog and MyHC. Using a target prediction program, we identified Caveolin‐1 (Cav1) as a target mRNA of miR‐3074‐3p and verified that miR‐3074‐3p directly interacted with the 3′ untranslated region (UTR) of Cav1 mRNA. Consistent with the findings in miR‐3074‐3p‐overexpressing myoblasts, knockdown of Cav1 promoted myogenesis in C2C12 cells and HSMMs. Taken together, our study suggests that miR‐3074‐3p is a positive regulator of myogenic differentiation by targeting Cav1.

Support or Funding Information

We thank S.‐Y. Kim (Genome Editing Research Center in KRIBB) for the advice and discussion in the miRNA analysis. This study was supported by grants from the Bio & Medical Technology Development Program (2017M3A9D8048708) of the National Research Foundation (NRF) funded by the Korean government (Ministry of Science and ICT), the UST Young Scientist Research Program through University of Science and Technology (2019YS07) and the KRIBB Research Initiative Program.