bluuebunny/crossref_metadata_2025_split huggingface dataset:
Investigating the Intestine‐Specific Role of Small Heterodimer Partner
Authors: Nguyen James , Riessen Ryan , Rodriguez-Otero Jannette , Anakk Sayeepriyadarshini 
Published: April 2020

Bile Acid (BA) is an essential physiological detergent synthesized in the liver and secreted into the intestine to help digest and absorb dietary lipids and nutrients. After aiding in digestion, BAs are reabsorbed and recycled back to the liver in a process called enterohepatic recirculation. Nuclear receptor called Small Heterodimer Partner (SHP) plays a fundamental role in coordinating this process. Although extensively studied in the liver, the role for SHP has not been elucidated in the intestine. Therefore, we generated and characterized the intestinal‐specific Shp knockout (IShpKO) mice. We challenged the control Floxed Shp (f/f Shp) and IShpKO with 1% Cholic Acid (CA) diet for 5 days and collected the liver and the intestine in fed and 6 hour fasted conditions. The gross phenotype (i.e. body weight change, liver‐to‐body weight ratio, intestinal length) was not altered with the loss of Shp but showed alterations when challenged with CA diet. Notably, the BA levels were increased in both the serum and intestine while triglyceride levels were increased in the serum under the absence of Shp on 1% CA diet. Despite changes in BA levels, the transcript levels of transporters and BA synthetic genes in the liver maintained their suppression upon CA feeding. This result suggests that loss of intestinal Shp does not affect liver Shp functions. However, we found that Shp‐mediated regulation of BA homeostasis was different in fed versus 6 hour fasted states. In contrast, the mRNA transcript levels in the intestine revealed that the loss of Shp misregulated the expression of BA regulators and transporters. Furthermore, region‐specific expression analysis revealed that many of the transporters and essential BA regulators including Shp are expressed in the ileum. Also, serum triglyceride levels were higher in the IShpKO group with and without excess CA diet after olive oil gavage, suggesting either (i) increased expression of fatty acid transporters or (ii) leaky gut secondary to excess BAs in IShpKO mice. To test the pathological consequence of Shp deletion in the intestine, we challenged mice with 2% Dextran sulfate Sodium (DSS) to induce colitis and found that IShpKO mice were more susceptible to intestinal damage. Taken together, we showed that Shp is a major regulator of intestinal barrier and nutrient absorption.Support or Funding InformationNational Institutes of Health (NIH) Research Grant Program (R01)
Hypothalamus mediates cardioinhibitory pathway from the paraventricular nucleus of the thalamus
Authors: Puigbonet Maria E. , Li Zhaohui , Ciriello John 
Published: April 2020

The paraventricular nucleus of the thalamus (PVT) is known to function as a site of integration of brainstem, limbic and cortical afferent information involved in affective behaviors, and visceral and homeostatic regulation. This study investigated the role of the hypothalamus in mediating the arterial pressure (AP) and heart rate (HR) changes elicited by activation of PVT neurons. In the first series of experiments, cardiovascular responsive sites were identified in PVT using L‐glutamate (Glu; 10 nl, 0.25 M) microinjections in chloralose‐anesthetized Wistar rats. Glu injections in the anterior PVT elicited decreases in mean AP (MAP, −20 ± 3 mmHg) and HR (−15 ± 5 bpm). In the second series, iontophoretic injections of the anterograde tract tracer PHA‐L (2.5%) were made at these depressor sites in the anterior PVT in Wistar rats. Within the hypothalamus, PHA‐L labelled fibers and presumptive terminals were predominantly found bilaterally in and around the anterior, dorsolateral and the ventromedial parvocellular components of the paraventricular nucleus of the hypothalamus (PVH). A few scattered PHA‐L labelled fibers were also observed within the posterior magnocellular component of PVH, the supraoptic nucleus, the lateral and dorsomedial hypothalamic areas, and the area of the tuber cinereum. In the final series, bilateral microinjection (100 nl) of either the synaptic blocker CoCl2, the non‐specific Glu antagonist kynurenic acid or the selective NMDA receptor antagonists 2‐amino‐5‐phosphonovalerate were made into the PVH in chloralose‐anesthetized Wistar rats. Injections of these compounds did not significantly alter the resting level of AP or HR. However, all injected compounds attenuated the MAP responses (grouped data; −15 ± 5 mmHg; p<0.01), and completely blocked the HR responses (grouped data, −3 ± 5 bpm; p<0.01) to PVT neuronal activation (control responses; MAP, −25 ± 3 mmHg; HR, −19 ± 7). These data suggest that PVT functions to alter cardiac sympathoinhibitory responses associated with arousal, stress, and affective behaviors through a glutamatergic pathway relaying in PVH.Support or Funding InformationSupported in part by the Heart and Stroke Foundation of Ontario
Differential regulation of cardiomyocyte cohesion by signaling pathways involve ERK1/2 or Plakoglobin
Authors: Shoykhet Maria , Trenz Sebastian , Kempf Ellen , Schinner Camilla , Yeruva Sunil , Waschke Jens 
Published: April 2020

Arrhythmogenic cardiomyopathy (AC) is a heart disease caused by mutations in genes encoding for desmosomal proteins such as desmoglein 2 (Dsg2) and plakoglobin (Pg) and partially paralleled with skin defects. However, therapy is symptomatic to limit arrhythmia since the mechanisms by which desmosomal components control cardiomyocyte adhesion and function are largely unknown. We have previously shown that adrenergic signaling and PKC enhance cardiomyocyte adhesion, the further of which is dependent on phosphorylation of Pg at S665. Here, we define a set of signaling pathways differentially regulating cardiomyocyte adhesion under basal as well as hyper‐adhesive, i.e., Ca2+‐ independent conditions, both of which are known to be important for epidermal integrity. In cardiomyocyte cell and cardiac slice cultures, adrenergic signaling, activation of PKC and inhibition of p38MAPK enhanced cardiomyocyte adhesion, which we refer to as positive adhesiotropy, and induced hyper‐adhesion. Positive adhesiotropy was paralleled by activation of and dependent on ERK1/2, whereas Pg phosphorylation and Dsg2 recruitment to cell junctions were induced by adrenergic signaling only. In contrast, inhibition of ERK signaling did not affect hyper‐adhesion. Finally, in heart slices from mice deficient for Pg, which displayed a strong AC phenotype, PKC activation and p38MAPK inhibition but not adrenergic signaling enhanced cardiomyocyte adhesion. Taken together, these results demonstrate that cardiomyocyte adhesion is tightly regulated by signaling mechanisms, which are in part off‐set in Pg‐dependent AC.Support or Funding InformationDFG grant to Jens Waschke with grant number WA2474/11‐1
miRNA‐Mediated Suppression of a Cardioprotective Cardiokine as a Novel Mechanism Exacerbating Post‐MI Remodeling by Sleep Breathing Disorders
Authors: Du Yunhui , Wei Yongxiang , Christopher Theodore , Lopez Bernard , Ma Xinliang , Wang Yajing 
Published: April 2020

BackgroundObstructive sleep apnea (OSA), a sleep breathing disorder in which chronic intermittent hypoxia (CIH) is the primary pathology, is associated with multiple cardiovascular diseases. However, whether and how CIH may affect cardiac remodeling following myocardial infarction (MI) remains unknown.Methods and ResultsAdult male mice were subjected to MI (4 weeks) with and without CIH (4 or 8 weeks). CIH prior to MI (CIH+MI) had no significant effect upon post‐MI remodeling. However, double CIH exposure (CIH+MI+CIH) or CIH only during the MI period (MI+CIH) significantly exacerbated pathologic remodeling and reduced survival rate. Mechanistically, CIH activated TGF‐b/Smad signaling and enhanced cardiac epithelial to mesenchymal transition, markedly increasing post‐MI cardiac fibrosis. Transcriptome analysis revealed that, among 15 genes significantly downregulated (MI+CIH versus MI), Ctrp9 (a novel cardioprotective cardiokine) was one of the most significantly inhibited genes. Rt‐PCR/Western analysis confirmed that cardiomyocyte Ctrp9 expression was significantly reduced in MI+CIH mice. RNA‐seq, Rt‐PCR, and dual‐luciferase reporter assays identified that miR‐214‐3p is a novel Ctrp9 targeting miRNA. Its upregulation is responsible for Ctrp9 gene suppression in MI+CIH. Finally, AAV9‐mediated cardiac‐specific Ctrp9 overexpression or rCTRP9 administration inhibited TGF‐b/Smad and Wnt/β‐catenin pathways, attenuated interstitial fibrosis, improved cardiac function, and enhanced survival rate in MI+CIH animals.ConclusionsThis study provides the first evidence that MI+CIH upregulates miR‐214‐3p, suppresses cardiac CTRP9 expression, and exacerbates cardiac remodeling, suggesting that CTRP9 may be a novel therapeutic target against pathologic remodeling in MI patients with OSA.
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 InformationNo 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 InformationLouisiana 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 InformationUSDA 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 InformationUniversity 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 InformationUSDA 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 InformationThis project is supported by China Scholarship Council (China) and University College Dublin (Ireland).