bluuebunny/crossref_metadata_2025 huggingface dataset:
Intestinal epithelial tight junction barrier regulation by autophagy-related protein ATG6/beclin 1
Authors: Wong Morgan , Ganapathy Ashwinkumar Subramenium , Suchanec Eric , Laidler Laura , Ma Thomas , Nighot Prashant
Published: March 2019

A defective tight junction (TJ) barrier is a key pathogenic factor for inflammatory bowel disease. Previously, we have shown that autophagy, a cell survival mechanism, enhances intestinal epithelial TJ barrier function. Autophagy-related protein-6 (ATG6/beclin 1), a key protein in the autophagy pathway, also plays a role in the endocytic pathway. The constitutive role of beclin 1 in the intestinal TJ barrier is not known. In Caco-2 cells, beclin 1 was found to be coimmunoprecipitated with the TJ protein occludin and colocalized with occludin on the membrane. Treatment of Caco-2 cells with beclin 1 peptide [transactivating regulatory protein (Tat)-beclin 1] reduced TJ barrier function. Activation of beclin 1 increased occludin endocytosis and reduced total occludin protein level. In contrast, beclin 1 siRNA transfection enhanced Caco-2 TJ barrier function. In pharmacologic and genetic autophagy inhibition studies, the constitutive function of beclin 1 in the TJ barrier was found to be autophagy independent. However, de novo induction of autophagy with starvation or rapamycin prevented Tat-beclin 1-induced increase in TJ permeability and reduction in occludin level. Induction of autophagy also resulted in reduced beclin 1-occludin association. In mouse colon, beclin 1 colocalized with occludin on the epithelial membrane. Perfusion of mouse colon with beclin 1 peptide caused an increase in colonic TJ permeability that was prevented by in vivo induction of autophagy. These findings show that beclin 1 plays a constitutive, autophagy-independent role in the regulation of intestinal TJ barrier function via endocytosis of occludin. Autophagy terminates constitutive beclin 1 function in the TJ barrier and enhances the TJ barrier.
Vascular TSP1-CD47 signaling promotes sickle cell-associated arterial vasculopathy and pulmonary hypertension in mice
Authors: Novelli Enrico M. , Little-Ihrig Lynda , Knupp Heather E. , Rogers Natasha M. , Yao Mingyi , Baust Jeffrey J. , Meijles Daniel , St. Croix Claudette M. , Ross Mark A. , Pagano Patrick J. , DeVallance Evan R. , Miles George , Potoka Karin P. , Isenberg Jeffrey S. , Gladwin Mark T.
Published: March 2019

Pulmonary hypertension (PH) is a leading cause of death in sickle cell disease (SCD) patients. Hemolysis and oxidative stress contribute to SCD-associated PH. We have reported that the protein thrombospondin-1 (TSP1) is elevated in the plasma of patients with SCD and, by interacting with its receptor CD47, limits vasodilation of distal pulmonary arteries ex vivo. We hypothesized that the TSP1-CD47 interaction may promote PH in SCD. We found that TSP1 and CD47 are upregulated in the lungs of Berkeley (BERK) sickling (Sickle) mice and patients with SCD-associated PH. We then generated chimeric animals by transplanting BERK bone marrow into C57BL/6J ( n = 24) and CD47 knockout (CD47KO, n = 27) mice. Right ventricular (RV) pressure was lower in fully engrafted Sickle-to-CD47KO than Sickle-to-C57BL/6J chimeras, as shown by the reduced maximum RV pressure ( P = 0.013) and mean pulmonary artery pressure ( P = 0.020). The afterload of the sickle-to-CD47KO chimeras was also lower, as shown by the diminished pulmonary vascular resistance ( P = 0.024) and RV effective arterial elastance ( P = 0.052). On myography, aortic segments from Sickle-to-CD47KO chimeras showed improved relaxation to acetylcholine. We hypothesized that, in SCD, TSP1-CD47 signaling promotes PH, in part, by increasing reactive oxygen species (ROS) generation. In human pulmonary artery endothelial cells, treatment with TSP1 stimulated ROS generation, which was abrogated by CD47 blockade. Explanted lungs of CD47KO chimeras had less vascular congestion and a smaller oxidative footprint. Our results show that genetic absence of CD47 ameliorates SCD-associated PH, which may be due to decreased ROS levels. Modulation of TSP1-CD47 may provide a new molecular approach to the treatment of SCD-associated PH.
Extracellular vesicles in lung health, disease, and therapy
Authors: McVey Mark J. , Maishan Mazharul , Blokland Kaj E. C. , Bartlett Nathan , Kuebler Wolfgang M.
Published: March 2019

Both physiological homeostasis and pathological disease processes in the lung typically result from complex, yet coordinated multicellular responses that are synchronized via paracrine and endocrine intercellular communication pathways. Of late, extracellular vesicles have emerged as important information shuttles that can coordinate and disseminate homeostatic and disease signals. In parallel, extracellular vesicles in biological fluids such as sputum, mucus, epithelial lining fluid, edema fluid, the pulmonary circulation, pleural fluid, and lymphatics have emerged as promising candidate biomarkers for diagnosis and prognosis in lung disease. Extracellular vesicles are small, subcellular, membrane-bound vesicles containing cargos from parent cells such as lipids, proteins, genetic information, or entire organelles. These cargos endow extracellular vesicles with biologically active information or functions by which they can reprogram their respective target cells. Recent studies show that extracellular vesicles found in lung-associated biological fluids play key roles as biomarkers and effectors of disease. Conversely, administration of naïve or engineered extracellular vesicles with homeostatic or reparative effects may provide a promising novel protective and regenerative strategy to treat lung disease. To highlight this rapidly developing field, the American Journal of Physiology-Lung Cellular and Molecular Physiology is now launching a special Call for Papers on extracellular vesicles in lung health, disease, and therapy. This review aims to set the stage for this call by introducing extracellular vesicles and their emerging roles in lung physiology and pathobiology.
P2X7 receptor deletion suppresses γ-radiation-induced hyposalivation
Authors: Gilman Kristy E. , Camden Jean M. , Klein Rob R. , Zhang Qionghui , Weisman Gary A. , Limesand Kirsten H.
Published: March 2019

Head and neck cancer treatments typically involve a combination of surgery and radiotherapy, often leading to collateral damage to nearby tissues causing unwanted side effects. Radiation damage to salivary glands frequently leads to irreversible dysfunction by poorly understood mechanisms. The P2X7 receptor (P2X7R) is a ligand-gated ion channel activated by extracellular ATP released from damaged cells as “danger signals.” P2X7R activation initiates apoptosis and is involved in numerous inflammatory disorders. In this study, we utilized P2X7R knockout (P2X7R−/−) mice to determine the role of the receptor in radiation-induced salivary gland damage. Results indicate a dose-dependent increase in γ-radiation-induced ATP release from primary parotid gland cells of wild-type but not P2X7R−/− mice. Despite these differences, apoptosis levels are similar in parotid glands of wild-type and P2X7R−/− mice 24–72 h after radiation. However, γ-radiation caused elevated prostaglandin E2 (PGE2) release from primary parotid cells of wild-type but not P2X7R−/− mice. To attempt to uncover the mechanism underlying differential PGE2 release, we evaluated the expression and activities of cyclooxygenase and PGE synthase isoforms. There were no consistent trends in these mediators following radiation that could explain the reduction in PGE2 release in P2X7R−/− mice. Irradiated P2X7R−/− mice have stimulated salivary flow rates similar to unirradiated controls, whereas irradiated wild-type mice have significantly decreased salivary flow rates compared with unirradiated controls. Notably, treatment with the P2X7R antagonist A438079 preserves stimulated salivary flow rates in wild-type mice following γ-radiation. These data suggest that P2X7R antagonism is a promising approach for preventing γ-radiation-induced hyposalivation.
Disrupting the medial prefrontal cortex alters hippocampal sequences during deliberative decision making
Authors: Schmidt Brandy , Duin Anneke A. , Redish A. David
Published: March 2019

Current theories of deliberative decision making suggest that deliberative decisions arise from imagined simulations that require interactions between the prefrontal cortex and hippocampus. In rodent navigation experiments, hippocampal theta sequences advance from the location of the rat ahead to the subsequent goal. To examine the role of the medial prefrontal cortex (mPFC) on the hippocampus, we disrupted the mPFC with DREADDs (designer receptors exclusively activated by designer drugs). Using the Restaurant Row foraging task, we found that mPFC disruption resulted in decreased vicarious trial and error behavior, reduced the number of theta sequences, and impaired theta sequences in hippocampus. mPFC disruption led to larger changes in the initiation of the hippocampal theta sequences that represent the current location of the rat rather than to the later portions that represent the future outcomes. These data suggest that the mPFC likely provides an important component to the initiation of deliberative sequences and provides support for an episodic-future thinking, working memory interpretation of deliberation.

NEW & NOTEWORTHY The medial prefrontal cortex (mPFC) and hippocampus interact during deliberative decision making. Disruption of the mPFC impaired hippocampal processes, including the local and nonlocal representations of space along each theta cycle and the initiation of hippocampal theta sequences, while sparing place cell firing characteristics and phase precession. mPFC disruption reduced the deliberative behavioral process vicarious trial and error and improved economic behaviors on this task.
Diagnosis for Conductor Breaks of Grounding Grids Based on the Wire Loop Method of the Transient Electromagnetic Method
Authors: Yu Shengbao , Dong Guanliang , Liu Nannan , Liu Xiyang , Xu Chang , Ji Yanju , Luan Hui
Published: March 2019

The wire loop method of the transient electromagnetic (TEM) method is used to nondestructively detect conductor breaks of grounding grid. For this purpose, grounding grids serve as an underground wire loop, and the measuring points are arranged on the ground. At each measuring point, a receiving loop is employed to detect the electromagnetic response generated by transmitting the current of the transmitting loop. Conductor breaks can be diagnosed by analyzing the slices of the electromagnetic response. We study the effect of loop size and height difference through the simulation of an intact 2×2 grounding grid, confirming that it is easier to obtain the topological structure using a small transmitting loop and a small height difference. Furthermore, simulations of an intact 4×4 grounding grid and grids with different locations of conductor breaks are also conducted with a small transmitting loop. It is easy to distinguish the topological structure of the grounding grid and the locations of conductor breaks. Finally, the detection method is applied experimentally. The experimental results confirm that the proposed method is an effective technique for conductor break diagnosis.
Results on Uniqueness of Solution of Nonhomogeneous Impulsive Retarded Equation Using the Generalized Ordinary Differential Equation
Authors: Igobi D. K. , Abasiekwere U.
Published: March 2019

In this work, we consider an initial value problem of a nonhomogeneous retarded functional equation coupled with the impulsive term. The fundamental matrix theorem is employed to derive the integral equivalent of the equation which is Lebesgue integrable. The integral equivalent equation with impulses satisfying the Carathéodory and Lipschitz conditions is embedded in the space of generalized ordinary differential equations (GODEs), and the correspondence between the generalized ordinary differential equation and the nonhomogeneous retarded equation coupled with impulsive term is established by the construction of a local flow by means of a topological dynamic satisfying certain technical conditions. The uniqueness of the equation solution is proved. The results obtained follow the primitive Riemann concept of integration from a simple understanding.
Groundwater Quality Assessment in a Karst Coastal Region of the West Aurunci Mountains (Central Italy)
Authors: Sappa Giuseppe , Iacurto Silvia , Ferranti Flavia , De Filippi Francesco M.
Published: March 2019

This paper presents the results of a groundwater quality assessment carried out in the karst coastal region of the West Aurunci Mountains (Central Italy). 55 spring and 18 well water samples, collected from 2016 to 2018, were analysed to study the main processes controlling the hydrogeochemical evolution and groundwater quality properties. In the study area, groundwater samples are mostly characterized by a Ca-HCO3 facies, indicating that the groundwater hydrogeochemical evolution is mainly controlled by the carbonate mineral dissolution/precipitation. The cationic and anionic concentrations confirm that groundwater samples belong to the order of Ca2+>Mg2+>Na+>K+ and HCO3−>Cl−>SO42−, respectively. Well water samples show, over time, an increasing mineralization with respect to the spring water samples. In more detail, the enrichment of Ca2+, Na+, and Cl- in well water samples is mainly due to the dissolution of calcite, dolomite, and halite minerals and secondly to a probable ion exchange related to seawater intrusion. Seawater intrusion, probably affecting the chemical composition of well water samples, was studied using ionic ratios, graphical approaches, and specific indices, such as the BEX index. Results suggest that carbonate weathering, ion exchange, and seawater intrusion in this karst coastal region are the major factors controlling groundwater geochemistry. This study shows that groundwater quality assessment, based on hydrogeochemical investigation techniques, has been a useful tool to characterize and model carbonate aquifers in Central Italy, with the aim of achieving proper management and protection of these important water resources.
Phantom-Like Behavior in Modified Teleparallel Gravity
Authors: Karimzadeh Sakineh , Shojaee Raheleh
Published: March 2019

The recent data from Planck2018 shows that the equation of state parameter of effective cosmic fluid today is w0=-1.03±0.03. This indicates that it is possible for the universe to be in a phantom dominated era today. While a phantom field is essentially capable of explaining this observation, it suffers from some serious problems such as instabilities and violation of the null energy condition. So, it would be interesting to realize this effective phantom behavior without adopting a phantom field. In this paper, we study possible realization of an effective phantom behavior in modified teleparallel gravity. We show that modified teleparallel gravity is able essentially to realize an effective phantom-like behavior in the absence of a phantom field. For this purpose, we choose some observationally viable f(T) functions and prove that there are some subspaces of the models parameter space capable of realizing a phantom-like behavior without adopting a phantom field.
A Systematic Review and Meta-Analysis of Epidemiology of Risky Sexual Behaviors in College and University Students in Ethiopia, 2018
Authors: Amare Tadele , Yeneabat Tebikew , Amare Yohannes
Published: March 2019

Background. Risk of sexual ill-health occurs with the onset of unsafe sexual activity, mostly among the adolescents, and continues as long as the risky activities are engaged in. Globally, and in Africa, adolescent AIDS-related mortality among adolescents has been increasing. Therefore, a systematic review and meta-analysis of epidemiology of risky sexual behaviors in college and university students in Ethiopia is mandatory. Methods. We conducted extensive search of articles as indicated in the guideline of reporting systematic review and meta-analysis (PRISMA). Databases such as PubMed, Global Health, Africa-wides, Google advance search, Scopus, and EMBASE were accessed for literature search. The pooled estimated effect of epidemiology of risky sexual behaviors and associated factors were analyzed by using the random effects model meta-analysis and 95% CI was also considered. PROSPERO registration number is CRD42018109277. Result. A total of 18 studies with 10,218 participants were encompassed in this meta-analysis. The estimated pooled prevalence of risky sexual behaviors among college and university students was 41.62%. Being male [OR: 2.35, with 95% (CI; 1.20, 4.59)], alcohol use [OR: 2.68, with 95% CI; (1.67, 4.33)] and watching pornography [OR: 4.74, with 95% CI; (3.21, 7.00)] were positively associated with risky sexual behaviors. Conclusion and recommendation. Risky sexual behavior among students was high. Educational institutions should give special attention for male sex, alcohol user, and students who watch pornography.
Genetic Algorithm-Based Particle Swarm Optimization Approach to Reschedule High-Speed Railway Timetables: A Case Study in China
Authors: Wang Mingming , Wang Li , Xu Xinyue , Qin Yong , Qin Lingqiao
Published: March 2019

In this study, a mixed integer programming model is proposed to address timetable rescheduling problem under primary delays. The model considers timetable rescheduling strategies such as retiming, reordering, and adjusting stop pattern. A genetic algorithm-based particle swarm optimization algorithm is developed where position vector and genetic evolution operators are reconstructed based on departure and arrival time of each train at stations. Finally, a numerical experiment of Beijing-Shanghai high-speed railway corridor is implemented to test the proposed model and algorithm. The results show that the objective value of proposed method is decreased by 15.6%, 48.8%, and 25.7% compared with the first-come-first-service strategy, the first-schedule-first-service strategy, and the particle swarm optimization, respectively. The gap between the best solution obtained by the proposed method and the optimum solution computed by CPLEX solver is around 19.6%. All delay cases are addressed within acceptable time (within 1.5 min). Moreover, the case study gives insight into the correlation between delay propagation and headway. The primary delays occur in high-density period (scheduled headway closes to the minimum headway), which results in a great delay propagation.
Effectiveness of Acupuncture Used for the Management of Postpartum Depression: A Systematic Review and Meta-Analysis
Authors: Li Wei , Yin Ping , Lao Lixing , Xu Shifen
Published: March 2019

Background. Previous studies have demonstrated that acupuncture was an effective alternative for treating major depressive disorders. However, the use of acupuncture for the treatment of postpartum depression remains controversial. This review summarizes the most significant studies in the area of acupuncture treatment for postpartum depression and provides a detailed overview of the efficacy of acupuncture for the treatment of postpartum depression. Methods. We undertook a systematic review of publicly available electronic databases to identify studies that evaluated acupuncture for the treatment of postpartum depression. Our meta-analysis selected randomized controlled trials (RCTs) and quasi-RCTs that reported on the treatment effect of acupuncture on postpartum depression. Results. Eight prospective trials reporting data on postpartum depression were included in our meta-analysis. The results demonstrated that acupuncture treatment could significantly reduce HAMD scores (SMD: -1.08; 95%CI: -2.11 to -0.05; P=0.040). However, with regard to EPDS, clinical response, and serum estradiol levels, pooled analysis suggested no beneficial effects of acupuncture for postpartum women in EPDS (RR: 1.23; 95%CI: 0.90 to 1.67; P=0.195); clinical response (RR: 1.00; 95%CI: 0.89 to 1.12; P=0.969); and the levels of serum estradiol (SMD: 1.96; 95%CI: -0.01 to 3.93; P=0.051). Limitations. First, there was relatively high heterogeneity among the studies, except for clinical response. In order to identify the sources of heterogeneity, we divided the studies into subgroups by way of controls. However, heterogeneity still existed, which suggested that it arose from participants rather than controls. Second, the sample size of the studies was small, causing the power of summary results to be low. This may result in over- or underestimating the interpretation of the results. Third, our analysis used pooled data, which restricted us from performing a more detailed analysis. Conclusions. Our meta-analysis suggested that acupuncture treatment may reduce HAMD scores, while no significant effects on EPDS, clinical response, and serum estradiol levels were observed.
Measurement of Disease Activity in Ecuadorian Patients with Rheumatoid Arthritis: Does RAPID3 Correlate with Traditional Indexes?
Authors: Zurita María Fernanda , Iglesias Adriana , Vanegas Emanuel , Luzuriaga Adriana , Zurita Luis
Published: March 2019

Objective. The aim of this study is to demonstrate if routine assessment of patient index data 3 has a correlation with disease’s activity as much as disease activity score 28, clinical disease activity index, and simplified disease activity index in Ecuadorian patients with rheumatoid arthritis seen in Unidad de Enfermedades Reumáticas y Autoinmunes [UNERA] from December 2016 to December 2017. Methods. This is a retrospective study in 200 patients that fulfill the American College of Rheumatology 2010 criteria for diagnosis of rheumatoid arthritis. The patients were evaluated from December 2016 to December 2017. Descriptive analyses were carried out, also Pearson correlation was used, and, to give a better clinical significance, a chi-square test was conducted. Whenever assumptions of chi-square test were violated, a Fisher’s exact test was reported. Results. RAPID3 correlated best with DAS28 (r.83, p < 0.001), followed by CDAI (r.80, p < 0.001) and then SDAI (r.77, p < 0.001). Conclusion. RAPID3 is a questionnaire that only takes 10 seconds to calculate and correlates in a significant way with traditional clinical measures that require more time to perform, saving time in busy health facilities.
A Metabonomics Investigation into the Therapeutic Effects of BuChang NaoXinTong Capsules on Reversing the Amino Acid-Protein Interaction Network of Cerebral Ischemia
Authors: Xu Jing , Liu Xin , Luo Liyu , Tang Liying , Guo Na , Liu Mengting , Li Hongmei , Zhang Fangbo , Zhang Yi , Li Defeng , Zhao Ye , Wu Hongwei , Yang Hongjun
Published: March 2019

Background. Amino acids (AAs) in cerebrospinal fluid (CSF) play a pivotal role in cerebral ischemia (CI). BuChang NaoXinTong Capsules (BNC) are widely prescribed in Chinese medicine for the treatment of cerebrovascular and cardiovascular diseases. Methods. In order to investigate the therapeutic effects and pharmacological mechanisms of BNC on reversing CI from a system level, an amino acid-protein interaction imbalanced network of CI containing metabolites of AAs, key regulatory enzymes, and proteins was constructed for the first time. Furthermore, a novel method for detecting the ten AAs in CSF was developed by UPLC-QQQ-MS in an effort to validate the imbalanced networks and the therapeutic effects of BNC via analysis of metabolites. Results. Based on a middle cerebral artery occlusion (MCAO) rat model, the dynamic levels of amino acids in CSF 3, 6, 12, and 24 h after MCAO were analyzed. Up to 24 h, the accumulated nine AA biomarkers were found to significantly change in the MCAO group compared to the sham group and exhibited an obvious tendency for returning to baseline values after BNC treatment. In addition, based on the imbalanced network of CI, four key enzymes that regulate the generation of BNC-mediated AA biomarkers were selected and validated using an enzyme-linked immunosorbent assay and western blotting. Finally, aromatic-L-amino-acid decarboxylase (AADC) was found to be one of the putative targets for BNC-mediated protection against CI. Conclusion. This study provides new strategies to explore the mechanism of cerebral ischemia and help discover the potential mechanism of BNC.
Diversity and Social Network Structure in Collective Decision Making: Evolutionary Perspectives with Agent‐Based Simulations
Authors: Dionne Shelley D. , Sayama Hiroki , Yammarino Francis J.
Published: March 2019

Collective, especially group‐based, managerial decision making is crucial in organizations. Using an evolutionary theoretic approach to collective decision making, agent‐based simulations were conducted to investigate how human collective decision making would be affected by the agents’ diversity in problem understanding and/or behavior in discussion, as well as by their social network structure. Simulation results indicated that groups with consistent problem understanding tended to produce higher utility values of ideas and displayed better decision convergence, but only if there was no group‐level bias in collective problem understanding. Simulation results also indicated the importance of balance between selection‐oriented (i.e., exploitative) and variation‐oriented (i.e., explorative) behaviors in discussion to achieve quality final decisions. Expanding the group size and introducing nontrivial social network structure generally improved the quality of ideas at the cost of decision convergence. Simulations with different social network topologies revealed collective decision making on small‐world networks with high local clustering tended to achieve highest decision quality more often than on random or scale‐free networks. Implications of this evolutionary theory and simulation approach for future managerial research on collective, group, and multilevel decision making are discussed.
Resource Scheduling for Postdisaster Management in IoT Environment
Authors: Kumar J. Sathish , Zaveri Mukesh A.
Published: March 2019

For postdisaster management, rescue and recovery operations are very critical. It is desired that the rescue and recovery operation should be handled through efficient resource management to minimize the postdisaster effects in terms of human loss and other types of damage. Resource management requires addressing various challenging issues like scheduling and monitoring of the resources which need real time information of various activities or events occurring anytime, anywhere, and anyplace. To satisfy such requirements, Internet of Things, an advanced upcoming technology, can be utilized for resource monitoring and scheduling. In this context, we propose resource scheduling algorithm for the postdisaster management. As mentioned above various tasks of rescue and recovery operation should be carried out with different priority and there should not be deadlock while availing the resources. In our approach, we estimate the waiting time using queuing theory for the availability of the resources for different activities that are to be performed at various locations. The simulation results of the proposed method are analyzed using different standard parameters like resource utilization and the waiting time for different activities. The proposed method is further visualized through real time annotation of resources and activities represented with the help of Google maps using android based application on the smartphone. The proposed algorithm is further compared in terms of computational complexity and fairness analysis for the effective utilization of the available resources.
Nutritional Preconditioning of Apigenin Alleviates Myocardial Ischemia/Reperfusion Injury via the Mitochondrial Pathway Mediated by Notch1/Hes1
Authors: Huang Huang , Lai Songqing , Luo Yong , Wan Qing , Wu Qicai , Wan Li , Qi Wanghong , Liu Jichun
Published: March 2019

Apigenin (Api), a natural flavone found in high amounts in several herbs, has shown potent cardioprotective effects in clinical studies, although the underlying mechanisms are not clear. We hypothesized that Api protects the myocardium from simulated ischemia/reperfusion (SI/R) injury via nutritional preconditioning (NPC). Rats fed with Api-containing food showed improvement in cardiac functions; lactate dehydrogenase (LDH) and creatine phosphokinase (CPK) activities; infarct size; apoptosis rates; malondialdehyde (MDA) levels; caspase-3, superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and catalase (CAT) activities; and ferric reducing antioxidant power (FRAP) compared to those fed standard chow following SI/R injury. In addition, Api pretreatment significantly improved the viability, decreased the LDH activity and intracellular reactive oxygen species (ROS) generation, alleviated the loss of mitochondrial membrane potential (MMP), prevented the opening of the mitochondrial permeability transition pore (mPTP), and decreased the caspase-3 activity, cytochrome c (Cyt C) release, and apoptosis induced by SI/R in primary cardiomyocytes. Mechanistically, Api upregulated Hes1 expression and was functionally neutralized by the Notch1γ-secretase inhibitor GSI, as well as the mPTP opener atractyloside (Atr). Taken together, Api protected the myocardium against SI/R injury via the mitochondrial pathway mediated by the Notch1/Hes1 signaling pathway.
Study on Preparation of Water-Soluble Chitosan with Varying Molecular Weights and Its Antioxidant Activity
Authors: Xuan Du Dang , Xuan Vuong Bui
Published: March 2019

The preparation of water-soluble chitosan (WSC) with various molecular weights by gamma Co-60 irradiation of chitosan solution (5%) in the presence of hydrogen peroxide (1%) combined with acetylated reaction was carried out. The average molecular weight (Mw) of chitosan was measured by gel permeation chromatography (GPC). The chemical structure and the crystallinity of chitosan and WSC were characterized by Fourier-transform infrared (FT-IR) spectroscopy and X-ray diffraction (XRD), respectively. The antioxidant activity of WSC and chitosan was investigated using the free radical 2,2′-azino-bis (3-ethylbenzothiazoline-6-sulphonic acid) (ABTS•+). Obtained results showed that chitosan with Mw of 18–90 kDa could be efficiently prepared by this technique in the dose range from 10 to 24.5 kGy. After the acetylated process, the resulting WSC possesses good solubility in a wide pH level of 2–12, and WSC with low molecular weight exhibited significantly higher antioxidant activity than the one with high molecular weight. In detail, the antioxidant activity was 14.7%, 70.5%, 84.2%, 89.4%, and 97.5% for WSC samples prepared from chitosan with Mw of 140.2 kDa, 91.4 kDa, 51.2 kDa, 35.3 kDa, and 18.1 kDa, respectively, at the same reaction time of 90 min. Moreover, the antioxidant activity of WSC was higher than that of chitosan. Thus, WSC prepared by gamma Co-60 irradiation and acetylated process can be potentially applied as a natural antioxidant agent.
Comparing the Predictive Power of Preoperative Risk Assessment Tools to Best Predict Major Adverse Cardiac Events in Kidney Transplant Patients
Authors: Dunn Colin P. , Emeasoba Emmanuel U. , Holtzman Ari J. , Hung Michael , Kaminetsky Joshua , Alani Omar , Greenstein Stuart M.
Published: March 2019

Background. Patients undergoing kidney transplantation have increased risk of adverse cardiovascular events due to histories of hypertension, end-stage renal disease, and dialysis. As such, they are especially in need of accurate preoperative risk assessment. Methods. We compared three different risk assessment models for their ability to predict major adverse cardiac events at 30 days and 1 year after transplant. These were the PORT model, the RCRI model, and the Gupta model. We used a method based on generalized U-statistics to determine statistically significant improvements in the area under the receiver operator curve (AUC), based on a common major adverse cardiac event (MACE) definition. For the top-performing model, we added new covariates into multivariable logistic regression in an attempt to create further improvement in the AUC. Results. The AUCs for MACE at 30 days and 1 year were 0.645 and 0.650 (PORT), 0.633 and 0.661 (RCRI), and finally 0.489 and 0.557 (Gupta), respectively. The PORT model performed significantly better than the Gupta model at 1 year (p=0.039). When the sensitivity was set to 95%, PORT had a significantly higher specificity of 0.227 compared to RCRI’s 0.071 (p=0.009) and Gupta’s 0.08 (p=0.017). Our additional covariates increased the receiver operator curve from 0.664 to 0.703, but this did not reach statistical significance (p=0.278). Conclusions. Of the three calculators, PORT performed best when the sensitivity was set at a clinically relevant level. This is likely due to the unique variables the PORT model uses, which are specific to transplant patients.
An Interactive Resource to Probe Genetic Diversity and Estimated Ancestry in Cancer Cell Lines
Authors: Dutil Julie , Chen Zhihua , Monteiro Alvaro N. , Teer Jamie K. , Eschrich Steven A.
Published: March 2019

Recent work points to a lack of diversity in genomics studies from genome-wide association studies to somatic (tumor) genome analyses. Yet, population-specific genetic variation has been shown to contribute to health disparities in cancer risk and outcomes. Immortalized cancer cell lines are widely used in cancer research, from mechanistic studies to drug screening. Larger collections of cancer cell lines better represent the genomic heterogeneity found in primary tumors. Yet, the genetic ancestral origin of cancer cell lines is rarely acknowledged and often unknown. Using genome-wide genotyping data from 1,393 cancer cell lines from the Catalogue of Somatic Mutations in Cancer (COSMIC) and Cancer Cell Line Encyclopedia (CCLE), we estimated the genetic ancestral origin for each cell line. Our data indicate that cancer cell line collections are not representative of the diverse ancestry and admixture characterizing human populations. We discuss the implications of genetic ancestry and diversity of cellular models for cancer research and present an interactive tool, Estimated Cell Line Ancestry (ECLA), where ancestry can be visualized with reference populations of the 1000 Genomes Project. Cancer researchers can use this resource to identify cell line models for their studies by taking ancestral origins into consideration.
The Critical Role of RNA m6A Methylation in Cancer
Authors: Lan Qing , Liu Pei Y. , Haase Jacob , Bell Jessica L. , Hüttelmaier Stefan , Liu Tao
Published: March 2019

Since the identification of the first RNA demethylase and the establishment of methylated RNA immunoprecipitation-sequencing methodology 6 to 7 years ago, RNA methylation has emerged as a widespread phenomenon and a critical regulator of transcript expression. This new layer of regulation is termed “epitranscriptomics.” The most prevalent RNA methylation, N6-methyladenosine (m6A), occurs in approximately 25% of transcripts at the genome-wide level and is enriched around stop codons, in 5′- and 3′-untranslated regions, and within long internal exons. RNA m6A modification regulates RNA splicing, translocation, stability, and translation into protein. m6A is catalyzed by the RNA methyltransferases METTL3, METTL14, and METTL16 (writers), is removed by the demethylases FTO and ALKBH5 (erasers), and interacts with m6A-binding proteins, such as YTHDF1 and IGF2BP1 (readers). RNA methyltransferases, demethylases, and m6A-binding proteins are frequently upregulated in human cancer tissues from a variety of organ origins, increasing onco-transcript and oncoprotein expression, cancer cell proliferation, survival, tumor initiation, progression, and metastasis. Although RNA methyltransferase inhibitors are not available yet, FTO inhibitors have shown promising anticancer effects in vitro and in animal models of cancer. Further screening for selective and potent RNA methyltransferase, demethylase, or m6A-binding protein inhibitors may lead to compounds suitable for future clinical trials in cancer patients.
Detailed Multi-Dimensional Assessment of Fatigue in Inflammatory Bowel Disease
Authors: Aluzaite Kristina , Al-Mandhari Rashid , Osborne Hamish , Ho Christine , Williams Merrilee , Sullivan Marie-Michelle , Hobbs Catherine E. , Schultz Michael
Published: March 2019

Background: Fatigue is a symptom commonly reported by patients with inflammatory bowel disease (IBD). Treating any underlying inflammation in active disease improves the health outcomes and decreases fatigue, but fatigue still persists in remission, negatively affecting patients’ quality of life and posing a challenge for the treating physician. The aim of this study was to describe the prevalence of fatigue in patients with IBD and investigate possible contributing factors. Methods: Recruited IBD patients from the Otago region in southern New Zealand were asked to complete demographic, physical activity (IPAQ) and fatigue questionnaires (Brief Fatigue Inventory, Multidimensional Fatigue Inventory). Disease activity and factors contributing to fatigue were assessed through self-reporting and laboratory biomarkers. Results: One hundred and thirteen of the contacted 469 IBD patients participated in the study. Depending on the questionnaire used, the prevalence of fatigue in IBD was high in remission (39.5–44.2%) but significantly higher (p < 0.001) in active disease (80.0–82.9%). Several factors such as age, disease duration, level of physical activity, gender and diet were found to be associated with increased fatigue and were attributed to either mental or physical fatigue categories. Multifactorial Fatigue Inventory provided insights into different types of fatigue, and revealed a significant mental fatigue component in both active and remission disease patients. Iron deficiency was not associated with fatigue levels. Conclusions: Fatigue in IBD is multi-faceted and highly prevalent in both active and remission IBD. Further investigations, addressing the complexity of the symptom and its reporting are needed.
Effects of an Oral CRTh2 Antagonist (AZD1981) on Eosinophil Activity and Symptoms in Chronic Spontaneous Urticaria
Authors: Oliver Eric Tyrell , Chichester Kris , Devine Kelly , Sterba Patricia Meghan , Wegner Craig , Vonakis Becky Marie , Saini Sarbjit Singh
Published: March 2019

Background: Approximately 50% of patients with chronic spontaneous urticaria (CSU) experience symptoms that are not fully controlled by antihistamines, indicating an unmet clinical need. Objective: To evaluate the effects of the selective CRTh2 antagonist AZD1981 on symptoms and targeted leukocytes in adults with persistent CSU despite treatment with H1-antihistamines. Methods: We performed a single-center, randomized, placebo-controlled study involving adult CSU subjects with symptoms despite daily antihistamines. The subjects underwent a 2-week placebo run-in and 4 weeks of double-blinded therapy with either AZD1981 40 mg TID or placebo, followed by a 2-week placebo washout. The primary objective was to assess the effect of AZD1981 on CSU signs and symptoms. Secondary objectives included the effects of AZD1981 on prostaglandin D2 (PGD2)-induced eosinophil shape change, circulating leukocyte subsets, CRTh2 expression on blood leukocytes, and total blood leukocyte histamine content. Results: Twenty-eight subjects were randomized to AZD1981 or placebo, with 26 subjects completing the study. The urticaria activity scores declined during the treatment phase in both groups, and they were significantly reduced in the AZD1981 group at the end of washout. AZD1981 treatment increased circulating eosinophils and significantly impaired PGD2-mediated eosinophil shape change. CRTh2 surface expression rose significantly on blood basophils during active treatment. No serious adverse events were observed. Conclusions: This is the first study to examine the efficacy of a CRTh2 antagonist in antihistamine-refractory CSU. AZD1981 treatment was well tolerated, effectively inhibited PGD2-mediated eosinophil shape change, shifted numbers of circulating eosinophils, and reduced weekly itch scores more than hives during treatment and into washout. Further studies are needed to determine whether inhibition of the PGD2/CRTh2 pathway will be an ­effective treatment for CSU.
Eradication of Helicobacter pylori Induces Immediate Regressive Changes in Early Gastric Adenocarcinomas
Authors: Nakagawa Mitsuru , Sakai Yasuhiro , Kiriyama Yuka , Tahara Tomomitsu , Horiguchi Noriyuki , Okabe Asako , Tahara Sayumi , Shibata Tomoyuki , Ohmiya Naoki , Kuroda Makoto , Sugioka Atsushi , Tsukamoto Tetsuya
Published: March 2019

Objective: Helicobacter pylori eradication is expected to prevent gastric cancer. However, morphological alterations after eradication often hinder accurate diagnosis. Therefore, we evaluated endoscopic and histological changes in gastric tumors after eradication of H. pylori in a time-dependent manner. Methods: We classified 144 cases of endoscopic submucosal dissection (ESD) of early gastric cancer into the following categories: (i) patients positive for H. pylori with no eradication history, (ii) patients positive for H. pylori who underwent ESD 2 months after eradication, (iii) patients negative for H. pylori with an eradication history of at least 6 months before ESD, and (iv) patients negative for H. pylori with an unknown history. We compared endoscopic and histological factors between the groups. Results: The characteristics of cancers positive for H. pylori were exploding shape, superficial high-grade atypical epithelium, and a surface proliferating zone. H. pylori eradication induced a series of endoscopic and histological changes, including shape ­depression, appearance of surface regenerative and lower-grade atypical epithelium, and a downward shift of the proliferative zone within a period as short as 2 months. Conclusion: H. pylori eradication rapidly causes cancer regression and leads to tumor shrinkage, diminished atypism, and shortened proliferative zone, resulting in drastic morphological changes.
Increased Prevalence of Esophageal Eosinophilia in Patients with Inflammatory Bowel Disease
Authors: Fan Y. Claire , Steele David , Kochar Bharati , Arsene Diana , Long Millie D. , Dellon Evan S. 
Published: March 2019

Background: The overlap between eosinophilic esophagitis (EoE) and inflammatory bowel disease (IBD) has not been extensively examined. We aimed to assess the prevalence of esophageal eosinophilia in patients with IBD. Methods: We conducted a retrospective cohort study using diagnostic codes to identify adults with EoE and IBD between 2008 and 2016 at a tertiary care center. Electronic medical records were reviewed to extract clinical, endoscopic, and treatment data. Patients with esophageal eosinophilia and IBD were compared to EoE cases without IBD. Results: Of 621 EoE patients and 4,814 IBD patients identified, 35 had a code for both diseases and 12 were confirmed to have overlapping IBD and esophageal eosinophilia. The prevalence of esophageal eosinophilia in IBD was 12/4814 (0.25%), and the prevalence of confirmed EoE in IBD was 5/4,814 (0.10%). There were no substantial clinical, endoscopic, or histologic differences between EoE patients with and without IBD. IBD was diagnosed before esophageal eosinophilia 92% of the time, with an average time between diagnoses of 9.6 years. Of the IBD patients, 71% were started on biologic anti-tumor necrosis factor-α therapy an average of 7.6 years prior to developing esophageal eosinophilia. Conclusions: The prevalence of esophageal eosinophilia in IBD is 5 times higher than expected in the general population (0.25 vs. 0.05%) and EoE in IBD is 2 times higher than expected (0.10 vs. 0.05%). Upper gastrointestinal (GI) symptoms in patients with IBD should merit evaluation not only for upper GI Crohn’s disease, but also for esophageal eosinophilia.
Emicizumab in the Treatment of Acquired Haemophilia: A Case Report
Authors: Möhnle Patrick , Pekrul Isabell , Spannagl Michael , Sturm Andreas , Singh Delila , Dechant Claudia
Published: March 2019

The prognosis of acquired haemophilia A (AHA) is severe and treatment options are limited. Emicizumab is a novel bispecific humanized monoclonal antibody in the treatment of inherited AHA with inhibitors. An 83-year-old AHA patient with congestive heart failure and a high risk for thromboembolic and cardiac events who had initially been treated successfully with steroids and substitution of recombinant B-domain-deleted porcine FVIII developed severe bleeding complications and a secondary increase in inhibitor titres after 4 weeks of treatment. Conventional therapeutic strategies failed, and the patient was subsequently treated with emicizumab on off-label and named patient use premises. After the application of emicizumab, the clinical conditions stabilized and no further substitution of coagulation factors was needed. The patient could be discharged and survived 36 days in a cardiac rehabilitation centre without indications for spontaneous bleeding or thromboembolic events. We suggest that the effects of emicizumab in acquired haemophilia should be evaluated in clinical trials.
Current Advancements in the Development and Characterization of Full-Thickness Adult Neuroretina Organotypic Culture Systems
Authors: Rettinger Christina L. , Wang Heuy-Ching
Published: March 2019

Retinal degenerative diseases such as macular degeneration, glaucoma, and diabetic retinopathy constitute the leading cause of blindness in the industrialized world. There is a continuous demand in investigative ophthalmic research for the development of new treatment modalities for retinal therapy. Unfortunately, efforts to identify novel neuroprotective and neuroregenerative agents have often been hindered by an experimental model gap that exists between high-throughput methods via dissociated cells and preclinical animal models. Even though dissociated cell culture is rapid and high-throughput, it is limited in its ability to reproduce the in vivo conditions. In contrast, preclinical animal models may offer greater fidelity, albeit they lack efficiency and experimental control. Retina explant cultures provide an ideal bridge to close this gap and have been used to study an array of biological processes such as retinal development and neurodegeneration. However, it is often difficult to interpret findings from these studies due to the wide variety of experimental species and culture methods used. This review provides a comprehensive overview of current ex vivo neuroretina culture methods and assessments, with a focus on their suitability, advantages, and disadvantages, along with novel insights and perspectives on the organotypic culture model as a high-throughput platform for screening promising molecules for retinal regeneration.
Viral Metagenomics of Blood Donors and Blood-Derived Products Using Next-Generation Sequencing
Authors: Waldvogel-Abramowski Sophie , Taleb Sofiane , Alessandrini Marco , Preynat-Seauve Olivier
Published: March 2019

Transfusion-transmitted infections remain a permanent threat in medicine. It keeps the burden of the past, marked by serious infections transmitted by transfusion, and is constantly threatened by emerging viruses. The global rise of immunosuppression among patients undergoing frequent transfusions exacerbates this problem. Over the past decade, criteria for donor selection have become increasingly more stringent. Although routine nucleic acid testing (NAT) for virus-specific detection has become more sensitive, these safety measures are only valuable for a limited number of select viruses. The scientific approach to this is however changing, with the goal of trying to identify infectious agents in donor units as early as possible to mitigate the risk of a clinically relevant infection. To this end, and in addition to an epidemiological surveillance of the general population, researchers are adopting new methods to discover emerging infectious agents, while simultaneously screening for an extended number of viruses in donors. Next-generation sequencing (NGS) offers the opportunity to explore the entire viral landscape in blood donors, the so-called metagenomics, to investigate severe transfusion reactions of unknown etiology. In the not too distant future, one could imagine this platform being used for routine testing of donated blood products.