bluuebunny/crossref_metadata_2025 huggingface dataset:
CAN THE OPAQUE PORCELAIN AND DENTIN PORCELAIN BE SUBSTITUTED IN TITANIUM–PORCELAIN PROSTHETIC?
Authors: TANG HUI , HAN YU , SUN HAO
Published: July 2016

Due to the biocompatibility, mechanical strength and esthetics properties, titanium–porcelain prosthetic plays an important role in prosthodontics. However, weak bonding strength and considerable thickness of the porcelain restrict its application. Whether we can find a method to increase the bonding strength and reduce the thickness of the porcelain is an acute problem. In this study, ceramic coatings with similar color of nature teeth are fabricated on the surface of pure titanium by micro-arc oxidation (MAO). The colors, thickness and bonding strength of the coatings can be controlled by adding ferrous sulfate into the electrolytes. These new coatings can be used in titanium–porcelain prosthetic to substitute the opaque and dentin porcelain which can enhance the bonding strength and decrease the thickness of the porcelain compared with the conventional technique.
A PIV COMPARISON OF THE FLOW FIELD AND WALL SHEAR STRESS IN RIGID AND COMPLIANT MODELS OF HEALTHY CAROTID ARTERIES
Authors: GEOGHEGAN PATRICK H. , JERMY MARK C. , NOBES DAVID S.
Published: July 2016

Certain systems relevant to circulatory disease have walls which are neither rigid nor static, for example, the coronary arteries, the carotid artery and the heart chambers. In vitro modeling allows the fluid mechanics of the circulatory system to be studied without the ethical and safety issues associated with animal and human experiments. Computational methods in which the equations are coupled governing the flow and the elastic walls are maturing. Currently there is a lack of experimental data in compliant arterial systems to validate the numerical predictions. Previous experimental work has commonly used rigid wall boundaries, ignoring the effect of wall compliance. Particle Image Velocimetry is used to provide a direct comparison of both the flow field and wall shear stress (WSS) observed in experimental phantoms of rigid and compliant geometries representing an idealized common carotid artery. The input flow waveform and the mechanical response of the phantom are physiologically realistic. The results show that compliance affects the velocity profile within the artery. A rigid boundary causes severe overestimation of the peak WSS with a maximum relative difference of 61% occurring; showing compliance protects the artery from exposure to high magnitude WSS. This is important when trying to understand the development of diseases like atherosclerosis. The maximum, minimum and time averaged WSS in the rigid geometry was 2.3, 0.51 and 1.03[Formula: see text]Pa and in the compliant geometry 1.4, 0.58 and 0.84[Formula: see text]Pa, respectively.
Groundwater recharge modelling in semi-arid regions; a case study of El Khairat alluvial plain (Tunisia)
Authors: Brini Naima , Zammouri Mounira
Published: July 2016

A regional decline of groundwater level is observed in the El Khairat plain. The increase in extraction is probably the main cause. The evaluation of groundwater recharge is an important step for the sustainable management of groundwater resources. A conceptual ‘rainfall–runoff’ model is developed to assess the El Khairat aquifer recharge. The model calibration aimed to reproduce the measured surface runoff and the observed water table level. Only 17% of rainfall recharges the aquifer, and the rest is mostly lost to evaporation. Analysis of the groundwater-level hydrographs indicated different hydraulic responses of the aquifer following rainfall events. Upstream, the water table rise is fast with a large amplitude, whereas a dampened response is observed downstream.
A combined surface and groundwater storage project: the Elmadag dam (Turkey)
Authors: Apaydin Ahmet , Zengin Ercan
Published: July 2016

Considering some of the problems of surface reservoirs, such as unsteady stream flow, high evaporation losses and loss of storage owing to sediment entrapment, subsurface dams may be an effective solution in arid–semiarid regions. Combined surface and groundwater dam projects can be developed to withdraw the additional water from the porous alluvial sediments beneath the surface reservoir. We describe the investigation, construction and operation of such a hydraulic structure: the Elmadag dam, near Ankara, Turkey, which stores both surface water and groundwater behind the dam. The height of the Elmadag dam is 26 m but most of the dam wall (15 m) is located beneath the surface, and is constructed in an alluvial sand–gravel aquifer. The surface and subsurface storage capacity of the dam is 3 × 10
6
 m
3
and on average 80 l s
−1
was pumped between January 2014 and October 2015, which equates to a rate almost equal to the 2015 domestic water demand of Elmadag town. If the surface reservoir dries up temporarily, the dam will continue to provide a supply from groundwater. More importantly, even if the surface reservoir is filled with sediments, the dam will ensure its function by subsurface storage.
Deccan Plateau uplift: insights from parts of Western Uplands, Maharashtra, India
Authors: Kale Vivek S. , Dole Gauri , Upasani Devdutt , Pillai Shilpa Patil
Published: July 2016

The western edge of the Deccan Plateau (=Western Uplands) has been depicted in its evolutionary models to be a contiguous crustal block exposing structurally undisturbed subhorizontal stacks of Deccan Trap basalts.

The geomorphological and morphometric characteristics of this terrain, Quaternary fluvial sediments capping the Deccan Traps in some river basins, compounded with deformation features in the basalts, and in the overlying sediments, are compiled here. They demonstrate that the Western Upland region of the Deccan Plateau may be constituted of no less than three blocks with differential Quaternary uplift histories, rather than the entire region experiencing a unified uplift.
Minimal Interaction Content Discovery in Recommender Systems
Authors: Kveton Branislav , Berkovsky Shlomo
Published: July 2016

Many prior works in recommender systems focus on improving the accuracy of item rating predictions. In comparison, the areas of recommendation interfaces and user-recommender interaction remain underexplored. In this work, we look into the interaction of users with the recommendation list, aiming to devise a method that simplifies content discovery and minimizes the cost of reaching an item of interest. We quantify this cost by the number of user interactions (clicks and scrolls) with the recommendation list. To this end, we propose generalized linear search (GLS), an adaptive combination of the established linear and generalized search (GS) approaches. GLS leverages the advantages of these two approaches, and we prove formally that it performs at least as well as GS. We also conduct a thorough experimental evaluation of GLS and compare it to several baselines and heuristic approaches in both an offline and live evaluation. The results of the evaluation show that GLS consistently outperforms the baseline approaches and is also preferred by users. In summary, GLS offers an efficient and easy-to-use means for content discovery in recommender systems.
Using Video to Automatically Detect Learner Affect in Computer-Enabled Classrooms
Authors: Bosch Nigel , D'mello Sidney K. , Ocumpaugh Jaclyn , Baker Ryan S. , Shute Valerie
Published: July 2016

Affect detection is a key component in intelligent educational interfaces that respond to students’ affective states. We use computer vision and machine-learning techniques to detect students’ affect from facial expressions (primary channel) and gross body movements (secondary channel) during interactions with an educational physics game. We collected data in the real-world environment of a school computer lab with up to 30 students simultaneously playing the game while moving around, gesturing, and talking to each other. The results were cross-validated at the student level to ensure generalization to new students. Classification accuracies, quantified as area under the receiver operating characteristic curve (AUC), were above chance (AUC of 0.5) for all the affective states observed, namely, boredom (AUC = .610), confusion (AUC = .649), delight (AUC = .867), engagement (AUC = .679), frustration (AUC = .631), and for off-task behavior (AUC = .816). Furthermore, the detectors showed temporal generalizability in that there was less than a 2% decrease in accuracy when tested on data collected from different times of the day and from different days. There was also some evidence of generalizability across ethnicity (as perceived by human coders) and gender, although with a higher degree of variability attributable to differences in affect base rates across subpopulations. In summary, our results demonstrate the feasibility of generalizable video-based detectors of naturalistic affect in a real-world setting, suggesting that the time is ripe for affect-sensitive interventions in educational games and other intelligent interfaces.
Face Processing Systems: From Neurons to Real-World Social Perception
Authors: Freiwald Winrich , Duchaine Bradley , Yovel Galit
Published: July 2016

Primate face processing depends on a distributed network of interlinked face-selective areas composed of face-selective neurons. In both humans and macaques, the network is divided into a ventral stream and a dorsal stream, and the functional similarities of the areas in humans and macaques indicate they are homologous. Neural correlates for face detection, holistic processing, face space, and other key properties of human face processing have been identified at the single neuron level, and studies providing causal evidence have established firmly that face-selective brain areas are central to face processing. These mechanisms give rise to our highly accurate familiar face recognition but also to our error-prone performance with unfamiliar faces. This limitation of the face system has important implications for consequential situations such as eyewitness identification and policing.
High glucose promotes the migration of retinal pigment epithelial cells through increased oxidative stress and PEDF expression
Authors: Farnoodian Mitra , Halbach Caroline , Slinger Cassidy , Pattnaik Bikash R. , Sorenson Christine M. , Sheibani Nader
Published: July 2016

Defects in the outer blood-retinal barrier have significant impact on the pathogenesis of diabetic retinopathy and macular edema. However, the detailed mechanisms involved remain largely unknown. This is, in part, attributed to the lack of suitable animal and cell culture models, including those of mouse origin. We recently reported a method for the culture of retinal pigment epithelial (RPE) cells from wild-type and transgenic mice. The RPE cells are responsible for maintaining the integrity of the outer blood-retinal barrier whose dysfunction during diabetes has a significant impact on vision. Here we determined the impact of high glucose on the function of RPE cells. We showed that high glucose conditions resulted in enhanced migration and increased the level of oxidative stress in RPE cells, but minimally impacted their rate of proliferation and apoptosis. High glucose also minimally affected the cell-matrix and cell-cell interactions of RPE cells. However, the expression of integrins and extracellular matrix proteins including pigment epithelium-derived factor (PEDF) were altered under high glucose conditions. Incubation of RPE cells with the antioxidant N-acetylcysteine under high glucose conditions restored normal migration and PEDF expression. These cells also exhibited increased nuclear localization of the antioxidant transcription factor Nrf2 and ZO-1, reduced levels of β-catenin and phagocytic activity, and minimal effect on production of vascular endothelial growth factor, inflammatory cytokines, and Akt, MAPK, and Src signaling pathways. Thus high glucose conditions promote RPE cell migration through increased oxidative stress and expression of PEDF without a significant effect on the rate of proliferation and apoptosis.
Inhibition of T-cell activation by the CTLA4-Fc Abatacept is sufficient to ameliorate proteinuric kidney disease
Authors: Herrera Marcela , Söderberg Magnus , Sabirsh Alan , Valastro Barbara , Mölne Johan , Santamaria Beatriz , Valverde Angela M. , Guionaud Silvia , Heasman Stephanie , Bigley Alison , Jermutus Lutz , Rondinone Cristina , Coghlan Matthew , Baker David , Quinn Carol Moreno
Published: July 2016

Diabetic nephropathy (DN) remains an unmet medical challenge as its prevalence is projected to continue to increase and specific medicines for treatment remain undeveloped. Activation of the immune system, in particular T-cells, is emerging as a possible mechanism underlying DN disease progression in humans and animal models. We hypothesized that inhibition of T-cell activation will ameliorate DN. Interaction of B7-1 (CD80) on the surface of antigen presenting cells with its binding partners, CTLA4 (CD152) and CD28 on T-cells, is essential for T-cell activation. In this study we used the soluble CTLA4-Fc fusion protein Abatacept to block cell surface B7-1, preventing the cellular interaction and inhibiting T-cell activation. When Abatacept was dosed in an animal model of diabetes-induced albuminuria, it reduced albuminuria in both prevention and intervention modes. The number of T-cells infiltrating the kidneys of DN animals correlated with the degree of albuminuria, and treatment with Abatacept reduced the number of renal T-cells. As B7-1 induction has been recently proposed to underlie podocyte damage in DN, Abatacept could be efficacious in DN by protecting podocytes. However, this does not appear to be the case as B7-1 was not expressed in 1) kidneys of DN animals; 2) stimulated human podocytes in culture; or 3) glomeruli of DN patients. We conclude that Abatacept ameliorates DN by blocking systemic T-cell activation and not by interacting with podocytes.
Transcriptional control, but not subcellular location, of PGC-1α is altered following exercise in a hot environment
Authors: Heesch Matthew W. , Shute Robert J. , Kreiling Jodi L. , Slivka Dustin R.
Published: July 2016

The purpose of this study was to determine mitochondrial biogenesis-related mRNA expression, binding of transcription factors to the peroxisome proliferator-activated receptor-γ coactivator 1-α (PGC-1α) promoter, and subcellular location of PGC-1α protein in human skeletal muscle following exercise in a hot environment compared with a room temperature environment. Recreationally trained males ( n = 11) completed two trials in a temperature- and humidity-controlled environmental chamber. Each trial consisted of cycling in either a hot (H) or room temperature (C) environment (33 and 20°C, respectively) for 1 h at 60% of maximum wattage (Wmax) followed by 3 h of supine recovery at room temperature. Muscle biopsies were taken from the vastus lateralis pre-, post-, and 3 h postexercise. PGC-1α mRNA increased post ( P = 0.039)- and 3 h postexercise in C ( P = 0.002). PGC-1α, estrogen-related receptor-α (ERRα), and nuclear respiratory factor 1 (NRF-1) mRNA was all lower in H than C post ( P = 0.038, P < 0.001, and P = 0.030, respectively)- and 3 h postexercise ( P = 0.035, P = 0.007, and P < 0.001, respectively). Binding of cAMP response element-binding protein (CREB) ( P = 0.005), myocyte enhancer factor 2 (MEF2) ( P = 0.047), and FoxO forkhead box class-O1 (FoxO1) ( P = 0.010) to the promoter region of the PGC-1α gene was lower in H than C. Nuclear PGC-1α protein increased postexercise in both H and C ( P = 0.029) but was not different between trials ( P = 0.602). These data indicate that acute exercise in a hot environment blunts expression of mitochondrial biogenesis-related mRNA, due to decreased binding of CREB, MEF2, and FoxO1 to the PGC-1α promoter.
Understanding location- and feature-based processing along the human intraparietal sulcus
Authors: Bettencourt Katherine C. , Xu Yaoda
Published: July 2016

Based on different cognitive tasks and mapping methods, the human intraparietal sulcus (IPS) has been subdivided according to multiple different organizational schemes. The presence of topographically organized regions throughout IPS indicates a strong location-based processing in this brain region. However, visual short-term memory (VSTM) studies have shown that while a region in the inferior IPS region (inferior IPS) is involved in object individuation and selection based on location, a region in the superior IPS (superior IPS) primarily encodes and stores object featural information. Here, we determined the localization of these two VSTM IPS regions with respect to the topographic IPS regions in individual participants and the role of different IPS regions in location- and feature-based processing. Anatomically, inferior IPS showed an 85.2% overlap with topographic IPS regions, with the greatest overlap seen in V3A and V3B, and superior IPS showed a 73.6% overall overlap, with the greatest overlap seen in IPS0-2. Functionally, there appeared to be a partial overlap between IPS regions involved in location- and feature-based processing, with more inferior and medial regions showing a stronger location-based processing and more superior and lateral regions showing a stronger feature-based processing. Together, these results suggest that understanding the multiplex nature of IPS in visual cognition may not be reduced to examining the functions of the different IPS topographic regions, but rather, it can only be accomplished by understanding how regions identified by different tasks and methods may colocalize with each other.
Comparison of Diaphragmatic Breathing Exercise, Volume and Flow Incentive Spirometry, on Diaphragm Excursion and Pulmonary Function in Patients Undergoing Laparoscopic Surgery: A Randomized Controlled Trial
Authors: Alaparthi Gopala Krishna , Augustine Alfred Joseph , Anand R. , Mahale Ajith
Published: July 2016

Objective.To evaluate the effects of diaphragmatic breathing exercises and flow and volume-oriented incentive spirometry on pulmonary function and diaphragm excursion in patients undergoing laparoscopic abdominal surgery.Methodology.We selected 260 patients posted for laparoscopic abdominal surgery and they were block randomization as follows: 65 patients performed diaphragmatic breathing exercises, 65 patients performed flow incentive spirometry, 65 patients performed volume incentive spirometry, and 65 patients participated as a control group. All of them underwent evaluation of pulmonary function with measurement of Forced Vital Capacity (FVC), Forced Expiratory Volume in the first second (FEV1), Peak Expiratory Flow Rate (PEFR), and diaphragm excursion measurement by ultrasonography before the operation and on the first and second postoperative days. With the level of significance set atp<0.05.Results.Pulmonary function and diaphragm excursion showed a significant decrease on the first postoperative day in all four groups (p<0.001) but was evident more in the control group than in the experimental groups. On the second postoperative day pulmonary function (Forced Vital Capacity) and diaphragm excursion were found to be better preserved in volume incentive spirometry and diaphragmatic breathing exercise group than in the flow incentive spirometry group and the control group. Pulmonary function (Forced Vital Capacity) and diaphragm excursion showed statistically significant differences between volume incentive spirometry and diaphragmatic breathing exercise group (p<0.05) as compared to that flow incentive spirometry group and the control group.Conclusion. Volume incentive spirometry and diaphragmatic breathing exercise can be recommended as an intervention for all patients pre- and postoperatively, over flow-oriented incentive spirometry for the generation and sustenance of pulmonary function and diaphragm excursion in the management of laparoscopic abdominal surgery.
Comparison of the Effects of Glutamine, Curcumin, and Nesfatin-1 on the Gastric Serosal Surface Neomucosa Formation: An Experimental Rodent Model
Authors: Gulcicek Osman Bilgin , Solmaz Ali , Yiğitbaş Hakan , Ercetin Candas , Yavuz Erkan , Ozdogan Kamil , Arici Sinan , Akkalp Asli Kahraman , Sarac Tulin , Çelebi Fatih , Celik Atilla
Published: July 2016

Introduction. Short bowel syndrome can crop up if more than 50% of small intestine is resected or when less than 100 cm of small bowel is left. Glutamine is the main food source of enterocytes. Curcumin has protective effects on intestinal ischemia-reperfusion damage. Nesfatin-1 is a satiety molecule. It has protective effects on gastric mucosa. The primary purpose of this study is to compare effects of glutamine, curcumin, and nesfatin-1 on the gastric serosal surface neomucosa formation on rats.Materials and Methods. 24 Wistar-Hannover rats were randomly divided into 4 groups and treated with saline, glutamine, curcumin, and nesfatin-1 after ileogastric anastomosis. After 14 days all rats were euthanized, and blood was collected. En bloc resection of anastomotic part was performed for histopathological examination.Results. PDGF, TGF-β, and VEGF levels and neomucosa formation were higher in glutamine group (p=0.003,p=0.003, andp=0.025). Glutamine promotes the intestinal neomucosa formation on the gastric serosal surface and augments growth factors essential for neomucosa formation on rats.Conclusion. Glutamine may be used in short bowel syndrome for increasing the absorption surface area. But that needs to be determined by adequately powered clinical trials.
Silver Nanoparticles Embedded in Natural Rubber Films: Synthesis, Characterization, and Evaluation ofIn VitroToxicity
Authors: Danna Caroline S. , Cavalcante Dalita G. S. M. , Gomes Andressa S. , Kerche-Silva Leandra E. , Yoshihara Eidi , Osorio-Román Igor O. , Salmazo Leandra O. , Rodríguez-Pérez Miguel A. , Aroca Ricardo F. , Job Aldo E.
Published: July 2016

Natural rubber (NR) films can reduce silver metal ions forming embedded metal nanoparticles, a process that could be described as green synthesis. The NR films acting as a reactor generate and incorporate silver nanoparticles (AgNPs). Organic acids and amino acids play a crucial role in the formation of AgNPs. The plasmon extinction obtained in the UV-visible spectrum shows the presence of nanoparticles in the film after dipping the NR film into a solution of silver nitrate at 80°C. Electron microscopic analysis confirms the presence of AgNPs in the NR film and characterization by atomic force microscopy shows a change in the roughness of the NR film with AgNPs. In addition, our preliminary results fromin vitrotoxicity studies (MTT and comet assays) of the NR films and NR films with silver nanoparticles (NR/Ag) show that they are not toxic to cell lineage CHO-K1 (cells from the ovary of a Chinese hamster), an important result for potential medical applications.
Clinical Outcomes and Complications of Cortical Button Distal Biceps Repair: A Systematic Review of the Literature
Authors: Panagopoulos Andreas , Tatani Irini , Tsoumpos Pantelis , Ntourantonis Dimitris , Pantazis Konstantinos , Triantafyllopoulos Ioannis K.
Published: July 2016

Objectives. The purpose of the present study was to investigate the clinical outcomes and complications of the cortical button distal biceps fixation method.Material and Methods. All methods followed the PRISMA guidelines. Included studies had to describe clinical outcomes and complications after acute distal biceps repair with cortical button fixation. Eligibility criteria also included English language, more than 5 cases with minimum follow-up of 6 months, and preferably usage of at least one relevant clinical score (MEPS, ASES, and/or DASH) for final outcome. A loss of at least 30° in motion—flexion, extension, pronation, or supination—and a loss of at least 30% of strength were considered an unsatisfactory result.Results. The review identified 7 articles including 105 patients (mean age 43.6 years) with 106 acute distal biceps ruptures. Mean follow-up was 26.3 months. Functional outcome of ROM regarding flexion/extension and pronation/supination was satisfactory in 94 (89.5%) and 86 (82%) patients in respect. Averaged flexion and supination strength had been reported in 6/7 studies (97 patients) and were satisfactory in 82.4% of them. The most common complication was transient nerve palsy (14.2%). The overall reoperation rate was 4.8% (5/105 cases).Conclusion. Cortical button fixation for acute distal biceps repair is a reproducible operation with good clinical results. Most of the complications can be avoided with appropriate surgical technique.
Robust Observer Based Disturbance Rejection Control for Euler-Lagrange Systems
Authors: Zhang Yanjun , Wang Lu , Zhang Jun , Su Jianbo
Published: July 2016

Robust disturbance rejection control methodology is proposed for Euler-Lagrange systems, and parameters optimization strategy for the observer is explored. First, the observer based disturbance rejection methodology is analyzed, based on which the disturbance rejection paradigm is proposed. Thus, a disturbance observer (DOB) with partial feedback linearization and a low-pass filter is proposed for nonlinear dynamic model under relaxed restrictions of the generalized disturbance. Then, the outer-loop backstepping controller is designed for desired tracking performance. Considering that the parameters of DOB cannot be obtained directly based on Lyapunov stability analysis, parameter of DOB is optimized under standardH∞control framework. By analyzing the influence of outer-loop controller on the inner-loop observer parameter, robust stability constraint is proposed to guarantee the robust stability of the closed-loop system. Experiment on attitude tracking of an aircraft is carried out to show the effectiveness of the proposed control strategy.
Model Tests on the Retaining Walls Constructed from Geobags Filled with Construction Waste
Authors: Wen Hua , Wu Jiu-jiang , Zou Jiao-li , Luo Xin , Zhang Min , Gu Chengzhuang
Published: July 2016

Geobag retaining wall using construction waste is a new flexible supporting structure, and the usage of construction waste to fill geobags can facilitate the construction recycling. In this paper, model tests were performed on geobag retaining wall using construction waste. The investigation was concentrated on the slope top settlement, the distribution characteristics of the earth pressures on retaining walls and horizontal wall displacements, and slope failure modes. The results indicated that the ultimate loads that the slope tops with retaining walls could bear were 87.5%~125% higher than that of the slope top without retaining walls. The ultimate loading of strengthened slopes with different slope ratios from 1 : 0.75 to 1 : 0.25 could be reduced by 11.8% to 29.4%. The horizontal displacements of the retaining walls constructed from geobags were distributed in a drum shape, with the greatest horizontal displacements occurring about 1/3~1/2 of the wall height away from the bottom of the wall. As the slope ratio increased, the failure of the slope soil supported by geobag retaining wall using construction waste changed from sliding to sliding-toppling (dominated by sliding) and then to toppling-sliding (dominated by toppling). The range of 1/3~1/2 of wall height is the weak part of the retaining walls, which should be strengthened with certain measures during the process of design and construction.
Increasing Dose of Autologous Bone Marrow Mononuclear Cells Transplantation Is Related to Stroke Outcome: Results from a Pooled Analysis of Two Clinical Trials
Authors: Moniche Francisco , Rosado-de-Castro Paulo Henrique , Escudero Irene , Zapata Elena , de la Torre Laviana Francisco Javier , Mendez-Otero Rosalia , Carmona Magdalena , Piñero Pilar , Bustamante Alejandro , Lebrato Lucía , Cabezas Juan Antonio , Gonzalez Alejandro , de Freitas Grabriel R. , Montaner Joan
Published: July 2016

Background and Purpose. BM‐MNC transplantation improves recovery in experimental models of ischemic stroke. Clinical trials are ongoing to test efficacy in stroke patients. However, whether cell dose is related to outcomes is not known. Methods. We performed a pooling data analysis of two pilot clinical trials with autologous BM‐MNCs transplantation in ischemic stroke patients. Cell dose and route were analyzed to evaluate their relation to good outcome (m‐Rankin scale [mRS] score 0–2) at 6 months. Results. Twenty‐two patients were included. A median of 153 × 106 (±121 × 106) BM‐MNCs was injected. Intra‐arterial route was used in 77.3% of cases. A higher number of cells injected were associated with better outcomes at 180 days (390 × 106 [320–422] BM‐MNCs injected in those patients with mRS of 0–2 at 6 months versus 130 × 106 [89–210] in those patients with mRS 3–6, p = 0.015). In the intra‐arterially treated patients, a strong correlation between dose of cells and disability was found (r = −0.63, p = 0.006). A cut point of 310 × 106 injected cells predicted good outcome with 80% sensitivity and 88.2% specificity. Conclusions. Similar to preclinical studies, a higher dose of autologous BM‐MNC was related to better outcome in stroke patients, especially when more than 310 × 106 cells are injected. Further interventional studies are warranted to confirm these data.
Dynamic Analysis for a Fractional-Order Autonomous Chaotic System
Authors: Zhang Jiangang , Nan Juan , Du Wenju , Chu Yandong , Luo Hongwei
Published: July 2016

We introduce a discretization process to discretize a modified fractional-order optically injected semiconductor lasers model and investigate its dynamical behaviors. More precisely, a sufficient condition for the existence and uniqueness of the solution is obtained, and the necessary and sufficient conditions of stability of the discrete system are investigated. The results show that the system’s fractional parameter has an effect on the stability of the discrete system, and the system has rich dynamic characteristics such as Hopf bifurcation, attractor crisis, and chaotic attractors.
Probiotics and the Microbiome in Celiac Disease: A Randomised Controlled Trial
Authors: Harnett Joanna , Myers Stephen P. , Rolfe Margaret
Published: July 2016

Background. There is limited research investigating the composition of the gastrointestinal microbiota in individuals with celiac disease (CoeD) reporting only partial symptom improvement despite adherence to a strict gluten‐free diet (GFD). The aim of this research was to determine if the gastrointestinal microbiota could be altered by probiotic bacteria and provide a potential new therapy for this subgroup. Methods. A multicentre RCT was conducted between January and August 2011 in Australia. Participants included 45 people with CoeD reporting only partial symptom improvement despite adherence to a strict GFD for a minimum of 12 months. Participants took 5 g of VSL#™ probiotic formulation (n = 23) or 5 g placebo (n = 22) orally twice daily for 12 weeks. The main outcome measured was the efficacy of the probiotic formula in altering faecal microbiota counts between baseline and week 12. Safety was determined by safety blood and monitoring adverse events. Results. SPSS™ multivariate repeated measures analysis (95th confidence level) revealed no statistically significant changes between the groups in the faecal microbiota counts or blood safety measures over the course of the study. Conclusion. The probiotic formula when taken orally over the 12‐week period did not significantly alter the microbiota measured in this population. The trial was registered with Australian and New Zealand Clinical Trials Register ACTRN12610000630011.
Bromodomain and Extraterminal Protein Inhibitor JQ1 Suppresses Thyroid Tumor Growth in a Mouse Model
Authors: Zhu Xuguang , Enomoto Keisuke , Zhao Li , Zhu Yuelin J. , Willingham Mark C. , Meltzer Paul , Qi Jun , Cheng Sheue-yann
Published: July 2016

Purpose: New therapeutic approaches are needed for patients with thyroid cancer refractory to radioiodine treatment. An inhibitor of bromodomain and extraterminal domain (BET) proteins, JQ1, shows potent antitumor effects in hematological cancers and solid tumors. To evaluate whether JQ1 is effective against thyroid cancer, we examined antitumor efficacy of JQ1 using the ThrbPV/PVKrasG12D mouse, a model of anaplastic thyroid cancer.

Experimental Design: We treated ThrbPV/PVKrasG12D mice with vehicle or JQ1 at a dose of 50 mg/kg body weight/day starting at the age of 8 weeks for a 10-week period and monitored thyroid tumor progression.

Results: JQ1 markedly inhibited thyroid tumor growth and prolonged survival of these mice. Global differential gene expression analysis showed that JQ1 suppressed the cMyc (hereafter referred to as Myc) transcription program by inhibiting mRNA expression of Myc, ccnd1, and other related genes. JQ1-suppressed Myc expression was accompanied by chromatin remodeling as evidenced by increased expression of histones and hexamethylene bis-acetamide inducible 1, a suppressor of RNA polymerase II transcription elongation. Analyses showed that JQ1 decreased MYC abundance in thyroid tumors and attenuated the cyclin D1–CDK4–Rb–E2F3 signaling to decrease tumor growth. Further analysis indicated that JQ1 inhibited the recruitment of BDR4 to the promoter complex of the Myc and Ccnd1 genes in rat thyroid follicular PCCL3 cells, resulting in decreased MYC expression at the mRNA and protein levels to inhibit tumor cell proliferation.

Conclusions: These preclinical findings suggest that BET inhibitors may be an effective agent to reduce thyroid tumor burden for the treatment of refractory thyroid cancer. Clin Cancer Res; 23(2); 430–40. ©2016 AACR.
Irreversible Inhibition of EGFR: Modeling the Combined Pharmacokinetic–Pharmacodynamic Relationship of Osimertinib and Its Active Metabolite AZ5104
Authors: Yates James W.T. , Ashton Susan , Cross Darren , Mellor Martine J. , Powell Steve J. , Ballard Peter
Published: July 2016

Osimertinib (AZD9291) is a potent, selective, irreversible inhibitor of EGFR-sensitizing (exon 19 and L858R) and T790M-resistant mutation. In vivo, in the mouse, it is metabolized to an active des-methyl metabolite, AZ5104. To understand the therapeutic potential in patients, this study aimed to assess the relationship between osimertinib pharmacokinetics, the pharmacokinetics of the active metabolite, the pharmacodynamics of phosphorylated EGFR reduction, and efficacy in mouse xenograft models of EGFR-driven cancers, including two NSCLC lines. Osimertinib was dosed in xenografted models of EGFR-driven cancers. In one set of experiments, changes in phosphorylated EGFR were measured to confirm target engagement. In a second set of efficacy studies, the resulting changes in tumor volume over time after repeat dosing of osimertinib were observed. To account for the contributions of both molecules, a mathematical modeling approach was taken to integrate the resulting datasets. The model was able to describe the pharmacokinetics, pharmacodynamics, and efficacy in A431, PC9, and NCI-H1975 xenografts, with the differences in sensitivity described by the varying potency against wild-type, sensitizing, and T790M-mutant EGFR and the phosphorylated EGFR reduction required to reduce tumor volume. It was inferred that recovery of pEGFR is slower after chronic dosing due to reduced resynthesis. It was predicted and further demonstrated that although inhibition is irreversible, the resynthesis of EGFR is such that infrequent intermittent dosing is not as efficacious as once daily dosing. Mol Cancer Ther; 15(10); 2378–87. ©2016 AACR.
Analysis of the Repertoire Features of TCR Beta Chain CDR3 in Human by High-Throughput Sequencing
Authors: Hou Xianliang , Wang Mingbang , Lu Chong , Xie Qian , Cui Guangying , Chen Jianing , Du Yu , Dai Yong , Diao Hongyan
Published: July 2016

Background/Aims: To ward off a wide variety of pathogens, the human adaptive immune system harbors a vast array of T-cell receptors, collectively referred to as the TCR repertoire. Assessment of the repertoire features of TCR is vital for us to deeper understand of immune behaviour and immune response. Methods: In this study, we used a combination of multiplex-PCR, Illumina sequencing and IMGT (ImMunoGeneTics)/HighV-QUEST for a standardized analysis of the repertoire features of TCR beta chain in the blood of healthy individuals, including the repertoire features of public TCR complementarity-determining regions (CDR3) sequences, highly expanded clones, long TCR CDR3 sequences. Results: We found that public CDR3 sequences and high-frequency sequences had the same characteristics, both of them had fewer nucleotide additions and shorter CDR3 length, which were closer to the germline sequence. Moreover, our studies provided evidence that public amino acid sequences are produced by multiple nucleotide sequences. Notably, there was skewed VDJ segment usage in long CDR3 sequences, the expression levels of 10 TRβV segments, 7 TRβJ segments and 2 TRβD segments were significantly different in the long CDR3 sequences compared to the short CDR3 sequences. Moreover, we identified that extensive N additions and increase of D gene usage contributing to TCR CDR3 length, and observed there was distinct usage frequency of amino acids in long CDR3 sequences compared to the short CDR3 sequences. Conclusions: Some repertoire features could be observed in the public sequences, highly abundance clones, and long TCR CDR3 sequences, which might be helpful for further study of immune behavior and immune response.
Seizures and Epilepsies due to Channelopathies and Neurotransmitter Receptor Dysfunction: A Parallel between Genetic and Immune Aspects
Authors: Lascano Agustina M. , Korff Christian M. , Picard Fabienne
Published: July 2016

Despite intensive research activity leading to many important discoveries, the pathophysiological mechanisms underlying seizures and epilepsy remain poorly understood. An important number of specific gene defects have been related to various forms of epilepsies, and autoimmunity and epilepsy have been associated for a long time. Certain central nervous system proteins have been involved in epilepsy or acute neurological diseases with seizures either due to underlying gene defects or immune dysfunction. Here, we focus on 2 of them that have been the object of particular attention and in-depth research over the past years: the N-methyl-D-aspartate receptor and the leucin-rich glioma-inactivated protein 1 (LGI1). We also describe illustrative examples of situations in which genetics and immunology meet in the complex pathways that underlie seizures and epilepsy.
Stratified Mucin-Producing Intraepithelial Lesion of the Cervix: Subtle Features Not to Be Missed
Authors: Schwock Joerg , Ko Hyang Mi , Dubé Valérie , Rouzbahman Marjan , Cesari Matthew , Ghorab Zeina , Geddie William R.
Published: July 2016

Objectives: Stratified mucin-producing intraepithelial lesion (SMILE) is an uncommon premalignant lesion of the uterine cervix. A detailed examination of preinvasive SMILE cases including a comparison of the cytologic features with usual-type adenocarcinoma in situ (AIS) and human papillomavirus (HPV) genotyping was performed. Study Design: Excisions and preceding Papanicolaou (Pap) tests were retrieved from the files of 2 tertiary care centers. Histologic review estimated the lesional SMILE proportion. Pap tests were reviewed and assessed for architectural, cellular and background features. Cobas® HPV test was performed. Results: 13 cases were identified. Mean/median patient age was 35/33 years (range 23-51 years). Concurrent high-grade squamous intraepithelial lesion was found in 10/13 (77%) and AIS in 8/13 (62%) cases. In 6 cases, SMILE was dominant (≥50%) and represented in 5/6 corresponding Pap tests. Cytology interpretations differed more often in the SMILE-dominant group (p < 0.05). SMILE and AIS had overlapping features. Feathering and prominent nucleoli were absent in SMILE. HPV DNA was detected in all 12 cases tested. HPV 18 was most common (7/12). Excisions with positive/suspicious margins were reported in 5/6 SMILE-dominant versus 3/7 nondominant cases. Conclusion: SMILE is best considered as an AIS variant for cytologic, etiologic and management purposes. Cytologic features overlap with AIS, but are more subtle and easily missed. HPV testing may play a role in facilitating SMILE detection.
Dose reduction of edoxaban preserves efficacy and safety for the treatment of venous thromboembolism
Authors: Wells Philip S. , Segers Annelise , Ageno Walter , Brekelmans Marjolein P. A. , Cohen Alexander T. , Meyer Guy , Grosso Michael A. , Raskob Gary , Weitz Jeffrey I. , Zhang George , Buller Harry , Verhamme Peter
Published: July 2016

Direct oral anticoagulants simplify venous thromboembolism (VTE) treatment by obviating the need for coagulation monitoring. Nonetheless, renal function, body weight and P-glycoprotein inhibitors influence drug levels. The objective of this analysis was to determine whether reduction in edoxaban dose based on clinical criteria avoids excess drug exposure and preserves efficacy and safety in the Hokusai-VTE study. After initial heparin, patients received edoxaban or warfarin for 3-12 months. Edoxaban was given once daily at a dose of 60 mg, which was reduced to 30 mg in patients with a creatinine clearance of 30–50 ml/minute, body weight ≤60 kg or receiving certain P-glycoprotein inhibitors. The primary efficacy outcome was recurrent VTE and the principal safety outcome was major or clinically relevant non-major bleeding. A total of 8292 patients with acute VTE were randomised, 733 and 719 patients in the edoxaban and warfarin groups met the criteria for dose reduction. These patients were older, more often female or Asian and had more extensive VTE. Edoxaban levels were lower in the 30 mg edoxaban group. Rates of recurrent VTE and bleeding with the 30 mg and 60 mg edoxaban dose were comparable: VTE rates were 3.0 % and 3.2 % and clinically relevant bleeding rates were 7.9 % and 8.6 %, respectively. Rates of recurrent VTE and bleeding in the warfarin-treated patients meeting the criteria for dose reduction were 4.2 % and 12.8 %, respectively. The reduced dose edoxaban regimen maintained efficacy and safety compared with the 60 mg dose but was safer than warfarin in patients meeting the criteria for dose reduction.

Supplementary Material to this article is available online at www.thrombosis-online.com.
AMP-Activated Protein Kinase Alpha 2 Deletion Induces VSMC Phenotypic Switching and Reduces Features of Atherosclerotic Plaque Stability
Authors: Ding Ye , Zhang Miao , Zhang Wencheng , Lu Qiulun , Cai Zhejun , Song Ping , Okon Imoh Sunday , Xiao Lei , Zou Ming-Hui
Published: July 2016

Rationale:

AMP-activated protein kinase (AMPK) has been reported to play a protective role in atherosclerosis. However, whether AMPKα2 controls atherosclerotic plaque stability remains unknown.

Objective:

The aim of this study was to evaluate the impact of AMPKα2 deletion on atherosclerotic plaque stability in advanced atherosclerosis at the brachiocephalic arteries and to elucidate the underlying mechanisms.

Methods and Results:

Features of atherosclerotic plaque stability and the markers for contractile or synthetic vascular smooth muscle cell (VSMC) phenotypes were monitored in the brachiocephalic arteries from
Apoe
−/−
AMPKα2
−/−
mice or VSMC-specific
AMPKα2
−/−
mice in an
Apoe
−/−
background (
Apoe
−/−
AMPKα2
sm−/−
) fed Western diet for 10 weeks. We identified that
Apoe
−/−
AMPKα2
−/−
mice and
Apoe
−/−
AMPKα2
sm−/−
mice exhibited similar unstable plaque features, aggravated VSMC phenotypic switching, and significant upregulation of Kruppel-like factor 4 (KLF4) in the plaques located in the brachiocephalic arteries compared with those found in
Apoe
−/−
and Apoe
−/−
AMPKα2
sm+/+
control mice. Pravastatin, an AMPK activator, suppressed VSMC phenotypic switching and alleviated features of atherosclerotic plaque instability in
Apoe
−/−
AMPKα2
sm+/+
mice, but not in
Apoe
−/−
AMPKα2
sm−/−
mice. VSMC isolated from
AMPKα2
−/−
mice displayed a significant reduction of contractile proteins(smooth muscle actin-α, calponin, and SM-MHC [smooth muscle-mysion heavy chain]) in parallel with increased detection of synthetic proteins (vimentin and osteopontin) and KLF4, as observed in vivo. KLF4-specific siRNA abolished AMPKα2 deletion–induced VSMC phenotypic switching. Furthermore, pharmacological or genetic inhibition of nuclear factor-κB significantly decreased KLF4 upregulation in VSMC from
AMPKα2
−/−
mice. Finally, we found that AMPKα2 deletion markedly promoted the binding of nuclear factor-κBp65 to KLF4 promoter.

Conclusions:

This study demonstrated that AMPKα2 deletion induces VSMC phenotypic switching and promotes features of atherosclerotic plaque instability in nuclear factor-κB–KLF4–dependent manner.
Political Models and the End of the World in Zephaniah
Authors: Timmer Daniel
Published: July 2016

This article pairs the lenses of religious studies and political analysis in order to understand better the utopian future envisioned by the Book of Zephaniah. Identifying prominent political elements in light of common ancient Near Eastern models of statehood, it focuses on the political process that the Book of Zephaniah sees as culminating world history. The elimination from Judah and from other nations of those who do not follow or submit to Yhwh is correlated with empire formation, followed by a surprising shift to a territorial state model in which the remaining citizens of the nations and of Judah form a unified religious community without sharing a common homeland. The study concludes with reflections on the utility of political analysis for understanding religious utopian visions of the future.
The Shepherd’s Risk: Thinking Metaphorically with John’s Gospel
Authors: Hylen Susan E.
Published: July 2016

One of the characteristics of the good shepherd of John 10:11–18 is a phrase that is usually translated “he lays down his life” (vv. 11, 15, 17, 18). Although interpreters often acknowledge the alternate meaning, “he risks his life,” this option is usually rejected. This article sees the notion of risk as an important element of John’s metaphorical presentation of Jesus as shepherd. Drawing on cultural conventions of shepherding, the literary context, and metaphor theory, the author argues that John portrays Jesus as one who risks his life for the sheep, and not simply as one who dies for them. This idea of a shepherd who risks his life for the flock can illuminate the reader’s understanding of Jesus’ life, death, and resurrection, and the way that disciples are called to follow him.
Going beyond the tip of the Drosophilidae iceberg: New Cladochaeta Coquillett, 1900 (Diptera: Drosophilidae) from Brazil
Authors: PIRANI GABRIELA , AMORIM DALTON DE SOUZA
Published: July 2016

Drosophilidae comprises more than 4,000 described species worldwide. Despite the huge number of papers published on the genus Drosophila Fallén, 1823, large parts of the family are still poorly known. The drosophiline genus Cladochaeta Coquillet, 1900 has more than 100 Neotropical and several southern Nearctic described species, but there is quite a large number of undescribed species. The Brazilian fauna of the genus was studied and 12 new species are herein described—Cladochaeta armatopsis nov. sp., C. balbiae nov. sp., C. paraitinga nov. sp., C. asapha nov. sp., C.chauliodactyla nov. sp., C. conicophallus nov. sp., C. dicrophallus nov. sp., C.grimaldii nov. sp., C. atlantica nov. sp., C. periotoi nov. sp., C. phallotrixa nov. sp. and C. stigmata nov. sp. We set the first record of C. arthrostyla Grimaldi & Nguyen, 1999 for northeastern Brazil a species otherwise known from Costa Rica, and the first record of C. bomplandi (Malloch, 1934) for the state of Minas Gerais, a species known for northeastern Argentina and southern Brazil. The descriptions include photographs for each species and detailed illustrations of the male terminalia in different views. A synopsis on the taxonomy and natural history of the genus is provided, as well as comments about the relationships of species in the genus, a discussion on problems of male terminalia sclerite homology and the problem of association between males and females.