bluuebunny/crossref_metadata_2025_split huggingface dataset:
Characterizing the Sources of Pharmacokinetic Variability for TAK‐117 (Serabelisib), an Investigational Phosphoinositide 3‐Kinase Alpha Inhibitor: A Clinical Biopharmaceutics Study to Inform Development Strategy
Authors: Patel Chirag G. , Rangachari Lakshmi , Patti Mark , Griffin Celina , Shou Yaping , Venkatakrishnan Karthik 
Published: August 2018

AbstractTAK‐117 (also known as MLN1117 or serabelisib) is an orally available inhibitor of phosphoinositide 3‐kinase alpha being developed for treatment of solid tumors. This clinical study in healthy subjects assessed the relative bioavailability of a TAK‐117 tablet compared with a capsule formulation (part 1) and the effect of food (part 2) and intragastric pH modulation (part 3) on TAK‐117 pharmacokinetics. In part 1, subjects received single doses of 900 mg TAK‐117 under fasting conditions as capsules and tablets on 2 different occasions in random order. In part 2, subjects received a single dose of 600 mg TAK‐117 under fed (high‐fat meal) or fasted conditions on 2 different occasions in random order. In part 3, subjects received a single dose of 900 mg TAK‐117 alone and in combination with lansoprazole in a fixed sequence. Blood samples were collected up to 72 hours after each TAK‐117 dose. The geometric mean ratios (90% confidence intervals) for the area under the TAK‐117 plasma concentration‐time curves were 1.53 (0.93‐2.51) for tablets versus capsules, 1.50 (1.00‐2.25) for fed versus fasted, and 0.02 (0.01‐0.04) for TAK‐117 plus lansoprazole compared with TAK‐117 alone. The most common adverse event was nausea, the incidence of which was reduced when TAK‐117 was administered with food despite the increased systemic exposure. The incidence of all adverse events was reduced when TAK‐117 was administered with lansoprazole, which was consistent with the substantial reduction in bioavailability. Intersubject variability of TAK‐117 was high. Careful management of intragastric pH‐modulatory concomitant medications and food intake may be required.
Accelerating the computation of FLAPW methods on heterogeneous architectures
Authors: Davidović Davor , Fabregat‐Traver Diego , Höhnerbach Markus , Di Napoli Edoardo 
Published: August 2018

SummaryLegacy codes in computational science and engineering have been very successful in providing essential functionality to researchers. However, they are not capable of exploiting the massive parallelism provided by emerging heterogeneous architectures. The lack of portable performance and scalability puts them at high risk, ie, either they evolve or they are destined to be executed on older platforms and small clusters. One example of a legacy code which would heavily benefit from a modern redesign is FLEUR, a software for electronic structure calculations. In previous work, the computational bottleneck of FLEUR was partially reengineered to have a modular design that relies on standard building blocks, namely, BLAS and LAPACK libraries. In this paper, we demonstrate how the initial redesign enables the portability to heterogeneous architectures. More specifically, we study different approaches to port the code to architectures consisting of multi‐core CPUs equipped with one or more coprocessors such as Nvidia GPUs and Intel Xeon Phis. Our final code attains over 70% of the architectures' peak performance, and outperforms Nvidia's and Intel's libraries. On JURECA, the large tier‐0 cluster where FLEUR is often executed, the code takes advantage of the full power of the computing nodes, attaining 5× speedup over the sole use of the CPUs.
Virtual machine migration algorithm for energy efficiency optimization in cloud computing
Authors: Zhou Zhou , Yu Junyang , Li Fangmin , Yang Fei 
Published: August 2018

SummaryCloud computing has gained more and more attention from industrial and academic circle since it offers pay‐as‐you‐go model, and business applications based on the cloud are also increasing. These applications meet the requirement of users while at the same time triggering the problem of high energy consumption in data centers. To deal with the problem, we propose a new algorithm named EEOM (Energy Efficiency Optimization of VM Migrations). Under considering CPU and memory factors, the key three steps for EEOM algorithm, including trigger time, VM selection, and host location, are optimized. EEOM algorithm takes use of the virtualization technology and migrates some VMs on the lightly loaded host and heavily loaded host to other hosts. The idle hosts are switched to low‐power mode or shut down so as to save energy consumption. The experimental results show that, as compared with Double Threshold (DT) algorithm, the EEOM algorithm saves 7% energy consumption and reduces 13% SLA violations.
Screening Strategies for the Discovery of Ion Channel Monoclonal Antibodies
Authors: Colley Caroline S. , England Elizabeth , Linley John E. , Wilkinson Trevor C. I. 
Published: August 2018

AbstractIon channels play crucial roles in physiology by modulation of cellular functions that include electrical excitability, secretion, cell migration, and gene transcription. They are an important target class for drug discovery and have historically been targeted using small molecule approaches. A significant opportunity exists to target these channels with antibodies and alternative forms of biologics. Antibodies display high specificity, selectivity, and affinity for their target antigen, thus having the potential to target ion channels very precisely. Nonetheless, isolating antibodies to ion channels is challenging due to the difficulties in expression and purification of ion channels in a format suitable for antibody drug discovery and due to the complexities of screening for function. In this overview, we focus on an array of screening methods, ranging from direct antibody binding screens to complex electrophysiological assays, and describe how these assays can be used to identify functional monoclonal antibodies. We also provide some insights into specific considerations which are required to enable these screens to be used for antibody drug discovery. © 2018 by John Wiley & Sons, Inc.
Overview of Transporters in Pharmacokinetics and Drug Discovery
Authors: Zhang Yan 
Published: August 2018

AbstractTransporters play important roles in absorption, distribution, metabolism, and elimination (ADME) processes, as well as drug pharmacokinetics (PK) and pharmacodynamics (PD). They are also important in maintaining the homeostasis of endogenous compounds and nutrients in the body. Increasing evidences also suggest that they are important in mediating drug‐drug interactions (DDIs). While the significance of transporters in drug pharmacodynamics and DDIs are beyond the scope of this overview, the basic concepts of transporters, their contributions in membrane permeation processes, and their roles in influencing drug ADME pathway and PK will be discussed. © 2018 by John Wiley & Sons, Inc.
Trajectory tracking and recovery attacks in VANET systems
Authors: Wang Kun , Wang Lei , Cui Minhao 
Published: August 2018

SummaryInvestigating the mechanisms of various attacks in vehicular ad hoc networks (VANETs) provides fundamental basis to develop safeguard techniques for network security issues. As they develops, attacking strategies are also needed to be established for people to learn how to defend. Previous works failed to consider multiple victims recovery and minimum road side units (RSUs) deployment issues. In this paper, we approach the attacking strategy from an adversarial point of view and develop a trajectory tracking and recovering attack based on matrix completion (TTRA). By randomly sampling locations of vehicles, TTRA is capable of recovering locations of any user with tolerable deviation. After that, the problem of how to minimize the number of RSUs while tracking all vehicles in the whole region is also considered by converting this problem into set covering problem. A heuristic algorithm based on hierarchical clustering is proposed accordingly. To the best of our knowledge, this is the first attempt of recovering mobile users' trajectories by applying these novel techniques. Finally, simulation analysis is used to show the performance of the proposed scheme. Simulation results demonstrate the merits of the scheme in terms of tracking results, location error, and influences of sampling ratio, among others.
Nanostructured high insulating autoclaved aerated concrete
Authors: Stumm Andreas , Schweike Uwe , Stemmermann Peter 
Published: August 2018

AbstractEfficient insulation for residential buildings is one of the keys for implementing an energy transition. The technology used for exterior walls is usually made by combining load‐bearing and difficult to recycle insulating components. For this reason, Celitement GmbH, Karlsruhe Institute of Technology and Xella Technology and Research have joined their forces to develop a high insulating AAC, which is also resource efficient using the main components quick lime, sand, and water. The thermal conductivity of the AAC was reduced. Macropores formed in the conventional production process by hydrogen gas, diameter of approximately 1 mm, could be partially replaced by lightweight aggregates, with an average pore diameter of 50 nm. A process for producing lightweight aggregate, which is based on optimized, hydraulically active calcium hydro silicate binders (Celitement), was developed. The aggregate quantity in AAC could be raised to 40% by weight through optimizing formulation and mixing. This project, sponsored by the German Federal Ministry of Education and Research, ended in 2017. Based on the results so far, it is worth pursuing this approach in the future, whereby the material properties of the CSH granules could be further improved to obtain the sought final AAC product.
FKBP51 modulates steroid sensitivity and NFκB signalling: A novel anti‐inflammatory drug target
Authors: Kästle Marc , Kistler Barbara , Lamla Thorsten , Bretschneider Tom , Lamb David , Nicklin Paul , Wyatt David 
Published: August 2018

AbstractSteroid refractory inflammation is an unmet medical need in the management of inflammatory diseases. Thus, mechanisms, improving steroid sensitivity and simultaneously decreasing inflammation have potential therapeutic utility. The FK506‐binding protein 51 (FKBP51) is reported to influence steroid sensitivity in mental disorders. Moreover, biochemical data highlight a connection between FKBP51 and the IKK complex. The aim of this study was to elucidate whether FKBP51 inhibition had utility in modulating steroid resistant inflammation by increasing the sensitivity of the glucocorticoid receptor (GR) signalling and simultaneously inhibiting NFκB‐driven inflammation. We have demonstrated that FKBP51 silencing in a bronchial epithelial cell line resulted in a 10‐fold increased potency for dexamethasone towards IL1beta‐induced IL6 and IL8, whilst FKBP51 over‐expression of FKBP51 reduced significantly the prednisolone sensitivity in a murine HDM‐driven pulmonary inflammation model. Immunoprecipitation experiments with anti‐FKBP51 antibodies, confirmed the presence of FKBP51 in a complex comprising Hsp90, GR and members of the IKK family. FKBP51 silencing reduced NFκB (p50/p65) nucleus translocation, resulting in reduced ICAM expression, cytokine and chemokine secretion. In conclusion, we demonstrate that FKBP51 has the potential to control inflammation in steroid insensitive patients in a steroid‐dependent and independent manner and thus may be worthy of further study as a drug target.
Impact of aerosols on reservoir inflow: A case study for Big Creek Hydroelectric System in California
Authors: Kabir Farzana , Yu Nanpeng , Yao Weixin , Wu Longtao , Jiang Jonathan H. , Gu Yu , Su Hui 
Published: August 2018

AbstractAccurate and reliable reservoir inflow forecast is instrumental to the efficient operation of the hydroelectric power systems. It has been discovered that natural and anthropogenic aerosols have a great influence on meteorological variables such as temperature, snow water equivalent, and precipitation, which in turn impact the reservoir inflow. Therefore, it is imperative for us to quantify the impact of aerosols on reservoir inflow and to incorporate the aerosol models into future reservoir inflow forecasting models. In this paper, a comprehensive framework was developed to quantify the impact of aerosols on reservoir inflow by integrating the Weather Research and Forecasting model with Chemistry (WRF‐Chem) and a dynamic regression model. The statistical dynamic regression model produces forecasts for reservoir inflow based on the meteorological output variables from the WRF‐Chem model. The case study was performed on the Florence Lake and Lake Thomas Alva Edison of the Big Creek Hydroelectric Project in the San Joaquin Region. The simulation results show that the presence of aerosols results in a significant reduction of annual reservoir inflow by 4–14%. In the summer, aerosols reduce precipitation, snow water equivalent, and snowmelt that leads to a reduction in inflow by 11–26%. In the spring, aerosols increase temperature and snowmelt which leads to an increase in inflow by 0.6–2%. Aerosols significantly reduce the amount of inflow in the summer when the marginal value of water is extremely high and slightly increase the inflow in the spring when the run‐off risk is high. In summary, the presence of aerosols is detrimental to the optimal utilization of hydroelectric power systems.
Histamine H1 receptor gene polymorphism acts as a biological indicator of the prediction of therapeutic efficacy in patients with allergic rhinitis in the Chinese Han population
Authors: Chu Jin‐Tao 
Published: August 2018

AbstractH1‐antihistamine has been shown to be effective in treating patients with allergic rhinitis (AR), but its mechanism is still uncertain. We investigated effects of histamine H1 receptor (HRH1) gene polymorphisms on the efficacy of oral H1‐antihistamine in perennial patients with AR caused by mites in the Chinese Han population for the first time. A total of 224 Han Chinese patients with AR and 165 Han Chinese healthy volunteers were selected. Genotype and allele frequency distribution of −17C/T in HRH1 gene in patients with AR, serum levels of eosinophil cationic protein (ECP), total immunoglobulin E (IgE), and specific IgE were detected. The clinical symptoms of patients with AR were evaluated with visual analogue scale (VAS). Direct counting method was applied to calculate genotype and allele frequencies. Higher levels of serum ECP and total IgE were shown in the AR group. Moreover, patients with CT, TT, or CT+TT genotype increased the risk of AR incidence in the in the −17C/T site of HRH1, and CC genotype and CT+TT genotype were associated with gender, asthma, VAS score, total IgE level, and specific IgE level in patients with AR. In addition, oral administration of H1‐antihistamines improves clinical symptoms of patients with AR. At last, patients with the CC genotype showed the increased efficacy of H1‐antihistamines in patients with AR. Our study provides evidence that HRH1 gene polymorphisms may correlate with oral H1‐antihistamine efficacy for the treatment of patients with AR, which can be used as a biological indicator of the prediction of therapeutic efficacy of patients with AR.
Identification of diagnostic biomarker in patients with gestational diabetes mellitus based on transcriptome‐wide gene expression and pattern recognition
Authors: Wang Yeping , Wang Zuo , Zhang Hongping 
Published: August 2018

AbstractGestational diabetes mellitus (GDM) is becoming a growing threat for all pregnancies. In this study, we set up an automatic screening method combining both transcriptomic databases and support vector machine (SVM)‐based pattern recognition to select biomarkers that can be used in predicting and preventing GDM for gravidas. We screened 63 samples (32 GDM samples and 31 normal controls) in GEO database for the GDM‐specific biomarkers. Differentially expressed genes between patients with GDM and normal controls were picked out using edgeR package. Enrichment analysis was performed using database for annotation, visualization, and integrated discovery. The regulatory gene network was constructed based on the KEGG pathway database. Genes in the hub of the network were selected as specific biomarkers of GDM and further validated through document investigation. Finally, the GDM prediction model was verified using the SVMs. In total, 189 probes corresponding to 69 genes that differentially expressed between GDM and controls were screened out by edgeR package. Nineteen pathways were clustered by KEGG enrichment analysis and were integrated into a regulatory network containing 572 nodes and 1874 edges. The intersection of 50 hub genes extracted from the network and 69 differential genes picked out by edgeR was a collection of six genes, including members of HLA superfamily. In the SVM model, the six genes had a good capacity of predicting GDM in both the training data set (area under curve [AUC] is 0.781) and the testing data set (AUC is 0.710) and had been reported to be associated with GDM. We found that the collection of six genes can be potentially applied as a biomarker for GDM diagnosis.
Challenges associated with the treatment of Buruli ulcer
Authors: Aboagye Sammy Yaw , Kpeli Grace , Tuffour Joseph , Yeboah-Manu Dorothy 
Published: August 2018

Abstract
Buruli ulcer (BU), caused by Mycobacterium ulcerans (MU), is the third most important mycobacterial diseases after tuberculosis and leprosy in immunocompetent individuals. Although the mode of transmission remains an enigma, disease incidence has been strongly linked to disturbed environment and wetlands. The blunt of the diseases is recorded in West African countries along the Gulf of Guinea, and children 15 years and below account for about 48% of all cases globally. Prior to 2004, wide surgical excisions and debridement of infected necrotic tissues followed by skin grafting was the accepted definitive treatment of BU. However, introduction of antibiotic therapy, daily oral rifampicin (10 mg/kg) plus intramuscular injection of streptomycin (15 mg/kg), for 8 weeks by the WHO in 2004 has reduced surgery as an adjunct for correction of deformities and improved wound healing. An all-oral regimen is currently on clinical trial to replace the injectable. It is thought that a protective cloud of the cytotoxic toxin mycolactone kills infiltrating leucocytes leading to local immunosuppression and down-regulation of the systemic immune system. Our studies of lesions from BU patients treated with SR have demonstrated treatment-associated initiation of vigorous immune responses and the development of ectopic lymphoid tissue in the BU lesions. Despite these interventions, there are still challenges that bedevil the management of BU including paradoxical reactions, evolution of lesions after therapy, prolong viability of MU in BU lesions, and development of secondary bacterial infection. In this paper, we will mainly focus on the critical and pertinent challenges that undermine BU treatment toward effective control of BU.
Review on the critical and pertinent challenges that undermine BU treatment toward effective control of Buruli ulcer.
Noncontrast Breast MRI During Pregnancy Using Diffusion Tensor Imaging: A Feasibility Study
Authors: Nissan Noam , Furman‐Haran Edna , Allweis Tanir , Menes Tehillah , Golan Orit , Kent Varda , Barsuk Daphna , Paluch‐Shimon Shani , Haas Ilana , Brodsky Malka , Bordsky Asia , Granot Liat Friedman , Halshtok‐Neiman Osnat , Faermann Renata , Shalmon Anat , Gotlieb Michael , Konen Eli , Sklair‐Levy Miri 
Published: August 2018

BackgroundPregnancy‐associated breast cancer (PABC) is often a delayed diagnosis and contrast‐enhanced MRI is contraindicated because gadolinium agents are known to cross the placenta.PurposeTo investigate the feasibility and clinical utility of noncontrast breast MRI using diffusion tensor imaging (DTI) in the diagnostic workup of PABC.Study TypeProspective.PopulationBetween November 2016 and January 2018, 25 pregnant participants (median gestational age: 17 weeks) were recruited from eight referral breast‐care centers nationwide. Imaging indications included: newly‐diagnosed PABC (n = 10, with 11 lesions), palpable mass/mastitis (n = 4), high‐risk screening (n = 10), and monitoring neoadjuvant‐chemotherapy response (n = 1).Field Strength/Sequence1.5T, T2‐weighted, and DTI sequences, prone position, with a scan duration of ∼12 minutes.AssessmentDTI parametric maps were generated and analyzed at pixel resolution, with reference to ultrasound (US) and pathology.Statistical TestsTwo‐tailed Student's t‐test was applied for evaluating differences between DTI parameters of PABC vs. healthy fibroglandular tissue. Pearson's correlation test was applied to measure the agreements between λ1‐based longest tumor diameter, US, and pathology.ResultsAll scans were technically completed and reached diagnostic quality, except one with notable motion artifacts due to positional discomfort, which was excluded. Nine out of 11 known PABC lesions and one newly‐diagnosed lesion were visible on λ1, λ2, λ3, mean diffusivity (MD), and λ1–λ3 maps, with substantial parametric contrast compared with the apparently normal contralateral fibroglandular tissue (P < 0.001 for all). Two lesions of 0.7 cm were not depicted by the diffusivity maps. Tumor diameter measured on a thresholded λ1 map correlated well with US (r = 0.97) and pathology (r = 0.95). Malignancy was excluded by DTI parametric maps in scans of symptomatic and high‐risk patients, in agreement with US follow‐up, except for one false‐positive case.Data ConclusionNoncontrast breast MRI is feasible and well‐tolerated during pregnancy. Further studies with a larger and homogeneous cohort are required to validate DTI's additive diagnostic value, albeit this study suggests a potential adjunct role for this noninvasive approach in breast evaluation during pregnancy.Level of Evidence: 2Technical Efficacy: Stage 1J. Magn. Reson. Imaging 2019;49:508–517.