bluuebunny/crossref_metadata_2025 huggingface dataset:
Presumed missense and synonymous mutations in ATP7B gene cause exon skipping in Wilson disease
Authors: Wang Chunli , Zhou Wei , Huang Yan , Yin Hanjun , Jin Yu , Jia Zhanjun , Zhang Aihua , Liu Zhifeng , Zheng Bixia
Published: April 2018

Background & Aims

Wilson disease is an inborn error of metabolism caused by abnormalities of the copper‐transporting protein‐encoding gene ATP7B. Recently, the phenomenon of exon skipping, in which exonic mutations result in abnormal splicing, has been associated with various diseases. The present study investigated the splicing defects of the ATP7B exonic variants identified in a cohort of 44 patients with Wilson disease.

Method

All patients were analysed for ATP7B gene by direct sequencing or multiplex ligation‐dependent probe amplification analysis. To identify the potential pathogenicity of the candidate mutations that may induce exon skipping, both in vivo RT‐PCR analysis using RNA from peripheral leukocytes and in vitro functional splicing by minigene construction were conducted.

Results

The patterns of inheritance of the mutations in ATP7B identified in 44 patients exhibited homozygotes (7 patients), compound heterozygotes (32 patients) and heterozygotes (5 patients). In all patients, we detected 25 different ATP7B mutations, including 17 missenses, 1 frameshift, 3 nonsenses, 2 exonic deletions and 2 splicing alteration. In these mutations, 4 mutations have not been previously described in the literature or entered in human genome mutation database. Furthermore, we identified synonymous mutation c.4014T>A and missense mutation R919G caused exon skipping in the ATP7B mRNA transcript.

Conclusion

Our results suggest that aberrant exon skipping associated to putative splicing enhancer disruption and silencer creation is one previously unrecognized mechanism in Wilson disease. What is more, the multiplex ligation‐dependent probe amplification assay for the detection of exon deletions may be valuable in individuals with clinical Wilson disease diagnosis where one or no mutation has been identified by sequencing.
Clinical bleeding and thrombin generation in admissions to critical care with prolonged prothrombin time: an exploratory study
Authors: Stanworth Simon J. , Desborough Michael J.R. , Simons Gemma , Seeney Frances , Powter Gillian , MacDonald Stephen , McKechnie Stuart , Green Laura , Young Neil , Walsh Timothy , Laffan Mike A.
Published: April 2018

BACKGROUND

Prolongation of prothrombin time (PT) is often recorded in critical illness, but has limited ability to predict risk of bleeding. This exploratory study was aimed at assessing a role for thrombin generation (TG) to predict bleeding.

STUDY DESIGN AND METHODS

TG was measured by calibrated automated thrombography in admissions to intensive care with prolonged PT. Bleeding events were recorded up to Day 5 after enrollment and correlated with results of PT ratio (PTR) and variables of TG.

RESULTS

A total of 306 patients were recruited. A total of 101 bleeding events developed in 46 patients during the period of observation. Many patients with prolonged PT had endogenous thrombin potential (ETP), which was within the normal range (120/251 patients, 47.8%) or even elevated (8%). Although some patients had a reduction in ETP or peak thrombin, these were present over a wide range of PTR. There was no suggestion by receiver operating characteristic analysis that variables of conventional TG were sensitive at predicting bleeding. No bleeding events were documented in patients defined as ETP high, despite elevated PTR.

CONCLUSION

Future studies need to explore a role for alternatives tests of coagulation in critical illness. Development of TG assays is required to positively identify more patients at increased bleeding risk or to exclude a larger number at low risk and how this relates to subgroups, such as patients with liver disease, and the need for prophylactic plasma transfusion.
An immersed interface method for the solution of the standard parabolic equation in range-dependent ocean environments
Authors: Sabatini Roberto , Cristini Paul
Published: April 2018

A numerical approach for the treatment of irregular ocean bottoms within the framework of the standard parabolic equation is proposed. The present technique is based on the immersed interface method originally developed by LeVeque and Li [(1994). SIAM J. Numer. Anal. 31(4), 1019–1044]. The method conserves energy to high order accuracy and naturally handles generic range-dependent bathymetries, without requiring any additional specific numerical procedure. An illustration of its capabilities is provided by solving the well-known wedge problem.
Light-induced dynamic structural color by intracellular 3D photonic crystals in brown algae
Authors: Lopez-Garcia Martin , Masters Nathan , O’Brien Heath E. , Lennon Joseph , Atkinson George , Cryan Martin J. , Oulton Ruth , Whitney Heather M.
Published: April 2018

A photosynthetic algal intracellular organelle containing a living opal responds dynamically to environmental illumination.
Isoprene photo-oxidation products quantify the effect of pollution on hydroxyl radicals over Amazonia
Authors: Liu Yingjun , Seco Roger , Kim Saewung , Guenther Alex B. , Goldstein Allen H. , Keutsch Frank N. , Springston Stephen R. , Watson Thomas B. , Artaxo Paulo , Souza Rodrigo A. F. , McKinney Karena A. , Martin Scot T.
Published: April 2018

Observational evidence of isoprene oxidation shows that nitrogen oxides amplify the OH concentrations over the Amazon forest.
Increased neutrophil extracellular trap formation promotes thrombosis in myeloproliferative neoplasms
Authors: Wolach Ofir , Sellar Rob S. , Martinod Kimberly , Cherpokova Deya , McConkey Marie , Chappell Ryan J. , Silver Alexander J. , Adams Dylan , Castellano Cecilia A. , Schneider Rebekka K. , Padera Robert F. , DeAngelo Daniel J. , Wadleigh Martha , Steensma David P. , Galinsky Ilene , Stone Richard M. , Genovese Giulio , McCarroll Steven A. , Iliadou Bozenna , Hultman Christina , Neuberg Donna , Mullally Ann , Wagner Denisa D. , Ebert Benjamin L.
Published: April 2018

Thrombosis in myeloproliferative neoplasms is associated with increased NETosis that can be targeted with JAK inhibitors.
Dual inhibition of MDMX and MDM2 as a therapeutic strategy in leukemia
Authors: Carvajal Luis A. , Neriah Daniela Ben , Senecal Adrien , Benard Lumie , Thiruthuvanathan Victor , Yatsenko Tatyana , Narayanagari Swathi-Rao , Wheat Justin C. , Todorova Tihomira I. , Mitchell Kelly , Kenworthy Charles , Guerlavais Vincent , Annis D. Allen , Bartholdy Boris , Will Britta , Anampa Jesus D. , Mantzaris Ioannis , Aivado Manuel , Singer Robert H. , Coleman Robert A. , Verma Amit , Steidl Ulrich
Published: April 2018

Dual inhibition of MDMX and MDM2 by an α-helical p53-stapled peptide (ALRN-6924) results in robust antitumor activity in acute myeloid leukemia.
Hematopoietic stem cell transplantation in its 60s: A platform for cellular therapies
Authors: Chabannon Christian , Kuball Jurgen , Bondanza Attilio , Dazzi Francesco , Pedrazzoli Paolo , Toubert Antoine , Ruggeri Annalisa , Fleischhauer Katharina , Bonini Chiara
Published: April 2018

This review summarizes the cellular therapy approaches stemming from hematopoietic stem cell transplantation, their challenges, and opportunities.
Adult neurogenesis in humans: Dogma overturned, again and again?
Authors: Andreae Laura C.
Published: April 2018

The controversy continues as to whether new neurons are born in adult human hippocampus.
Draft Genome Sequence of the Intimin-Positive Enteropathogenic Escherichia albertii Strain MBT-EA1, Isolated from Lettuce
Authors: Fiedler Gregor , Brinks Erik , Böhnlein Christina , Cho Gyu-Sung , Koberg Sabrina , Kabisch Jan , Franz Charles M. A. P.
Published: April 2018

The genome of the intimin (
eae
)-harboring
Escherichia albertii
strain MBT-EA1, isolated from lettuce in Germany, was sequenced. Sequence analysis showed the assembled draft genome size to be 4,560,948 bp, containing a predicted total of 4,414 protein-encoding genes, 11 rRNAs, and 82 tRNAs. Furthermore, three plasmid sequences were found.
Draft Genome Sequence of Raoultella ornithinolytica Strain HH3
Authors: Huang Hongsheng , Duceppe Marc-Olivier , Phipps-Todd Beverley
Published: April 2018

Raoultella ornithinolytica
is a Gram-negative, nonmotile, encapsulated, and aerobic bacillus and an emerging hospital-related bacterial pathogen of humans. Here, we report a 5,977,517-bp draft genome sequence for
Raoultella ornithinolytica
strain HH3, isolated from a pretreatment sample collected at a Canadian wastewater treatment facility.
Draft Genome Sequence of the Mercury-Resistant Strain Acinetobacter baumannii I43
Authors: de Siqueira Kátia Aparecida , Mello Ivani Souza , Pietro-Souza William , Mendes Tiago Antônio de Oliveira , Soares Marcos Antônio
Published: April 2018

Here, we report the draft genome sequence of the
Acinetobacter baumannii
strain I43, which is highly resistant to mercury. The Illumina-based sequence analysis revealed a genome of approximately 4,520,353 bp composed of 4,091 coding sequences.
Draft Genome Sequence of Actinobacterial Strain Kineosporia sp. R_H_3, a Neutrophilic Iron-Depositing Bacterium
Authors: Braun Burga , Künzel Sven , Schröder Josephin , Szewzyk Ulrich
Published: April 2018

The draft genome sequence of a neutrophilic iron-depositing actinobacterial strain,
Kineosporia
sp. R_H_3, is reported here. Detailed analysis of the genome can elucidate the role of specific cytochromes for Fe oxidation and how this organism might receive energy from Fe oxidation. To date, this is the second publicly available genome sequence of a
Kineosporia
strain.
Using machine learning techniques to develop forecasting algorithms for postoperative complications: protocol for a retrospective study
Authors: Fritz Bradley A , Chen Yixin , Murray-Torres Teresa M , Gregory Stephen , Ben Abdallah Arbi , Kronzer Alex , McKinnon Sherry Lynn , Budelier Thaddeus , Helsten Daniel L , Wildes Troy S , Sharma Anshuman , Avidan Michael Simon
Published: April 2018

Introduction

Mortality and morbidity following surgery are pressing public health concerns in the USA. Traditional prediction models for postoperative adverse outcomes demonstrate good discrimination at the population level, but the ability to forecast an individual patient’s trajectory in real time remains poor. We propose to apply machine learning techniques to perioperative time-series data to develop algorithms for predicting adverse perioperative outcomes.

Methods and analysis

This study will include all adult patients who had surgery at our tertiary care hospital over a 4-year period. Patient history, laboratory values, minute-by-minute intraoperative vital signs and medications administered will be extracted from the electronic medical record. Outcomes will include in-hospital mortality, postoperative acute kidney injury and postoperative respiratory failure. Forecasting algorithms for each of these outcomes will be constructed using density-based logistic regression after employing a Nadaraya-Watson kernel density estimator. Time-series variables will be analysed using first and second-order feature extraction, shapelet methods and convolutional neural networks. The algorithms will be validated through measurement of precision and recall.

Ethics and dissemination

This study has been approved by the Human Research Protection Office at Washington University in St Louis. The successful development of these forecasting algorithms will allow perioperative healthcare clinicians to predict more accurately an individual patient’s risk for specific adverse perioperative outcomes in real time. Knowledge of a patient’s dynamic risk profile may allow clinicians to make targeted changes in the care plan that will alter the patient’s outcome trajectory. This hypothesis will be tested in a future randomised controlled trial.
What attributions do Australian high-performing general practices make for their success? Applying the clinical microsystems framework: a qualitative study
Authors: Dunham Annette H , Dunbar James A , Johnson Julie K , Fuller Jeff , Morgan Mark , Ford Dale
Published: April 2018

Objectives

To identify the success attributions of high-performing Australian general practices and the enablers and barriers they envisage for practices wishing to emulate them.

Design

Qualitative study using semi-structured interviews and content analysis of the data. Responses were recorded, transcribed verbatim and coded according to success characteristics of high-performing clinical microsystems.

Setting

Primary healthcare with the participating general practices representing all Australian states and territories, and representing metropolitan and rural locations.

Participants

Twenty-two general practices identified as high performing via a number of success criteria. The 52 participants were 19 general practitioners, 18 practice managers and 15 practice nurses.

Results

Participants most frequently attributed success to the interdependence of the team members, patient-focused care and leadership of the practice. They most often signalled practice leadership, team interdependence and staff focus as enablers that other organisations would need to emulate their success. They most frequently identified barriers that might be encountered in the form of potential deficits or limitations in practice leadership, staff focus and mesosystem support.

Conclusions

Practice leaders need to empower their teams to take action through providing inclusive leadership that facilitates team interdependence. Mesosystem support for quality improvement in general practice should focus on enabling this leadership and team building, thereby ensuring improvement efforts are converted into effective healthcare provision.
Controlling the electromagnetic density of modes in one-dimensional photonic crystal with defect using acoustic wave
Authors: Aman Ayush , Prasad S.
Published: April 2018

We have theoretically analyzed the effect of acoustic parameters on the electromagnetic density of modes (DOM) in a one-dimensional photonic crystal featuring a defect mode. The whole structure is modulated by a longitudinal acoustic wave. The transfer matrix method and Wigner time approach are used to calculate the transmittance and electromagnetic DOM, respectively. The results show that the electromagnetic DOM is dynamically controlled by the acoustic amplitude. A sharp peak in DOM is found at the defect site whose magnitude decreases with the increase in acoustic amplitude and shows periodic swing with fractional change in time period of acoustic wave. Furthermore, the result of polarization of electromagnetic wave is also discussed and it is found that the location of the defect mode can be modulated in a large frequency rage without changing the structure of the photonic crystal.
Constraining extended scalar sectors at the LHC and beyond
Authors: Ilnicka Agnieszka , Robens Tania , Stefaniak Tim
Published: April 2018

We give a brief overview of beyond the Standard Model (BSM) theories with an extended scalar sector and their phenomenological status in the light of recent experimental results. We discuss the relevant theoretical and experimental constraints, and show their impact on the allowed parameter space of two specific models: the real scalar singlet extension of the Standard Model (SM) and the Inert Doublet Model. We emphasize the importance of the LHC measurements, both the direct searches for additional scalar bosons, as well as the precise measurements of properties of the Higgs boson of mass 125 GeV. We show the complementarity of these measurements to electroweak and dark matter observables.
Measuring Corporate Social Responsibility Based on Fuzzy Analytic Networking Process-Based Balance Scorecard Model
Authors: Debnath Animesh , Roy Jagannath , Chatterjee Kajal , Kar Samarjit
Published: April 2018

Over the last few decades, Corporate Social Responsibility (CSR) disclosures become a powerful driver of overall stakeholders’ development while the relationship between CSR and its performance has provided conflicting results due to the most used intersecting circle representation of assessment of CSR. This study fills an important gap by analyzing the framework of CSR assessment practices on identification of five criteria and 17 indicators encompassing the strategies of accountability, transparency and compliance of CSR. To achieve the goal of CSR, the strategies have been defined in connection with different literatures and quaternary survey for criteria selection, where the criteria are expressed in a fuzzy horizon. This multi-criteria decision-making (MCDM) model has been solved using a fuzzy analytical networking process and balanced scorecard (BSC) method to develop selection strategy and criteria for implementation of CSR. The paper’s outcomes help administrators of corporate sectors, particularly in developing countries, to follow sustainable actions as CSR providers effectively and to gain a significant reasonable advantage. The findings exposed the CSR assessment structure and interrelationships among BSC perspectives/criteria and indicators on which managers are needed to emphasize to get optimum CSR performance. In this study, the most important strategy and criteria to perform optimum CSR level are as follows: “accountability of CSR project” is the best strategy; “Project team work, incentives, Environmental resources, Communication for motivation, Reporting initiative of stockholders, CSR project with stockholder capital, Strategic governance, Mission sustainability, political role, Human resources”, respectively, are criteria.
Digital Educational Games
Authors: Heintz Stephanie , Law Effie L.-C.
Published: April 2018

Our main research question is how the choice of game type influences the success of digital educational games (DEGs), where success is defined as significant domain-specific knowledge gain (learning outcome) with positive player experience.

We propose a methodological framework to address this question. The comparison of different game types is based on the previously developed Game Elements-Attributes Model (GEAM) and the Game Genre Map, which summarise game features and their relations. In addition, we present a research model considering the impact of player characteristics on learning outcome and player experience as well as their interrelation.

Two empirical studies were conducted with 280 students. The application domain was computer programming. Study 1 compared three DEGs of the Mini-Game genre, differing in a single GEAM attribute—time pressure vs. puzzle solving and abstract vs. realistic settings. Study 2 compared DEGs of different genres, which vary in the implementation of several GEAM attributes. None of the player characteristics were found to be statistically significant factors. For both studies, significant differences were found in learning outcomes, for Study 2 also in some of the player experience dimensions. GEAM was demonstrated as a promising framework for games user research.
Arterial Venous Differentiation for Vascular Bioengineering
Authors: Niklason Laura , Dai Guohao
Published: April 2018

The development processes of arteries and veins are fundamentally different, leading to distinct differences in anatomy, structure, and function as well as molecular profiles. Understanding the complex interaction between genetic and epigenetic pathways, as well as extracellular and biomechanical signals that orchestrate arterial venous differentiation, is not only critical for the understanding of vascular diseases of arteries and veins but also valuable for vascular tissue engineering strategies. Recent research has suggested that certain transcriptional factors not only control arterial venous differentiation during development but also play a critical role in adult vessel function and disease processes. This review summarizes the signaling pathways and critical transcription factors that are important for arterial versus venous specification. We focus on those signals that have a direct relation to the structure and function of arteries and veins, and have implications for vascular disease processes and tissue engineering applications.
Time course of red blood cell intracellular pH recovery following short-circuiting in relation to venous transit times in rainbow trout,Oncorhynchus mykiss
Authors: Harter Till S. , May Alexandra G. , Federspiel William J. , Supuran Claudiu T. , Brauner Colin J.
Published: April 2018

Accumulating evidence is highlighting the importance of a system of enhanced hemoglobin-oxygen (Hb-O2) unloading for cardiovascular O2transport in teleosts. Adrenergically stimulated sodium-proton exchangers (β-NHE) create H+gradients across the red blood cell (RBC) membrane that are short-circuited in the presence of plasma-accessible carbonic anhydrase (paCA) at the tissues; the result is a large arterial-venous pH shift that greatly enhances O2unloading from pH-sensitive Hb. However, RBC intracellular pH (pHi) must recover during venous transit (31–90 s) to enable O2loading at the gills. The halftimes ( t1/2) and magnitudes of RBC β-adrenergic stimulation, short-circuiting with paCA and recovery of RBC pHi, were assessed in vitro, on rainbow trout whole blood, and using changes in closed-system partial pressure of O2as a sensitive indicator for changes in RBC pHi. In addition, the recovery rate of RBC pHiwas assessed in a continuous-flow apparatus that more closely mimics RBC transit through the circulation. Results indicate that: 1) the t1/2of β-NHE short-circuiting is likely within the residence time of blood in the capillaries, 2) the t1/2of RBC pHirecovery is 17 s and within the time of RBC venous transit, and 3) after short-circuiting, RBCs reestablish the initial H+gradient across the membrane and can potentially undergo repeated cycles of short-circuiting and recovery. Thus, teleosts have evolved a system that greatly enhances O2unloading from pH-sensitive Hb at the tissues, while protecting O2loading at the gills; the resulting increase in O2transport per unit of blood flow may enable the tremendous athletic ability of salmonids.
Development, form, and function of the mouse visual thalamus
Authors: Guido William
Published: April 2018

The dorsal lateral geniculate nucleus (dLGN) of the thalamus is the exclusive relay of retinal information en route to the visual cortex. Although much of our understanding about dLGN comes from studies done in higher mammals, such as the cat and primate, the mouse as a model organism has moved to the forefront as a tractable experimental platform to examine cell type-specific relations. This review highlights our current knowledge about the development, structure, and function of the mouse dLGN.
State anxiety disorganizes finger movements during musical performance
Authors: Kotani Shuntaro , Furuya Shinichi
Published: April 2018

Skilled performance, in many situations, exposes an individual to psychological stress and fear, thus triggering state anxiety and compromising motor dexterity. Suboptimal skill execution in people under pressure affects the future career prospects of trained individuals, such as athletes, clinicians, and musicians. However, it has not been elucidated in what manner state anxiety affects multijoint movements and thereby degrades fine motor control. Using principal component analysis of hand kinematics recorded by a data glove during piano performances, we tested whether state anxiety affects the organization of movements of multiple joints or merely constrains the amplitude of the individual joints without affecting joint movement coordination. The result demonstrated changes in the coordination of movements across joints in piano performances by experts under psychological stress. Overall, the change was characterized by reduction of synergistic movements between the finger responsible for the keypress and its adjacent fingers. A regression analysis further identified that the attenuation of the movement covariation between the fingers was associated with an increase in temporal error during performance under pressure. In contrast, neither the maximum nor minimum angles of the individual joints of the hand were susceptible to induced anxiety. These results suggest that degradation of fine motor control under pressure is mediated by incoordination of movements between the fingers in skilled piano performances.

NEW & NOTEWORTHY A key issue in neuromuscular control of coordinated movements is how the nervous system organizes multiple degrees of freedom for production of skillful motor behaviors. We found that state anxiety disorchestrates the organization of finger movements so as to decrease synergistic motions between the fingers in musical performance, which degrades fine motor control. The findings are important to shed light on mechanisms underlying loss of motor dexterity under pressure.
MicroRNA-126 Priming Enhances Functions of Endothelial Progenitor Cells under Physiological and Hypoxic Conditions and Their Therapeutic Efficacy in Cerebral Ischemic Damage
Authors: Pan Qunwen , Zheng Jieyi , Du Donghui , Liao Xiaorong , Ma Chunlian , Yang Yi , Chen Yanyu , Zhong Wangtao , Ma Xiaotang
Published: April 2018

Endothelial progenitor cells (EPCs) have shown the potential for treating ischemic stroke (IS), while microRNA-126 (miR-126) is reported to have beneficial effects on endothelial function and angiogenesis. In this study, we investigated the effects of miR-126 overexpression on EPCs and explore the efficacy of miR-126-primed EPCs (EPCmiR-126) in treating IS. The effects of miR-126 overexpression on EPC proliferation, migratory, tube formation capacity, reactive oxygen species (ROS) production, and nitric oxide (NO) generation were determined. In in vivo study, the effects of EPCmiR-126 on the cerebral blood flow (CBF), neurological deficit score (NDS), infarct volume, cerebral microvascular density (cMVD), and angiogenesis were determined. Moreover, the levels of circulating EPCs (cEPCs) and their contained miR-126 were measured. We found (1) miR-126 overexpression promoted the proliferation, migration, and tube formation abilities of EPCs; decreased ROS; and increased NO production of EPCs via activation of PI3K/Akt/eNOS pathway; (2) EPCmiR-126 was more effective than EPCs in attenuating infarct volume and NDS and enhancing cMVD, CBF, and angiogenesis; and (3) infusion of EPCmiR-126 increased the number and the level of miR-126 in cEPCs. Our data indicate that miR-126 overexpression enhanced the function of EPCs in vitro and in vivo.
Dowel Behavior of Rebars in Small Concrete Block for Sliding Slab Track on Railway Bridges
Authors: Lee Seong-Cheol , Park Sangmin , Lee Jaeha , Lee Kyoung-Chan
Published: April 2018

In recent years, several studies have investigated the sliding slab track for railway bridges. In the design of sliding slab tracks, one of the most important considerations is to evaluate the shear capacity of the lateral supporting concrete blocks in which dowel rebars are embedded. The predictions of the dowel behavior of rebars by existing models are considerably different. Therefore, in this study, the actual dowel behavior of the rebars embedded in a small concrete block was extensively investigated through experiments. Test variables were concrete compressive strength, dowel rebar diameter and yield strength, specimen thickness, and dowel rebar spacing. Existing model predictions were considerably different from test results. The maximum dowel force increased as concrete compressive strength and dowel rebar diameter increased, while it did not increase considerably with other test variables. Unlike in existing models, the shear slip at the maximum dowel force decreased as the dowel rebar diameter increased. Existing models significantly underestimated the maximum dowel force of the dowel rebars with small diameters and overestimated it for the dowel rebars with large diameters. This work can be useful for developing a more rational model to represent the actual dowel behavior of the rebars embedded in small concrete blocks.
Threshold Selection for POT Framework in the Extreme Vehicle Loads Analysis Based on Multiple Criteria
Authors: Wu Guangrun , Qiu Wenliang
Published: April 2018

Extreme value of vehicle load plays an important role in bridge design and risk assessment. Peaks over threshold (POT) is a method commonly used in extreme load estimation. The selection of thresholds for the POT method is extremely crucial, but the selected optimal threshold varies under different test criteria. Therefore, a method to select the suitable threshold is developed based on multiple criteria decision analysis (MCDA) in the paper. In MCDA, Chi‐Square (χ2) test, Kolmogorov–Smirnov (K–S) test, and Root Mean Square Error (RMSE) in probability distribution functions (PDF) are employed as the test criteria and the weight of these criteria is calculated using the entropy method. Finally, vehicle loads obtained from simulation and field measurement are adopted to validate the effectiveness and feasibility of the proposed method. The results indicate that the proposed MCDA is a useful and complementary tool for threshold selection in the extreme value analysis.
Effect of Deformation Structure and Annealing Temperature on Corrosion of Ultrafine-Grain Fe-Cr Alloy Prepared by Equal Channel Angular Pressing
Authors: Rifai Muhammad , Yuasa Motohiro , Miyamoto Hiroyuki
Published: April 2018

The effect of the deformation structure and annealing temperature on the corrosion of ultrafine-grain (UFG) Fe-Cr alloys with 8 to 12% Cr prepared by equal channel angular pressing (ECAP) was investigated with particular emphasis on the stability of the passivation layer. Fe-Cr alloys were processed by ECAP using up to eight passes at 423 K by the Bc route, followed by annealing at temperatures of 473 to 1173 K for 1 h. Passivity appeared in all alloys as a result of ECAP, and the stability of the passivation layer was evaluated by anodic polarization measurements in a 1000 mol·m−3NaCl solution. The stability of the passivation layer increased as the degree of deformation became more extensive with successive ECAP passes, and distinct escalation occurred with the formation of a UFG microstructure. In the early stages of annealing at moderate temperatures, the stability of the passivation layer deteriorated, although no visible grain growth occurred, and this effect increased monotonically with increasing annealing temperature. The high degree of stability of the passivation layer on UFG alloys following ECAP can be attributed to the large number of high-angle nonequilibrium grain boundaries, which may lead to Cr enrichment of the surface region. The deterioration of the passivation layer in the early stages of annealing may be attributed to a change in the grain boundaries to an equilibrium state. The present results show that the superiority of as-ECAPed materials of the Fe-Cr alloy to recovered ones by heat treatment can be achieved with 8–10% Cr as observed in 20% Cr.
Estimation and Modeling of Fluctuating Wind Amplitude and Phase Spectrum Using APES Algorithm Based on Field Monitored Data
Authors: Dan Dan-hui , Wang Xiang-jie , Yan Xing-fei , Cheng Wei
Published: April 2018

The fluctuating wind power spectrum (FWPS) in given specifications could only represent the second‐order probabilistic characteristic, which indicates that it is not capable of fully expressing the stochastic wind field. Estimation and modeling of the fluctuating wind amplitude spectrum (FWAS) as well as the fluctuating wind phase spectrum (FWPhS) by using measured wind velocity data can make up for the deficiencies mentioned above. A high‐resolution nonparametric spectral estimation algorithm—amplitude and phase estimation (APES)—is used to estimate the FWAS and the FWPhS, using the field measured wind velocity data of a certain cable‐stayed bridge in Shanghai, China. An empirical expression (eFWAS) is introduced by dimensional analysis to model the random FWAS, and its specific Davenport form is proposed according to field measured data. The parameters of the Davenport eFWAS model are estimated by using the above measured FWAS, and three specific applications of this model are put forward when different known conditions are met. Compared with the measured FWAS, the stochastic Davenport eFWAS model proposed in this paper can accurately describe the statistical properties of the local wind field and improve the modeling accuracy of the FWAS, which is important in antiwind structural design and safety assessment.
Stroke Subtype Clustering by Multifractal Bayesian Denoising with Fuzzy C Means and K‐Means Algorithms
Authors: Karaca Yeliz , Cattani Carlo , Moonis Majaz , Bayrak Şengül
Published: April 2018

Multifractal denoising techniques capture interest in biomedicine, economy, and signal and image processing. Regarding stroke data there are subtle details not easily detectable by eye physicians. For the stroke subtypes diagnosis, details are important due to including hidden information concerning the possible existence of medical history, laboratory results, and treatment details. Recently, K‐means and fuzzy C means (FCM) algorithms have been applied in literature with many datasets. We present efficient clustering algorithms to eliminate irregularities for a given set of stroke dataset using 2D multifractal denoising techniques (Bayesian (mBd), Nonlinear (mNold), and Pumping (mPumpD)). Contrary to previous methods, our method embraces the following assets: (a) not applying the reduction of the stroke datasets’ attributes, leading to an efficient clustering comparison of stroke subtypes with the resulting attributes; (b) detecting attributes that eliminate “insignificant” irregularities while keeping “meaningful” singularities; (c) yielding successful clustering accuracy performance for enhancing stroke data qualities. Therefore, our study is a comprehensive comparative study with stroke datasets obtained from 2D multifractal denoised techniques applied for K‐means and FCM clustering algorithms. Having been done for the first time in literature, 2D mBd technique, as revealed by results, is the most successful feature descriptor in each stroke subtype dataset regarding the mentioned algorithms’ accuracy rates.
Region-Dependent Alterations in Cognitive Function and ERK1/2 Signaling in the PFC in Rats after Social Defeat Stress
Authors: Wang Qiong , Shao Feng , Wang Weiwen
Published: April 2018

Cognitive dysfunctions are highly comorbid with depression. Impairments of cognitive flexibility, which are modulated by the monoaminergic system of the prefrontal cortex (PFC), are increasingly recognized as an important component of the pathophysiology and treatment of depression. However, the downstream molecular mechanisms remain unclear. Using a classical model of depression, this study investigated the effects of social defeat stress on emotional behaviors, on cognitive flexibility in the attentional set-shifting task (AST), and on the expression of extracellular signal-regulated kinase 1 and 2 (ERK1 and ERK2) and their downstream signaling molecules cAMP-response element binding protein (CREB) and brain-derived neurotrophic factor (BDNF) in two subregions of the PFC, the medial prefrontal cortex (mPFC), and the orbitofrontal cortex (OFC). The results showed that stress induced emotional and cognitive alterations associated with depression, including a decreased sucrose intake ratio and impaired reversal learning and set-shifting performance in the AST. Additionally, rats in the stress group showed a significant decrease only in ERK2 signaling in the mPFC, while more extensive decreases in both ERK1 signaling and ERK2 signaling were observed in the OFC. Along with the decreased ERK signaling, compared to controls, stressed rats showed downregulation of CREB phosphorylation and BDNF expression in both the OFC and the mPFC. Further analysis showed that behavioral changes were differentially correlated with several molecules in subregions of the PFC. These results suggested that social defeat stress was an effective animal model to induce both emotional and cognitive symptoms of depression and that the dysfunction of ERK signaling activities in the PFC might be a potential underlying biological mechanism.
Harnessing the Digital Exhaust: Incorporating Wellness into the Pharma Model
Authors: Wright Justin M. , Jones Graham Barry
Published: April 2018

The increasing availability of devices capable of tracking biomarkers presents major opportunities in contemporary healthcare. Herein we advocate a new role for the pharmaceutical industry to capitalize on these opportunities and, in doing so, incorporate wellness and patient engagement programs into their standard business models. Medical-grade decision-making using diagnostic, prognostic, and monitoring biomarkers will require coordinated approaches between the pharmaceutical and technology industries and the careful design of longitudinal clinical studies to validate their efficacy. These studies will also require data capture, archiving, curating, and sharing on a previously unprecedented scale, and raise additional concerns with regard to data security and ownership. Concurrently, systems-based approaches to the capture and interpretation of a new class of digital biomarkers are emerging, and they hold promise for heightened levels of patient engagement and remote sensing. Collectively, if these new opportunities are approached within the context of the patient-provider ecosystem, major repositioning of the pharmaceutical industry may be possible in the near future.
Angiopoietin-2, Renal Deterioration, Major Adverse Cardiovascular Events and All-Cause Mortality in Patients with Diabetic Nephropathy
Authors: Tsai Yi-Chun , Lee Chee-Siong , Chiu Yi-Wen , Lee Jia-Jung , Lee Su-Chu , Hsu Ya-Ling , Kuo Mei-Chuan
Published: April 2018

Background/Aims: Diabetic nephropathy is the leading cause of end-stage renal disease and accounts for 30∼40% of patients requiring maintenance dialysis, thereby increasing the burden on health insurance programs. Diabetic nephropathy is also the strongest predictor of cardiovascular morbidity and mortality. The aim of this study was to examine whether angiopoietin-2 (Angpt2), a modulator of endothelial function, affects the clinical outcomes of diabetic patients. Methods: This study enrolled 236 patients with diabetes mellitus with estimated glomerular filtration rate (eGFR) < 60ml/min/1.73m2 from January 2006 to December 2011, who were followed until June 2017. Clinical outcomes included renal outcomes (commencing dialysis and rapid decline in renal function (eGFR decline > 3 ml/min per 1.73 m2/year)), major adverse cardiovascular events (MACEs), and all-cause mortality. Results: Over a mean follow-up period of 3.9±2.7 years, 135 (57.2%) patients commenced dialysis, 106 (44.9%) had rapid decline in renal function, and 50 (21.2%) had MACEs or died from all-causes. Log-formed Angpt2 was significantly associated with increased risks of commencing dialysis (HR: 3.91, 95% CI: 1.56-9.76), rapid renal function decline (OR: 6.81, 95% CI: 1.06-43.88), and MACEs or all-cause mortality (HR: 6.34, 95% CI: 1.18-33.97) in the adjusted analysis. Patients in the highest quartile had hazard ratios of 2.90 and 3.11 for commencing dialysis and rapid renal function decline, respectively, compared to those in the lowest quartile after adjustments. Similar significant dose-response results were found in composite outcomes of either MACEs or all-cause mortality. Conclusion: Angpt2 is an independent predictor of adverse clinical outcomes in diabetic patients. Further studies are needed to identify the pathogenic role of Angpt2 in renal deterioration and cardiovascular complications of diabetes mellitus.
Pulmonary Effective Arterial Elastance as a Measure of Right Ventricular Afterload and Its Prognostic Value in Pulmonary Hypertension Due to Left Heart Disease
Authors: Tampakakis Emmanouil , Shah Sanjiv J. , Borlaug Barry A. , Leary Peter J. , Patel Harnish H. , Miller Wayne L. , Kelemen Benjamin W. , Houston Brian A. , Kolb Todd M. , Damico Rachel , Mathai Stephen C. , Kasper Edward K. , Hassoun Paul M. , Kass David A. , Tedford Ryan J.
Published: April 2018

Background:

Patients with combined post- and precapillary pulmonary hypertension due to left heart disease have a worse prognosis compared with isolated postcapillary. However, it remains unclear whether increased mortality in combined post- and precapillary pulmonary hypertension is simply a result of higher total right ventricular load. Pulmonary effective arterial elastance (Ea) is a measure of total right ventricular afterload, reflecting both resistive and pulsatile components. We aimed to test whether pulmonary Ea discriminates survivors from nonsurvivors in patients with pulmonary hypertension due to left heart disease and if it does so better than other hemodynamic parameters associated with combined post- and precapillary pulmonary hypertension.

Methods and Results:

We combined 3 large heart failure patient cohorts (n=1036) from academic hospitals, including patients with pulmonary hypertension due to heart failure with preserved ejection fraction (n=232), reduced ejection fraction (n=335), and a mixed population (n=469). In unadjusted and 2 adjusted models, pulmonary Ea more robustly predicted mortality than pulmonary vascular resistance and the transpulmonary gradient. Along with pulmonary arterial compliance, pulmonary Ea remained predictive of survival in patients with normal pulmonary vascular resistance. The diastolic pulmonary gradient did not predict mortality. In addition, in a subset of patients with echocardiographic data, Ea and pulmonary arterial compliance were better discriminators of right ventricular dysfunction than the other parameters.

Conclusions:

Pulmonary Ea and pulmonary arterial compliance more consistently predicted mortality than pulmonary vascular resistance or transpulmonary gradient across a spectrum of left heart disease with pulmonary hypertension, including patients with heart failure with preserved ejection fraction, heart failure with reduced ejection fraction, and pulmonary hypertension with a normal pulmonary vascular resistance.
Incidence, Predictors, and Outcomes Associated With Hypotensive Episodes Among Heart Failure Patients Receiving Sacubitril/Valsartan or Enalapril
Authors: Vardeny Orly , Claggett Brian , Kachadourian Jessica , Pearson Scott M. , Desai Akshay S. , Packer Milton , Rouleau Jean , Zile Michael R. , Swedberg Karl , Lefkowitz Martin , Shi Victor , McMurray John J.V. , Solomon Scott D.
Published: April 2018

Background:

In PARADIGM-HF (Prospective Comparison of Angiotensin Receptor Neprilysin Inhibitor With Angiotensin-Converting Enzyme Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure), heart failure treatment with sacubitril/valsartan reduced the primary composite outcome of cardiovascular death or heart failure hospitalization compared with enalapril but resulted in more symptomatic hypotension. Concern on hypotension may be limiting use of sacubitril/valsartan in appropriate patients.

Methods and Results:

We characterized patients in PARADIGM-HF by whether they reported hypotension during study run-in periods (enalapril, followed by sacubitril/valsartan) and after randomization and assessed whether hypotension modified the efficacy of sacubitril/valsartan. Of the 10 513 patients entering the enalapril run-in, 136 (1.3%) experienced hypotension and 93 (68%) were unable to continue to the next phase; of 9419 patients entering the sacubitril/valsartan run-in period, 228 (2.4%) patients experienced hypotension and 51% were unable to successfully complete the run-in. After randomization, 388 (9.2%) participants had 501 hypotensive events with enalapril, and 588 (14.0%) participants had 803 hypotensive events with sacubitril/valsartan (
P
<0.001). There was no difference between randomized treatment groups in the number of participants who discontinued therapy because of hypotension. Individuals with a hypotensive event in either group were older, had lower blood pressure at randomization, and were more likely to have an implantable cardioverter defibrillator. Participants with hypotensive events during run-in who were ultimately randomized derived similar efficacy from sacubitril/valsartan compared with enalapril as those without hypotensive events (
P
interaction>0.90).

Conclusions:

Hypotension was more common with sacubitril/valsartan relative to enalapril in PARADIGM-HF but did not differentially affect permanent discontinuations. Patients with hypotension during run-in derived similar benefit from sacubitril/valsartan compared with enalapril as those who did not experience hypotension.
Critical Role of Flavin and Glutathione in Complex I–Mediated Bioenergetic Failure in Brain Ischemia/Reperfusion Injury
Authors: Kahl Anja , Stepanova Anna , Konrad Csaba , Anderson Corey , Manfredi Giovanni , Zhou Ping , Iadecola Costantino , Galkin Alexander
Published: April 2018

Background and Purpose—

Ischemic brain injury is characterized by 2 temporally distinct but interrelated phases: ischemia (primary energy failure) and reperfusion (secondary energy failure). Loss of cerebral blood flow leads to decreased oxygen levels and energy crisis in the ischemic area, initiating a sequence of pathophysiological events that after reoxygenation lead to ischemia/reperfusion (I/R) brain damage. Mitochondrial impairment and oxidative stress are known to be early events in I/R injury. However, the biochemical mechanisms of mitochondria damage in I/R are not completely understood.

Methods—

We used a mouse model of transient focal cerebral ischemia to investigate acute I/R-induced changes of mitochondrial function, focusing on mechanisms of primary and secondary energy failure.

Results—

Ischemia induced a reversible loss of flavin mononucleotide from mitochondrial complex I leading to a transient decrease in its enzymatic activity, which is rapidly reversed on reoxygenation. Reestablishing blood flow led to a reversible oxidative modification of mitochondrial complex I thiol residues and inhibition of the enzyme. Administration of glutathione-ethyl ester at the onset of reperfusion prevented the decline of complex I activity and was associated with smaller infarct size and improved neurological outcome, suggesting that decreased oxidation of complex I thiols during I/R-induced oxidative stress may contribute to the neuroprotective effect of glutathione ester.

Conclusions—

Our results unveil a key role of mitochondrial complex I in the development of I/R brain injury and provide the mechanistic basis for the well-established mitochondrial dysfunction caused by I/R. Targeting the functional integrity of complex I in the early phase of reperfusion may provide a novel therapeutic strategy to prevent tissue injury after stroke.
“The Indian Factors: Kinship, Trade, and Authority in the Creek Nation & American South, 1740–1800”
Authors: Rindfleisch Bryan
Published: April 2018

This article explores the lives of the countless “Indian Factors” who straddled Native and European worlds during the eighteenth century. For the most part, these individuals were born of mixed unions between European men and Creek women, and were employed as traders and intermediaries in the deerskin trade and Creek-British politics. However, after the Seven Years’ War, Indian factors triggered a political contest within the Creek Nation, by empowering younger generations of men who challenged micos—the traditional leaders—for authority in their communities. Such tension led to increasing violence with Europeans and contributed to the revolutionary crisis in the South. After 1783, factors again evolved in response to the threat of the United States, this time as voices of Creek sovereignty. All in all, Indian factors embodied the multifaceted definitions and transformative changes that swept the Creek world and the American South during the eighteenth century.