bluuebunny/crossref_metadata_2025 huggingface dataset:
NMR and DFT Insight into the Synergistic Role of Bovine Serum Albumin–Ionic Liquid for Multicomponent Cascade Aldol/Knoevenagel–thia‐Michael/Michael Reactions in One Pot
Authors: Thopate Yogesh , Singh Richa , Sinha Arun K. , Kumar Vikash , Siddiqi Mohammad Imran
Published: September 2016

The synergistic combination of two catalysts is an emerging strategy towards the formation of unprecedented complex molecules, and herein bovine serum albumin (BSA) and the neutral ionic liquid 1‐butyl‐3‐methylimidazolium bromide ([bmim]Br) are used together for the first time towards multiple C−C and C−S bond‐formation reactions in one pot under metal‐free, acid‐free, and base‐free conditions by merging two classical named reactions, that is, aldol condensation (AC) and thia‐Michael addition (TMA) for the cascade chemoselective generation of β‐aryl‐β‐sulfido carbonyl compounds from aliphatic ketones, aromatic aldehydes, and thiols. NMR spectroscopy and DFT calculations studies provided insight into the synergism, progress, and mechanism of the reaction, and control experiments highlighted that the single catalysts (BSA or IL) alone did not allow even the first AC step to proceed. Moreover this synergistic BSA–[bmim]Br catalytic system offers the step‐economical synthesis of the anticoagulant warfarin through sequential aldol–Michael addition reactions and potent pyridine analogues through a Knoevenagel–Michael route. Besides, the recyclability of the catalytic system (up to 5 times) with the generation of water as a byproduct makes our one‐pot protocol more economically efficient and synthetically attractive than traditional methods.
Accelerating Pre‐stack Kirchhoff Time Migration by Manual Vectorization
Authors: Melo Alves Maicon , da Cruz Pestana Reynam , Alves Prado da Silva Rodrigo , Drummond Lúcia M. A.
Published: September 2016

The Pre‐stack Kirchhoff Time Migration (PKTM) is a central process in petroleum exploration. As PKTM is computationally intensive, many works have proposed the use of accelerators like GPU and FPGA to improve its execution time. On the other hand, although many off‐the‐shelf processors are endowed with a set of SIMD vector instructions, few papers tackle the problem considering vectorization and all of them consider that compilers can successfully vectorize the code. In this paper, we show that programming PKTM by using SIMD vector instructions manually is more efficient than the automatically and semi‐automatically vectorized codes, provided by a hardware specific compiler and library. Experiments considering both real and synthetic datasets showed that our solution is more than four times faster than the traditional code. It also outperformed automatically vectorized codes in all tests. We believe that the proposed strategy can be used together with the other ones to accelerate seismic migration methods in general without new investments in hardware. Copyright © 2016 John Wiley & Sons, Ltd.
Safety‐Critical Java: level 2 in practice
Authors: Luckcuck Matt , Wellings Andy , Cavalcanti Ana
Published: September 2016

Safety‐Critical Java (SCJ) is a profile of the Real‐Time Specification for Java that brings to the safety‐critical industry the possibility of using Java. SCJ defines three compliance levels: Level 0, Level 1 and Level 2. The SCJ specification is clear on what constitutes a Level 2 application in terms of its use of the defined API but not the occasions on which it should be used. This paper broadly classifies the features that are only available at Level 2 into three groups: nested mission sequencers, managed threads and global scheduling across multiple processors. We explore the first two groups to elicit programming requirements that they support. We identify several areas where the SCJ specification needs modifications to support these requirements fully; these include the following: support for terminating managed threads, the ability to set a deadline on the transition between missions and augmentation of the mission sequencer concept to support composibility of timing constraints. We also propose simplifications to the termination protocol of missions and their mission sequencers. To illustrate the benefit of our changes, we present excerpts from a formal model of SCJ Level 2 written in Circus, a state‐rich process algebra for refinement. Copyright © 2016 John Wiley & Sons, Ltd.
Automatic source‐to‐source error compensation of floating‐point programs: code synthesis to optimize accuracy and time
Authors: Thévenoux Laurent , Langlois Philippe , Martel Matthieu
Published: September 2016

Numerical programs with IEEE 754 floating‐point computations may suffer from inaccuracies because finite precision arithmetic is an approximation of real arithmetic. Solutions that reduce the loss of accuracy are available, such as compensated algorithms or double‐double precision floating‐point arithmetic. Our goal is to automatically improve the numerical quality of a numerical program with the smallest impact on its performance. We define and implement source code transformations in order to derive automatically compensated programs. We present several experimental results to compare the transformed programs and existing solutions. The transformed programs are as accurate and efficient as the implementations of compensated algorithms when the latter exist. Furthermore, we propose some transformation strategies allowing us to partially improve the accuracy of programs and to tune the impact on execution time. Trade‐offs between accuracy and performance are assured by code synthesis. Experimental results show that user‐defined trade‐offs are achievable in a reasonable amount of time, with the help of the tools we present in the paper. Copyright © 2016 John Wiley & Sons, Ltd.
Towards a multi‐layers anomaly detection framework for analyzing network traffic
Authors: Li Bo , Zhang Simin , Li Ke
Published: September 2016

Anomaly detection plays a crucial part in identifying unforeseen attacks for network and information security. However, the accuracy of existing network anomaly detection approaches is limited because of the lack of sufficient and high‐quality features. Most research works only take information from one network layer into account, which leads to a situation that some key features of other network layers are omitted. To address this issue, we propose a novel approach, named Multi‐Layers Anomaly Detection, which extracts and combines features from different network layers. In order to reduce redundancy and noise derived from the combination of multiple layers, an algorithm called RanPF is designed by applying principal components analysis (PCA) into random forest (RF) algorithm. RanPF uses features selected by PCA to decide the height of every tree in RF and provides a method to select which features for tree nodes to use according to the weights of principal components. To obtain high‐quality features, we adopt an attribute learning mechanism. Naive Bayes is used to characterize the attribute information, which is fast and simple compared with other learning algorithms such as SVM. In addition, a series of experiments conducted on two real‐life datasets demonstrate that our approach outperforms the state‐of‐the‐art methods in terms of detection rate and false alarm rate. MLAD achieves about 99% detection rate and about 0.6% false alarm rate on average when the ratio of the training set is 60%. Copyright © 2016 John Wiley & Sons, Ltd.
Systematic adaptation of stencil‐based 3D MPDATA to GPU architectures
Authors: Rojek Krzysztof , Wyrzykowski Roman , Kuczynski Lukasz
Published: September 2016

In this work, we focus on a systematic adaptation of the stencil‐based multidimensional positive definite advection transport algorithm (MPDATA) to different graphics processing unit (GPU)‐based computing platforms. Another objective of this work is to compare the performance of MPDATA on several platforms, including a multi‐GPU system with two NVIDIA Tesla K80 cards, and single‐card platforms with Tesla K20X, GeForce GTX TITAN, and GeForce GTX 980. The usage of the following optimization methods is proposed to improve the overall performance: (i) reducing the number of operations by the subexpression elimination when implementing 2.5D blocking; (ii) reorganization of boundary conditions for reducing branch instructions; (iii) advanced memory management to increase the coalesced memory access; and (iv) warps rearrangement for optimizing the data access to GPU global memory. The presented methods of the MPDATA adaptation to GPU architectures allow us to efficiently use many graphics processors within a single node by applying peer‐to‐peer data transfers between GPU global memories. We propose an auto‐tuning procedure to compensate architectural differences between the considered platforms. This procedure takes into account algorithm/GPU‐specific parameters. The proposed approach to adaptation of MPDATA to GPU architectures allows us to achieve up to 482.5 Gflop/s for the platform equipped with two NVIDIA K80 GPUs. Copyright © 2016 John Wiley & Sons, Ltd.
Encapsulated Ionic Liquids for CO2 Capture: Using 1‐Butyl‐methylimidazolium Acetate for Quick and Reversible CO2 Chemical Absorption.
Authors: Moya Cristian , Alonso‐Morales Noelia , Gilarranz Miguel A. , Rodriguez Juan J. , Palomar Jose
Published: September 2016

The potential advantages of applying encapsulated ionic liquid (ENIL) to CO2 capture by chemical absorption with 1‐butyl‐3‐methylimidazolium acetate [bmim][acetate] are evaluated. The [bmim][acetate]‐ENIL is a particle material with solid appearance and 70 % w/w in ionic liquid (IL). The performance of this material as CO2 sorbent was evaluated by gravimetric and fixed‐bed sorption experiments at different temperatures and CO2 partial pressures. ENIL maintains the favourable thermodynamic properties of the neat IL regarding CO2 absorption. Remarkably, a drastic increase of CO2 sorption rates was achieved using ENIL, related to much higher contact area after discretization. In addition, experiments demonstrate reversibility of the chemical reaction and the efficient ENIL regeneration, mainly hindered by the unfavourable transport properties. The common drawback of ILs as CO2 chemical absorbents (low absorption rate and difficulties in solvent regeneration) are overcome by using ENIL systems.
A new method for maximum power extraction using a singular perturbation theory for a PMSG‐based wind turbine
Authors: Ganjefar Soheil , Mohammadi Ali
Published: September 2016

This study uses the singular perturbation theory to obtain a reduced‐order subsystem for a wind‐energy conversion system (WECS) based on use of a permanent magnet synchronous generator (PMSG) to extract maximum power from a WECS. The system consists of a variable‐speed wind turbine directly coupled to a PMSG, a diode bridge rectifier, a DC‐to‐DC boost converter, and a battery bank. Singular perturbation theory is used to decompose the dynamic system into slow and fast time scales. The optimal controller is then designed for singular and original systems and applied to the original system to achieve maximum power from a PMSG. Simulations using MatLab/Simulink show the effectiveness of the proposed control strategy for a PMSG based on the singular perturbation theory. © 2016 American Institute of Chemical Engineers Environ Prog, 36: 586–594, 2017
Controls on deep critical zone architecture: a historical review and four testable hypotheses
Authors: Riebe Clifford S. , Hahm W. Jesse , Brantley Susan L.
Published: September 2016

The base of Earth's critical zone (CZ) is commonly shielded from study by many meters of overlying rock and regolith. Though deep CZ processes may seem far removed from the surface, they are vital in shaping it, preparing rock for infusion into the biosphere and breaking Earth materials down for transport across landscapes. This special issue highlights outstanding challenges and recent advances of deep CZ research in a series of articles that we introduce here in the context of relevant literature dating back to the 1500s. Building on several contributions to the special issue, we highlight four exciting new hypotheses about factors that drive deep CZ weathering and thus influence the evolution of life‐sustaining CZ architecture. These hypotheses have emerged from recently developed process‐based models of subsurface phenomena including: fracturing related to subsurface stress fields; weathering related to drainage of bedrock under hydraulic head gradients; rock damage from frost cracking due to subsurface temperature gradients; and mineral reactions with reactive fluids in subsurface chemical potential gradients. The models predict distinct patterns of subsurface weathering and CZ thickness that can be compared with observations from drilling, sampling and geophysical imaging. We synthesize the four hypotheses into an overarching conceptual model of fracturing and weathering that occurs as Earth materials are exhumed to the surface across subsurface gradients in stress, hydraulic head, temperature, and chemical potential. We conclude with a call for a coordinated measurement campaign designed to comprehensively test the four hypotheses across a range of climatic, tectonic and geologic conditions. Copyright © 2016 John Wiley & Sons, Ltd.
Improved noninvasive prediction of liver fibrosis by liver stiffness measurement in patients with nonalcoholic fatty liver disease accounting for controlled attenuation parameter values
Authors: Petta Salvatore , Wong Vincent Wai‐Sun , Cammà Calogero , Hiriart Jean‐Baptiste , Wong Grace Lai‐Hung , Marra Fabio , Vergniol Julien , Chan Anthony Wing‐Hung , Di Marco Vito , Merrouche Wassil , Chan Henry Lik‐Yuen , Barbara Marco , Le‐Bail Brigitte , Arena Umberto , Craxì Antonio , de Ledinghen Victor
Published: September 2016

Liver stiffness measurement (LSM) frequently overestimates the severity of liver fibrosis in nonalcoholic fatty liver disease (NAFLD). Controlled attenuation parameter (CAP) is a new parameter provided by the same machine used for LSM and associated with both steatosis and body mass index, the two factors mostly affecting LSM performance in NAFLD. We aimed to determine whether prediction of liver fibrosis by LSM in NAFLD patients is affected by CAP values. Patients (n = 324) were assessed by clinical and histological (Kleiner score) features. LSM and CAP were performed using the M probe. CAP values were grouped by tertiles (lower 132‐298, middle 299‐338, higher 339‐400 dB/m). Among patients with F0‐F2 fibrosis, mean LSM values, expressed in kilopascals, increased according to CAP tertiles (6.8 versus 8.6 versus 9.4, P = 0.001), and along this line the area under the curve of LSM for the diagnosis of F3‐F4 fibrosis was progressively reduced from lower to middle and further to higher CAP tertiles (0.915, 0.848‐0.982; 0.830, 0.753‐0.908; 0.806, 0.723‐0.890). As a consequence, in subjects with F0‐F2 fibrosis, the rates of false‐positive LSM results for F3‐F4 fibrosis increased according to CAP tertiles (7.2% in lower versus 16.6% in middle versus 18.1% in higher). Consistent with this, a decisional flowchart for predicting fibrosis was suggested by combining both LSM and CAP values. Conclusions: In patients with NAFLD, CAP values should always be taken into account in order to avoid overestimations of liver fibrosis assessed by transient elastography. (Hepatology 2017;65:1145‐1155).
Forms and drivers of annual streamflow variability in the headwaters of Canadian Prairies during the 20th century
Authors: Nazemi Ali , Wheater Howard S. , Chun Kwok Pan , Bonsal Barrie , Mekonnen Muluneh
Published: September 2016

Headwater streamflows in the Rocky Mountain foothills are the key to water availability in the Canadian Prairies. Headwater characteristics, however, have been and continue to be subject to major variability and change. Here, we identify various forms of change in the annual mean streamflow and timing of the annual peak and attempt to distinguish between the effects of multiple drivers using a generalized regression scheme. Our investigation shows that the Pacific Decadal Oscillation (PDO) is the main driver of significant monotonic trends and shifts in the central tendency of annual mean streamflow in major headwaters. In parallel, the cumulative effects of non‐PDO climatic drivers and human‐induced land use and land management are the main causes of significant variations in the timing of the annual peak. Additional analyses show that time sequences with significant trends in annual mean streamflow and timing of the annual peak coincide with those that show significant trends in the PDO or non‐PDO component of the air temperature, respectively. The natural streamflow characteristics are substantially perturbed by anthropogenic river flow regulation, depending on the form of change and/or the level of regulation. Evidence suggests that the general tendency of human regulation is to alleviate the severity of above‐ and below‐average streamflow conditions; however, it may also intensify the variability in natural streamflow characteristics during drier years and/or those with earlier annual peak timing. These are circumstances to which the regional water resource system is vulnerable. Our findings are important for the provision of effective regional water resource management in the Canadian Prairies and contribute to a better understanding of the complex interactions between natural and anthropogenic drivers in coupled human–water systems.
Extracellular Phosphate Induces the Expression of Dentin Matrix Protein 1 Through the FGF Receptor in Osteoblasts
Authors: Nishino Jin , Yamazaki Miwa , Kawai Masanobu , Tachikawa Kanako , Yamamoto Keiko , Miyagawa Kazuaki , Kogo Mikihiko , Ozono Keiichi , Michigami Toshimi
Published: September 2016

Dentin matrix protein 1 (Dmp1) is an extracellular matrix protein involved in phosphate metabolism and biomineralization, and its expression markedly increases during the maturation of osteoblasts into osteocytes. We previously reported that an increased level of inorganic phosphate (Pi) in media up‐regulated the expression of Dmp1 in primary osteocytes isolated from mouse bones. In the present study, we found that elevated extracellular Pi strongly induced the expression of Dmp1 in osteoblasts and explored its underlying mechanism of action. In an osteoblastic cell line MC3T3‐E1, increases in extracellular Pi induced the phosphorylation of ERK1/2 and up‐regulated the expression of Dmp1, fibroblast growth factor 2 (Fgf2), and Fgf receptor 1 (Fgfr1). A co‐treatment with the MEK inhibitor U0126 abolished the increase in the expression of Dmp1 and Fgfr1 by elevated Pi, suggesting the involvement of the MEK/ERK pathway in this up‐regulation. Elevated extracellular Pi also resulted in the phosphorylation of FGF receptor substrate 2α (FRS2α), which was diminished by knockdown of Slc20a1 encoding Pit1 sodium‐phosphate co‐transporter. The co‐treatment with an inhibitor against FGFR (SU5402) abolished the up‐regulation of Dmp1 induced by elevated extracellular Pi. In primary osteoblasts, a treatment with 4 mM Pi transiently increased the expression of early growth response 1 (Egr1) before the up‐regulation of Dmp1. These results indicate that FGFR mediates the direct effects of extracellular Pi on the expression of Dmp1 in osteoblasts and enhance the close relationship between the signaling evoked by elevated extracellular Pi and FGF/FGFR signaling. J. Cell. Biochem. 118: 1151–1163, 2017. © 2016 Wiley Periodicals, Inc.
Human Brain Malignant Glioma (BMG‐1) 3D Aggregate Morphology and Screening for Cytotoxicity and Anti‐Proliferative Effects
Authors: Ravi Maddaly , Ramesh Aarthi , Pattabhi Aishwarya
Published: September 2016

Two interesting aspects of cell lines grown in 3 Dimensional (3D) conditions are their distinct morphology and production of extracellular matrix (ECM). Also, it is known that 3D aggregates have different susceptibilities to damage‐inducing agents compared to their 2D monolayer counterparts. We describe the effect of ECM on 3D aggregate morphology, the effect of cisplatin, bleomycin, and UV on the 3D aggregates and 2 Dimensional (2D) monolayers of the BMG‐1 cell line. We also present a rapid method for analyzing cytotoxicity and anti‐proliferative effects of 3D aggregates in 96‐well plates. We utilized a single‐step protocol using the dye resazurin. BMG‐1 cells formed floating aggregates on 1% agarose hydrogels. The extent of ECM formed by them was dependent on number of cells seeded irrespective of the seeding density, which in turn directed the 3D aggregate compactness. The 3D aggregates were less susceptible to cisplatin and UV‐induced cytotoxicity compared to 2D counterparts. The IC50 value of cisplatin was elevated at 210 μg/ml for the aggregates compared to 170 μg/ml for the monolayers. Exposure to UV for 0, 10, 20, and 30 min gave inhibition values of 2.98%, 8%, 22.99%, and 31.8% for the aggregates as compared to 3.06%, 7.5%, 39.4%, and 46.7% for the monolayers. While bleomycin‐induced effects were unapparent when analyzed by vital staining for the doses used, the rapid, single‐step method in 96‐well plates was able to provide a dose‐response for cytotoxicity and anti‐proliferative effects. Also, comparative analysis of results obtained from vital staining and the single‐step method demonstrates the reliability of the assay described. J. Cell. Physiol. 232: 685–690, 2017. © 2016 Wiley Periodicals, Inc.
My encounters with Krabbe disease: A personal recollection of a 40‐Year journey with young colleagues
Authors: Suzuki Kunihiko
Published: September 2016

In this hybrid of a personal essay and a subjective review, I am attempting to convey the sense of an adventure I myself experienced in exploring various aspects of Krabbe disease, which occupied a significant portion of my life as a biomedical researcher. This is meant to be a personal summary, and I have no pretense of this being an objective scholarly review. Since the first description of the disease by Krabbe 100 years ago, knowledge about the disease has advanced significantly. The main contributions from my laboratory, always the fruits of dedicated efforts of talented young colleagues, include the identification of the genetic defect as deficiency of galactosylceramidase, proposal of the psychosine hypothesis as the pathogenetic mechanism to explain the unique phenotypic characteristics of the disease, detailed delineations of the substrate specificities of the two lysosomal β‐galactosidases, discovery of the twitcher mutant as a convenient and useful mouse model, and identification of saposin A as a specific galactosylceramide activator protein and as the second causative gene for globoid cell leukodystrophy. Now, attempts are being made in many laboratories for meaningful therapy, unthinkable when I started working on this disease. Despite these advances, there are still many unknowns and uncertainties about Krabbe disease waiting to be clarified. © 2016 Wiley Periodicals, Inc.
Fluid levity of the cell: Role of membrane lipid architecture in genetic sphingolipidoses
Authors: D'Auria Ludovic , Bongarzone Ernesto R.
Published: September 2016

Sphingolipidoses arise from inherited loss of function of key enzymes regulating the sphingolipid (SL) metabolism and the accumulation of large quantities of these lipids in affected cells. Most frequently, toxicity is manifested in the nervous system, where survival and function of neurons and glial cells are most affected. Although detailed information is available on neuroglial alterations during terminal stages of the disease, the initial pathogenic mechanisms triggering neuropathology are largely unclear. Because they are key components of biological membranes, changes in the local concentration of SLs are likely to impact the organization of membrane domains and functions. This Commentary proposes that SL toxicity involves initial defects in the integrity of lipid domains, membrane fluidity, and membrane bending, leading to membrane deformation and deregulation of cell signaling and function. Understanding how SLs alter membrane architecture may provide breakthroughs for more efficient treatment of sphingolipidoses. © 2016 Wiley Periodicals, Inc.
Perspective on innovative therapies for globoid cell leukodystrophy
Authors: Ricca Alessandra , Gritti Angela
Published: September 2016

Globoid cell leukodystrophy (GLD), or Krabbe's disease, is a lysosomal storage disorder resulting from deficiency of the lysosomal hydrolase galactosylceramidase. The infantile forms are characterized by a unique relentless and aggressive progression with a wide range of neurological symptoms and complications. Here we review and discuss the basic concepts and the novel mechanisms identified as key contributors to the peculiar GLD pathology, highlighting their therapeutic implications. Then, we evaluate evidence from extensive experimental studies on GLD animal models that have highlighted fundamental requirements to obtain substantial therapeutic benefit, including early and timely intervention, high levels of enzymatic reconstitution, and global targeting of affected tissues. Continuous efforts in understanding GLD pathophysiology, the interplay between various therapies, and the mechanisms of disease correction upon intervention may allow advancing research with innovative approaches and prioritizing treatment strategies to develop more efficacious treatments. © 2016 Wiley Periodicals, Inc.
Zoledronate derivatives as potential inhibitors of uridine diphosphate‐galactose ceramide galactosyltransferase 8: A combined molecular docking and dynamic study
Authors: Pannuzzo Giovanna , Graziano Adriana Carol Eleonora , Pannuzzo Martina , Masman Marcelo Fabricio , Avola Rosanna , Cardile Venera
Published: September 2016

Krabbe's disease is a neurodegenerative disorder caused by deficiency of galactocerebrosidase activity that affects the myelin sheath of the nervous system, involving dysfunctional metabolism of sphingolipids. It has no cure. Because substrate inhibition therapy has been shown to be effective in some human lysosomal storage diseases, we hypothesize that a substrate inhibition therapeutic approach might be appropriate to allow correction of the imbalance between formation and breakdown of glycosphingolipids and to prevent pathological storage of psychosine. The enzyme responsible for the biosynthesis of galactosylceramide and psychosine is uridine diphosphate‐galactose ceramide galactosyltransferase (2‐hydroxyacylsphingosine 1‐β‐galactosyltransferase; UGT8; EC 2.4.1.45), which catalyzes the transferring of galactose from uridine diphosphate‐galactose to ceramide or sphingosine, an important step of the biosynthesis of galactosphingolipids. Because some bisphosphonates have been identified as selective galactosyltransferase inhibitors, we verify the binding affinity to a generated model of the enzyme UGT8 and investigate the molecular mechanisms of UGT8–ligand interactions of the bisphosphonate zoledronate by a multistep framework combining homology modeling, molecular docking, and molecular dynamics simulations. From structural information on UGTs’ active site stereochemistry, charge density, and access through the hydrophobic environment, the molecular docking procedure allowed us to identify zoledronate as a potential inhibitor of human ceramide galactosyltransferase. More importantly, zoledronate derivates were designed through computational modeling as putative new inhibitors. Experiments in vivo and in vitro have been planned to verify the possibility of using zoledronate and/or the newly identified inhibitors of UGT8 for a substrate inhibition therapy useful for treatment of Krabbe's disease and/or other lysosomal disorders. © 2016 Wiley Periodicals, Inc.
How membrane dysfunction influences neuronal survival pathways in sphingolipid storage disorders
Authors: Sural‐Fehr Tuba , Bongarzone Ernesto R.
Published: September 2016

Sphingolipidoses are a class of inherited diseases that result from the toxic accumulation of undigested sphingolipids in lysosomes and other cellular membranes. Sphingolipids are particularly enriched in cells of the nervous system, and their excessive accumulation during disease has a significant impact on the nervous system. Neuronal dysfunction followed by neurological compromise is a common feature in many of these diseases; however, the underlying mechanisms that cause vulnerability of neurons are not fully understood. The plasma membrane plays a critical role in regulating cellular survival pathways, and its dysfunction has been implicated in neuronal failure in various adult‐onset neuropathies. In the context of sphingolipidoses, we hypothesize that gradual accumulation of undigested lipids in plasma membranes causes local disruptions in lipid raft domains, leading to deregulation of multiple signaling pathways important for neuronal survival and function. We propose that defects in downstream signaling as a result of membrane dysfunction are common mechanisms underlying neuronal vulnerability in sphingolipid storage disorders with neurological compromise. © 2016 Wiley Periodicals, Inc.
Axonal pathology in Krabbe's disease: The cytoskeleton as an emerging therapeutic target
Authors: Nogueira‐Rodrigues Joana , Brites Pedro , Sousa Mónica Mendes
Published: September 2016

In Krabbe's disease (KD), demyelination and myelin‐independent axonal and neuronal defects contribute to the severe neuropathology. The toxic substrate that accumulates in this disease, psychosine, induces alterations in membrane lipid rafts with downstream consequences to cellular signaling pathways that include impaired protein kinase C, ERK, and AKT‐glycogen synthase kinase‐3β (GSK3β) activation. In addition to impaired recruitment of signaling proteins to lipid rafts, endocytosis and axonal transport are affected in KD. Defects in AKT‐GSK3β activation, a central pathway regulating microtubule stability, together with alterations in neurofilaments and microtubules and severely defective axonal transport, highlight the importance of the neuronal cytoskeleton in KD. This Review critically discusses these primary neuronal defects as well as new windows for action opened by their identification that may contribute to effectively correct the neuropathology that underlies this disorder. © 2016 Wiley Periodicals, Inc.
A microglial hypothesis of globoid cell leukodystrophy pathology
Authors: Nicaise Alexandra M. , Bongarzone Ernesto R. , Crocker Stephen J.
Published: September 2016

Globoid cell leukodystrophy (GLD), also known as Krabbe's disease, is a fatal demyelinating disease accompanied by the formation of giant, multinucleated cells called globoid cells. Previously believed to be a byproduct of inflammation, these cells can be found early in disease before evidence of any damage. The precise mechanism by which these globoid cells cause oligodendrocyte dysfunction is not completely understood, nor is their cell type defined. This Review outlines the idea that microglial cells are transformed into an unknown and undefined novel M3 phenotype in GLD, which is cytotoxic to oligodendrocytes, leading to disease progression. © 2016 Wiley Periodicals, Inc.
Newborn screening for Krabbe's disease
Authors: Orsini Joseph J. , Saavedra‐Matiz Carlos A. , Gelb Michael H. , Caggana Michele
Published: September 2016

Live newborn screening for Krabbe's disease (KD) was initiated in New York on August 7, 2006, and started in Missouri in August, 2012. As of August 7, 2015, nearly 2.5 million infants had been screened, and 443 (0.018%) infants had been referred for followup clinical evaluation; only five infants had been determined to have KD. As of August, 2015, the combined incidence of infantile KD in New York and Missouri is ∼1 per 500,000; however, patients who develop later‐onset forms of KD may still emerge. This Review provides an overview of the processes used to develop the screening and followup algorithms. It also includes updated results from screening and discussion of observations, lessons learned, and suggested areas for improvement that will reduce referral rates and the number of infants defined as at risk for later‐onset forms of KD. Although current treatment options for infants with early‐infantile Krabbe's disease are not curative, over time treatment options should improve; in the meantime, it is essential to evaluate the lessons learned and to ensure that screening is completed in the best possible manner until these improvements can be realized. © 2016 Wiley Periodicals, Inc.
Metabolic profiling reveals biochemical pathways and potential biomarkers associated with the pathogenesis ofKrabbe disease
Authors: Weinstock Nadav I. , Wrabetz Lawrence , Feltri M. Laura , Shin Daesung
Published: September 2016

Krabbe disease (KD) is caused by mutations in the galactosylceramidase (GALC) gene, which encodes a lysosomal enzyme that degrades galactolipids, including galactosylceramide and galactosylsphingosine (psychosine). GALC deficiency results in progressive intracellular accumulation of psychosine, which is believed to be the main cause for the demyelinating neurodegeneration in KD pathology. Umbilical cord blood transplantation slows disease progression when performed presymptomatically but carries a significant risk of morbidity and mortality. Accurate presymptomatic diagnosis is therefore critical to facilitate the efficacy of existing transplant approaches and to avoid unnecessary treatment of children who will not develop KD. Unfortunately, current diagnostic criteria, including GALC activity, genetic analysis, and psychosine measurement, are insufficient for secure presymptomatic diagnosis. This study performs a global metabolomic analysis to identify pathogenetic metabolic pathways and novel biomarkers implicated in the authentic mouse model of KD known astwitcher. At a time point before onset of signs of disease, twitcher hindbrains had metabolic profiles similar to WT, with the exception of a decrease in metabolites related to glucose energy metabolism. Many metabolic pathways were altered after early signs of disease in the twitcher, including decreased phospholipid turnover, restricted mitochondrial metabolism of branched‐chain amino acids, increased inflammation, and changes in neurotransmitter metabolism and osmolytes. Hypoxanthine, a purine derivative, is increased before signs of disease appear, suggesting its potential as a biomarker for early diagnosis of KD. Additionally, given the early changes in glucose metabolism in the pathogenesis of KD, diagnostic modalities that report metabolic function, such as positron emission tomography, may be useful in KD. © 2016 Wiley Periodicals, Inc.
Gene therapy for metachromatic leukodystrophy
Authors: Rosenberg Jonathan B. , Kaminsky Stephen M. , Aubourg Patrick , Crystal Ronald G. , Sondhi Dolan
Published: September 2016

Leukodystrophies (LDs) are rare, often devastating genetic disorders with neurologic symptoms. There are currently no disease‐specific therapeutic approaches for these diseases. In this review we use metachromatic leukodystrophy as an example to outline in the brief the therapeutic approaches to MLD that have been tested in animal models and in clinical trials, such as enzyme‐replacement therapy, bone marrow/umbilical cord blood transplants, ex vivo transplantation of genetically modified hematopoietic stem cells, and gene therapy. These studies suggest that to be successful the ideal therapy for MLD must provide persistent and high level expression of the deficient gene, arylsulfatase A in the CNS. Gene therapy using adeno‐associated viruses is therefore the ideal choice for clinical development as it provides the best balance of potential for efficacy with reduced safety risk. Here we have summarized the published preclinical data from our group and from others that support the use of a gene therapy with AAVrh.10 serotype for clinical development as a treatment for MLD, and as an example of the potential of gene therapy for LDs especially for Krabbe disease, which is the focus of this special issue. © 2016 Wiley Periodicals, Inc.
Treatment for Krabbe's disease: Finding the combination
Authors: Mikulka Christina R. , Sands Mark S.
Published: September 2016

Globoid cell leukodystrophy (GLD) is an autosomal recessive neurodegenerative disorder caused by a deficiency of the lysosomal enzyme galactocerebrosidase (GALC). GALC is responsible for catabolism of certain glycolipids, including the toxic compound galactosylsphingosine (psychosine). Histological signs of disease include the widespread loss of myelin in the central and peripheral nervous systems, profound neruroinflammation, and axonal degeneration. Patients suffering from GLD also display neurological deterioration. Many different individual therapies have been investigated in the murine model of the GLD, the Twitcher mouse, with minimal success. The current standard of care for GLD patients, hematopoietic stem cell transplantation, serves only to delay disease progression and is not an effective cure. However, combination therapies that target different pathogenic mechanisms/pathways have been more effective at reducing histological signs of disease, delaying disease onset, prolonging life span, and improving behavioral/cognitive functions in rodent models of Krabbe's disease. In some cases, dramatic synergy between the various therapies has been observed. © 2016 Wiley Periodicals, Inc.
Intrathecal administration of AAV/GALC vectors in 10–11‐day‐old twitcher mice improves survival and is enhanced by bone marrow transplant
Authors: Karumuthil‐Melethil Subha , Marshall Michael S. , Heindel Clifford , Jakubauskas Benas , Bongarzone Ernesto R. , Gray Steven J.
Published: September 2016

Globoid cell leukodystrophy (GLD), or Krabbe disease, is an autosomal recessive neurodegenerative disease caused by the deficiency of the lysosomal enzyme galactocerebrosidase (GALC). Hematopoietic stem cell transplantation (HSCT) provides modest benefit in presymptomatic patients but is well short of a cure. Gene transfer experiments using viral vectors have shown some success in extending the survival in the mouse model of GLD, twitcher mice. The present study compares three single‐stranded (ss) AAV serotypes, two natural and one engineered (with oligodendrocyte tropism), and a self‐complementary (sc) AAV vector, all packaged with a codon‐optimized murine GALC gene. The vectors were delivered via a lumbar intrathecal route for global CNS distribution on PND10–11 at a dose of 2 × 1011 vector genomes (vg) per mouse. The results showed a similar significant extension of life span of the twitcher mice for all three serotypes (AAV9, AAVrh10, and AAV‐Olig001) as well as the scAAV9 vector, compared to control cohorts. The rAAV gene transfer facilitated GALC biodistribution and detectable enzymatic activity throughout the CNS as well as in sciatic nerve and liver. When combined with BMT from syngeneic wild‐type mice, there was significant improvement in survival for ssAAV9. Histopathological analysis of brain, spinal cord, and sciatic nerve showed significant improvement in preservation of myelin, with ssAAV9 providing the greatest benefit. In summary, we demonstrate that lumbar intrathecal delivery of rAAV/mGALCopt can significantly enhance the life span of twitcher mice treated at PND10–11 and that BMT synergizes with this treatment to improve the survival further. © 2016 Wiley Periodicals, Inc.
Lysosphingolipids and sphingolipidoses: Psychosine in Krabbe's disease
Authors: Spassieva Stefka , Bieberich Erhard
Published: September 2016

Until recently, lipids were considered inert building blocks of cellular membranes. This changed three decades ago when lipids were found to regulate cell polarity and vesicle transport, and the “lipid raft” concept took shape. The lipid‐driven membrane anisotropy in form of “rafts” that associate with proteins led to the view that organized complexes of lipids and proteins regulate various cell functions. Disturbance of this organization can lead to cellular, tissue, and organ malfunction. Sphingolipidoses, lysosomal storage diseases that are caused by enzyme deficiencies in the sphingolipid degradation pathway, were found to be particularly detrimental to the brain. These enzyme deficiencies result in accumulation of sphingolipid metabolites in lysosomes, although it is not yet clear how this accumulation affects the organization of lipids in cellular membranes. Krabbe's disease (KD), or globoid cell leukodystrophy, was one of the first sphingolipidosis for which the raft concept offered a potential mechanism. KD is caused by mutations in the enzyme β‐galactocerebrosidase; however, elevation of its substrate, galactosylceramide, is not observed or considered detrimental. Instead, it was found that a byproduct of galactosylceramide metabolism, the lysosphingolipid psychosine, is accumulated. The “psychosine hypothesis” has been refined by showing that psychosine disrupts lipid rafts and vesicular transport critical for the function of glia and neurons. The role of psychosine in KD is an example of how the disruption of sphingolipid metabolism can lead to elevation of a toxic lysosphingolipid, resulting in disruption of cellular membrane organization and neurotoxicity. © 2016 Wiley Periodicals, Inc.
The Facilitative Effects of Ambiguous Figures on Creative Solution
Authors: Wu Xiaofei , Gu Xiaojing , Zhang Hao
Published: September 2016

Empirical studies of creativity emphasize the importance of ambiguity advantage in idea generation and creative problem‐solving. This study examined whether ambiguous figures could directly induce a mind‐set that would transfer to the creative problem‐solving. In Experiment 1, we examined whether presentation of ambiguous figures would influence participants' performance in alternative uses tasks, and the results showed that prior exposure to ambiguous figures significantly enhanced participants' performance in the dimension of fluency, flexibility, and originality than those exposed to non‐ambiguous figures; in general uses tasks, there were no significant difference in the reaction time and originality between the ambiguous figure condition and non‐ambiguous figure condition. In Experiment 2, the facilitative effect of ambiguous figures on creative thinking was further examined with creative story generation tasks that demand more mental effort and increased cognitive load. Results showed that creativity of stories generated in ambiguous figure condition was scored significantly higher than those in non‐ambiguous figure condition. The current research extends our understanding of the facilitative effect of ambiguous figures on creative problem‐solving.
How subscription‐based scholarly journals can convert to open access: A review of approaches
Authors: Laakso Mikael , Solomon David , Björk Bo‐Christer
Published: September 2016

This article reviews the ways through which subscription‐based scholarly journals have converted to open access. The methodology included a comprehensive literature review of both published and ‘grey’ literature, such as blog posts and press releases. Eight interviews were also conducted with stakeholders representing different parts of the scholarly publishing landscape. Strategies of conversion for different types of journals are presented at multiple levels (publishers, national, research funders, organizational, and so on). The identified scenarios are split into two main categories, those that rely heavily on article processing charges and those that can operate without relying on author‐side financing. Despite there being interesting and important shared traits among many converted journals, individual circumstances largely dictate what options for conversion are viable for a journal. There is no single solution that works for every journal but rather a broad selection of different solutions, among which selection should be well informed.
Quaternary Ammonium Cation Functionalized Poly(Ionic Liquid)s with Poly(Ethylene Oxide) Main Chains
Authors: Ikeda Taichi , Moriyama Satoshi , Kim Jedeok
Published: September 2016

Eight types of cationic glycidyl triazole polymers (GTPs) are prepared from combinations of four quaternary ammonium cationic units (pyrrolidinium, piperidinium, morpholinium, and N,N‐diethyl‐substituted ammonium) and two N‐alkyl substituents (methyl and ethyl groups). These poly(ionic liquid)s are prepared using Cu(I)‐catalyzed azide‐alkyne cycloaddition reaction between the alkyne derivatives of ionic liquids and glycidyl azide polymer. The ionic conductivity is characterized by impedance measurement. The ionic conductivity depends on the type of the cationic unit, but the type of the N‐alkyl substituent shows little influence on the ionic conductivity. The order of the cationic units that afford high ionic conductivity is as follows: pyrrolidinium >N,N‐diethyl‐substituted ammonium > piperidinium > morpholinium. The highest anhydrous ionic conductivity obtained in this study is 9.8 × 10−6 S cm−1 at 30 °C for the GTPs with the 1‐methylpyrrolidinium unit. Based on electrode polarization analysis, the conducting ion (carrier) concentration and mobility are calculated.

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GPS for QSP: A Summary of the ACoP6 Symposium on Quantitative Systems Pharmacology and a Stage for Near‐Term Efforts in the Field
Authors: Musante CJ , Abernethy DR , Allerheiligen SR , Lauffenburger DA , Zager MG
Published: September 2016

Quantitative Systems Pharmacology (QSP) is experiencing increased application in the drug discovery and development process. Like its older sibling, systems biology, the QSP field is comprised of a mix of established disciplines and methods, from molecular biology to engineering to pharmacometrics. As a result, there exist critical segments of the discipline that differ dramatically in approach and a need to bring these groups together toward a common goal.
A Population Pharmacokinetic Model for Vancomycin in Adult Patients Receiving Extracorporeal Membrane Oxygenation Therapy
Authors: Moore JN , Healy JR , Thoma BN , Peahota MM , Ahamadi M , Schmidt L , Cavarocchi NC , Kraft WK
Published: September 2016

The literature on the pharmacokinetics of vancomycin in patients undergoing extracorporeal membrane oxygenation (ECMO) therapy is sparse. A population pharmacokinetic (PK) model for vancomycin in ECMO patients was developed using a nonlinear mixed effects modeling on the concentration–time profiles of 14 ECMO patients who received intravenous vancomycin. Model selection was based on log‐likelihood criterion, goodness of fit plots, and scientific plausibility. Identification of covariates was done using a full covariate model approach. The pharmacokinetics of vancomycin was adequately described with a two‐compartment model. Parameters included clearance of 2.83 L/hr, limited central volume of distribution 24.2 L, and low residual variability 0.67%. Findings from the analysis suggest that standard dosing recommendations for vancomycin in non‐ECMO patients are adequate to achieve therapeutic trough concentrations in ECMO patients. This further shows that ECMO minimally affects the PK of vancomycin in adults including in higher‐weight patients.