bluuebunny/crossref_metadata_2025_split huggingface dataset:
Quantitative Structure‐Activity Relationship Analysis and a Combined Ligand‐Based/Structure‐Based Virtual Screening Study for Glycogen Synthase Kinase‐3
Authors: Fu Gang , Liu Sheng , Nan Xiaofei , Dale Olivia R. , Zhao Zhendong , Chen Yixin , Wilkins Dawn E. , Manly Susan P. , Cutler Stephen J. , Doerksen Robert J. 
Published: September 2014

AbstractGlycogen synthase kinase‐3 (GSK‐3) is a multifunctional serine/threonine protein kinase which regulates a wide range of cellular processes, involving various signalling pathways. GSK‐3β has emerged as an important therapeutic target for diabetes and Alzheimer’s disease. To identify structurally novel GSK‐3β inhibitors, we performed virtual screening by implementing a combined ligand‐based/structure‐based approach, which included quantitative structure‐activity relationship (QSAR) analysis and docking prediction. To integrate and analyze complex data sets from multiple experimental sources, we drafted and validated a hierarchical QSAR method, which adopts a two‐level structure to take data heterogeneity into account. A collection of 728 GSK‐3 inhibitors with diverse structural scaffolds was obtained from published papers that used different experimental assay protocols. Support vector machines and random forests were implemented with wrapper‐based feature selection algorithms to construct predictive learning models. The best models for each single group of compounds were then used to build the final hierarchical QSAR model, with an overall R2 of 0.752 for the 141 compounds in the test set. The compounds obtained from the virtual screening experiment were tested for GSK‐3β inhibition. The bioassay results confirmed that 2 hit compounds are indeed GSK‐3β inhibitors exhibiting sub‐micromolar inhibitory activity, and therefore validated our combined ligand‐based/structure‐based approach as effective for virtual screening experiments.
Fractal Dimensions of Macromolecular Structures
Authors: Todoroff Nickolay , Kunze Jens , Schreuder Herman , Hessler Gerhard , Baringhaus Karl‐Heinz , Schneider Gisbert 
Published: September 2014

AbstractQuantifying the properties of macromolecules is a prerequisite for understanding their roles in biochemical processes. One of the less‐explored geometric features of macromolecules is molecular surface irregularity, or ‘roughness’, which can be measured in terms of fractal dimension (D). In this study, we demonstrate that surface roughness correlates with ligand binding potential. We quantified the surface roughnesses of biological macromolecules in a large‐scale survey that revealed D values between 2.0 and 2.4. The results of our study imply that surface patches involved in molecular interactions, such as ligand‐binding pockets and protein‐protein interfaces, exhibit greater local fluctuations in their fractal dimensions than ‘inert’ surface areas. We expect approximately 22 % of a protein’s surface outside of the crystallographically known ligand binding sites to be ligandable. These findings provide a fresh perspective on macromolecular structure and have considerable implications for drug design as well as chemical and systems biology.
Cardiac lipid levels show diurnal changes and long‐term variations in healthy human subjects
Authors: Ith Michael , Stettler Christoph , Xu Jian , Boesch Chris , Kreis Roland 
Published: September 2014

1H‐MRS is regularly applied to determine lipid content in ectopic tissue – mostly skeletal muscle and liver – to investigate physiological and/or pathologic conditions, e.g. insulin resistance. Technical developments also allow non‐invasive in vivo assessment of cardiac lipids; however, basic data about methodological reliability (repeatability) and physiological variations are scarce. The aim of the presented work was to determine potential diurnal changes of cardiac lipid stores in humans, and to put the results in relation to methodological repeatability and normal physiological day‐to‐day variations.Optimized cardiac‐ and respiratory‐gated 1H‐MRS was used for non‐invasive quantification of intracardiomyocellular lipids (ICCL), creatine, trimethyl‐ammonium compounds (TMA), and taurine in nine healthy young men at three time points per day on two days separated by one week. This design allowed determination of (a) diurnal changes, (b) physiological variation over one week and (c) methodological repeatability of the ICCL levels.Comparison of fasted morning to post‐absorptive evening measurements revealed a significant 37 ± 19% decrease of ICCL during the day (p = 0.0001). There was a significant linear correlation between ICCL levels in the morning and their decrease during the day (p = 0.015). Methodological repeatability for the ICCL/creatine ratio was excellent, with a coefficient of variance of ~5%, whereas physiological variation was found to be considerably higher (22%) in spite of a standardized physiological preparation protocol. In contrast, TMA levels remained stable over this time period.The proposed 1H‐MRS technique provides a robust way to investigate relevant physiological changes in cardiac metabolites, in particular ICCL. The present results suggest that ICCL reveal a diurnal course, with higher levels in the morning as compared to evening. In addition, a considerable long‐term variation of ICCL levels, in both the morning and evening, was documented. Given the high methodological repeatability, these effects should be taken into account in studies investigating the metabolic role of ICCL. Copyright © 2014 John Wiley & Sons, Ltd.
Im Nebel perfekt getarnt
Authors: Schittny Robert , Bückmann Tiemo , Wegener Martin 
Published: September 2014

AbstractPerfekte makroskopische Tarnkappen in Luft sind unmöglich, sie verletzen Einsteins Relativitätstheorie. In lichtstreuenden Medien können sie jedoch realisiert werden, wie unsere Gruppe am Karlsruher Institut für Technologie (KIT) kürzlich experimentell demonstriert hat.
Schnelles Verblassen leuchtender Spuren
Authors: Vollmer Michael , Möllmann Klaus‐Peter 
Published: September 2014

AbstractWohl jeder, der schon einmal mit Physik zu tun hatte, kennt die meist grünlichen Leuchtspuren von Oszillographen. Sie ermöglichen es, zeitabhängige Signale zu visualisieren und quantitativ auszumessen, insbesondere auch dann, wenn die Phänomene sehr schnell ablaufen. Die Reaktionsdynamik der leuchtenden Phosphore auf den Bildschirmen wird mit Hochgeschwindigkeits‐Videos deutlich sichtbar.
Mefloquine, an anti‐malaria agent, causes reactive oxygen species‐dependent cell death in mast cells via a secretory granule‐mediated pathway
Authors: Paivandy Aida , Calounova Gabriela , Zarnegar Behdad , Öhrvik Helena , Melo Fabio R. , Pejler Gunnar 
Published: September 2014

AbstractMast cells are known to have a detrimental impact on a variety of pathological conditions. There is therefore an urgent need of developing strategies that limit their harmful effects. The aim of this study was to accomplish this by developing a means of inducing mast cell apoptosis. The strategy was to identify novel compounds that induce mast cell apoptosis by permeabilization of their secretory lysosomes (granules). As a candidate, we assessed mefloquine, an anti‐malarial drug that has been proposed to have lysosome‐permeabilizing activity. Mefloquine was added to mast cells and administered in vivo, followed by assessment of the extent and mechanisms of mast cell death. Mefloquine was cytotoxic to murine and human mast cells. Mefloquine induced apoptotic cell death of wild‐type mast cells whereas cells lacking the granule compounds serglycin proteoglycan or tryptase were shown to undergo necrotic cell death, the latter finding indicating a role of the mast cell granules in mefloquine‐induced cell death. In support of this, mefloquine was shown to cause compromised granule integrity and to induce leakage of granule components into the cytosol. Mefloquine‐induced cell death was refractory to caspase inhibitors but was completely abrogated by reactive oxygen species inhibition. These findings identify mefloquine as a novel anti‐mast cell agent, which induces mast cell death through a granule‐mediated pathway. Mefloquine may thus become useful in therapy aiming at limiting harmful effects of mast cells.
Metabolomic evaluation of Mitomycin C and rapamycin in a personalized treatment of pancreatic cancer
Authors: Navarrete Alicia , Armitage Emily G. , Musteanu Monica , García Antonia , Mastrangelo Annalaura , Bujak Renata , López‐Casas Pedro P. , Hidalgo Manuel , Barbas Coral 
Published: September 2014

AbstractIn a personalized treatment designed for a patient with pancreatic cancer resistant to other treatments, the success of Mitomycin C (MMC) has been highlighted. This was revealed in a murine xenograft tumor model encompassing pancreatic adenocarcinoma cells extracted from the patient. The patient was found to exhibit a biallelic inactivation of the PALB2 gene, involved in DNA repair in addition to another mutation in the TSC2 gene that induces susceptibility of the tumor to therapeutic targets of the PI3K‐mTOR pathway. The aim of the study was to apply metabolomics to elucidate the modes of action of each therapy, suggesting why MMC was so successful in this patient and why it could be a more popular choice in future pancreatic cancer treatment. The effectiveness of MMC compared to rapamycin (RM), another relevant therapeutic agent has been evaluated through liquid‐ and gas‐chromatography mass spectrometry‐based metabolomic analyses of the xenograft tumors. The relative concentrations of many metabolites in the xenograft tumors were found to be increased by MMC relative to other treatments (RM and a combination of both), including a number that are involved in central carbon metabolism (CCM). Metabolic fingerprinting revealed statistically significantly altered pathways including, but not restricted to, the pentose phosphate pathway, glycolysis, TCA cycle, purine metabolism, fatty acid biosynthesis, in addition to many significant lipid and amino acid alterations. Given the genetic background of the patient, it was expected that the combined therapy would be most effective; however, the most effective was MMC alone. It is proposed that the effectiveness of MMC is owed to its direct effect on CCM, a vital region of tumor metabolism.
Oxidation of catechols during positive ion electrospray mass spectrometric analysis: Evidence for in‐source oxidative dimerization
Authors: Sojo Luis E. , Chahal Navjot , Keller Bernd O. 
Published: September 2014

RATIONALECatechols are an important class of analytes occurring in many natural and synthetic products. Electrospray ionization in negative mode is the preferred way of ion generation for these compounds; however, studies in positive ion mode can reveal their potential for in‐source oxidation and further structural changes, some of which may also occur in the solution phase. Therefore in‐source oxidation can provide a forward look into the potential for solution oxidation.METHODS1:1 Acetonitrile/water solutions of catechol (Cat), 4,5‐dichlorocatechol (4,5‐DCC), 3,4‐dichlorocatechol (3,4‐DCC) and tetrachlorocatechol (TCC) were analyzed by positive ion ultrahigh‐performance liquid chromatography (UHPLC/ESI‐MS) and UHPLC/ESI‐MS/MS under various emitter voltages to assess their liability towards in‐source oxidation. Structural information for in‐source generated compounds was obtained through the use of product ion scans.RESULTSUsing catechols as probe compounds, we have demonstrated that under the conditions used in many analytical laboratories in‐source oxidation can severely affect the sensitivity and response functions of an analyte. Under standard UHPLC conditions (300 μL/min flow rate), Cat, 3,4‐DCC, 4,5‐DCC and TCC can undergo in‐source oxidation. The extent of oxidation is dependent either on the instrument or on the characteristics of the emitter. This is evident by a change in the isotopic pattern of these compounds and the generation of ions at lower m/z values due to a loss of 1 and/or 2 hydrogens and electrons. In the case of catechol, the formation of a dimer resulting from in‐source oxidation reactions was observed. This dimer has the same fragmentation pattern as the dimer generated by oxidation in the solution phase.CONCLUSIONSThe present work demonstrates the potential of positive ion ESI for oxidizing electroactive compounds during regular analytical operation using commercially available mass spectrometers. Using Cat and some of its chlorinated analogues as probe compounds, we have demonstrated that under the conditions used in many analytical laboratories in‐source oxidation and dimerization can and does take place. Copyright © 2014 John Wiley & Sons, Ltd.
Rapid and mild silylation of β‐amino alcohols at room temperature mediated by N‐methylimidazole for enhanced detectability by gas chromatography/electron ionization mass spectrometry
Authors: Valdez Carlos A. , Leif Roald N. , Hart Bradley R. 
Published: September 2014

RATIONALEIn this work, we expand the use of in situ activation of chloro(dimethyl)phenylsilane using N‐methylimidazole (NMI) for the effective derivatization of β‐aminoethyl alcohols. Due to its enhanced nucleophilic character, NMI is expected to act as an efficient activator in these reactions.METHODSThe derivatization of a panel of β‐aminoethyl alcohols was accomplished by reacting the analyte with chloro(dimethyl)phenylsilane in the presence of either NMI or pyridine. After the addition of chloro(dimethyl)phenylsilane, the vials were gently tumbled for 1 h at ambient temperature. The phenyldimethylsilyl derivatives were identified using gas chromatography/electron ionization mass spectrometry (GC/EI‐MS).RESULTSA total of ten β‐aminoethyl alcohols were successfully derivatized via in situ activation of chloro(dimethyl)‐phenylsilane with NMI. Derivatization with NMI was significantly more efficient than with pyridine by a factor of 3–6 for the studied alcohols. The derivatizations in the presence of NMI were found to occur in just 1 h and were conveniently executed at ambient temperature.CONCLUSIONSThe use of the nitrogenous base NMI in order to activate chloro(dimethyl)phenylsilane for the efficient silylation of a panel of β‐aminoethyl alcohols has been demonstrated. The present work shows that NMI is an efficient base for the smooth derivatization of these types of alcohols. Furthermore, the installation of the bulky PDMS group onto these alcohols adds to the certainty that this is a viable approach for the installation of the more commonly employed, trimethylsilyl group. Published in 2014. This article is a U.S. Government work and is in the public domain in the USA.
An ultra‐rigid close‐stacked piezo motor for harsh condition scanning probe microscopy
Authors: Guo Ying , Hou Yubin , Lu Qingyou 
Published: September 2014

SummaryWe designed and produced a nearly closest packed stack motor with only one tiny gap of 0.15 mm in the middle of the stack. A low‐voltage method of controlling the motor is introduced for the first time. Besides, the test results of the motor and the corresponding scanning tunneling microscope are also presented. To our surprise, it turns out to be so rigid that even running two oil pumps and one ultrasonic cleaner within 1 m range from a STM directly driven by this new motor cannot cause the STM to produce any visible difference in its the atomic resolution quality. This is a leap in building a true harsh condition atomic resolution SPM. SCANNING 36:554–559, 2014. © 2014 Wiley Periodicals, Inc.
Behaviour of laminated glass beams reinforced with pre‐stressed cables
Authors: Jordão Sandra , Pinho Marco , Martin João Pedro , Santiago Aldina , Neves Luís Costa 
Published: September 2014

AbstractStructural glass corresponds to an innovative material with extraordinary aesthetical and architectonic potential that has undergone significant technological advances in recent years, yielding it stronger and safer. For this reason, the use of structural glass has increased considerably in the last decade and is now an unavoidable presence in most of recent reference buildings.The structural capacity of glass elements is brought in from reinforcing techniques of different types. One of the possibilities corresponds to pre stressed cables reinforcement. This technique is very effective in terms of resistance and deformability and corresponds to a light reinforcing element rendering the so called spider web effect. In the framework of the research project “S‐Glass: Structural performance and design rules of glass beams externally reinforced” [1] study the behavior of laminated glass beams reinforced by too twin external steel rods.The work presented in the current paper is within the framework of S‐Glass project aiming at characterizing the behavior of reinforced laminated glass beams in the non‐crack regimen. For this purpose experimental and numerical analysis were prepared. The numerical model was used for a cable layout optimization analysis. Furthermore an analytical solution is put forward, which tackles the beam‐cable load transfer indetermination. Final conclusions are established on the bases of a comparison established between experimental, numerical and analytical results.
Fire resistance of slender section beams
Authors: Prachar Martin , Jandera Michal , Wald František , Zhaob Bin 
Published: September 2014

AbstractThe paper shows experimental and numerical research into slender cross‐section beams in case of fire. The topic is very important because little investigation has been made and little experimental data has been collected so far. In the framework of the RFCS project FIDESC4 – Fire Design of Steel Members with Welded or Hot‐rolled Class 4 Cross‐sections, several simple supported beams were tested at elevated temperature at the Czech Technical University in Prague.Currently, Eurocode 3 contains a number of simple rules for design of slender Class 4 cross‐sections which, based on recent numerical simulations, proved themselves to be over‐conservative. Through refining these rules, material savings could be achieved, which would lead to greater competitiveness of the steel structures. This is being covered in existing research, but is not published in this paper, which is limited to lateral torsional buckling behaviour only.Determination of the bending resistance for members subjected to lateral torsional buckling of Class 1–3 cross‐sections at elevated temperature is based on the same principles as the design at room temperature, according to EC 3 part 1‐1 [1]. However, it differs in using only one imperfection factor for all types of cross‐sections. The informative Annex E of the standard (EC 3 part 1‐2 [2]) recommends using the design formulas for slender (Class 4) sections as well. But there is a restriction of the critical temperature value and a different reduction of yield strength is used (0.2 % proof strength for Class 4 instead of 2.0 % proof strength for stockier Class 1–3 sections). For the non‐uniform members (variable section height), a limited design procedure is given in EC 3 part 1‐1 [1]. This is applicable for room temperature only. The possibility of using these rules for fire design is not yet confirmed.
Influence of fire scenarios on progressive collapse mechanisms of steel framed structures
Authors: Jiang Jian , Li Guo‐Qiang , Usmani Asif 
Published: September 2014

AbstractOpenSees is an open‐source object‐oriented software framework developed at UC Berkeley. The OpenSees framework has been recently extended to deal with structural behaviour under fire conditions. This paper presents the results of a numerical study, using OpenSees, of the progressive collapse of steel frames exposed to fire. After validating the capability of OpenSees against available analytical and experimental results of fire tests on steel members, a parametric study is carried out to find the progressive collapse mechanism of steel frames exposed to fire and corresponding influencing factors. The factors include load levels, lateral restraint, beam strength and fire scenarios. The catenary action of beams is considered by using a temperature‐dependent corotational beam/column element. The results show that different progressive collapse mechanisms can happen due to the sequence of the buckling of columns. High load levels lead to the downward collapse of the whole structure compared with the lateral collapse for low load levels. The existing of lateral restraint causes the premature buckling of bottom columns which triggers the whole frame collapse. As the beam section increases, the collapse mechanism of steel frames changes from beam failure mode to column failure mode. The fire scenarios have significant effect on the collapse mode of steel frames. The work presented in this paper is a preliminary study of the progressive collapse of steel frames. Further work is underway to combine the influence of the effect of concrete floors. A simple design method is then expected to be proposed to investigate the robustness of steel structures against progressive collapse due to fire.
Optogenetics Reveal Delayed Afferent Synaptogenesis on Grafted Human-Induced Pluripotent Stem Cell-Derived Neural Progenitors
Authors: Avaliani Natalia , Sørensen Andreas Toft , Ledri Marco , Bengzon Johan , Koch Philipp , Brüstle Oliver , Deisseroth Karl , Andersson My , Kokaia Merab 
Published: September 2014

Abstract
Reprogramming of somatic cells into pluripotency stem cell state has opened new opportunities in cell replacement therapy and disease modeling in a number of neurological disorders. It still remains unknown, however, to what degree the grafted human-induced pluripotent stem cells (hiPSCs) differentiate into a functional neuronal phenotype and if they integrate into the host circuitry. Here, we present a detailed characterization of the functional properties and synaptic integration of hiPSC-derived neurons grafted in an in vitro model of hyperexcitable epileptic tissue, namely organotypic hippocampal slice cultures (OHSCs), and in adult rats in vivo. The hiPSCs were first differentiated into long-term self-renewing neuroepithelial stem (lt-NES) cells, which are known to form primarily GABAergic neurons. When differentiated in OHSCs for 6 weeks, lt-NES cell-derived neurons displayed neuronal properties such as tetrodotoxin-sensitive sodium currents and action potentials (APs), as well as both spontaneous and evoked postsynaptic currents, indicating functional afferent synaptic inputs. The grafted cells had a distinct electrophysiological profile compared to host cells in the OHSCs with higher input resistance, lower resting membrane potential, and APs with lower amplitude and longer duration. To investigate the origin of synaptic afferents to the grafted lt-NES cell-derived neurons, the host neurons were transduced with Channelrhodopsin-2 (ChR2) and optogenetically activated by blue light. Simultaneous recordings of synaptic currents in grafted lt-NES cell-derived neurons using whole-cell patch-clamp technique at 6 weeks after grafting revealed limited synaptic connections from host neurons. Longer differentiation times, up to 24 weeks after grafting in vivo, revealed more mature intrinsic properties and extensive synaptic afferents from host neurons to the lt-NES cell-derived neurons, suggesting that these cells require extended time for differentiation/maturation and synaptogenesis. However, even at this later time point, the grafted cells maintained a higher input resistance. These data indicate that grafted lt-NES cell-derived neurons receive ample afferent input from the host brain. Since the lt-NES cells used in this study show a strong propensity for GABAergic differentiation, the host-to-graft synaptic afferents may facilitate inhibitory neurotransmitter release, and normalize hyperexcitable neuronal networks in brain diseases, for example, such as epilepsy. Stem Cells 2014;32:3088–3098