bluuebunny/crossref_metadata_2025_split huggingface dataset:
Multitarget Therapeutic Leads for Alzheimer’s Disease: Quinolizidinyl Derivatives of Bi‐ and Tricyclic Systems as Dual Inhibitors of Cholinesterases and β‐Amyloid (Aβ) Aggregation
Authors: Tonelli Michele , Catto Marco , Tasso Bruno , Novelli Federica , Canu Caterina , Iusco Giovanna , Pisani Leonardo , Stradis Angelo De , Denora Nunzio , Sparatore Anna , Boido Vito , Carotti Angelo , Sparatore Fabio 
Published: April 2015

AbstractMultitarget therapeutic leads for Alzheimer’s disease were designed on the models of compounds capable of maintaining or restoring cell protein homeostasis and of inhibiting β‐amyloid (Aβ) oligomerization. Thirty‐seven thioxanthen‐9‐one, xanthen‐9‐one, naphto‐ and anthraquinone derivatives were tested for the direct inhibition of Aβ(1–40) aggregation and for the inhibition of electric eel acetylcholinesterase (eeAChE) and horse serum butyrylcholinesterase (hsBChE). These compounds are characterized by basic side chains, mainly quinolizidinylalkyl moieties, linked to various bi‐ and tri‐cyclic (hetero)aromatic systems. With very few exceptions, these compounds displayed inhibitory activity on both AChE and BChE and on the spontaneous aggregation of β‐amyloid. In most cases, IC50 values were in the low micromolar and sub‐micromolar range, but some compounds even reached nanomolar potency. The time course of amyloid aggregation in the presence of the most active derivative (IC50=0.84 μM) revealed that these compounds might act as destabilizers of mature fibrils rather than mere inhibitors of fibrillization. Many compounds inhibited one or both cholinesterases and Aβ aggregation with similar potency, a fundamental requisite for the possible development of therapeutics exhibiting a multitarget mechanism of action. The described compounds thus represent interesting leads for the development of multitarget AD therapeutics.
MS565: A SPECT Tracer for Evaluating the Brain Penetration of BAF312 (Siponimod)
Authors: Briard Emmanuelle , Rudolph Bettina , Desrayaud Sandrine , Krauser Joel A. , Auberson Yves P. 
Published: April 2015

AbstractBAF312 (siponimod) is a sphingosine‐1‐phosphate (S1P) receptor modulator in clinical development for the treatment of multiple sclerosis, with faster organ/tissue distribution and elimination kinetics than its precursor FTY720 (fingolimod). Our aim was to develop a tracer to better quantify the penetration of BAF312 in the human brain, with the potential to be labeled for positron emission tomography (PET) or single‐photon emission computed tomography (SPECT). Although the PET radioisotopes 11C and 18F could have been introduced in BAF312 without modifying its structure, they do not have decay kinetics compatible with the time required for observing the drug′s organ distribution in patients. In contrast, the SPECT radioisotope 123I has a longer half‐life and would suit this purpose. Herein we report the identification of an iodinated derivative of BAF312, (E)‐1‐(4‐(1‐(((4‐cyclohexyl‐3‐iodobenzyl)oxy)imino)ethyl)‐2‐ethylbenzyl)azetidine‐3‐carboxylic acid (18, MS565), as a SPECT tracer candidate with affinity, S1P receptor selectivity, overall physicochemical properties, and blood pharmacokinetics similar to those of the original molecule. A whole‐body autoradiography study performed with [14C]MS565 subsequently confirmed that its organ distribution is similar to that of BAF312. This validates the selection of MS565 for 123I radiolabeling and for use in imaging studies to quantify the brain penetration of BAF312.
Multitarget‐Directed Tricyclic Pyridazinones as G Protein‐Coupled Receptor Ligands and Cholinesterase Inhibitors
Authors: Pau Amedeo , Catto Marco , Pinna Giovanni , Frau Simona , Murineddu Gabriele , Asproni Battistina , Curzu Maria M. , Pisani Leonardo , Leonetti Francesco , Loza Maria Isabel , Brea José , Pinna Gérard A. , Carotti Angelo 
Published: April 2015

AbstractBy following a multitarget ligand design approach, a library of 47 compounds was prepared, and they were tested as binders of selected G protein‐coupled receptors (GPCRs) and inhibitors of acetyl and/or butyryl cholinesterase. The newly designed ligands feature pyridazinone‐based tricyclic scaffolds connected through alkyl chains of variable length to proper amine moieties (e.g., substituted piperazines or piperidines) for GPCR and cholinesterase (ChE) molecular recognition. The compounds were tested at three different GPCRs, namely serotoninergic 5‐HT1A, adrenergic α1A, and dopaminergic D2 receptors. Our main goal was the discovery of compounds that exhibit, in addition to ChE inhibition, antagonist activity at 5‐HT1A because of its involvement in neuronal deficits typical of Alzheimer’s and other neurodegenerative diseases. Ligands with nanomolar affinity for the tested GPCRs were discovered, but most of them behaved as dual antagonists of α1A and 5‐HT1A receptors. Nevertheless, several compounds displaying this GPCR affinity profile also showed moderate to good inhibition of AChE and BChE, thus deserving further investigations to exploit the therapeutic potential of such unusual biological profiles.
Medicinal Chemists of the 21st Century—Who Are We and Where to Go?
Authors: Nussbaumer Peter 
Published: April 2015

AbstractMany recent articles have dealt with the future challenges in medicinal chemistry. Here, I discuss my concerns over the future of medicinal chemists, who have to be skilled and knowledgeable in many different fields, particularly in the context of the ever‐growing requirements, the request for even broader diversification, and the substantial structural change in industrial drug discovery. In my opinion, we have to do the following in order to ensure sustained high quality and achievements: 1) to focus on superior design without excluding complex structures a priori; 2) to proactively shape the future of our discipline; 3) to discuss specialization; 4) to intensify exchange between academia and industry; and 5) to remodel education of the next generation of medicinal chemists. By providing my opinion on these aspects, I hope to stimulate discussions and change within the community.
Androgen deprivation therapy and the risk of death from prostate cancer among men with favorable or unfavorable intermediate‐risk disease
Authors: Keane Florence K. , Chen Ming‐Hui , Zhang Danjie , Moran Brian J. , Braccioforte Michelle H. , D'Amico Anthony V. 
Published: April 2015

BACKGROUNDRadiotherapy (RT), short‐course androgen deprivation therapy (ADT), and brachytherapy in various combinations are treatment options for patients with intermediate‐risk prostate cancer (PC), but the question of which combination if any is necessary to minimize PC‐specific mortality (PCSM) risk in patients with favorable or unfavorable intermediate‐risk PC is unknown. The authors assessed PCSM risk after commonly used treatments.METHODSThe cohort consisted of 2510 men with favorable (1902 men; 75.78%) or unfavorable (608 men; 24.22%) intermediate‐risk PC who were treated from 1997 to 2013. Treatment included brachytherapy with or without neoadjuvant ADT among men with favorable disease and brachytherapy with neoadjuvant RT or ADT among men with unfavorable disease. Fine and Gray's competing‐risks regression model was used to assess whether ADT among men with favorable disease or RT or ADT among men with unfavorable disease decreased PCSM risk after adjusting for treatment propensity score, year of brachytherapy, and PC prognostic factors.RESULTSAfter a median follow‐up of 7.78 years, 366 deaths (14.58%) were observed, 29 of which (7.92%) were from PC. There was a significant reduction in PCSM risk in men with unfavorable disease who were treated with ADT versus RT (adjusted hazard ratio, 0.34; 95% confidence interval, 0.13‐0.91 [P = .03]), but no significant difference in PCSM risk in men with favorable disease who received ADT and brachytherapy versus brachytherapy (adjusted hazard ratio, 0.67; 95% confidence interval, 0.18‐2.57 [P =.56]).CONCLUSIONSNeoadjuvant ADT does not appear to reduce PCSM risk in men undergoing brachytherapy for favorable intermediate‐risk PC and should not be considered a standard; however, it appears superior to neoadjuvant RT in men with unfavorable intermediate‐risk PC undergoing brachytherapy, making neoadjuvant ADT and brachytherapy a preferred option in these men. Cancer 2015;121:2713‐2719. © 2015 American Cancer Society
Direct projections from the dorsal premotor cortex to the superior colliculus in the macaque (macaca mulatta)
Authors: Distler Claudia , Hoffmann Klaus‐Peter 
Published: April 2015

ABSTRACTThe dorsal premotor cortex (PMd) is part of the cortical network for arm movements during reach‐related behavior. Here we investigate the neuronal projections from the PMd to the midbrain superior colliculus (SC), which also contains reach‐related neurons, to investigate how the SC integrates into a cortico‐subcortical network responsible for initiation and modulation of goal‐directed arm movements. By using anterograde transport of neuronal tracers, we found that the PMd projects most strongly to the deep layers of the lateral part of the SC and the underlying reticular formation corresponding to locations where reach‐related neurons have been recorded, and from where descending tectofugal projections arise. A somewhat weaker projection targets the intermediate layers of the SC. By contrast, terminals originating from prearcuate area 8 mainly project to the intermediate layers of the SC. Thus, this projection pattern strengthens the view that different compartments in the SC are involved in the control of gaze and in the control or modulation of reaching movements. The PMD–SC projection assists in the participation of the SC in the skeletomotor system and provides the PMd with a parallel path to elicit forelimb movements. J. Comp. Neurol. 523:2390–2408, 2015. © 2015 Wiley Periodicals, Inc.
Quantum private comparison protocol with cloud quantum computing
Authors: Tan Xiaoqing , Zhang Xiaoqian 
Published: April 2015

SummaryBecause privacy problems with big data impede progress at all phases of the pipeline that can create value from data, Alice and Bob have to perform private queries in order to obtain the private comparison results of big data. Suppose that the cloud devices are with the capacity of conventional and quantum computation, an efficient quantum private comparison protocol with ring‐trip transmission by safe cloud quantum computing in the quantum Internet is proposed. Two participant parties Alice and Bob, with the help of a semi‐trusted third party and cloud device by simple quantum measurements and mathematical operation, can compare the equality of their secret information without revealing the content of secret information. We show that our protocol can resist the eavesdropper Eve's intercept–resend attack, entangle–measure attack, and Trojan horse attack to cloud device, participant's intercept–measure–resend attack, and third party's attack. The qubit efficiency of our protocol approaches to 100%. We also analyze the connection between Eve's obtained information and the fidelity of secret information in detail. Copyright © 2015 John Wiley & Sons, Ltd.
Designing and evaluating weighted delegatable authorizations
Authors: Ruan Chun 
Published: April 2015

SummaryThis paper studies logic‐based methods for representing and evaluating complex access control policies needed by modern applications. In our framework, authorization and delegation rules are specified in a weighted delegatable authorization program, which is an extended logic program. We show how extended logic programs can be used to specify complex security policies, which support weighted administrative privilege delegation, weighted positive and negative authorizations, and weighted authorization propagations. We also present a conflict resolution method that enables flexible delegation control by considering priorities of authorization grantors and weights of authorizations. We show how this method can be specialized to achieve many of the current existing conflict resolution methods. A number of rules are provided to achieve delegation depth control, conflict resolution, and authorization and delegation propagations. We also show how to use SMODELS to implement weighted delegatable authorization program. Copyright © 2015 John Wiley & Sons, Ltd.
An iteration‐based hybrid parallel algorithm for tridiagonal systems of equations on multi‐core architectures
Authors: Tang Guangping , Yang Wangdong , Li Kenli , Ye Yu , Xiao Guoqing , Li Keqin 
Published: April 2015

SummaryAn optimized parallel algorithm is proposed to solve the problem occurred in the process of complicated backward substitution of cyclic reduction during solving tridiagonal linear systems. Adopting a hybrid parallel model, this algorithm combines the cyclic reduction method and the partition method. This hybrid algorithm has simple backward substitution on parallel computers comparing with the cyclic reduction method. In this paper, the operation count and execution time are obtained to evaluate and make comparison for these methods. On the basis of results of these measured parameters, the hybrid algorithm using the hybrid approach with a multi‐threading implementation achieves better efficiency than the other parallel methods, that is, the cyclic reduction and the partition methods. In particular, the approach involved in this paper has the least scalar operation count and the shortest execution time on a multi‐core computer when the size of equations meets some dimension threshold. The hybrid parallel algorithm improves the performance of the cyclic reduction and partition methods by 19.2% and 13.2%, respectively. In addition, by comparing the single‐iteration and multi‐iteration hybrid parallel algorithms, it is found that increasing iteration steps of the cyclic reduction method does not affect the performance of the hybrid parallel algorithm very much. Copyright © 2015 John Wiley & Sons, Ltd.
Improved Photocurrents for Water Oxidation by Using Metal–Organic Framework Derived Hybrid Porous Co3O4@Carbon/BiVO4 as a Photoanode
Authors: Hou Chun‐Chao , Li Ting‐Ting , Chen Yong , Fu Wen‐Fu 
Published: April 2015

AbstractEfforts to improve the overall efficiency of photoelectrochemical water splitting by promoting interfacial charge transfer and suppressing electron–hole recombination remain a challenge. Highly porous Co3O4@carbon derived from metal–organic frameworks was successfully embedded on the surface of BiVO4 nanosheets. The Co3O4@carbon/BiVO4 composites were fully characterised by a variety of techniques, including powder XRD, diffuse reflectance UV/Vis spectroscopy, BET surface area calculations, SEM, TEM, energy‐dispersive X‐ray spectroscopy, high‐angle annular dark‐field scanning TEM, and X‐ray photoelectron spectroscopy. The construction of a heterojunction between porous Co3O4 (p‐Co3O4) and BiVO4 significantly promoted charge transfer and suppressed the recombination of holes and electrons. Consequently, the p‐Co3O4@carbon/BiVO4 photoanode demonstrated approximately tenfold higher photocurrent density relative to bare BiVO4 and bulk Co3O4/BiVO4 for water oxidation under the same conditions. Also, this system displayed good durability for water oxidation and could be recycled at least three times without any loss of catalytic activity.
Carbonaceous Materials and Their Advances as a Counter Electrode in Dye‐Sensitized Solar Cells: Challenges and Prospects
Authors: Kouhnavard Mojgan , Ludin Norasikin Ahmad , Ghaffari Babak V. , Sopian Kamarozzaman , Ikeda Shoichiro 
Published: April 2015

AbstractDye‐sensitized solar cells (DSSCs) serve as low‐costing alternatives to silicon solar cells because of their low material and fabrication costs. Usually, they utilize Pt as the counter electrode (CE) to catalyze the iodine redox couple and to complete the electric circuit. Given that Pt is a rare and expensive metal, various carbon materials have been intensively investigated because of their low costs, high surface areas, excellent electrochemical stabilities, reasonable electrochemical activities, and high corrosion resistances. In this feature article, we provide an overview of recent studies on the electrochemical properties and photovoltaic performances of carbon‐based CEs (e.g., activated carbon, nanosized carbon, carbon black, graphene, graphite, carbon nanotubes, and composite carbon). We focus on scientific challenges associated with each material and highlight recent advances achieved in overcoming these obstacles. Finally, we discuss possible future directions for this field of research aimed at obtaining highly efficient DSSCs.
Design Principles of Perovskites for Thermochemical Oxygen Separation
Authors: Ezbiri Miriam , Allen Kyle M. , Gàlvez Maria E. , Michalsky Ronald , Steinfeld Aldo 
Published: April 2015

AbstractSeparation and concentration of O2 from gas mixtures is central to several sustainable energy technologies, such as solar‐driven synthesis of liquid hydrocarbon fuels from CO2, H2O, and concentrated sunlight. We introduce a rationale for designing metal oxide redox materials for oxygen separation through “thermochemical pumping” of O2 against a pO2 gradient with low‐grade process heat. Electronic structure calculations show that the activity of O vacancies in metal oxides pinpoints the ideal oxygen exchange capacity of perovskites. Thermogravimetric analysis and high‐temperature X‐ray diffraction for SrCoO3−δ, BaCoO3−δ and BaMnO3−δ perovskites and Ag2O and Cu2O references confirm the predicted performance of SrCoO3−δ, which surpasses the performance of state‐of‐the‐art Cu2O at these conditions with an oxygen exchange capacity of 44 mmol mol−1 exchanged at 12.1 μmol min−1 g−1 at 600–900 K. The redox trends are understood due to lattice expansion and electronic charge transfer.
Modified CFOA, its transpose, and applications
Authors: Swamy M. N. S. 
Published: April 2015

SummaryIt is shown that the recently‐proposed modified current feedback operational amplifier (MCFOA) is quite a versatile element in that given a realization for a system function using MCFOAs, we can obtain three alternate realizations using the same MCFOA but by appropriately connecting the y, x, w, and z terminals of the MCFOA to the remaining part of the original realization. Using the results concerning the transpose of a multi‐terminal element, it is further shown that the transpose of an MCFOA is another MCFOA. Thus, using the results of transposition, given a voltage‐mode circuit using MCFOAs, we can directly obtain four current‐mode circuits using the same MCFOAs or vice versa. Copyright © 2015 John Wiley & Sons, Ltd.
Too Many Cooks Spoil the Broth – Variable Potencies of Oxidizing Mn Complexes of a Hexadentate Carboxylato Ligand
Authors: Deville Claire , Finsel Maik , de Sousa David P. , Szafranowska Barbara , Behnken Julian , Svane Simon , Bond Andrew D. , Seidler‐Egdal Rune Kirk , McKenzie Christine J. 
Published: April 2015

AbstractGiven the hexadenticity of the monoanionic ligand in the procatalyst [Mn(tpena)(H2O)](ClO4) {tpena– = N,N,N′‐tris(2‐pyridylmethyl)ethylenediamine‐N′‐acetate}, it is perhaps surprising that this complex can catalyze the epoxidation of alkenes. When peracetic acid is used as terminal oxidant, the selectivity and rates of reactions are comparable with those reported for the manganese complexes of the commonly employed neutral tetradentate N4 ligands under analogous conditions. Cyclooctene conversion rates are similar when tert‐butyl hydroperoxide (TBHP) is used; however, the selectivity is greatly diminished. In the absence of organic substrates, [MnII(tpena)]+ catalyzes water oxidation by TBHP (initial rate ca. 23 mmol/h when [Mn] = 0.1 mM, at room temp.). To explain the variations in the selectivity of catalytic epoxidations and the observation of competing water oxidation, we propose that several metal‐based oxidants (the “cooks”) can be generated from [MnII(tpena)]+. These embody different potencies. The most powerful, and hence least selective, is proposed to be the isobaric isomer of [MnIV2(O)2(tpena)2]2+, namely an oxylic radical complex, [(tpena)MnIII(μ2‐O)MnIV(O·)(tpena)]2+. The formation of this species depends on the catalyst concentration, and it is favoured when TBHP is used as the terminal oxidant. The generation of the less potent [MnIV(O)(tpena)]+, which we propose as the direct oxidant in epoxidation reactions, is favoured in non‐aqueous solutions when peracetic acid is used as the terminal oxidant.
A Total Synthesis of Galanthamine Involving De Novo Construction of the Aromatic C‐Ring
Authors: Nugent Jeremy , Matoušová Eliška , Banwell Martin G. 
Published: April 2015

AbstractThe tetracyclic alkaloid galanthamine is used clinically in a number of countries for the symptomatic treatment of mild to moderate forms of Alzheimer's disease, and this feature coupled with its novel molecular architecture has prompted an extensive focus on its synthesis. The present study reports a new and distinct synthesis of galanthamine wherein the AB‐ring substructure and associated quaternary carbon centre are constructed by using a palladium‐catalyzed intramolecular Alder‐ene reaction. The product of this process is engaged in a Tsuji–Trost‐type reaction to generate a semicyclic diene that participates in a normal‐electron‐demand Diels–Alder reaction to generate, after oxidation of the initially formed adduct, the aromatic C‐ring of the target alkaloid. Modified Bischler–Napieralski chemistry is then deployed to construct the seven‐membered D‐ring and thereby furnishing narwedine, an established precursor to both (+)‐ and (–)‐galanthamine.
Valuation of Child Health‐Related Quality of Life in the United States
Authors: Craig Benjamin M. , Greiner Wolfgang , Brown Derek S. , Reeve Bryce B. 
Published: April 2015

AbstractMany economic analyses fail to incorporate evidence on child health‐related quality of life because of a paucity of quality‐adjusted life year (QALY) estimates. This health valuation study is the first to summarize the EQ‐5D‐Y on a QALY scale. Drawn from a nationally representative panel, 5207 adult respondents were asked to choose between two losses in child health‐related quality of life. Based on their choices, a 1‐year increase in child pain/discomfort from ‘some’ to ‘a lot’ equals a loss of 4 QALYs (95% CI, 3.8–4.4). Likewise, a 1‐year increase in child anxiety/depression from ‘a bit’ to ‘very worried, sad, or unhappy’ equals a loss of 2 QALYs (95% CI, 1.9–2.2). These findings enable the integration of child‐reported outcomes with adult preferences to inform economic analysis. Results inform both clinical practice and resource allocation decisions by enhancing understanding of difficult tradeoffs in child‐reported outcomes. Copyright © 2015 John Wiley & Sons, Ltd.