bluuebunny/crossref_metadata_2025 huggingface dataset:
Contamination in electron observations of the silicon detector on board Cluster/RAPID/IES instrument in Earth's radiation belts and ring current
Authors: Kronberg E. A. , Rashev M. V. , Daly P. W. , Shprits Y. Y. , Turner D. L. , Drozdov A. , Dobynde M. , Kellerman A. C. , Fritz T. A. , Pierrard V. , Borremans K. , Klecker B. , Friedel R.
Published: June 2016

Since more than 15 years, the Cluster mission passes through Earth's radiation belts at least once every 2 days for several hours, measuring the electron intensity at energies from 30 to 400 keV. These data have previously been considered not usable due to contamination caused by penetrating energetic particles (protons at >100 keV and electrons at >400 keV). In this study, we assess the level of distortion of energetic electron spectra from the Research with Adaptive Particle Imaging Detector (RAPID)/Imaging Electron Spectrometer (IES) detector, determining the efficiency of its shielding. We base our assessment on the analysis of experimental data and a radiation transport code (Geant4). In simulations, we use the incident particle energy distribution of the AE9/AP9 radiation belt models. We identify the Roederer L values, L⋆, and energy channels that should be used with caution: at 3≤L⋆≤4, all energy channels (40–400 keV) are contaminated by protons (≃230 to 630 keV and >600 MeV); at L⋆≃1 and 4–6, the energy channels at 95–400 keV are contaminated by high‐energy electrons (>400 keV). Comparison of the data with electron and proton observations from RBSP/MagEIS indicates that the subtraction of proton fluxes at energies ≃ 230–630 keV from the IES electron data adequately removes the proton contamination. We demonstrate the usefulness of the corrected data for scientific applications.
Community‐wide validation of geospace model local K‐index predictions to support model transition to operations
Authors: Glocer A. , Rastätter L. , Kuznetsova M. , Pulkkinen A. , Singer H. J. , Balch C. , Weimer D. , Welling D. , Wiltberger M. , Raeder J. , Weigel R. S. , McCollough J. , Wing S.
Published: June 2016

We present the latest result of a community‐wide space weather model validation effort coordinated among the Community Coordinated Modeling Center (CCMC), NOAA Space Weather Prediction Center (SWPC), model developers, and the broader science community. Validation of geospace models is a critical activity for both building confidence in the science results produced by the models and in assessing the suitability of the models for transition to operations. Indeed, a primary motivation of this work is supporting NOAA/SWPC's effort to select a model or models to be transitioned into operations. Our validation efforts focus on the ability of the models to reproduce a regional index of geomagnetic disturbance, the local K‐index. Our analysis includes six events representing a range of geomagnetic activity conditions and six geomagnetic observatories representing midlatitude and high‐latitude locations. Contingency tables, skill scores, and distribution metrics are used for the quantitative analysis of model performance. We consider model performance on an event‐by‐event basis, aggregated over events, at specific station locations, and separated into high‐latitude and midlatitude domains. A summary of results is presented in this report, and an online tool for detailed analysis is available at the CCMC.
Intergenerational Ethics
Authors: Mulgan Tim
Published: June 2016

Unless something goes drastically wrong in the next few centuries, most of the people who will ever live are yet to be born. Our actions have little impact on those who are dead, considerable impact on those currently alive, and potentially enormous impact on those who will live in the future. Our decisions affect who those future people will be, and even if there will be any future people at all. The threat of environmental crisis gives us some inkling of the magnitude of our impact on future generations. Only in the last few decades have moral philosophers really begun to grapple with the complexities of intergenerational ethics. Underlying their often technical debates are some of the deepest moral questions. What makes life worth living? What do we owe to our descendants? How do we balance their needs against our own?
Disagreement, Moral
Authors: Tersman Folke
Published: June 2016

The discussion in which moral disagreement has received most attention is metaethical and concerns the objectivity of ethics. Consider a moral opinion, such as the view that it is morally wrong to eat meat. Could such an opinion be true? If so, could it be objectively true – that is, roughly, could it be true independently of whether anyone thinks that it is true? According to the position known as moral realism, the answer to both questions is yes. Moral realism is usually construed as the combination of two views. First, moral claims express beliefs about the way things are, states that purport to represent objective aspects of reality. Second, some of those beliefs are in fact true. It is often suggested that the fact that there is deep and widespread disagreement over moral issues is difficult to reconcile with this objectivist picture of ethics, and that the diversity is better accounted for by the competitors to realism.
Rashdall, Hastings
Authors: Skelton Anthony
Published: June 2016

Hastings Rashdall's (1858–1924) moral view comprises two elements: that “acts are right or wrong according as they do or do not tend to promote the greatest quantity of [general] good”; and that there are four goods: virtue (loving and willing what is intrinsically good), intellectual activities, “various kinds of affection or social emotion,” and pleasure. His basic position is that an agent's act is right insofar as it tends to produce at least as much virtuous willing, intellectual activity, affection or social emotion, and pleasure for the aggregate as any other act she could have performed in her situation. He calls this view ideal utilitarianism. Rashdall's most important contribution to ethics is his articulation and defense of this position, which appears inThe Theory of Good and Evil(1907) andEthics(1913).
Equality
Authors: Young Robert
Published: June 2016

Equality is a comparative notion: thus, for example, there is equality between two people in relation to a benefit or a burden when each receives the same benefit or shoulders the same burden. That it is a comparative notion is common to all accounts of equality. This essay considers the nature of equality when viewed as a substantive component of social distributive justice; outlines and reviews some suggested measurements of equality; outlines and critically discusses some frequently voiced criticisms of the pursuit of equality; and notes some ongoing controversies about the scope of equality among those who consider it central to issues of social distributive justice.
Wollaston, William
Authors: Tilley John J.
Published: June 2016

William Wollaston (1659–1724) was one of several early modern British philosophers known today as “moral rationalists.” Others in this group included John Balguy, Samuel Clarke, Ralph Cudworth, and Richard Price. They were foils or opponents of such “moral sentimentalists” as David Hume, Francis Hutcheson, and Lord Shaftesbury, their disagreements with whom anticipated and influenced many later debates over moral cognitivism and moral intuitionism. Uniting the rationalists was the view that reason, rather than feeling, sentiment, or a moral sense, is the source of moral perceptions. Many rationalists held also that what we detect when we perceive moral rightness is some sort of “fitness,” reasonableness, or agreement with truth. Wollaston held a form of the latter view according to which an act is morally right just in case it agrees with truth in this sense: it affirms no falsehoods. Although this view was untenable, it drew much favorable attention. The book in which it appeared, Wollaston'sReligion of Nature Delineated(1724), went through eight editions by 1759 and sold many thousands of copies. However, Wollaston's theory also drew harsh objections, some of which receive attention in this essay.
Methodology in Metaethics
Authors: Tersman Folke
Published: June 2016

The aim of normative ethics is to answer moral questions, such as whether euthanasia should be legalized, or whether we have an obligation to give to charity. The aim of metaethics, by contrast, is to figure out what
kind
of questions they are. We may wonder, for example, whether our answers to moral issues can be true or false, and also about the nature of the commitments we express with sentences such as “Giving to charity is right.” Are those commitments beliefs about the way the world is, or are they better seen as a type of preference or emotional response? A number of competing theories have emerged. How are those theories to be evaluated? On what grounds, and on the basis of what evidence, may we prefer one of those theories to the others? It is to such methodological issues that this entry is devoted. A number of different approaches and possible sources of evidence are discussed.
Barth, Karl
Authors: Clough David
Published: June 2016

Karl Barth (1886–1968) was a Swiss Protestant, widely considered to be the leading Christian theologian of the twentieth century. He was active in German and Swiss Church and public life from 1920 until shortly before his death, was a leading figure in the German Confessing Church which resisted Hitler, and was expelled from Germany in 1935 after refusing to swear an oath of allegiance to Hitler. His theology represented a significant break with the liberal theology of his university education and became known as “neo‐orthodox.” It emphasized the importance of starting theology with the revelation of God in Jesus Christ, rather than with the human experience of God that had characterized the approach of Friedrich Schleiermacher and the liberal Protestant theology that he inspired. Barth adopted the Reformed framework for ethics as divine command as best able to convey his sense of the importance of seeing ethics as response of the human subject to the address of God. The fullest development of his ethical thought is in his unfinished major workChurch Dogmatics, especially focused in volumes II/2, III/4, and IV/4 (2009), but earlier sources exhibit key aspects of the shape of his later ethical thought.
Intimidation
Authors: Calhoun Cheshire
Published: June 2016

Intimidation is most often mentioned, across a wide range of disciplinary literatures, as one in a set of hostile and agency‐interfering behaviors that include bullying, harassing, coercing, and terrorizing. The most commonly discussed instances of intimidation – witness intimidation, voter intimidation, racial intimidation, political intimidation, and intimidation in the context of domestic violence – involve explicit or implied threats of serious harm, and thus raise the question of how, if at all, intimidation differs from coercion. Although the most morally worrisome instances of intimidation are ones where persons or regimes intentionally aim to intimidate through explicit or implied threats in order to control behavior, the scope of “intimidating” is significantly broader, applying also to what is difficult, unfamiliar, unpredictable, or potentially embarrassing. We use the term in reference to contexts where there are no explicit or implied threats, and indeed where there may even be no intimidator.
Relational Ethics
Authors: Metz Thaddeus , Miller Sarah Clark
Published: June 2016

Although relational conceptions of morality have existed for many centuries, indeed probably long before alternative views, it is only lately that relationalism has been articulated as a distinct kind of ethic in English‐speaking philosophy. Recent awareness of it has been occasioned mainly by twentieth‐century challenges to characteristically male and Western approaches to normativity. On the one hand, some feminists have argued that girls and women are more likely to adhere to a relational ethic, often one of care (perhaps for reasons of nurture as opposed to nature). On the other hand, greater intercultural exchanges have made English speakers more aware of African and Asian moral philosophies, which tend to place familial bonds at the core of how to live.
Holism
Authors: McShane Katie
Published: June 2016

In ethics, holism is most commonly taken to be the view that moral consideration is owed not only to individuals (e.g., individual people or individual animals) but also and independently to at least some of the larger wholes that they form (e.g., nations or ecosystems). However, holism encompasses an even broader range of theoretical claims than this very general position, even within ethics. And these multiple forms of holism within ethics are related to a further array of holisms outside ethics. In this essay, I first canvas the range of holisms in philosophy generally and use this to distinguish a number of different ways in which a theory might be said to be holist. I then use those distinctions to assess the three main kinds of holism within ethics: holism about reasons, holism about value, and holism about moral standing.
Patience
Authors: Kawall Jason
Published: June 2016

Is patience a moral virtue or merely prudential? Is it even really a virtue at all? For the Stoics, patience is a fundamental virtue, arising from, yet also sustaining, the reasoned detachment crucial to Stoic ethics. Through patient study we gain an understanding of the world and come to see there is only one genuine good: virtue. This knowledge allows us to calmly accept burdens and delays that would frustrate most people because we realize that wealth, pleasure, and other commonly pursued objects are only indifferents, and not in fact real goods. A proper understanding of the world enables us to avoid the passions that undermine our virtue and self‐control. Early writers in the Christian tradition also treat patience as a central moral virtue. For them, patience involves turning ourselves over to God's will, and accepting our own weakness. In enduring burdens calmly and demonstrating forbearance with others, we accept God's will, and imitate God's own patience and forbearance with us. These writers would reject a Stoic understanding of patience, with its emphasis on detachment from the external world and self‐mastery. For them, this would reflect both a rejection of God's creation, and a problematic pride.
Temporal Modulation of Stem Cell Activity Using Magnetoactive Hydrogels
Authors: Abdeen Amr A. , Lee Junmin , Bharadwaj N. Ashwin , Ewoldt Randy H. , Kilian Kristopher A.
Published: June 2016

Cell activity is coordinated by dynamic interactions with the extracellular matrix, often through stimuli‐mediated spatiotemporal stiffening and softening. Dynamic changes in mechanics occur in vivo through enzymatic or chemical means, processes which are challenging to reconstruct in cell culture materials. Here a magnetoactive hydrogel material formed by embedding magnetic particles in a hydrogel matrix is presented whereby elasticity can be modulated reversibly by attenuation of a magnetic field. Orders of magnitude change in elasticity using low magnetic fields are shown and reversibility of stiffening with simple permanent magnets is demonstrated. The broad applicability of this technique is demonstrated with two therapeutically relevant bioactivities in mesenchymal stem cells: secretion of proangiogenic molecules, and dynamic control of osteogenesis. The ability to reversibly stiffen cell culture materials across the full spectrum of soft tissue mechanics, using simple materials and commercially available permanent magnets, makes this approach viable for a broad range of laboratory environments.
Spectral Characteristics of Noble Metal Nanoparticle–Molybdenum Disulfide Heterostructures
Authors: Forcherio Gregory T. , Roper D. Keith
Published: June 2016

Energy and damping of resonances which occur in spectra of monolayer molybdenum disulfide (MoS2) decorated by noble metal nanospheres and prisms are examined by comparing discrete dipole approximation (DDA) simulations and transmission UV–vis measurements. Localized surface plasmon resonance (LSPR) as well as A and B exciton transitions of the semiconductor are characterized individually and in tandem on a silica substrate. Extinction energies for LSPR and direct bandgap transition of MoS2 estimated by DDA are within 2% of measured values for gold nanospheres and silver nanoprisms. Resonant near‐fields mapped at nanoparticle–MoS2 interfaces show plasmon damping via energy dissipation to the MoS2 and direct bandgap excitation. Linewidth analysis of resonant far‐field damping estimates energy transfer efficiencies for putative hot electron transfer, corroborated by experiment. Use of DDA simulations to characterize and inform induction and damping of electric resonance modes in nanoparticle–MoS2 heterostructures is illustrated.
Influence of Soluble Electrospun Co‐Polyethersulfone Veils on Dynamic Mechanical and Morphological Properties of Epoxy Composites: Effect of Polymer Molar Mass
Authors: Cicala Gianluca , Latteri Alberta , Mannino Salvatore , Ognibene Giulia , Blanco Ignazio
Published: June 2016

Electrospun veils from copolyethersulfones (coPES) with a number‐average molar mass (Mn) of 9000 g/mol (coPES9k) and 20,000 g/mol (coPES20k) were prepared as soluble interlaminar veils for carbon fiber/epoxy composites. Dry carbon fabrics were covered with electrospun veils and then infused with an unmodified epoxy resin to prepare reinforced laminates. CoPES powder was predissolved in the unmodified epoxy to obtain an epoxy/coPES blend used for preimpregnation of laminates which were compared to the laminates obtained with resin infusion. The thermoplastic content varied from 10wt% to 20wt% for coPES9k and from 5wt% to 10wt% for coPES20k. Unreinforced samples with no carbon fabrics were also studied. The coPES9k veils showed full solubility and homogeneous morphology when added to the epoxy resin. Unreinforced samples, modified by coPES9k veils, showed only minor morphological differences compared to epoxy/coPES blends obtained from coPES9k powder predissolution. The glass transition temperatures for these samples displayed differences less than 10°C. Carbon‐reinforced samples obtained using the same route showed larger differences. The coPES20k veils showed undissolved fibers and inhomogeneous morphologies when blended with an epoxy in the unreinforced samples.
Etiologies of uterine malformations
Authors: Jacquinet Adeline , Millar Debra , Lehman Anna
Published: June 2016

Ranging from aplastic uterus (including Mayer–Rokitansky–Kuster–Hauser syndrome) to incomplete septate uterus, uterine malformations as a group are relatively frequent in the general population. Specific causes remain largely unknown. Although most occurrences ostensibly seem sporadic, familial recurrences have been observed, which strongly implicate genetic factors. Through the study of animal models, human syndromes, and structural chromosomal variation, several candidate genes have been proposed and subsequently tested with targeted methods in series of individuals with isolated, non‐isolated, or syndromic uterine malformations. To date, a few genes have garnered strong evidence of causality, mainly in syndromic presentations (HNF1B, WNT4, WNT7A, HOXA13). Sequencing of candidate genes in series of individuals with isolated uterine abnormalities has been able to suggest an association for several genes, but confirmation of a strong causative effect is still lacking for the majority of them. We review the current state of knowledge about the developmental origins of uterine malformations, with a focus on the genetic variants that have been implicated or associated with these conditions in humans, and we discuss potential reasons for the high rate of negative results. The evidence for various environmental and epigenetic factors is also reviewed. © 2016 Wiley Periodicals, Inc.
Is one diagnosis the whole story? patients with double diagnoses
Authors: Kurolap Alina , Orenstein Naama , Kedar Inbal , Weisz Hubshman Monika , Tiosano Dov , Mory Adi , Levi Zohar , Marom Daphna , Cohen Lior , Ekhilevich Nina , Douglas Jessica , Nowak Catherine Bearce , Tan Wen‐Hann , Baris Hagit N.
Published: June 2016

One of the goals of evaluating a patient in the genetics clinic is to find the diagnosis that would explain his or her clinical presentation. Sometimes the patient's diagnosis remains undefined or does not explain all of the clinical findings. As clinicians are often guided by a “single disorder” paradigm, diagnosing multiple genetic conditions in the same patient requires a heightened sense of awareness. Over the last few years, we evaluated several patients (n = 14) who were found to have more than one genetic diagnosis. In this paper, we will describe their natural history and diagnoses, and draw on the lessons learned from this phenomenon, which we expect to grow in this era of next‐generation diagnostic technologies. To our knowledge, this is by far the largest series of patients with double diagnoses. Based on our findings, we strongly recommend that physicians question every diagnosis to determine whether it indeed explains all of the patients' symptoms, and consider whether they should continue the diagnostic evaluation to look for a more accurate and complete set of diagnoses. © 2016 Wiley Periodicals, Inc.
Aiming low: A resident male's rank predicts takeover success by challenging males in Yunnan snub‐nosed monkeys
Authors: Zhu Pingfen , Ren Baoping , Garber Paul A. , Xia Fan , Grueter Cyril C. , Li Ming
Published: June 2016

In many primate species that form one‐male breeding units (OMUs), the threat of a takeover by a bachelor male represents a major challenge to group stability and individual reproductive success. In the case of snub‐nosed monkeys, which live in large multilevel or modular societies (MLS) comprising several OMUs that travel, feed and rest together and as well as one or more all male units (AMUs), the process by which rival males challenge resident OMU males for access to females is poorly understood. From September 2012 to October 2013, we recorded 48 cases in which rival males visited an OMU in a MLS of Yunnan snub‐nosed monkeys (Rhinopithecus bieti) inhabiting the Baimaxueshan National Nature Reserve, Yunnan Province, China. In 40 cases, rival males engaged in mild agonistic interactions (approaching, staring, teeth‐baring and chasing) but failed to take over the group; we counted these visits as failed takeovers, recognizing that they may nevertheless allow rival males to assess the competitive ability of residents. During eight successful takeovers, however, there was severe physical aggression between challenging and resident males, with serious injuries to participants. We found that neither the number of adult and subadult females in an OMU, the number of non‐pregnant, non‐lactating adult females in an OMU, nor the rank of a resident male relative to other resident males in the MLS predicted which OMU a challenging male targeted for takeover. However, a resident male's rank significantly predicted whether takeover attempts were successful. Specifically, challenging males were more successful in displacing a lower‐ranking resident male than a higher‐ranking male. Given that a Yunnan snub‐nosed monkey MLS may contain as many as 40 resident and 36 bachelor males, continued research is required to determine the set of factors that enable resident males to maintain high social rank and successfully defend their harems. Am. J. Primatol. 78:974–982, 2016. © 2016 Wiley Periodicals, Inc.
The Reasons Behind Reasoned Arbitration Awards
Authors: Strong S.I.
Published: June 2016

What constitutes a reasoned arbitration award in international commercial arbitration? And why are reasoned awards necessary or at least useful in those cross‐border arbitration settings?
Ferrocenyl Quinone Methide–Thiol Adducts as New Antiproliferative Agents: Synthesis, Metabolic Formation from Ferrociphenols, and Oxidative Transformation
Authors: Wang Yong , Richard Marie‐Aude , Top Siden , Dansette Patrick M. , Pigeon Pascal , Vessières Anne , Mansuy Daniel , Jaouen Gérard
Published: June 2016

Ferrociphenols (FCs) and their oxidized, electrophilic quinone methide metabolites (FC‐QMs) are organometallic compounds related to tamoxifen that exhibit strong antiproliferative properties. To evaluate the reactivity of FC‐QMs toward cellular nucleophiles, we studied their reaction with selected thiols. A series of new compounds resulting from the addition of these nucleophiles, the FC‐SR adducts, were thus synthesized and completely characterized. Such conjugates are formed upon metabolism of FCs by liver microsomes in the presence of NADPH and thiols. Some of the FC‐SR adducts exhibit antiproliferative properties comparable to those of their FC precursors. Under oxidizing conditions they either revert to their FC‐QM precursors or transform into new quinone methides (QMs) containing the SR moiety, FC‐SR‐QM. These results provide interesting data about the reactivity and mechanism of antiproliferative effects of FCs, and also open the way to a new series of organometallic antitumor compounds.
Site‐Selective Tertiary Alkyl–Fluorine Bond Formation from α‐Bromoamides Using a Copper/CsF Catalyst System
Authors: Nishikata Takashi , Ishida Syo , Fujimoto Ryo
Published: June 2016

A copper‐catalyzed site‐selective fluorination of α‐bromoamides possessing multiple reaction sites, such as primary and secondary alkyl−Br bonds, using inexpensive CsF is reported. Tertiary alkyl−F bonds, which are very difficult to synthesize, can be formed by this fluorination reaction with the aid of an amide group. Control experiments revealed that in situ generated CuF2 is a key fluorinating reagent that reacts with the tertiary alkyl radicals generated by the reaction between an α‐bromocarbonyl compound and a copper(I) salt.
Flocculation behavior of cationic pea starch prepared by the graft copolymerization of acrylamide for wastewater treatment
Authors: Zou Yongqiang , Li Shanshan , Wang Yuqi , Yuan Chenxi , Yuan Weijian , Zheng Lan , Han Xiaolong
Published: June 2016

To improve the flocculation efficiency of coal mine wastewater treatment, we synthesized a cationic flocculant by grafting acrylamide (AM) onto pea starch, and we performed the characterization with elemental analysis, Fourier transform infrared spectrometry, scanning electron microscopy, thermogravimetric analysis, and NMR. The effects of the synthesis conditions were also investigated, and the optimal synthesis parameters of the cationic flocculant were obtained. The mass ratio between pea starch and AM was 0.5 with a reaction temperature of 65 °C. The dosages of ceric ammonium nitrate and 3‐chloro‐2‐hydroxypropyl‐trimethylammonium chloride were 0.02 and 0.11 mol/L, respectively. Application experiments for wastewater treatment were carried out consequently, and the optimal dosage of cationic pea starch was 40 mg/L within the pH range 6–8. Compared with other traditional flocculation products, the cationic pea starch showed the best flocculation behavior for coal mine wastewater. Therefore, the cationic pea‐starch‐grafted AM may be applicable as a novel flocculant in wastewater treatment and has already demonstrated outstanding features. It is bound to replace other traditional flocculants in the future. © 2016 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2016, 133, 43922.
Structural studies and SH3 domain binding properties of a human antiviral salivary proline‐rich peptide
Authors: Righino Benedetta , Pirolli Davide , Radicioni Giorgia , Marzano Valeria , Longhi Renato , Arcovito Alessandro , Sanna Maria Teresa , De Rosa Maria Cristina , Paoluzi Serena , Cesareni Gianni , Messana Irene , Castagnola Massimo , Vitali Alberto
Published: June 2016

Human saliva contains hundreds of small proline‐rich peptides originated by the proteolytic cleavage of the salivary basic Proline‐Rich Proteins. Nevertheless only for few of them a specific biological activity has been assigned to date. Among them, the 1932 Da peptide (p1932) has been patented as an anti‐HIV agent. In order to shed light on the possible mechanism of action of this peptide, we assessed in this study, by means of molecular dynamics calculations, circular dichroism and FTIR spectroscopic techniques, that p1932 has an intrinsic propensity to adopt a polyproline‐II helix arrangement. This structural feature combined with the presence of PxxP motifs in its primary structure, represents an essential property for the exploitation of several biological activities. Next to these findings, we recently demonstrated the ability of this peptide to be internalized within cells of the oral mucosa, thus we focused onto a possible intracellular target, represented by the SH3 domains family. Its ability to interact with selected SH3 domains was finally assayed by Surface Plasmon Resonance spectroscopy. As a result, only Fyn, Hck, and c‐Src SH3 domains gave positive results in terms of interaction, showing dissociation constants ranging from nanomolar to micromolar values having the best performer a KD of 148 nM. It is noteworthy that all the interacting domains belong to the Src kinases family, suggesting a role for p1932 as a modulator of the signal transduction pathways mediated by these kinases. © 2016 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 106: 714–725, 2016.
ROS‐responsive drug delivery systems
Authors: Liang Jing , Liu Bin
Published: June 2016

Reactive oxygen species (ROS) play an important role in signal transduction and metabolism. Over‐produced ROS in cells or tissues, however, often leads to oxidation stress that has implications in a series of diseases including cancer, aging, atherosclerosis and inflammation. Driven by the need for on‐demand drug delivery and fuelled by recent development of ROS‐responsive materials and nanomedicine, responsive drug delivery systems (DDSs) have gained increasing research interest. ROS‐responsive DDS is designed to release therapeutic agents only in targets of interest that produce excessive ROS, which may lead to both enhanced therapeutic efficiency and reduced side effects. Multiple‐stimuli responsive DDSs that are also sensitive to other stimuli can further enhance controlled drug release in sites where multiple stimuli coexist. Beyond drug delivery, multifunctional DDSs have great potential in achieving simultaneous imaging, combinatorial therapy and targeting ability by introducing multifunctional elements such as signal reporter, targeting elements and photosensitizer. This review will summarize the latest development of ROS‐responsive DDSs and discuss their design principle and biomedical applications.
A framework to learn graph theory using simple wireless network models
Authors: Dapena Adriana , Vázquez‐Araujo Francisco J. , Castro Paula M. , Souto‐Salorio Maria J.
Published: June 2016

In order to improve the student learning process, we present a framework to define attractive computer laboratory lessons in Engineering Degrees. Theoretical concepts are illustrated from a practical point of view using a graphical user interface designed to establish the relationship between wireless network models and graph theory concepts. In this paper, we will explain some simple routing protocols to illustrate both Dijkstra's algorithm and the graph dominant set. © 2016 Wiley Periodicals, Inc. Comput Appl Eng Educ 24:843–852, 2016; View this article online at wileyonlinelibrary.com/journal/cae; DOI 10.1002/cae.21753
Fluorescent Mechanism‐Based Probe for Aerobic Flavin‐Dependent Enzyme Activity
Authors: McCulloch Ian P. , La Clair James J. , Jaremko Matt J. , Burkart Michael D.
Published: June 2016

Diversity in non‐ribosomal peptide and polyketide secondary metabolism is facilitated by interactions between biosynthetic domains with discrete monomer loading and their cognate tailoring enzymes, such as oxidation or halogenation enzymes. The cooperation between peptidyl carrier proteins and flavin‐dependent enzymes offers a specialized strategy for monomer selectivity for oxidization of small molecules from within a complex cellular milieu. In an effort to study this process, we have developed fluorescent probes to selectively label aerobic flavin‐dependent enzymes. Here we report the preparation and implementation of these tools to label oxidase, monooxygenase, and halogenase flavin‐dependent enzymes.
Semi‐supervised kernel partial least squares fault detection and identification approach with application to HGPWLTP
Authors: Jia Qilong , Du Wenyou , Zhang Yingwei
Published: June 2016

In this paper, fault detection and identification methods based on semi‐supervised Laplacian regularization kernel partial least squares (LRKPLS) are proposed. In Laplacian regularization learning framework, unlabeled and labeled samples are used to improve estimate of data manifold so that one can establish a more robust data model. We show that LRKPLS can avoid the over‐fitting problem which may be caused by sample insufficient and outliers present. Moreover, the proposed LRKPLS approach has no special restriction on data distribution, in other words, it can be used in the case of nonlinear or non‐Gaussian data. On the basis of LRKPLS, corresponding fault detection and identification methods are proposed. Those methods are used to monitor a numerical example and Hot Galvanizing Pickling Waste Liquor Treatment Process (HGPWLTP), and the cases study show effeteness of the proposed approaches. Copyright © 2016 John Wiley & Sons, Ltd.
Gold‐Catalyzed Oxidation/C−H Functionalization of Ynones: Efficient and Rapid Access to Functionalized Polycyclic Salicyl Ketones
Authors: Ji Kegong , Yang Fang , Gao Shiyue , Tang Jiangjiang , Gao Jinming
Published: June 2016

An efficient strategy to construct salicyl ketones through gold‐catalyzed oxidation/C−H functionalization of ynones is reported. A variety of functionalized salicyl ketones are readily accessed by utilizing this non‐diazo approach, thus providing a viable alternative to synthetically useful salicyl ketones with a yield up to 98 %. The α‐oxo gold carbenes generated in situ through gold‐catalyzed oxidation of ynones can be trapped effectively by internal aryl and heteroaromatic groups. Electronic and steric effects were also investigated in this reaction. The anticancer activity of one salicyl ketone analogue was investigated and its cytotoxicity assays against the PC‐3 prostate cancer cell line and SKOV‐3 human ovarian carcinoma cell line yield IC50 were 0.81±0.05 and 0.87±0.15 μm, respectively, demonstrating that salicyl ketone analogues showed good anticancer activity.
New Experimental Insight into the Nature of Metal−Metal Bonds in Digallium Compounds: J Coupling between Quadrupolar Nuclei
Authors: Kobera Libor , Southern Scott A. , Rao Gyandshwar Kumar , Richeson Darrin S. , Bryce David L.
Published: June 2016

Multiple bonding between atoms is of ongoing fundamental and applied interest. Here, we report a multinuclear (1H, 13C, and 71Ga) solid‐state magnetic resonance spectroscopic study of digallium compounds which have been proposed, albeit somewhat controversially, to contain single, double, and triple Ga−Ga bonds. Of particular relevance to the nature of these bonds, we have carried out two‐dimensional 71Ga J/D‐resolved NMR experiments which provide a direct measurement of J(71Ga,71Ga) spin–spin coupling constants across the gallium−gallium bonds. When placed in the context of clear‐cut experimental data for analogous singly, doubly, and triply bonded carbon spin pairs or boron spin pairs, the 71Ga NMR data clearly support the notion of a different bonding paradigm in the gallium systems. Our findings are consistent with an increasing role across the purported gallane–gallene–gallyne series for classical and/or slipped π‐type bonding orbitals.
Formation of Oxazoles from Elusive Gold(I) α‐Oxocarbenes: A Mechanistic Study
Authors: Schulz Jiří , Jašík Juraj , Gray Andrew , Roithová Jana
Published: June 2016

The gold(I) catalyzed reaction between phenylacetylene, pyridine N‐oxide and acetonitrile leading, via a putative gold‐α‐oxocarbene intermediate, towards an oxazole product has been investigated. A novel mass spectrometric method called “delayed reactant labeling” is used to track consecutive and parallel reactions. It clearly shows that the intramolecular formation of a pyridine adduct of gold‐α‐oxocarbene is in competition with the formation of the oxazole product. The reaction mechanism most probably corresponds to competition between acetonitrile and pyridine in an almost barrierless reaction with putative gold‐α‐oxocarbene within the solvent cage. The detected ionic species have been characterized by helium tagging infrared photodissociation spectroscopy.
Cobalt‐Catalyzed C(sp2)−H Methylation by using Dicumyl Peroxide as both the Methylating Reagent and Hydrogen Acceptor
Authors: Li Qun , Li Yanrong , Hu Weipeng , Hu Renjian , Li Guigen , Lu Hongjian
Published: June 2016

The first cobalt‐catalyzed direct methylation of a C(sp2)−H bond using dicumyl peroxide (DCP) as both the methylating reagent and hydrogen acceptor has been established. The reaction proceeded without the use of any additives, and was proven to be applicable to various amides bearing a 2‐pyridinylisopropyl (PIP) directing group, providing an efficient access to o‐methyl aryl amides with high functional‐group tolerance. Preliminary mechanistic studies suggest a radical process would be involved in the catalytic process.
c‐FOS expression in the visual system of tree shrews after monocular inactivation
Authors: Takahata Toru , Kaas Jon H.
Published: June 2016

Tree shrews possess an unusual segregation of ocular inputs to sublayers rather than columns in the primary visual cortex (V1). In this study, the lateral geniculate nucleus (LGN), superior colliculus (SC), pulvinar, and V1 were examined for changes in c‐FOS, an immediate‐early gene, expression after 1 or 24 hours of monocular inactivation with tetrodotoxin (TTX) in tree shrews. Monocular inactivation greatly reduced gene expression in LGN layers related to the blocked eye, whereas normally high to moderate levels were maintained in the layers that receive inputs from the intact eye. The SC and caudal pulvinar contralateral to the blocked eye had greatly (SC) or moderately (pulvinar) reduced gene expressions reflective of dependence on the contralateral eye. c‐FOS expression in V1 was greatly reduced contralateral to the blocked eye, with most of the expression that remained in upper layer 4a and lower 4b and lower layer 6 regions. In contrast, much of V1 contralateral to the active eye showed normal levels of c‐FOS expression, including the inner parts of sublayers 4a and 4b and layers 2, 3, and 6. In some cases, upper layer 4a and lower 4b showed a reduction of gene expression. Layers 5 and sublayer 3c had normally low levels of gene expression. The results reveal the functional dominance of the contralateral eye in activating the SC, pulvinar, and V1, and the results from V1 suggest that the sublaminar organization of layer 4 is more complex than previously realized. J. Comp. Neurol. 525:151–165, 2017. © 2016 Wiley Periodicals, Inc.
Pharmacokinetic and Pharmacodynamic Drug Interaction Study of Piragliatin, a Glucokinase Activator, and Glyburide, a Sulfonylurea, in Type 2 Diabetic Patients
Authors: Zhai S. , Georgy A. , Liang Z. , Zhi J.
Published: June 2016

A glucokinase activator and a sulfonylurea might be coprescribed to synergize treatment success for type 2 diabetes (T2D). This clinical pharmacology study was designed to investigate the potential glucose‐lowering effect or pharmacodynamic (PD), pharmacokinetic (PK), and safety/tolerability interactions between piragliatin and glyburide in T2D patients already taking glyburide but not adequately controlled. This was an open‐label, multiple‐dose, 3‐period, single‐sequence crossover design: on days –1, 6, and 12, PD and PK samples were drawn with glyburide alone (period 0), piragliatin + glyburide (period 1), and piragliatin alone (period 2) treatments. The glucose‐lowering effect, including fasting plasma glucose (FPG), of piragliatin was more pronounced when it was administered concomitantly with glyburide as compared to piragliatin or glyburide administered alone. However, this enhancement cannot be explained by a potential PK interaction between piragliatin and glyburide. Other than hypoglycemia, there were no clinically relevant safety findings. Thus, the enhanced PD effect warrants further investigation to define the optimal dose combination between glucokinase activators and sulfonylureas with regard to efficacy, safety, and tolerability.
Pharmacokinetic Interactions Between Isavuconazole and the Drug Transporter Substrates Atorvastatin, Digoxin, Metformin, and Methotrexate in Healthy Subjects
Authors: Yamazaki Takao , Desai Amit , Goldwater Ronald , Han David , Lasseter Kenneth C. , Howieson Corrie , Akhtar Shahzad , Kowalski Donna , Lademacher Christopher , Rammelsberg Diane , Townsend Robert
Published: June 2016

This article summarizes 4 phase 1 trials that explored interactions between the novel, triazole antifungal isavuconazole and substrates of the drug transporters breast cancer resistance protein (BCRP), multidrug and toxin extrusion protein‐1 (MATE1), organic anion transporters 1/3 (OAT1/OAT3), organic anion‐transporting polypeptide 1B1 (OATP1B1), organic cation transporters 1/2 (OCT1/OCT2), and P‐glycoprotein (P‐gp). Healthy subjects received single doses of atorvastatin (20 mg; OATP1B1 and P‐gp substrate), digoxin (0.5 mg; P‐gp substrate), metformin (850 mg; OCT1, OCT2, and MATE1 substrate), or methotrexate (7.5 mg; BCRP, OAT1, and OAT3 substrate) in the presence and absence of clinical doses of isavuconazole (200 mg 3 times a day for 2 days; 200 mg once daily thereafter). Coadministration with isavuconazole increased mean area under the plasma concentration‐time curves (90% confidence interval) of atorvastatin, digoxin, and metformin to 137% (129, 145), 125% (117, 134),  and 152% (138, 168) and increased mean maximum plasma concentrations to 103% (88, 121), 133% (119, 149), and 123% (109, 140), respectively. Methotrexate parameters were unaffected by isavuconazole. There were no serious adverse events. These findings indicate that isavuconazole is a weak inhibitor of P‐gp, as well as OCT1, OCT2, MATE1, or a combination thereof but not of BCRP, OATP1B1, OAT1, or OAT3.
Pharmacokinetic Effects of Isavuconazole Coadministration With the Cytochrome P450 Enzyme Substrates Bupropion, Repaglinide, Caffeine, Dextromethorphan, and Methadone in Healthy Subjects
Authors: Yamazaki Takao , Desai Amit , Goldwater Ronald , Han David , Howieson Corrie , Akhtar Shahzad , Kowalski Donna , Lademacher Christopher , Pearlman Helene , Rammelsberg Diane , Townsend Robert
Published: June 2016

This report describes phase 1 clinical trials performed to assess interactions of oral isavuconazole at the clinically targeted dose (200 mg, administered as isavuconazonium sulfate 372 mg, 3 times a day for 2 days; 200 mg once daily [QD] thereafter) with single oral doses of the cytochrome P450 (CYP) substrates: bupropion hydrochloride (CYP2B6; 100 mg; n = 24), repaglinide (CYP2C8/CYP3A4; 0.5 mg; n = 24), caffeine (CYP1A2; 200 mg; n = 24), dextromethorphan hydrobromide (CYP2D6/CYP3A4; 30 mg; n = 24), and methadone (CYP2B6/CYP2C19/CYP3A4; 10 mg; n = 23). Compared with each drug alone, coadministration with isavuconazole changed the area under the concentration‐time curves (AUC∞) and maximum concentrations (Cmax) as follows: bupropion, AUC∞ reduced 42%, Cmax reduced 31%; repaglinide, AUC∞ reduced 8%, Cmax reduced 14%; caffeine, AUC∞ increased 4%, Cmax reduced 1%; dextromethorphan, AUC∞ increased 18%, Cmax increased 17%; R‐methadone, AUC∞ reduced 10%, Cmax increased 3%; S‐methadone, AUC∞ reduced 35%, Cmax increased 1%. In all studies, there were no deaths, 1 serious adverse event (dextromethorphan study; perioral numbness, numbness of right arm and leg), and adverse events leading to study discontinuation were rare. Thus, isavuconazole is a mild inducer of CYP2B6 but does not appear to affect CYP1A2‐, CYP2C8‐, or CYP2D6‐mediated metabolism.
Pharmacokinetic Assessment of Drug‐Drug Interactions of Isavuconazole With the Immunosuppressants Cyclosporine, Mycophenolic Acid, Prednisolone, Sirolimus, and Tacrolimus in Healthy Adults
Authors: Groll Andreas H. , Desai Amit , Han David , Howieson Corrie , Kato Kota , Akhtar Shahzad , Kowalski Donna , Lademacher Christopher , Lewis William , Pearlman Helene , Mandarino Debra , Yamazaki Takao , Townsend Robert
Published: June 2016

This report summarizes phase 1 studies that evaluated pharmacokinetic interactions between the novel triazole antifungal agent isavuconazole and the immunosuppressants cyclosporine, mycophenolic acid, prednisolone, sirolimus, and tacrolimus in healthy adults. Healthy subjects received single oral doses of cyclosporine (300 mg; n = 24), mycophenolate mofetil (1000 mg; n = 24), prednisone (20 mg; n = 21), sirolimus (2 mg; n = 22), and tacrolimus (5 mg; n = 24) in the presence and absence of clinical doses of oral isavuconazole (200 mg 3 times daily for 2 days; 200 mg once daily thereafter). Coadministration with isavuconazole increased the area under the concentration‐time curves (AUC0–∞) of tacrolimus, sirolimus, and cyclosporine by 125%, 84%, and 29%, respectively, and the AUCs of mycophenolic acid and prednisolone by 35% and 8%, respectively. Maximum concentrations (Cmax) of tacrolimus, sirolimus, and cyclosporine were 42%, 65%, and 6% higher, respectively; Cmax of mycophenolic acid and prednisolone were 11% and 4% lower, respectively. Isavuconazole pharmacokinetics were mostly unaffected by the immunosuppressants. Two subjects experienced elevated creatinine levels in the cyclosporine study; most adverse events were not considered to be of clinical concern. These results indicate that isavuconazole is an inhibitor of cyclosporine, mycophenolic acid, sirolimus, and tacrolimus metabolism.
Pharmacokinetic Evaluation of CYP3A4‐Mediated Drug‐Drug Interactions of Isavuconazole With Rifampin, Ketoconazole, Midazolam, and Ethinyl Estradiol/Norethindrone in Healthy Adults
Authors: Townsend Robert , Dietz Albert , Hale Christine , Akhtar Shahzad , Kowalski Donna , Lademacher Christopher , Lasseter Kenneth , Pearlman Helene , Rammelsberg Diane , Schmitt‐Hoffmann Anne , Yamazaki Takao , Desai Amit
Published: June 2016

This report describes the phase 1 trials that evaluated the metabolism of the novel triazole antifungal isavuconazole by cytochrome P450 3A4 (CYP3A4) and isavuconazole's effects on CYP3A4‐mediated metabolism in healthy adults. Coadministration of oral isavuconazole (100 mg once daily) with oral rifampin (600 mg once daily; CYP3A4 inducer) decreased isavuconazole area under the concentration‐time curve (AUCτ) during a dosing interval by 90% and maximum concentration (Cmax) by 75%. Conversely, coadministration of isavuconazole (200 mg single dose) with oral ketoconazole (200 mg twice daily; CYP3A4 inhibitor) increased isavuconazole AUC from time 0 to infinity (AUC0‐∞) and Cmax by 422% and 9%, respectively. Isavuconazole was coadministered (200 mg 3 times daily for 2 days, then 200 mg once daily) with single doses of oral midazolam (3 mg; CYP3A4 substrate) or ethinyl estradiol/norethindrone (35 μg/1 mg; CYP3A4 substrate). Following coadministration, AUC0‐∞ increased 103% for midazolam, 8% for ethinyl estradiol, and 16% for norethindrone; Cmax increased by 72%, 14%, and 6%, respectively. Most adverse events were mild to moderate in intensity; there were no deaths, and serious adverse events and adverse events leading to study discontinuation were rare. These results indicate that isavuconazole is a sensitive substrate and moderate inhibitor of CYP3A4.