bluuebunny/crossref_metadata_2025 huggingface dataset:
Journalistic Objectivity
Authors: Meyers Christopher
Published: June 2015

The traditional conception of journalistic objectivity holds that the reporter's task is to be seemingly invisible in the process of acquiring and disseminating news; if she does her job well, she is like a “mirror,” merely reflecting – absent distortion – the world to readers and viewers. This article, first, provides the historical origins of the traditional standard of objectivity; second, it argues that society is best served when its news media at least reach for the
core elements
of that traditional version, namely, accurate and thorough information; third, it looks at four of the more telling critiques of the traditional model; and, fourth, it concludes with a recommended
systems‐based
alternative that captures those core elements and thereby the moral import of objectivity, while also avoiding the critiques.
Professional Ethics
Authors: Meyers Christopher
Published: June 2015

The first task in an essay of this sort is to identify what distinguishes the topic – professional ethics – from other areas of ethics. The aim here, thus, will be to explain what makes professional ethics distinctive and to discuss its critical role within broader concerns in practical ethics. The thesis is that the practice of professions has a structural normativity: to accept the role of a professional is to have a moral commitment to the acquisition and reliance on a technical expertise practiced, first and foremost, in service of one's client's vital needs. This commitment thus creates, reflects, and reinforces the normative foundation of professionalism: a professional/client relationship rooted intrust.
Body
Authors: Weiss Gail
Published: June 2015

What does the body have to do with ethics? Many different answers have been provided to this question over the centuries. Indeed, the body's needs, desires, and affective responses have more often than not been seen as detrimental influences upon the “pure” reasoning that philosophers have historically claimed is both necessary and sufficient for making moral choices. For instance, although Plato and Aristotle, Descartes, and Kant all emphasize, in accordance with the rationalist tradition, that reason alone must guide us in choosing the best course of action in any given situation, they all also recognize that it is difficult to exercise reason if the body's own needs are not being attended to, since an unhealthy body and/or the experience of severe bodily discomfort can distract us from utilizing reason properly. To avoid being unduly influenced by our carnal appetites, they suggest that reason should govern our bodily impulses so as to prevent our committing irrational and/or immoral actions. Since, for the rationalists, reason is a perfect, God‐given faculty that only human beings possess that will unerringly lead us to make the right (rational) decisions if we use it properly, making the wrong decisions cannot be the fault of reason itself, but is rather due to our letting ourselves be guided by nonrational forces, which, not surprisingly, most frequently turn out to be our bodily needs and desires. The body, then, is historically associated with the nonrational parts of the soul or self that we share with other animals.
Condorcet
Authors: Ansart Guillaume
Published: June 2015

A mathematician by training, Condorcet (1743–94) is most famous today for pioneering the application of mathematics to the study of social phenomena, for his contributions to political science, especially the theory of voting or social choice, and for fervently championing human rights, including the political rights of women. His ethical theory is inscribed within the broader context of an empiricist/sensualist theory of knowledge inherited from Locke. It also reflects the influence of sentimentalist moral philosophies such as those of Hume and Adam Smith. In Condorcet's view, moral ideas have their origin in natural moral sentiments, which themselves can be traced back to sensations. Like Hume and Smith, he rejects moral rationalism: although our rational faculty plays an important role in the formation of fully developed moral ideas, the moral sentiments that constitute their foundation are not derived from reason. Similarly, Condorcet is hostile to a purely utilitarian approach to ethics. Whereas elaborate moral ideas often involve calculations based on enlightened self‐interest, the moral sentiments themselves do not result from any calculation of interest.
Edwards, Jonathan
Authors: Cochran Elizabeth Agnew
Published: June 2015

Jonathan Edwards was an American Puritan theologian and philosopher. He is known primarily for his sermon “Sinners in the Hands of an Angry God” and for his involvement with the First Great Awakening, but he was also a prolific writer and a complex thinker who engaged with a range of early modern philosophical positions, particularly those associated with British thought. He was influential in his own time, and his works are still widely studied. Edwards's upbringing was deeply informed by Puritan Calvinism; his father and grandfather were both Puritan pastors. He studied at Yale and became a pastor, and his work in the religious awakenings drew international attention, with Isaac Watts overseeing the publishing in London of one of Edwards's accounts of these revivals. Edwards wrote extensively throughout his adulthood, engaging contemporary theological and philosophical debates. He was named President of Princeton University in 1758, but died a few months later after contracting smallpox through an inoculation.
Expert Testimony, Ethics of
Authors: Borenstein Jason
Published: June 2015

Individuals who are deemed to be experts are often asked to provide testimony before legislative committees, regulatory bodies, and the courts (both civil and criminal). Their testimony can greatly influence the decision‐making of these bodies. Yet before deciding what role such testimony should play, we should determine what makes someone an expert, what bounds an area of expertise, and how a non‐expert can effectively evaluate an expert's claims. Intertwined with the epistemological issues of what expertise is and how to identify an expert are ethical considerations. Considering how important an expert's influence can be on a criminal or civil case and a government's deliberations, many ethical issues related to expert witness testimony emerge, including whether, and to what degree, we should accept their testimony. Although the scope of these issues is quite broad, this article focuses on the use of expert testimony in the courtroom.
Grief
Authors: Cholbi Michael
Published: June 2015

That human beings are mortal, social, and interdependent ensures that virtually everyone experiences grief during the course of their lives. While it is arguable that we experience grief in response to a wide array of losses or life‐transforming events (e.g., divorce, loss of a job or career), this entry will focus on the paradigm cause of grief, namely, the death of a loved one. Despite the ubiquity of grief in human experience, philosophical interest in the topic has waxed and waned over the centuries. Grief was a central concern of the ancient Roman philosophical schools, serving as part of those schools’ larger project of using philosophy to investigate our own mortality and to prepare us for death. In contrast, interest in grief among contemporary ethicists has been sporadic and scant. Claims about the nature or value of grief are occasionally made, but rarely are they carefully interrogated or systematically engaged. As a result, we lack at present any developed philosophical “theories of grief.” This essay will not attempt to offer such a theory; rather, it addresses several interrelated ethical questions concerning grief, concluding by highlighting their interrelations.
Hospitality
Authors: Still Judith
Published: June 2015

At first glance, hospitality can be seen as an everyday practice of welcoming friends or family into one's home, and today the term is also commonly used in the commercial domain. However, philosophers and other writers over the centuries have presented hospitality, in particular the welcome accorded to strangers, as fundamental to the constitution of the human subject as ethical being. This essay focuses on this second aspect, although more quotidian elements should not simply be excluded from consideration of the philosophical conceptualization. The main source will be the writings of Jacques Derrida, who, following Emmanuel Levinas, suggests that in some ways ethics is hospitality. After introducing the term, the essay considers, first, Derrida's opposition between theabsolute Lawand the social or juridicallawsof hospitality, then the related question ofreciprocity, and finally the danger ofviolencethat haunts hospitality.
Niebuhr, H. Richard
Authors: Lovin Robin
Published: June 2015

Helmut Richard Niebuhr was an American theologian whose work was characterized by a realistic understanding of the social forces that shape Christian doctrine and systematic attention to the theological presuppositions of the Christian moral life. As a professor at Yale Divinity School, he influenced generations of students with a historical, philosophical, and ecumenical approach to the study of Christian ethics. Niebuhr was born in Wright City, Missouri, and grew up in parsonages of the Evangelical Synod, an American denomination whose members were predominantly from German immigrant families like the Niebuhrs. Helmut was a gifted student, graduating from Elmhurst College and Eden Theological Seminary and serving as a pastor for several years before joining the Eden faculty in 1919. In two years of further study at Yale, he completed a second theological degree and his PhD. He then became, in rapid succession, president of Elmhurst College and academic dean of Eden Theological Seminary, and he helped lead the Evangelical Synod into a new union known as the Evangelical and Reformed Church, which would later become part of the United Church of Christ. These early experiences of pastoral, institutional, and denominational leadership were formative for Niebuhr, but the rest of his life would be devoted to the scholarship and teaching that began when he joined the faculty of Yale Divinity School in 1931.
3D‐Printed Atsttrin‐Incorporated Alginate/Hydroxyapatite Scaffold Promotes Bone Defect Regeneration with TNF/TNFR Signaling Involvement
Authors: Wang Quan , Xia Qingqing , Wu Yan , Zhang Xiaolei , Wen Feiqiu , Chen Xiaowen , Zhang Shufang , Heng Boon Chin , He Yong , Ouyang Hong‐Wei
Published: June 2015

High expression levels of pro‐inflammatory tumor necrosis factor (TNF)‐α within bone defects can decelerate and impair bone regeneration. However, there are few available bone scaffolds with anti‐inflammatory function. The progranulin (PGRN)‐derived engineered protein, Atsttrin, is known to exert antagonistic effects on the TNF‐α function. Hence, this study investigates whether 3D‐printed Atsttrin‐incorporated alginate(Alg)/hydroxyapatite(nHAp) scaffolds can facilitate bone healing through affecting the TNF/TNFR signaling. A 3D bioprinting system is used to fabricate Atsttrin‐Alg/nHAp composite scaffolds, and the Atsttrin release from this scaffold is characterized, followed by evaluation of its efficacy on bone regeneration both in vitro and in vivo. The 3D‐printed Atsttrin‐Alg/nHAp scaffold exhibits a precisely defined structure, can sustain Atsttrin release for at least 5 days, has negligible cytotoxicity, and supports cell adhesion. Atsttrin can also attenuate the suppressive effects of TNF‐α on BMP‐2‐induced osteoblastic differentiation in vitro. The 3D‐printed Atsttrin‐Alg/nHAp scaffold significantly reduces the number of TNF‐α positive cells within wound sites, 7 days after post‐calvarial defect surgery. Additionally, histological staining and X‐ray scanning results also show that the 3D‐printed Atsttrin‐Alg/nHAp scaffold enhances the regeneration of mice calvarial bone defects. These findings thus demonstrate that the precise structure and anti‐inflammatory properties of 3D‐printed Atsttrin‐Alg/nHAp scaffolds may promote bone defect repair.
Gold(I)‐Catalyzed Tandem Reaction of γ‐Amino‐Substituted Propargylic Esters to Pyrrolines and its Application in the Formal Synthesis of (±)‐Aphanorphine
Authors: Wang Zhengshen , Zheng Huaiji , Yang Juan , Xie Xingang , She Xuegong
Published: June 2015

An effective synthesis of structurally diverse pyrroline derivatives has been accomplished by a gold(I)‐catalyzed tandem 1,3‐acyloxy rearrangement/intramolecular azacylization reaction of γ‐amino‐substituted propargylic esters in good to excellent chemical yields (52–98%). The reaction proceeds under extremely mild conditions and has also demonstrated its potential in a concise formal synthesis of (±)‐aphanorphine with a catalyst loading as low as 0.5 mol% to provide the key intermediate 5‐(4‐methoxybenzyl)‐1‐tosyl‐2,5‐dihydro‐1H‐pyrrol‐3‐yl pivalate on a gram scale.

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2,6‐Bis(amido)benzoic Acid with Internal Hydrogen Bond as Brønsted Acid Catalyst for Friedel–Crafts Reaction of Indoles
Authors: Moriyama Katsuhiko , Sugiue Toru , Saito Yuki , Katsuta Shoichi , Togo Hideo
Published: June 2015

Benzoic acid catalysts bearing two amide groups that increase the Brønsted acidity of the carboxylic acid moiety by internal hydrogen‐bonding interactions were designed as a novel class of carboxylic acid catalysts for the Friedel–Crafts reaction of indoles with β‐nitrostyrenes and 3,3‐disubstituted 3H‐indoles to obtain the corresponding Friedel–Crafts adducts in high yields. The internal hydrogen‐bonding benzoic acid catalysts have a relatively high Brønsted acidity compared with benzoic acid based on the pKa measurements in DMSO by UV spectrophotometric titration.

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Direct ortho‐Hydroxylation of 2‐Phenylpyridines using Palladium(II) Chloride and Hydrogen Peroxide
Authors: Yamaguchi Tomoaki , Yamaguchi Eiji , Tada Norihiro , Itoh Akichika
Published: June 2015

Direct functionalization of the ubiquitous CH bond is receiving much attention because complex structures can be formed from simple precursors. This paper reports a useful method for the direct hydroxylation of 2‐phenylpyridines using palladium(II) chloride and aqueous hydrogen peroxide. In this method, hydrogen peroxide, which has high atom efficiency, is employed as the oxidant and phenol derivatives are generated via CH activation.

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Nonlinear PI controllers with output transformations
Authors: Lee Jietae , Edgar Thomas F.
Published: June 2015

Well‐designed nonlinear proportional‐integral (PI) controllers are successful for nonlinear dynamical processes like linear PI controllers are for linear processes. Two nonlinear blocks representing proportional and integral terms can be designed so that the linearized controllers perform the same as linear PI controllers for linearized processes at the given operating points. For some nonlinear processes, nonlinear blocks for nonlinear PI controllers can be singular at some operating points, and control performances can be poor for set points near those points. To mitigate such disadvantages, new nonlinear PI controllers that introduce output transformations are proposed. Several examples are given, showing the performance of the proposed nonlinear PI controllers. © 2015 American Institute of Chemical Engineers AIChE J, 61: 4264–4269, 2015
Sauerstoffmessung in der Biomedizin – von der Makro‐ zur Mikroebene
Authors: Roussakis Emmanuel , Li Zongxi , Nichols Alexander J. , Evans Conor L.
Published: June 2015

Der Messung von Sauerstoff sind wegen dessen zentraler Rolle in der Biochemie des Lebens bereits umfassende Studien gewidmet worden. Um Mechanismen unter normalen physiologischen Verhältnissen ebenso wie bei Krankheitszuständen untersuchen und verstehen zu können, ist es notwendig, die physiologische Verteilung und die Dynamik von Sauerstoff auf subzellulärer und makroskopischer Ebene in Echtzeit quantifizieren zu können. Dieser Aufsatz diskutiert die wichtigsten aktuellen Fortschritte bei der Entwicklung von Sauerstoffsensormaterialien und stellt dabei polarographische, nuklearmedizinische, Magnetresonanz‐basierte und optische Techniken vor, die eine spezifische Verfolgung der Sauerstoffdynamik in Zell‐ und Gewebsumgebungen in Echtzeit ermöglichen. Da einige der interessantesten Fortschritte bezüglich Synthesemethoden und biomedizinischen Anwendungen auf dem Gebiet der optischen Sauerstoffsensoren zu verzeichnen sind, werden wir einen Schwerpunkt auf die Entwicklung dieser Konzepte legen.
Eine additivarme photoredoxkatalysierte reduktive Kupplung von Aldehyden, Ketonen und Iminen mit sichtbarem Licht
Authors: Nakajima Masaki , Fava Eleonora , Loescher Sebastian , Jiang Zhen , Rueping Magnus
Published: June 2015

Ketylradikale und Aminoradikalanionen sind interessante reaktive Intermediate für C‐C‐Kupplungen. Dennoch ist die Verwendung dieser reaktiven Intermediate in der Katalyse nur spärlich beschrieben. Grund hierfür sind die thermodynamisch ungünstigen Verhältnisse einer Carbonyl‐ oder Imin‐Umpolung mittels der Redoxkatalysatoren. Im Rahmen des reduktiven Löschzyklus in der Photoredoxkatalyse kommen gewöhnlich tertiäre Amine als Coreduktionsmittel zum Einsatz, die keine weitere nennenswerte Funktion erfüllen. Wir zeigen hier, dass dem Amin eine duale Rolle zukommen kann und für eine organokatalytische Präaktivierung der Substrate entscheidend ist. Die Kombination von Photoredoxkatalyse und Carbonyl/Imin‐Aktivierung ermöglichte uns erstmals die reduktive Kupplung von Benzaldehyden, Ketonen und Iminen unter milden Bedingungen.
The Mechanism of the Interactions of Pironetin Analog/Combretastatin A‐4 Hybrids with Tubulin
Authors: Torijano‐Gutiérrez Sandra , Vilanova Concepción , Díaz‐Oltra Santiago , Murga Juan , Falomir Eva , Carda Miguel , Redondo‐Horcajo Mariano , Díaz José Fernando , Barasoain Isabel , Marco Juan Alberto
Published: June 2015

We here report an investigation of the interactions with tubulin of two types of molecules of a hybrid structural type consisting in a combretastatin A‐4 moiety and a simplified pironetin fragment. The cytotoxicities of the molecules on two reference tumoral cell lines were measured. In addition, the effects of the compounds on the cell cycle and on microtubule assembly were observed. The dynamics of microtubule polymerization was investigated by means of immunofluorescence assays. It was thus established that at least some of the compounds under study exert their cytotoxic action by means of interaction with tubulin.
Physiologically based pharmacokinetic modeling to predict complex drug–drug interactions: a case study of AZD2327 and its metabolite, competitive and time‐dependent CYP3A inhibitors
Authors: Guo Jian , Zhou Diansong , Li Yan , Khanh Bui H.
Published: June 2015

4‐{(R)‐(3‐Aminophenyl)[4‐(4‐fluorobenzyl)‐piperazin‐1‐yl]methyl}‐N,N‐diethylbenzamide (AZD2327) is a highly potent and selective agonist of the δ‐opioid receptor. AZD2327 and N‐deethylated AZD2327 (M1) are substrates of cytochrome P450 3A (CYP3A4) and comprise a complex multiple inhibitory system that causes competitive and time‐dependent inhibition of CYP3A4. The aim of the current work was to develop a physiologically based pharmacokinetic (PBPK) model to predict quantitatively the magnitude of CYP3A4 mediated drug–drug interaction with midazolam as the substrate. Integrating in silico, in vitro and in vivo PK data, a PBPK model was successfully developed to simulate the clinical accumulation of AZD2327 and its primary metabolite. The inhibition of CYP3A4 by AZD2327, using midazolam as a probe drug, was reasonably predicted. The predicted maximum concentration (Cmax) and area under the concentration–time curve (AUC) for midazolam were increased by 1.75 and 2.45‐fold, respectively, after multiple dosing of AZD2327, indicating no or low risk for clinically relevant drug–drug interactions (DDI). These results are in agreement with those obtained in a clinical trial with a 1.4 and 1.5‐fold increase in Cmax and AUC of midazolam, respectively. In conclusion, this model simulated DDI with less than a two‐fold error, indicating that complex clinical DDI associated with multiple mechanisms, pathways and inhibitors (parent and metabolite) can be predicted using a well‐developed PBPK model. Copyright © 2015 John Wiley & Sons, Ltd.
Evolution of vertebrate adaptive immunity: Immune cells and tissues, and AID/APOBEC cytidine deaminases
Authors: Hirano Masayuki
Published: June 2015

All surviving jawed vertebrate representatives achieve diversity in immunoglobulin‐based B and T cell receptors for antigen recognition through recombinatorial rearrangement of V(D)J segments. However, the extant jawless vertebrates, lampreys and hagfish, instead generate three types of variable lymphocyte receptors (VLRs) through a template‐mediated combinatorial assembly of different leucine‐rich repeat (LRR) sequences. The clonally diverse VLRB receptors are expressed by B‐like lymphocytes, while the VLRA and VLRC receptors are expressed by lymphocyte lineages that resemble αβ and γδ T lymphocytes, respectively. These findings suggest that three basic types of lymphocytes, one B‐like and two T‐like, are an essential feature of vertebrate adaptive immunity. Around 500 million years ago, a common ancestor of jawed and jawless vertebrates evolved a genetic program for the development of prototypic lymphoid cells as a foundation for an adaptive immune system. This acquisition preceded the convergent evolution of alternative types of clonally diverse receptors for antigens in all vertebrates, as reviewed in this article.
Modelling microbial competition in nitrifying biofilm reactors
Authors: Vannecke T. P. W. , Volcke E. I. P.
Published: June 2015

A large variety of microbial parameter values for nitrifying microorganisms has been reported in literature and was revised in this study. Part of the variety was attributed to the variety of analysis methods applied; it also reflects the large biodiversity in nitrifying systems. This diversity is mostly neglected in conventional nitrifying biofilm models. In this contribution, a one‐dimensional, multispecies nitrifying biofilm model was set up, taking into account the large variety of the maximum growth rate, the substrate affinity and the yield of nitrifiers reported in literature. Microbial diversity was implemented in the model by considering 60 species of ammonia‐oxidizing bacteria (AOB) and 60 species of nitrite‐oxidizing bacteria (NOB). A steady‐state analysis showed that operational conditions such as the nitrogen loading rate and the bulk liquid oxygen concentration influence both the macroscopic output as well as the microbial composition of the biofilm through the prevailing concentration of substrates throughout the biofilm. Considering two limiting resources (nitrogen and oxygen), the coexistence of two species of the same functional guild (AOB or NOB) was possible at steady state. Their spatial distribution in the biofilm could be explained using the r‐ and K‐selection theory. Biotechnol. Bioeng. 2015;112: 2550–2561. © 2015 Wiley Periodicals, Inc.
Revascularization for chronic limb-threatening ischaemia
Authors: Conte M S , Farber A
Published: June 2015

Trials hampered by poor definitions
Step up your hazing prevention, response initiatives
Authors: McCarthy Claudine
Published: June 2015

More than half of college students who are members of a club, team or organization experience hazing. And 40 percent of college students admit to knowing that hazing is occurring on campus, while 20 percent admit the coach or advisor was involved. That's according to a University of Maine study by Elizabeth Allen and Mary Madden.
Consider whether the Green Dot program could help stop sexual assault on campus
Authors: Bessette Lee Skallerup
Published: June 2015

In fall 2014, sexual assault and rape on campus were forced to the forefront; high‐profile stories from Columbia University, the University of Virginia and Vassar College prove that we have a long way to go in order to curb sexual assault on campus.
The Direct Non‐Perturbing Leaching Test in the Phosphine‐Free Suzuki–Miyaura Reaction Catalyzed by Palladium Nanoparticles
Authors: Kashin Alexander N. , Ganina Olga G. , Cheprakov Andrey V. , Beletskaya Irina P.
Published: June 2015

The aryl halides normally unreactive in the reaction with phenylboronic acid in the presence of a palladium nanoparticle catalyst were shown to become involved, if a more reactive aryl iodide is simultaneously participating in the process. The involvement phenomenon can be interpreted as a direct evidence of the formation of smaller and more reactive palladium nanoparticles through leaching from the initial nanocatalyst. The involvement test was applied both to free unsupported Pd nanoparticles and supported species, thus exhibiting essentially the same character of evolutions of various nanomaterials during the catalytic transformation associated with leaching of reactive species from the initial particles. The system allows for concurrent processing of less reactive aryl bromides and even chlorides together with much more reactive aryl iodides. The interpretation of the observed phenomena and implications for practical realization of nanoparticle catalysts are discussed.
Three‐Dimensional Pseudocapacitive Interface for Enhanced Power Production in a Microbial Fuel Cell
Authors: Gong Xiao‐Bo , You Shi‐Jie , Yuan Yuan , Zhang Jin‐Na , Sun Kai , Ren Nan‐Qi
Published: June 2015

Interface properties are crucial to anodic extracellular electron transfer (EET) and power production of microbial fuel cells (MFCs), because they determine the local density of electroactive biofilms and the efficiency of electron transfer. To enhance MFC performance by improving EET, a 3D‐structured pseudocapacitive interface is created by in situ deposition of MnO2 on a carbon electrode through the redox reaction between permanganate and carbon. The electrochemical performance of the MnO2‐modified carbon paper electrode is increased considerably compared with an unmodified electrode, due to the increased local density of the exoelectrogenic biofilm and effective interfacial shuttling of electrons facilitated by the pseudocapacitive MnO2. The process for constructing 3D MnO2‐based interfaces is technologically simple, environmentally friendly, and cost‐effective. This study provides a new and promising strategy for improving power production in MFCs for scaled‐up applications.
Are Nanoparticles Spherical or Quasi‐Spherical?
Authors: Sokolov Stanislav V. , Batchelor‐McAuley Christopher , Tschulik Kristina , Fletcher Stephen , Compton Richard G.
Published: June 2015

The geometry of quasi‐spherical nanoparticles is investigated. The combination of SEM imaging and electrochemical nano‐impact experiments is demonstrated to allow sizing and characterization of the geometry of single silver nanoparticles.
Absolute Asymmetric Synthesis: Viedma Ripening of [Co(bpy)3]2+ and Solvent‐Free Oxidation to [Co(bpy)3]3+
Authors: Björemark Per Martin , Jönsson Johan , Håkansson Mikael
Published: June 2015

Syntheses of [Co(bpy)3]2+ yield racemic solutions because the Δ‐ and Λ‐enantiomers are stereochemically labile. However, crystallization and attrition‐enhanced deracemization can give homochiral crystal batches of either handedness in quantitative yield. Subsequently, solvent‐free oxidation with bromine vapour fixes the chirality because [Co(bipy)3]3+ does not enantiomerize in solution at ambient temperature. This combination of Viedma ripening and the labile/inert CoII/CoIII couple constitutes a convenient method of absolute asymmetric synthesis.
On the Functional Group Tolerance of Ester Hydrogenation and Polyester Depolymerisation Catalysed by Ruthenium Complexes of Tridentate Aminophosphine Ligands
Authors: Fuentes José A. , Smith Samuel M. , Scharbert M. Theresa , Carpenter Ian , Cordes David B. , Slawin Alexandra M. Z. , Clarke Matthew L.
Published: June 2015

The synthesis of a range of phosphine‐diamine, phosphine‐amino‐alcohol, and phosphine‐amino‐amide ligands and their ruthenium(II) complexes are reported. Five of these were characterised by X‐ray crystallography. The activities of this collection of catalysts were initially compared for the hydrogenation of two model ester hydrogenations. Catalyst turnover frequencies up to 2400 h−1 were observed at 85 °C. However, turnover is slow at near ambient temperatures. By using a phosphine‐diamine RuII complex, identified as the most active catalyst, a range of aromatic esters were reduced in high yield. The hydrogenation of alkene‐, diene‐, and alkyne‐functionalised esters was also studied. Substrates with a remote, but reactive terminal alkene substituent could be reduced chemoselectively in the presence of 4‐dimethylaminopyridine (DMAP) co‐catalyst. The chemoselective reduction of the ester function in conjugated dienoate ethyl sorbate could deliver (2E,4E)‐hexa‐2,4‐dien‐1‐ol, a precursor to leaf alcohol. The monounsaturated alcohol (E)‐hex‐4‐en‐1‐ol was produced with reasonable selectivity, but complete chemoselectivity of CO over the diene is elusive. High chemoselectivity for the reduction of an ester over an alkyne group was observed in the hydrogenation of an alkynoate for the first time. The catalysts were also active in the depolymerisation reduction of samples of waste poly(ethylene terephthalate) (PET) to produce benzene dimethanol. These depolymerisations were found to be poisoned by the ethylene glycol side product, although good yields could still be achieved.
The “Speedy” Synthesis of Atom‐Specific 15N Imino/Amido‐Labeled RNA
Authors: Neuner Sandro , Santner Tobias , Kreutz Christoph , Micura Ronald
Published: June 2015

Although numerous reports on the synthesis of atom‐specific 15N‐labeled nucleosides exist, fast and facile access to the corresponding phosphoramidites for RNA solid‐phase synthesis is still lacking. This situation represents a severe bottleneck for NMR spectroscopic investigations on functional RNAs. Here, we present optimized procedures to speed up the synthesis of 15N(1) adenosine and 15N(1) guanosine amidites, which are the much needed counterparts of the more straightforward‐to‐achieve 15N(3) uridine and 15N(3) cytidine amidites in order to tap full potential of 1H/15N/15N‐COSY experiments for directly monitoring individual Watson–Crick base pairs in RNA. Demonstrated for two preQ1 riboswitch systems, we exemplify a versatile concept for individual base‐pair labeling in the analysis of conformationally flexible RNAs when competing structures and conformational dynamics are encountered.
Faithful PCR Amplification of an Unnatural Base‐Pair Analogue with Four Hydrogen Bonds
Authors: Tarashima Noriko , Komatsu Yasuo , Furukawa Kazuhiro , Minakawa Noriaki
Published: June 2015

In vitro replication of an unnatural imidazopyridopyridine:naphthyridine base pair, (i.e., ImNN:NaOO), having four hydrogen bonds was investigated. Kinetic studies of single‐nucleotide insertion revealed that ImNN and NaOO were recognized as complementary bases by an exonuclease‐deficient Klenow fragment with higher specificity and efficiency than two previously described pairs (ImNO:NaON and ImON:NaNO) because of higher thermal and thermodynamic stabilities and the DAAD:ADDA (D=donor, A=acceptor) hydrogen‐bonding pattern of the ImNN:NaOO pair. Faithful polymerase chain reaction (PCR) amplification of a DNA fragment containing the ImNN:NaOO pair was achieved by using DNA polymerases possessing 3′→5′ exonuclease activity (≈99.5 % per doubling).
Palladium/Copper‐Cocatalyzed Oxidative Amidobrominations of Alkenes
Authors: Chen Xiao Yun , Bohmann Rebekka Anna , Wang Long , Dong Shunxi , Räuber Christoph , Bolm Carsten
Published: June 2015

In the presence of LiBr, a palladium/copper combination catalyzes dehydrogenative amidobrominations of acrylates with NH‐sulfoximines, leading to N‐vinylated products by dual NH/CH coupling, followed by oxidative enamide bromination. Mechanistically, the domino process is proposed to involve palladium(II) species as key intermediates. First synthetic applications of the products have been demonstrated.
Synthesis of C1–C9 Domain of the Nominal Didemnaketal A
Authors: Zhang Shunji , Shi Yong , Tian Weisheng
Published: June 2015

Based on chiral pool strategy, a synthesis of the C1–C9 domain of the proposed structure of didemnaketal A, a natural product with potent HIV‐1 protease inhibitory activity, has been achieved. Key transformations are a Sharpless asymmetric dihydroxylation and a chelation‐controlled allylation.
Classical pathology and mutational load of breast cancer – integration of two worlds
Authors: Budczies Jan , Bockmayr Michael , Denkert Carsten , Klauschen Frederick , Lennerz Jochen K , Györffy Balázs , Dietel Manfred , Loibl Sibylle , Weichert Wilko , Stenzinger Albrecht
Published: June 2015

Breast cancer is a complex molecular disease comprising several biological subtypes. However, daily routine diagnosis is still based on a small set of well‐characterized clinico‐pathological variables. Here, we try to link the two worlds of surgical pathology and multilayered molecular profiling by analyzing the relationships between clinico‐pathological phenotypes and mutational loads of breast cancer. We evaluated the number of mutated genes with somatic non‐silent mutations in different subgroups of breast cancer based on clinico‐pathological, including immunohistochemical and tumour characteristics. The analysis was performed for a cohort of 687 primary breast cancer patients with mutational profiling, gene expression and clinico‐pathological data available from The Cancer Genome Atlas (TCGA) project. The number of mutated genes was strongly positively associated with higher tumour grade (p = 1.4e−14) and with the different immunohistochemical and PAM50 molecular subtypes of breast cancer (p = 1.4e−10 and p = 4.3e−10, respectively). We observed significant associations (|R| > 0.4) between the abundance of mutated genes and expression levels of genes related to proliferation in the overall cohort and hormone receptor positive cohort, including the Recurrence Score gene signature (e.g., MYBL2 and BIRC5). Specific mutated genes (TP53, NCOR1, NF1, PTPRD and RB1) were highly significantly associated with high loads of mutated genes. Multivariate analysis for overall survival (OS) revealed a worse survival for patients with high numbers of mutated genes (hazard ratio = 4.6, 95% CI: 1.0 – 20.0, p = 0.044). Here, we report a strong association of the number of mutated genes with immunohistochemical and PAM50 subtypes and tumour grade in breast cancer. We provide evidence that specific levels of the mutational load underlie different morphological and biological phenotypes, which collectively constitute the current basis of pathological diagnosis. Our study is a step towards genomics‐informed breast pathology and will provide a basis for future studies in this field bridging the gap between morphology, tumour biology and medical oncology.
Freezing the Bioactive Conformation to Boost Potency: The Identification of BAY 85‐8501, a Selective and Potent Inhibitor of Human Neutrophil Elastase for Pulmonary Diseases
Authors: von Nussbaum Franz , Li Volkhart M.‐J. , Allerheiligen Swen , Anlauf Sonja , Bärfacker Lars , Bechem Martin , Delbeck Martina , Fitzgerald Mary F. , Gerisch Michael , Gielen‐Haertwig Heike , Haning Helmut , Karthaus Dagmar , Lang Dieter , Lustig Klemens , Meibom Daniel , Mittendorf Joachim , Rosentreter Ulrich , Schäfer Martina , Schäfer Stefan , Schamberger Jens , Telan Leila A. , Tersteegen Adrian
Published: June 2015

Human neutrophil elastase (HNE) is a key protease for matrix degradation. High HNE activity is observed in inflammatory diseases. Accordingly, HNE is a potential target for the treatment of pulmonary diseases such as chronic obstructive pulmonary disease (COPD), acute lung injury (ALI), acute respiratory distress syndrome (ARDS), bronchiectasis (BE), and pulmonary hypertension (PH). HNE inhibitors should reestablish the protease–anti‐protease balance. By means of medicinal chemistry a novel dihydropyrimidinone lead‐structure class was identified. Further chemical optimization yielded orally active compounds with favorable pharmacokinetics such as the chemical probe BAY‐678. While maintaining outstanding target selectivity, picomolar potency was achieved by locking the bioactive conformation of these inhibitors with a strategically positioned methyl sulfone substituent. An induced‐fit binding mode allowed tight interactions with the S2 and S1 pockets of HNE. BAY 85‐8501 ((4S)‐4‐[4‐cyano‐2‐(methylsulfonyl)phenyl]‐3,6‐dimethyl‐2‐oxo‐1‐[3‐(trifluoromethyl)phenyl]‐1,2,3,4‐tetrahydropyrimidine‐5‐carbonitrile) was shown to be efficacious in a rodent animal model related to ALI. BAY 85‐8501 is currently being tested in clinical studies for the treatment of pulmonary diseases.
Cinnamamide Derivatives for Central and Peripheral Nervous System Disorders—A Review of Structure–Activity Relationships
Authors: Gunia‐Krzyżak Agnieszka , Pańczyk Katarzyna , Waszkielewicz Anna M. , Marona Henryk
Published: June 2015

The cinnamamide scaffold has been incorporated in to the structure of numerous organic compounds with therapeutic potential. The scaffold enables multiple interactions, such as hydrophobic, dipolar, and hydrogen bonding, with important molecular targets. Additionally, the scaffold has multiple substitution options providing the opportunity to optimize and modify the pharmacological activity of the derivatives. In particular, cinnamamide derivatives have exhibited therapeutic potential in animal models of both central and peripheral nervous system disorders. Some have undergone clinical trials and were introduced on to the pharmaceutical market. The diverse activities observed in the nervous system included anticonvulsant, antidepressant, neuroprotective, analgesic, anti‐inflammatory, muscle relaxant, and sedative properties. Over the last decade, research has focused on the molecular mechanisms of action of these derivatives, and the data reported in the literature include targeting the γ‐aminobutyric acid type A (GABAA) receptors, N‐methyl‐D‐aspartate (NMDA) receptors, transient receptor potential (TRP) cation channels, voltage‐gated potassium channels, histone deacetylases (HDACs), prostanoid receptors, opioid receptors, and histamine H3 receptors. Here, the literature data from reports evaluating cinnamic acid amide derivatives for activity in target‐based or phenotypic assays, both in vivo and in vitro, relevant to disorders of the central and peripheral nervous systems are analyzed and structure–activity relationships discussed.
Resonance Character of Copper/Silver/Gold Bonding in Small Molecule⋅⋅⋅MX (X=F, Cl, Br, CH3, CF3) Complexes
Authors: Zhang Guiqiu , Yue Huanjing , Weinhold Frank , Wang Hui , Li Hong , Chen Dezhan
Published: June 2015

The resonance character of Cu/Ag/Au bonding is investigated in B⋅⋅⋅MX (M=Cu, Ag, Au; X=F, Cl, Br, CH3, CF3; B=CO, H2O, H2S, C2H2, C2H4) complexes. The natural bond orbital/natural resonance theory results strongly support the general resonance‐type three‐center/four‐electron (3c/4e) picture of Cu/Ag/Au bonding, B:MX↔B+M:X−, which mainly arises from hyperconjugation interactions. On the basis of such resonance‐type bonding mechanisms, the ligand effects in the more strongly bound OC⋅⋅⋅MX series are analyzed, and distinct competition between CO and the axial ligand X is observed. This competitive bonding picture directly explains why CO in OC⋅⋅⋅AuCF3 can be readily replaced by a number of other ligands. Additionally, conservation of the bond order indicates that the idealized relationship bB⋅⋅⋅M+bMX=1 should be suitably generalized for intermolecular bonding, especially if there is additional partial multiple bonding at one end of the 3c/4e hyperbonded triad.
The Active Molybdenum Oxide Phase in the Methanol Oxidation to Formaldehyde (Formox Process): A DFT Study
Authors: Rellán‐Piñeiro Marcos , López Núria
Published: June 2015

Methanol is oxidised to formaldehyde by the Formox process, in which molybdenum oxides, usually doped with iron, are the catalyst. The active phase of the catalysts and the reasons for the selectivity observed are still unknown. We present a density functional theory based study that indicates the unique character of MoVIMoIV pairs as the most active and selective sites and indicates the active sites on the surface, the controlling factors of selectivity, and the role of the dopant. Iron reduces the energy requirements of the redox MoVIMoIV pair by acting as an electron reservoir that sets in if required. Our present study paves the way towards a better understanding of the process.
Reactive T cells by flow cytometry distinguish Hodgkin lymphomas from T cell/histiocyte‐rich large B cell lymphoma
Authors: Wu David , Thomas Anju , Fromm Jonathan R.
Published: June 2015

Background

Classical Hodgkin lymphoma (CHL), nodular lymphocyte predominant Hodgkin lymphoma (NLPHL), and T‐cell/histiocyte rich large B‐cell lymphoma (T/HRLBCL) are B‐cell lymphomas in which tumor cells are rare as compared with the background reactive infiltrate. We hypothesized that characterization of the reactive infiltrates can provide information to help diagnose these lymphomas.

Methods

Lymphocyte subsets by flow cytometry were analyzed for 27 NLPHL, 20 T/HRLBCL, 34 CHL, and 49 reactive lymph nodes (RLN). CD4+ T cells with bright expression of CD7 and CD45 (CD3+CD4+CD7brightCD45bright), CD4:CD8 ratio, and percentage of T cells, B cells, NK cells, CD4+ T cells, CD8+ T cells, T cells coexpressing CD4, and CD8 (CD4+CD8+), and plasma cells were measured.

Results

The CD3+CD4+CD7brightCD45bright T‐cell population was present in the reactive infiltrate of CHL (76.5%) and T/HRLBCL (92.3%) but not in NLPHL (8.3%) or RLN (4.1%). In a separate analysis of 387 samples, the CD3+CD4+CD7brightCD45bright T‐cell population was also observed in some CD10+ B‐NHL. The mean percentage of CD4+CD8+ T cells was highest for NLPHL (11.7%) and differed significantly from T/HRLBCL, CHL, and RLN. Interestingly, the highest CD4:CD8 ratios were seen with T/HRLBCL. Finally, the percentage of B cells is decreased in T/HRLBCL relative to CHL and NLPHL.

Conclusions

Differences in the reactive inflammatory infiltrate of CHL, NLPHL, and T/HRLBCL and can suggest these diagnoses. Additionally, in contrast to published studies, T/HRLBCL demonstrates both low and very high CD4 to CD8 T‐cell ratios. © 2015 International Clinical Cytometry Society
Flow cytometry used to identify histiocytic sarcoma: A case report
Authors: Wang Huiping , Zhang Jiakui , Tao Qianshan , Bian Hengjuan , Shen Yuanyuan , Li Yingwei , Tao Lili , Wang Chunhuai , Wang Yiping , Zhai Zhimin
Published: June 2015

Histiocytic sarcoma (HS) is an extremely rare but aggressive malignancy of hematopoietic origin. The diagnosis of HS mainly relies on pathological morphology and immunohistochemical staining combined with clinical symptoms. However, whether histiocytic sarcoma can be detected using flow cytometry (FCM) is not clear. We report the case of a 61‐year‐old female patient with a group of abnormal cells identified primarily by FCM. Largeabnormal cells ‐CD68+CD11c+CD14+HLA‐DR+CD123+CD45+ presented in upper forward scatter and side scatter, indicating that a malignancy originally derived from monocyte/macrophage could be histocytic sarcoma. This patient with histiocytic sarcoma was finally confirmed with pathology and immunohistochemistry. In conclusion, HS can be detected by assessment of CD68+CD11c+CD14+HLA‐DR+CD123+CD45+ cells using FCM, suggesting that FCM can be an effective tool for early finding of HS. © 2015 International Clinical Cytometry Society
Consumer trait variation influences tritrophic interactions in salt marsh communities
Authors: Hughes Anne Randall , Hanley Torrance C. , Orozco Nohelia P. , Zerebecki Robyn A.
Published: June 2015

The importance of intraspecific variation has emerged as a key question in community ecology, helping to bridge the gap between ecology and evolution. Although much of this work has focused on plant species, recent syntheses have highlighted the prevalence and potential importance of morphological, behavioral, and life history variation within animals for ecological and evolutionary processes. Many small‐bodied consumers live on the plant that they consume, often resulting in host plant‐associated trait variation within and across consumer species. Given the central position of consumer species within tritrophic food webs, such consumer trait variation may play a particularly important role in mediating trophic dynamics, including trophic cascades. In this study, we used a series of field surveys and laboratory experiments to document intraspecific trait variation in a key consumer species, the marsh periwinkle Littoraria irrorata, based on its host plant species (Spartina alterniflora or Juncus roemerianus) in a mixed species assemblage. We then conducted a 12‐week mesocosm experiment to examine the effects of Littoraria trait variation on plant community structure and dynamics in a tritrophic salt marsh food web. Littoraria from different host plant species varied across a suite of morphological and behavioral traits. These consumer trait differences interacted with plant community composition and predator presence to affect overall plant stem height, as well as differentially alter the density and biomass of the two key plant species in this system. Whether due to genetic differences or phenotypic plasticity, trait differences between consumer types had significant ecological consequences for the tritrophic marsh food web over seasonal time scales. By altering the cascading effects of the top predator on plant community structure and dynamics, consumer differences may generate a feedback over longer time scales, which in turn influences the degree of trait divergence in subsequent consumer populations.
Early vs. late worsening heart failure during acute heart failure hospitalization: insights from the PROTECT trial
Authors: Mentz Robert J. , Metra Marco , Cotter Gad , Milo Olga , McKendry Colleen , Chiswell Karen , Davison Beth A. , Cleland John G.F. , Bloomfield Daniel M. , Dittrich Howard C. , Fiuzat Mona , Ponikowski Piotr , Givertz Michael M. , Voors Adriaan A. , Teerlink John R. , O'Connor Christopher M.
Published: June 2015

Background

Worsening heart failure (WHF) symptoms despite initial therapy during admission for acute heart failure (AHF) is associated with worse outcomes. The association between the time of the WHF event and the intensity of WHF therapy with outcomes is unknown.

Methods and results

In the PROTECT trial of 2033 AHF patients, we investigated the association between time of occurrence of WHF and intensity of therapy, with subsequent outcomes. WHF was defined by standardized, physician‐determined assessment. Early WHF was defined as occurring on days 2–3 and late on days 4–7. Low intensity included restarting/increasing diuretics or vasodilators and high intensity included initiation of inotropes, vasopressors, inodilators, or mechanical support. Outcomes were death or cardiovascular/renal hospitalization over 60 days and death over 180 days. Of the 1879 patients with complete follow‐up after day 7, 12.7% (n = 238) experienced WHF: 47.9% early and 52.1% late. Treatment intensity was low in 72.3% and high in 24.8% (2.9% missing). After adjusting for baseline predictors of outcome, WHF was associated with a trend toward increased 60‐day death or cardiovascular/renal hospitalization [hazard ratio (HR) 1.26; 95% confidence interval (CI) 0.99–1.60; P = 0.063] and increased 180‐day death (HR 1.77; 95% CI 1.33–2.34; P < 0.001). There was no evidence of a differential association between the time of occurrence of WHF and outcomes. High‐intensity therapy was not significantly associated with increased event rates (180‐day mortality: HR 1.44; 95% CI 0.80–2.59 vs. low).

Conclusions

Inhospital WHF was associated with increased 180‐day death. The time of occurrence and intensity of WHF therapy may provide less prognostic information than whether or not WHF occurred.