bluuebunny/crossref_metadata_2025 huggingface dataset:
Regioselective Ring‐Opening Polymerization of a Polyhydroxycarboxylic Acid for the Synthesis of a Nanoscale Carrier Material with pH‐Dependent Stability and Sustained Drug Release
Authors: Ewe Alexander , Jansen de Salazar Anita , Lemmnitzer Katharina , Marsch Michael , Aigner Achim , Geyer Armin
Published: April 2015

Synthetic polyesters are usually composed of monohydroxycarboxylic acids to avoid the problem of regioselectivity during ring‐opening polymerization. In contrast, the linear polyester BICpoly contains four secondary OH groups and is nevertheless esterified regioselectively at only one of these positions. Neither the synthesis of the tricyclic monomers nor the ring‐opening polymerization requires protecting groups, making BICpoly an attractive novel and biocompatible polymer. BICpoly nanoparticles can be loaded with low‐molecular weight drugs or coated onto surfaces as thin films. The release of loaded compounds makes BICpoly an attractive depot for drug release, as shown herein by loading BICpoly with dyes or the cytostatic drug doxorubicin. BICpoly is distinguishable from other polymers by its characteristic pH‐dependent degradation.
Shape without Structure: An Intriguing Formation Mechanism in the Solvothermal Synthesis of the Phase‐Change Material Sb2Te3
Authors: Saltzmann Tobias , Bornhöfft Manuel , Mayer Joachim , Simon Ulrich
Published: April 2015

We introduce a novel solvothermal synthesis of individual single crystalline Sb2Te3 micro‐ and nanocrystals as a model material for phase‐change switching. We identified different intermediates along the reaction path to the final Sb2Te3 hexagonal platelets (HPs) and discuss their forming mechanism. By means of nanodiffraction (ND) in a scanning transmission electron microscope we demonstrate that the intermediates follow a hexagonal shape evolution in the amorphous state. In situ nanomanipulator measurements reveal electrical phase‐change switching properties of the individual Sb2Te3 hexagonal platelets.
LP99: Discovery and Synthesis of the First Selective BRD7/9 Bromodomain Inhibitor
Authors: Clark Peter G. K. , Vieira Lucas C. C. , Tallant Cynthia , Fedorov Oleg , Singleton Dean C. , Rogers Catherine M. , Monteiro Octovia P. , Bennett James M. , Baronio Roberta , Müller Susanne , Daniels Danette L. , Méndez Jacqui , Knapp Stefan , Brennan Paul E. , Dixon Darren J.
Published: April 2015

The bromodomain‐containing proteins BRD9 and BRD7 are part of the human SWI/SNF chromatin‐remodeling complexes BAF and PBAF. To date, no selective inhibitor for BRD7/9 has been reported despite its potential value as a biological tool or as a lead for future therapeutics. The quinolone‐fused lactam LP99 is now reported as the first potent and selective inhibitor of the BRD7 and BRD9 bromodomains. Development of LP99 from a fragment hit was expedited through balancing structure‐based inhibitor design and biophysical characterization against tractable chemical synthesis: Complexity‐building nitro‐Mannich/lactamization cascade processes allowed for early structure–activity relationship studies whereas an enantioselective organocatalytic nitro‐Mannich reaction enabled the synthesis of the lead scaffold in enantioenriched form and on scale. This epigenetic probe was shown to inhibit the association of BRD7 and BRD9 to acetylated histones in vitro and in cells. Moreover, LP99 was used to demonstrate that BRD7/9 plays a role in regulating pro‐inflammatory cytokine secretion.
Sensory Hairs in the Bowhead Whale, Balaena mysticetus (Cetacea, Mammalia)
Authors: Drake Summer E. , CRISH Samuel D. , George John C. , Stimmelmayr Raphaella , Thewissen J.G.M.
Published: April 2015

We studied the histology and morphometrics of the hairs of bowhead whales (Balaena mysticetus). These whales are hairless except for two patches of more than 300 hairs on the rostral tip of the lower lip and chin, the rostral tip of the upper lip, and a bilateral row of approximately ten hairs caudal to the blowhole. Histological data indicate that hairs in all three of these areas are vibrissae: they show an outermost connective tissue capsule, a circumferential blood sinus system surrounding the hair shaft, and dense innervation to the follicle. Morphometric data were collected on hair diameters, epidermal recess diameters, hair follicle length, and external hair lengths. The main difference between the hairs in the different regions is that blowhole hairs have larger diameters than the hairs in the chin and rostrum regions. We speculate that the hair shaft thickness patterns in bowheads reflect functional specializations. Anat Rec, 298:1327–1335, 2015. © 2015 Wiley Periodicals, Inc.
Pectin: A new perspective from the biorefinery standpoint
Authors: Ciriminna Rosaria , Chavarría‐Hernández Norberto , Inés Rodríguez Hernández Adriana , Pagliaro Mario
Published: April 2015

Pectin is a natural product of central importance in the emerging biorefinery that uses fruit waste as a raw material. Generally obtained from lemon peel or from apple pomace, pectin is mainly used as a thickener and a stabilizer in the food industry. Due to its unique chemical properties and biochemical activity, however, its use is growing in many other sectors. Providing a unified view of the main research and utilization trends, this study identifies open opportunities toward larger scale production of a valued biopolymer that, we argue, will shortly emerge as a central product of the biorefinery, and of the citrus‐based biorefinery in particular. © 2015 Society of Chemical Industry and John Wiley & Sons, Ltd
Projecting human pharmacokinetics of monoclonal antibodies from nonclinical data: comparative evaluation of prediction approaches in early drug development
Authors: Wang Jing , Iyer Suhasini , Fielder Paul J. , Davis John D. , Deng Rong
Published: April 2015

Currently, more than 350 monoclonal antibodies (mAbs) and mAb derivatives are under development as therapeutics. The prediction of mAb pharmacokinetics (PK)/pharmacodynamics (PD) plays a key role in starting dose selection for first‐in‐human (FIH) studies. This article presents a brief overview of the biology and mechanisms of absorption, distribution, metabolism and excretion (ADME) for mAbs. In addition, a detailed review of mAb human PK/PD prediction from nonclinical data is provided, including allometry for mAbs with linear or nonlinear PK, species‐invariant time method, physiologically based PK (PBPK) modeling and target‐mediated drug disposition (TMDD) model, bioavailability projection and immunogenicity impact on PK prediction. Finally, from an industry perspective a decision tree of mAb human PK projection is proposed to facilitate drug development. Copyright © 2015 John Wiley & Sons, Ltd.
Reading for pleasure and progress in vocabulary and mathematics
Authors: Sullivan Alice , Brown Matt
Published: April 2015

This paper examines inequalities in attainment in vocabulary and mathematics at age 16 for a nationally representative cohort of people born in Britain in 1970 (the 1970 British Cohort Study). Our analytical sample is n = 3,583 cohort members who completed vocabulary and mathematics tests at age 16. We explore whether inequalities as a result of childhood social background are similar across the linguistic and mathematical domains, or whether they differ, and to what extent these inequalities are accounted for by families’ social class position, parents’ education and home reading resources, as well as by children's own reading for pleasure. As reading can be seen as an indicator of ‘cultural capital’, we also test the influence of an alternative indicator of cultural capital, playing a musical instrument. Our longitudinal analysis addresses the question of the extent to which differences in attainment are determined by age 10; and which factors are linked to a growth in differentials during adolescence. We show that childhood reading is linked to substantial cognitive progress between the ages of 10 and 16, whereas playing an instrument is not. Reading is most strongly linked to progress in vocabulary, with a weaker, but still substantial link to progress in mathematics. Strikingly, reading for pleasure is more strongly linked than parental education to cognitive progress in adolescence.
Plasma thrombospondin 1 as a predictor of postoperative liver dysfunction
Authors: Starlinger P , Haegele S , Wanek D , Zikeli S , Schauer D , Alidzanovic L , Fleischmann E , Gruenberger B , Gruenberger T , Brostjan C
Published: April 2015

Background

Liver regeneration following liver resection involves a complex interplay of growth factors and their antagonists. Thrombospondin 1 has recently been identified as a critical inhibitor of liver regeneration by the activation of transforming growth factor β1 in mice, and preliminary data seem to confirm its relevance in humans. This study aimed to confirm these observations in an independent validation cohort.

Methods

Perioperative circulating levels of thrombospondin 1 were measured in patients undergoing liver resection between January 2012 and September 2013. Postoperative liver dysfunction was defined according to the International Study Group of Liver Surgery and classification of morbidity was based on the criteria by Dindo et al.

Results

In 85 patients (44 major and 41 minor liver resections), plasma levels of thrombospondin 1 increased 1 day after liver resection (mean 51·6 ng/ml before surgery and 68·3 ng/ml on postoperative day 1; P = 0·001). Circulating thrombospondin 1 concentration on the first postoperative day specifically predicted liver dysfunction (area under the receiver operating characteristic (ROC) curve 0·818, P = 0·003) and was confirmed as a significant predictor in multivariable analysis (Exp(B) 1·020, 95 per cent c.i. 1·005 to 1·035; P = 0·009). Patients with a high thrombospondin 1 concentration (over 80 ng/ml) on postoperative day 1 more frequently had postoperative liver dysfunction than those with a lower level (28 versus 2 per cent) and severe morbidity (44 versus 15 per cent), and their length of hospital stay was more than doubled (19·7 versus 9·9 days).

Conclusion

Thrombospondin 1 may prove a helpful clinical marker to predict postoperative liver dysfunction as early as postoperative day 1.
Information policy: Introduction
Authors: Loveday‐Chesley Brandi
Published: April 2015

EDITOR'S SUMMARY

The ASIS&T Special Interest Group/Information Policy (SIG/IFP) analyzes local, national and global developments affecting multiple aspects of information access and use. This issue of the Bulletin explores trust, security and privacy, SIG/IFP's focus for the Association's 2014 Annual Meeting. The controversial and timely topic of net neutrality is examined from a historical perspective. Federal efforts in the area of cybersecurity and the practical implications of its failures are detailed. The importance of digital reader privacy is raised, comparing legal privacy assurances and gaps for brick and mortar libraries with security of readers' personal data in the cloud. A look at eHealth literacy reveals how the digital divide negatively affects health for various populations.
Questioning trust in the era of big (and small) data
Authors: Unsworth Kristene
Published: April 2015

EDITOR'S SUMMARY

Information policy extends to our acknowledgements of website statements about data privacy and sharing, as we routinely check a box to gain access to a site. Users rarely give much thought to whether they can trust the site sponsor to protect personal information. While privacy is often the chief concern in discussions of gathering, storing and using information, trust in the sponsor, whether governmental or corporate, is crucial. Governing bodies recognize democracy, fairness and a right to information, covering both access and privacy, as part of a social and political contract. Yet with data being collected on a massive scale, legitimate concerns about data misuse can undermine our trust in such fundamental understandings, leaving transparency as a critical element. The ASIS&T Special Interest Group/Information Policy (SIG/IFP) will explore the issue of trust during a workshop at the 2014 Annual Meeting, considering its foundations and evolution and questioning its justification in the age of big data.
Mapping graphene science and development: Focused research with multiple application areas
Authors: Kay Luciano , Porter Alan L. , Youtie Jan , Rafols Ismael , Newman Nils
Published: April 2015

EDITOR'S SUMMARY

Focusing on graphene, a material made from carbon atoms, researchers constructed a map illustrating the material in the context of scientific developments and patent activity over time. Two basemaps reflecting general science and patent activity were created, in addition to two overlay maps reflecting scientific publication and patenting activities specific to graphene. The science and patent overlay maps together display how the material was discovered and used between 2000 and 2013. The maps reveal 222 Web of Science categories and 466 International Patent Classification categories and identify 18 macro‐disciplines and 35 macro‐patent categories. Graphene research is shown to focus on material sciences and closely related fields such as engineering and physical chemistry, while graphene inventions cover technologies from catalysis and semiconductors to the pharmaceutical arena. The node size, density of relationships and colors of the map give additional information on research and development efforts and relationships among subset topics. The process employed text mining, visualization and graphics software tools in addition to a mapping kit available from the authors.
Interstitial organizations as conversational bridges
Authors: Korff Valeska P. , Oberg Achim , Powell Walter W.
Published: April 2015

EDITOR'S SUMMARY

A novel approach to evaluating the impact of nonprofit organizations is proposed, combining social network and linguistic analysis. The authors examined data from nonprofit organizations' websites and site hyperlinks to other organizations. They identified 369 sites of organizations that measure social impact and captured inbound and outbound weblinks to construct a relational structure. Keywords from the sites were categorized as reflecting scientific, civil society or managerial domains and located the entity in a triangular semantic space. While most organizations fell into one of the three communities, some were in an interstitial space spanning these domains. The interstitial organizations used a mix of terminology, were densely interconnected and connected extensively to organizations across domains, but there were few direct connections among the three domains. The resulting map integrates cultural and relational dimensions and reveals hidden patterns and clusters. The approach can be used with other social systems combining rich text with relational data.
Genomic alterations in DNA repair and chromatin remodeling genes in estrogen receptor‐positive metastatic breast cancer patients with exceptional responses to capecitabine
Authors: Levin Maren K. , Wang Kai , Yelensky Roman , Cao Ying , Ramos Corinne , Hoke Nicholas , Pippen John , Blum Joanne L. , Brooks Barry , Palmer Gary , Palma Norma , Balasubramanian Sohail , Ross Jeffrey S. , O'Shaughnessy Joyce
Published: April 2015

We analyzed the genomic and phosphoproteomic profiles of breast cancer tissue obtained from six patients with estrogen receptor (ER)‐positive, HER2‐negative metastatic breast cancer who had highly durable (≥5 years) and, in some cases, ongoing clinical responses with capecitabine. Formalin‐fixed, paraffin‐embedded tissue samples from patients' primary (n = 4) or metastatic (n = 2) breast cancers were utilized for targeted next‐generation sequencing and reversed phase protein microarray. Two patients received capecitabine monotherapy. Four patients received capecitabine in combination with paclitaxel; three of these continued single‐agent capecitabine after stopping paclitaxel. Capecitabine was discontinued for progressive disease after a mean of 66 months in four patients (range 54–86 months), and two patients remain on therapy, having received capecitabine for >91 months and >122 months, respectively. Three patients' cancers (50%) had likely functional alterations in DNA repair and chromatin remodeling genes, while three other patients' cancers had variants of unknown significance in these pathways. Mutations in PIK3CA, amplifications of FGFR1 or ZNF703, or phosphorylation of HER family receptors and their downstream proteins did not preclude exceptional responses to capecitabine. None of the patients' tumors harbored TP53 or PTEN mutations. Four of the patients had breast cancer tissue available for PTEN immunohistochemistry, and all four patients' cancers were positive for PTEN. These surprising findings in a group of phenotypically similar patients with ER‐positive, endocrine therapy‐pretreated, HER2‐negative metastases, are supported by preclinical data showing that sensitivity to 5‐fluorouracil is enhanced by deficiencies in chromatin remodeling and homologous recombination genes. Our findings suggest that mutations that inactivate homologous recombination and/or chromatin remodeling genes within ER‐positive, HER2‐negative breast cancers may predict for highly durable responses to capecitabine.
A Comprehensive Study of Formic Acid Oxidation on Palladium Nanocrystals with Different Types of Facets and Twin Defects
Authors: Choi Sang‐Il , Herron Jeffrey A. , Scaranto Jessica , Huang Hongwen , Wang Yi , Xia Xiaohu , Lv Tian , Park Jinho , Peng Hsin‐Chieh , Mavrikakis Manos , Xia Younan
Published: April 2015

Palladium has been recognized as the best anodic, monometallic electrocatalyst for the formic acid oxidation (FAO) reaction in a direct formic acid fuel cell. Here we report a systematic study of FAO on a variety of Pd nanocrystals, including cubes, right bipyramids, octahedra, tetrahedra, decahedra, and icosahedra. These nanocrystals were synthesized with approximately the same size, but different types of facets and twin defects on their surfaces. Our measurements indicate that the Pd nanocrystals enclosed by {1 0 0} facets have higher specific activities than those enclosed by {1 1 1} facets, in agreement with prior observations for Pd single‐crystal substrates. If comparing nanocrystals predominantly enclosed by a specific type of facet, {1 0 0} or {1 1 1}, those with twin defects displayed greatly enhanced FAO activities compared to their single‐crystal counterparts. To rationalize these experimental results, we performed periodic, self‐consistent DFT calculations on model single‐crystal substrates of Pd, representing the active sites present in the nanocrystals used in the experiments. The calculation results suggest that the enhancement of FAO activity on defect regions, represented by Pd(2 1 1) sites, compared to the activity of both Pd(1 0 0) and Pd(1 1 1) surfaces, could be attributed to an increased flux through the HCOO‐mediated pathway rather than the COOH‐mediated pathway on Pd(2 1 1). Since COOH has been identified as a precursor to CO, a site‐poisoning species, a lower coverage of CO at the defect regions will lead to a higher activity for the corresponding nanocrystal catalysts, containing those defect regions.
Polyaniline‐Grafted VO(acac)2: An Effective Catalyst for the Synthesis of 2,5‐Diformylfuran from 5‐Hydroxymethylfurfural and Fructose
Authors: Xu Fenghua , Zhang Zehui
Published: April 2015

Herein, polyaniline‐grafted vanadyl acetylacetonate [VO(acac)2] was prepared and used as an effective catalyst for the oxidation of 5‐hydroxymethylfurfural (HMF) under atmospheric oxygen pressure. A high HMF conversion of 99.2 % was obtained after 12 h at 110 °C, and 2,5‐diformylfuran (DFF) was obtained in 86.2 % yield. More importantly, the one‐pot conversion of fructose into DFF was also realized with two binary catalysts: Amberlyst‐15 and polyaniline–VO(acac)2. Amberlyst‐15 was used for the acid‐catalyzed dehydration of fructose into HMF, followed by the in situ oxidation of HMF catalyzed by polyaniline–VO(acac)2. DFF could be obtained in a yield of 42.1 % from fructose by using the one‐pot reaction, whereas two consecutive steps gave a higher DFF yield of 71.1 %. Owing to the facile catalyst preparation and low cost, this method showed a promising potential for the synthesis of DFF from abundant carbohydrates.
Torands Revisited: Metal Sequestration and Self‐Assembly of Cyclo‐2,9‐tris‐1,10‐phenanthroline Hexaaza Macrocycles
Authors: Schwab Matthias Georg , Takase Masayoshi , Mavrinsky Alexey , Pisula Wojciech , Feng Xinliang , Gámez José A. , Thiel Walter , Mali Kunal S. , de Feyter Steven , Müllen Klaus
Published: April 2015

A series of novel toroidal cyclo‐2,9‐tris‐1,10‐phenanthroline macrocycles with an unusual hexaaza cavity are reported. Nickel‐mediated Yamamoto aryl–aryl coupling was found to be a versatile tool for the cyclotrimerization of functionalized 1,10‐phenathroline precursors. Due to the now improved processability, both liquid‐crystalline behavior in the bulk phase and two‐dimensional self‐assembly at the molecular level could be studied, for the first time, for a torand system. The macrocycles exhibited a strong affinity for the complexation of different metal cations, as evidenced by MALDI‐TOF analysis and spectroscopic methods. Experimental results were correlated to an extensive computational study of the cyclo‐2,9‐tris‐1,10‐phenanthroline cavity and its binding mode for metal cations. Due to the combination of several interesting features, toroidal macrocycles may find future applications in the field of ion and charge transport through molecular channels, as well as for chemical sensing and molecular writing in surface‐confined monolayers under STM conditions.
Rational Topological Design for Fluorescence Enhancement upon Aggregation of Distyrylfuran Derivatives
Authors: Mallet Charlotte , Moussallem Chady , Faurie Alexandre , Allain Magali , Gohier Frédéric , Skene William G. , Frère Pierre
Published: April 2015

A series of 2,5‐distyrylfuran derivatives bearing pentafluorophenyl‐ and cyanovinyl units have been synthesized for aggregation‐induced emission (AIE). The effect of the type and extent of the supramolecular connections on the AIE of the furan derivatives were examined and correlated with their X‐ray crystal structures. It was found that the simultaneous presence of cyano and perfluorophenyl units strongly enhances the fluorescence upon aggregation. Single‐crystal X‐ray diffraction analysis confirmed that CH⋅⋅⋅F, F⋅⋅⋅F, CH⋅⋅⋅nitrile, Ar⋅⋅⋅ArF (Ar=aryl, ArF=fluoroaryl), and nitrile⋅⋅⋅ArF intra‐ and intermolecular interactions drive the topology of the molecule and that solid‐state supramolecular contacts favor AIE of the furan derivatives.
Stable [48]‐, [50]‐, and [52]Dodecaphyrins(1.1.0.1.1.0.1.1.0.1.1.0): The Largest Hückel Aromatic Molecules
Authors: Soya Takanori , Kim Woojae , Kim Dongho , Osuka Atsuhiro
Published: April 2015

[52]Dodecaphyrin(1.1.0.1.1.0.1.1.0.1.1.0) was quantitatively oxidized with 2,3‐dichloro‐5,6‐dicyano‐1,4‐benzoquinone (DDQ) to the corresponding [50]dodecaphyrin. Further oxidation of [50]dodecaphyrin with MnO2 quantitatively afforded [48]dodecaphyrin. Of the three, [50]dodecaphyrin showed Hückel aromatic character as the largest aromatic molecule reported to date. Protonation of [50]dodecaphyrin with methanesulfonic acid (MSA) led to the formation of a planar tetraprotonated species that displayed a sharp and intense Soret‐like band at 906 nm with ε=6.5×105 M−1 cm−1 and Q‐band‐like bands at 1346 and 1600 nm.
(S)‐BINOL Immobilized onto Multiwalled Carbon Nanotubes through Covalent Linkage: A New Approach for Hybrid Nanomaterials Characterization
Authors: Monteiro Carlos J. P. , Carabineiro Sónia A. C. , Lauterbach Tobias , Hubbert Christoph , Hashmi A. Stephen K. , Figueiredo José L. , Pereira Mariette M.
Published: April 2015

(S)‐6‐(4‐(Methoxycarbonyl)phenyl)‐1,1′‐bis‐2‐naphthol, a chiral 1,1′‐bis‐2‐naphthol (BINOL) derivative, was prepared via Suzuki C−C coupling and immobilized onto diamine‐functionalized multiwalled carbon nanotubes. The BINOL was first derivatized with a carboxylic acid, capable of forming an amide linkage with the amine–carbon nanotube modified surface. The 4‐methoxyphenylboronic acid was replaced by 3‐fluoro‐4‐(methoxycarbonyl)phenylboronic acid and (S)‐6‐(3‐fluoro‐4‐(methoxycarbonyl)phenyl)‐1,1′‐bis‐2‐naphthol was obtained and used as a probe to better quantify the organic material. It was found that in the hybrid material, 1/3 of amine groups have been transformed into the corresponding amide (S)‐BINOL derivative. The chemical and electronic integrity of the chiral BINOL ligand is maintained after the ligand immobilization. Evaluation in diethyl zinc and Ti(OiPr)4‐catalyzed alkylation of benzaldehyde showed that both methoxycarbonylphenyl and fluoromethoxycarbonylphenyl BINOL moieties do not significantly influence the catalytic activity or selectivity of the process. However, when hybrid materials were used, similar activities were obtained, but with lower enantioselectivities. This result could be due to a competitive alkylation reaction occurring on the carbon surface or by the constraint caused by the ligand proximity on the support surface.
Ligand‐Induced Evolution of Intrinsic Fluorescence and Catalytic Activity from Cobalt Ferrite Nanoparticles
Authors: Pal Monalisa , Kundu Anirban , Rakshit Rupali , Mandal Kalyan
Published: April 2015

To develop CoFe2O4 as magneto‐fluorescent nanoparticles (NPs) for biomedical applications, it would be advantageous to identify any intrinsic fluorescence of this important magnetic material by simply adjusting the surface chemistry of the NPs themselves. Herein, we demonstrate that intrinsic multicolor fluorescence, covering the whole visible region, can be induced by facile functionalization of CoFe2O4 NPs with Na‐tartrate. Moreover, the functionalized CoFe2O4 NPs also show unprecedented catalytic efficiency in the degradation of both biologically and environmentally harmful dyes, pioneering the potential application of these NPs in therapeutics and wastewater treatment. Detailed investigation through various spectroscopic tools unveils the story behind the emergence of this unique optical property of CoFe2O4 NPs upon functionalization with tartrate ligands. We believe our developed multifunctional CoFe2O4 NPs hold great promise for advanced biomedical and technological applications.
Microdosing of a Carbon‐14 Labeled Protein in Healthy Volunteers Accurately Predicts Its Pharmacokinetics at Therapeutic Dosages
Authors: Vlaming MLH , van Duijn E , Dillingh MR , Brands R , Windhorst AD , Hendrikse NH , Bosgra S , Burggraaf J , de Koning MC , Fidder A , Mocking JAJ , Sandman H , de Ligt RAF , Fabriek BO , Pasman WJ , Seinen W , Alves T , Carrondo M , Peixoto C , Peeters PAM , Vaes WHJ
Published: April 2015

Preclinical development of new biological entities (NBEs), such as human protein therapeutics, requires considerable expenditure of time and costs. Poor prediction of pharmacokinetics in humans further reduces net efficiency. In this study, we show for the first time that pharmacokinetic data of NBEs in humans can be successfully obtained early in the drug development process by the use of microdosing in a small group of healthy subjects combined with ultrasensitive accelerator mass spectrometry (AMS). After only minimal preclinical testing, we performed a first‐in‐human phase 0/phase 1 trial with a human recombinant therapeutic protein (RESCuing Alkaline Phosphatase, human recombinant placental alkaline phosphatase [hRESCAP]) to assess its safety and kinetics. Pharmacokinetic analysis showed dose linearity from microdose (53 μg) [14C]‐hRESCAP to therapeutic doses (up to 5.3 mg) of the protein in healthy volunteers. This study demonstrates the value of a microdosing approach in a very small cohort for accelerating the clinical development of NBEs.
Optimizing Central Nervous System Drug Development Using Molecular Imaging
Authors: Hargreaves RJ , Hoppin J , Sevigny J , Patel S , Chiao P , Klimas M , Verma A
Published: April 2015

Advances in multimodality fusion imaging technologies promise to accelerate the understanding of the systems biology of disease and help in the development of new therapeutics. The use of molecular imaging biomarkers has been proven to shorten cycle times for central nervous system (CNS) drug development and thereby increase the efficiency and return on investment from research. Imaging biomarkers can be used to help select the molecules, doses, and patients most likely to test therapeutic hypotheses by stopping those that have little chance of success and accelerating those with potential to achieve beneficial clinical outcomes. CNS imaging biomarkers have the potential to drive new medical care practices for patients in the latent phases of progressive neurodegenerative disorders by enabling the detection, preventative treatment, and tracking of disease in a paradigm shift from today's approaches that have to see the overt symptoms of disease before treating it.
Pharmacogenetic Markers of Drug Efficacy and Toxicity
Authors: Yip VLM , Hawcutt DB , Pirmohamed M
Published: April 2015

The action of a drug is dictated by its pharmacokinetic and pharmacodynamics properties, both of which can vary in different individuals because of environmental and genetic factors. Pharmacogenetics, the study of genetic factors determining drug response, has the potential to improve clinical outcomes through targeting therapies, individualizing dosing, preventing adverse drug reactions, and potentially rescuing previously failed therapies. Although there have been significant advances in pharmacogenetics over the last decade, only a few have been translated into clinical practice. However, with new rapid genotyping technologies, regulatory modernization, novel clinical trial designs, systems approaches, and integration of pharmacogenetic data into decision support systems, there is hope that pharmacogenetics, as an important component of the overall drive towards personalized medicine, will advance more quickly in the future. There will continue to be a need for collaboration between centers all over the world, and multisector working, capitalizing on the current data revolution.
Biomarker Qualification: Toward a Multiple Stakeholder Framework for Biomarker Development, Regulatory Acceptance, and Utilization
Authors: Amur S , LaVange L , Zineh I , Buckman‐Garner S , Woodcock J
Published: April 2015

The discovery, development, and use of biomarkers for a variety of drug development purposes are areas of tremendous interest and need. Biomarkers can become accepted for use through submission of biomarker data during the drug approval process. Another emerging pathway for acceptance of biomarkers is via the biomarker qualification program developed by the Center for Drug Evaluation and Research (CDER, US Food and Drug Administration). Evidentiary standards are needed to develop and evaluate various types of biomarkers for their intended use and multiple stakeholders, including academia, industry, government, and consortia must work together to help develop this evidence. The article describes various types of biomarkers that can be useful in drug development and evidentiary considerations that are important for qualification. A path forward for coordinating efforts to identify and explore needed biomarkers is proposed for consideration.
Advances in toponomics drug discovery: Imaging cycler microscopy correctly predicts a therapy method of amyotrophic lateral sclerosis
Authors: Schubert Walter
Published: April 2015

An imaging cycler microscope (ICM) is a fully automated (epi)fluorescence microscope which overcomes the spectral resolution limit resulting in parameter‐ and dimension‐unlimited fluorescence imaging. This enables the spatial resolution of large molecular systems with their emergent topological properties (toponome) in morphologically intact cells and tissues displaying thousands of multi protein assemblies at a time. The resulting combinatorial geometry of these systems has been shown to be key for in‐vivo/in‐situ detection of lead proteins controlling protein network topology and (dys)function: If lead proteins are blocked or downregulated the corresponding disease protein network disassembles. Here, correct therapeutic predictions are exemplified for ALS. ICM drug target studies have discovered an 18‐dimensional cell surface molecular system in ALS‐PBMC with a lead drug target protein, whose therapeutic downregulation is now reported to show statistically significant effect with stop of disease progression in one third of the ALS patients. Together, this clinical and the earlier experimental validations of the ICM approach indicate that ICM readily discovers in vivo robustness nodes of disease with lead proteins controlling them. Breaking in vivo robustness nodes using drugs against their lead proteins is likely to overcome current high drug attrition rates. © 2015 The Author. Published by Wiley Periodicals, Inc, on behalf of ISAC.
Indirect selection of thermal tolerance during experimental evolution of Drosophila melanogaster
Authors: Condon Catriona , Acharya Ajjya , Adrian Gregory J. , Hurliman Alex M. , Malekooti David , Nguyen Phivu , Zelic Maximilian H. , Angilletta Michael J.
Published: April 2015

Natural selection alters the distribution of a trait in a population and indirectly alters the distribution of genetically correlated traits. Long‐standing models of thermal adaptation assume that trade‐offs exist between fitness at different temperatures; however, experimental evolution often fails to reveal such trade‐offs. Here, we show that adaptation to benign temperatures in experimental populations of Drosophila melanogaster resulted in correlated responses at the boundaries of the thermal niche. Specifically, adaptation to fluctuating temperatures (16–25°C) decreased tolerance of extreme heat. Surprisingly, flies adapted to a constant temperature of 25°C had greater cold tolerance than did flies adapted to other thermal conditions, including a constant temperature of 16°C. As our populations were never exposed to extreme temperatures during selection, divergence of thermal tolerance likely reflects indirect selection of standing genetic variation via linkage or pleiotropy. We found no relationship between heat and cold tolerances in these populations. Our results show that the thermal niche evolves by direct and indirect selection, in ways that are more complicated than assumed by theoretical models.
Warming experiments elucidate the drivers of observed directional changes in tundra vegetation
Authors: Hollister Robert D. , May Jeremy L. , Kremers Kelseyann S. , Tweedie Craig E. , Oberbauer Steven F. , Liebig Jennifer A. , Botting Timothy F. , Barrett Robert T. , Gregory Jessica L.
Published: April 2015

Few studies have clearly linked long‐term monitoring with in situ experiments to clarify potential drivers of observed change at a given site. This is especially necessary when findings from a site are applied to a much broader geographic area. Here, we document vegetation change at Barrow and Atqasuk, Alaska, occurring naturally and due to experimental warming over nearly two decades. An examination of plant cover, canopy height, and community indices showed more significant differences between years than due to experimental warming. However, changes with warming were more consistent than changes between years and were cumulative in many cases. Most cases of directional change observed in the control plots over time corresponded with a directional change in response to experimental warming. These included increases in canopy height and decreases in lichen cover. Experimental warming resulted in additional increases in evergreen shrub cover and decreases in diversity and bryophyte cover. This study suggests that the directional changes occurring at the sites are primarily due to warming and indicates that further changes are likely in the next two decades if the regional warming trend continues. These findings provide an example of the utility of coupling in situ experiments with long‐term monitoring to accurately document vegetation change in response to global change and to identify the underlying mechanisms driving observed changes.
Effects of flow regulation on the movement patterns and habitat use of a potamodromous cyprinid species
Authors: Alexandre C. M. , Almeida P. R. , Neves T. , Mateus C. S. , Costa J. L. , Quintella B. R.
Published: April 2015

River regulation for hydroelectricity production results in rapid changes of flow and habitat features, but its effects in the movement patterns of freshwater fish are not well understood. Radiotelemetry was used to track Iberian barbel during a year cycle in non‐regulated and regulated rivers. We applied a kernel density method to estimate and compare home range sizes of the two populations. Seasonal patterns of movement and the intra‐annual variation in habitat preferences were also compared. Barbel inhabiting regulated river exhibit larger and more continuous home and core ranges, in opposition to the smaller and patchy areas used by fish inhabiting the non‐regulated river. Seasonal movements of both populations were differentiated by the drought period. Barbel from the non‐regulated river had to search for suitable refuges, with specific habitat characteristics, in which they remained aggregated during harsh summer conditions. Conversely, barbel from regulated river kept a continuous distribution along the river. This study contributes to the management of regulated rivers by providing insights about which flow components are more altered by hydropeaking operations and which are the most critical annual periods for fish movements. It also suggests several restoration actions, such as the protection of fish summer refuges, the restoration of large‐scale temporal streamflow variability and the reduction of daily rates of discharge rise and fall, which should be continuously monitored in order to increase their efficiency and provide new knowledge. Copyright © 2015 John Wiley & Sons, Ltd.
Electrochemical and Spectroelectrochemical Analysis of 4‐(4‐(5‐Phenyl‐1,3,4‐oxadiazole‐2‐yl)phenoxy)‐Substituted Cobalt(II), Lead(II) and Metal‐Free Phthalocyanines
Authors: Nas Asiye , Kantekin Halit , Koca Atıf
Published: April 2015

Electrochemical and spectroelectrochemical analyses of 4‐(4‐(5‐phenyl‐1,3,4‐oxadiazole‐2‐yl)phenoxy)‐substituted metal‐free phthalocyanine (H2Pc (1)) and metallated phthalocyanines (PbPc (2) and CoPc (3)) were performed in solution. Voltammetric characterizations of the phthalocyanine complexes were investigated by using cyclic voltammetry and square wave voltammetry techniques. CoPc (3) gave common metal and ring based electron transfer reactions; however they split due to the aggregation. Although PbPc (2) illustrated reversible reduction processes during the voltammetric measurements, it was de‐metallized and thus turned to the metal free phthalocyanine during repetitive voltammetric cycles and in situ spectroelectrochemical measurements.
Nanostructured Cobalt(II) Tetracarboxyphthalocyanine Complex Supported Within the MWCNT Frameworks: Electron Transport and Charge Storage Capabilities
Authors: Pillay Sherilee , Pillay Jeseelan , Ejikeme Paul M. , Makgopa Katlego , Ozoemena Kenneth I.
Published: April 2015

The electrochemical redox properties of a surface‐confined thin solid film of nanostructured cobalt(II) tetracarboxyphthalocyanine integrated with multiwalled carbon nanotube (nanoCoTCPc/MWCNT) have been investigated. This novel nanoCoTCPc/MWCNT material was characterized using SEM, TEM, zeta analysis and electrochemical methods. The nanoCoTCPc/MWCNT nanohybrid material exhibited an extra‐ordinarily high conductivity (15 mS cm−1), which is more than an order of magnitude greater than that of the MWCNT‐SO3H (527 µS cm−1) and three orders of a magnitude greater than the nanoCoTCPc (4.33 µS cm−1). The heterogeneous electron transfer rate constant decreases as follows: nanoCoTCPc/MWCNT (kapp≈19.73×10−3 cm s−1)>MWCNT‐SO3H (kapp≈11.63×10−3 cm s−1)>nanoCoTCPc (kapp≈1.09×10−3 cm s−1). The energy‐storage capability was typical of pseudocapacitive behaviour; at a current density of 10 µA cm−2, the pseudocapacitance decreases as nanoCoTCPc/MWCNT (3.71×10−4 F cm−2)>nanoCoTCPc (2.57×10−4 F cm−2)>MWCNT‐SO3H (2.28×10−4 F cm−2). The new nanoCoTCPc/MWCNT nanohybrid material promises to serve as a potential material for the fabrication of thin film electrocatalysts or energy‐storage devices.
Partially Oxidized Graphene/Metallic Single‐Walled Carbon Nanotubes Film‐Coated Electrode for Nanomolar Detection of Dopamine
Authors: Sundramoorthy Ashok K. , Gunasekaran Sundaram
Published: April 2015

Enriched metallic single‐walled carbon nanotubes (mSWCNTs) were dispersed in aqueous solution of partially oxidized graphene (po‐Gr). As‐prepared po‐Gr/mSWCNTs suspension was used to modify glassy carbon electrode (GCE) surface, which showed high electrocatalytic activity for dopamine (DA) oxidation in pH 7.0 phosphate buffered saline (PBS) solution. Using po‐Gr/mSWCNTs/GCE we could detect DA from 350 to 3600 nM, with a detection limit down to 25 nM in physiological condition (in pH 7.0 PBS); whereas, po‐Gr/GCE (without mSWCNTs) and bare GCE produced measurable signals only at or above 200 nM DA. Thus, the po‐Gr/mSWCNTs film we fabricated is a promising nanomaterial for fabrication of biosensors for nanomolar detection of DA.
Wings as a new route of exposure to pesticides in the honey bee
Authors: Poquet Yannick , Kairo Guillaume , Tchamitchian Sylvie , Brunet Jean-Luc , Belzunces Luc P.
Published: April 2015

In pesticide risk assessment, estimating the routes and levels of exposure is critical. For honey bees subjected to pesticide spray, toxicity is assessed by thorax contact to account for all possible contact exposures. In the present study, the authors tested 6 active substances with different hydrophobicity. For the first time, the authors demonstrated that it is possible to induce mortality by pesticide contact with only the wings of the honey bee. The toxicities induced by contact with the wings and thorax were similar, with the wing median lethal dose (LD50) being 0.99 to 2.23 times higher than that of the thorax. This finding demonstrates that the wings represent a relevant route of exposure in the honey bee. In a second approach, the authors estimated the air volume displaced by the wings during 1 beating cycle to be 0.51 ± 0.03 cm3, which corresponds to a volume of 116.8 ± 5.8 cm3 s–1 at a wing beat frequency of 230 Hz. The authors then tested realistic scenarios of exposure for bees flying through a pesticide cloud at different concentrations. In the worst-case scenario, the dose accumulated during the flight reached 525 ng bee–1 s–1. These results show that the procedure used to assess the risk posed by contact with pesticides could be improved by accounting for wing exposure. Environ Toxicol Chem 2015;34:1983–1988. © 2015 SETAC
An energy‐reduced dietary pattern, including moderate protein and increased nonfat dairy intake combined with walking promotes beneficial body composition and metabolic changes in women with excess adiposity: a randomized comparative trial
Authors: Shlisky Julie D. , Durward Carrie M. , Zack Melissa K. , Gugger Carolyn K. , Campbell Jessica K. , Nickols‐Richardson Sharon M.
Published: April 2015

Moderate protein and nonfat dairy intake within an energy‐reduced diet (ERD) may contribute to health benefits achieved with body weight (BW) loss. The current study examined the effectiveness of a weight‐loss/weight‐loss maintenance intervention using an ERD with moderate dietary protein (30% of kcals) and increased nonfat dairy intake (4–5 svg/d), including yogurt (INT group) and daily walking compared to an ERD with standard protein (16–17% of kcals) and standard nonfat dairy intake (3 svg/d) (COM group) with daily walking. A randomized comparative trial with 104 healthy premenopausal women with overweight/obesity was conducted in a university setting. Women were randomized to INT group or COM group. Anthropometric measurements, as well as dietary intake, selected vital signs, resting energy expenditure, blood lipids, glucose, insulin, and selected adipose‐derived hormones were measured at baseline, and weeks 2, 12, and 24. Targets for dietary protein and nonfat dairy intake, while initially achieved, were not sustained in the INT group. There were no significant effects of diet group on anthropometric measurements. Women in the INT group and COM group, respectively, reduced BW (−4.9 ± 3.2 and −4.3 ± 3.3 kg, P < 0.001) and fat mass (−3.0 ± 2.2 and −2.3 ± 2.3 kg, P < 0.001) during the 12‐week weight‐loss phase and maintained these losses at 24 weeks. Both groups experienced significant decreases in body mass index, fat‐free soft tissue mass, body fat percentage, waist and hip circumferences and serum triglycerides, total cholesterol, and leptin (all P < 0.001). Healthy premenopausal women with excess adiposity effectively lost BW and fat mass and improved some metabolic risk factors following an ERD with approximately 20% protein and 3 svg/d of nonfat dairy intake.
Ectopic intravagal parathyroid adenoma
Authors: Daruwalla Jurstine , Sachithanandan Nirupa , Andrews David , Miller Julie A.
Published: April 2015

Background

Intraneural parathyroid adenomas are rare, with only 9 cases of intravagal adenomas reported. All but one of the reported cases was found after multiple neck explorations. To the best of our knowledge, we report the first case of nonsupernumerary ectopic intravagal parathyroid identified at primary exploration.

Methods and Results

A 17‐year‐old girl with primary hyperparathyroidism and nephrolithiasis was referred with a sestamibi scan reporting a left lower parathyroid adenoma. No eutopic parathyroid tissue was identified during full exploration of the left side of the neck. Exploration of the carotid sheath revealed a fusiform swelling of the vagus nerve at the level of the carotid bifurcation. Longitudinal incision of the vagal perineurium revealed a 7‐mm parathyroid adenoma, which was enucleated. The patient recovered uneventfully, with normalization of serum calcium, parathyroid hormone (PTH), and normal vocal cord function.

Conclusion

We believe that this is the first reported case of nonsupernumerary intravagal parathyroid adenoma resected at initial exploration. The vagus nerve is a rare location for a parathyroid adenoma, but one that should be considered, even during primary exploration. © 2015 Wiley Periodicals, Inc. Head Neck 37: E200–E204, 2015