bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phenotypic and biomarker evaluation of zebrafish larvae as an alternative model to predict mammalian hepatotoxicity
Authors: Verstraelen Sandra , Peers Bernard , Maho Walid , Hollanders Karen , Remy Sylvie , Berckmans Pascale , Covaci Adrian , Witters Hilda 
Published: March 2016

AbstractZebrafish phenotypic assays have shown promise to assess human hepatotoxicity, though scoring of liver morphology remains subjective and difficult to standardize. Liver toxicity in zebrafish larvae at 5 days was assessed using gene expression as the biomarker approach, complementary to phenotypic analysis and analytical data on compound uptake. This approach aimed to contribute to improved hepatotoxicity prediction, with the goal of identifying biomarker(s) as a step towards the development of transgenic models for prioritization. Morphological effects of hepatotoxic compounds (acetaminophen, amiodarone, coumarin, methapyrilene and myclobutanil) and saccharin as the negative control were assessed after exposure in zebrafish larvae. The hepatotoxic compounds induced the expected zebrafish liver degeneration or changes in size, whereas saccharin did not have any phenotypic adverse effect. Analytical methods based on liquid chromatography–mass spectrometry were optimized to measure stability of selected compounds in exposure medium and internal concentration in larvae. All compounds were stable, except amiodarone for which precipitation was observed. There was a wide variation between the levels of compound in the zebrafish larvae with a higher uptake of amiodarone, methapyrilene and myclobutanil. Detection of hepatocyte markers (CP, CYP3A65, GC and TF) was accomplished by in situ hybridization of larvae to coumarin and myclobutanil and confirmed by real‐time reverse transcription–quantitative polymerase chain reaction. Experiments showed decreased expression of all markers. Next, other liver‐specific biomarkers (i.e. FABP10a and NR1H4) and apoptosis (i.e. CASP‐3 A and TP53) or cytochrome P450‐related (CYP2K19) and oxidoreductase activity‐related (ZGC163022) genes, were screened. Links between basic mechanisms of liver injury and results of biomarker responses are described. Copyright © 2016 John Wiley & Sons, Ltd.
Skeletal muscle regeneration via engineered tissue culture over electrospun nanofibrous chitosan/PVA scaffold
Authors: Kheradmandi Mahsa , Vasheghani‐Farahani Ebrahim , Ghiaseddin Ali , Ganji Fariba 
Published: March 2016

AbstractSkeletal muscle tissue shows a remarkable potential in regeneration of injured tissue. However, in some of chronic and volumetric muscle damages, the native tissue is incapable to repair and remodeling the trauma. In the same condition, stem‐cell therapy increased regeneration in situations of deficient muscle repair, but the major problem seems to be the lack of ability to attachment and survive of injected cells on the exact location. In this study, chitosan/poly(vinyl alcohol) nanofibrous scaffold was studied to promote cell attachment and provide mechanical support during regeneration. Scaffold was characterized using scanning electron microscope, X‐ray diffraction, and tensile test. Degradation and swelling behavior of scaffold were studied for 20 days. The cell‐scaffold interaction was characterized by MTT assay for 10 days andin vivobiocompatibility of scaffold in a rabbit model was evaluated. Results showed that cells had a good viability, adhesion, growth, and spread on the scaffold, which make this mat a desirable engineered muscular graft. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 1720–1727, 2016.
Decellularized extracellular matrix microparticles as a vehicle for cellular delivery in a model of anastomosis healing
Authors: Hoganson David M. , Owens Gwen E. , Meppelink Amanda M. , Bassett Erik K. , Bowley Chris M. , Hinkel Cameron J. , Finkelstein Eric B. , Goldman Scott M. , Vacanti Joseph P. 
Published: March 2016

AbstractExtracellular matrix (ECM) materials from animal and human sources have become important materials for soft tissue repair. Microparticles of ECM materials have increased surface area and exposed binding sites compared to sheet materials. Decellularized porcine peritoneum was mechanically dissociated into 200 µm microparticles, seeded with fibroblasts and cultured in a low gravity rotating bioreactor. The cells avidly attached and maintained excellent viability on the microparticles. When the seeded microparticles were placed in a collagen gel, the cells quickly migrated off the microparticles and through the gel. Cells from seeded microparticles migrated to and across an in vitro anastomosis model, increasing the tensile strength of the model. Cell seeded microparticles of ECM material have potential for paracrine and cellular delivery therapies when delivered in a gel carrier. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 1728–1735, 2016.
Hypochlorhydria‐induced calcium malabsorption does not affect fracture healing but increases post‐traumatic bone loss in the intact skeleton
Authors: Haffner‐Luntzer Melanie , Heilmann Aline , Heidler Verena , Liedert Astrid , Schinke Thorsten , Amling Michael , Yorgan Timur Alexander , vom Scheidt Annika , Ignatius Anita 
Published: March 2016

ABSTRACTEfficient calcium absorption is essential for skeletal health. Patients with impaired gastric acidification display low bone mass and increased fracture risk because calcium absorption is dependent on gastric pH. We investigated fracture healing and post‐traumatic bone turnover in mice deficient in Cckbr, encoding a gastrin receptor that affects acid secretion by parietal cells. Cckbr−/− mice display hypochlorhydria, calcium malabsorption, and osteopenia. Cckbr−/− and wildtype (WT) mice received a femur osteotomy and were fed either a standard or calcium‐enriched diet. Healed and intact bones were assessed by biomechanical testing, histomorphometry, micro‐computed tomography, and quantitative backscattering. Parathyroid hormone (PTH) serum levels were determined by enzyme‐linked immunosorbent assay. Fracture healing was unaffected in Cckbr−/− mice. However, Cckbr−/− mice displayed increased calcium mobilization from the intact skeleton during bone healing, confirmed by significantly elevated PTH levels and osteoclast numbers compared to WT mice. Calcium supplementation significantly reduced secondary hyperparathyroidism and bone resorption in the intact skeleton in both genotypes, but more efficiently in WT mice. Furthermore, calcium administration improved bone healing in WT mice, indicated by significantly increased mechanical properties and bone mineral density of the fracture callus, whereas it had no significant effect in Cckbr−/− mice. Therefore, under conditions of hypochlorhydria‐induced calcium malabsorption, calcium, which is essential for callus mineralization, appears to be increasingly mobilized from the intact skeleton in favor of fracture healing. Calcium supplementation during fracture healing prevented systemic calcium mobilization, thereby maintaining bone mass and improving fracture healing in healthy individuals whereas the effect was limited by gastric hypochlorhydria. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:1914–1921, 2016.
Helical Polymers Showing Inverse Helicity and Synergistic Effect in Chiral Catalysis: Catalytic Functionality Determining Enantioconfiguration and Helical Frameworks Providing Asymmetric Microenvironment
Authors: Zhang Haiyang , Deng Jianping 
Published: March 2016

This article reports optically active helical polymers showing inverse helicity, which is controlled by copolymer composition. L‐Proline‐derived monomer and an achiral monomer have been copolymerized, affording copolymers with optical activity and remarkable catalytic ability. By adjusting relative content of the two monomers, a series of copolymers with varied optical activity has been obtained. More notably, the handedness of the macromolecular helices inverses at specific monomer feed ratios. Copolymers with opposite helicity have been applied as chiral catalysts for asymmetric aldol reaction to investigate the exact role of helical structures in catalysis. The variation in the stereoselectivity of product has demonstrated an intriguing synergistic effect occurring between the helical macromolecular frameworks and pendent prolineamide groups. The macromolecular helices provide asymmetric microenvironment for the reaction while enantioconfiguration of the product is determined by the specific catalytic functionality. This study opens up new opportunities for manufacturing macromolecules as mimetic enzymes catalyzing asymmetric reactions.
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Validation and optimization of adiabatic T1ρ and T2ρ for quantitative imaging of articular cartilage at 3 T
Authors: Casula Victor , Autio Joonas , Nissi Mikko J. , Auerbach Edward J. , Ellermann Jutta , Lammentausta Eveliina , Nieminen Miika T. 
Published: March 2016

PurposeThe aim of the present work was to validate and optimize adiabatic T1ρ and T2ρ mapping for in vivo measurements of articular cartilage at 3 Tesla (T).MethodsPhantom and in vivo experiments were systematically performed on a 3T clinical system to evaluate the sequences using hyperbolic secant HS1 and HS4 pulses. R1ρ and R2ρ relaxation rates were studied as a function of agarose and chondroitin sulfate concentration and pulse duration. Optimal in vivo protocol was determined by imaging the articular cartilage of two volunteers and varying the sequence parameters, and successively applied in eight additional subjects. Reproducibility was assessed in phantoms and in vivo.ResultsRelaxation rates depended on agarose and chondroitin sulfate concentration. The sequences were able to generate relaxation time maps with pulse lengths of 8 and 6 ms for HS1 and HS4, respectively. In vivo findings were in good agreement with the phantoms. The implemented adiabatic T1ρ and T2ρ sequences demonstrated regional variation in relaxation time maps of femorotibial cartilage. Reproducibility in phantoms and in vivo was good to excellent for both adiabatic T1ρ and T2ρ.ConclusionsThe findings indicate that sequences are suitable for quantitative in vivo assessment of articular cartilage at 3 T. Magn Reson Med 77:1265–1275, 2017. © 2016 International Society for Magnetic Resonance in Medicine
Monomer volume fraction profiles in pH responsive planar polyelectrolyte brushes
Authors: Mahalik J. P. , Yang Yubo , Deodhar Chaitra , Ankner John F. , Lokitz Bradley S. , Kilbey S. Michael , Sumpter Bobby G. , Kumar Rajeev 
Published: March 2016

ABSTRACTSpatial dependencies of monomer volume fraction profiles of pH responsive polyelectrolyte brushes were investigated using field theories and neutron reflectivity experiments. In particular, planar polyelectrolyte brushes in good solvent were studied and direct comparisons between predictions of the theories and experimental measurements are presented. The comparisons between the theories and the experimental data reveal that solvent entropy and ion‐pairs resulting from adsorption of counterions from the added salt play key roles in affecting the monomer distribution and must be taken into account in modeling polyelectrolyte brushes. Furthermore, the utility of this physics‐based approach based on these theories for the prediction and interpretation of neutron reflectivity profiles in the context of pH responsive planar polyelectrolyte brushes such as polybasic poly(2‐(dimethylamino)ethyl methacrylate) (PDMAEMA) and polyacidic poly(methacrylic acid) (PMAA) brushes is demonstrated. The approach provides a quantitative way of estimating molecular weights of the polymers polymerized using surface‐initiated atom transfer radical polymerization. © 2016 Wiley Periodicals, Inc. J. Polym. Sci., Part B: Polym. Phys. 2016, 54, 956–964
Blind testing of cross‐linking/mass spectrometry hybrid methods in CASP11
Authors: Schneider Michael , Belsom Adam , Rappsilber Juri , Brock Oliver 
Published: March 2016

ABSTRACTHybrid approaches combine computational methods with experimental data. The information contained in the experimental data can be leveraged to probe the structure of proteins otherwise elusive to computational methods. Compared with computational methods, the structures produced by hybrid methods exhibit some degree of experimental validation. In spite of these advantages, most hybrid methods have not yet been validated in blind tests, hampering their development. Here, we describe the first blind test of a specific cross‐link based hybrid method in CASP. This blind test was coordinated by the CASP organizers and utilized a novel, high‐density cross‐linking/mass‐spectrometry (CLMS) approach that is able to collect high‐density CLMS data in a matter of days. This experimental protocol was developed in the Rappsilber laboratory. This approach exploits the chemistry of a highly reactive, photoactivatable cross‐linker to produce an order of magnitude more cross‐links than homobifunctional cross‐linkers. The Rappsilber laboratory generated experimental CLMS data based on this protocol, submitted the data to the CASP organizers which then released this data to the CASP11 prediction groups in a separate, CLMS assisted modeling experiment. We did not observe a clear improvement of assisted models, presumably because the properties of the CLMS data—uncertainty in cross‐link identification and residue‐residue assignment, and uneven distribution over the protein—were largely unknown to the prediction groups and their approaches were not yet tailored to this kind of data. We also suggest modifications to the CLMS‐CASP experiment and discuss the importance of rigorous blind testing in the development of hybrid methods. Proteins 2016; 84(Suppl 1):152–163. © 2016 The Authors Proteins: Structure, Function, and Bioinformatics Published by Wiley Periodicals, Inc.
Mechanisms of the gabapentinoids and α2δ‐1 calcium channel subunit in neuropathic pain
Authors: Patel Ryan , Dickenson Anthony H. 
Published: March 2016

AbstractThe gabapentinoid drugs gabapentin and pregabalin are key front‐line therapies for various neuropathies of peripheral and central origin. Originally designed as analogs of GABA, the gabapentinoids bind to the α2δ‐1 and α2δ‐2 auxiliary subunits of calcium channels, though only the former has been implicated in the development of neuropathy in animal models. Transgenic approaches also identify α2δ‐1 as key in mediating the analgesic effects of gabapentinoids, however the precise molecular mechanisms remain unclear. Here we review the current understanding of the pathophysiological role of the α2δ‐1 subunit, the mechanisms of analgesic action of gabapentinoid drugs and implications for efficacy in the clinic. Despite widespread use, the number needed to treat for gabapentin and pregabalin averages from 3 to 8 across neuropathies. The failure to treat large numbers of patients adequately necessitates a novel approach to treatment selection. Stratifying patients by sensory profiles may imply common underlying mechanisms, and a greater understanding of these mechanisms could lead to more direct targeting of gabapentinoids.
Pharmacological evaluation of a series of smoothened antagonists in signaling pathways and after topical application in a depilated mouse model
Authors: Lauressergues Emilie , Heusler Peter , Lestienne Fabrice , Troulier David , Rauly‐Lestienne Isabelle , Tourette Amélie , Ailhaud Marie‐Christine , Cathala Claudie , Tardif Stéphanie , Denais‐Laliève Delphine , Calmettes Marie‐Thérèse , Degryse Anne‐Dominique , Dumoulin Antoine , De Vries Luc , Cussac Didier 
Published: March 2016

AbstractThe Hedgehog (HH) pathway has been linked to the formation of basal cell carcinoma (BCC), medulloblastoma, and other cancers. The recently approved orally active drugs vismodegib (GDC‐0449) and sonidegib (LDE–225) were not only efficacious for the treatment of advanced or metastatic BCC by antagonizing the smoothened (SMO) receptor, but also produced important side effects, limiting their use for less invasive BCC. Herein, we compared a large series of SMO antagonists, including GDC‐0449 and LDE‐225, the clinically tested BMS‐833923, CUR‐61414, cyclopamine, IPI‐926 (saridegib), itraconazole, LEQ‐506, LY‐2940680 (taladegib), PF‐04449913 (glasdegib), and TAK‐441 as well as preclinical candidates (PF‐5274857, MRT‐83) in two SMO‐dependent cellular assays and for G‐protein activation. We report marked differences in inhibitor potencies between compounds as well as a notable disparity between the G‐protein assay and the cellular tests, suggesting that classification of drugs is assay dependent. Furthermore, we explored topical efficacies of SMO antagonists on depilated mice using Gli1 and Ptch1 mRNA quantification in skin as biomarkers of the HH signaling inhibition. This topical model rapidly discriminated drugs in terms of efficacies and potencies for inhibition of both biomarkers. SMO antagonists showed also a large variation in their blood and skin partition, suggesting that some drugs are more favorable for topical application. Overall, our data suggested that in vitro and in vivo efficacious drugs such as LEQ‐506 and TAK‐441 may be of interest for topical treatment of less invasive BCC with minimal side effects.
Gastrointestinal safety, chemotherapeutic potential, and classic pharmacological profile of NOSH‐naproxen (AVT‐219) a dual NO‐ and H2S‐releasing hybrid
Authors: Chattopadhyay Mitali , Kodela Ravinder , Duvalsaint Pascale L. , Kashfi Khosrow 
Published: March 2016

AbstractNaproxen (NAP) is a potent nonsteroidal anti‐inflammatory drug (NSAID) with a favorable cardiovascular profile. However, its long‐term use may lead to serious gastrointestinal and renal side effects. NOSH‐ (nitric oxide and hydrogen sulfide) releasing naproxen (NOSH‐NAP, AVT‐219) belongs to a new class of anti‐inflammatory agents designed to overcome these limitations. We compared the gastrointestinal safety, anti‐inflammatory, analgesic, antipyretic, and antiplatelet properties of AVT‐219 to that of NAP in preclinical animal models. We also evaluated its anticancer effects in 11 human cancer cell (HCC) lines of six different tissue origins and in a chemotherapeutic xenograft mouse model of colon cancer. AVT‐219: (1) was orders of magnitude more potent than NAP in inhibiting the growth of cultured HCC; (2) was safe to the stomach, whereas NAP caused significant ulceration; (3) showed strong anti‐inflammatory, analgesic, antipyretic, and antiplatelet properties comparable to NAP; and (4) NAP caused a significant rise in plasma tumor necrosis factor‐alpha (TNFα), whereas in the AVT‐219‐treated rats this rise was significantly less. Mechanistically, AVT‐219 was a strong antioxidant, inhibited cyclooxygenase (COX)‐1 and ‐2, thus reducing prostaglandin (PG) E2. In xenografts, AVT‐219 significantly reduced tumor growth and tumor mass with no sign of GI toxicity, whereas NAP‐treated mice died due to GI bleeding. AVT‐219 displayed considerable safety and potency in inhibiting HCC growth; was an effective analgesic, antipyretic, antiplatelet, and anti‐inflammatory; and was significantly more efficacious than NAP in reducing the growth of established tumors in a xenograft mouse model.
Effect of yeast assimilable nitrogen on the synthesis of phenolic aroma compounds by Hanseniaspora vineae strains
Authors: Martin Valentina , Boido Eduardo , Giorello Facundo , Mas Albert , Dellacassa Eduardo , Carrau Francisco 
Published: March 2016

AbstractIn several grape varieties, the dominating aryl alkyl alcohols found are the volatile group of phenylpropanoid‐related compounds, such as glycosylated benzyl and 2‐phenylethyl alcohol, which contribute to wine with floral and fruity aromas after being hydrolysed during fermentation. Saccharomyces cerevisiae is largely recognized as the main agent in grape must fermentation, but yeast strains belonging to other genera, including Hanseniaspora, are known to predominate during the first stages of alcoholic fermentation. Although non‐Saccharomyces yeast strains have a well‐recognized genetic diversity, understanding of their impact on wine flavour richness is still emerging. In this study, 11 Hansenisapora vineae strains were used to ferment a chemically defined simil‐grape fermentation medium, resembling the nutrient composition of grape juice but devoid of grape‐derived secondary metabolites. GC–MS analysis was performed to determine volatile compounds in the produced wines. Our results showed that benzyl alcohol, benzyl acetate and 2‐phenylethyl acetate are significantly synthesized by H. vineae strains. Levels of these compounds found in fermentations with 11 H. vineae different strains were one or two orders of magnitude higher than those measured in fermentations with a known S. cerevisiae wine strain. The implications for winemaking in response to the negative correlation of benzyl alcohol, benzyl acetate and 2‐phenylethyl acetate production with yeast assimilable nitrogen concentrations are discussed. Copyright © 2016 John Wiley & Sons, Ltd.
ThePlasmodium falciparumDrugome And Its Polypharmacological Implications
Authors: Zhang Yinliang , Xie Li , Xie Lei , Bourne Philip E. 
Published: March 2016

ABSTRACTMalaria is a disease contracted by over 200 million people each year, mostly in developing countries. The primary causative agent,Plasmodium falciparum(P. falciparum) has shown increased resistance to existing drugs, hence new treatments are needed quickly. To this end we performed a high-throughput systems-level analysis, mapping existing FDA drugs with the potential for repurposing against targets from theP. falciparumstructural proteome. The resultingP. falciparumdrugome (P.falciparum-drugome) was used to prioritize potential new anti-malaria candidate targets and highlight some novel FDA approved drugs that have apparent anti-malaria effects for possible use as multi-target therapeutics.