bluuebunny/crossref_metadata_2025_split huggingface dataset:
Metabolic profiles of neratinib in rat by using ultra‐high‐performance liquid chromatography coupled with diode array detector and Q‐Exactive Orbitrap tandem mass spectrometry
Authors: Liu Wen , Li Sha , Wu Yangke , Yan Xiao , Zhu Y.‐M. , Huang J.‐H. , Chen Zhuo 
Published: May 2018

AbstractNeratinib is a tyrosine kinase inhibitor that has been approved by the US Food and Drug Administration for the treatment of breast cancer. However, its metabolism remains unknown. This study was carried out to investigate the in vitro and in vivo metabolism of neratinib using an UHPLC‐DAD‐Q Exactive Orbitrap‐MS instrument with dd‐MS2 on‐line data acquisition mode. The post‐acquisition data was processed using MetWorks software. Under the current conditions, a total of 12 metabolites were detected and structurally identified based on their accurate masses, fragment ions and chromatographic retention times. Among these metabolites, M3, M10 and M12 were unambiguously identified using chemically synthesized reference standards. M6 and M7 (GSH conjugates) were the major metabolites. The metabolic pathways of neratinib were proposed accordingly. Our findings suggested that neratinib was mainly metabolized via O‐dealkylation (M3), oxygenation (M8), N‐demethylation (M10), N‐oxygenation (M12), GSH conjugation (M1, M2, M4, M5, M6 and M7) and N‐acetylcysteine conjugation (M9 and M11). The α,β‐unsaturated ketone was the major metabolic site and GSH conjugation was the predominant metabolic pathway. In conclusion, this study provided valuable metabolic data and would benefit the assessment of the contributions to the overall activity or toxicity from the key metabolites.
Development and validation of a UPLC–MS method for the determination of galantamine in guinea pig plasma and its application to a pre‐clinical bioavailability study of novel galantamine formulations
Authors: Wang Jiang , Pavurala Naresh , Xu Xiaoming , Krishnaiah Yellela S. R. , Faustino Patrick J. 
Published: May 2018

AbstractTo evaluate the bioavailability and pharmacokinetic profiles of two novel galantamine formulations as medical countermeasure products, an ultra‐performance liquid chromatography–single quadrupole mass spectrometry (UPLC–MS) method was developed and validated for quantifying galantamine in guinea pig plasma using solid‐phase extraction with a mixed mode strong cation exchange reversed‐phase cartridge. Chromatographic separation was achieved on a Waters Acquity UPLC BEH C18 column maintained at 40°C. The mobile phases were solution A, acetonitrile–water, 5:95 (v/v) and solution B, acetonitrile–water 90:10 (v/v), both containing 2 mM ammonium formate and 0.2% formic acid. The mobile phase was delivered utilizing a 3 min gradient program start with 95%A–5%B at a flow rate of 0.6 mL/min. The analyte and internal standard, galantamine‐d3, were detected by selected ion monitoring mode on a Waters 3100 single quadrupole mass spectrometer with positive electrospray ionization. The method was validated according to the US Food and Drug Administration bioanalytical guidance. The method was selective and was linear over the analytical range of 2–2000 ng/mL. Accuracy and precision were acceptable with intra‐ and inter‐day accuracies between 96.8 and 101% and precisions (RSD) <4.88%. The method was successfully implemented to measure galantamine plasma levels in a series of pre‐clinical bioavailability studies for the evaluation of novel galantamine formulations.
The impact of diabetes on the prognostic value of left ventricular function following percutaneous coronary intervention: Insights from the British Cardiovascular Intervention Society
Authors: Jackson Matthew , Austin David , Kwok Chun Shing , Rashid Muhammad , Kontopantelis Evangelos , Ludman Peter , de Belder Mark , Mamas Mamas A. , Zaman Azfar 
Published: May 2018

AbstractObjectivesTo study the relationship between diabetes mellitus (DM) and left ventricular (LV) function on outcomes following percutaneous coronary intervention (PCI).BackgroundDM is a growing public health challenge worldwide and a significant risk factor for cardiovascular disease and heart failure.MethodsAll PCI procedures performed between 2006 and 2013 with LV function and diabetic status recorded in the BCIS‐NICOR database were included. Demographic, procedural, and clinical outcomes data were collected. Multivariable logistic regression was used to provide adjusted estimates of clinical outcome by LV function and DM, including DM sub‐type.ResultsOf 260,726 patients, DM was present in 52,160 (20%); moderate LV systolic dysfunction (LVSD) was present in 51,266 (20%), and severe LVSD in 18,148 (7%). Worsening LVSD in diabetic patients was associated with poorer prognosis following PCI; moderate LVSD odds ratio (OR) 2.03 (95% CI 1.72–2.38) and severe LVSD OR 4.17 (95% CI 3.52–4.93). There was a higher crude and adjusted mortality rate for patients with DM across all grades of LVSD. However, the relative effect of DM appeared attenuated in the severe LVSD group compared with moderate or good LV function, particularly evident in patients with insulin requiring DM (good LV OR 2.09 [95% CI 1.66–2.65]; moderate LVSD OR 1.56 [95% CI 1.26–1.93], poor LV OR 1.40 [95% CI 1.13–1.74]).ConclusionsDM was associated with increased 30‐day mortality for all grades of LV function. The prognostic impact of DM was strongest in patients with normal LV function and less evident in patients with severe LV systolic dysfunction.
Computational simulation of vibrationally resolved spectra for spin‐forbidden transitions
Authors: Egidi Franco , Fusè Marco , Baiardi Alberto , Bloino Julien , Li Xiaosong , Barone Vincenzo 
Published: May 2018

AbstractIn this computational study, we illustrate a method for computing phosphorescence and circularly polarized phosphorescence spectra of molecular systems, which takes into account vibronic effects including both Franck‐Condon and Herzberg‐Teller contributions. The singlet and triplet states involved in the phosphorescent emission are described within the harmonic approximation, and the method fully takes mode‐mixing effects into account when evaluating Franck‐Condon integrals. Spin‐orbit couplings, which are responsible for these otherwise forbidden phenomena, are accounted for by means of a relativistic two‐component time‐dependent density functional theory method. The model is applied to two types of chiral systems: camphorquinone, a rigid organic system that allows for an extensive benchmark, and some members of a class of iridium complexes. The merits and shortcomings of the methods are discussed, and some perspectives for future developments are offered.
Thermodynamic Insight into the Effects of Water Displacement and Rearrangement upon Ligand Modifications using Molecular Dynamics Simulations
Authors: Wahl Joel , Smieško Martin 
Published: May 2018

AbstractComputational methods, namely molecular dynamics (MD) simulations in combination with inhomogeneous fluid solvation theory (IFST) were used to retrospectively investigate various cases of ligand structure modifications that led to the displacement of binding site water molecules. Our findings are that water displacement per se is energetically unfavorable in the discussed examples, and that it is merely the fine balance between change in protein–ligand interaction energy, ligand solvation free energies, and binding site solvation free energies that determine if water displacement is favorable or not. We furthermore evaluated if we can reproduce experimental binding affinities by a computational approach combining changes in solvation free energies with changes in protein–ligand interaction energies and entropies. In two of the seven cases, this estimation led to large errors, implying that accurate predictions of relative binding free energies based on solvent thermodynamics is challenging. Nevertheless, MD simulations can provide insight regarding which water molecules can be targeted for displacement.
Fast approximation algorithms for task‐based runtime systems
Authors: Beaumont Olivier , Eyraud‐Dubois Lionel , Kumar Suraj 
Published: May 2018

SummaryIn High Performance Computing, heterogeneity is now the norm with specialized accelerators like GPUs providing efficient computational power. Resulting complexity led to the development of task‐based runtime systems, where complex computations are described as task graphs, and scheduling decisions are made at runtime to perform load balancing between all the resources of the platforms. Developing good scheduling strategies, even at the scale of a single node, and analyzing them both theoretically and in practice are expected to have a very high impact on the performance of current HPC systems. The special case of 2 kinds of resources, typically CPUs and GPUs, is already of great practical interest. The scheduling policy HeteroPrio has been proposed in the context of fast multipole computations (FMM) and has been extended to general task graphs with very promising results. In this paper, we provide a theoretical study of the performance of HeteroPrio, by proving approximation bounds compared to the optimal schedule, both in the case of independent tasks and in the case of general task graphs. Interestingly, our results establish that spoliation (a technique that enables resources to restart uncompleted tasks on another resource) is enough to prove bounded approximation ratios for a list scheduling algorithm on two unrelated resources, which is known to be impossible otherwise. This result holds true both for the independent and dependent tasks graphs. Additionally, we provide an experimental evaluation of HeteroPrio on real task graphs from dense linear algebra computation, which establishes its strong performance in practice.
Zebrafish: Development of a Vertebrate Model Organism
Authors: Meyers Jason R. 
Published: May 2018

AbstractZebrafish (Danio rerio) are a small‐bodied tropical, freshwater fish species originally from South Asia. The ease of care, year‐round prolific breeding, and transparent, external development have made these fish a popular model vertebrate for many fields of biology. Over the past 40 years, the development of methods for genetic and developmental manipulation have driven a rapid rise in their use in research. This review provides an orientation to the zebrafish as a model system, from its ecology and life history to its early use in research and adoption as a key genetic model for vertebrate development. Its current uses and key techniques that highlight future areas of development of the system are also discussed. Finally, an introduction to the essentials of zebrafish use and care are presented, highlighting the ease of adoption of this system for teaching and research use. © 2018 by John Wiley & Sons, Inc.
Reconstitution and Electrophysiological Characterization of Ion Channels in Lipid Bilayers
Authors: Klaerke Dan A. , Tejada Maria de los Angeles , Christensen Vibeke Grøsfjeld , Lassen Mette , Pedersen Per Amstrup , Calloe Kirstine 
Published: May 2018

AbstractDetergent‐solubilized purified ion channels can be reconstituted into lipid bilayers for electrophysiological analysis. Traditionally, ion channels were inserted into vesicles and subsequently fused with planar “black lipid membranes” formed from lipids dissolved in a hydrophobic solvent such as decane. Provided in this article is a step‐by‐step guide to reconstitute purified ion channel proteins into giant unilamellar vesicles (GUVs). This procedure results in the formation of proteoliposomes that can be used for planar bilayer formation and electrophysiological characterization of single‐channel currents. By using preformed GUVs it is possible to omit the membrane solvent. Compared to traditional preparations, the lipid bilayers formed from GUVs provide an environment that more closely resembles the native cell membrane. Also described is an alternate protocol that entails the production of planar lipid bilayers from GUVs onto which proteins in detergent are added. © 2018 by John Wiley & Sons, Inc.
Diabetic foot syndrome in patients with diabetes. A multicenter German/Austrian DPV analysis on 33 870 patients
Authors: Bohn Barbara , Grünerbel Arthur , Altmeier Marcus , Giesche Carsten , Pfeifer Martin , Wagner Christian , Heise Nikolai , Best Frank , Fasching Peter , Holl Reinhard W. 
Published: May 2018

AbstractAimsThe diabetic foot syndrome (DFS) is a serious complication in patients with diabetes increasing the risk for minor/major amputations. This analysis aimed to examine differences in diabetes patients with or without DFS stratified by type 1 (T1D) or type 2 diabetes (T2D).Material and MethodsAdult patients (≥20y of age) with diabetes from the German/Austrian diabetes patients follow‐up registry (DPV) were included. The cross‐sectional study comprised 45 722 subjects with T1D (nDFS = 2966) and 313 264 with T2D (nDFS = 30 904). In DFS, minor/major amputations were analysed. To compare HbA1C, neuropathy, nephropathy, cardiovascular disease risk factors, and macrovascular complications between patients with or without DFS, regression models were conducted. Confounders: age, sex, diabetes duration.ResultsIn patients with DFS, a minor amputation was documented in 27.2% (T1D) and 25.9% (T2D), a major amputation in 10.2% (T1D) and 11.3% (T2D). Regression models revealed that neuropathy was more frequent in subjects with DFS compared with patients without DFS (T1D: 70.7 vs 29.8%; T2D: 59.4% vs 36.9%; both P < 0.0001). Hypertension, nephropathy, peripheral vascular disease, stroke, or myocardial infarction was more common compared with patients without DFS (all P < 0.0001). In T1D with DFS, a slightly higher HbA1C (8.11% vs 7.95%; P < 0.0001) and in T2D with DFS a lower HbA1C (7.49% vs 7.69%; P < 0.0001) was observed.ConclusionsOne third of the patients with DFS had an amputation of the lower extremity. Especially neuropathy or peripheral vascular disease was more prevalent in patients with DFS. New concepts to prevent DFS‐induced amputations and to reduce cardiovascular risk factors before the occurrence of DFS are necessary.
Phase I metabolism of the carbazole‐derived synthetic cannabinoids EG‐018, EG‐2201, and MDMB‐CHMCZCA and detection in human urine samples
Authors: Mogler Lukas , Franz Florian , Wilde Maurice , Huppertz Laura M. , Halter Sebastian , Angerer Verena , Moosmann Bjoern , Auwärter Volker 
Published: May 2018

AbstractSynthetic cannabinoids (SCs) are a structurally diverse class of new psychoactive substances. Most SCs used for recreational purposes are based on indole or indazole core structures. EG‐018 (naphthalen‐1‐yl(9‐pentyl‐9H‐carbazol‐3‐yl)methanone), EG‐2201 ((9‐(5‐fluoropentyl)‐9H‐carbazol‐3‐yl)(naphthalen‐1‐yl)methanone), and MDMB‐CHMCZCA (methyl 2‐(9‐(cyclohexylmethyl)‐9H‐carbazole‐3‐carboxamido)‐3,3‐dimethylbutanoate) are 3 representatives of a structural subclass of SCs, characterized by a carbazole core system. In vitro and in vivo phase I metabolism studies were conducted to identify the most suitable metabolites for the detection of these substances in urine screening. Detection and characterization of metabolites were performed by liquid chromatography–electrospray ionization–tandem mass spectrometry (LC–ESI–MS/MS) and liquid chromatography–electrospray ionization–quadrupole time‐of‐flight–mass spectrometry (LC–ESI–QToF–MS). Eleven in vivo metabolites were detected in urine samples positive for metabolites of EG‐018 (n = 8). A hydroxypentyl metabolite, most probably the 4‐hydroxypentyl isomer, and an N‐dealkylated metabolite mono‐hydroxylated at the carbazole core system were most abundant. In vitro studies of EG‐018 and EG‐2201 indicated that oxidative defluorination of the 5‐fluoropentyl side chain of EG‐2201 as well as dealkylation led to common metabolites with EG‐018. This has to be taken into account for interpretation of analytical findings. A differentiation between EG‐018 and EG‐2201 (n = 1) uptake is possible by the detection of compound‐specific in vivo phase I metabolites evaluated in this study. Out of 30 metabolites detected in urine samples of MDMB‐CHMCZCA users (n = 20), a metabolite mono‐hydroxylated at the cyclohexyl methyl tail is considered the most suitable compound‐specific consumption marker while a biotransformation product of mono‐hydroxylation in combination with hydrolysis of the terminal methyl ester function provides best sensitivity due to its high abundance.
Insights into the phylogenetic and molecular evolutionary histories of Fad and Elovl gene families in Actiniaria
Authors: Surm Joachim M. , Toledo Tarik M. , Prentis Peter J. , Pavasovic Ana 
Published: May 2018

AbstractThe biosynthesis of long‐chain polyunsaturated fatty acids (LC‐PUFAs, ≥ C20) is reliant on the action of desaturase and elongase enzymes, which are encoded by the fatty acyl desaturase (Fad) and elongation of very long‐chain fatty acid (Elovl) gene families, respectively. In Metazoa, research investigating the distribution and evolution of these gene families has been restricted largely to Bilateria. Here, we provide insights into the phylogenetic and molecular evolutionary histories of the Fad and Elovl gene families in Cnidaria, the sister phylum to Bilateria. Four model cnidarian genomes and six actiniarian transcriptomes were interrogated. Analysis of the fatty acid composition of a candidate cnidarian species, Actinia tenebrosa, was performed to determine the baseline profile of this species. Phylogenetic analysis revealed lineage‐specific gene duplication in actiniarians for both the Fad and Elovl gene families. Two distinct cnidarian Fad clades clustered with functionally characterized Δ5 and Δ6 proteins from fungal and plant species, respectively. Alternatively, only a single cnidarian Elovl clade clustered with functionally characterized Elovl proteins (Elovl4), while two additional clades were identified, one actiniarian‐specific (Novel ElovlA) and the another cnidarian‐specific (Novel ElovlB). In actiniarians, selection analyses revealed pervasive purifying selection acting on both gene families. However, codons in the Elovl gene family show patterns of nucleotide variation consistent with the action of episodic diversifying selection following gene duplication events. Significantly, these codons may encode amino acid residues that are functionally important for Elovl proteins to target and elongate different precursor fatty acids. In A. tenebrosa, the fatty acid analysis revealed an absence of LC‐PUFAs > C20 molecules and implies that the Elovl enzymes are not actively contributing to the elongation of these LC‐PUFAs. Overall, this study has revealed that actiniarians possess Fad and Elovl genes required for the biosynthesis of some LC‐PUFAs, and that these genes appear to be distinct from bilaterians.
Everything Should Be as Simple as It Can Be. But Not Simpler. Does Food Lipid Oxidation Require an Omics Approach?
Authors: Paradiso Vito M. , Pasqualone Antonella , Summo Carmine , Caponio Francesco 
Published: May 2018

Lipid oxidation remains a major challenge for the food industry and for researchers. Current methods and knowledge often fail to adequately represent what is consistently observed in real systems. Practical experience strongly suggests the need for new paradigms to fully comprehend lipid oxidation. This viewpoint article aims to mention some critical aspects of current approaches in evaluating lipid oxidation in food systems, and to search for new epistemological and therefore experimental approaches by adopting an interdisciplinary perspective. Herein, suggestions are formulated for a holistic perspective by combining elements ranging from philology to community ecology and systems biology. Lipids undergoing oxidation are compared to ecological communities and living systems, to be considered as a whole, whose patterns change with space and time. As omics is an inductive, hypothesis‐generating, circular approach, involving multiparametric analysis, data integration/fusion, and multivariate statistical analysis (both supervised and unsupervised), it could thus provide a useful contribution to better understanding of oxidation and antioxidation processes, enabling laboratory results to be matched with what is observed in real complex foods.Practical applications: There is still a large gap between the wealth of natural compounds with antioxidant activity and the availability of natural products able to prevent rancidity in food products. Moreover, healthy, highly unsaturated fatty acids still require appropriate methods to monitor oxidative spoilage. Dispersed systems and multidomain foods pose new daily challenges regarding oxidation assessment and control. These are critical issues in the food industry, indicating the need to identify a new approach to lipid oxidation in food systems, and this viewpoint article is a contribution to the ongoing debate.A new epistemological paradigm for lipid oxidation in food systems. It consists of the reiteration of hypothesis‐generating studies (oxidomics), requiring multiparametric, comprehensive profiling of the oxidation patterns (oxidome) and their changes. The outcome is a progressive improvement in the knowledge of complex systems and the selection of appropriate predisposition, prognostic and diagnostic marker patterns for the oxidation process.
Sediment accumulation in embayments controlled by bathymetric slope and wave energy: Implications for beach formation and persistence
Authors: Preston John , Hurst Martin D. , Mudd Simon M. , Goodwin Guillaume C.H. , Newton Anthony J. , Dugmore Andrew J. 
Published: May 2018

AbstractHigh energy, rocky coastlines often feature sandy beaches within headland‐bound embayments. Not all such embayments have beaches however, and beaches in embayments can be removed by storms and may subsequently reform. What dictates the presence or absence of an embayed beach and its resilience to storms? In this paper, we explore the effect of offshore slope and wind conditions on nearshore sediment transport within idealised embayments to give insight into nearshore sediment supplies. We use numerical simulations to show that sand can accumulate near shore if the offshore slope is >0.025 m/m, but only under persistent calm conditions. Our modelling also suggests that if sediment in an embayment with an offshore gradient steeper than 0.025 m/m is removed during a period of persistent stormy conditions, it will be unlikely to return in sub‐decadal timescales. In contrast, sediment located in embayments with shallower gradients can reform swiftly in both calm and stormy conditions. Our findings have wide implications for contemporary coastal engineering in the face of future global climate change, but also for Quaternary environmental reconstruction. Our simple method to predict beach stability based on slope can be used to interpret differing responses of embayments to periods of changing coastal storminess such as the medieval climate anomaly‐little ice age (MCA‐LIA) transition. © 2018 The Authors. Earth Surface Processes and Landforms published by John Wiley & Sons Ltd.