bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pharmacokinetics and pharmacodynamics utilizing unbound target tissue exposure as part of a disposition-based rationale for lead optimization of benzoxaboroles in the treatment of Stage 2 Human African Trypanosomiasis
Authors: WRING STEPHEN , GAUKEL ERIC , NARE BAKELA , JACOBS ROBERT , BEAUDET BETH , BOWLING TANA , MERCER LUKE , BACCHI CYRUS , YARLETT NIGEL , RANDOLPH RYAN , PARHAM ROBIN , REWERTS CINDY , PLATNER JACOB , DON ROBERT 
Published: September 2013

SUMMARYThis review presents a progression strategy for the discovery of new anti-parasitic drugs that usesin vitrosusceptibility, time-kill and reversibility measures to define the therapeutically relevant exposure required in target tissues of animal infection models. The strategy is exemplified by the discovery of SCYX-7158 as a potential oral treatment for stage 2 (CNS) Human African Trypanosomiasis (HAT). A critique of current treatments for stage 2 HAT is included to provide context for the challenges of achieving target tissue disposition and the need for establishing pharmacokinetic–pharmacodynamic (PK–PD) measures early in the discovery paradigm. The strategy comprises 3 stages. Initially, compounds demonstrating promisingin vitroactivity and selectivity for the target organism over mammalian cells are advanced toin vitrometabolic stability, barrier permeability and tissue binding assays to establish that they will likely achieve and maintain therapeutic concentrations during in-life efficacy studies. Secondly,in vitrotime-kill and reversibility kinetics are employed to correlate exposure (based on unbound concentrations) within vitroactivity, and to identify pharmacodynamic measures that would best predict efficacy. Lastly, this information is used to design dosing regimens for pivotal pharmacokinetic–pharmacodyamic studies in animal infection models.
The use of second generation antipsychotics for post-traumatic stress disorder in a US Veterans Health Administration Medical Center
Authors: Hermes E. , Sernyak M. , Rosenheck R. 
Published: September 2013

Background.Prior studies of antipsychotic use in individuals with post-traumatic stress disorder (PTSD) are limited because administrative data lacks information on why providers choose particular medications.Methods.This study examined 2613 provider surveys completed at the time any second generation antipsychotic (SGA) was prescribed over a 20-month period at a single Veterans Affairs medical center. Clinical correlates and reasons for SGA selection among individuals with PTSD compared to those with other psychiatric disorders were identified using chi-square.Results.PTSD was the sole diagnosis inn = 339 (13%) and one of several psychiatric diagnoses inn = 236 (9%) surveys. ‘Efficacy’ was the most common reason given for the prescriptions of SGAs in all surveys (51%) and among individuals with PTSD (46%). ‘Sleep/sedation’ was the only reason cited, significantly more frequently among those with PTSD (39% with PTSD only, 35% with PTSD plus another diagnosis, and 31% without PTSD [χ2 = 12.86,p < 0.0016)]. The proportion identifying ‘efficacy’ as a reason for SGA use was smaller in patients with PTSD (44% with PTSD only, 49% with PTSD and another diagnosis, and 53% without PTSD [χ2 = 8.78,p < 0.0125)]. Quetiapine was the most frequently prescribed SGA in the entire sample and among veterans with PTSD (47%).Conclusions.Clinician use of SGAs is often driven by efficacy, for which there is limited evidence, and distinctly driven by the goal of sedation among patients with PTSD.
IAPs on the move: role of inhibitors of apoptosis proteins in cell migration
Authors: Oberoi-Khanuja T K , Murali A , Rajalingam K 
Published: September 2013

AbstractInhibitors of Apoptosis Proteins (IAPs) are a class of highly conserved proteins predominantly known for the regulation of caspases and immune signaling. However, recent evidence suggests a crucial role for these molecules in the regulation of tumor cell shape and migration by controlling MAPK, NF-κB and Rho GTPases. IAPs directly control Rho GTPases, thus regulating cell shape and migration. For instance, XIAP and cIAP1 function as the direct E3 ubiquitin ligases of Rac1 and target it for proteasomal degradation. IAPs are differentially expressed in tumor cells and have been targeted by several cancer therapeutic drugs that are currently in clinical trials. Here, we summarize the current knowledge on the role of IAPs in the regulation of cell migration and discuss the possible implications of these observations in regulating tumor cell metastases.
Nitrate-based niche differentiation by distinct sulfate-reducing bacteria involved in the anaerobic oxidation of methane
Authors: Green-Saxena A , Dekas A E , Dalleska N F , Orphan V J 
Published: September 2013

Abstract
Diverse associations between methanotrophic archaea (ANME) and sulfate-reducing bacterial groups (SRB) often co-occur in marine methane seeps; however, the ecophysiology of these different symbiotic associations has not been examined. Here, we applied a combination of molecular, geochemical and Fluorescence in situ hybridization (FISH) coupled to nanoscale secondary ion mass spectrometry (FISH-NanoSIMS) analyses of in situ seep sediments and methane-amended sediment incubations from diverse locations (Eel River Basin, Hydrate Ridge and Costa Rican Margin seeps) to investigate the distribution and physiology of a newly identified subgroup of the Desulfobulbaceae (seepDBB) found in consortia with ANME-2c archaea, and compared these with the more commonly observed associations between the same ANME partner and the Desulfobacteraceae (DSS). FISH analyses revealed aggregates of seepDBB cells in association with ANME-2 from both environmental samples and laboratory incubations that are distinct in their structure relative to co-occurring ANME/DSS consortia. ANME/seepDBB aggregates were most abundant in shallow sediment depths below sulfide-oxidizing microbial mats. Depth profiles of ANME/seepDBB aggregate abundance revealed a positive correlation with elevated porewater nitrate relative to ANME/DSS aggregates in all seep sites examined. This relationship with nitrate was supported by sediment microcosm experiments, in which the abundance of ANME/seepDBB was greater in nitrate-amended incubations relative to the unamended control. FISH-NanoSIMS additionally revealed significantly higher 15N-nitrate incorporation levels in individual aggregates of ANME/seepDBB relative to ANME/DSS aggregates from the same incubation. These combined results suggest that nitrate is a geochemical effector of ANME/seepDBB aggregate distribution, and provides a unique niche for these consortia through their utilization of a greater range of nitrogen substrates than the ANME/DSS.
Geometry of Quantum Computation with Qutrits
Authors: Li Bin , Yu Zu-Huan , Fei Shao-Ming 
Published: September 2013

AbstractDetermining the quantum circuit complexity of a unitary operation is an important problem in quantum computation. By using the mathematical techniques of Riemannian geometry, we investigate the efficient quantum circuits in quantum computation with n qutrits. We show that the optimal quantum circuits are essentially equivalent to the shortest path between two points in a certain curved geometry of SU(3n). As an example, three-qutrit systems are investigated in detail.
Human junctophilin-2 undergoes a structural rearrangement upon binding PtdIns(3,4,5)P3 and the S101R mutation identified in hypertrophic cardiomyopathy obviates this response
Authors: Bennett Hayley J. , Davenport John Bernard , Collins Richard F. , Trafford Andrew W. , Pinali Christian , Kitmitto Ashraf 
Published: September 2013

JP2 (junctophilin-2) is believed to hold the transverse tubular and jSR (junctional sarcoplasmic reticulum) membranes in a precise geometry that facilitates excitation–contraction coupling in cardiomyocytes. We have expressed and purified human JP2 and shown using electron microscopy that the protein forms elongated structures ~15 nm long and 2 nm wide. Employing lipid-binding assays and quartz crystal microbalance with dissipation we have determined that JP2 is selective for PS (phosphatidylserine), with a Kd value of ~0.5 μM, with the N-terminal domain mediating this interaction. JP2 also binds PtdIns(3,4,5)P3 at a different site than PS, resulting in the protein adopting a more flexible conformation; this interaction is modulated by both Ca2+ and Mg2+ ions. We show that the S101R mutation identified in patients with hypertrophic cardiomyopathy leads to modification of the protein secondary structure, forming a more flexible molecule with an increased affinity for PS, but does not undergo a structural transition in response to binding PtdIns(3,4,5)P3. In conclusion, the present study provides new insights into the structural and lipid-binding properties of JP2 and how the S101R mutation may have an effect upon the stability of the dyad organization with the potential to alter JP2–protein interactions regulating Ca2+ cycling.
Hypoxia activates muscle-restricted coiled-coil protein (MURC) expression via transforming growth factor-β in cardiac myocytes
Authors: Shyu Kou-Gi , Cheng Wen-Pin , Wang Bao-Wei , Chang Hang 
Published: September 2013

The expression of MURC (muscle-restricted coiled-coil protein), a hypertrophy-regulated gene, increases during pressure overload. Hypoxia can cause myocardial hypertrophy; however, how hypoxia affects the regulation of MURC in cardiomyocytes undergoing hypertrophy is still unknown. The aim of the present study was to test the hypothesis that hypoxia induces MURC expression in cardiomyocytes during hypertrophy. The expression of MURC was evaluated in cultured rat neonatal cardiomyocytes subjected to hypoxia and in an in vivo model of AMI (acute myocardial infarction) to induce myocardial hypoxia in adult rats. MURC protein and mRNA expression were significantly enhanced by hypoxia. MURC proteins induced by hypoxia were significantly blocked after the addition of PD98059 or ERK (extracellular-signal-regulated kinase) siRNA 30 min before hypoxia. Gel-shift assay showed increased DNA-binding activity of SRF (serum response factor) after hypoxia. PD98059, ERK siRNA and an anti-TGF-β (transforming growth factor-β) antibody abolished the SRF-binding activity enhanced by hypoxia or exogenous administration of TGF-β. A luciferase promoter assay demonstrated increased transcriptional activity of SRF in cardiomyocytes by hypoxia. Increased βMHC (β-myosin heavy chain) and BNP (B-type natriuretic peptide) protein expression and increased protein synthesis was identified after hypoxia with the presence of MURC in hypertrophic cardiomyocytes. MURC siRNA inhibited the hypertrophic marker protein expression and protein synthesis induced by hypoxia. AMI in adult rats also demonstrated increased MURC protein expression in the left ventricular myocardium. In conclusion, hypoxia in cultured rat neonatal cardiomyocytes increased MURC expression via the induction of TGF-β, SRF and the ERK pathway. These findings suggest that MURC plays a role in hypoxia-induced hypertrophy in cardiomyocytes.
Synthesis of superparamagnetic iron oxide nanoparticles in carbon reduction method
Authors: Zhang Qiang , Li Junyang , Chou Xiujian , Gao Libo , Hai Zhenyin , Xue Chenyang 
Published: September 2013

Owing to the superparamagnetic iron oxide nanoparticles’ wide applications, a new approach in the synthesis of mainly superparamagnetic iron oxide nanoparticles is reported. The Fe3O4 nanoparticles (∼500 nm) were synthesised through the carbon reduction method, which is a brand new method. The best parameters of synthesis of the nanoparticles are fixed through characterising by transmission electron microscope (TEM), X‐ray diffraction and a vibrating sample magnetometer of the Fe3O4 nanoparticles obtained under different experimental conditions. The TEM characterisation results show that the best ratio of the carbon and ferric chloride is 3:1 and the most suitable heating time is 3 h. The nanoparticles, which were obtained with furnace cooling under vacuum condition after 3 h heating, have the best magnetic properties and most stable crystal from. The characterisations of SiO2 protected nanoparticles demonstrate that the component of the nanoparticles is Fe3O4. The UV–vis absorption spectrum of the Fe3O4 nanoparticles demonstrates wide‐range light absorption of the Fe3O4 nanoparticles. Moreover, quantitative analysis of this new method is conducted to confirm repeatability. The actual qualities of the Fe3O4 nanoparticles are always consistent with the theoretical ones, which indicate that the repeatability of this method is excellent.
Cultural interfaces of self-determination and the rise of the neo-Biafran movement in Nigeria
Authors: Onuoha Godwin 
Published: September 2013

This article examines the ‘cultural repertoires’ of neo-Biafran separatist Igbo groups in south-eastern Nigeria, pointing to the ways in which cultural repertoires, narratives and emblems are deployed to forge a separatist ethno-political project in a multi-ethnic state. The neo-Biafran movement reveals the robustness of political resistance and the existence of multiple frameworks through which ethno-nationalist groups resist and challenge extant power structures of the state in the quest for self-determination. The article argues that ethnic groups have the capacity to initiate their own ‘cultural repertoires’ in order to construct group identity, identify forms of external identity (the ‘other’) and shore up the boundaries of their own collective group identity. Myths of origin, narratives of the past, images and symbols are rooted in certain cultural repertoires, and are elaborated, interpreted, invented and reinvented to produce political identities that are complex and fluid in the struggle for political power.
[Interfaces culturelles d'autodétermination et montée du mouvement néo-biafrais au Nigeria.] Cet article examine les « répertoires culturels » des groupes igbo séparatistes du néo-Biafra au sud-est du Nigeria, désignant les façons dont les répertoires culturels, récits et symboles sont développés pour forger un projet séparatiste ethno-politique dans un État multiethnique. Le mouvement néo-biafrais prouve la robustesse de la résistance politique et l'existence de multiples cadres au travers desquels les groupes ethno-nationalistes résistent et défient les structures de pouvoir existantes en quête d'auto-détermination. L'article affirme que les groupes ethniques ont la capacité d'initier leurs propres « répertoires culturels » afin de construire une identité de groupe, identifier des formes d'identité extérieure (« l'autre ») et construire les frontières de leur propre identité collective. Mythe des origines, récits du passé, images et symboles sont ancrés dans des répertoires culturels propres et sont élaborés, interprétés, inventés et réinventés pour produire des identités politiques qui sont complexes et fluides dans la lutte pour le pouvoir politique.

Mots-clés : culture ; politique ; auto-détermination ; identité ethnique ; Igbo ; Nigeria
Genetic influences of sports participation in Portuguese families
Authors: Seabra André F. , Mendonça Denisa M. , Göring Harald H. H. , Thomis Martine A. , Maia José A. 
Published: September 2013

AbstractTo estimate familial aggregation and quantify the genetic and environmental contribution to the phenotypic variation on sports participation (SP) among Portuguese families. The sample consisted of 2375 nuclear families (parents and two offspring each) from different regions of Portugal with a total of 9500 subjects. SP assessment was based on a psychometrically established questionnaire. Phenotypes used were based on the participation in sports (yes/no), intensity of sport, weekly amount of time in SP and the proportion of the year in which a sport was regularly played. Familial correlations were calculated using family correlations (FCOR) in the SAGE software. Heritability was estimated using variance‐components methods implemented in Sequential Oligogenic Linkage Analysis Routines (SOLAR) software. Subjects of the same generation tend to be more similar in their SP habits than the subjects of different generations. In all SP phenotypes studied, adjusted for the effects of multiple covariates, the proportion of phenotypic variance due to additive genetic factors ranged between 40% and 50%. The proportion of variance attributable to environmental factors ranged from 50% for the participation in sports to 60% for intensity of sport. In this large population‐based family study, there was significant familial aggregation on SP. These results highlight that the variation on SP phenotypes have a significant genetic contribution although environmental factors are also important in the familial resemblance of SP.
Invited Commentary: Off-Roading With Social Epidemiology—Exploration, Causation, Translation
Authors: Glymour M. Maria , Osypuk Theresa L. , Rehkopf David H. 
Published: September 2013

Abstract
Population health improvements are the most relevant yardstick against which to evaluate the success of social epidemiology. In coming years, social epidemiology must increasingly emphasize research that facilitates translation into health improvements, with continued focus on macro-level social determinants of health. Given the evidence that the effects of social interventions often differ across population subgroups, systematic and transparent exploration of the heterogeneity of health determinants across populations will help inform effective interventions. This research should consider both biological and social risk factors and effect modifiers. We also recommend that social epidemiologists take advantage of recent revolutionary improvements in data availability and computing power to examine new hypotheses and expand our repertoire of study designs. Better data and computing power should facilitate underused analytic approaches, such as instrumental variables, simulation studies and models of complex systems, and sensitivity analyses of model biases. Many data-driven machine-learning approaches are also now computationally feasible and likely to improve both prediction models and causal inference in social epidemiology. Finally, we emphasize the importance of specifying exposures corresponding with realistic interventions and policy options. Effect estimates for directly modifiable, clearly defined health determinants are most relevant for building translational social epidemiology to reduce disparities and improve population health.
Guidance for implementation of integrated ecosystem assessments: a US perspective
Authors: Levin Phillip S. , Kelble Christopher R. , Shuford Rebecca L. , Ainsworth Cameron , deReynier Yvonne , Dunsmore Rikki , Fogarty Michael J. , Holsman Kirstin , Howell Evan A. , Monaco Mark E. , Oakes Stephanie A. , Werner Francisco 
Published: September 2013

Abstract
Ecosystem-based management (EBM) has emerged as a basic approach for managing human activities in marine ecosystems, with the aim of recovering and conserving marine ecosystems and the services they deliver. Integrated ecosystem assessments (IEAs) further the transition of EBM from principle to practice by providing an efficient, transparent means of summarizing the status of ecosystem components, screening and prioritizing potential risks, and evaluating alternative management strategies against a backdrop of environmental variability. In this paper, we draw upon lessons learned from the US National Oceanic and Atmospheric Administration's IEA programme to outline steps required for IEA implementation. We provide an overview of the conceptual framework for IEAs, the practical constraints that shape the structure of individual IEAs, and the uses and outcomes of IEAs in support of EBM.
Solution structure of the major G-quadruplex formed in the human VEGF promoter in K+: insights into loop interactions of the parallel G-quadruplexes
Authors: Agrawal Prashansa , Hatzakis Emmanuel , Guo Kexiao , Carver Megan , Yang Danzhou 
Published: September 2013

Abstract
Vascular endothelial growth factor (VEGF) proximal promoter region contains a poly G/C-rich element that is essential for basal and inducible VEGF expression. The guanine-rich strand on this tract has been shown to form the DNA G-quadruplex structure, whose stabilization by small molecules can suppress VEGF expression. We report here the nuclear magnetic resonance structure of the major intramolecular G-quadruplex formed in this region in K+ solution using the 22mer VEGF promoter sequence with G-to-T mutations of two loop residues. Our results have unambiguously demonstrated that the major G-quadruplex formed in the VEGF promoter in K+ solution is a parallel-stranded structure with a 1:4:1 loop-size arrangement. A unique capping structure was shown to form in this 1:4:1 G-quadruplex. Parallel-stranded G-quadruplexes are commonly found in the human promoter sequences. The nuclear magnetic resonance structure of the major VEGF G-quadruplex shows that the 4-nt middle loop plays a central role for the specific capping structures and in stabilizing the most favored folding pattern. It is thus suggested that each parallel G-quadruplex likely adopts unique capping and loop structures by the specific middle loops and flanking segments, which together determine the overall structure and specific recognition sites of small molecules or proteins.
LAY SUMMARY: The human VEGF is a key regulator of angiogenesis and plays an important role in tumor survival, growth and metastasis. VEGF overexpression is frequently found in a wide range of human tumors; the VEGF pathway has become an attractive target for cancer therapeutics. DNA G-quadruplexes have been shown to form in the proximal promoter region of VEGF and are amenable to small molecule drug targeting for VEGF suppression. The detailed molecular structure of the major VEGF promoter G-quadruplex reported here will provide an important basis for structure-based rational development of small molecule drugs targeting the VEGF G-quadruplex for gene suppression.
Two Phloem Nitrate Transporters, NRT1.11 and NRT1.12, Are Important for Redistributing Xylem-Borne Nitrate to Enhance Plant Growth
Authors: Hsu Po-Kai , Tsay Yi-Fang 
Published: September 2013

Abstract
This study of the Arabidopsis (Arabidopsis thaliana) nitrate transporters NRT1.11 and NRT1.12 reveals how the interplay between xylem and phloem transport of nitrate ensures optimal nitrate distribution in leaves for plant growth. Functional analysis in Xenopus laevis oocytes showed that both NRT1.11 and NRT1.12 are low-affinity nitrate transporters. Quantitative reverse transcription-polymerase chain reaction and immunoblot analysis showed higher expression of these two genes in larger expanded leaves. Green fluorescent protein and β-glucuronidase reporter analyses indicated that NRT1.11 and NRT1.12 are plasma membrane transporters expressed in the companion cells of the major vein. In nrt1.11 nrt1.12 double mutants, more root-fed 15NO3 − was translocated to mature and larger expanded leaves but less to the youngest tissues, suggesting that NRT1.11 and NRT1.12 are required for transferring root-derived nitrate into phloem in the major veins of mature and larger expanded leaves for redistributing to the youngest tissues. Distinct from the wild type, nrt1.11 nrt1.12 double mutants show no increase of plant growth at high nitrate supply. These data suggested that NRT1.11 and NRT1.12 are involved in xylem-to-phloem transfer for redistributing nitrate into developing leaves, and such nitrate redistribution is a critical step for optimal plant growth enhanced by increasing external nitrate.