bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evaluation of assay interference and interpretation of CXCR4 receptor occupancy results in a preclinical study with MEDI3185, a fully human antibody to CXCR4
Authors: Schwickart Martin , Chavez Carlos , Henderson Simon , Vainshtein Inna , Standifer Nathan , DelNagro Christopher , Mehrzai Freshta , Schneider Amy , Roskos Lorin , Liang Meina 
Published: September 2015

BackgroundReceptor occupancy (RO) assays provide a means to measure the direct interaction of therapeutics with their cell surface targets. Free receptor assays quantify cell‐surface receptors not bound by a therapeutic while total receptor assays quantify the amount of target on the cell surface.MethodsWe developed both a flow cytometry‐based free RO assay to detect free surface CXCR4, and a total surface CXCR4 assay. In an effort to evaluate potential displacement interference, we performed in vitro experiments to compare on‐cell affinity with the IC50 values from in vitro and in vivo from the free CXCR4 assay. We determined free and total surface CXCR4 on circulating blood cells in cynomolgus monkeys dosed with MEDI3185, a fully human monoclonal antibody to CXCR4.ResultsWe devised an approach to evaluate displacement interference during assay development and showed that our free assay demonstrated little to no displacement interference. After dosing cynomolgus monkeys with MEDI3185, we observed dose‐dependence in the magnitude and duration of receptor occupancy and found CXCR4 to increase on lymphocytes, monocytes, and granulocytes. In a multiple dose study, we observed time points where surface CXCR4 appeared fully occupied but MEDI3185 was not detectable in serum. These paradoxical results represented a type of assay interference, and by comparing pharmacokinetic, ADA and total CXCR4 results, the most likely reason for the free CXCR4 results was the emergence of neutralizing anti‐drug antibodies (ADA). The total CXCR4 assay was unaffected by ADA and provided a reliable marker of target modulation in both in vivo studies. © 2015 The Authors Cytometry Part B: Clinical Cytometry Published byWiley Periodicals, Inc.
Saxagliptin improves glycaemic control and C‐peptide secretion in latent autoimmune diabetes in adults (LADA)
Authors: Buzzetti R. , Pozzilli P. , Frederich R. , Iqbal N. , Hirshberg B. 
Published: September 2015

AbstractBackgroundTo assess the efficacy and tolerability of saxagliptin and C‐peptide secretion in patients with diagnosed type 2 diabetes classified as glutamic acid decarboxylase antibody (GADA)‐positive or GADA‐negative.MethodsPost hoc analysis of data pooled from five randomized, placebo‐controlled, 24‐week phase 3 studies (n = 2709) was conducted. We evaluated mean change from baseline at week 24 in HbA1c, fasting plasma glucose, postprandial plasma glucose, fasting and postprandial C‐peptide, and HOMA2‐%β and the proportion of patients achieving HbA1c < 7% (53 mmol/mol) at week 24.ResultsSaxagliptin produced greater adjusted mean reductions from baseline in HbA1c versus placebo for GADA‐negative [difference vs placebo (95% CI), −0.62% (−0.71% to −0.54%); −6.8 mmol/mol (−7.8, −5.9)] and GADA‐positive patients [−0.64% (−1.01% to −0.27%); −7.0 mmol/mol (−11.0, −3.0)]. Consistently, saxagliptin produced a greater reduction from baseline in fasting plasma glucose and postprandial plasma glucose versus placebo in GADA‐positive versus GADA‐negative patients, and more patients achieved HbA1c < 7% (53 mmol/mol) with saxagliptin versus placebo in both GADA‐negative and GADA‐positive patients. Saxagliptin increased β‐cell function as assessed by HOMA2‐%β and postprandial C‐peptide area under the curve from baseline in patients in both GADA‐positive and GADA‐negative patients. Adverse events and hypoglycaemic events were similar across treatment groups and GADA categories.ConclusionSaxagliptin was effective in lowering blood glucose levels and generally well tolerated in GADA‐positive patients. Interestingly, saxagliptin appears to improve β‐cell function in these patients, although a longer treatment duration may be needed to confirm this finding. Copyright © 2015 John Wiley & Sons, Ltd.
Early network activity propagates bidirectionally between hippocampus and cortex
Authors: Barger Zeke , Easton Curtis R. , Neuzil Kevin E. , Moody William J. 
Published: September 2015

ABSTRACTSpontaneous activity in the developing brain helps refine neuronal connections before the arrival of sensory‐driven neuronal activity. In mouse neocortex during the first postnatal week, waves of spontaneous activity originating from pacemaker regions in the septal nucleus and piriform cortex propagate through the neocortex. Using high‐speed Ca2+ imaging to resolve the spatiotemporal dynamics of wave propagation in parasagittal mouse brain slices, we show that the hippocampus can act as an additional source of neocortical waves. Some waves that originate in the hippocampus remain restricted to that structure, while others pause at the hippocampus‐neocortex boundary and then propagate into the neocortex. Blocking GABAergic neurotransmission decreases the likelihood of wave propagation into neocortex, whereas blocking glutamatergic neurotransmission eliminates spontaneous and evoked hippocampal waves. A subset of hippocampal and cortical waves trigger Ca2+ waves in astrocytic networks after a brief delay. Hippocampal waves accompanied by Ca2+ elevation in astrocytes are more likely to propagate into the neocortex. Finally, we show that two structures in our preparation that initiate waves—the hippocampus and the piriform cortex—can be electrically stimulated to initiate propagating waves at lower thresholds than the neocortex, indicating that the intrinsic circuit properties of those regions are responsible for their pacemaker function. © 2015 Wiley Periodicals, Inc. Develop Neurobiol 76: 661–672, 2016
Zebra finch as a developmental model
Authors: Mak Siu‐Shan , Wrabel Anna , Nagai Hiroki , Ladher Raj K. , Sheng Guojun 
Published: September 2015

SummaryThe domesticated zebra finch (Taeniopygia guttata) is a well‐established animal model for studying vocal learning. It is also a tractable model for developmental analyses. The finch genome has been sequenced and methods for its transgenesis have been reported. Hatching and sexual maturation in this species takes only two weeks and three months, respectively. Finch colonies can be established relatively easily and its eggs are laid at a stage earlier than in other common avian experimental models, facilitating the analysis of very early avian development. Representing the Neoaves to which 95% of all bird species belong, the finch can potentially complement two existing, Galloanserae developmental models, the chick, and quail. Here, we provide a step‐by‐step guide for how to set up a finch colony in a conventional laboratory environment. Technical tips are offered to optimize hens’ productivity and ensure a constant supply of fertilized finch eggs. Methods of handling finch eggs and embryos for subsequent embryological, cellular, or molecular analyses are also discussed. We conclude by emphasizing scientific values and cost effectiveness of maintaining a finch colony for avian developmental studies. genesis 53:669–677, 2015. © 2015 Wiley Periodicals, Inc.
Emulsifying properties of hydrolysed and low HLB sunflower lecithin mixtures
Authors: Cabezas Dario M. , Diehl Bernd W. K. , Tomás Mabel C. 
Published: September 2015

Most commonly processes for lecithin modification are deoling, fractionation with absolute ethanol to produce phosphatidylcholine or phosphatidylinositol‐enriched fractions, or enzymatic hydrolysis of these compounds. These modifications are important for achieving an optimal balance between hydrophilic and lipophilic compounds (HLB) and ensure a good food processing ability. The aim of this work was to improve the O/W emulsifying properties of modified lecithins with low HLB mixing them with hydrolysed sunflower lecithin obtained using a microbial phospholipase A2 (PLA2). Thereby, three modified sunflower lecithins (hydrolysed (HL), deoiled (DSL), and PI fraction (PIf)) were obtained. These modified lecithins and their mixtures were applied as emulsifying agent of coarse and fine O/W emulsions (Φm = 0.3). Stability of different emulsions was evaluated through the evolution of backscattering profiles, particle size distribution, and mean particle diameters. Mixtures with a hydrolysed lecitihin increased the HLB (addition of lysophospholipids) and improved the O/W emulsifying properties of DSL and PIf in each case. Mixtures 0.5:0.5 of DSL/HL or PIf/HL produced a similar behavior than 1% HL emulsions, constituting a good alternative for production of new bioactive agents.Practical applications: This study deals about the increase of the O/W emulsifying properties and thereby the commercial value of modified sunflower lecithins with low HLB values. The main target of this research work is to contribute with useful information to the food industry.Flow diagram of the process used for producing different modified lecithins to analyze their emulsifier properties in mixtures.
Effect of microrelief on water erosion and their changes during rainfall
Authors: Zhao Longshan , Huang Chihua , Wu Faqi 
Published: September 2015

AbstractSoil surface roughness contains two elementary forms, depressions and mounds, which affect water flow on the surface differently. While depressions serve as temporary water storage, mounds divert water away from their local summits. Although roughness impacts on runoff and sediment production have been studied, almost no studies have been designed explicitly to quantify the evolution of depressions and mounds and how this impacts runoff generation and sediment delivery. The objectives of this study were to analyze how different surface forms affect runoff and sediment delivery and to measure the changes in surface depressions and mounds during rainfall events. A smooth surface was used as the control. Both mounds and depressions delayed the runoff initiating time, but to differing degrees; and slightly reduced surface runoff when compared to the runoff process from the smooth surface. Surface mounds significantly increased sediment delivery, whilst depressions provided surface storage and hence reduced sediment delivery. However, as rainfall continued and rainfall intensity increased, the depression effect on runoff and erosion gradually decreased and produced even higher sediment delivery than the smooth surface. Depressions and mounds also impacted the particle size distribution of the discharged sediments. Many more sand‐sized particles were transported from the surface with mounds than with depressions. The morphology of mounds and depressions changed significantly due to rainfall, but to different extents. The difference in change had a spatial scale effect, i.e. erosion from each mound contributed to its own morphological change while sediments deposited in a depression came from a runoff contributing area above the depression, hence a much greater source area than a single mound. The results provide a mechanistic understanding of how soil roughness affects runoff and sediment production. Copyright © 2015 John Wiley & Sons, Ltd.
Impact of draining hilly lands on runoff and on‐site erosion: a case study from humid Ethiopia
Authors: Monsieurs Elise , Dessie Mekete , Verhoest Niko E. C. , Poesen Jean , Adgo Enyew , Deckers Jozef , Nyssen Jan 
Published: September 2015

AbstractThe use of drainage ditches on farmland has an impact on erosion processes both on‐site and off‐site, though their environmental impacts are not unequivocal. Here we study the runoff response and related rill erosion after installing drainage ditches and assess the effects of stone bunds in north Ethiopia. Three different land management systems were studied in 10 cropland catchments around Wanzaye during the rainy season of 2013: (1) the exclusive use of drainage ditches (locally called feses), (2) the exclusive use of stone bunds, and (3) a mixture of both systems. Stone bunds are an effective soil and water conservation technique, making the land more resistant against on‐site erosion, and allowing feses to be installed at a larger angle with the contour. The mean rill volumes for the 10 studied cropland catchments during the rainy season of 2013 was 3.73 ± 4.20 m3 ha−1 corresponding to a soil loss of 5.72 ± 6.30 ton ha−1. The establishment of feses causes larger rill volumes (R = 0.59, N = 10), although feses are perceived as the best way to avoid soil erosion when no stone bunds are present. The use of feses increases event‐based runoff coefficients (RCs) on cropland from c. 5% to values up to 39%. Also, a combination of low stone bund density and high feses density results in a higher RC, whereas catchments with a high stone bund density and low feses density have a lower RC. Peak runoff discharges decrease when stone bund density increases, whereas feses density is positively related to the peak runoff discharge. A multiple linear relation in which both feses and stone bund densities are used as explanatory variable, performs best in explaining runoff hydrograph peakedness (R2 = 83%). Copyright © 2015 John Wiley & Sons, Ltd.
“Y'all Always Told Me to Stand Up for What I Believe In”
Authors: Haddix Marcelle , Everson Josanique , Hodge Reba Y. 
Published: September 2015

AbstractIn this article, the authors share their individual and connected experiences—as a youth writer, a workshop facilitator, and the program director—of writing together in a community‐engaged writing project in efforts to support the civically engaged activist work of youth writers. The authors draw on their personal narratives and conversations to share an example of what happened when a youth writer called for social action and change, when her call was heard by supportive adults in her community, and when her writing contributed to moving forward a school reform agenda.
Test–retest reliability of the electromyographic fatigue threshold for cycle ergometry
Authors: MahmutoviĆ Selim , Sprout Erick Y. , Fontaine John C. , Buskirk Travis M. , Galen Sujay S. , Malek Moh H. 
Published: September 2015

ABSTRACTIntroduction: The purpose of this study was to determine the intersession reliability of the electromyographic fatigue threshold (EMGFT) for cycle ergometry. Methods: On separate occasions, 10 healthy, college‐aged men performed an incremental test to voluntary exhaustion on a cycle ergometer. The EMG amplitude vs. time relationships for each power output from the quadriceps femoris muscles were analyzed using linear regression. EMGFT was defined operationally as the average of the highest power output that resulted in a non‐significant slope coefficient (P >  0.05) and the lowest power output that resulted in a significant (P <  0.05) positive slope coefficient. The EMGFT values for trials 1 and 2 were used to calculate the intraclass correlation coefficient (ICC). Results: Overall, the reliability of the EMGFT (ICC2,1 = 0.85; 95% confidence interval 0.49–0.96) was in the “excellent” category. Conclusions: The EMGFT for cycle ergometry is a reliable measure for assessing muscular fatigue. Muscle Nerve 53: 803–807, 2016
A coupled discrete element‐finite difference approach for modeling mechanical response of fluid‐saturated porous materials
Authors: Psakhie S. G. , Dimaki A. V. , Shilko E. V. , Astafurov S. V. 
Published: September 2015

SummaryA model of fluid‐saturated poroelastic medium was developed based on a combination of the discrete element method and grid method. The developed model adequately accounts for the deformation, fracture, and multiscale internal structure of a porous solid skeleton. The multiscale porous structure is taken into account implicitly by assigning the porosity and permeability values for the enclosing skeleton, which determine the rate of filtration of a fluid. Macroscopic pores and voids are taken into account explicitly by specifying the computational domain geometry. The relationship between the stress–strain state of the solid skeleton and pore fluid pressure is described in the approximations of simply deformable discrete element and Biot's model of poroelasticity. The developed model was applied to study the mechanical response of fluid‐saturated samples of brittle material. Based on simulation results, we constructed a generalized logistic dependence of uniaxial compressive strength on loading rate, mechanical properties of fluid and enclosing skeleton, and on sample dimensions. The logistic form of the generalized dependence of strength of fluid‐saturated elastic–brittle porous materials is due to the competition of two interrelated processes, such as pore fluid pressure increase under solid skeleton compression and fluid outflow from the enclosing skeleton to the environment. Copyright © 2015 John Wiley & Sons, Ltd.
Comparative study of the clinical features of patients with a tubo‐ovarian abscess and patients with severe pelvic inflammatory disease
Authors: Sordia‐Hernández Luis H , Serrano Castro Laura G. , Sordia‐Piñeyro María O , Morales Martinez Arturo , Sepulveda Orozco Mary C. , Guerrero‐Gonzalez Geraldina 
Published: September 2015

AbstractObjectiveTo determine the clinical characteristics that indicate the presence of tubo‐ovarian abscess (TOA) among patients with severe pelvic inflammatory disease (PID).MethodsAn observational cohort study was performed from October 2011 to March 2013. The study included all patients with a diagnosis of TOA and PID admitted to a university hospital in Mexico. A complete medical history and physical examination were performed, and laboratory studies were reviewed. A logistic regression analysis was performed on variables with statistical significance.ResultsOverall, 26 patients with PID and TOA (TOA group) and 26 with PID without TOA (PID group) were included in the study. Significant differences between patients with TOA and PID were found with regard to the patients’ age (39.3 years vs 33.1 years; P = 0.04), educational level (only elementary, 13 [50%] vs 5 [19%]; P = 0.14), presentation with fever (23 [88%] vs 16 [62%]; P = 0.025), white blood cell count (21.8 × 109/L vs 14.9 × 109/L; P < 0.001), number of deliveries (2.2 vs 1.1; P = 0.01), and presence of diarrhea (16 [62%] vs 5 [19%]; P < 0.001). The triad of fever, leukocytosis, and diarrhea was positively related to the presence of TOA.ConclusionThe triad of fever, leukocytosis, and diarrhea should alert clinicians to the possibility of TOA formation in patients with PID.
Bayesian logistic mixed-effects modelling of transect data: relating red tree coral presence to habitat characteristics
Authors: Masuda Michele M. , Stone Robert P. 
Published: September 2015

AbstractThe collection of continuous data on transects is a common practice in habitat and fishery stock assessments; however, the application of standard regression models that assume independence to serially correlated data is problematic. We show that generalized linear mixed models (GLMMs), i.e. generalized linear models for longitudinal data, that are normally used for studies performed over time can also be applied to other types of clustered or serially correlated data. We apply a specific GLMM for longitudinal data, a hierarchical Bayesian logistic mixed-effects model (BLMM), to a marine ecology dataset obtained from submersible video recordings of the seabed on transects at two sites in the Gulf of Alaska. The BLMM was effective in relating the presence of red tree corals (Primnoa pacifica; i.e. binary data) to habitat characteristics: the presence of red tree corals is highly associated with bedrock as the primary substrate (estimated odds ratio 9–19), high to very high seabed roughness (estimated odds ratio 3–5), and medium to high slope (estimated odds ratio 2–3). The covariate depth was less important at the sites. We also demonstrate and compare two methods of model checking: full and mixed posterior predictive assessments, the latter of which provided a more realistic assessment, and we calculate the variance partition coefficient for reporting the variation explained by multiple levels of the hierarchical model.
Methadone Pharmacogenetics
Authors: Kharasch Evan D. , Regina Karen J. , Blood Jane , Friedel Christina 
Published: September 2015

AbstractAbstract
Compared with wild-type individuals, methadone metabolism and clearance were diminished in CYP2B6*6 carriers and increased in CYP2B6*4 carriers. Methadone metabolism and clearance were significantly lower in African Americans because of a larger proportion of CYP2B6*6 carriers and the absence of CYP2B6*4 carriers. These results may permit identification of individuals at risk for methadone overdose and may suggest genetically guided methadone dosing.

Background
Interindividual variability in methadone disposition remains unexplained, and methadone accidental overdose in pain therapy is a significant public health problem. Cytochrome P4502B6 (CYP2B6) is the principle determinant of clinical methadone elimination. The CYP2B6 gene is highly polymorphic, with several variant alleles. CYP2B6.6, the protein encoded by the CYP2B6*6 polymorphism, deficiently catalyzes methadone metabolism in vitro. This investigation determined the influence of CYP2B6*6, and other allelic variants encountered, on methadone concentrations, clearance, and metabolism.

Methods
Healthy volunteers in genotype cohorts CYP2B6*1/*1 (n = 21), CYP2B6*1/*6 (n = 20), and CYP2B6*6/*6 (n = 17), and also CYP2B6*1/*4 (n = 1), CYP2B6*4/*6 (n = 3), and CYP2B6*5/*5 (n = 2) subjects, received single doses of IV and oral methadone. Plasma and urine methadone and metabolite concentrations were determined by tandem mass spectrometry.

Results
Average S-methadone apparent oral clearance was 35 and 45% lower in CYP2B6*1/*6 and CYP2B6*6/*6 genotypes, respectively, compared with CYP2B6*1/*1. R-methadone apparent oral clearance was 25 and 35% lower in CYP2B6*1/*6 and CYP2B6*6/*6 genotypes, respectively, compared with CYP2B6*1/*1. R- and S-methadone apparent oral clearance was threefold and fourfold greater in CYP2B6*4 carriers. IV and oral R- and S-methadone metabolism was significantly lower in CYP2B6*6 carriers compared with that of CYP2B6*1 homozygotes and greater in CYP2B6*4 carriers. Methadone metabolism and clearance were lower in African Americans in part because of the CYP2B6*6 genetic polymorphism.

Conclusions

CYP2B6 polymorphisms influence methadone plasma concentrations, because of altered methadone metabolism and thus clearance. Genetic influence is greater for oral than IV methadone and S- than R-methadone. CYP2B6 pharmacogenetics explains, in part, interindividual variability in methadone elimination. CYP2B6 genetic effects on methadone metabolism and clearance may identify subjects at risk for methadone toxicity and drug interactions.