bluuebunny/crossref_metadata_2025 huggingface dataset:
Review: Insights into molecular mechanisms of disease in neurodegeneration with brain iron accumulation: unifying theories
Authors: Arber C. E. , Li A. , Houlden H. , Wray S.
Published: April 2015

Neurodegeneration with brain iron accumulation (NBIA) is a group of disorders characterized by dystonia, parkinsonism and spasticity. Iron accumulates in the basal ganglia and may be accompanied by Lewy bodies, axonal swellings and hyperphosphorylated tau depending on NBIA subtype. Mutations in 10 genes have been associated with NBIA that include Ceruloplasmin (Cp) and ferritin light chain (FTL), both directly involved in iron homeostasis, as well as Pantothenate Kinase 2 (PANK2), Phospholipase A2 group 6 (PLA2G6), Fatty acid hydroxylase 2 (FA2H), Coenzyme A synthase (COASY), C19orf12, WDR45 and DCAF17 (C2orf37). These genes are involved in seemingly unrelated cellular pathways, such as lipid metabolism, Coenzyme A synthesis and autophagy. A greater understanding of the cellular pathways that link these genes and the disease mechanisms leading to iron dyshomeostasis is needed. Additionally, the major overlap seen between NBIA and more common neurodegenerative diseases may highlight conserved disease processes. In this review, we will discuss clinical and pathological findings for each NBIA‐related gene, discuss proposed disease mechanisms such as mitochondrial health, oxidative damage, autophagy/mitophagy and iron homeostasis, and speculate the potential overlap between NBIA subtypes.
The blood clotting Factor XIIIa forms unique complexes with amyloid‐beta (Aβ) and colocalizes with deposited Aβ in cerebral amyloid angiopathy
Authors: de Jager M. , Boot M. V. , Bol J. G. J. M. , Brevé J. J. P. , Jongenelen C. A. M. , Drukarch B. , Wilhelmus M. M. M.
Published: April 2015

Aims

Cerebral amyloid angiopathy (CAA) is a key pathological hallmark of Alzheimer's disease (AD) characterized by accumulation of amyloid‐beta (Aβ) protein in blood vessel walls. CAA impairs vessel functioning, affects blood brain barrier integrity and accelerates cognitive decline of AD patients. Unfortunately, mechanisms underlying Aβ deposition in the vessel wall remain largely unknown. Factor XIIIa (FXIIIa) is a blood‐derived transglutaminase crucial in blood coagulation by cross‐linking fibrin molecules. Evidence is mounting that blood‐derived factors are present in CAA and may play a role in protein deposition in the vessel wall. We therefore investigated whether FXIIIa is present in CAA and if FXIIIa cross‐link activity affects Aβ aggregation.

Methods

Using immunohistochemistry, we investigated the distribution of FXIIIa, its activator thrombin and in situ FXIIIa activity in CAA in post‐mortem AD tissue. We used surface plasmon resonance and Western blot analysis to study binding of FXIIIa to Aβ and the formation of FXIIIa‐Aβ complexes, respectively. In addition, we studied cytotoxicity of FXIIIa‐Aβ complexes to cerebrovascular cells.

Results

FXIIIa, thrombin and in situ FXIIIa activity colocalize with the Aβ deposition in CAA. Furthermore, FXIIIa binds to Aβ with a higher binding affinity for Aβ1–42 compared with Aβ1–40. Moreover, highly stable FXIIIa‐Aβ complexes are formed independently of FXIIIa cross‐linking activity that protected cerebrovascular cells from Aβ‐induced toxicity in vitro.

Conclusions

Our data showed that FXIIIa colocalizes with Aβ in CAA and that FXIIIa forms unique protein complexes with Aβ that might play an important role in Aβ deposition and persistence in the vessel wall.
The effect of FAAH, MAGL, and Dual FAAH/MAGL inhibition on inflammatory and colorectal distension‐induced visceral pain models in Rodents
Authors: Sakin Y. S. , Dogrul A. , Ilkaya F. , Seyrek M. , Ulas U. H. , Gulsen M. , Bagci S.
Published: April 2015

Background

Recent studies showed that the pharmacological inhibition of endocannabinoid degrading enzymes such as fatty acid amide hydrolase (FAAH) and monoacyl glycerol lipase (MAGL) elicit promising analgesic effects in a variety of nociceptive models without serious side effects. However, the full spectrum of activities is not observed upon inhibition of either FAAH or MAGL enzymes alone and thus dual FAAH and MAGL inhibitors have been described. Visceral pain is strongly associated with inflammation and distension of the gut. Thus, we explored the comparable effects of FAAH, MAGL, and dual FAAH/MAGL inhibitors on inflammatory and mechanically evoked visceral pain models.

Methods

Visceral inflammatory and distension‐induced pain were assessed with the 0.6% acetic acid writhing test in mice and colorectal distension (CRD) test in rats, respectively. The selective FAAH inhibitor PF 3845, MAGL inhibitor JZL 184, dual inhibitor JZL 195, and the cannabis analog CP 55,940 were given systemically 30 min prior to nociceptive testing.

Key Results

PF 3845 (5, 10, and 20 mg/kg), JZL 184 (5, 10, and 20 mg/kg), and JZL 195 (5, 10, and 20 mg/kg) elicit dose‐dependent antinociceptive in the acetic acid writhing test. In the CRD model, while JZL 195 (5, 10, or 20 mg/kg) and PF3845 (10, 20, and 40 mg/kg) produced dose‐dependent antinociceptive effects comparable to those of CP 55,940 (0.1, 0.3, or 1 mg/kg), JZL 184 (10, 20, and 40 mg/kg) alone did not alter the visceromotor response (VMR).

Conclusions & Inferences

The selective FAAH inhibitor and dual FAAH/MAGL inhibitors were effective in both inflammatory and mechanically evoked visceral pain, while the MAGL inhibitor elicited an analgesic effect in inflammatory, but not in distension‐induced, visceral pain.
Estimating phylogenetic trees from genome‐scale data
Authors: Liu Liang , Xi Zhenxiang , Wu Shaoyuan , Davis Charles C. , Edwards Scott V.
Published: April 2015

The heterogeneity of signals in the genomes of diverse organisms poses challenges for traditional phylogenetic analysis. Phylogenetic methods known as “species tree” methods have been proposed to directly address one important source of gene tree heterogeneity, namely the incomplete lineage sorting that occurs when evolving lineages radiate rapidly, resulting in a diversity of gene trees from a single underlying species tree. Here we review theory and empirical examples that help clarify conflicts between species tree and concatenation methods, and misconceptions in the literature about the performance of species tree methods. Considering concatenation as a special case of the multispecies coalescent model helps explain differences in the behavior of the two methods on phylogenomic data sets. Recent work suggests that species tree methods are more robust than concatenation approaches to some of the classic challenges of phylogenetic analysis, including rapidly evolving sites in DNA sequences and long‐branch attraction. We show that approaches, such as binning, designed to augment the signal in species tree analyses can distort the distribution of gene trees and are inconsistent. Computationally efficient species tree methods incorporating biological realism are a key to phylogenetic analysis of whole‐genome data.
Defence against vertebrate herbivores trades off into architectural and low nutrient strategies amongst savanna Fabaceae species
Authors: Tomlinson Kyle W. , van Langevelde Frank , Ward David , Prins Herbert H.T. , de Bie Steven , Vosman Ben , Sampaio Everardo V. S. B. , Sterck Frank J.
Published: April 2015

Herbivory contributes substantially to plant functional diversity and in ways that move far beyond direct defence trait patterns, as effective growth strategies under herbivory require modification of multiple functional traits that are indirectly related to defence. In order to understand how herbivory has shaped plant functional diversity, we need to consider the physiology and architecture of the herbivores and how this constrains effective defence strategies. Here we consider herbivory by mammals in savanna communities that range from semi‐arid to humid conditions. We posited that the saplings of savanna trees can be grouped into two contrasting defence strategies against mammals, namely architectural defence versus low nutrient defence. We provide a mechanistic explanation for these different strategies based on the fact that plants are under competing selection pressures to limit herbivore damage and outcompete neighbouring plants. Plant competitiveness depends on growth rate, itself a function of leaf mass fraction (LMF) and leaf nitrogen per unit mass (Nm). Architectural defence against vertebrates (which includes spinescence) limits herbivore access to plant leaf materials, and partly depends on leaf‐size reduction, thereby compromising LMF. Low nutrient defence requires that leaf material is of insufficient nutrient value to support vertebrate metabolic requirements, which depends on low Nm. Thus there is an enforced tradeoff between LMF and Nm, leading to distinct trait suites for each defence strategy. We demonstrate this tradeoff by showing that numerous traits can be distinguished between 28 spinescent (architectural defenders) and non‐spinescent (low nutrient defenders) Fabaceae tree species from savannas, where mammalian herbivory is an important constraint on plant growth. Distributions of the strategies along an LMF‐Nm tradeoff further provides a predictive and parsimonious explanation for the uneven distribution of spinescent and non‐spinescent species across water and nutrient gradients.
Tobacco guard cells fix CO2 by both Rubisco and PEPcase while sucrose acts as a substrate during light‐induced stomatal opening
Authors: Daloso Danilo M. , Antunes Werner C. , Pinheiro Daniela P. , Waquim Jardel P. , AraÚJo Wagner L. , Loureiro Marcelo E. , Fernie Alisdair R. , Williams Thomas C. R.
Published: April 2015

Transcriptomic and proteomic studies have improved our knowledge of guard cell function; however, metabolic changes in guard cells remain relatively poorly understood. Here we analysed metabolic changes in guard cell‐enriched epidermal fragments from tobacco during light‐induced stomatal opening. Increases in sucrose, glucose and fructose were observed during light‐induced stomatal opening in the presence of sucrose in the medium while no changes in starch were observed, suggesting that the elevated fructose and glucose levels were a consequence of sucrose rather than starch breakdown. Conversely, reduction in sucrose was observed during light‐ plus potassium‐induced stomatal opening. Concomitant with the decrease in sucrose, we observed an increase in the level as well as in the 13C enrichment in metabolites of, or associated with, the tricarboxylic acid cycle following incubation of the guard cell‐enriched preparations in 13C‐labelled bicarbonate. Collectively, the results obtained support the hypothesis that sucrose is catabolized within guard cells in order to provide carbon skeletons for organic acid production. Furthermore, they provide a qualitative demonstration that CO2 fixation occurs both via ribulose‐1,5‐biphosphate carboxylase/oxygenase (Rubisco) and phosphoenolpyruvate carboxylase (PEPcase). The combined data are discussed with respect to current models of guard cell metabolism and function.
Stüve–Wiedemann syndrome in a neonate
Authors: Sarafidis Kosmas , Piretzi Kaliopi , Agakidou Eleni , Kohlhase Jürgen , Zafeiriou Dimitrios
Published: April 2015

We describe a female neonate with Stüve–Wiedemann syndrome. The facial dysmorphism, joint contracture, distinctive skeletal changes, and myotonic discharges on electromyogram raised a suspicion of the rare autosomal recessive syndrome, which was later confirmed on molecular analysis of leukemia inhibitory factor receptor. She developed recurrent attacks of hyperpyrexia and died at age 3 months.
Rare causes of gastrointestinal hemorrhage in infancy
Authors: Karakus Suleyman Cuneyt , Buyukbese Sarsu Sevgi , Celtık Coskun , Gokce Selim , Koku Naim
Published: April 2015

Gastrointestinal hemorrhage in children is a critical condition that demands quick and effective management. The differential diagnosis of gastrointestinal hemorrhage is wide. Heterotopic pancreas is a rare congenital anomaly and usually discovered incidentally. It is generally asymptomatic, but symptoms may occur when complicated by inflammation, bleeding, obstruction or malign transformation. Heterotopic pancreas may present throughout the gastrointestinal tract, but it is most commonly found in the stomach, duodenum and proximal jejunum. Juvenile polyps are common during childhood and present most often with painless rectal hemorrhage. They remain the most common colonic polyps in children. Colonoscopic polypectomy is the most effective procedure in the treatment of juvenile polyps. In this study, we describe rare causes of gastrointestinal system hemorrhage in infancy and discuss some diagnostic and therapeutic approaches.
Effective eculizumab therapy followed by BMT in a boy with paroxysmal nocturnal hemoglobinuria
Authors: Oshiro Hiroko , Goi Kumiko , Akahane Koshi , Inukai Takeshi , Sugita Kanji
Published: April 2015

A 9‐year‐old boy with paroxysmal nocturnal hemoglobinuria/aplastic anemia syndrome (PNH/AA) developed hemolytic crisis after receiving immunosuppressive therapy. Eculizumab dramatically relieved the signs and symptoms and then he safely underwent unrelated bone marrow transplantation, suggesting the feasibility and effectiveness of eculizumab before stem cell transplantation in children with PNH/AA in hemolytic crisis.
Severe intrinsic acute kidney injury associated with therapeutic doses of acetaminophen
Authors: Ito Tatsuya , Watanabe Shojiro , Tsuruga Kazushi , Aizawa Tomomi , Hirono Koji , Ito Etsuro , Joh Kensuke , Tanaka Hiroshi
Published: April 2015

Acetaminophen is a commonly used medication to manage fever and pain in children and the drug is generally considered to be safe when used at appropriate therapeutic dosages. Recently, we encountered the case of a 3‐year‐old Japanese girl who suffered from severe intrinsic acute kidney injury (AKI) after therapeutic doses of acetaminophen for a fever due to viral infection. Renal biopsy indicated severe acute tubular necrosis with a significant striped interstitial fibrosis and mild interstitial inflammation. Unfortunately, she developed chronic kidney disease thereafter. This is the youngest case of biopsy‐proven severe intrinsic AKI associated with therapeutic doses of acetaminophen. Acetaminophen, even if administered at therapeutic dosages, may be dangerous in selected children, especially with possible pre‐existing volume depletion.
A Better Appraisal of Wittgenstein's Tractatus Manuscript
Authors: Bazzocchi Luciano
Published: April 2015

This paper substitutes a structural hermeneutics for the sequential approach to the Tractatus and its manuscript, which leaves the manuscript completely unexplained. All the pieces come together only if we recognise that Wittgenstein's book is a hierarchical object that was composed following a top‐down strategy. Therefore, we realise that the “summary on scattered sheets” represents the perspicuous version of the manuscript, the correlations with the Notebooks become obvious and the “supplements” can be reconstructed. A correct dating of the composition allows us to understand how it was possible, without digital technologies except from an ingenious application of the decimal system, to achieve this formal masterpiece.
The dynamics of doping:LanceArmstrong, theUnitedStatesAnti‐DopingAgency and the regulatory governance of professional cycling
Authors: de Bruijn Hans , Groenleer Martijn , van Ruijven Theo
Published: April 2015

On 10October 2012, theUnitedStatesAnti‐DopingAgency published an investigative report on the use of performance‐enhancing drugs by professional cyclistLanceArmstrong. The report paints a disconcerting picture of the doping program that Armstrong and hisUSPostal Service professional cycling team managed to carry out for several years, despite being subject to many inspections. It contains a wealth of unique empirical data, including a large number of affidavits. In this article, we use this data to answer the question of how Armstrong was able to prolong prohibited behavior. In doing so, we focus in particular on the interactions between Armstrong and the many doping inspectors he encountered. Our analysis results in a variety of answers to this question. First, inspectors were confronted with an inspectee who behaved as an “amoral calculator” and acted strategically. The strategies of inspectors were not adequately attuned to such behavior. Second, the team's internal professional control was neutralized by various factors, including its strict hierarchy and the many friendships within the team. And, finally, the environment created strong incentives to start doping and subsequently deny doing so. We argue that the dynamics underlying doping necessitate a combination of measures to regulate the use of performance‐enhancing drugs in the field of professional cycling and beyond.
Bronchial epithelial cells: The key effector cells in the pathogenesis of chronic obstructive pulmonary disease?
Authors: Gao Wei , Li Lingling , Wang Yujie , Zhang Sini , Adcock Ian M , Barnes Peter J. , Huang Mao , Yao Xin
Published: April 2015

The primary function of the bronchial epithelium is to act as a defensive barrier aiding the maintenance of normal airway function. Bronchial epithelial cells (BEC) form the interface between the external environment and the internal milieu, making it a major target of inhaled insults. However, BEC can also serve as effectors to initiate and orchestrate immune and inflammatory responses by releasing chemokines and cytokines, which recruit and activate inflammatory cells. They also produce excess reactive oxygen species as a result of an oxidant/antioxidant imbalance that contributes to chronic pulmonary inflammation and lung tissue damage. Accumulated mucus from hyperplastic BEC obstructs the lumen of small airways, whereas impaired cell repair, squamous metaplasia and increased extracellular matrix deposition underlying the epithelium is associated with airway remodelling particularly fibrosis and thickening of the airway wall. These alterations in small airway structure lead to airflow limitation, which is critical in the clinical diagnosis of chronic obstructive pulmonary disease (COPD). In this review, we discuss the abnormal function of BEC within a disturbed immune homeostatic environment consisting of ongoing inflammation, oxidative stress and small airway obstruction. We provide an overview of recent insights into the function of the bronchial epithelium in the pathogenesis of COPD and how this may provide novel therapeutic approaches for a number of chronic lung diseases.
Estimation of Fibre Length Distributions from Fibre Endpoints
Authors: Kuhlmann Malte , Redenbach Claudia
Published: April 2015

Estimating the fibre length distribution in composite materials is of practical relevance in materials science. We propose an estimator for the fibre length distribution using the point process of fibre endpoints as input. Assuming that this point process is a realization of a Neyman–Scott process, we use results for the reduced second moment measure to derive a consistent and unbiased estimator for the fibre length distribution. We introduce various versions of the estimator taking anisotropy or errors in the observation into account. The estimator is evaluated using a heuristic for its mean squared error as well as a simulation study. Finally, the estimator is applied to the fibre endpoint process extracted from a tomographic image of a glass fibre composite.
Generalized Maximum Spacing Estimation for Multivariate Observations
Authors: Kuljus Kristi , Ranneby Bo
Published: April 2015

In this paper, the maximum spacing method is considered for multivariate observations. Nearest neighbour balls are used as a multidimensional analogue to univariate spacings. A class of information‐type measures is used to generalize the concept of maximum spacing estimators. Weak and strong consistency of these generalized maximum spacing estimators are proved both when the assigned model class is correct and when the true density is not a member of the model class. An example of the generalized maximum spacing method in model validation context is discussed.
The Intertwined Relationship between Self‐esteem and Peer Stress Among Korean Adolescents: A Prospective Longitudinal Study
Authors: Yu Jeong Jin
Published: April 2015

Although the association between self‐esteem and peer stress among adolescents is not unidirectional, and the two constructs probably coevolve and coexist over time, these two constructs and their possible mutual influence have rarely been tested in one single study. The present study examined whether there are bidirectional interactions between self‐esteem and perceptions of peer stress across five or six annual waves using a nationally representative sample of two cohorts of South Korean youth. The sample comprised 2844 fourth graders (M = 9.86 years) and 3449 eighth graders (M = 13.79 years) at wave 1. Findings suggested that self‐esteem was positively associated with peer stress in early and middle adolescence, whereas peer stress was negatively associated with self‐esteem in early adolescence, but had positive links in middle and late adolescence. The implications of the results were discussed.
Vaccinia Virus Infection Requires Maturation of Macropinosomes
Authors: Rizopoulos Zaira , Balistreri Giuseppe , Kilcher Samuel , Martin Caroline K. , Syedbasha Mohammedyaseen , Helenius Ari , Mercer Jason
Published: April 2015

The prototypic poxvirus, vaccinia virus (VACV), occurs in two infectious forms, mature virions (MVs) and extracellular virions (EVs). Both enter HeLa cells by inducing macropinocytic uptake. Using confocal microscopy, live‐cell imaging, targeted RNAi screening and perturbants of endosome maturation, we analyzed the properties and maturation pathway of the macropinocytic vacuoles containing VACV MVs in HeLa cells. The vacuoles first acquired markers of early endosomes [Rab5, early endosome antigen 1 and phosphatidylinositol(3)P]. Prior to release of virus cores into the cytoplasm, they contained markers of late endosomes and lysosomes (Rab7a, lysosome‐associated membrane protein 1 and sorting nexin 3). RNAi screening of endocytic cell factors emphasized the importance of late compartments for VACV infection. Follow‐up perturbation analysis showed that infection required Rab7a and PIKfyve, confirming that VACV is a late‐penetrating virus dependent on macropinosome maturation. VACV EV infection was inhibited by depletion of many of the same factors, indicating that both infectious particle forms share the need for late vacuolar conditions for penetration.
Learning Patient Safety in Academic Settings: A Comparative Study of Finnish and British Nursing Students’ Perceptions
Authors: Tella Susanna , Smith Nancy‐Jane , Partanen Pirjo , Turunen Hannele
Published: April 2015

Background

Globalization of health care demands nursing education programs that equip students with evidence‐based patient safety competences in the global context. Nursing students’ entrance into clinical placements requires professional readiness. Thus, evidence‐based learning activities about patient safety must be provided in academic settings prior to students’ clinical placements.

Aims

To explore and compare Finnish and British nursing students’ perceptions of learning about patient safety in academic settings to inform nursing educators about designing future education curriculum.

Methods

A purpose‐designed instrument, Patient Safety in Nursing Education Questionnaire (PaSNEQ) was used to examine the perceptions of Finnish (n = 195) and British (n = 158) nursing students prior to their final year of registration. Data were collected in two Finnish and two English nursing schools in 2012. Logistic regressions were used to analyze the differences.

Results

British students reported more inclusion (p < .001) of “gaining knowledge,” “training skills,” and “highlighting affirmative attitudes and motivation” related to patient safety in their programs. Both student groups considered patient safety education to be more valuable for their own learning than what their programs had provided. Training patient safety skills in the academic settings were the strongest predictors for differences (odds ratio [OR] = 34.69, 95% confidence interval [CI] 7.39–162.83), along with work experience in the healthcare sector (OR = 3.02, 95% CI 1.39–6.58).

Linking Evidence to Action

To prepare nursing students for practical work, training related to clear communication, reporting errors, systems‐based approaches, interprofessional teamwork, and use of simulation in academic settings requires comprehensive attention, especially in Finland. Overall, designing patient safety‐affirming nursing curricula in collaboration with students may enhance their positive experiences on teaching and learning about patient safety. An international collaboration between educators could help to develop and harmonize patient safety education and to better prepare nurses for practice in the global context.
Effect of O2 on etch characteristics of Co2MnSi thin films in CH4/O2/Ar gas mixture
Authors: Hwang Su Min , Garay Adrian Adalberto , Chung Chee Won
Published: April 2015

Co2MnSi thin films masked with TiN films were etched in CH4/Ar and CH4/O2/Ar plasmas by inductively coupled plasma reactive ion etching. The etch rates decreased with increasing CH4 concentration in CH4/Ar gas, whereas the etch selectivity increased. The addition of O2 to CH4/Ar gas resulted in significant improvement in the etch profile but a decrease in the etch rates. Optical emission spectroscopy showed that a variety of COx, OH, and H2O species were formed in the CH4/O2/Ar plasma, acting a role as a passivation layer to protect the pattern sidewalls. X-ray photoelectron spectroscopy also confirmed the formation of metal oxides on the film surface, which could be sputtered off easily by Ar ion bombardment. A high degree of anisotropy of Co2MnSi films was obtained in the CH4/O2/Ar etch gas.
Alternating Sitting and Standing Increases the Workplace Energy Expenditure of Overweight Adults
Authors: Thorp Alicia Ann , Kingwell Bronwyn A. , English Coralie , Hammond Louise , Sethi Parneet , Owen Neville , Dunstan David W.
Published: April 2015

Background:

To determine whether alternating bouts of sitting and standing at work influences daily workplace energy expenditure (EE).

Methods:

Twenty-three overweight/obese office workers (mean ± SD; age: 48.2 ± 7.9 y, body mass index: 29.6 ± 4.0 kg/m2) undertook two 5-day experimental conditions in an equal, randomized order. Participants wore a “metabolic armband” (SenseWear Armband Mini) to estimate daily workplace EE (KJ/8 h) while working (1) in a seated work posture (SIT condition) or (2) alternating between a standing and seated work posture every 30 minutes using a sit-stand workstation (STAND-SIT condition). To assess the validity of the metabolic armband, a criterion measure of acute EE (KJ/min; indirect calorimetry) was performed on day 4 of each condition.

Results:

Standing to work acutely increased EE by 0.7 [95% CI 0.3–1.0] KJ/min (13%), relative to sitting (P = .002). Compared with indirect calorimetry, the metabolic armband provided a valid estimate of EE while standing to work (mean bias: 0.1 [–0.3 to 0.4] KJ/min) but modestly overestimated EE while sitting (P = .005). Daily workplace EE was greatest during the STAND-SIT condition (mean condition difference [95% CI]: 76 [8–144] KJ/8-h workday, P = .03).

Conclusions:

Intermittent standing at work can modestly increase daily workplace EE compared with seated work in overweight/obese office workers.
Predicting Physical Activity in 10-12 Year Old Children: A Social Ecological Approach
Authors: Zhang Tao , Thomas Katherine , Weiller Karen
Published: April 2015

The purpose of this study was to investigate the associations among predisposing (perceived competence and enjoyment), reinforcing (social environments), enabling factors (motor skills, fitness, physical environments) and physical activity among 288 children, and to identify the age and gender differences among participants. The children completed previously validated questionnaires assessing their perceived competence, enjoyment, school social and physical environments, and physical activity. Physical fitness was measured by FITNESSGRAM fitness testing. Students’ motor skills were assessed by PE Metrics. The results indicated that perceived competence and enjoyment predicted physical activity for boys, while perceived competence was the only predictor for girls. Age effects for fitness and skill were significant, as were gender differences for skill, social environment and perceived competence. This study suggests the importance of supportive teachers who provide enjoyable physical education that builds perceived competence for children to improve fitness, motor skill development and physical activity participation. The results support associations between predisposing factors and self-reported physical activity as theorized within the social ecological model.
Changes in Children’s Autonomous Motivation Toward Physical Education During Transition From Elementary to Secondary School: A Self-Determination Perspective
Authors: Rutten Cindy , Boen Filip , Vissers Nathalie , Seghers Jan
Published: April 2015

Based on Self-Determination Theory (Deci & Ryan, 2000), this study tested whether changes in autonomous motivation toward physical education (AMPE) during the transition from elementary to secondary school can be predicted by changes in perceived need support from the physical education (PE) teacher and perceived physical school environment. Self-reported data were gathered from 472 Flemish (northern part of Belgium) students in 6th grade (2009) and again in 8th grade (2011). Mediation analyses showed that an increase in perceived need support from the PE teacher was related to an increase in AMPE (boys: β = .42; girls: β = .50). In boys, this relation was mediated by changes in perceived competence (β = .08). In girls, this relation was mediated by changes in perceived autonomy (β = .12), perceived competence (β = .14), and perceived relatedness (β = .05). This study shows that PE teachers should be need-supportive to maintain a good quality of motivation in students.
Development and Initial Validation of the Chinese Version of Psychological Needs Thwarting Scale in Physical Education
Authors: Liu Jing Dong , Chung Pak-kwong
Published: April 2015

The current study presents the development process and initial validation of a measure designed for assessing psychological needs thwarting (frustration) in a secondary school physical education context (Psychological Needs Thwarting Scale in Physical Education, PNTSPE). Secondary school students (grades 7–9) from Hong Kong (N = 1258) were invited to participate in three studies. In Study 1, item generation and initial content validity of the PNTSPE were achieved. In Study 2, the factorial structure of the measure was tested using exploratory and confirmatory factor analysis. Internal consistency reliabilities of the subscales were also examined. In Study 3, the reliability and validity of the scores derived from the PNTSPE were further examined in an independent sample. Overall, the findings from the three studies provided initial psychometric evidence for the PNTSPE and suggested that the PNTSPE could be used as a valid and reliable measure to assess Hong Kong secondary school students’ psychological needs thwarting in physical education.
Amino acid uptake in erythropoiesis
Authors: Nathan David G.
Published: April 2015

mTORC1 inhibitors may prevent hemoglobin production, thus potentially explaining why their use can be associated with anemias.
Single-molecule assay of ubiquitylation
Authors: Ray L. Bryan
Published: April 2015

The basis of an important enzyme-target recognition strategy is revealed at the single-molecule level.
Biased memories
Authors: Prabakaran Sudhakaran
Published: April 2015

Drugs targeting β-arrestin–biased signaling by β-adrenergic receptors may be helpful in memory-related disorders.
MIV-150/Zinc Acetate Gel Inhibits Cell-Associated Simian-Human Immunodeficiency Virus Reverse Transcriptase Infection in a Macaque Vaginal Explant Model
Authors: Barnable Patrick , Calenda Giulia , Bonnaire Thierry , Menon Radhika , Levendosky Keith , Gettie Agegnehu , Blanchard James , Cooney Michael L. , Fernández-Romero José A. , Zydowsky Thomas M. , Teleshova Natalia
Published: April 2015

The transmission of both cell-free and cell-associated immunodeficiency viruses has been demonstrated directly in multiple animal species and possibly occurs in humans, as suggested by genotyping of the infecting human immunodeficiency virus (HIV) in acutely infected women and in semen from their partners. Therefore, a microbicide may need to block both mechanisms of HIV transmission to achieve maximum efficacy. To date, most of the preclinical evaluation of candidate microbicides has been performed using cell-free HIV. New models of mucosal transmission of cell-associated HIV are needed to evaluate candidate microbicide performance. The MIV-150/zinc acetate/carrageenan (MZC) gel protects Depo-Provera-treated macaques against cell-free simian-human immunodeficiency virus reverse transcriptase (SHIV-RT) infection when applied vaginally up to 8 h before challenge. We recently demonstrated the potent activity of MZC gel against cell-free SHIV-RT in macaque vaginal explants. In the current study, we established a cell-associated SHIV-RT infection model of macaque vaginal tissues and tested the activity of MZC gel in this model. MZC gel protected tissues against cell-associated SHIV-RT infection when present at the time of viral exposure or when applied up to 4 days prior to viral challenge. These data support clinical testing of the MZC gel. Overall, our
ex vivo
model of cell-associated SHIV-RT infection in macaque vaginal mucosa complements the cell-free infection models, providing tools for prioritization of products that block both modes of HIV transmission.
Molecular Characterization of IS
CR1
-Mediated
bla
PER-1
in a Non-O1, Non-O139 Vibrio cholerae Strain from China
Authors: Wu Jun , Xie Lianyan , Zhang Fangfang , Ni Yuxing , Sun Jingyong
Published: April 2015

We report the detection of PER-1 extended-spectrum β-lactamase (ESBL) in a clinical non-O1, non-O139
Vibrio cholerae
strain from China. IS
CR1
-mediated
bla
PER-1
was embedded in a complex In
4
family class 1 integron belonging to the lineage of Tn
1696
on a conjugative IncA/C plasmid. A free 8.98-kb circular molecule present with the IS
CR1-bla
PER-1
–truncated 3′-conserved sequence (CS) structure was detected in this isolate. These findings may provide insight into the mobilization of
bla
PER-1
.
Limited Sampling Strategy and Target Attainment Analysis for Levofloxacin in Patients with Tuberculosis
Authors: Alsultan Abdullah , An Guohua , Peloquin Charles A.
Published: April 2015

There is an urgent need to improve and shorten the treatment of tuberculosis (TB) and multidrug resistant tuberculosis (MDR-TB). Levofloxacin, a newer fluoroquinolone, has potent activity against TB both
in vitro
and
in vivo
. Levofloxacin dosing can be optimized to improve the treatment of both TB and MDR-TB. Levofloxacin efficacy is linked primarily to the ratio of the area under the concentration-time curve for the free fraction of drug (
f
AUC) to the MIC. Since obtaining a full-time concentration profile is not feasible in the clinic, we developed a limited sampling strategy (LSS) to estimate the AUC. We also utilized Monte Carlo simulations to evaluate the dosing of levofloxacin. Pharmacokinetic data were obtained from 10 Brazilian TB patients. The pharmacokinetic data were fitted with a one-compartment model. LSSs were developed using two methods: linear regression and Bayesian approaches. Several LSSs predicted levofloxacin AUC with good accuracy and precision. The most accurate were the method using two samples collected at 4 and 6 h (
R
2
= 0.91 using linear regression and 0.97 using Bayesian approaches) and that using samples collected at 2 and 6 h (
R
2
= 0.90 using linear regression and 0.96 using Bayesian approaches). The 2-and-6-h approach also provides a good estimate of the maximum concentration of the drug in serum (
C
max
). Our target attainment analysis showed that higher doses (17 to 20 mg/kg of body weight) of levofloxacin might be needed to improve its activity. Doses in the range of 17 to 20 mg/kg showed good target attainment for MICs from 0.25 to 0.50. At an MIC of 2, poor target attainment was observed across all doses. This LSS for levofloxacin can be used for therapeutic drug monitoring and for future pharmacokinetic/pharmacodynamic studies.
Pharmacokinetic Determinants of Virological Response to Raltegravir in the
In Vitro
Pharmacodynamic Hollow-Fiber Infection Model System
Authors: Brown Ashley N. , Adams Jonathan R. , Baluya Dodge L. , Drusano George L.
Published: April 2015

Daily administration (q24h) of raltegravir has been shown to be as efficacious as twice-daily administration (q12h) in the hollow-fiber infection model (HFIM) system. However, q24h regimens were not noninferior to q12h dosing in a clinical trial. We hypothesized that between-patient variability in raltegravir pharmacokinetics (PK) was responsible for the discordance in conclusions between the
in vitro
and
in vivo
studies. Hollow-fiber cartridges were inoculated with HIV-infected H9 cells and uninfected CEM-SS cells. Four cartridges received the total daily exposure (800 mg) q24h and four received half the daily exposure (400 mg) q12h. PK profiles with half-lives of 8, 4, 3, and 2 h were simulated for each dosing interval. Cell-to-cell viral spread was assessed by flow cytometry. Viral inhibition was similar between q24h and q12h dosing at the 8- and 4-h half-lives. The q24h dosing was not as efficacious as the q12h dosing when faster half-lives were simulated; a lack of viral suppression was observed at days 3 and 4 for the 2- and 3-h half-lives, respectively. The discrepancy in conclusions between the
in vitro
HFIM system studies and clinical trials is likely due to the large interindividual variation in raltegravir PK.
Factors Associated with Antibiotic Misuse in Outpatient Treatment for Upper Respiratory Tract Infections
Authors: Schroeck Jennifer L. , Ruh Christine A. , Sellick John A. , Ott Michael C. , Mattappallil Arun , Mergenhagen Kari A.
Published: April 2015

The Centers for Disease Control and Prevention has promoted the appropriate use of antibiotics since 1995 when it initiated the National Campaign for Appropriate Antibiotic Use in the Community. This study examined upper respiratory tract infections included in the campaign to determine the degree to which antibiotics were appropriately prescribed and subsequent admission rates in a veteran population. This study was a retrospective chart review conducted among outpatients with a diagnosis of a respiratory tract infection, including bronchitis, pharyngitis, sinusitis, or nonspecific upper respiratory tract infection, between January 2009 and December 2011. The study found that 595 (35.8%) patients were treated appropriately, and 1,067 (64.2%) patients received therapy considered inappropriate based on the Get Smart Campaign criteria. Overall the subsequent readmission rate was 1.5%. The majority (77.5%) of patients were prescribed an antibiotic. The most common antibiotics prescribed were azithromycin (39.0%), amoxicillin-clavulanate (13.2%), and moxifloxacin (7.5%). A multivariate regression analysis demonstrated significant predictors of appropriate treatment, including the presence of tonsillar exudates (odds ratio [OR], 0.6; confidence interval [CI], 0.3 to 0.9), fever (OR, 0.6; CI, 0.4 to 0.9), and lymphadenopathy (OR, 0.4; CI, 0.3 to 0.6), while penicillin allergy (OR, 2.9; CI, 1.7 to 4.7) and cough (OR, 1.6; CI, 1.1 to 2.2) were significant predictors for inappropriate treatment. Poor compliance with the Get Smart Campaign was found in outpatients for respiratory infections. Results from this study demonstrate the overprescribing of antibiotics, while providing a focused view of improper prescribing. This article provides evidence that current efforts are insufficient for curtailing inappropriate antibiotic use.
MAPK1 of Leishmania donovani Modulates Antimony Susceptibility by Downregulating P-Glycoprotein Efflux Pumps
Authors: Garg Mansi , Goyal Neena
Published: April 2015

Emergence of resistance to pentavalent antimonials has become a severe obstacle in the treatment of visceral leishmaniasis (VL) in the Indian subcontinent. Mitogen-activated protein kinases (MAPKs) are well-known mediators of signal transduction of eukaryotes, regulating important processes, like proliferation, differentiation, stress response, and apoptosis. In
Leishmania
, MAPK1 has been shown to be consistently downregulated in antimony-resistant field isolates, suggesting that it has a role in antimony resistance. The present work investigates the molecular mechanism of MAPK1 in antimony resistance in
Leishmania donovani
. The
L. donovani
MAPK1 (LdMAPK1) single-allele replacement mutants exhibited increased resistance to Sb(III) (5.57-fold) compared to wild-type promastigotes, while overexpressing parasites became much more susceptible to antimony. The LdMAPK1-mediated drug sensitivity was directly related to antimony-induced apoptotic death of the parasite, as was evidenced by a 4- to 5-fold decrease in cell death parameters in deletion mutants and a 2- to 3-fold increase in MAPK1-overexpressing cells. LdMAPK1-underexpressing parasites also exhibited increased P-glycoprotein (P-gp)-mediated efflux pump activity, while a significant decrease in pump activity was observed in overexpressing cells. This change in efflux pump activity was directly related to expression levels of P-gp in all cell lines. However, episomal complementation of the gene restored normal growth, drug sensitivity, P-gp expression, and efflux pump activity. The data indicate that LdMAPK1 negatively regulates the expression of P-glycoprotein-type efflux pumps in the parasite. The decrease in efflux pump activity with an increase in LdMAPK1 expression may result in increased antimony accumulation in the parasite, making it more vulnerable to the drug.
Genetic and Biochemical Characterization of OXA-405, an OXA-48-Type Extended-Spectrum β-Lactamase without Significant Carbapenemase Activity
Authors: Dortet Laurent , Oueslati Saoussen , Jeannot Katy , Tandé Didier , Naas Thierry , Nordmann Patrice
Published: April 2015

The epidemiology of carbapenemases worldwide is showing that OXA-48 variants are becoming the predominant carbapenemase type in
Enterobacteriaceae
in many countries. However, not all OXA-48 variants possess significant activity toward carbapenems (e.g., OXA-163). Two
Serratia marcescens
isolates with resistance either to carbapenems or to extended-spectrum cephalosporins were successively recovered from the same patient. A genomic comparison using pulsed-field gel electrophoresis and automated Rep-PCR typing identified a 97.8% similarity between the two isolates. Both strains were resistant to penicillins and first-generation cephalosporins. The first isolate was susceptible to expanded-spectrum cephalosporins, was resistant to carbapenems, and had a significant carbapenemase activity (positive Carba NP test) related to the expression of OXA-48. The second isolate was resistant to expanded-spectrum cephalosporins, was susceptible to carbapenems, and did not express a significant imipenemase activity, (negative for the Carba NP test) despite possessing a
bla
OXA-48
-type gene. Sequencing identified a novel OXA-48-type β-lactamase, OXA-405, with a four-amino-acid deletion compared to OXA-48. The
bla
OXA-405
gene was located on a ca. 46-kb plasmid identical to the prototype IncL/M
bla
OXA-48
-carrying plasmid except for a ca. 16.4-kb deletion in the
tra
operon, leading to the suppression of self-conjugation properties. Biochemical analysis showed that OXA-405 has clavulanic acid-inhibited activity toward expanded-spectrum activity without significant imipenemase activity. This is the first identification of a successive switch of catalytic activity in OXA-48-like β-lactamases, suggesting their plasticity. Therefore, this report suggests that the first-line screening of carbapenemase producers in
Enterobacteriaceae
may be based on the biochemical detection of carbapenemase activity in clinical settings.
The Role of CD1d-Restricted NKT Cells in the Clearance of Pseudomonas aeruginosa from the Lung Is Dependent on the Host Genetic Background
Authors: Benoit Patrick , Sigounas Vaia Yioula , Thompson Jenna L. , van Rooijen Nico , Poynter Matthew E. , Wargo Matthew J. , Boyson Jonathan E.
Published: April 2015

Pseudomonas aeruginosa
is an important human opportunistic pathogen, accounting for a significant fraction of hospital-acquired lung infections. CD1d-restricted NKT cells comprise an unusual innate-like T cell subset that plays important roles in both bacterial and viral infections. Previous reports have differed in their conclusions regarding the role of NKT cells in clearance of
P. aeruginosa
from the lung. Since there is significant strain-dependent variation in NKT cell number and function among different inbred strains of mice, we investigated whether the role of NKT cells was dependent on the host genetic background. We found that NKT cells did indeed play a critical role in the clearance of
P. aeruginosa
from the lungs of BALB/c mice but that they played no discernible role in clearance from the lungs of C57BL/6 mice. We found that the strain-dependent role of NKT cells was associated with significant strain-dependent differences in cytokine production by lung NKT cells and that impaired clearance of
P. aeruginosa
in BALB/c CD1d
−/−
mice was associated with an increase in neutrophil influx to the lung and increased levels of proinflammatory cytokines and chemokines after infection. Finally, we found that the role of alveolar macrophages was also dependent on the genetic background. These data provide further support for a model in which the unusually high level of variability in NKT cell number and function among different genetic backgrounds may be an important contributor to infectious-disease susceptibility and pathology.