bluuebunny/crossref_metadata_2025_split huggingface dataset:
Non‐parametric Copula Estimation Under Bivariate Censoring
Authors: Gribkova Svetlana , Lopez Olivier 
Published: April 2015

AbstractIn this paper, we consider non‐parametric copula inference under bivariate censoring. Based on an estimator of the joint cumulative distribution function, we define a discrete and two smooth estimators of the copula. The construction that we propose is valid for a large range of estimators of the distribution function and therefore for a large range of bivariate censoring frameworks. Under some conditions on the tails of the distributions, the weak convergence of the corresponding copula processes is obtained in l∞([0,1]2). We derive the uniform convergence rates of the copula density estimators deduced from our smooth copula estimators. Investigation of the practical behaviour of these estimators is performed through a simulation study and two real data applications, corresponding to different censoring settings. We use our non‐parametric estimators to define a goodness‐of‐fit procedure for parametric copula models. A new bootstrap scheme is proposed to compute the critical values.
Friendship, Negative Peer Experiences, and Daily Positive and Negative Mood
Authors: Reavis Rachael D. , Donohue Laura J. , Upchurch Mikayla C. 
Published: April 2015

AbstractWe examined the effect of negative peer experiences (NPEs; peer victimization and exclusion) on mood (depressed, angry, positive). Seventy‐seven (43 female) fifth graders from elementary schools located in a small town in the Midwest completed a friendship quality measure, in addition to daily reports (seven school days) of mood and peer experiences. Multilevel modeling showed that children who had NPEs in which no one intervened had more negative and less positive mood. For negative mood, this result was attenuated if the child had a friend who was generally helpful. The results demonstrate the positive role of bystanders during NPEs and highlight the protective role of high‐quality friendships.
Understanding the Accuracy of Parental Perceptions of Child Physical Activity: A Mixed Methods Analysis
Authors: Kesten Joanna M. , Jago Russ , Sebire Simon J. , Edwards Mark J. , Pool Laura , Zahra Jesmond , Thompson Janice L. 
Published: April 2015

Background:Interventions to increase children’s physical activity (PA) have achieved limited success. This may be attributed to inaccurate parental perceptions of their children’s PA and a lack of recognition of a need to change activity levels.Methods:Fifty-three parents participated in semistructured interviews to determine perceptions of child PA. Perceptions were compared with children’s measured MVPA (classified as meeting or not meeting UK guidelines) to produce 3 categories: “accurate,” “over-estimate,” and “under-estimate.” Deductive content analysis was performed to understand the accuracy of parental perceptions.Results:All parents of children meeting the PA guidelines accurately perceived their child’s PA; while the majority of parents whose child did not meet the guidelines overestimated their PA. Most parents were unconcerned about their child’s PA level, viewing them as naturally active and willing to be active. Qualitative explanations for perceptions of insufficient activity included children having health problems and preferences for inactive pursuits, and parents having difficulty facilitating PA in poor weather and not always observing their child’s PA level. Social comparisons also influenced parental perceptions.Conclusions:Strategies to improve parental awareness of child PA are needed. Perceptions of child PA may be informed by child “busyness,” being unaware of activity levels, and social comparisons.
Differential Cytochrome P450 2D Metabolism Alters Tafenoquine Pharmacokinetics
Authors: Vuong Chau , Xie Lisa H. , Potter Brittney M. J. , Zhang Jing , Zhang Ping , Duan Dehui , Nolan Christina K. , Sciotti Richard J. , Zottig Victor E. , Nanayakkara N. P. Dhammika , Tekwani Babu L. , Walker Larry A. , Smith Philip L. , Paris Robert M. , Read Lisa T. , Li Qigui , Pybus Brandon S. , Sousa Jason C. , Reichard Gregory A. , Smith Bryan , Marcsisin Sean R. 
Published: April 2015

ABSTRACT

Cytochrome P450 (CYP) 2D metabolism is required for the liver-stage antimalarial efficacy of the 8-aminoquinoline molecule tafenoquine in mice. This could be problematic for
Plasmodium vivax
radical cure, as the human CYP 2D ortholog (2D6) is highly polymorphic. Diminished CYP 2D6 enzyme activity, as in the poor-metabolizer phenotype, could compromise radical curative efficacy in humans. Despite the importance of CYP 2D metabolism for tafenoquine liver-stage efficacy, the exact role that CYP 2D metabolism plays in the metabolism and pharmacokinetics of tafenoquine and other 8-aminoquinoline molecules has not been extensively studied. In this study, a series of tafenoquine pharmacokinetic experiments were conducted in mice with different CYP 2D metabolism statuses, including wild-type (WT) (reflecting extensive metabolizers for CYP 2D6 substrates) and CYP
mouse
2D knockout (KO) (reflecting poor metabolizers for CYP 2D6 substrates) mice. Plasma and liver pharmacokinetic profiles from a single 20-mg/kg of body weight dose of tafenoquine differed between the strains; however, the differences were less striking than previous results obtained for primaquine in the same model. Additionally, the presence of a 5,6-
ortho
-quinone tafenoquine metabolite was examined in both mouse strains. The 5,6-
ortho
-quinone species of tafenoquine was observed, and concentrations of the metabolite were highest in the WT extensive-metabolizer phenotype. Altogether, this study indicates that CYP 2D metabolism in mice affects tafenoquine pharmacokinetics and could have implications for human tafenoquine pharmacokinetics in polymorphic CYP 2D6 human populations.
Contribution of Stress Responses to Antibiotic Tolerance in Pseudomonas aeruginosa Biofilms
Authors: Stewart Philip S. , Franklin Michael J. , Williamson Kerry S. , Folsom James P. , Boegli Laura , James Garth A. 
Published: April 2015

ABSTRACT

Enhanced tolerance of biofilm-associated bacteria to antibiotic treatments is likely due to a combination of factors, including changes in cell physiology as bacteria adapt to biofilm growth and the inherent physiological heterogeneity of biofilm bacteria. In this study, a transcriptomics approach was used to identify genes differentially expressed during biofilm growth of
Pseudomonas aeruginosa
. These genes were tested for statistically significant overlap, with independently compiled gene lists corresponding to stress responses and other putative antibiotic-protective mechanisms. Among the gene groups tested were those associated with biofilm response to tobramycin or ciprofloxacin, drug efflux pumps, acyl homoserine lactone quorum sensing, osmotic shock, heat shock, hypoxia stress, and stationary-phase growth. Regulons associated with Anr-mediated hypoxia stress, RpoS-regulated stationary-phase growth, and osmotic stress were significantly enriched in the set of genes induced in the biofilm. Mutant strains deficient in
rpoS
,
relA
and
spoT
, or
anr
were cultured in biofilms and challenged with ciprofloxacin and tobramycin. When challenged with ciprofloxacin, the mutant strain biofilms had 2.4- to 2.9-log reductions in viable cells compared to a 0.9-log reduction of the wild-type strain. Interestingly, none of the mutants exhibited a statistically significant alteration in tobramycin susceptibility compared to that with the wild-type biofilm. These results are consistent with a model in which multiple genes controlled by overlapping starvation or stress responses contribute to the protection of a
P. aeruginosa
biofilm from ciprofloxacin. A distinct and as yet undiscovered mechanism protects the biofilm bacteria from tobramycin.
In Vivo
Cluster Formation of Nisin and Lipid II Is Correlated with Membrane Depolarization
Authors: Tol Menno B. , Morales Angeles Danae , Scheffers Dirk-Jan 
Published: April 2015

ABSTRACT
Nisin and related lantibiotics kill bacteria by pore formation or by sequestering lipid II. Some lantibiotics sequester lipid II into clusters, which were suggested to kill cells through delocalized peptidoglycan synthesis. Here, we show that cluster formation is always concomitant with (i) membrane pore formation and (ii) membrane depolarization. Nisin variants that cluster lipid II kill L-form bacteria with similar efficiency, suggesting that delocalization of peptidoglycan synthesis is not the primary killing mechanism of these lantibiotics.
Intrauterine Infection with Plasmid-Free Chlamydia muridarum Reveals a Critical Role of the Plasmid in Chlamydial Ascension and Establishes a Model for Evaluating Plasmid-Independent Pathogenicity
Authors: Chen Jianlin , Yang Zhangsheng , Sun Xin , Tang Lingli , Ding Yiling , Xue Min , Zhou Zhiguang , Baseman Joel , Zhong Guangming 
Published: April 2015

ABSTRACT

Intravaginal infection with plasmid-competent but not plasmid-free
Chlamydia muridarum
induces hydrosalpinx in mouse upper genital tract, indicating a critical role of the plasmid in chlamydial pathogenicity. To evaluate the contribution of the plasmid to chlamydial ascension and activation of tubal inflammation, we delivered plasmid-free
C. muridarum
directly into the endometrium by intrauterine inoculation. We found that three of the six mouse strains tested, including CBA/J, C3H/HeJ, and C57BL/6J, developed significant hydrosalpinges when 1 × 10
7
inclusion-forming units (IFU) of plasmid-free
C. muridarum
were intrauterinally inoculated. Even when the inoculum was reduced to 1 × 10
4
IFU, the CBA/J mice still developed robust hydrosalpinx. The hydrosalpinx development in CBA/J mice correlated with increased organism ascension to the oviduct following the intrauterine inoculation. The CBA/J mice intravaginally infected with the same plasmid-free
C. muridarum
strain displayed reduced ascending infection and failed to develop hydrosalpinx. These observations have demonstrated a critical role of the plasmid in chlamydial ascending infection. The intrauterine inoculation of the CBA/J mice with plasmid-free
C. muridarum
not only resulted in more infection in the oviduct but also stimulated more inflammatory infiltration and cytokine production in the oviduct than the intravaginal inoculation, suggesting that the oviduct inflammation can be induced by plasmid-independent factors, which makes the hydrosalpinx induction in CBA/J mice by intrauterine infection with plasmid-free
C. muridarum
a suitable model for investigating plasmid-independent pathogenic mechanisms.
Variation in Plasmodium falciparum Erythrocyte Invasion Phenotypes and Merozoite Ligand Gene Expression across Different Populations in Areas of Malaria Endemicity
Authors: Bowyer Paul W. , Stewart Lindsay B. , Aspeling-Jones Harvey , Mensah-Brown Henrietta E. , Ahouidi Ambroise D. , Amambua-Ngwa Alfred , Awandare Gordon A. , Conway David J. 
Published: April 2015

ABSTRACT

Plasmodium falciparum
merozoites use diverse alternative erythrocyte receptors for invasion and variably express cognate ligands encoded by the erythrocyte binding antigen (
eba
) and reticulocyte binding-like homologue (
Rh
) gene families. Previous analyses conducted on parasites from single populations in areas of endemicity revealed a wide spectrum of invasion phenotypes and expression profiles, although comparisons across studies have been limited by the use of different protocols. For direct comparisons within and among populations, clinical isolates from three different West African sites of endemicity (in Ghana, Guinea, and Senegal) were cryopreserved and cultured
ex vivo
after thawing in a single laboratory to assay invasion of target erythrocytes pretreated with enzymes affecting receptor subsets. Complete invasion assay data from 67 isolates showed no differences among the populations in the broad range of phenotypes measured by neuraminidase treatment (overall mean, 40.6% inhibition) or trypsin treatment (overall mean, 83.3% inhibition). The effects of chymotrypsin treatment (overall mean, 79.2% inhibition) showed heterogeneity across populations (Kruskall-Wallis
P
= 0.023), although the full phenotypic range was seen in each. Schizont-stage transcript data for a panel of 8 invasion ligand genes (
eba175
,
eba140
,
eba181
,
Rh1
,
Rh2a
,
Rh2b
,
Rh4
, and
Rh5
) were obtained for 37 isolates, showing similar ranges of variation in each population except that
eba175
levels tended to be higher in parasites from Ghana than in those from Senegal (whereas levels of
eba181
and
Rh2b
were lower in parasites from Ghana). The broad diversity in invasion phenotypes and gene expression seen within each local population, with minimal differences among them, is consistent with a hypothesis of immune selection maintaining parasite variation.
The Type VI Secretion System Modulates Flagellar Gene Expression and Secretion in Citrobacter freundii and Contributes to Adhesion and Cytotoxicity to Host Cells
Authors: Liu Liyun , Hao Shuai , Lan Ruiting , Wang Guangxia , Xiao Di , Sun Hui , Xu Jianguo 
Published: April 2015

ABSTRACT

The type VI secretion system (T6SS) as a virulence factor-releasing system contributes to virulence development of various pathogens and is often activated upon contact with target cells.
Citrobacter freundii
strain CF74 has a complete T6SS genomic island (GI) that contains
clpV
,
hcp-2
, and
vgr
T6SS genes. We constructed
clpV
,
hcp-2
,
vgr
, and T6SS GI deletion mutants in CF74 and analyzed their effects on the transcriptome overall and, specifically, on the flagellar system at the levels of transcription and translation. Deletion of the T6SS GI affected the transcription of 84 genes, with 15 and 69 genes exhibiting higher and lower levels of transcription, respectively. Members of the cell motility class of downregulated genes of the CF74ΔT6SS mutant were mainly flagellar genes, including effector proteins, chaperones, and regulators. Moreover, the production and secretion of FliC were also decreased in
clpV
,
hcp-2
,
vgr
, or T6SS GI deletion mutants in CF74 and were restored upon complementation. In swimming motility assays, the mutant strains were found to be less motile than the wild type, and motility was restored by complementation. The mutant strains were defective in adhesion to HEp-2 cells and were restored partially upon complementation. Further, the CF74ΔT6SS, CF74Δ
clpV
, and CF74Δ
hcp-2
mutants induced lower cytotoxicity to HEp-2 cells than the wild type. These results suggested that the T6SS GI in CF74 regulates the flagellar system, enhances motility, is involved in adherence to host cells, and induces cytotoxicity to host cells. Thus, the T6SS plays a wide-ranging role in
C. freundii
.
Biochemical and Functional Characterization of the NurA-HerA Complex from Deinococcus radiodurans
Authors: Cheng Kaiying , Chen Xuanyi , Xu Guangzhi , Wang Liangyan , Xu Hong , Yang Su , Zhao Ye , Hua Yuejin 
Published: April 2015

ABSTRACT

In archaea, the NurA nuclease and HerA ATPase/helicase, together with the Mre11-Rad50 complex, function in 3′ single-stranded DNA (ssDNA) end processing during homologous recombination (HR). However, bacterial homologs of NurA and HerA have not been characterized. From
Deinococcus radiodurans
, we identified the manganese-dependent 5′-to-3′ ssDNA/double-stranded DNA (dsDNA) exonuclease/endonuclease NurA (DrNurA) and the ATPase HerA (DrHerA). These two proteins stimulated each other's activity through direct protein-protein interactions. The N-terminal HAS domain of DrHerA was the key domain for this interaction. Several critical residues of DrNurA and DrHerA were verified by site-directed mutational analysis. Temperature-dependent activity assays confirmed that the two proteins had mesophilic features, with optimum activity temperatures 10°C to 15°C higher than their optimum growth temperatures. Knocking out either
nurA
or
herA
affected cell proliferation by shortening the growth phase, especially for growth at a high temperature (37°C). In addition, both mutant strains displayed almost 10-fold-reduced intermolecular recombination efficiency, indicating that DrNurA and DrHerA might be involved in homologous recombination
in vivo
. However, single- and double-gene deletions did not show significantly decreased radioresistance. Our results confirmed that the biochemical activities of bacterial NurA and HerA proteins were conserved with archaea. Our phenotypical results suggested that these proteins might have different functions in bacteria.

IMPORTANCE
Deinococcus radiodurans
NurA (DrNurA) was identified as a manganese-dependent 5′-to-3′ ssDNA/dsDNA exonuclease/endonuclease, and
Deinococcus radiodurans
HerA (DrHerA) was identified as an ATPase. Physical interactions between DrNurA and DrHerA explained mutual stimulation of their activities. The N-terminal HAS domain on DrHerA was identified as the interaction domain. Several essential functional sites on DrNurA and DrHerA were characterized. Both DrHerA and DrNurA showed mesophilic biochemical features, with their optimum activity temperatures 10°C to 15°C higher than their optimum growth temperatures
in vitro
. Knockout of
nurA
or
herA
led to abnormal cell proliferation and reduced intermolecular recombination efficiency but no obvious effect on radioresistence.
Involvement of the TetR-Type Regulator PaaR in the Regulation of Pristinamycin I Biosynthesis through an Effect on Precursor Supply in Streptomyces pristinaespiralis
Authors: Zhao Yawei , Feng Rongrong , Zheng Guosong , Tian Jinzhong , Ruan Lijun , Ge Mei , Jiang Weihong , Lu Yinhua 
Published: April 2015

ABSTRACT

Pristinamycin I (PI), produced by
Streptomyces pristinaespiralis
, is a streptogramin type B antibiotic, which contains two proteinogenic and five aproteinogenic amino acid precursors. PI is coproduced with pristinamycin II (PII), a member of streptogramin type A antibiotics. The PI biosynthetic gene cluster has been cloned and characterized. However, thus far little is understood about the regulation of PI biosynthesis. In this study, a TetR family regulator (encoded by
SSDG_03033
) was identified as playing a positive role in PI biosynthesis. Its homologue, PaaR, from
Corynebacterium glutamicum
serves as a transcriptional repressor of the
paa
genes involved in phenylacetic acid (PAA) catabolism. Herein, we also designated the identified regulator as PaaR. Deletion of
paaR
led to an approximately 70% decrease in PI production but had little effect on PII biosynthesis. Identical to the function of its homologue from
C. glutamicum
, PaaR is also involved in the suppression of
paa
expression. Given that phenylacetyl coenzyme A (PA-CoA) is the common intermediate of the PAA catabolic pathway and the biosynthetic pathway of
l
-phenylglycine (
l
-Phg), the last amino acid precursor for PI biosynthesis, we proposed that derepression of the transcription of
paa
genes in a Δ
paaR
mutant possibly diverts more PA-CoA to the PAA catabolic pathway, thereby with less PA-CoA metabolic flux toward
l
-Phg formation, thus resulting in lower PI titers. This hypothesis was verified by the observations that PI production of a Δ
paaR
mutant was restored by
l
-Phg supplementation as well as by deletion of the
paaABCDE
operon in the Δ
paaR
mutant. Altogether, this study provides new insights into the regulation of PI biosynthesis by
S. pristinaespiralis
.

IMPORTANCE
A better understanding of the regulation mechanisms for antibiotic biosynthesis will provide valuable clues for
Streptomyces
strain improvement. Herein, a TetR family regulator PaaR, which serves as the repressor of the transcription of
paa
genes involved in phenylacetic acid (PAA) catabolism, was identified as playing a positive role in the regulation of pristinamycin I (PI) by affecting the supply of one of seven amino acid precursors,
l
-phenylglycine, in
Streptomyces pristinaespiralis
. To our knowledge, this is the first report describing the interplay between PAA catabolism and antibiotic biosynthesis in
Streptomyces
strains. Considering that the PAA catabolic pathway and its regulation by PaaR are widespread in antibiotic-producing actinomycetes, it could be suggested that PaaR-dependent regulation of antibiotic biosynthesis might commonly exist.
Trends and social differentials in child mortality in Rwanda 1990–2010: results from three demographic and health surveys
Authors: Musafili Aimable , Essén Birgitta , Baribwira Cyprien , Binagwaho Agnes , Persson Lars-Åke , Selling Katarina Ekholm 
Published: April 2015

BackgroundRwanda has embarked on ambitious programmes to provide equitable health services and reduce mortality in childhood. Evidence from other countries indicates that advances in child survival often have come at the expense of increasing inequity. Our aims were to analyse trends and social differentials in mortality before the age of 5 years in Rwanda from 1990 to 2010.MethodsWe performed secondary analyses of data from three Demographic and Health Surveys conducted in 2000, 2005 and 2010 in Rwanda. These surveys included 34 790 children born between 1990 and 2010 to women aged 15–49 years. The main outcome measures were neonatal mortality rates (NMR) and under-5 mortality rates (U5MR) over time, and in relation to mother's educational level, urban or rural residence and household wealth. Generalised linear mixed effects models and a mixed effects Cox model (frailty model) were used, with adjustments for confounders and cluster sampling method.ResultsMortality rates in Rwanda peaked in 1994 at the time of the genocide (NMR 60/1000 live births, 95% CI 51 to 65; U5MR 238/1000 live births, 95% CI 226 to 251). The 1990s and the first half of the 2000s were characterised by a marked rural/urban divide and inequity in child survival between maternal groups with different levels of education. Towards the end of the study period (2005–2010) NMR had been reduced to 26/1000 (95% CI 23 to 29) and U5MR to 65/1000 (95% CI 61 to 70), with little or no difference between urban and rural areas, and household wealth groups, while children of women with no education still had significantly higher U5MR.ConclusionsRecent reductions in child mortality in Rwanda have concurred with improved social equity in child survival. Current challenges include the prevention of newborn deaths.
High hepatitis C virus prevalence and incidence in a community cohort of young heroin injectors in a context of extensive harm reduction programmes
Authors: Vallejo Fernando , Barrio Gregorio , Brugal M Teresa , Pulido Jose , Toro Carlos , Sordo Luis , Espelt Albert , Bravo María J ,   the Itinere Project Group
Published: April 2015

BackgroundCohort studies on hepatitis C virus (HCV) among drug injectors are scarcer than studies on HIV. Combined harm reduction interventions (HRIs) can prevent HCV infection. Spain has a medium–high coverage of HRIs.Methods513 young heroin users who injected drugs in the past 12 months (recent injectors) were street-recruited in 2001–2003 and followed until 2006 in three Spanish cities; 137 were anti-HCV seronegative, 77 of whom had ≥1 follow-up visit. Dried blood spots were tested for anti-HCV. HCV incidence and predictors of infection were estimated using Poisson models.ResultsAt baseline, 73% were anti-HCV positive. Overall incidence (n=77) of HCV seroconversion was 39.8/100 person-years (py) (95% CI 28.7 to 53.8). Excluding non-injectors during follow-up from the analysis (n=57), HCV incidence was 52.9/100 py (95% CI 37.4 to 72.5). Injecting at least weekly (incidence rate ratio (IRR)=5.2 (95% CI 2.5 to 11.1)) and having ≥2 sexual partners (IRR=2.2 (95% CI 1.1 to 4.7)) were independent predictors of HCV seroconversion; drug-injection history <2 years was marginally associated (IRR=2.4 (95% CI 0.9 to 4.7)). HCV incidence may have been underestimated due to differential attrition.ConclusionsDespite fairly high HRI coverage among Spanish drug injectors, a distressingly high incidence of HCV in a context of high HCV prevalence was found among young heroin injectors.