bluuebunny/crossref_metadata_2025_split huggingface dataset:
High folate levels are not associated with increased malaria risk but with reduced anaemia rates in the context of high‐dosed folate supplements and intermittent preventive treatment against malaria in pregnancy with sulphadoxine–pyrimethamine in Benin
Authors: Moya‐Alvarez Violeta , Ouédraogo Smaila , Accrombessi Manfred , Cot Michel 
Published: April 2018

AbstractObjectivesTo investigate whether high‐dosed folate supplements might diminish the efficacy of malaria intermittent preventive treatment in pregnancy (IPTp) with sulphadoxine–pyrimethamine (SP) in a cohort of pregnant women in Benin, where malaria is holoendemic.MethodsWe followed 318 women during the entire pregnancy and analysed haematological and Plasmodium falciparum indicators in the context of an intermittent preventive treatment trial in Benin. During the follow‐up, women received two‐dose IPTp (1500/75 mg of SP per dose) at the maternity clinic and 600 mg of albendazole, 200 mg ferrous sulphate and 5 mg folic acid per day for home treatment.ResultsHigh folate levels were not associated with increased malaria risk (adjusted OR (aOR) = 0.51 (95% CI: 0.17; 1.56, P‐value = 0.24)), nor with increased P. falciparum density (beta coefficient = −0.26 (95% CI: −0.53; 0.02), P‐value = 0.07) in a randomised trial of IPTp in Benin. On the contrary, higher iron levels were statistically associated with increased odds of a positive blood smear (aOR = 1.7 95% CI (1.2; 2.3), P‐value < 0.001) and P. falciparum parasite density (beta coefficient = 0.2 95% CI (0.1; 0.3), P‐value < 0.001). High folate levels were statistically associated with decreased odds of anaemia (aOR = −0.30 95% CI (0.10; 0.88), P‐value = 0.03).ConclusionsHigh folate levels are not associated with increased malarial risk in a prospective longitudinal cohort in the context of both iron and high‐dosed folate supplements and IPTp. They are associated with reduced risk of anaemia, which is particularly important because iron, also given to treat anaemia, might be associated with increased malaria risk.
Characterization of DCL4 missense alleles provides insights into its ability to process distinct classes of dsRNA substrates
Authors: Montavon Thomas , Kwon Yerim , Zimmermann Aude , Hammann Philippe , Vincent Timothée , Cognat Valérie , Bergdoll Marc , Michel Fabrice , Dunoyer Patrice 
Published: April 2018

SummaryIn the model plant Arabidopsis thaliana, four Dicer‐like proteins (DCL1–4) mediate the production of various classes of small RNAs (sRNAs). Among these four proteins, DCL4 is by far the most versatile RNaseIII‐like enzyme, and previously identified dcl4 missense alleles were shown to uncouple the production of the various classes of DCL4‐dependent sRNAs. Yet little is known about the molecular mechanism behind this uncoupling. Here, by studying the subcellular localization, interactome and binding to the sRNA precursors of three distinct dcl4 missense alleles, we simultaneously highlight the absolute requirement of a specific residue in the helicase domain for the efficient production of all DCL4‐dependent sRNAs, and identify, within the PAZ domain, an important determinant of DCL4 versatility that is mandatory for the efficient processing of intramolecular fold‐back double‐stranded RNA (dsRNA) precursors, but that is dispensable for the production of small interfering RNAs (siRNAs) from RDR‐dependent dsRNA susbtrates. This study not only provides insights into the DCL4 mode of action, but also delineates interesting tools to further study the complexity of RNA silencing pathways in plants, and possibly other organisms.
The Effects of Differential Learning and Traditional Learning Trainings on Technical Development of Football Players
Authors: Bozkurt Sinan 
Published: April 2018

There are several different methods of learning motor skills, like traditional (linear) and differential (nonlinear) learning training. The traditional motor learning approach proposes that learners improve a skill just by repeating it. According to the teaching principles, exercises are selected along continua from easy to hard and from simple to complex. The differential learning approach is mainly characterized by taking advantage, for the purpose of learning, of fluctuations that occur, without movement repetitions and without corrections during the skill acquisition process. The purpose of this study is to examine the effects of differential and traditional training on technical development of 15-year-old football players who have been continuing football education. Twelve (12) football players who were 15 years old from the youth football team (Under 15) of Istanbul Kavacik Club were tested voluntarily in this study. In this study, the Mor-Christian soccer passing test, German Football Association agility/dribbling test, and feet-juggling test were applied on the football field with synthetic grass of the Istanbul Kavacik Sports Club in 2016. The Mann-Whitney U test for paired comparison of the groups and the Wilcoxon test for the comparison of pre- and post-tests of the groups were used for statistical analyses. In conclusion, the findings suggest that the results of the technique tests for groups offer no clear evidence for the superiority of the differential learning approach in comparison to the classical training approach. However, participants of the Differential Group (DG) were able to improve their performance in all tests and techniques compared to those of the Classical Group (CG). These findings may be useful for trainers and physical education teachers in the selection process of players and in preparing football training programs.
Community Development betweenPorphyromonas gingivalisandCandida albicansMediated by InlJ and Als3
Authors: Sztukowska Maryta N. , Dutton Lindsay C. , Delaney Christopher , Ramsdale Mark , Ramage Gordon , Jenkinson Howard F. , Nobbs Angela H. , Lamont Richard J. 
Published: April 2018

ABSTRACTThe pleiomorphic yeastCandida albicansis a significant pathogen in immunocompromised individuals. In the oral cavity,C. albicansis an inhabitant of polymicrobial communities, and interspecies interactions promote hyphal formation and biofilm formation.C. albicanscolonizes the subgingival area, and the frequency of colonization increases in periodontal disease. In this study, we investigated the interactions betweenC. albicansand the periodontal pathogenPorphyromonas gingivalis.C. albicansandP. gingivaliswere found to coadhere in both the planktonic and sessile phases. Loss of the internalin-family protein InlJ abrogated adhesion ofP. gingivalistoC. albicans, and recombinant InlJ protein competitively inhibited interspecies binding. A mutant ofC. albicansdeficient in expression of major hyphal protein Als3 showed diminished binding toP. gingivalis, and InlJ interacted with Als3 heterologously expressed inSaccharomyces cerevisiae. Transcriptional profiling by RNA sequencing (RNA-Seq) established that 57 genes were uniquely upregulated in an InlJ-dependent manner inP. gingivalis-C. albicanscommunities, with overrepresentation of those corresponding to 31 gene ontology terms, including those associated with growth and division. Of potential relevance to the disease process,C. albicansinduced upregulation of components of the type IX secretion apparatus. Collectively, these findings indicate that InlJ-Als3-dependent binding facilitates interdomain community development betweenC. albicansandP. gingivalisand thatP. gingivalishas the potential for increased virulence within such communities.IMPORTANCEMany diseases involve the concerted actions of microorganisms assembled in polymicrobial communities. Inflammatory periodontal diseases are among the most common infections of humans and result in destruction of gum tissue and, ultimately, in loss of teeth. In periodontal disease, pathogenic communities can include the fungusCandida albicans; however, the contribution ofC. albicansto the synergistic virulence of the community is poorly understood. Here we characterize the interactions betweenC. albicansand the keystone bacterial pathogenPorphyromonas gingivalisand show that coadhesion mediated by specific proteins results in major changes in gene expression byP. gingivalis, which could serve to increase pathogenic potential. The work provides significant insights into interdomain interactions that can enhance our understanding of diseases involving a multiplicity of microbial pathogens.
Novel Insights into Staphylococcus aureus Deep Bone Infections: the Involvement of Osteocytes
Authors: Yang Dongqing , Wijenayaka Asiri R. , Solomon Lucian B. , Pederson Stephen M. , Findlay David M. , Kidd Stephen P. , Atkins Gerald J. 
Published: April 2018

ABSTRACTPeriprosthetic joint infection (PJI) is a potentially devastating complication of orthopedic joint replacement surgery. PJI with associated osteomyelitis is particularly problematic and difficult to cure. Whether viable osteocytes, the predominant cell type in mineralized bone tissue, have a role in these infections is not clear, although their involvement might contribute to the difficulty in detecting and clearing PJI. Here, usingStaphylococcus aureus, the most common pathogen in PJI, we demonstrate intracellular infection of human-osteocyte-like cellsin vitroandS. aureusadaptation by forming quasi-dormant small-colony variants (SCVs). Consistent patterns of host gene expression were observed betweenin vitro-infected osteocyte-like cultures, anex vivohuman bone infection model, and bone samples obtained from PJI patients. Finally, we confirmS. aureusinfection of osteocytes in clinical cases of PJI. Our findings are consistent with osteocyte infection being a feature of human PJI and suggest that this cell type may provide a reservoir for silent or persistent infection. We suggest that elucidating the molecular/cellular mechanism(s) of osteocyte-bacterium interactions will contribute to better understanding of PJI and osteomyelitis, improved pathogen detection, and treatment.IMPORTANCEPeriprosthetic joint infections (PJIs) are increasing and are recognized as one of the most common modes of failure of joint replacements. Osteomyelitis arising from PJI is challenging to treat and difficult to cure and increases patient mortality 5-fold.Staphylococcus aureusis the most common pathogen causing PJI. PJI can have subtle symptoms and lie dormant or go undiagnosed for many years, suggesting persistent bacterial infection. Osteocytes, the major bone cell type, reside in bony caves and tunnels, the lacuno-canalicular system. We report here thatS. aureuscan infect and reside in human osteocytes without causing cell death both experimentally and in bone samples from patients with PJI. We demonstrate that osteocytes respond to infection by the differential regulation of a large number of genes.S. aureusadapts during intracellular infection of osteocytes by adopting the quasi-dormant small-colony variant (SCV) lifestyle, which might contribute to persistent or silent infection. Our findings shed new light on the etiology of PJI and osteomyelitis in general.
A Viral Suppressor Modulates the Plant Immune Response Early in Infection by Regulating MicroRNA Activity
Authors: Pertermann Robert , Tamilarasan Selvaraj , Gursinsky Torsten , Gambino Giorgio , Schuck Jana , Weinholdt Claus , Lilie Hauke , Grosse Ivo , Golbik Ralph Peter , Pantaleo Vitantonio , Behrens Sven-Erik 
Published: April 2018

ABSTRACT

Many viral suppressors (VSRs) counteract antiviral RNA silencing, a central component of the plant’s immune response by sequestration of virus-derived antiviral small interfering RNAs (siRNAs). Here, we addressed how VSRs affect the activities of cellular microRNAs (miRNAs) during a viral infection by characterizing the interactions of two unrelated VSRs, the
Tombusvirus
p19 and the
Cucumovirus
2b, with miRNA 162 (miR162), miR168, and miR403. These miRNAs regulate the expression of the important silencing factors Dicer-like protein 1 (DCL1) and Argonaute proteins 1 and 2 (AGO1 and AGO2), respectively. Interestingly, while the two VSRs showed similar binding profiles, the miRNAs were bound with significantly different affinities, for example, with the affinity of miR162 greatly exceeding that of miR168.
In vitro
silencing experiments revealed that p19 and 2b affect miRNA-mediated silencing of the
DCL1
,
AGO1
, and
AGO2
mRNAs in strict accordance with the VSR’s miRNA-binding profiles. In
Tombusvirus
-infected plants, the miRNA-binding behavior of p19 closely corresponded to that
in vitro
. Most importantly, in contrast to controls with a Δp19 virus, infections with wild-type (wt) virus led to changes of the levels of the miRNA-targeted mRNAs, and these changes correlated with the miRNA-binding preferences of p19. This was observed exclusively in the early stage of infection when viral genomes are proposed to be susceptible to silencing and viral siRNA (vsiRNA) concentrations are low. Accordingly, our study suggests that differential binding of miRNAs by VSRs is a widespread viral mechanism to coordinately modulate cellular gene expression and the antiviral immune response during infection initiation.

IMPORTANCE
Plant viruses manipulate their hosts in various ways. Viral suppressor proteins (VSRs) interfere with the plant’s immune response by sequestering small, antivirally acting vsiRNAs, which are processed from viral RNAs during the plant’s RNA-silencing response. Here, we examined the effects of VSRs on cellular microRNAs (miRNAs), which show a high degree of similarity with vsiRNAs. Binding experiments with two unrelated VSRs and three important regulatory miRNAs revealed that the proteins exhibit similar miRNA-binding profiles but bind different miRNAs at considerably different affinities. Most interestingly, experiments in plants showed that in the early infection phase, the
Tombusvirus
VSR p19 modulates the activity of these miRNAs on their target mRNAs very differently and that this differential regulation strictly correlates with the binding affinities of p19 for the respective miRNAs. Our data suggest that VSRs may specifically control plant gene expression and the early immune response by differential sequestration of miRNAs.
Outbreak of Invasive Wound Mucormycosis in a Burn Unit Due to Multiple Strains of Mucor circinelloides f. circinelloides Resolved by Whole-Genome Sequencing
Authors: Garcia-Hermoso Dea , Criscuolo Alexis , Lee Soo Chan , Legrand Matthieu , Chaouat Marc , Denis Blandine , Lafaurie Matthieu , Rouveau Martine , Soler Charles , Schaal Jean-Vivien , Mimoun Maurice , Mebazaa Alexandre , Heitman Joseph , Dromer Françoise , Brisse Sylvain , Bretagne Stéphane , Alanio Alexandre 
Published: April 2018

ABSTRACT

Mucorales are ubiquitous environmental molds responsible for mucormycosis in diabetic, immunocompromised, and severely burned patients. Small outbreaks of invasive wound mucormycosis (IWM) have already been reported in burn units without extensive microbiological investigations. We faced an outbreak of IWM in our center and investigated the clinical isolates with whole-genome sequencing (WGS) analysis. We analyzed
M. circinelloides
isolates from patients in our burn unit (BU1, Hôpital Saint-Louis, Paris, France) together with nonoutbreak isolates from Burn Unit 2 (BU2, Paris area) and from France over a 2-year period (2013 to 2015). A total of 21 isolates, including 14 isolates from six BU1 patients, were analyzed by whole-genome sequencing (WGS). Phylogenetic classification based on
de novo
assembly and assembly free approaches showed that the clinical isolates clustered in four highly divergent clades. Clade 1 contained at least one of the strains from the six epidemiologically linked BU1 patients. The clinical isolates were specific to each patient. Two patients were infected with more than two strains from different clades, suggesting that an environmental reservoir of clonally unrelated isolates was the source of contamination. Only two patients from BU1 shared one strain, which could correspond to direct transmission or contamination with the same environmental source. In conclusion, WGS of several isolates per patients coupled with precise epidemiological data revealed a complex situation combining potential cross-transmission between patients and multiple contaminations with a heterogeneous pool of strains from a cryptic environmental reservoir.

IMPORTANCE
Invasive wound mucormycosis (IWM) is a severe infection due to environmental molds belonging to the order Mucorales. Severely burned patients are particularly at risk for IWM. Here, we used whole-genome sequencing (WGS) analysis to resolve an outbreak of IWM due to
Mucor circinelloides
that occurred in our hospital (BU1). We sequenced 21 clinical isolates, including 14 from BU1 and 7 unrelated isolates, and compared them to the reference genome (1006PhL). This analysis revealed that the outbreak was mainly due to multiple strains that seemed patient specific, suggesting that the patients were more likely infected from a pool of diverse strains from the environment rather than from direct transmission among them. This study revealed the complexity of a Mucorales outbreak in the settings of IWM in burn patients, which has been highlighted based on WGS combined with careful sampling.
Maternal caffeine intake during pregnancy and childhood growth and overweight: results from a large Norwegian prospective observational cohort study
Authors: Papadopoulou Eleni , Botton Jérémie , Brantsæter Anne-Lise , Haugen Margaretha , Alexander Jan , Meltzer Helle Margrete , Bacelis Jonas , Elfvin Anders , Jacobsson Bo , Sengpiel Verena 
Published: April 2018

ObjectivesTo study the association between maternal caffeine intake during pregnancy and the child’s weight gain and overweight risk up to 8 years.DesignProspective nationwide pregnancy cohort.SettingThe Norwegian Mother and Child Cohort Study.ParticipantsA total of 50 943 mothers recruited from 2002 to 2008 and their children, after singleton pregnancies, with information about average caffeine intake assessed at mid-pregnancy.Outcome measureChild’s body size information at 11 age points from 6 weeks to 8 years. We defined excess growth in infancy as a WHO weight gain z-score of >0.67 from birth to age 1 year, and overweight according to the International Obesity Task Force. We used a growth model to assess individual growth trajectories.ResultsCompared with pregnant women with low caffeine intake (<50 mg/day, 46%), women with average (50–199 mg/day, 44%), high (≥200–299 mg/day, 7%) and very high (≥300 mg/day, 3%) caffeine intakes had an increased risk of their child experiencing excess growth in infancy, after adjustment for confounders (OR=1.15, 95% CI 1.09 to 1.22, OR=1.30, 95% CI 1.16 to 1.45, OR=1.66, 95% CI 1.42 to 1.93, respectively). In utero exposure to any caffeine was associated with higher risk of overweight at age 3 years and 5 years, while the association persisted at 8 years, only for very high exposures. Any caffeine intake was associated with increased body mass index from infancy to childhood. Children prenatally exposed to caffeine intake >200 mg/day had consistently higher weight. Very high caffeine exposures were associated with higher weight gain velocity from infancy to age 8 years.ConclusionAny caffeine consumption during pregnancy is associated with a higher risk of excess infant growth and of childhood overweight, mainly at preschool ages. Maternal caffeine intake may modify the overall weight growth trajectory of the child from birth to 8 years. This study adds supporting evidence for the current advice to reduce caffeine intake during pregnancy.
Combination Therapy and the Evolution of Resistance: The Theoretical Merits of Synergism and Antagonism in Cancer
Authors: Saputra Elysia C. , Huang Lu , Chen Yihui , Tucker-Kellogg Lisa 
Published: April 2018

Abstract
The search for effective combination therapies for cancer has focused heavily on synergistic combinations because they exhibit enhanced therapeutic efficacy at lower doses. Although synergism is intuitively attractive, therapeutic success often depends on whether drug resistance develops. The impact of synergistic combinations (vs. antagonistic or additive combinations) on the process of drug-resistance evolution has not been investigated. In this study, we use a simplified computational model of cancer cell numbers in a population of drug-sensitive, singly-resistant, and fully-resistant cells to simulate the dynamics of resistance evolution in the presence of two-drug combinations. When we compared combination therapies administered at the same combination of effective doses, simulations showed synergistic combinations most effective at delaying onset of resistance. Paradoxically, when the therapies were compared using dose combinations with equal initial efficacy, antagonistic combinations were most successful at suppressing expansion of resistant subclones. These findings suggest that, although synergistic combinations could suppress resistance through early decimation of cell numbers (making them “proefficacy” strategies), they are inherently fragile toward the development of single resistance. In contrast, antagonistic combinations suppressed the clonal expansion of singly-resistant cells, making them “antiresistance” strategies. The distinction between synergism and antagonism was intrinsically connected to the distinction between offensive and defensive strategies, where offensive strategies inflicted early casualties and defensive strategies established protection against anticipated future threats. Our findings question the exclusive focus on synergistic combinations and motivate further consideration of nonsynergistic combinations for cancer therapy.
Significance: Computational simulations show that if different combination therapies have similar initial efficacy in cancers, then nonsynergistic drug combinations are more likely than synergistic drug combinations to provide a long-term defense against the evolution of therapeutic resistance. Cancer Res; 78(9); 2419–31. ©2018 AACR.
Clinicopathological Risk Factors for an Invasive Breast Cancer Recurrence after Ductal CarcinomaIn Situ—A Nested Case–Control Study
Authors: Visser Lindy L. , Elshof Lotte E. , Schaapveld Michael , van de Vijver Koen , Groen Emma J. , Almekinders Mathilde M. , Bierman Carolien , van Leeuwen Flora E. , Rutgers Emiel J. , Schmidt Marjanka K. , Lips Esther H. , Wesseling Jelle 
Published: April 2018

AbstractPurpose: Ductal carcinoma in situ (DCIS) is treated to prevent progression to invasive breast cancer. Yet, most lesions will never progress, implying that overtreatment exists. Therefore, we aimed to identify factors distinguishing harmless from potentially hazardous DCIS using a nested case–control study.Experimental Design: We conducted a case–control study nested in a population-based cohort of patients with DCIS treated with breast-conserving surgery (BCS) alone (N = 2,658) between 1989 and 2005. We compared clinical, pathologic, and IHC DCIS characteristics of 200 women who subsequently developed ipsilateral invasive breast cancer (iIBC; cases) and 474 women who did not (controls), in a matched setting. Median follow-up time was 12.0 years (interquartile range, 9.0–15.3). Conditional logistic regression models were used to assess associations of various factors with subsequent iIBC risk after primary DCIS.Results: High COX-2 protein expression showed the strongest association with subsequent iIBC [OR = 2.97; 95% confidence interval (95% CI), 1.72–5.10]. In addition, HER2 overexpression (OR = 1.56; 95% CI, 1.05–2.31) and presence of periductal fibrosis (OR = 1.44; 95% CI, 1.01–2.06) were associated with subsequent iIBC risk. Patients with HER2+/COX-2high DCIS had a 4-fold higher risk of subsequent iIBC (vs. HER2−/COX-2low DCIS), and an estimated 22.8% cumulative risk of developing subsequent iIBC at 15 years.Conclusions: With this unbiased study design and representative group of patients with DCIS treated by BCS alone, COX-2, HER2, and periductal fibrosis were revealed as promising markers predicting progression of DCIS into iIBC. Validation will be done in independent datasets. Ultimately, this will aid individual risk stratification of women with primary DCIS. Clin Cancer Res; 24(15); 3593–601. ©2018 AACR.