bluuebunny/crossref_metadata_2025_split huggingface dataset:
Penicillin Binding Protein 1 Is Important in the Compensatory Response of Staphylococcus aureus to Daptomycin-Induced Membrane Damage and Is a Potential Target for β-Lactam–Daptomycin Synergy
Authors: Berti Andrew D. , Theisen Erin , Sauer John-Demian , Nonejuie Poochit , Olson Joshua , Pogliano Joseph , Sakoulas George , Nizet Victor , Proctor Richard A. , Rose Warren E. 
Published: November 2015

ABSTRACT

The activity of daptomycin (DAP) against methicillin-resistant
Staphylococcus aureus
(MRSA) is enhanced in the presence of β-lactam antibiotics. This effect is more pronounced with β-lactam antibiotics that exhibit avid binding to penicillin binding protein 1 (PBP1). Here, we present evidence that PBP1 has a significant role in responding to DAP-induced stress on the cell. Expression of the
pbpA
transcript, encoding PBP1, was specifically induced by DAP exposure whereas expression of
pbpB
,
pbpC
, and
pbpD
, encoding PBP2, PBP3, and PBP4, respectively, remained unchanged. Using a MRSA COL strain with
pbpA
under an inducible promoter, increased
pbpA
transcription was accompanied by reduced susceptibility to, and killing by, DAP
in vitro
. Exposure to β-lactams that preferentially inactivate PBP1 was not associated with increased DAP binding, suggesting that synergy in the setting of anti-PBP1 pharmacotherapy results from increased DAP potency on a per-molecule basis. Combination exposure in an
in vitro
pharmacokinetic/pharmacodynamic model system with β-lactams that preferentially inactivate PBP1 (DAP-meropenem [MEM] or DAP-imipenem [IPM]) resulted in more-rapid killing than did combination exposure with DAP-nafcillin (NAF) (nonselective), DAP-ceftriaxone (CRO) or DAP-cefotaxime (CTX) (PBP2 selective), DAP-cefaclor (CEC) (PBP3 selective), or DAP-cefoxitin (FOX) (PBP4 selective). Compared to β-lactams with poor PBP1 binding specificity, exposure of
S. aureus
to DAP plus PBP1-selective β-lactams resulted in an increased frequency of septation and cell wall abnormalities. These data suggest that PBP1 activity may contribute to survival during DAP-induced metabolic stress. Therefore, targeted inactivation of PBP1 may enhance the antimicrobial efficiency of DAP, supporting the use of DAP–β-lactam combination therapy for serious MRSA infections, particularly when the β-lactam undermines the PBP1-mediated compensatory response.
Quantitative Analysis of Single-Nucleotide Polymorphism for Rapid Detection of TR
34
/L98H- and TR
46
/Y121F/T289A-Positive Aspergillus fumigatus Isolates Obtained from Patients in Iran from 2010 to 2014
Authors: Mohammadi Faezeh , Hashemi Seyed Jamal , Zoll Jan , Melchers Willem J. G. , Rafati Haleh , Dehghan Parvin , Rezaie Sasan , Tolooe Ali , Tamadon Yalda , van der Lee Henrich A. , Verweij Paul E. , Seyedmousavi Seyedmojtaba 
Published: November 2015

ABSTRACT

We employed an endpoint genotyping method to update the prevalence rate of positivity for the TR
34
/L98H mutation (a 34-bp tandem repeat mutation in the promoter region of the
cyp51A
gene in combination with a substitution at codon L98) and the TR
46
/Y121F/T289A mutation (a 46-bp tandem repeat mutation in the promoter region of the
cyp51A
gene in combination with substitutions at codons Y121 and T289) among clinical
Aspergillus fumigatus
isolates obtained from different regions of Iran over a recent 5-year period (2010 to 2014). The antifungal activities of itraconazole, voriconazole, and posaconazole against 172 clinical
A. fumigatus
isolates were investigated using the European Committee on Antimicrobial Susceptibility Testing (EUCAST) broth microdilution method. For the isolates with an azole resistance phenotype, the
cyp51A
gene and its promoter were amplified and sequenced. In addition, using a LightCycler 480 real-time PCR system, a novel endpoint genotyping analysis method targeting single-nucleotide polymorphisms was evaluated to detect the L98H and Y121F mutations in the
cyp51A
gene of all isolates. Of the 172
A. fumigatus
isolates tested, the MIC values of itraconazole (≥16 mg/liter) and voriconazole (>4 mg/liter) were high for 6 (3.5%). Quantitative analysis of single-nucleotide polymorphisms showed the TR
34
/L98H mutation in the
cyp51A
genes of six isolates. No isolates harboring the TR
46
/Y121F/T289A mutation were detected. DNA sequencing of the
cyp51A
gene confirmed the results of the novel endpoint genotyping method. By microsatellite typing, all of the azole-resistant isolates had genotypes different from those previously recovered from Iran and from the Dutch TR
34
/L98H controls. In conclusion, there was not a significant increase in the prevalence of azole-resistant
A. fumigatus
isolates harboring the TR
34
/L98H resistance mechanism among isolates recovered over a recent 5-year period (2010 to 2014) in Iran. A quantitative assay detecting a single-nucleotide polymorphism in the
cyp51A
gene of
A. fumigatus
is a reliable tool for the rapid screening and monitoring of TR
34
/L98H- and TR
46
/Y121F/T289A-positive isolates and can easily be incorporated into clinical mycology algorithms.
New Role of Nod Proteins in Regulation of Intestinal Goblet Cell Response in the Context of Innate Host Defense in an Enteric Parasite Infection
Authors: Wang Huaqing , Kim Janice J. , Denou Emmanuel , Gallagher Amanda , Thornton David J. , Shajib M. Sharif , Xia Lijun , Schertzer Jonathan D. , Grencis Richard K. , Philpott Dana J. , Khan Waliul I. 
Published: November 2015

ABSTRACT

Mucins secreted by intestinal goblet cells are considered an important component of innate defense in a number of enteric infections, including many parasitic infections, but also likely provide protection against the gut microbiota. Nod proteins are intracellular receptors that play key roles in innate immune response and inflammation. Here, we investigated the role of Nod proteins in regulation of intestinal goblet cell response in naive mice and mice infected with the enteric parasite
Trichuris muris
. We observed significantly fewer periodic acid-Schiff (PAS)-stained intestinal goblet cells and less mucin (Muc2) in Nod1 and Nod2 double-knockout (Nod DKO) mice after
T. muris
infection than in wild-type (WT) mice. Expulsion of parasites from the intestine was significantly delayed in Nod DKO mice. Treatment of naive WT mice with Nod1 and Nod2 agonists simultaneously increased numbers of PAS-stained goblet cells and Muc2-expressing cells, whereas treatment with Nod1 or Nod2 separately had no significant effect. Stimulation of mucin-secreting LS174T cells with Nod1 and Nod2 agonists upregulated core 3 β1,3-
N
-acetylglucosaminyltransferase (C3GnT; an important enzyme in mucin synthesis) and MUC2. We also observed lower numbers of PAS-stained goblet cells and less Muc2 in germfree mice. Treatment with Nod1 and Nod2 agonists enhanced the production of PAS-stained goblet cells and Muc2 in germfree mice. These data provide novel information on the role of Nod proteins in goblet cell response and Muc2 production in relation to intestinal innate defense.
A DinB Ortholog Enables Mycobacterial Growth under dTTP-Limiting Conditions Induced by the Expression of a Mycobacteriophage-Derived Ribonucleotide Reductase Gene
Authors: Ghosh Shreya , Samaddar Sourabh , Kirtania Prithwiraj , Das Gupta Sujoy K. 
Published: November 2015

ABSTRACT

Mycobacterium
species such as
M. smegmatis
and
M. tuberculosis
encode at least two translesion synthesis (TLS) polymerases, DinB1 and DinB2, respectively. Although predicted to be linked to DNA repair, their role
in vivo
remains enigmatic.
M. smegmatis
mc
2
155, a strain commonly used to investigate mycobacterial genetics, has two copies of
dinB2
, the gene that codes for DinB2, by virtue of a 56-kb chromosomal duplication. Expression of a mycobacteriophage D29 gene (gene 50) encoding a class II ribonucleotide reductase in
M. smegmatis
ΔDRKIN, a strain derived from mc
2
155 in which one copy of the duplication is lost, resulted in DNA replication defects and growth inhibition. The inhibitory effect could be linked to the deficiency of dTTP that resulted under these circumstances. The selective inhibition observed in the ΔDRKIN strain was found to be due solely to a reduced dosage of
dinB2
in this strain.
Mycobacterium bovis
, which is closely related to
M. tuberculosis
, the tuberculosis pathogen, was found to be highly susceptible to gene 50 overexpression. Incidentally, these slow-growing pathogens harbor one copy of
dinB2
. The results indicate that the induction of a dTTP-limiting state can lead to growth inhibition in mycobacteria, with the effect being maximum in cells deficient in DinB2.

IMPORTANCE
Mycobacterium
species, such as
M. tuberculosis
, the tuberculosis pathogen, are known to encode several Y family DNA polymerases, one of which is DinB2, an ortholog of the DNA repair-related protein DinP of
Escherichia coli
. Although this protein has been biochemically characterized previously and found to be capable of translesion synthesis
in vitro
, its
in vivo
function remains unknown. Using a novel method to induce dTTP deficiency in mycobacteria, we demonstrate that DinB2 can aid mycobacterial survival under such conditions. Apart from unraveling a specific role for the mycobacterial Y family DNA polymerase DinB2 for the first time, this study also paves the way for the development of drugs that can kill mycobacteria by inducing a dTTP-deficient state.
Phenotypes Associated with the Essential Diadenylate Cyclase CdaA and Its Potential Regulator CdaR in the Human Pathogen Listeria monocytogenes
Authors: Rismondo Jeanine , Gibhardt Johannes , Rosenberg Jonathan , Kaever Volkhard , Halbedel Sven , Commichau Fabian M. 
Published: November 2015

ABSTRACTCyclic diadenylate monophosphate (c-di-AMP) is a second messenger utilized by diverse bacteria. In many species, including the Gram-positive human pathogenListeria monocytogenes, c-di-AMP is essential for growth. Here we show that the single diadenylate cyclase ofL. monocytogenes, CdaA, is an integral membrane protein that interacts with its potential regulatory protein, CdaR, via the transmembrane protein domain. The presence of the CdaR protein is not required for the membrane localization and abundance of CdaA. We have also found that CdaR negatively influences CdaA activity inL. monocytogenesand that the role of CdaR is most evident at a high growth temperature. Interestingly, acdaRmutant strain is less susceptible to lysozyme. Moreover, CdaA contributes to cell division, and cells depleted of CdaA are prone to lysis. The observation that the growth defect of a CdaA depletion strain can be partially restored by increasing the osmolarity of the growth medium suggests that c-di-AMP is important for maintaining the integrity of the protective cell envelope. Overall, this work provides new insights into the relationship between CdaA and CdaR.IMPORTANCECyclic diadenylate monophosphate (c-di-AMP) is a recently identified second messenger that is utilized by the Gram-positive human pathogenListeria monocytogenes. Here we show that the single diadenylate cyclase ofL. monocytogenes, CdaA, is an integral membrane protein that interacts with CdaR, its potential regulatory protein. We show that CdaR is not required for membrane localization or abundance of the diadenylate cyclase, but modulates its activity. Moreover, CdaA seems to contribute to cell division. Overall, this work provides new insights into the relationship between CdaA and CdaR and their involvement in cell growth.
How do Systematic Reviews of Acupuncture for Pain Relief Incorporate Risk of Bias Assessments into the Synthesis? A Methodological Study
Authors: Li Xiao-qian , Tao Kun-ming , Yang Ge-liang , Zhou Qing-hui , Ling Chang-quan 
Published: November 2015

Objective By reviewing the assessment of internal validity in relevant systematic reviews (SRs), the aim of this study was to identify how critical appraisals of risk of bias (RoB) inform the synthesis of evidence in SRs of acupuncture for pain relief. Methods SRs were searched in Medline, EMBASE, and the Cochrane Database of SRs from their inception to 30 December 2014. Only SRs of acupuncture for pain relief were included. Basic information, types of RoB appraisal tool, whether or not there was domain-level assessment of RoB, whether or not the reviews ranked studies by RoB, plus whether or not (and, if so, how) RoB appraisal was incorporated into the synthesis were determined. Results A total of 91 SRs met the inclusion criteria and were included in the final analysis. Over half of the SRs (85, 64.8%) used standard tools, such as the Jadad quality score and the Cochrane RoB tool, followed by adapted tools (n=23, 25.3%). Of the 85 SRs that assessed RoB, 29 (34.1%) presented domain-level assessment and 71 SRs (83.5%) included ranking of the studies based on RoB assessment. Of these 71, 35 (49.4%) used a cut-off threshold score and 26 (36.6%) required all criteria sum-up. Of the 85 SRs that assessed RoB, 48 (56.5%) incorporated RoB appraisal into the data synthesis. Conclusions Although most SRs of acupuncture for pain relief conducted some form of RoB assessment, nearly half of them failed to incorporate the RoB assessment into the synthesis.
Poor oral health including active caries in 187 UK professional male football players: clinical dental examination performed by dentists
Authors: Needleman Ian , Ashley Paul , Meehan Lyndon , Petrie Aviva , Weiler Richard , McNally Steve , Ayer Chris , Hanna Rob , Hunt Ian , Kell Steven , Ridgewell Paul , Taylor Russell 
Published: November 2015

BackgroundThe few studies that have assessed oral health in professional/elite football suggest poor oral health with minimal data on impact on performance. The aim of this research was to determine oral health in a representative sample of professional footballers in the UK and investigate possible determinants of oral health and self-reported impact on well-being, training and performance.MethodsClinical oral health examination of senior squad players using standard methods and outcomes carried out at club training facilities. Questionnaire data were also collected. 8 teams were included, 5 Premier League, 2 Championship and 1 League One.Results6 dentists examined 187 players who represented >90% of each senior squad. Oral health was poor: 37% players had active dental caries, 53% dental erosion and 5% moderate-severe irreversible periodontal disease. 45% were bothered by their oral health, 20% reported an impact on their quality of life and 7% on training or performance. Despite attendance for dental check-ups, oral health deteriorated with age.ConclusionsThis is the first large, representative sample study in professional football. Oral health of professional footballers is poor, and this impacts on well-being and performance. Successful strategies to promote oral health within professional football are urgently needed, and research should investigate models based on best evidence for behaviour change and implementation science. Furthermore, this study provides strong evidence to support oral health screening within professional football.
Treatment ofClostridium difficileinfection in mice with vancomycin alone is as effective as treatment with vancomycin and metronidazole in combination
Authors: Erikstrup Lise Tornvig , Aarup Mie , Hagemann-Madsen Rikke , Dagnaes-Hansen Frederik , Kristensen Brian , Olsen Katharina Elisabeth Pribil , Fuursted Kurt 
Published: November 2015

ObjectiveClostridium difficileis a major cause of nosocomial infectious diarrhoea. Treatment ofC. difficileinfection (CDI) depends on disease severity. A combination of vancomycin and metronidazole is often recommended in severe cases. The aim of this study was to examine, in a murine model of CDI, if mice treated with a combination of vancomycin and metronidazole had a better clinical outcome than mice treated with vancomycin or metronidazole alone.DesignC57BL/6J mice pretreated with an antimicrobial mixture were challenged withC. difficileVPI 10463 or phosphate-buffered saline by oral gavage. After the challenge, the mice were treated with placebo, vancomycin, metronidazole or a combination of vancomycin and metronidazole for 10 days. The mice were monitored for 20 days with weight and a clinical score. Stool samples were examined forC. difficilespore load and presence ofC. difficiletoxins.ResultsNone of the mice in the vancomycin-treated group died during the treatment phase compared to a mortality of 17%, 33% and 55% in the combination, metronidazole and infected control group, respectively. Mice treated with vancomycin alone or in combination with metronidazole recovered from CDI faster than mice treated with metronidazole alone. However, after discontinuation of treatment, vancomycin-treated and combination-treated mice succumbed to clinical and bacteriological relapse.ConclusionsMice treated with vancomycin alone had a better clinical outcome in the treatment phase of CDI than mice treated with metronidazole alone. A combination of vancomycin and metronidazole did not improve the clinical outcome when compared to treatment with vancomycin alone.Trial registration numberThe trial registration number from the Danish Experimental Animal Inspectorate is J number 2012-15-2934-00422.
How different terminology for ductal carcinoma in situ impacts women's concern and treatment preferences: a randomised comparison within a national community survey
Authors: McCaffery Kirsten , Nickel Brooke , Moynihan Ray , Hersch Jolyn , Teixeira-Pinto Armando , Irwig Les , Barratt Alexandra 
Published: November 2015

ObjectiveThere have been calls to remove ‘carcinoma’ from terminology for in situ cancers such as ductal carcinoma in situ (DCIS), to reduce overdiagnosis and overtreatment. We investigated the effect of describing DCIS as ‘abnormal cells’ versus ‘pre-invasive breast cancer cells’ on women's concern and treatment preferences.Setting and participantsCommunity sample of Australian women (n=269) who spoke English as their main language at home.DesignRandomised comparison within a community survey. Women considered a hypothetical scenario involving a diagnosis of DCIS described as either ‘abnormal cells’ (arm A) or ‘pre-invasive breast cancer cells’ (arm B). Within each arm, the initial description was followed by the alternative term and outcomes reassessed.ResultsWomen in both arms indicated high concern, but still indicated strong initial preferences for watchful waiting (64%). There were no differences in initial concern or preferences by trial arm. However, more women in arm A (‘abnormal cells’ first term) indicated they would feel more concerned if given the alternative term (‘pre-invasive breast cancer cells’) compared to women in arm B who received the terms in the opposite order (67% arm A vs 52% arm B would feel more concerned, p=0.001). More women in arm A also changed their preference towards treatment when the terminology was switched from ‘abnormal cells’ to ‘pre-invasive breast cancer cells’ compared to arm B. In arm A, 18% of women changed their preference to treatment while only 6% changed to watchful waiting (p=0.008). In contrast, there were no significant changes in treatment preference in arm B when the terminology was switched (9% vs 8% changed their stated preference).ConclusionsIn a hypothetical scenario, interest in watchful waiting for DCIS was high, and changing terminology impacted women's concern and treatment preferences. Removal of the cancer term from DCIS may assist in efforts towards reducing overtreatment.
Disability pension and symptoms of anxiety and depression: a prospective comparison of farmers and other occupational groups. The HUNT Study, Norway
Authors: Torske Magnhild Oust , Hilt Bjørn , Bjørngaard Johan Håkon , Glasscock David , Krokstad Steinar 
Published: November 2015

ObjectivesAgriculture has undergone major changes, and farmers have been found to have a high prevalence of depression symptoms. We investigated the risk of work disability in Norwegian farmers compared with other occupational groups, as well as the associations between symptoms of anxiety and depression and future disability pension.MethodsWe linked working participants of the HUNT2 Survey (1995–97) aged 20–61.9 years, of whom 3495 were farmers and 25 521 had other occupations, to national registry data on disability pension, with follow-up until 31 December 2010. We used Cox proportional hazards regression to estimate hazard ratios (HRs) of disability pension, and to investigate the associations between symptoms of anxiety and depression caseness at baseline (score on the anxiety or depression subscales of the Hospital Anxiety and Depression Scale (HADS) ≥8) and disability pension.ResultsFarmers had a twofold increased risk of disability pension (age-adjusted and sex-adjusted HR 2.07, 95% CI 1.80 to 2.38) compared with higher grade professionals. Farmers with symptoms of depression caseness had a 53% increased risk of disability pension (HR 1.53, 95% CI 1.25 to 1.87) compared with farmers below the cut-off point of depression caseness symptoms, whereas farmers with symptoms of anxiety caseness had a 51% increased risk (HR 1.51, 95% CI 1.23 to 1.86).ConclusionsFarmers have an increased risk of disability pension compared with higher grade professionals, but the risk is lower than in most other manual occupational groups. Farmers who report high levels of depression or anxiety symptoms are at substantially increased risk of future work disability, and the risk increase appears to be fairly similar across most occupational groups.
Sedentary behaviour among elite professional footballers: health and performance implications
Authors: Weiler Richard , Aggio Daniel , Hamer Mark , Taylor Tom , Kumar Bhavesh 
Published: November 2015

BackgroundElite athletes should have little concern about meeting recommended guidelines on physical activity. However, sedentary behaviour is considered a health risk independent of physical activity, and is recognised in public health guidelines advising against prolonged sedentary time. There has been very little research on athletes’ physical activity behaviour outside elite sport.MethodsGiven health and performance links, we investigated in-season post-training activity levels in 28 elite professional footballers during the English Premiership season. Players volunteered to wear a triaxial wrist accelerometer for 1 week, removing it only for training and matches. In total, 25 players met the inclusion criteria for analysis. Players recorded on average 632.6 min wear time p/day during the post-training period (SD±52.9) for a mean of 3.8 days (SD±1.5).ResultsOn average, players recorded 76.2 min p/day (SD±28.8) of moderate or vigorous activity post-training. The majority (79%) of post-training time was spent in sedentary activities (500.6 min per day±59.0).ConclusionsProfessional footballers are alarmingly sedentary in their leisure time, and comparatively more so than non-athletic groups of a similar age and older. This raises questions over optimum recovery and performance, as well as long-term health and cardiovascular risk. Worryingly, retirement from elite sport is likely to further imbalance activity and sedentary behaviour. Promoting regular periodic light to moderate leisure time activity could be beneficial. Further research and provision of education and support for players is required in this area.