bluuebunny/crossref_metadata_2025_split huggingface dataset:
Type II Secretion Is Necessary for Optimal Association of the Legionella-Containing Vacuole with Macrophage Rab1B but Enhances Intracellular Replication Mainly by Rab1B-Independent Mechanisms
Authors: White Richard C. , Cianciotto Nicholas P. 
Published: September 2016

ABSTRACT

Previously, we documented that type II secretion (T2S) promotes intracellular infection of macrophages by
Legionella pneumophila
. In the present study, we identified infection events that are modulated by T2S by comparing the behaviors of wild-type and T2S mutant bacteria in murine bone marrow-derived macrophages and human U937 cells. Although the two strains behaved similarly for entry into the host cells and evasion of lysosomal fusion, the mutant was impaired in the ability to initiate replication between 4 and 8 h postentry and to grow to large numbers in the
Legionella
-containing vacuole (LCV), as evident at 12 h. At 4 h postinoculation, mutant LCVs had a significantly reduced association with Rab1B, a host GTPase that facilitates the tethering of endoplasmic reticulum (ER)-derived vesicles to LCVs. The mutant did not lose expression or translocation of six type IV secretion effectors (e.g., SidM) that are well known for mediating Rab1B association with the LCV, indicating that T2S promotes the interaction between the LCV and Rab1B via a novel mechanism. Interestingly, the mutant's growth defect was exacerbated in macrophages that had been depleted of Rab1B by short hairpin RNA (shRNA) treatment, indicating that T2S also potentiates events beyond Rab1B association. In support of this, a
sidM lspF
double mutant had an intracellular growth defect that was more dramatic than that of the
lspF
mutant (and a
sidM
mutant) and showed a growth difference of as much as a 400-fold compared to the wild type. Together, these data reveal a new role for T2S in intracellular infection that involves both Rab1B-dependent and Rab1B-independent processes.
A Putative Bacterial ABC Transporter Circumvents the Essentiality of Signal Peptidase
Authors: Morisaki J. Hiroshi , Smith Peter A. , Date Shailesh V. , Kajihara Kimberly K. , Truong Chau Linda , Modrusan Zora , Yan Donghong , Kang Jing , Xu Min , Shah Ishita M. , Mintzer Robert , Kofoed Eric M. , Cheung Tommy K. , Arnott David , Koehler Michael F. T. , Heise Christopher E. , Brown Eric J. , Tan Man-Wah , Hazenbos Wouter L. W. 
Published: September 2016

ABSTRACT

The type I signal peptidase of
Staphylococcus aureus
, SpsB, is an attractive antibacterial target because it is essential for viability and extracellularly accessible. We synthesized compound 103, a novel arylomycin-derived inhibitor of SpsB with significant potency against various clinical
S. aureus
strains (MIC of ~1 µg/ml). The predominant clinical strain USA300 developed spontaneous resistance to compound 103 with high frequency, resulting from single point mutations inside or immediately upstream of
cro
/
cI
, a homolog of the lambda phage transcriptional repressor
cro
. These
cro
/
cI
mutations led to marked (>50-fold) overexpression of three genes encoding a putative ABC transporter. Overexpression of this ABC transporter was both necessary and sufficient for resistance and, notably, circumvented the essentiality of SpsB during
in vitro
culture. Mutation of its predicted ATPase gene abolished resistance, suggesting a possible role for active transport; in these bacteria, resistance to compound 103 occurred with low frequency and through mutations in
spsB
. Bacteria overexpressing the ABC transporter and lacking SpsB were capable of secreting a subset of proteins that are normally cleaved by SpsB and instead were cleaved at a site distinct from the canonical signal peptide. These bacteria secreted reduced levels of virulence-associated proteins and were unable to establish infection in mice. This study reveals the mechanism of resistance to a novel arylomycin derivative and demonstrates that the nominal essentiality of the
S. aureus
signal peptidase can be circumvented by the upregulation of a putative ABC transporter
in vitro
but not
in vivo
.

IMPORTANCE
The type I signal peptidase of
Staphylococcus aureus
(SpsB) enables the secretion of numerous proteins by cleavage of the signal peptide. We synthesized an SpsB inhibitor with potent activity against various clinical
S. aureus
strains. The predominant
S. aureus
strain USA300 develops resistance to this inhibitor by mutations in a novel transcriptional repressor (
cro
/
cI
), causing overexpression of a putative ABC transporter. This mechanism promotes the cleavage and secretion of various proteins independently of SpsB and compensates for the requirement of SpsB for viability
in vitro
. However, bacteria overexpressing the ABC transporter and lacking SpsB secrete reduced levels of virulence-associated proteins and are unable to infect mice. This study describes a bacterial resistance mechanism that provides novel insights into the biology of bacterial secretion.
FtsZ-Dependent Elongation of a Coccoid Bacterium
Authors: Pereira Ana R. , Hsin Jen , Król Ewa , Tavares Andreia C. , Flores Pierre , Hoiczyk Egbert , Ng Natalie , Dajkovic Alex , Brun Yves V. , VanNieuwenhze Michael S. , Roemer Terry , Carballido-Lopez Rut , Scheffers Dirk-Jan , Huang Kerwyn Casey , Pinho Mariana G. 
Published: September 2016

ABSTRACT

A mechanistic understanding of the determination and maintenance of the simplest bacterial cell shape, a sphere, remains elusive compared with that of more complex shapes. Cocci seem to lack a dedicated elongation machinery, and a spherical shape has been considered an evolutionary dead-end morphology, as a transition from a spherical to a rod-like shape has never been observed in bacteria. Here we show that a
Staphylococcus aureus
mutant (M5) expressing the
ftsZ
G193D
allele exhibits elongated cells. Molecular dynamics simulations and
in vitro
studies indicate that FtsZ
G193D
filaments are more twisted and shorter than wild-type filaments.
In vivo
, M5 cell wall deposition is initiated asymmetrically, only on one side of the cell, and progresses into a helical pattern rather than into a constricting ring as in wild-type cells. This helical pattern of wall insertion leads to elongation, as in rod-shaped cells. Thus, structural flexibility of FtsZ filaments can result in an FtsZ-dependent mechanism for generating elongated cells from cocci.

IMPORTANCE
The mechanisms by which bacteria generate and maintain even the simplest cell shape remain an elusive but fundamental question in microbiology. In the absence of examples of coccus-to-rod transitions, the spherical shape has been suggested to be an evolutionary dead end in morphogenesis. We describe the first observation of the generation of elongated cells from truly spherical cocci, occurring in a
Staphylococcus aureus
mutant containing a single point mutation in its genome, in the gene encoding the bacterial tubulin homologue FtsZ. We demonstrate that FtsZ-dependent cell elongation is possible, even in the absence of dedicated elongation machinery.
Redefining the Chronic-Wound Microbiome: Fungal Communities Are Prevalent, Dynamic, and Associated with Delayed Healing
Authors: Kalan Lindsay , Loesche Michael , Hodkinson Brendan P. , Heilmann Kristopher , Ruthel Gordon , Gardner Sue E. , Grice Elizabeth A. 
Published: September 2016

ABSTRACTChronic nonhealing wounds have been heralded as a silent epidemic, causing significant morbidity and mortality especially in elderly, diabetic, and obese populations. Polymicrobial biofilms in the wound bed are hypothesized to disrupt the highly coordinated and sequential events of cutaneous healing. Both culture-dependent and -independent studies of the chronic-wound microbiome have almost exclusively focused on bacteria, omitting what we hypothesize are important fungal contributions to impaired healing and the development of complications. Here we show for the first time that fungal communities (the mycobiome) in chronic wounds are predictive of healing time, associated with poor outcomes, and form mixed fungal-bacterial biofilms. We longitudinally profiled 100, nonhealing diabetic-foot ulcers with high-throughput sequencing of the pan-fungal internal transcribed spacer 1 (ITS1) locus, estimating that up to 80% of wounds contain fungi, whereas cultures performed in parallel captured only 5% of colonized wounds. The “mycobiome” was highly heterogeneous over time and between subjects. Fungal diversity increased with antibiotic administration and onset of a clinical complication. The proportions of the phylumAscomycotawere significantly greater (P= 0.015) at the beginning of the study in wounds that took >8 weeks to heal. Wound necrosis was distinctly associated with pathogenic fungal species, while taxa identified as allergenic filamentous fungi were associated with low levels of systemic inflammation. Directed culturing of wounds stably colonized by pathogens revealed that interkingdom biofilms formed between yeasts and coisolated bacteria. Combined, our analyses provide enhanced resolution of the mycobiome during impaired wound healing, its role in chronic disease, and impact on clinical outcomes.IMPORTANCEWounds are an underappreciated but serious complication for a diverse spectrum of diseases. High-risk groups, such as persons with diabetes, have a 25% lifetime risk of developing a wound that can become chronic. The majority of microbiome research related to chronic wounds is focused on bacteria, but the association of fungi with clinical outcomes remains to be elucidated. Here we describe the dynamic fungal communities in 100 diabetic patients with foot ulcers. We found that communities are unstable over time, but at the first clinical presentation, the relative proportions of different phyla predict healing times. Pathogenic fungi not identified by culture reside in necrotic wounds and are associated with a poor prognosis. In wounds stably colonized by fungi, we identified yeasts capable of forming biofilms in concert with bacteria. Our findings illuminate the associations of the fungal mycobiome with wound prognosis and healing.
Does preoperative depression and/or serotonin transporter gene polymorphism predict outcome after laparoscopic cholecystectomy?
Authors: Wright Barry , Alexander David , Aghahoseini Assad 
Published: September 2016

ObjectiveTo determine whether preoperative psychological depression and/or serotonin transporter gene polymorphism are associated with poor outcomes after the common procedure of laparoscopic cholecystectomy.DesignPatients undergoing laparoscopic cholecystectomy were genotyped for the serotonin transporter gene 5-HTTLPR polymorphism and assessed for psychological morbidity before and 6 weeks after surgery. The main outcome was postoperative depression; secondary outcomes included fatigue, perceived pain, quality of life and subjective perception about return to usual.ResultsFull genetic and psychological data were obtained from 273 out of 330 patients consented to the study (82% female). Significantly fewer people with preoperative depression (Beck Depression Inventory (BDI) score >5) had returned to employment (57% vs 86%, p<0.001) or made a full recovery (11% vs 44%, p<0.001) 6 weeks after surgery. Independent predictors for subjective return to usual after surgery included preoperative depression, body mass index and postoperative pain scores. Independent predictors of postoperative depression included preoperative antidepressant use and preoperative depression. SS genotype was associated with use of antidepressants preoperatively and higher anxiety levels after surgery. However, it was not associated with other salient postoperative psychosocial outcomes.ConclusionsDepressive psychological morbidity preoperatively, pain and body mass index appear to be important factors in predicting recovery after this common surgical procedure. There may be a place to include preoperative brief psychological screening to enable targeted support. Our results suggest that the serotonin transporter gene is unlikely to be a useful clinical predictor of outcome in this group.Trial registration numberISRCTN40219584.
Protocol for a multicentre, prospective, observational cohort study of variation in practice in perioperative analgesic strategies in elective laparoscopic colorectal surgery: the LapCoGesic Study
Authors:   Northern Surgical Trainees Research Association (NoSTRA), Burnell Phillippa , Coates Rachael , Dixon Steven , Grant Lucy , Grey Matthew , Griffiths Ben , Jones Mike , Madhavan Anantha , McCallum Iain , McClean Ross , Naru Karen , Newton Lydia , O'Loughlin Paul , Shaban Fadlo , Sukha Anisha , Somnath Sameer , Shumon Syed , Harji Deena 
Published: September 2016

IntroductionLaparoscopic surgery combined with enhanced recovery programmes has become the gold standard in the elective management of colorectal disease. However, there is no consensus with regard to the optimal perioperative analgesic regime in this cohort of patients, with a number of options available, including thoracic epidural spinal analgesia, patient-controlled analgesia, subcutaneous and/or intraperitoneal local anaesthetics, local anaesthetic wound infiltration catheters and transversus abdominis plane blocks. This study aims to explore any differences in analgesic strategies employed across the North East of England and to assess whether any variation in practice has an impact on clinical outcomes.Methods and analysisAll North East Colorectal units will be recruited for participation by the Northern Surgical Trainees Research Association (NoSTRA). Data will be collected over a consecutive 2-month period. Outcome measures will include postoperative pain score, postoperative opioid analgesic use and side effects, length of stay, 30-day complication rates, 30-day reoperative rates and 30-day readmission rates.Ethics and disseminationEthical approval for this study has been granted by the National Research Ethics Service. The protocol will be disseminated through NoSTRA. Individual unit data will be presented at local meetings. Overall collective data will be published in peer-reviewed journals and presented at relevant surgical meetings.
Predictors of physical functioning after total hip arthroplasty: a systematic review
Authors: Buirs L D , Van Beers L W A H , Scholtes V A B , Pastoors T , Sprague S , Poolman R W 
Published: September 2016

ObjectiveThe objective of this systematic review of the literature was to identify the predictors of functional outcome after total hip arthroplasty (THA).MethodA systematic literature search in Web of Science, CINAHL, EMBASE and PubMed was conducted on 23 June 2015. The articles were selected based on their quality, relevance and measurement of the predictive factor. The level of evidence of all studies was determined using the GRADE rating scheme.ResultsThe initial search resulted in 1092 citations. After application of the inclusion and exclusion criteria, 33 articles met our eligibility criteria and were graded. Included studies were classified as level of evidence low (11), moderate (17) or high (5). Of the included studies, 18 evaluated body mass index (BMI), 17 evaluated preoperative physical functions, 15 evaluated age, 15 evaluated gender and 13 evaluated comorbidity. There was strong evidence suggesting an association between BMI, age, comorbidity, preoperative physical functions and mental health with functional outcome after THA. There was weak evidence suggesting an association between quadriceps strength and education with functional outcome after THA. The evidence was inconsistent for associations with gender and socioeconomic status and functional outcome following THA. We found limited evidence suggesting that alcohol consumption, vitamin D insufficiency and allergies were predictors of functional outcome following THA.ConclusionsWe have identified multiple predictors of functional outcome after THA, which will enable general practitioners and orthopaedic surgeons to better predict the improvement in physical functioning for their patients with THA. They can use this information to provide patient-specific advice regarding the referral for THA and the expected outcomes after THA. Further research with consistent measurement tools, outcomes and duration of follow-up across studies is needed to confirm the influence of these factors.
Effect of religious involvement on cognition from a life-course perspective: protocol for a systematic review and meta-analysis
Authors: Hosseini Shera , Chaurasia Ashok , Cooke Martin , Oremus Mark 
Published: September 2016

IntroductionPreserving cognitive health is a crucial aspect of healthy ageing. Both abnormal and normal cognitive decline can adversely affect the health of ageing populations. Evidence suggests religious involvement (RI) can preserve cognition in ageing populations. The primary purpose of this review is to examine the evidence regarding the association between RI and cognition from a life-course perspective.Methods and analysisThis systematic review and meta-analysis has been registered with PROSPERO (registration number CRD42016032331). We will search MEDLINE, PSYCHINFO and EMBASE, and include primary studies with a comparison group, for example, cohort, cross-sectional and case–control studies. To supplement the database search, we will also search the grey literature and the reference lists of included studies. Two reviewers will independently assess and extract data from the articles. Risk of bias and the strength of evidence will be assessed. For sufficiently homogeneous data in domains such as study methods and measures of RI and cognition, we will pool the results using DerSimonian and Laird meta-analysis.Ethics and disseminationSince this is a protocol for a systematic review, ethics approval is not required. The findings of this review will be extensively disseminated through peer-reviewed publications and conference presentations.
Sodium channel-inhibiting drugs and cancer survival: protocol for a cohort study using the CPRD primary care database
Authors: Fairhurst Caroline , Martin Fabiola , Watt Ian , Doran Tim , Bland Martin , Brackenbury William J 
Published: September 2016

IntroductionVoltage-gated sodium channel (VGSC)-inhibiting drugs are commonly used to treat epilepsy and cardiac arrhythmia. VGSCs are also widely expressed in various cancers, including those of the breast, bowel and prostate. A number of VGSC-inhibiting drugs have been shown to inhibit cancer cell proliferation, invasion, tumour growth and metastasis in preclinical models, suggesting that VGSCs may be novel molecular targets for cancer treatment. Surprisingly, we previously found that prior exposure to VGSC-inhibiting drugs may be associated with reduced overall survival in patients with cancer, but we were unable to control for the cause of death or indication for prescription. The purpose of the present study is to interrogate a different database to further investigate the relationship between VGSC-inhibiting drugs and cancer-specific survival.Methods and analysisA cohort study using primary care data from the Clinical Practice Research Datalink database will include patients with diagnosis of breast, bowel and prostate cancer (13 000). The primary outcome will be cancer-specific survival from the date of cancer diagnosis. Cox proportional hazards regression will be used to compare survival of patients taking VGSC-inhibiting drugs (including antiepileptic drugs and class I antiarrhythmic agents) with patients with cancer not taking these drugs, adjusting for cancer type, age and sex. Drug exposure will be treated as a time-varying covariate to account for potential immortal time bias. Various sensitivity and secondary analyses will be performed.Ethics and disseminationThe project has been reviewed and approved by the University of York Ethical Review Process. Results will be presented at an international conference and published in open access peer-reviewed journals according to the STROBE and RECORD guidelines.
Cost-effectiveness of screening for hepatitis C virus: a systematic review of economic evaluations
Authors: Coward Stephanie , Leggett Laura , Kaplan Gilaad G , Clement Fiona 
Published: September 2016

ObjectivesWith the developments of near-cures for hepatitis C virus (HCV), who to screen has become a high-priority policy issue in many western countries. Cost-effectiveness of screening programmes should be one consideration when developing policy. The objective of this work is to synthesise the cost-effectiveness of HCV screening programmes.SettingA systematic review was completed. 5 databases were searched until May 2016 (NHSEED, MEDLINE, the HTA Health Technology Assessment Database, EMBASE, EconLit).ParticipantsAny study reporting an economic evaluation (any type) of screening compared with opportunistic or no screening for HCV was included. Exclusion criteria were: (1) abstracts or commentaries, (2) economic evaluations of other interventions for HCV, including blood donors screening, diagnosis tests for HCV, screening for concurrent disease or medications for treatment.Primary and secondary outcome measuresData extraction included type of model, target population, perspective, comparators, time horizon, discount rate, clinical inputs, cost inputs and outcome. Quality was evaluated using the Consolidated Health Economic Evaluation Reporting Standards checklist. Data are summarised using narrative synthesis by population.Results2305 abstracts were identified with 52 undergoing full-text review. 30 papers met inclusion criteria addressing 7 populations: drug users (n=6), high risk (n=5), pregnant (n=4), prison (n=3), birth cohort (n=8), general population (n=5) and other (n=6). The majority (77%) of the studies were high quality. Drug users, birth cohort and high-risk populations were associated with cost-effectiveness ratios of under £30 000 per quality-adjusted-life-year (QALY). The remaining populations were associated with cost-effectiveness ratios that exceeded £30 000 per QALY.ConclusionsEconomic evidence for screening populations is robust. If a cost per QALY of £30 000 is considered reasonable value for money, then screening birth cohorts, drug users and high-risk populations are policy options that should be considered.
Environmental factors and cardiovascular diseases: the association of income inequality and green spaces in elderly residents of São Paulo, Brazil
Authors: Massa Kaio Henrique Correa , Pabayo Roman , Lebrão Maria Lúcia , Chiavegatto Filho Alexandre Dias Porto 
Published: September 2016

ObjectiveWe aimed to analyse the individual and contextual determinants associated with cardiovascular diseases (CVDs) morbidity among the elderly.MethodsThe sample consisted of 1333 individuals aged 60 or older residing in the city of São Paulo, from the Health, Welfare and Aging (SABE) study survey performed in 2010. The association between CVD with both income inequality and green spaces was analysed using Bayesian multilevel models, controlling for individual and contextual factors.ResultsWe found a significant association between income inequality and green spaces, and risk of CVD. In comparison to elderly residents in areas with low-income inequality, there was an increased risk for CVD among those residing in the medium–low (OR=1.35, 95% CI 1.15 to 1.59), medium–high (OR=2.71, 95% CI 2.18 to 3.36) and high (OR=1.43, 95% CI 1.14 to 1.79) quartiles of income inequality. Those living in medium–low (OR=0.44, 95% CI 0.39 to 0.49), medium–high (OR=0.56, 95% CI 0.48 to 0.65) and high (OR=0.48, 95% CI 0.43 to 0.55) green spaces levels had lower risk of CVD.ConclusionsThese findings highlight the importance of area-level characteristics on CVD risk and the need to develop healthcare policies focused on the effect of individual and contextual characteristics.