bluuebunny/crossref_metadata_2025_split huggingface dataset:
Terbinafine Resistance of Trichophyton Clinical Isolates Caused by Specific Point Mutations in the Squalene Epoxidase Gene
Authors: Yamada Tsuyoshi , Maeda Mari , Alshahni Mohamed Mahdi , Tanaka Reiko , Yaguchi Takashi , Bontems Olympia , Salamin Karine , Fratti Marina , Monod Michel 
Published: April 2017

ABSTRACT

Terbinafine is one of the allylamine antifungal agents whose target is squalene epoxidase (SQLE). This agent has been extensively used in the therapy of dermatophyte infections. The incidence of patients with tinea pedis or unguium tolerant to terbinafine treatment prompted us to screen the terbinafine resistance of all
Trichophyton
clinical isolates from the laboratory of the Centre Hospitalier Universitaire Vaudois collected over a 3-year period and to identify their mechanism of resistance. Among 2,056 tested isolates, 17 (≈1%) showed reduced terbinafine susceptibility, and all of these were found to harbor
SQLE
gene alleles with different single point mutations, leading to single amino acid substitutions at one of four positions (Leu
393
, Phe
397
, Phe
415
, and His
440
) of the SQLE protein. Point mutations leading to the corresponding amino acid substitutions were introduced into the endogenous
SQLE
gene of a terbinafine-sensitive
Arthroderma vanbreuseghemii
(formerly
Trichophyton mentagrophytes
) strain. All of the generated
A. vanbreuseghemii
transformants expressing mutated SQLE proteins exhibited obvious terbinafine-resistant phenotypes compared to the phenotypes of the parent strain and of transformants expressing wild-type SQLE proteins. Nearly identical phenotypes were also observed in
A. vanbreuseghemii
transformants expressing mutant forms of
Trichophyton rubrum
SQLE proteins. Considering that the genome size of dermatophytes is about 22 Mb, the frequency of terbinafine-resistant clinical isolates was strikingly high. Increased exposure to antifungal drugs could favor the generation of resistant strains.
Colistin-Resistant
mcr-1
-Positive Escherichia coli on Public Beaches, an Infectious Threat Emerging in Recreational Waters
Authors: Fernandes Miriam R. , Sellera Fábio P. , Esposito Fernanda , Sabino Caetano P. , Cerdeira Louise , Lincopan Nilton 
Published: April 2017

ABSTRACT

The emergence and rapid spread of colistin-resistant
Escherichia coli
carrying the
mcr-1
gene have generated an urgent need to strengthen surveillance. We performed a meticulous investigation of strains of this sort, which resulted in the identification of international clones of
E. coli
carrying IncX4-plasmid-mediated
mcr-1
and
bla
CTX-M
genes in recreational waters of public urban beaches in cities with high tourist turnover, highlighting a new environmental reservoir.
Mycobacterium tuberculosis Proteome Response to Antituberculosis Compounds Reveals Metabolic “Escape” Pathways That Prolong Bacterial Survival
Authors: Danelishvili Lia , Shulzhenko Natalia , Chinison Jessica J. J. , Babrak Lmar , Hu Jialu , Morgun Andriy , Burrows Gregory , Bermudez Luiz E. 
Published: April 2017

ABSTRACT

Tuberculosis (TB) continues to be one of the most common bacterial infectious diseases and is the leading cause of death in many parts of the world. A major limitation of TB therapy is slow killing of the infecting organism, increasing the risk for the development of a tolerance phenotype and drug resistance. Studies indicate that
Mycobacterium tuberculosis
takes several days to be killed upon treatment with lethal concentrations of antibiotics both
in vitro
and
in vivo
. To investigate how metabolic remodeling can enable transient bacterial survival during exposure to bactericidal concentrations of compounds,
M. tuberculosis
strain H37Rv was exposed to twice the MIC of isoniazid, rifampin, moxifloxacin, mefloquine, or bedaquiline for 24 h, 48 h, 4 days, and 6 days, and the bacterial proteomic response was analyzed using quantitative shotgun mass spectrometry. Numerous sets of
de novo
bacterial proteins were identified over the 6-day treatment. Network analysis and comparisons between the drug treatment groups revealed several shared sets of predominant proteins and enzymes simultaneously belonging to a number of diverse pathways. Overexpression of some of these proteins in the nonpathogenic
Mycobacterium smegmatis
extended bacterial survival upon exposure to bactericidal concentrations of antimicrobials, and inactivation of some proteins in
M. tuberculosis
prevented the pathogen from escaping the fast killing
in vitro
and in macrophages, as well. Our biology-driven approach identified promising bacterial metabolic pathways and enzymes that might be targeted by novel drugs to reduce the length of tuberculosis therapy.
Efflux Attenuates the Antibacterial Activity of Q203 in Mycobacterium tuberculosis
Authors: Jang Jichan , Kim Ryangyeo , Woo Minjeong , Jeong Jinsun , Park Da Eun , Kim Guehye , Delorme Vincent 
Published: April 2017

ABSTRACT

New and improved treatments for tuberculosis (TB) are urgently needed. Recently, it has been demonstrated that verapamil, an efflux inhibitor, can reduce bacterial drug tolerance caused by efflux pump activity when administered in combination with available antituberculosis agents. The aim of this study was to evaluate the effectiveness of verapamil in combination with the antituberculosis drug candidate Q203, which has recently been developed and is currently under clinical trials as a potential antituberculosis agent. We evaluated changes in Q203 activity in the presence and absence of verapamil
in vitro
using the resazurin microplate assay and
ex vivo
using a microscopy-based phenotypic assay for the quantification of intracellular replicating mycobacteria. Verapamil increased the potency of Q203 against
Mycobacterium tuberculosis
both
in vitro
and
ex vivo
, indicating that efflux pumps are associated with the activity of Q203. Other efflux pump inhibitors also displayed an increase in Q203 potency, strengthening this hypothesis. Therefore, the combination of verapamil and Q203 may be a promising combinatorial strategy for anti-TB treatment to accelerate the elimination of
M. tuberculosis
.
Spheres of Hope, Packets of Doom: the Good and Bad of Outer Membrane Vesicles in Interspecies and Ecological Dynamics
Authors: Lynch Jonathan B. , Alegado Rosanna A. 
Published: April 2017

ABSTRACT
Outer membrane vesicles (OMVs) are proteoliposome nanoparticles ubiquitously produced by Gram-negative bacteria. Typically bearing a composition similar to those of the outer membrane and periplasm of the cells from which they are derived, OMVs package an array of proteins, lipids, and nucleic acids. Once considered inconsequential by-products of bacterial growth, OMVs have since been demonstrated to mediate cellular stress relief, promote horizontal gene transfer and antimicrobial activity, and elicit metazoan inflammation. Recently, OMVs have gained appreciation as critical moderators of interorganismal dynamics. In this review, we focus on recent progress toward understanding the functions of OMVs with regard to symbiosis and ecological contexts, and we propose potential avenues for future OMV studies.
Distinct Domains of CheA Confer Unique Functions in Chemotaxis and Cell Length in Azospirillum brasilense Sp7
Authors: Gullett Jessica M. , Bible Amber , Alexandre Gladys 
Published: April 2017

ABSTRACT

Chemotaxis is the movement of cells in response to gradients of diverse chemical cues. Motile bacteria utilize a conserved chemotaxis signal transduction system to bias their motility and navigate through a gradient. A central regulator of chemotaxis is the histidine kinase CheA. This cytoplasmic protein interacts with membrane-bound receptors, which assemble into large polar arrays, to propagate the signal. In the alphaproteobacterium
Azospirillum brasilense
, Che1 controls transient increases in swimming speed during chemotaxis, but it also biases the cell length at division. However, the exact underlying molecular mechanisms for Che1-dependent control of multiple cellular behaviors are not known. Here, we identify specific domains of the CheA1 histidine kinase implicated in modulating each of these functions. We show that CheA1 is produced in two isoforms: a membrane-anchored isoform produced as a fusion with a conserved seven-transmembrane domain of unknown function (TMX) at the N terminus and a soluble isoform similar to prototypical CheA. Site-directed and deletion mutagenesis combined with behavioral assays confirm the role of CheA1 in chemotaxis and implicate the TMX domain in mediating changes in cell length. Fluorescence microscopy further reveals that the membrane-anchored isoform is distributed around the cell surface while the soluble isoform localizes at the cell poles. Together, the data provide a mechanism for the role of Che1 in controlling multiple unrelated cellular behaviors via acquisition of a new domain in CheA1 and production of distinct functional isoforms.

IMPORTANCE
Chemotaxis provides a significant competitive advantage to bacteria in the environment, and this function has been transferred laterally multiple times, with evidence of functional divergence in different genomic contexts. The molecular principles that underlie functional diversification of chemotaxis in various genomic contexts are unknown. Here, we provide a molecular mechanism by which a single CheA protein controls two unrelated functions: chemotaxis and cell length. Acquisition of this multifunctionality is seemingly a recent evolutionary event. The findings illustrate a mechanism by which chemotaxis function may be co-opted to regulate additional cellular functions.
Prognostication in critically ill patients with severe traumatic brain injury: the TBI-Prognosis multicentre feasibility study
Authors: Turgeon Alexis F , Lauzier François , Zarychanski Ryan , Fergusson Dean A , Léger Caroline , McIntyre Lauralyn A , Bernard Francis , Rigamonti Andrea , Burns Karen , Griesdale Donald E , Green Robert , Scales Damon C , Meade Maureen O , Savard Martin , Shemilt Michèle , Paquet Jérôme , Gariépy Jean-Luc , Lavoie André , Reddy Kesh , Jichici Draga , Pagliarello Giuseppe , Zygun David , Moore Lynne 
Published: April 2017

ObjectiveSevere traumatic brain injury is a significant cause of morbidity and mortality in young adults. Assessing long-term neurological outcome after such injury is difficult and often characterised by uncertainty. The objective of this feasibility study was to establish the feasibility of conducting a large, multicentre prospective study to develop a prognostic model of long-term neurological outcome in critically ill patients with severe traumatic brain injury.DesignA prospective cohort study.Setting9 Canadian intensive care units enrolled patients suffering from acute severe traumatic brain injury. Clinical, biological, radiological and electrophysiological data were systematically collected during the first week in the intensive care unit. Mortality and functional outcome (Glasgow Outcome Scale extended) were assessed on hospital discharge, and then 3, 6 and 12 months following injury.OutcomesThe compliance to protocolised test procedures was the primary outcome. Secondary outcomes were enrolment rate and compliance to follow-up.ResultsWe successfully enrolled 50 patients over a 12-month period. Most patients were male (80%), with a median age of 45 years (IQR 29.0–60.0), a median Injury Severity Score of 38 (IQR 25–50) and a Glasgow Coma Scale of 6 (IQR 3–7). Mortality was 38% (19/50) and most deaths occurred following a decision to withdraw life-sustaining therapies (18/19). The main reasons for non-enrolment were the time window for inclusion being after regular working hours (35%, n=23) and oversight (24%, n=16). Compliance with protocolised test procedures ranged from 92% to 100% and enrolment rate was 43%. No patients were lost to follow-up at 6 months and 2 were at 12 months.ConclusionsIn this multicentre prospective feasibility study, we achieved feasibility objectives pertaining to compliance to test, enrolment and follow-up. We conclude that the TBI-Prognosis prospective multicentre study in severe traumatic brain injury patients in Canada is feasible.
Has the role of personal income in alcohol drinking among teenagers changed between 1983 and 2013: a series of nationally representative surveys in Finland
Authors: Lintonen Tomi , Nevalainen Jaakko 
Published: April 2017

ObjectiveAffordability is known to be a key determinant of alcohol consumption, possibly even more important in adolescence. Relating adolescent drinking pattern developments over a period of time to trends in adolescent income can yield information on the significance of parental control of adolescent income.DesignBiannual repeated cross-sectional surveys.SettingNationally representative samples.Participants14-year-old adolescents in the period 1983–2013 in Finland (N=33 771).ResultsAdolescents' alcohol drinking pattern was significantly associated with their disposable income. The OR for monthly drunkenness versus abstinence was 6.6 (95% CI 5.0 to 8.8) among girls and 9.0 (6.3 to 13.0) among boys in the highest income group compared with the lowest. However, the association between income and drinking pattern weakened considerably during the 30-year period.ConclusionsDisposable income has been a significant predictor of adolescent alcohol drinking in the past 30 years. However, in the recent years, the amount of disposable money has decreased in importance.
Cluster randomised controlled trial of a consumer behaviour intervention to improve healthy food purchases from online canteens: study protocol
Authors: Delaney Tessa , Wyse Rebecca , Yoong Sze Lin , Sutherland Rachel , Wiggers John , Ball Kylie , Campbell Karen , Rissel Chris , Wolfenden Luke 
Published: April 2017

IntroductionSchool canteens represent an opportune setting in which to deliver public health nutrition strategies given their wide reach, and frequent use by children. Online school canteen ordering systems, where students order and pay for their lunch online, provide an avenue to improve healthy canteen purchases through the application of consumer behaviour strategies that impact on purchasing decisions. The aim of this study is to assess the efficacy of a consumer behaviour intervention implemented in an online school canteen ordering system in reducing the kilojoule, saturated fat, sugar and sodium content of primary student lunch orders.Methods and analysisThe study will employ a cluster randomised controlled trial design. Approximately 1040 students (aged 5–12 years) from 10 primary schools in New South Wales, Australia, currently using an online canteen ordering system will be invited to participate. Schools will be randomised in a 1:1 ratio to receive either the intervention (enhanced system) or control (standard online ordering only). The intervention will include evidence-based strategies shown to influence healthy food purchasing (strategies targeting availability, menu labelling, placement and prompting). The primary outcomes of the trial will be the mean content per student online lunch order of (1) energy (kJ), (2) saturated fat (g), (3) sugar (g) and (4) sodium (mg). The impact of the intervention will be determined by between-group assessment of the nutritional content of lunch purchases over a 2-month period postintervention initiation.Ethics and disseminationThe study was approved by the Hunter New England Human Research Ethics Committee, University of Newcastle Human Research Ethics Committee and New South Wales Department of Education and School Communities. Study findings will be disseminated widely through peer-reviewed publications and relevant presentations in international conferences and to stakeholders.Trial registration numberACTRN12616000499482.
Absent progesterone receptor expression in the lymph node metastases of ER-positive, HER2-negative breast cancer is associated with relapse on tamoxifen
Authors: Snell Cameron E , Gough Madeline , Middleton Kathryn , Hsieh Michael , Furnas Lauren , Seidl Brenton , Gibbons Kristen , Pyke Christopher , Shannon Catherine , Woodward Natasha , Armes Jane E 
Published: April 2017

AimsProgesterone receptor (PR) expression is prognostic in early stage breast cancer. There are several reports of discordant expression between primary tumour and axillary lymph node (ALN) metastasis expression of oestrogen receptor (ER) and PR. We sought to determine whether expression of these biomarkers in the synchronous ALN metastases of ER positive (+), HER2 negative (−) breast cancer could provide more accurate prognostic information.MethodsThe retrospective cohort included 229 patients from a single institution with ER+, HER2− breast cancer who had synchronous ALN metastatic disease (2005–2014). PR expression was correlated with relapse-free survival, and subset analysis was performed for patients who received adjuvant tamoxifen or an aromatase inhibitor.ResultsOne patient had an ER+ primary tumour, which was ER− in the ALN metastasis. 27 (11.3%) were PR− in the primary tumour and 56 (23.6%) in the ALN metastasis. The predominant change was from PR+ in the primary tumour to PR− in the lymph node. Absence of PR expression in the ALN was significantly associated with relapse; however, this was not the case in the primary tumour. In a subset analysis of patients taking adjuvant endocrine therapy, poorer prognosis was limited to those with PR− metastases on tamoxifen (HR=5.203, 95% CI 1.649 to 16.416, p=0.005). No significant prognostic effect of PR− metastases in patients taking aromatase inhibitors was seen (HR=1.519, 95% CI 0.675 to 3.418, p=0.312).ConclusionsEvaluation of PR expression in ALN metastasis may enable prediction of patients who are less likely to benefit from adjuvant tamoxifen. This study should be replicated in other cohorts.
Association between smoking and health outcomes in an economically deprived population: the Liverpool Lung Project
Authors: Sherratt F C , Field J K , Marcus M W 
Published: April 2017

BackgroundThe association between smoking and several health outcomes among those from the most deprived communities in the UK has not previously been detailed. The aim of this study is to examine the impact of smoking on health outcomes specifically among a particularly deprived population in a developed country (Liverpool; one of the most deprived local authorities in England).MethodsThe Liverpool Lung Project recruited a prospective cohort of 8753 participants from across Liverpool, aged 45–79 years between 1998 and 2008. Participants were followed annually through the Hospital Episode Statistics until 31 January 2013. Logistic regression models were used to identify health outcomes of smoking.ResultsFrom our study population, 5195 were smokers and 3558 were non-smokers. Smoking was associated with male gender (OR 1.62, 95% CI 1.48 to 1.77), pneumonia (1.28, 95% CI 1.10 to 1.49), chronic obstructive pulmonary disease (1.30, 95% CI 1.14 to 1.48), emphysema (5.46, 95% CI 3.48 to 8.55), bronchitis (1.85, 95% CI 1.65 to 2.07), other cancers (1.69, 95% CI 1.44 to 1.99), lung cancer (6.0, 95% CI 3.72 to 9.69), diabetes (1.21, 95% CI 1.02 to 1.43) and cardiovascular disease (1.45, 95% CI 1.25 to 1.67).ConclusionsSmokers from deprived backgrounds in Liverpool showed increased risk of developing pneumonia, emphysema, chronic obstructive pulmonary disease, bronchitis, lung cancer, other types of cancer, cardiovascular disease and diabetes. These findings are in line with the literature and may help to inform public health policies and ultimately work towards addressing smoking-related health inequalities.
Changes in directly alcohol-attributable mortality during the great recession by employment status in Spain: a population cohort of 22 million people
Authors: Alonso Ignacio , Vallejo Fernando , Regidor Enrique , Belza M José , Sordo Luis , Otero-García Laura , Barrio Gregorio 
Published: April 2017

BackgroundMacroeconomic fluctuations can impact differentially on alcohol-related problems across sociodemographic groups. We assess trend changes in directly alcohol-attributable (DAA) mortality in the population aged 25–64 during the post-2008 recession in Spain according to employment status and other sociodemographic factors.MethodsNationwide cohort study covering 21.9 million people living in Spain in 2001. People were classified by employment status and other factors. The annual percentage change (APC) in mortality rates during 2002–2007 (precrisis) and 2008–2011 (crisis) was estimated by the Poisson regression. The period effect size was then calculated as the difference between crisis and precrisis APCs.ResultsThe age-adjusted APCs in DAA mortality were 6.9% in 2002–2007 and 3.7% in 2008–2011 among employed people, and −4.3% and −0.4%, respectively, among non-employed people. Statistically significant trend changes in such mortality during the crisis were found, which were favourable in certain employed subgroups (manual workers and employees aged 25–49), and unfavourable in the total non-employed population and certain non-employed subgroups (men, non-married and especially medium/high-wealth people). The greatest unfavourable change corresponded to non-employed people living in households of 72–104 m2who had 2 or more cars. Favourable changes were also found in the remaining employed subgroups, especially women and non-married people, although they did not reach statistical significance.ConclusionsOur findings suggest that the post-2008 Spanish crisis had a heterogeneous impact across sociodemographic subgroups on DAA mortality, and that employment status seemed to have an important effect. The impact was especially unfavourable on the non-employed, particularly those with substantial material wealth.
Activation of NOTCH Signaling by Tenascin-C Promotes Growth of Human Brain Tumor-Initiating Cells
Authors: Sarkar Susobhan , Mirzaei Reza , Zemp Franz J. , Wei Wu , Senger Donna L. , Robbins Stephen M. , Yong V. Wee 
Published: April 2017

Abstract
Oncogenic signaling by NOTCH is elevated in brain tumor-initiating cells (BTIC) in malignant glioma, but the mechanism of its activation is unknown. Here we provide evidence that tenascin-C (TNC), an extracellular matrix protein prominent in malignant glioma, increases NOTCH activity in BTIC to promote their growth. We demonstrate the proximal localization of TNC and BTIC in human glioblastoma specimens and in orthotopic murine xenografts of human BTIC implanted intracranially. In tissue culture, TNC was superior amongst several extracellular matrix proteins in enhancing the sphere-forming capacity of glioma patient-derived BTIC. Exogenously applied or autocrine TNC increased BTIC growth through an α2β1 integrin-mediated mechanism that elevated NOTCH ligand Jagged1 (JAG1). Microarray analyses and confirmatory PCR and Western analyses in BTIC determined that NOTCH signaling components including JAG1, ADAMTS15, and NICD1/2 were elevated in BITC after TNC exposure. Inhibition of γ-secretase and metalloproteinase proteolysis in the NOTCH pathway, or silencing of α2β1 integrin or JAG1, reduced the proliferative effect of TNC on BTIC. Collectively, our findings identified TNC as a pivotal initiator of elevated NOTCH signaling in BTIC and define the establishment of a TN-α2β1-JAG1-NOTCH signaling axis as a candidate therapeutic target in glioma patients. Cancer Res; 77(12); 3231–43. ©2017 AACR.