bluuebunny/crossref_metadata_2025_split huggingface dataset:
Transcriptional Repressor PtvR Regulates Phenotypic Tolerance to Vancomycin in Streptococcus pneumoniae
Authors: Liu Xue , Li Jing-Wen , Feng Zhixing , Luo Youfu , Veening Jan-Willem , Zhang Jing-Ren 
Published: May 2017

ABSTRACT

Reversible or phenotypic tolerance to antibiotics within microbial populations has been implicated in treatment failure of chronic infections and development of persister cells. However, the molecular mechanisms regulating phenotypic drug tolerance are largely unknown. In this study, we identified a four-gene operon in
Streptococcus pneumoniae
that contributes to
p
henotypic
t
olerance to
v
ancomycin (
ptv
). RNA sequencing, quantiative reverse transcriptase PCR, and transcriptional luciferase reporter experiments revealed that transcription of the
ptv
operon (consisting of
ptvR
,
ptvA
,
ptvB
, and
ptvC
) is induced by exposure to vancomycin. Further investigation showed that transcription of the
ptv
operon is repressed by PtvR, a PadR family repressor. Transcriptional induction of the
ptv
operon by vancomycin was achieved by transcriptional derepression of this locus, which was mediated by PtvR. Importantly, fully derepressing
ptvABC
by deleting
ptvR
or overexpressing the
ptv
operon with an exogenous promoter significantly enhanced vancomycin tolerance. Gene deletion analysis revealed that PtvA, PtvB, and PtvC are all required for the PtvR-regulated phenotypic tolerance to vancomycin. Finally, the results of an electrophoretic mobility shift assay with recombinant PtvR showed that PtvR represses the transcription of the
ptv
operon by binding to two palindromic sequences within the
ptv
promoter. Together, the
ptv
locus represents an inducible system in
S. pneumoniae
in response to stressful conditions, including those caused by antibiotics.

IMPORTANCE
Reversible or phenotypic tolerance to antibiotics within microbial populations is associated with treatment failure of bacterial diseases, but the underlying mechanisms regulating phenotypic drug tolerance remain obscure. This study reports our finding of a multigene locus that contributes to inducible tolerance to vancomycin in
Streptococcus pneumoniae
, an important opportunistic human pathogen. The vancomycin tolerance phenotype depends on the PtvR transcriptional repressor and three predicted membrane-associated proteins encoded by the
ptv
locus. This represents the first example of a gene locus in
S. pneumoniae
that is responsible for antibiotic tolerance and has important implications for further understanding bacterial responses and phenotypic tolerance to antibiotic treatment in this and other pathogens.
A Proteomic Signature of Dormancy in the Actinobacterium Micrococcus luteus
Authors: Mali Sujina , Mitchell Morgan , Havis Spencer , Bodunrin Abiodun , Rangel Jonathan , Olson Gabriella , Widger William R. , Bark Steven J. 
Published: May 2017

ABSTRACT

Dormancy is a protective state in which diverse bacteria, including
Mycobacterium tuberculosis
,
Staphylococcus aureus
,
Treponema pallidum
(syphilis), and
Borrelia burgdorferi
(Lyme disease), curtail metabolic activity to survive external stresses, including antibiotics. Evidence suggests dormancy consists of a continuum of interrelated states, including viable but nonculturable (VBNC) and persistence states. VBNC and persistence contribute to antibiotic tolerance, reemergence from latent infections, and even quorum sensing and biofilm formation. Previous studies indicate that the protein mechanisms regulating persistence and VBNC states are not well understood. We have queried the VBNC state of
Micrococcus luteus
NCTC 2665 (MI-2665) by quantitative proteomics combining gel electrophoresis, high-performance liquid chromatography, and tandem mass spectrometry to elucidate some of these mechanisms. MI-2665 is a nonpathogenic actinobacterium containing a small (2.5-Mb), high-GC-content genome which exhibits a well-defined VBNC state induced by nutrient deprivation. The MI-2665 VBNC state demonstrated a loss of protein diversity accompanied by increased levels of 18 proteins that are conserved across actinobacteria, 14 of which have not been previously identified in VNBC. These proteins implicate an anaplerotic strategy in the transition to VBNC, including changes in the glyoxylate shunt, redox and amino acid metabolism, and ribosomal regulatory processes. Our data suggest that MI-2665 is a viable model for dissecting the protein mechanisms underlying the VBNC stress response and provide the first protein-level signature of this state. We expect that this protein signature will enable future studies deciphering the protein mechanisms of dormancy and identify novel therapeutic strategies effective against antibiotic-tolerant bacterial infections.

IMPORTANCE
Dormancy is a protective state enabling bacteria to survive antibiotics, starvation, and the immune system. Dormancy is comprised of different states, including persistent and viable but nonculturable (VBNC) states that contribute to the spread of bacterial infections. Therefore, it is imperative to identify how bacteria utilize these different dormancy states to survive antibiotic treatment. The objective of our research is to eliminate dormancy as a route to antibiotic tolerance by understanding the proteins that control dormancy in
Micrococcus luteus
NCTC 2665. This bacterium has unique advantages for studying dormancy, including a small genome and a well-defined and reproducible VBNC state. Our experiments implicate four previously identified and 14 novel proteins upregulated in VBNC that may regulate this critical survival mechanism.
Comparison of four Fitbit and Jawbone activity monitors with a research-grade ActiGraph accelerometer for estimating physical activity and energy expenditure
Authors: Imboden Mary T , Nelson Michael B , Kaminsky Leonard A , Montoye Alexander HK 
Published: May 2017

Background/aimConsumer-based physical activity (PA) monitors have become popular tools to track PA behaviours. Currently, little is known about the validity of the measurements provided by consumer monitors. We aimed to compare measures of steps, energy expenditure (EE) and active minutes of four consumer monitors with one research-grade accelerometer within a semistructured protocol.MethodsThirty men and women (18–80 years old) wore Fitbit One (worn at the waist), Fitbit Zip (waist), Fitbit Flex (wrist), Jawbone UP24 (wrist) and one waist-worn research-grade accelerometer (ActiGraph) while participating in an 80 min protocol. A validated EE prediction equation and active minute cut-points were applied to ActiGraph data. Criterion measures were assessed using direct observation (step count) and portable metabolic analyser (EE, active minutes). A repeated measures analysis of variance (ANOVA) was used to compare differences between consumer monitors, ActiGraph, and criterion measures. Similarly, a repeated measures ANOVA was applied to a subgroup of subjects who didn’t cycle.ResultsParticipants took 3321±571 steps, had 28±6 active min and expended 294±56 kcal based on criterion measures. Comparatively, all monitors underestimated steps and EE by 13%–32% (p<0.01); additionally the Fitbit Flex, UP24, and ActiGraph underestimated active minutes by 35%–65% (p<0.05). Underestimations of PA and EE variables were found to be similar in the subgroup analysis.ConclusionConsumer monitors had similar accuracy for PA assessment as the ActiGraph, which suggests that consumer monitors may serve to track personal PA behaviours and EE. However, due to discrepancies among monitors, individuals should be cautious when comparing relative and absolute differences in PA values obtained using different monitors.
Reduced first-phase insulin secretion increases postprandial lipidemia in subjects with impaired glucose tolerance
Authors: Gómez-Sámano Miguel Ángel , Cuevas-Ramos Daniel , Grajales-Gómez Mariana , Escamilla-Márquez Marco , López-Estrada Angelina , Guillén-Pineda Luz Elizabeth , López-Carrasco Guadalupe , Gómez-Pérez Francisco J 
Published: May 2017

ObjectiveIt is not clear which phase of insulin secretion is more important to regulate lipoprotein lipase (LPL) activity. After a meal, insulin is released and acts as a major regulator of LPL activity. Postprandial hyperlipidemia is a common comorbidity in subjects with insulin resistance (IR). Therefore this study aimed to evaluate the role of the first-phase insulin secretion (FPIS) on postprandial lipidemia in subjects with IR and impaired glucose tolerance (IGT).Research design and methodsThis is a cross-sectional, observational and comparative study. We included male and female subjects between 40 and 60 years with a body mass index (BMI) between 23 and 30 kg/m2. Then, patients were divided into three groups. Group 1 consisted of control subjects with normal glucose tolerance and preserved FPIS. Group 2 included patients with IGT and a reduced FPIS. Group 3 consisted of subjects with IGT but normal FPIS. Both groups were paired by age and BMI with subjects in the control group. Subjects underwent an intravenous glucose tolerance test to classify each case, and then a load with a mixed meal load to measure postprandial lipidemia.ResultsA total of 32 subjects were evaluated: 10 were control subjects, 8 subjects with IGT with a reduced FPIS and 14 subjects with IGT and preserved FPIS. After administration of a standardized meal, group 2 showed a greater glucose area under the curve (AUC) at 30 and 120 min (p=0.001, for both). This group also showed a statistically significant increase (p<0.001) in triglyceride AUC.ConclusionsA reduced FPIS is significantly and independently associated with a larger postprandial hyperlipidemia in subjects with IGT.
Coffee, including caffeinated and decaffeinated coffee, and the risk of hepatocellular carcinoma: a systematic review and dose–response meta-analysis
Authors: Kennedy Oliver John , Roderick Paul , Buchanan Ryan , Fallowfield Jonathan Andrew , Hayes Peter Clive , Parkes Julie 
Published: May 2017

ObjectivesTo examine the association between coffee, including caffeinated and decaffeinated coffee, with hepatocellular carcinoma (HCC) and assess the influence of HCC aetiology and pre-existing liver disease.DesignWe performed a systematic review and meta-analysis. We calculated relative risks (RRs) of HCC according to caffeinated and decaffeinated coffee consumption using a random-effects dose–response meta-analysis. We tested for modification of the effect estimate by HCC aetiology and pre-existing liver disease. We judged the quality of evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) criteria.ResultsWe found 18 cohorts, involving 2 272 642 participants and 2905 cases, and 8 case–control studies, involving 1825 cases and 4652 controls. An extra two cups per day of coffee was associated with a 35% reduction in the risk of HCC (RR 0.65, 95% CI 0.59 to 0.72). The inverse association was weaker for cohorts (RR 0.71, 95% CI 0.65 to 0.77), which were generally of higher quality than case–control studies (RR 0.53, 95% CI 0.41 to 0.69). There was evidence that the association was not significantly altered by stage of liver disease or the presence/absence of high alcohol consumption, high body mass index, type 2 diabetes mellitus, smoking, or hepatitis B and C viruses. An extra two cups of caffeinated and decaffeinated coffee (2 and 3 cohort studies, respectively) were associated with reductions of 27% (RR 0.73, 95% CI 0.63 to 0.85) and 14% (RR 0.86, 95% CI 0.74 to 1.00) in the risk of HCC. However, due to a lack of randomised controlled trials, potential publication bias and there being no accepted definition of coffee, the quality of evidence under the GRADE criteria was ‘very low’.ConclusionsIncreased consumption of caffeinated coffee and, to a lesser extent, decaffeinated coffee are associated with reduced risk of HCC, including in pre-existing liver disease. These findings are important given the increasing incidence of HCC globally and its poor prognosis.
Extracolonic cancer risk in Dutch patients with APC (adenomatous polyposis coli)-associated polyposis
Authors: Ghorbanoghli Zeinab , Bastiaansen Barbara AJ , Langers Alexandra MJ , Nagengast Fokko M , Poley Jan-Werner , Hardwick James CH , Koornstra Jan J , Sanduleanu Silvia , de Vos tot Nederveen Cappel Wouter H , Witteman Ben JM , Morreau H , Dekker Evelien , Vasen Hans FA 
Published: May 2017

BackgroundScreening of patients with familial adenomatous polyposis (FAP) have led to a substantial reduction in mortality due to colorectal cancer (CRC). Recent guidelines suggest that surveillance of non-intestinal malignancies should also be considered in those patients. However, the value of these surveillance programmes is unknown. The aims of this study were (1) to assess the occurrence of extracolonic malignancies in a large series of adenomatous polyposis coli (APC) mutation carriers and (2) to evaluate the causes of death.MethodsAll APC mutation carriers were selected from the Dutch polyposis registry. Data on causes of death were collected. Pathology reports were retrieved from the Dutch Pathology Registry.ResultsA total of 85 extracolonic malignancies were diagnosed in 74 of 582 APC mutation carriers. Duodenal and skin cancers were the most prevalent cancers. Thyroid cancer was observed in only 1.5% of the cases. The main cause of death was cancer (59% of all deaths), with 42% due to CRC and 21% due to duodenal cancer. One patient died from thyroid cancer. The second and third most common causes of death were cardiovascular disease (13% of all deaths) and desmoid tumours (11% of all deaths), respectively.ConclusionExtending surveillance programmes to other cancers will not contribute significantly to the survival of patients with FAP.
Content analysis of age verification, purchase and delivery methods of internet e-cigarette vendors, 2013 and 2014
Authors: Williams Rebecca S , Derrick Jason , Liebman Aliza Kate , LaFleur Kevin , Ribisl Kurt M 
Published: May 2017

ObjectiveIdentify the population of internet e-cigarette vendors (IEVs) and conduct content analyses of their age verification, purchase and delivery methods in 2013 and 2014.MethodsWe used multiple sources to identify IEV websites, primarily complex search algorithms scanning more than 180 million websites. In 2013, we manually screened 32 446 websites, identifying 980 IEVs, selecting the 281 most popular for content analysis. This methodology yielded 31 239 websites for screening in 2014, identifying 3096 IEVs, with 283 selected for content analysis.ResultsThe proportion of vendors that sold online-only, with no retail store, dropped significantly from 2013 (74.7%) to 2014 (64.3%) (p<0.01), with a corresponding significant decrease in US-based vendors (71.9% in 2013 and 65% in 2014). Most vendors did little to prevent youth access in either year, with 67.6% in 2013 and 63.2% in 2014 employing no age verification or relying exclusively on strategies that cannot effectively verify age. Effective age verification strategies such as online age verification services (7.1% in 2013 and 8.5% in 2014), driving licences (1.8% in 2013 and 7.4% in 2014, p<0.01) or age verification at delivery (6.4% in 2013 and 8.1% in 2104) were rarely advertised on IEV websites. Nearly all vendors advertised accepting credit cards, and about ¾ shipping via United States Postal Service, similar to the internet cigarette industry prior to federal bans.ConclusionsThe number of IEVs grew sharply from 2013 to 2014, with poor age verification practices. New and expanded regulations for online e-cigarette sales are needed, including strict age and identity verification requirements.
Intermediate layer, microstructure and mechanical properties of aluminum alloy/stainless steel butt joint using laser–MIG hybrid welding–brazing method
Authors: Zhu Zongtao , Wan Zhandong , Li Yuanxing , Xue Junyu , Hui Chen 
Published: May 2017

Butt joining of AA6061 aluminum (Al) alloy and 304 stainless steel of 2-mm thickness was conducted using laser–MIG hybrid welding–brazing method with ER4043 filler metal. To promote the mechanical properties of the welding–brazing joints, two kinds of intermediate layers (Al–Si–Mg alloy and Ag-based alloy) are used to adjust the microstructures of the joints. The brazing interface and the tensile strength of the joints were characterized. The results showed that the brazing interface between Al alloy and stainless steel consisted of double layers of Fe2Al5 (near stainless steel) and Fe4Al[Formula: see text] intermetallic compounds (IMCs) with a total thickness of 3.7 [Formula: see text]m, when using Al–Si–Mg alloy as the intermediate layer. The brazing interface of the joints using Ag-based alloy as intermediate layer also consists of double IMC layers, but the first layer near stainless steel was FeAl2 and the total thickness of these two IMC layers decreased to 3.1 [Formula: see text]m. The tensile strength of the joints using Al–Si–Mg alloy as the intermediate layer was promoted to 149 MPa, which was 63 MPa higher than that of the joints using Al–Si–Mg alloy as the intermediate layer. The fractures occurred in the brazing interface between Al alloy and stainless steel.
Heat pipe cooling system of high-power three-level explosion-proof inverter based on the loss calculation and finite element analysis
Authors: Li Yuan 
Published: May 2017

The special using condition of high-power three-level explosion-proof inverter limits its cooling system within heat pipe and water-cooled cooling systems. How to calculate these two systems quantitatively to provide references for engineering application becomes one of the critical problems. In this paper, the principle of three-level explosion-proof was introduced first, and the power-loss generation theory was described and deduced into equations. Secondly, the heat pipe cooling system theory calculation was conducted based on the power losses of power devices, and the whole cooling system model was built by using finite element analysis. Finally, the temperature rise experiment was carried out on a 1 MW high-power three-level explosion-proof inverter, and the results proved the feasibility of this theory and its accuracy of analysis.
TWIST1-WDR5-Hottip Regulates Hoxa9 Chromatin to Facilitate Prostate Cancer Metastasis
Authors: Malek Reem , Gajula Rajendra P. , Williams Russell D. , Nghiem Belinda , Simons Brian W. , Nugent Katriana , Wang Hailun , Taparra Kekoa , Lemtiri-Chlieh Ghali , Yoon Arum R. , True Lawrence , An Steven S. , DeWeese Theodore L. , Ross Ashley E. , Schaeffer Edward M. , Pienta Kenneth J. , Hurley Paula J. , Morrissey Colm , Tran Phuoc T. 
Published: May 2017

Abstract
TWIST1 is a transcription factor critical for development that can promote prostate cancer metastasis. During embryonic development, TWIST1 and HOXA9 are coexpressed in mouse prostate and then silenced postnatally. Here we report that TWIST1 and HOXA9 coexpression are reactivated in mouse and human primary prostate tumors and are further enriched in human metastases, correlating with survival. TWIST1 formed a complex with WDR5 and the lncRNA Hottip/HOTTIP, members of the MLL/COMPASS–like H3K4 methylases, which regulate chromatin in the Hox/HOX cluster during development. TWIST1 overexpression led to coenrichment of TWIST1 and WDR5 as well as increased H3K4me3 chromatin at the Hoxa9/HOXA9 promoter, which was dependent on WDR5. Expression of WDR5 and Hottip/HOTTIP was also required for TWIST1-induced upregulation of HOXA9 and aggressive cellular phenotypes such as invasion and migration. Pharmacologic inhibition of HOXA9 prevented TWIST1-induced aggressive prostate cancer cellular phenotypes in vitro and metastasis in vivo. This study demonstrates a novel mechanism by which TWIST1 regulates chromatin and gene expression by cooperating with the COMPASS-like complex to increase H3K4 trimethylation at target gene promoters. Our findings highlight a TWIST1–HOXA9 embryonic prostate developmental program that is reactivated during prostate cancer metastasis and is therapeutically targetable. Cancer Res; 77(12); 3181–93. ©2017 AACR.
Genome-wide DNA Methylation Analysis Reveals GABBR2 as a Novel Epigenetic Target for EGFR 19 Deletion Lung Adenocarcinoma with Induction Erlotinib Treatment
Authors: Niu Xiaomin , Liu Fatao , Zhou Yi , Zhou Zhen , Zhou Daizhan , Wang Ting , Li Ziming , Ye Xiangyun , Yu Yongfeng , Weng Xiaoling , Zhang Hong , Ye Junyi , Liao Meilin , Liu Yun , Chen Zhiwei , Lu Shun 
Published: May 2017

Abstract
Purpose: The past decade has witnessed the rapid development of personalized targeted therapies in lung cancer. It is still unclear whether epigenetic changes are involved in the response to tyrosine kinase inhibitor (TKI) treatment in epidermal growth factor receptor (EGFR)-mutated lung cancer.
Experimental Design: Methyl-sensitive cut counting sequencing (MSCC) was applied to investigate the methylation changes in paired tissues before and after erlotinib treatment for 42 days with partial response (PR) from stage IIIa (N2) lung adenocarcinoma patients (N = 2) with EGFR 19 deletion. The Sequenom EpiTYPER assay was used to validate the changed methylated candidate genes. Up- or downregulation of the candidate gene was performed to elucidate the potential mechanism in the regulation of erlotinib treatment response.
Results: Sixty aberrant methylated genes were screened using MSCC sequencing. Two aberrant methylated genes, CBFA2T3 and GABBR2, were clearly validated. A same differential methylated region (DMR) between exon 2 and exon 3 of GABBR2 gene was confirmed consistently in both patients. GABBR2 was significantly downregulated in EGFR 19 deletion cells, HCC4006 and HCC827, but remained conserved in EGFR wild-type A549 cells after erlotinib treatment. Upregulation of GABBR2 expression significantly rescued erlotinib-induced apoptosis in HCC827 cells. GABBR2 was significantly downregulated, along with the reduction of S6, p-p70 S6, and p-ERK1/2, demonstrating that GABBR2 may play an important role in EGFR signaling through the ERK1/2 pathway.
Conclusions: We demonstrated that GABBR2 gene might be a novel potential epigenetic treatment target with induction erlotinib treatment for stage IIIa (N2) EGFR 19 deletion lung adenocarcinoma. Clin Cancer Res; 23(17); 5003–14. ©2017 AACR.
High-Affinity Internalizing Human scFv-Fc Antibody for Targeting FGFR1-Overexpressing Lung Cancer
Authors: Sokolowska-Wedzina Aleksandra , Chodaczek Grzegorz , Chudzian Julia , Borek Aleksandra , Zakrzewska Malgorzata , Otlewski Jacek 
Published: May 2017

AbstractTargeted delivery of anticancer drugs using antibodies specific for tumor-associated antigens represents one of the most important approaches in current immuno-oncology research. Fibroblast growth factor receptor 1 (FGFR1) has been demonstrated to be a high-frequency targetable oncogene specific for smoking-associated lung cancers, present in over 20% of lung squamous cell carcinoma cases. This report describes the generation of a potent, fully human antibody fragment in scFv-Fc format efficiently targeting FGFR1. Antibody phage display was used to select high-affinity scFv antibody fragments against the extracellular domain of FGFR1(IIIc). Enzyme immunoassay (ELISA) and surface plasmon resonance (SPR) analysis were used for antibody screening and characterization. The best binder (named D2) was cloned to diabody and Fc fusion formats. All D2 antibodies demonstrated high affinity for FGFR1 with dissociation constants of 18 nmol/L (scFvD2), 0.82 nmol/L (scFvD2 diabody), and 0.59 nmol/L (scFvD2-Fc). scFvD2 was found to be exquisitely selective for FGFR1 versus other FGFR family members and bound FGFR1 even in the presence of its natural ligand FGF2, as shown by competitive analysis. Confocal microscopy revealed that scFvD2-Fc was specifically and rapidly internalized by a panel of cell lines overexpressing FGFR1. Finally, it was demonstrated that scFvD2-Fc mediated specific delivery of a cytotoxic payload into lung cancer cells harboring oncogenic FGFR1 gene amplifications.Implications: This study reports a highly specific internalizing antibody fragment that can serve as a therapeutic targeting agent for efficient delivery of cytotoxic drugs into FGFR1-positive lung cancer cells. Mol Cancer Res; 15(8); 1040–50. ©2017 AACR.