bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dynamics of the SetCD-Regulated Integration and Excision of Genomic Islands Mobilized by Integrating Conjugative Elements of the SXT/R391 Family
Authors: Daccord Aurélie , Mursell Mathias , Poulin-Laprade Dominic , Burrus Vincent 
Published: August 2012

ABSTRACT

Mobilizable genomic islands (MGIs) are small genomic islands that are mobilizable by SXT/R391 integrating conjugative elements (ICEs) due to similar origins of transfer. Their site-specific integration and excision are catalyzed by the integrase that they encode, but their conjugative transfer entirely depends upon the conjugative machinery of SXT/R391 ICEs. In this study, we report the mechanisms that control the excision and integration processes of MGIs. We found that while the MGI-encoded integrase Int
MGI
is sufficient to promote MGI integration, efficient excision from the host chromosome requires the combined action of Int
MGI
and of a novel recombination directionality factor, RdfM. We determined that the genes encoding these proteins are activated by SetCD, the main transcriptional activators of SXT/R391 ICEs. Although they share the same regulators, we found that unlike
rdfM
,
int
MGI
has a basal level of expression in the absence of SetCD. These findings explain how an MGI can integrate into the chromosome of a new host in the absence of a coresident ICE and shed new light on the cross talk that can occur between mobilizable and mobilizing elements that mobilize them, helping us to understand part of the rules that dictate horizontal transfer mechanisms.
Role of EscP (Orf16) in Injectisome Biogenesis and Regulation of Type III Protein Secretion in Enteropathogenic Escherichia coli
Authors: Monjarás Feria Julia , García-Gómez Elizabeth , Espinosa Norma , Minamino Tohru , Namba Keiichi , González-Pedrajo Bertha 
Published: August 2012

ABSTRACT

Enteropathogenic
Escherichia coli
employs a type III secretion system (T3SS) to translocate virulence effector proteins directly into enterocyte host cells, leading to diarrheal disease. The T3SS is encoded within the chromosomal locus of enterocyte effacement (LEE). The function of some of the LEE-encoded proteins remains unknown. Here we investigated the role of the Orf16 protein in T3SS biogenesis and function. An
orf16
deletion mutant showed translocator and effector protein secretion profiles different from those of wild-type cells. The
orf16
null strain produced T3S structures with abnormally long needles and filaments that caused weak hemolysis of red blood cells. Furthermore, the number of fully assembled T3SSs was also reduced in the
orf16
mutant, indicating that Orf16, though not essential, is required for efficient T3SS assembly. Analysis of protein secretion revealed that Orf16 is a T3SS-secreted substrate and regulates the secretion of the inner rod component EscI. Both pulldown and yeast two-hybrid assays showed that Orf16 interacts with the C-terminal domain of an inner membrane component of the secretion apparatus, EscU; the inner rod protein EscI; the needle protein EscF; and the multieffector chaperone CesT. These results suggest that Orf16 regulates needle length and, along with EscU, participates in a substrate specificity switch from early substrates to translocators. Taken together, our results suggest that Orf16 acts as a molecular measuring device in a way similar to that of members of the
Yersinia
YscP and flagellar FliK protein family. Therefore, we propose that this protein be renamed EscP.
An Extracelluar Protease, SepM, Generates Functional Competence-Stimulating Peptide in Streptococcus mutans UA159
Authors: Hossain Mohammad Shahnoor , Biswas Indranil 
Published: August 2012

ABSTRACT

Cell-cell communication in Gram-positive bacteria often depends on the production of extracellular peptides. The cariogenic bacterium
Streptococcus mutans
employs so-called competence-stimulating peptide (CSP) to stimulate mutacin (bacteriocin) production and competence development through the activation of the ComDE two-component pathway. In
S. mutans
, CSP is secreted as a 21-residue peptide; however, mass spectrometric analysis of culture supernatant indicates the presence of an 18-residue proteolytically cleaved species. In this study, using a transposon mutagenesis screening, we identified a cell surface protease that is involved in the processing of 21-residue CSP to generate the 18-residue CSP. We named this protease SepM for
s
treptococcal
e
xtracellular
p
rotease required for
m
utacin production. We showed that the truncated 18-residue peptide is the biologically active form and that the specific postexport cleavage is a prerequisite to activate the ComDE two-component signal transduction pathway. We also showed that the CSP and the mutacins are exported outside the cell by the same ABC transporter, NlmTE. Our study further confirmed that the ComDE two-component system is absolutely necessary for mutacin production in
S. mutans
.
Analysing falls in coronary heart disease mortality in the West Bank between 1998 and 2009
Authors: Abu-Rmeileh Niveen M E , Shoaibi Azza , O'Flaherty Martin , Capewell Simon , Husseini Abdullatif 
Published: August 2012

ObjectivesTo analyse coronary heart disease (CHD) mortality and risk factor trends in the West Bank, occupied Palestinian territory between 1998 and 2009.DesignModelling study using CHD IMPACT model.SettingThe West Bank, occupied Palestinian territory.ParticipantsData on populations, mortality, patient groups and numbers, treatments and cardiovascular risk factor trends were obtained from national and local surveys, routine national and WHO statistics, and critically appraised. Data were then integrated and analysed using a previously validated CHD model.Primary and secondary outcome measuresCHD deaths prevented or postponed are the main outcome.ResultsCHD death rates fell by 20% in the West Bank, between 1998 and 2009. Smoking prevalence was initially high in men, 51%, but decreased to 42%. Population blood pressure levels and total cholesterol levels also decreased. Conversely, body mass index rose by 1–2 kg/m2and diabetes increased by 2–8%. Population modelling suggested that more than two-thirds of the mortality fall was attributable to decreases in major risk factors, mainly total cholesterol, blood pressure and smoking. Approximately one-third of the CHD mortality decreases were attributable to treatments, particularly for secondary prevention and heart failure. However, the contributions from statins, surgery and angioplasty were consistently small.ConclusionsCHD mortality fell by 20% between 1998 and 2009 in the West Bank. More than two-third of this fall was due to decreases in major risk factors, particularly total cholesterol and blood pressure. Our results clearly indicate that risk factor reductions in the general population compared save substantially more lives to specific treatments for individual patients. This emphasizes the importance of population-wide primary prevention strategies.
Seasonality, incidence and prognosis in atrial fibrillation and stroke in Denmark and New Zealand
Authors: Christensen Anette Luther , Rasmussen Lars Hvilsted , Baker Michael G , Lip Gregory Y H , Dethlefsen Claus , Larsen Torben Bjerregaard 
Published: August 2012

ObjectivesThere are relatively few large studies of seasonal variation in the occurrence of stroke in patients with atrial fibrillation (AF). We investigated the seasonal variation in incidence rates of hospitalisation with stroke in patients from Denmark and New Zealand.DesignCohort study.SettingNationwide hospital discharge data from Denmark and New Zealand.Participants243 381 (median age 75) subjects having a first-time hospitalisation with AF in Denmark and 51 480 (median age 76) subjects in New Zealand constituted the study population. Subjects with previous hospitalisation with stroke were excluded.Primary and secondary effect measuresPeak-to-trough ratio of the seasonal variation in incidence rates of stroke in AF patients adjusted for an overall trend was primary effect measure and was assessed using a log-linear Poisson regression model. Secondary effect measures were incidence rate ratios of AF and 30-day case fatality for stroke patients.ResultsIncidence rates of AF per 1000 person-years in Denmark increased by 5.4% (95% CI 5.3% to 5.7%) for patients aged <65 and 5% (95% CI 4.9% to 5.1%) for patients aged ≥65, whereas the increase was 0.2% (95% CI −0.2% to 0.6%) for patients aged <65 and 2.6% (95% CI 2.4% to 2.8%) for patients aged ≥65 in New Zealand. In Denmark 36 088 subjects were hospitalised with stroke, and 7518 subjects in New Zealand, both showing peaks during winter with peak-to-trough ratios of 1.22 and 1.27, respectively and a decreasing trend. The 30-day case fatality risk for stroke patients having AF is now (2000–2008) about 20% in both countries.ConclusionsAlthough incidence rates of hospitalisation with stroke in patients with AF have decreased in recent years, stroke remains a common AF complication with a high case fatality risk. The marked winter peak in incidence rates of hospitalisation with stroke in AF patients suggests that there are opportunities to reduce this complication. Further studies are necessary to identify how to optimise treatment of AF and prevention of stroke.
Prevalence, awareness, treatment and control of hypertension in a self-selected sub-Saharan African urban population: a cross-sectional study
Authors: Dzudie Anastase , Kengne André Pascal , Muna Walinjom F T , Ba Hamadou , Menanga Alain , Kouam Kouam Charles , Abah Joseph , Monkam Yves , Biholong Christian , Mintom Pierre , Kamdem Félicité , Djomou Armel , Ndjebet Jules , Wambo Cyrille , Luma Henry , Ngu Kathleen Blackett , Kingue Samuel 
Published: August 2012

ObjectivesHypertension has been established as a major public health problem in Africa, but its specific contributions to disease burden are still incompletely understood. We report the prevalence and determinants of hypertension, detection, treatment and control rates among adults in major cities in Cameroon.DesignCross-sectional study.SettingsCommunity-based multicentre study in major cities in Cameroon.ParticipantsParticipants were self-selected urban dwellers from the Center, Littoral, North-West and West Regions, who attended on 17 May 2011 a screening campaign advertised through mass media.Primary and secondary outcomes measuresHypertension defined as systolic (and/or diastolic) blood pressure (BP)≥ 140 (90) mm Hg, or ongoing BP-lowering medications.ResultsIn all, 2120 participants (1003 women) were included. Among them, 1007 (prevalence rate 47.5%) had hypertension, including 319 (awareness rate 31.7%) who were aware of their status. The prevalence of hypertension increased with age overall and by sex and region. Among aware hypertensive participants, 191 (treatment rate 59.9%) were on regular BP-lowering medication, and among those treated, 47 (controlled rate 24.6%) were at target BP levels (ie, systolic (and diastolic) BP<140 (90) mm Hg). In multivariable logistic regression analysis, male gender, advanced age, parental history of hypertension, diabetes mellitus, elevated waist and elevated body mass index (BMI) were the significant predictors of hypertension. Likewise, male gender, high BMI and physical inactivity were associated with poor control.ConclusionsHigh prevalence of hypertension with low awareness, treatment and control were found in this urban population; these findings are significant and alarming with consideration to the various improvements in the access to healthcare and the continuing efforts to educate communities over the last few decades.
Do ω-3 or other fatty acids influence the development of ‘growing pains’? A prebirth cohort study
Authors: Golding Jean , Northstone Kate , Emmett Pauline , Steer Colin , Hibbeln Joseph R 
Published: August 2012

ObjectivesTo assess whether the prevalence of growing pains varies with indicators of fatty acid exposure. Growing pains (limb pains of no obvious explanation) have been shown to be strongly linked to a family history of arthritis, and are thought to predict an increased risk of the development of arthritis in adulthood. Much has been made of the possibility of fatty acids, particularly the ω-3 fatty acids, playing a preventive role in the development of arthritis, but little research has been undertaken to determine whether such fatty acids might reduce the risk of growing pains. We aimed to assess whether the prevalence of growing pains varies with indicators of fatty acid exposures.DesignCase–control study nested within a prospective longitudinal cohort comparing prenatal and postnatal diet, blood measures and variants in fatty acid desaturase (FADS) genes that influence the metabolism of fatty acids. Statistical analysis took account of factors such as gender, smoke exposure, maternal age and education, social class and parity.SettingAvon Longitudinal Study of Parents & Children.ParticipantsAll children born between 1 April 1991 and 31 December 1992 (approximately14 000) within the Avon area (only that part of Avon under the South-West Regional Health Authority). This project compared 1676 children who reported ‘growing pains’ at age 8 with 6155 with no such pain.Primary outcomeReported limb pains of no apparent origin.ResultsThere was no indication that the affected children had diets that differed with regard to ω-3, plasma levels of fatty acids, or the FADS genetic variants. We also assessed fetal and infant exposure but neither maternal prenatal blood levels nor maternal dietary intake, or duration of breast feeding showed any significant relationships even after adjustment for confounders.ConclusionsThus, there is no evidence that ω-3 fatty acid status protects against the development of growing pains in childhood.
Retrospective study of the prevalence of postanaesthetic hypothermia in dogs
Authors: Redondo J. I. , Suesta P. , Serra I. , Soler C. , Soler G. , Gil L. , Gómez‐Villamandos R. J. 
Published: August 2012

The anaesthetic records of 1525 dogs were examined to determine the prevalence of postanaesthetic hypothermia, its clinical predictors and consequences. Temperature was recorded throughout the anaesthesia. At the end of the procedure, details coded in were: hyperthermia (>39.50°C), normothermia (38.50°C–39.50°C), slight (38.49°C–36.50°C), moderate (36.49°C–34.00°C) and severe hypothermia (<34.00°C). Statistical analysis consisted of multiple regression to identify the factors that are associated with the temperature at the end of the procedure. Before premedication, the temperature was 38.7 ± 0.6°C (mean ± sd). At 60, 120 and 180 minutes from induction, the temperature was 36.7 ± 1.3°C, 36.1 ± 1.4°C and 35.8 ± 1.5°C, respectively. The prevalence of hypothermia was: slight, 51.5 per cent (95 per cent CI 49.0 to 54.0 per cent); moderate, 29.3 per cent (27.1–31.7 per cent) and severe: 2.8% (2.0–3.7%). The variables that associated with a decrease in the temperature recorded at the end of the anaesthesia were: duration of the preanesthetic time, duration of the anaesthesia, physical condition (ASA III and ASA IV dogs showed lower temperatures than ASA I dogs), the reason for anaesthesia (anaesthesia for diagnostic procedures or thoracic surgery reduce the temperature when compared with minor procedures), and the recumbency during the procedure (sternal and dorsal recumbencies showed lower temperatures than lateral recumbency). The temperature before premedication and the body surface (BS) were associated with a higher temperature at the end of the anaesthesia, and would be considered as protective factors.
Arylsulfonamide KCN1 InhibitsIn VivoGlioma Growth and Interferes with HIF Signaling by Disrupting HIF-1α Interaction with Cofactors p300/CBP
Authors: Yin Shaoman , Kaluz Stefan , Devi Narra S. , Jabbar Adnan A. , de Noronha Rita G. , Mun Jiyoung , Zhang Zhaobin , Boreddy Purushotham R. , Wang Wei , Wang Zhibo , Abbruscato Thomas , Chen Zhengjia , Olson Jeffrey J. , Zhang Ruiwen , Goodman Mark M. , Nicolaou K.C. , Van Meir Erwin G. 
Published: August 2012

AbstractPurpose: The hypoxia-inducible factor-1 (HIF-1) plays a critical role in tumor adaptation to hypoxia, and its elevated expression correlates with poor prognosis and treatment failure in patients with cancer. In this study, we determined whether 3,4-dimethoxy-N-[(2,2-dimethyl-2H-chromen-6-yl)methyl]-N-phenylbenzenesulfonamide, KCN1, the lead inhibitor in a novel class of arylsulfonamide inhibitors of the HIF-1 pathway, had antitumorigenic properties in vivo and further defined its mechanism of action.Experimental Design: We studied the inhibitory effect of systemic KCN1 delivery on the growth of human brain tumors in mice. To define mechanisms of KCN1 anti-HIF activities, we examined its influence on the assembly of a functional HIF-1α/HIF-1β/p300 transcription complex.Results: KCN1 specifically inhibited HIF reporter gene activity in several glioma cell lines at the nanomolar level. KCN1 also downregulated transcription of endogenous HIF-1 target genes, such as VEGF, Glut-1, and carbonic anhydrase 9, in a hypoxia-responsive element (HRE)-dependent manner. KCN1 potently inhibited the growth of subcutaneous malignant glioma tumor xenografts with minimal adverse effects on the host. It also induced a temporary survival benefit in an intracranial model of glioma but had no effect in a model of melanoma metastasis to the brain. Mechanistically, KCN1 did not downregulate the levels of HIF-1α or other components of the HIF transcriptional complex; rather, it antagonized hypoxia-inducible transcription by disrupting the interaction of HIF-1α with transcriptional coactivators p300/CBP.Conclusions: Our results suggest that the new HIF pathway inhibitor KCN1 has antitumor activity in mouse models, supporting its further translation for the treatment of human tumors displaying hypoxia or HIF overexpression. Clin Cancer Res; 18(24); 6623–33. ©2012 AACR.
Phase I Study of Vorinostat in Combination with Temozolomide in Patients with High-Grade Gliomas: North American Brain Tumor Consortium Study 04-03
Authors: Lee Eudocia Q. , Puduvalli Vinay K. , Reid Joel M. , Kuhn John G. , Lamborn Kathleen R. , Cloughesy Timothy F. , Chang Susan M. , Drappatz Jan , Yung W. K. Alfred , Gilbert Mark R. , Robins H. Ian , Lieberman Frank S. , Lassman Andrew B. , McGovern Renee M. , Xu Jihong , Desideri Serena , Ye Xiabu , Ames Matthew M. , Espinoza-Delgado Igor , Prados Michael D. , Wen Patrick Y. 
Published: August 2012

Abstract
Purpose: A phase I, dose-finding study of vorinostat in combination with temozolomide (TMZ) was conducted to determine the maximum tolerated dose (MTD), safety, and pharmacokinetics in patients with high-grade glioma (HGG).
Experimental Design: This phase I, dose-finding, investigational study was conducted in two parts. Part 1 was a dose-escalation study of vorinostat in combination with TMZ 150 mg/m2/day for 5 days every 28 days. Part 2 was a dose-escalation study of vorinostat in combination with TMZ 150 mg/m2/day for 5 days of the first cycle and 200 mg/m2/day for 5 days of the subsequent 28-day cycles.
Results: In part 1, the MTD of vorinostat administered on days 1 to 7 and 15 to 21 of every 28-day cycle, in combination with TMZ, was 500 mg daily. Dose-limiting toxicities (DLT) included grade 3 anorexia, grade 3 ALT, and grade 5 hemorrhage in the setting of grade 4 thrombocytopenia. In part 2, the MTD of vorinostat on days 1 to 7 and 15 to 21 of every 28-day cycle, combined with TMZ, was 400 mg daily. No DLTs were encountered, but vorinostat dosing could not be escalated further due to thrombocytopenia. The most common serious adverse events were fatigue, lymphopenia, thrombocytopenia, and thromboembolic events. There were no apparent pharmacokinetic interactions between vorinostat and TMZ. Vorinostat treatment resulted in hyperacetylation of histones H3 and H4 in peripheral mononuclear cells.
Conclusion: Vorinostat in combination with temozolomide is well tolerated in patients with HGG. A phase I/II trial of vorinostat with radiotherapy and concomitant TMZ in newly diagnosed glioblastoma is underway. Clin Cancer Res; 18(21); 6032–9. ©2012 AACR.
Novel Role of Proline-Rich Nonreceptor Tyrosine Kinase 2 in Vascular Wall Remodeling After Balloon Injury
Authors: Gadepalli Ravisekhar , Singh Nikhlesh K. , Kundumani-Sridharan Venkatesh , Heckle Mark R. , Rao Gadiparthi N. 
Published: August 2012

Objective—
To investigate the role of Pyk2, a proline-rich nonreceptor tyrosine kinase, in G protein−coupled receptor agonist, thrombin-induced human aortic smooth muscle cell growth and migration, and injury-induced vascular wall remodeling.

Methods and Results—
Thrombin, a G protein–coupled receptor agonist, activated Pyk2 in a time-dependent manner and inhibition of its stimulation attenuated thrombin-induced human aortic smooth muscle cell migration and proliferation. Thrombin also activated Grb2-associated binder protein 1, p115 Rho guanine nucleotide exchange factor, Rac1, RhoA, and p21-activated kinase 1 (Pak1) and interference with stimulation of these molecules attenuated thrombin-induced human aortic smooth muscle cell migration and proliferation. In addition, adenovirus-mediated expression of dominant negative Pyk2 inhibited thrombin-induced Grb2-associated binder protein 1, p115 rho guanine nucleotide exchange factor, Rac1, RhoA and Pak1 stimulation. Balloon injury also caused activation of Pyk2, Grb2-associated binder protein 1, p115 rho guanine nucleotide exchange factor, Rac1, RhoA, and Pak1 in the carotid artery of rat, and these responses were sensitive to inhibition by the dominant negative Pyk2. Furthermore, inhibition of Pyk2 activation resulted in reduced recruitment of smooth muscle cells onto the luminal surface and their proliferation in the intimal region leading to suppression of neointima formation.

Conclusion—
Together, these results demonstrate for the first time that Pyk2 plays a crucial role in G protein–coupled receptor agonist thrombin-induced human aortic smooth muscle cell growth and migration, as well as balloon injury–induced neointima formation.
Simultaneous Exposure of Sites in von Willebrand Factor for Glycoprotein Ib Binding and ADAMTS13 Cleavage
Authors: Chen Junmei , Ling Minhua , Fu Xiaoyun , López José A. , Chung Dominic W. 
Published: August 2012

Objective—
Platelet-bound von Willebrand factor (VWF) was recently demonstrated to be a better substrate for ADAMTS13, suggesting that 1 conformational change exposes both the glycoprotein Ibα binding site in the A1 domain and the ADAMTS13 cleavage site in the A2 domain. Because ristocetin induces VWF to bind glycoprotein Ibα in the absence of shear stress, we evaluated whether it could also enhance ADAMTS13 proteolysis of VWF.

Methods and Results—
We used several VWF sources: plasma, purified plasma VWF, recombinant VWF fragments encompassing A1A2A3, A1A2, and 2 A2 domains, 1 containing a ristocetin-binding site (Asp1459–His1472) and the other lacking it. Ristocetin accelerated ADAMTS13 cleavage of multimeric VWF and of each of the recombinant VWF fragments except for the A2 domain lacking the ristocetin-binding site. We also examined the effect of ristocetin on the conformation of the A2 domain by assessing its effect on the susceptibility of Met1606 at the ADAMTS13 cleavage site to be oxidized by hypochlorous acid. Ristocetin markedly enhanced oxidation of Met1606 and Met1521 of the A2 domain.

Conclusion—
These data indicate that exposure of the sites for glycoprotein Ibα and ADAMTS13 are coupled, explaining why platelet-bound VWF is a better ADAMTS13 substrate and why enhanced proteolysis is often observed in type 2B von Willebrand disease.