bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tumor Necrosis Factor Receptor-Associated Factor 6 (TRAF6) Mediates Ubiquitination-Dependent STAT3 Activation upon Salmonella enterica Serovar Typhimurium Infection
Authors: Ruan Hai-Hua , Zhang Zhen , Wang Su-Ying , Nickels Logan M. , Tian Li , Qiao Jian-Jun , Zhu Jun 
Published: May 2017

ABSTRACT

Salmonella enterica
serovar Typhimurium can inject effector proteins into host cells via type III secretion systems (T3SSs). These effector proteins modulate a variety of host transcriptional responses to facilitate bacterial growth and survival. Here we show that infection of host cells with
S
. Typhimurium specifically induces the ubiquitination of tumor necrosis factor receptor-associated factor 6 (TRAF6). This TRAF6 ubiquitination is triggered by the
Salmonella
pathogenicity island 1 (SPI-1) T3SS effectors SopB and SopE2. We also demonstrate that TRAF6 is involved in the SopB/SopE2-induced phosphorylation of signal transducer and activator of transcription 3 (STAT3), a signaling event conducive to the intracellular growth of
S
. Typhimurium. Specifically, TRAF6 mediates lysine-63 ubiquitination within the Src homology 2 (SH2) domain of STAT3, which is an essential step for STAT3 membrane recruitment and subsequent phosphorylation in response to
S
. Typhimurium infection. TRAF6 ubiquitination participates in STAT3 phosphorylation rather than serving as only a hallmark of E3 ubiquitin ligase activation. Our results reveal a novel strategy in which
S
. Typhimurium T3SS effectors broaden their functions through the activation of host proteins in a ubiquitination-dependent manner to manipulate host cells into becoming a
Salmonella
-friendly zone.
The Mycobacterium tuberculosis MmpL11 Cell Wall Lipid Transporter Is Important for Biofilm Formation, Intracellular Growth, and Nonreplicating Persistence
Authors: Wright Catherine C. , Hsu Fong Fu , Arnett Eusondia , Dunaj Jennifer L. , Davidson Patrick M. , Pacheco Sophia A. , Harriff Melanie J. , Lewinsohn David M. , Schlesinger Larry S. , Purdy Georgiana E. 
Published: May 2017

ABSTRACTThe mycobacterial cell wall is crucial to the host-pathogen interface, because it provides a barrier against antibiotics and the host immune response. In addition, cell wall lipids are mycobacterial virulence factors. Themycobacterialmembraneproteinlarge (MmpL) proteins are cell wall lipid transporters that are important for basic mycobacterial physiology andMycobacterium tuberculosispathogenesis. MmpL3 and MmpL11 are conserved across pathogenic and nonpathogenic mycobacteria, a feature consistent with an important role in the basic physiology of the bacterium. MmpL3 is essential and transports trehalose monomycolate to the mycobacterial surface. In this report, we characterize the role of MmpL11 inM. tuberculosis. M. tuberculosismmpL11mutants have altered biofilms associated with lower levels of mycolic acid wax ester and long-chain triacylglycerols than those for wild-type bacteria. While the growth rate of themmpL11mutant is similar to that of wild-typeM. tuberculosisin macrophages, the mutant exhibits impaired survival in anin vitrogranuloma model. Finally, we show that the survival or recovery of themmpL11mutant is impaired when it is incubated under conditions of nutrient and oxygen starvation. Our results suggest that MmpL11 and its cell wall lipid substrates are important for survival in the context of adaptive immune pressure and for nonreplicating persistence, both of which are critically important aspects ofM. tuberculosispathogenicity.
The Pneumococcal Type 1 Pilus Genes Are Thermoregulated and Are Repressed by a Member of the Snf2 Protein Family
Authors: Basset Alan , Herd Muriel , Daly Raecliffe , Dove Simon L. , Malley Richard 
Published: May 2017

ABSTRACT

In
Streptococcus pneumoniae
, the type 1 pilus is involved in many steps of pathogenesis, including adherence to epithelial cells, mediation of inflammation, escape from macrophages, and the formation of biofilms. The type 1 pilus genes are expressed in a bistable fashion with cells switching between “on” and “off” expression states. Bistable expression of these genes is due to their control by RlrA, a positive regulator subject to control by a positive-feedback loop. The type 1 pilus genes are also thought to be negatively regulated by a large number of repressors. Here we show that expression of the type 1 pilus genes is thermosensitive and switched off at growth temperatures below 31°C. We also report that the on expression state of the type 1 pilus genes is highly stable, a phenomenon which we show likely contributed to the erroneous identification of many proteins as negative regulators of these genes. Finally, we exploited the effect of low temperature on pilus gene expression to help identify SP_1523, an Snf2-type protein, as a novel negative regulator of the pilus genes. Our findings establish that the type 1 pilus genes are thermoregulated and are repressed by a member of the Snf2 protein family. They also refute the notion that these genes are controlled by 8 previously described negative regulators.

IMPORTANCE
Streptococcus pneumoniae
is the leading cause of death from respiratory infections in children. Many bacterial factors contribute to pneumococcal virulence and nasopharyngeal colonization. The type 1 pneumococcal pilus plays an important role in mouse models and in epithelial adherence and is expressed in a bistable fashion. Here we show that the “on” state is highly stable, which may explain the prior misidentification of negative regulators of pilus expression. We also show that expression of pilus genes is thermosensitive: virtually no expression can be detected at temperatures found in the anterior nares of humans. We took advantage of this property to identify a negative regulator of pilus expression, a member of a family of proteins widely conserved across Gram-positive bacteria.
An Amino Acid Substitution in RNA Polymerase That Inhibits the Utilization of an Alternative Sigma Factor
Authors: Wang Erickson Anna F. , Deighan Padraig , Garcia Cinthia P. , Weinzierl Robert O. J. , Hochschild Ann , Losick Richard 
Published: May 2017

ABSTRACT

Sigma (σ) factors direct gene transcription by binding to and determining the promoter recognition specificity of RNA polymerase (RNAP) in bacteria. Genes transcribed under the control of alternative sigma factors allow cells to respond to stress and undergo developmental processes, such as sporulation in
Bacillus subtilis
, in which gene expression is controlled by a cascade of alternative sigma factors. Binding of sigma factors to RNA polymerase depends on the coiled-coil (or clamp helices) motif of the β′ subunit. We have identified an amino acid substitution (L257P) in the coiled coil that markedly inhibits the function of σ
H
, the earliest-acting alternative sigma factor in the sporulation cascade. Cells with this mutant RNAP exhibited an early and severe block in sporulation but not in growth. The mutant was strongly impaired in σ
H
-directed gene expression but not in the activity of the stress-response sigma factor σ
B
. Pulldown experiments showed that the mutant RNAP was defective in associating with σ
H
but could still associate with σ
A
and σ
B
. The differential effects of the L257P substitution on sigma factor binding to RNAP are likely due to a conformational change in the β′ coiled coil that is specifically detrimental for interaction with σ
H
. This is the first example, to our knowledge, of an amino acid substitution in RNAP that exhibits a strong differential effect on a particular alternative sigma factor.

IMPORTANCE
In bacteria, all transcription is mediated by a single multisubunit RNA polymerase (RNAP) enzyme. However, promoter-specific transcription initiation necessitates that RNAP associates with a σ factor. Bacteria contain a primary σ factor that directs transcription of housekeeping genes and alternative σ factors that direct transcription in response to environmental or developmental cues. We identified an amino acid substitution (L257P) in the
B. subtilis
β′ subunit whereby RNAP
L257P
associates with some σ factors (σ
A
and σ
B
) and enables vegetative cell growth but is defective in utilization of σ
H
and is consequently blocked for sporulation. To our knowledge, this is the first identification of an amino acid substitution within the core enzyme that affects utilization of a specific sigma factor.
Uncommon presentation of adult-form scimitar syndrome associated with single left pulmonary vein in a pregnant woman
Authors: Althomali Sarah Ali , Alhefny Ashraf Ahmad , Almalki Mohammad Salih 
Published: May 2017

Scimitar syndrome is the constellation of malformations including an abnormal venous drainage of the right lung into the inferior vena cava, associated with the right lung and systemic supply to the right lung. The anomalous vein looks like the curved, Turkish sword (scimitar), hence the name.The adult form of scimitar syndrome is rare, and it is usually an incidental diagnosis based on the characteristic finding on radiological imaging since the patients are usually asymptomatic or with minimal symptoms.Our patient presented with a rare presentation of scimitar syndrome, which is tachyarrhythmia (sinus tachycardia, with episodes of supraventricular tachycardia). The diagnosis of scimitar syndrome was made based on the typical radiological finding of the anomalous venous drainage on CT angiography. Our patient does not have the full spectrum of the scimitar syndrome; therefore, she did not suffer from the usual complication (pulmonary hypertension). She was treated with ablation without surgical intervention.
The not so over-the-counter status of emergency contraception in Ontario: A mixed methods study with pharmacists
Authors: Chaumont Andréanne , Foster Angel M. 
Published: May 2017

Introduction: In Canada, the progestin-only dedicated pill is the most widely used method of emergency contraception (EC). This method gained over-the-counter status in Ontario in 2008. Our mixed methods study explored the progestin-only EC knowledge, attitudes, and provision practices of Ontario pharmacists. Methods: From June 2015 to October 2015, we collected 198 mailed surveys from Ontarian pharmacy representatives and conducted 17 in-depth interviews with a subset of respondents. We analyzed these data using descriptive statistics and for content and themes. Results: Results from our English/French bilingual survey indicate that respondents’ knowledge is generally accurate, but confusion persists about the mechanism of action and the number of times the drug can be used in one menstrual cycle. Nearly half (49%) of our survey respondents indicated that progestin-only EC pills are only available behind the counter. Interviewees strongly supported the introduction and promotion of more effective methods of EC in Ontario. Conclusion: Continuing education focusing on both the regulatory status of progestin-only EC and information about the medication appears warranted. Health Canada’s recent approval of ulipristal acetate for use as a post-coital contraceptive may provide a window of opportunity for engaging with health service providers, including pharmacists, about all available modalities of EC in Canada.
Value of Soft Tissue Release Procedure around the Shoulder to Improve Shoulder Abduction in Birth Brachial Plexus Palsy and Analysis of the Factors Affecting Outcome
Authors: Sabapathy S. Raja , Bhardwaj Praveen , Venkatramani Hari 
Published: May 2017

Background: A lack of shoulder abduction in spontaneously recovered birth brachial plexus palsy (BBPP) is a common presentation. We have performed a soft tissue release operation in these patients to remove the tethering effect of the tight and cocontracting shoulder adductors. This study was undertaken in order to assess the outcome of this surgical procedure.Methods: We performed a retrospective analysis of 120 patients who displayed spontaneous recovery from BBPP and subsequently underwent soft tissue release procedure to improve shoulder abduction. The operation involved release of the pectoralis major, latissimus dorsi (LD) and teres major (TM) with axillary nerve neurolysis and transfer of LD and TM to teres minor at a lower position. Outcomes were assessed at a minimum follow up of two years. The primary outcome measures were range of shoulder abduction and Mallet score. Parents were interviewed and their satisfaction was graded on a Likert scale. We also explored prognostic factors responsible for better outcomes namely, age at operation, extent of involvement; preoperative shoulder abduction range, internal rotation deformity, triceps power and Mallet score.Results: The average patient age was 5.8 years(range 1–17). Follow up ranged from 2–6 years. Average preoperative shoulder abduction was 85° (range 30°–140°). Postoperatively the average shoulder abduction was 161° (range 80°–180°). The mean improvement in abduction was 76° (range 20°–110°) [p < 0.001]. Mallet score improved from 16.4 to 19.5 (p < 0.001). High parental satisfaction was recorded by Likert scale assessment. Regression analysis indicated a favourable outcome in patients who are younger, have a better preoperative abduction range and a preoperative triceps power > grade 3.Conclusions: Soft tissue release procedure employed in this series is effective in improving shoulder abduction. Patients who are of younger age, have better preoperative abduction and triceps power of > grade 3 are expected to achieve the best outcome.
Midterm Follow-up of Treating Volar Marginal Rim Fractures with Variable Angle Lcp Volar Rim Distal Radius Plates
Authors: Goorens Chul Ki , Geeurickx Stijn , Wernaers Pascal , Staelens Barbara , Scheerlinck Thierry , Goubau Jean 
Published: May 2017

Background: Specific treatment of the volar marginal rim fragment of distal radius fractures avoids occurance of volar radiocarpal dislocation. Although several fixation systems are available to capture this fragment, adequately maintaining internal fixation is difficult. We present our experience of the first 10 cases using the 2.4 mm variable angle LCP volar rim distal radius plate (Depuy Synthes®, West Chester, US), a low-profile volar rim-contouring plate designed for distal plate positioning and stable buttressing of the volar marginal fragment.Methods: Follow-up patient satisfaction, range of motion, grips strength, functional scoring with the QuickDASH and residual pain with a numeric rating scale were assessed. Radiological evaluation consisted in evaluating fracture consolidation, ulnar variance, volar angulation and maintenance of the volar rim fixation.Results: The female to male ratio was 5:5 and the mean age was 52.2 (range, 17–80) years. The mean follow-up period was 11 (range, 5–19) months postoperatively. Patient satisfaction was high. The mean total flexion/extension range was 144° (range, 100–180°) compared to the contralateral uninjured side 160° (range, 95–180°). The mean total pronation/supination range was 153° (range, 140–180°) compared to the contralateral uninjured side 170° (range, 155–180°). Mean grip strength was 14 kg (range, 9–22), compared to the contralateral uninjured side 20 kg (range, 12–25 kg). Mean pre-injury level activity QuickDASH was 23 (range, 0–34.1), while post-recovery QuickDASH was 25 (range 0–43.2). Residual pain was 1.5 on the visual numerical pain rating scale. Radiological evaluation revealed in all cases fracture consolidation, satisfactory reconstruction of ulnar variance, volar angulation and volar rim. We encountered no flexor tendon complications, although plate removal was systematically performed after fracture consolidation.Conclusions: The 2.4 mm variable angle LCP volar rim distal radius plates is a valid treatment option for treating the volar marginal fragment in distal radius fractures.
Engel type identities with generalized derivations in prime rings
Authors: Dhara Basudeb , Pradhan Krishna Gopal , Tiwari Shailesh Kumar 
Published: May 2017

Let [Formula: see text] be a noncommutative prime ring with its Utumi ring of quotients [Formula: see text], [Formula: see text] the extended centroid of [Formula: see text], [Formula: see text] a generalized derivation of [Formula: see text] and [Formula: see text] a nonzero ideal of [Formula: see text]. If [Formula: see text] satisfies any one of the following conditions: (i) [Formula: see text], [Formula: see text], [Formula: see text], (ii) [Formula: see text], where [Formula: see text] is a fixed integer, then one of the following holds: (1) there exists [Formula: see text] such that [Formula: see text] for all [Formula: see text]; (2) [Formula: see text] satisfies [Formula: see text] and there exist [Formula: see text] and [Formula: see text] such that [Formula: see text] for all [Formula: see text]; (3) char [Formula: see text], [Formula: see text] satisfies [Formula: see text] and there exist [Formula: see text] and an outer derivation [Formula: see text] of [Formula: see text] such that [Formula: see text] for all [Formula: see text].
Do Aspirin and Other NSAIDs Confer a Survival Benefit in Men Diagnosed with Prostate Cancer? A Pooled Analysis of NIH-AARP and PLCO Cohorts
Authors: Zhou Cindy Ke , Daugherty Sarah E. , Liao Linda M. , Freedman Neal D. , Abnet Christian C. , Pfeiffer Ruth , Cook Michael B. 
Published: May 2017

Abstract
Prostate cancer is one of the leading causes of cancer-related death in U.S. men. There is an unmet need to identify modifiable risk factors for prostate cancer survival. Experimental studies have suggested that nonsteroidal anti-inflammatory drugs (NSAIDs) may improve prostate cancer survival through antithrombotic and anti-inflammation mechanisms. Results from previous observational studies have been equivocal, and few have assessed whether an etiologically relevant time window of exposure exists. We sampled incident prostate cancer cases from two large U.S. prospective cohorts, NIH-AARP Diet and Health Study and PLCO Cancer Screening Trial, to investigate whether pre- and postdiagnostic aspirin and non-aspirin NSAID use were associated with prostate cancer-specific and all-cause mortality. Cox proportional hazards regression models estimated hazard ratios (HRs) and 95% confidence intervals (CIs). Study-specific results were meta-analyzed using fixed-effects models. Pre- and postdiagnostic aspirin or non-aspirin NSAID use were not statistically significantly associated with prostate cancer–specific mortality. However, occasional (less than daily) and daily aspirin users five years or more before prostate cancer diagnosis had 18% (HR = 0.82; 95% CI = 0.75–0.90) and 15% (HR = 0.85; 95% CI = 0.77–0.94) reduced all-cause mortality versus nonusers. Similarly, postdiagnostic occasional and daily aspirin use were associated with 17% (HR = 0.83; 95% CI=0.72–0.95) and 25% (HR = 0.75; 95% CI = 0.66–0.86) reduced all-cause mortality, independent of prediagnostic aspirin use. This study suggests that aspirin or non-aspirin NSAIDs are not associated with prostate cancer survival. However, aspirin use both before and after prostate cancer diagnosis was associated with longer overall survival, highlighting the importance of comorbidity prevention among prostate cancer survivors. Cancer Prev Res; 10(7); 410–20. ©2017 AACR.
Familial Analysis of Epistatic and Sex-Dependent Association of Genes of the Renin–Angiotensin–Aldosterone System and Blood Pressure
Authors: Scurrah Katrina J. , Lamantia Angela , Ellis Justine A. , Harrap Stephen B. 
Published: May 2017

Background—
Renin–angiotensin–aldosterone system genes have been inconsistently associated with blood pressure, possibly because of unrecognized influences of sex-dependent genetic effects or gene–gene interactions (epistasis).

Methods and Results—

We tested association of systolic blood pressure with single-nucleotide polymorphisms (SNPs) at renin (
REN
), angiotensinogen (
AGT
), angiotensin-converting enzyme (
ACE
), angiotensin II type 1 receptor (
AGTR1
), and aldosterone synthase (
CYP11B2
), including sex–SNP or SNP–SNP interactions. Eighty-eight tagSNPs were tested in 2872 white individuals in 809 pedigrees from the Victorian Family Heart Study using variance components models. Three SNPs (rs8075924 and rs4277404 at
ACE
and rs12721297 at
AGTR1
) were individually associated with lower systolic blood pressure with significant (
P
<0.00076) effect sizes ≈1.7 to 2.5 mm Hg. Sex-specific associations were seen for 3 SNPs in men (rs2468523 and rs2478544 at
AGT
and rs11658531 at
ACE
) and 1 SNP in women (rs12451328 at
ACE
). SNP–SNP interaction was suggested (
P
<0.005) for 14 SNP pairs, none of which had shown individual association with systolic blood pressure. Four SNP pairs were at the same gene (2 for
REN
, 1 for
AGT
, and 1 for
AGTR1
). The SNP rs3097 at
CYP11B2
was represented in 5 separate pairs.

Conclusions—
SNPs at key renin–angiotensin–aldosterone system genes associate with systolic blood pressure individually in both sexes, individually in one sex only and only when combined with another SNP. Analyses that incorporate sex-dependent and epistatic effects could reconcile past inconsistencies and account for some of the missing heritability of blood pressure and are generally relevant to SNP association studies for any phenotype.
Impact of Ezetimibe on the Rate of Cardiovascular-Related Hospitalizations and Associated Costs Among Patients With a Recent Acute Coronary Syndrome
Authors: Pokharel Yashashwi , Chinnakondepalli Khaja , Vilain Katherine , Wang Kaijun , Mark Daniel B. , Davies Glenn , Blazing Michael A. , Giugliano Robert P. , Braunwald Eugene , Cannon Christopher P. , Cohen David J. , Magnuson Elizabeth A. 
Published: May 2017

Background—
Ezetimibe, when added to simvastatin therapy, reduces cardiovascular events after recent acute coronary syndrome. However, the impact of ezetimibe on cardiovascular-related hospitalizations and associated costs is unknown.

Methods and Results—

We used patient-level data from the IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial) to examine the impact of simvastatin–ezetimibe versus simvastatin–placebo on cardiovascular-related hospitalizations and related costs (excluding drug costs) over 7 years follow-up. Medicare Severity–Diagnosis Related Groups were assigned to all cardiovascular hospitalizations. Hospital costs were estimated using Medicare reimbursement rates for 2013. Associated physician costs were estimated as a percentage of hospital costs. The impact of treatment assignment on hospitalization rates and costs was estimated using Poisson and linear regression, respectively. There was a significantly lower cardiovascular hospitalization rate with ezetimibe compared with placebo (risk ratio, 0.95; 95% confidence interval, 0.90–0.99;
P
=0.031), mainly attributable to fewer hospitalizations for percutaneous coronary intervention, angina, and stroke. Consequently, cardiovascular-related hospitalization costs over 7 years were $453 per patient lower with ezetimibe (95% confidence interval, −$38 to −$869;
P
=0.030). Although all prespecified subgroups had lower cost with ezetimibe therapy, patients with diabetes mellitus, patients aged ≥75 years, and patients at higher predicted risk for recurrent ischemic events had even greater cost offsets.

Conclusions—
Addition of ezetimibe to statin therapy in patients with a recent acute coronary syndrome leads to reductions in cardiovascular-related hospitalizations and associated costs, with the greatest cost offsets in high-risk patients. These cost reductions may completely offset the cost of the drug once ezetimibe becomes generic, and may lead to cost savings from the perspective of the healthcare system, if treatment with ezetimibe is targeted to high-risk patients.

Clinical Trial Registration—

URL:
https://www.clinicaltrials.gov
. Unique Identifier: NCT00202878