bluuebunny/crossref_metadata_2025_split huggingface dataset:
Expanding Role of Type II Secretion in Bacterial Pathogenesis and Beyond
Authors: Cianciotto Nicholas P. , White Richard C. 
Published: March 2017

ABSTRACTType II secretion (T2S) is one means by which Gram-negative pathogens secrete proteins into the extracellular milieu and/or host organisms. Based upon recent genome sequencing, it is clear that T2S is largely restricted to theProteobacteria, occurring in many, but not all, genera in theAlphaproteobacteria,Betaproteobacteria,Gammaproteobacteria, andDeltaproteobacteriaclasses. Prominent human and/or animal pathogens that express a T2S system(s) includeAcinetobacter baumannii,Burkholderia pseudomallei,Chlamydia trachomatis,Escherichia coli,Klebsiella pneumoniae,Legionella pneumophila,Pseudomonas aeruginosa,Stenotrophomonas maltophilia,Vibrio cholerae, andYersinia enterocolitica. T2S-expressing plant pathogens includeDickeya dadantii,Erwinia amylovora,Pectobacterium carotovorum,Ralstonia solanacearum,Xanthomonas campestris,Xanthomonas oryzae, andXylella fastidiosa. T2S also occurs in nonpathogenic bacteria, facilitating symbioses, among other things. The output of a T2S system can range from only one to dozens of secreted proteins, encompassing a diverse array of toxins, degradative enzymes, and other effectors, including novel proteins. Pathogenic processes mediated by T2S include the death of host cells, degradation of tissue, suppression of innate immunity, adherence to host surfaces, biofilm formation, invasion into and growth within host cells, nutrient assimilation, and alterations in host ion flux. The reach of T2S is perhaps best illustrated by those bacteria that clearly use it for both environmental survival and virulence; e.g.,L. pneumophilaemploys T2S for infection of amoebae, growth within lung cells, dampening of cytokines, and tissue destruction. This minireview provides an update on the types of bacteria that have T2S, the kinds of proteins that are secreted via T2S, and how T2S substrates promote infection.
Optogenetic Manipulation of Cyclic Di-GMP (c-di-GMP) Levels Reveals the Role of c-di-GMP in Regulating Aerotaxis Receptor Activity in Azospirillum brasilense
Authors: O'Neal Lindsey , Ryu Min-Hyung , Gomelsky Mark , Alexandre Gladys 
Published: March 2017

ABSTRACT

Bacterial chemotaxis receptors provide the sensory inputs that inform the direction of navigation in changing environments. Recently, we described the bacterial second messenger cyclic di-GMP (c-di-GMP) as a novel regulator of a subclass of chemotaxis receptors. In
Azospirillum brasilense
, c-di-GMP binds to a chemotaxis receptor, Tlp1, and modulates its signaling function during aerotaxis. Here, we further characterize the role of c-di-GMP in aerotaxis using a novel dichromatic optogenetic system engineered for manipulating intracellular c-di-GMP levels in real time. This system comprises a red/near-infrared-light-regulated diguanylate cyclase and a blue-light-regulated c-di-GMP phosphodiesterase. It allows the generation of transient changes in intracellular c-di-GMP concentrations within seconds of irradiation with appropriate light, which is compatible with the time scale of chemotaxis signaling. We provide experimental evidence that binding of c-di-GMP to the Tlp1 receptor activates its signaling function during aerotaxis, which supports the role of transient changes in c-di-GMP levels as a means of adjusting the response of
A. brasilense
to oxygen gradients. We also show that intracellular c-di-GMP levels in
A. brasilense
change with carbon metabolism. Our data support a model whereby c-di-GMP functions to imprint chemotaxis receptors with a record of recent metabolic experience, to adjust their contribution to the signaling output, thus allowing the cells to continually fine-tune chemotaxis sensory perception to their metabolic state.

IMPORTANCE
Motile bacteria use chemotaxis to change swimming direction in response to changes in environmental conditions. Chemotaxis receptors sense environmental signals and relay sensory information to the chemotaxis machinery, which ultimately controls the swimming pattern of cells. In bacteria studied to date, differential methylation has been known as a mechanism to control the activity of chemotaxis receptors and modulates their contribution to the overall chemotaxis response. Here, we used an optogenetic system to perturb intracellular concentrations of the bacterial second messenger c-di-GMP to show that in some chemotaxis receptors, c-di-GMP functions in a similar feedback loop to connect the metabolic status of the cells to the sensory activity of chemotaxis receptors.
GigA and GigB are Master Regulators of Antibiotic Resistance, Stress Responses, and Virulence in Acinetobacter baumannii
Authors: Gebhardt Michael J. , Shuman Howard A. 
Published: March 2017

ABSTRACT

A critical component of bacterial pathogenesis is the ability of an invading organism to sense and adapt to the harsh environment imposed by the host's immune system. This is especially important for opportunistic pathogens, such as
Acinetobacter baumannii
, a nutritionally versatile environmental organism that has recently gained attention as a life-threatening human pathogen. The emergence of
A. baumannii
is closely linked to antibiotic resistance, and many contemporary isolates are multidrug resistant (MDR). Unlike many other MDR pathogens, the molecular mechanisms underlying
A. baumannii
pathogenesis remain largely unknown. We report here the characterization of two recently identified virulence determinants, GigA and GigB, which comprise a signal transduction pathway required for surviving environmental stresses, causing infection and antibiotic resistance. Through transcriptome analysis, we show that GigA and GigB coordinately regulate the expression of many genes and are required for generating an appropriate transcriptional response during antibiotic exposure. Genetic and biochemical data demonstrate a direct link between GigA and GigB and the nitrogen phosphotransferase system (PTS
Ntr
), establishing a novel connection between a novel stress response module and a well-conserved metabolic-sensing pathway. Based on the results presented here, we propose that GigA and GigB are master regulators of a global stress response in
A. baumannii
, and coupling this pathway with the PTS
Ntr
allows
A. baumannii
to integrate cellular metabolic status with external environmental cues.

IMPORTANCE
Opportunistic pathogens, including
Acinetobacter baumannii
, encounter many harsh environments during the infection cycle, including antibiotic exposure and the hostile environment within a host. While the development of antibiotic resistance in
A. baumannii
has been well studied, how this organism senses and responds to environmental cues remain largely unknown. Herein, we investigate two previously identified virulence determinants, GigA and GigB, and report that they are required for
in vitro
stress resistance, likely comprising upstream elements of a global stress response pathway. Additional experiments identify a connection between GigA/GigB and a widely conserved metabolic-sensing pathway, the nitrogen phosphotransferase system. We propose that coordination of these two pathways allows
A. baumannii
to respond appropriately to changing environmental conditions, including those encountered during infection.
Cost-effectiveness analysis of an 18-week exercise programme for patients with breast and colon cancer undergoing adjuvant chemotherapy: the randomised PACT study
Authors: May Anne M , Bosch Marcel J C , Velthuis Miranda J , van der Wall Elsken , Steins Bisschop Charlotte N , Los Maartje , Erdkamp Frans , Bloemendal Haiko J , de Roos Marnix A J , Verhaar Marlies , ten Bokkel Huinink Daan , Peeters Petra H M , de Wit G Ardine 
Published: March 2017

ObjectiveMeta-analyses show that exercise interventions during cancer treatment reduce cancer-related fatigue. However, little is known about the cost-effectiveness of such interventions. Here we aim to assess the cost-effectiveness of the 18-week physical activity during cancer treatment (PACT) intervention for patients with breast and colon cancer. The PACT trial showed beneficial effects for fatigue and physical fitness.DesignCost-effectiveness analyses with a 9-month time horizon (18 weeks of intervention and 18 weeks of follow-up) within the randomised controlled multicentre PACT study.SettingOutpatient clinics of 7 hospitals in the Netherlands (1 academic and 6 general hospitals)Participants204 patients with breast cancer and 33 with colon cancer undergoing adjuvant treatment including chemotherapy.InterventionSupervised 1-hour aerobic and resistance exercise (twice per week for 18 weeks) or usual care.Main outcome measuresCosts, quality-adjusted life years (QALY) and the incremental cost-effectiveness ratio.ResultsFor colon cancer, the cost-effectiveness analysis showed beneficial effects of the exercise intervention with incremental costs savings of €4321 and QALY improvements of 0.03. 100% of bootstrap simulations indicated that the intervention is dominant (ie, cheaper and more effective). For breast cancer, the results did not indicate that the exercise intervention was cost-effective. Incremental costs were €2912, and the incremental effect was 0.01 QALY. At a Dutch threshold value of €20 000 per QALY, the probability that the intervention is cost-effective was 2%.ConclusionsOur results suggest that the 18-week exercise programme was cost-effective for colon cancer, but not for breast cancer.Trial registration numberISRCTN43801571.
Effects of school breaks on influenza-like illness incidence in a temperate Chinese region: an ecological study from 2008 to 2015
Authors: Chu Yanhui , Wu Zhenyu , Ji Jiayi , Sun Jingyi , Sun Xiaoyu , Qin Guoyou , Qin Jingning , Xiao Zheng , Ren Jian , Qin Di , Zheng Xueying , Wang Xi-Ling 
Published: March 2017

ObjectiveTo assess the effects of winter/summer school breaks on occurrences of influenza-like illness (ILI).MethodsWe jointly analysed ILI surveillance data with the timing of school breaks in a temperate district in Beijing, China from 2008 to 2015. ILI incidence rate ratios (IRRs) of schoolchildren (5–14 and 15–24 years of age) to adults (25–59 and >60 years of age) were used to measure the age shift of ILI incidence before, during and after the 4-week winter/7-week summer breaks. Serfling-based Poisson regression model with adjustment for unmeasured confounders was built to further assess the effect of winter school breaks.ResultsILI incidences were consistently lower during winter breaks than before winter breaks for all age groups. IRRs of younger schoolchildren aged 5–14 to adults were higher during winter school breaks than before breaks, while the opposite was true for the IRRs of older schoolchildren aged 15–24 to adults. Schoolchildren-to-adults IRRs during summer breaks were significantly lower than before or after school breaks (p<0.001).ConclusionsBoth winter and summer breaks were associated with reductions of ILI incidences among schoolchildren and adults. Our study contributes additional evidence on the effects of school breaks on ILI incidence, suggesting school closure could be effective in controlling influenza transmission in developing countries.
Head-to-head comparison of procalcitonin and presepsin for the diagnosis of sepsis in critically ill adult patients: a protocol for a systematic review and meta-analysis
Authors: Hayashida Kei , Kondo Yutaka , Hara Yoshitaka , Aihara Morio , Yamakawa Kazuma 
Published: March 2017

IntroductionEarly diagnosis and immediate therapeutic intervention, including appropriate antibiotic therapy and goal-directed resuscitation, are necessary to reduce mortality in patients with sepsis. However, a single clinical or biological marker indicative of sepsis has not been adopted unanimously. Although procalcitonin and presepsin are promising biomarkers that can effectively differentiate between sepsis/infection and systemic inflammatory response syndrome of non-infectious origin, little is known about which marker is superior.Methods and analysisWe will conduct a systematic review and meta-analysis of procalcitonin and presepsin for the diagnosis of sepsis/infection in critically ill adult patients. The primary objective is to evaluate the diagnostic accuracy of these 2 biomarkers to a reference standard of sepsis/infection and to compare the diagnostic accuracy with each other. We will search electronic bibliographic databases such as MEDLINE, EMBASE and Cochrane Central Register of Controlled Trials for retrospective and prospective diagnostic test studies. We will assign 2 reviewers to review all collected titles and associated abstracts, review full articles, and extract study data. We will use the Quality of Diagnostic Accuracy Studies-II tool to report study characteristics and to evaluate methodological quality. If pooling is possible, we will use bivariate random effects and hierarchical summary receiver operating characteristic (ROC) models to calculate parameter estimates to output summary ROCs, pooled sensitivity and specificity data, and 95% CIs around the summary operating point. We will also assess heterogeneity via clinical and methodological subgroup and sensitivity analyses.Ethics and disseminationThis systematic review will provide guidance on the triage of these tests, help to determine whether existing tests should be revised or replaced, and may also identify knowledge gaps in sepsis diagnosis that could direct further research in the field. Research ethics is not required for this review. The findings will be reported at conferences and in peer-reviewed publications.Trial registration numberCRD42016035784.
Tourniquet parent artery occlusion after flow diversion
Authors: Srinivasan Visish M , Mokin Maxim , Duckworth Edward A M , Chen Stephen , Puri Ajit , Kan Peter 
Published: March 2017

BackgroundThe Pipeline Embolization Device (PED) is increasingly used for both on- and off-label purposes for treatment of intracranial aneurysms. The device gradually slows flow of blood into the aneurysm, but the high metal coverage of PED promotes endothelialization of the device. Occasionally, this leads to in-stent stenosis that is clinically well tolerated. We present a multi-institutional Pipeline series that includes three cases of gradual asymptomatic occlusion within the PED and parent vessel.MethodsInstitutional databases at each participating center were searched for patients treated with the PED. Patients with at least 50% stenosis or occlusion were selected and all relevant clinical and radiographic data were reviewed.ResultsA total of 326 cases performed by five neurointerventionalists across four institutions were reviewed. Among these there were three cases of complete occlusion and two cases of stenosis of more than 50%, for an occlusion rate of 0.9%. All patients were clinically asymptomatic.ConclusionsA gradual tourniquet-like occlusion can occur following placement of the PED, leading to vessel occlusion. This has been clinically well tolerated by patients in our series due to the formation of pial collaterals as the stenosis progresses, likely due to ischemic preconditioning. Small parent vessel, pre-existing stenosis, fusiform pathology, overlapping devices, and suboptimal antiplatelet therapy seem to be predisposing factors. Further experience and follow-up will allow us to characterize the risk factors and optimize post-procedural therapy for these patients.
Algorithmic and Enumerative Aspects of the Moser-Tardos Distribution
Authors: Harris David G. , Srinivasan Aravind 
Published: March 2017

Moser and Tardos have developed a powerful algorithmic approach (henceforth MT) to the Lovász Local Lemma (LLL); the basic operation done in MT and its variants is a search for “bad” events in a current configuration. In the initial stage of MT, the variables are set independently. We examine the distributions on these variables that arise during intermediate stages of MT. We show that these configurations have a more or less “random” form, building further on the MT-distribution concept of Haeupler et al. in understanding the (intermediate and) output distribution of MT. This has a variety of algorithmic applications; the most important is that bad events can be found relatively quickly, improving on MT across the complexity spectrum. It makes some polynomial-time algorithms sublinear (e.g., for Latin transversals, which are of basic combinatorial interest), gives lower-degree polynomial runtimes in some settings, transforms certain superpolynomial-time algorithms into polynomial-time algorithms, and leads to Las Vegas algorithms for some coloring problems for which only Monte Carlo algorithms were known.
We show that, in certain conditions when the LLL condition is violated, a variant of the MT algorithm can still produce a distribution that avoids most of the bad events. We show in some cases that this MT variant can run faster than the original MT algorithm itself and develop the first-known criterion for the case of the asymmetric LLL. This can be used to find partial Latin transversals—improving on earlier bounds of Stein (1975)—among other applications. We furthermore give applications in enumeration, showing that most applications (for which we aim for all or most of the bad events to be avoided) have large solution sets. We do this by showing that the MT distribution has large Rényi entropy.
A Prospective Cohort Study of Cigarette Prices and Smoking Cessation in Older Smokers
Authors: Stevens Victoria L. , Diver W. Ryan , Stoklosa Michal , Flanders W. Dana , Westmaas J. Lee , Jemal Ahmedin , Drope Jeffrey M. , Gapstur Susan M. , Jacobs Eric J. 
Published: March 2017

Abstract
Background: Cigarette price increases effectively prevent smoking initiation and reduce cigarette consumption among young smokers. However, the impact of cigarette prices on smoking cessation among older smokers is less clear, particularly for those aged 65 years and older, a group that is at highest risk of smoking-related disease and will almost double in the United States between 2012 and 2050.
Methods: Biennial questionnaires administered between 1997 and 2013 assessed smoking status for 9,446 Cancer Prevention Study-II Nutrition Cohort participants who were ≥50 years old and lived in Washington, DC, and 48 states. For each interval between biennial questionnaires, change in price per pack and average price level per pack were calculated. The separate associations between these price variables and smoking cessation during the same time interval were determined.
Results: In multivariable-adjusted models, each $1.00 price increase was associated with a 9% higher rate of quitting [rate ratio (RR) = 1.09; 95% confidence interval (CI), 1.04–1.14). Each $1.00 increase in average price was associated with a 6% higher rate of quitting (RR = 1.06; 95% CI, 1.02–1.10). The association with average price was strongest among smokers aged 65 years and older (RR = 1.07; 95% CI, 1.04–1.11) and, for price change, for smokers with no major prevalent disease (RR = 1.13; 95% CI, 1.07–1.19).
Conclusions: These results suggest that increasing cigarette prices will promote quitting even among smokers aged 65 years and older.
Impact: Increasing cigarette prices through higher taxes could reduce smoking rates among older adults and decrease risk of smoking-related cancers and diseases in this high-risk group. Cancer Epidemiol Biomarkers Prev; 26(7); 1071–7. ©2017 AACR.
Genetically Predicted Telomere Length is not Associated with Pancreatic Cancer Risk
Authors: Antwi Samuel O. , Bamlet William R. , Broderick Brendan T. , Chaffee Kari G. , Oberg Ann , Jatoi Aminah , Boardman Lisa A. , Petersen Gloria M. 
Published: March 2017

Abstract
Background: Epidemiologic associations of leukocyte telomere length (LTL) and pancreatic ductal adenocarcinoma (PDAC) have been inconsistent owing, in part, to variation in telomere length (TL) assessment across studies. To overcome this limitation and address concerns of potential reverse causation, we used carriage of telomere-related alleles to genetically predict TL and examined its association with PDAC.
Methods: A case–control study of 1,500 PDAC cases and 1,500 controls, frequency-matched on age and sex was performed. Eight of nine polymorphisms previously associated with variation in LTL were analyzed. Genetic risk scores (GRS) consisting of the TL-related polymorphisms were computed as the number of long TL alleles carried by an individual scaled to published kilobase pairs of TL associated with each allele. Participants were further categorized on the basis of the number of short TL alleles they carry across all eight SNPs. Associations were examined in additive and dominant models using logistic regression to calculate ORs and 95% confidence intervals (CI).
Results: In age- and sex-adjusted models, one short TL allele (rs10936599, T) was associated with reduced risk, whereas another short TL allele (rs2736100, A) was associated with increased risk, with per-allele ORs of 0.89 (95% CI, 0.79–0.99) and 1.13 (95% CI, 1.01–1.24), respectively. No association was observed with GRS or short TL allele counts, and no associations were observed in the dominant models.
Conclusions: Findings suggest that genetically predicted short TL is not associated with PDAC risk.
Impact: Common genetic determinants of short TL do not appear to influence PDAC risk. Cancer Epidemiol Biomarkers Prev; 26(6); 971–4. ©2017 AACR.
A Phase I–II Study of the Oral PARP Inhibitor Rucaparib in Patients with Germline BRCA1/2-Mutated Ovarian Carcinoma or Other Solid Tumors
Authors: Kristeleit Rebecca , Shapiro Geoffrey I. , Burris Howard A. , Oza Amit M. , LoRusso Patricia , Patel Manish R. , Domchek Susan M. , Balmaña Judith , Drew Yvette , Chen Lee-may , Safra Tamar , Montes Ana , Giordano Heidi , Maloney Lara , Goble Sandra , Isaacson Jeff , Xiao Jim , Borrow Jen , Rolfe Lindsey , Shapira-Frommer Ronnie 
Published: March 2017

Abstract
Purpose: Rucaparib is a potent, oral, small-molecule PARP inhibitor. This phase I–II study was the first to evaluate single-agent oral rucaparib at multiple doses.
Experimental Design: Part 1 (phase I) sought to determine the MTD, recommended phase II dose (RP2D), and pharmacokinetics of oral rucaparib administered in 21-day continuous cycles in patients with advanced solid tumors. Part 2A (phase II) enrolled patients with platinum-sensitive, high-grade ovarian carcinoma (HGOC) associated with a germline BRCA1/2 mutation who received two to four prior regimens and had a progression-free interval of 6 months or more following their most recent platinum therapy. The primary endpoint was investigator-assessed objective response rate (ORR) by RECIST version 1.1.
Results: In part 1, 56 patients received oral rucaparib (40 to 500 mg once daily and 240 to 840 mg twice daily). No MTD was identified per protocol-defined criteria; 600 mg twice daily was selected as the RP2D based on manageable toxicity and clinical activity. Pharmacokinetics were approximately dose-proportional across all dose levels. In part 2A, 42 patients with germline BRCA1/2–mutated HGOC received rucaparib 600 mg twice daily. Investigator-assessed ORR was 59.5%. The most common treatment-emergent adverse events (all grades) were asthenia/fatigue (85.7%; 36/42), nausea (83.3%; 35/42), anemia (71.4%; 30/42), alanine transaminase and/or aspartate transaminase elevations (57.1%; 24/42), and vomiting (54.8%; 23/42). Among 98 patients, 5 (5.1%) discontinued because of an adverse event (excluding disease progression).
Conclusions: Rucaparib was tolerable and had activity in patients with platinum-sensitive germline BRCA1/2–mutated HGOC. Clin Cancer Res; 23(15); 4095–106. ©2017 AACR.