bluuebunny/crossref_metadata_2025_split huggingface dataset:
Host Defense Proteins Derived from Human Saliva Bind to Staphylococcus aureus
Authors: Heo Seok-Mo , Choi Kyoung-Soo , Kazim Latif A. , Reddy Molakala S. , Haase Elaine M. , Scannapieco Frank A. , Ruhl Stefan 
Published: February 2013

ABSTRACTProteins in human saliva are thought to modulate bacterial colonization of the oral cavity. Yet, information is sparse on how salivary proteins interact with systemic pathogens that transiently or permanently colonize the oral environment.Staphylococcus aureusis a pathogen that frequently colonizes the oral cavity and can cause respiratory disease in hospitalized patients at risk. Here, we investigated salivary protein binding to this organism upon exposure to saliva as a first step toward understanding the mechanism by which the organism can colonize the oral cavity of vulnerable patients. By using fluorescently labeled saliva and proteomic techniques, we demonstrated selective binding of major salivary components byS. aureusto include DMBT1gp-340, mucin-7, secretory component, immunoglobulin A, immunoglobulin G, S100-A9, and lysozyme C. Biofilm-grownS. aureusstrains bound fewer salivary components than in the planctonic state, particularly less salivary immunoglobulins. A corresponding adhesive component on theS. aureussurface responsible for binding salivary immunoglobulins was identified as staphylococcal protein A (SpA). However, SpA did not mediate binding of nonimmunoglobulin components, including mucin-7, indicating the involvement of additional bacterial surface adhesive components. These findings demonstrate that a limited number of salivary proteins, many of which are associated with various aspects of host defense, selectively bind toS. aureusand lead us to propose a possible role of saliva in colonization of the human mouth by this pathogen.
Phase Variation of PorA, a Major Outer Membrane Protein, Mediates Escape of Bactericidal Antibodies by Neisseria meningitidis
Authors: Tauseef Isfahan , Ali Youssif M. , Bayliss Christopher D. 
Published: February 2013

ABSTRACT

Several outer membrane proteins of
Neisseria meningitidis
are subject to phase variation due to alterations in simple sequence repeat tracts. The PorA protein is a major outer membrane protein and a target for protective host immune responses. Phase variation of PorA is mediated by a poly-G repeat tract present within the promoter, leading to alterations in protein expression levels.
N. meningitidis
strain 8047 was subjected to serial passage in the presence of P1.2, a PorA-specific bactericidal monoclonal antibody. Rapid development of resistance to bactericidal activity was associated with a switch in the PorA repeat tract from 11G to 10G. Phase variants with a 10G repeat tract exhibited a 2-fold reduction in surface expression of PorA protein. A
mutS
mutant of strain 8047, with an elevated phase variation rate, exhibited a higher rate of escape and an association of escape with 10G and 9G variants, the latter having a 13-fold reduction in surface expression of PorA. We conclude that graduated reductions in the surface expression of outer membrane proteins mediated by phase variation enable meningococci to escape killing
in vitro
by bactericidal antibodies. These findings indicate how phase variation could have a major impact on immune escape and host persistence of meningococci.
RpoS Contributes to Phagocyte Oxidase-Mediated Stress Resistance during Urinary Tract Infection by Escherichia coli CFT073
Authors: Hryckowian Andrew J. , Welch Rodney A. 
Published: February 2013

ABSTRACT

Uropathogenic
Escherichia coli
(UPEC) is the most common causative agent of community-acquired urinary tract infection (UTI). In order to cause UTI, UPEC must endure stresses ranging from nutrient limitation to host immune components. RpoS (σ
S
), the general stress response sigma factor, directs gene expression under a variety of inhibitory conditions. Our study of
rpoS
in UPEC strain CFT073 began after we discovered an
rpoS-
frameshift mutation in one of our laboratory stocks of “wild-type” CFT073. We demonstrate that an
rpoS
-deletion mutation in CFT073 leads to a colonization defect during UTI of CBA/J mice at 48 hours postinfection (hpi). There is no difference between the growth rates of CFT073 and CFT073
rpoS
in urine. This indicates that
rpoS
is needed for replication and survival in the host rather than being needed to address limitations imposed by urine nutrients. Consistent with previous observations in
E. coli
K-12, CFT073
rpoS
is more sensitive to oxidative stress than the wild type. We demonstrate that peroxide levels are elevated in voided urine from CFT073-infected mice compared to urine from mock-infected mice, which supports the notion that oxidative stress is generated by the host in response to UPEC. In mice that lack phagocyte oxidase, the enzyme complex expressed by phagocytes that produces superoxide, the competitive defect of CFT073
rpoS
in bladder colonization is lost. These results demonstrate that σ
S
is important for UPEC survival under conditions of phagocyte oxidase-generated stress during UTI. Though σ
S
affects the pathogenesis of other bacterial species, this is the first work that directly implicates σ
S
as important for UPEC pathogenesis.

IMPORTANCE
UPEC must cope with a variety of stressful conditions in the urinary tract during infection. RpoS (σ
S
), the general stress response sigma factor, is known to direct the expression of many genes under a variety of stressful conditions in laboratory-adapted
E. coli
K-12. Here, we show that σ
S
is needed by the model UPEC strain CFT073 to cope with oxidative stress provided by phagocytes during infection. These findings represent the first report that implicates σ
S
in the fitness of UPEC during infection and support the idea of the need for a better understanding of the effects of this global regulator of gene expression during UTI.
A Genetic Resource for Rapid and Comprehensive Phenotype Screening of Nonessential Staphylococcus aureus Genes
Authors: Fey Paul D. , Endres Jennifer L. , Yajjala Vijaya Kumar , Widhelm Todd J. , Boissy Robert J. , Bose Jeffrey L. , Bayles Kenneth W. 
Published: February 2013

ABSTRACT

To enhance the research capabilities of investigators interested in
Staphylococcus aureus
, the Nebraska Center for Staphylococcal Research (CSR) has generated a sequence-defined transposon mutant library consisting of 1,952 strains, each containing a single mutation within a nonessential gene of the epidemic community-associated methicillin-resistant
S. aureus
(CA-MRSA) isolate USA300. To demonstrate the utility of this library for large-scale screening of phenotypic alterations, we spotted the library on indicator plates to assess hemolytic potential, protease production, pigmentation, and mannitol utilization. As expected, we identified many genes known to function in these processes, thus validating the utility of this approach. Importantly, we also identified genes not previously associated with these phenotypes. In total, 71 mutants displayed differential hemolysis activities, the majority of which were not previously known to influence hemolysin production. Furthermore, 62 mutants were defective in protease activity, with only 14 previously demonstrated to be involved in the production of extracellular proteases. In addition, 38 mutations affected pigment formation, while only 7 influenced mannitol fermentation, underscoring the sensitivity of this approach to identify rare phenotypes. Finally, 579 open reading frames were not interrupted by a transposon, thus providing potentially new essential gene targets for subsequent antibacterial discovery. Overall, the Nebraska Transposon Mutant Library represents a valuable new resource for the research community that should greatly enhance investigations of this important human pathogen.

IMPORTANCE
Infections caused by
Staphylococcus aureus
cause significant morbidity and mortality in both community and hospital environments. Specific-allelic-replacement mutants are required to study the biology of this organism; however, this process is costly and time-consuming. We describe the construction and validation of a sequence-defined transposon mutant library available for use by the scientific community through the Network on Antimicrobial Resistance in
Staphylococcus aureus
(NARSA) strain repository. In addition, complementary resources, including a website (
http://app1.unmc.edu/fgx/
) and genetic tools that expedite the allelic replacement of the transposon in the mutants with useful selectable markers and fluorescent reporter fusions, have been generated. Overall, this library and associated tools will have a significant impact on studies investigating
S. aureus
pathogenesis and biology and serve as a useful paradigm for the study of other bacterial systems.
Steps to a better Belfast: physical activity assessment and promotion in primary care
Authors: Heron Neil , Tully Mark A , McKinley Michelle C , Cupples Margaret E 
Published: February 2013

BackgroundLow physical activity (PA) levels which increase the risk of chronic disease are reported by two-thirds of the general UK population. Promotion of PA by primary healthcare professionals is advocated but more evidence is needed regarding effective ways of integrating this within everyday practice. This study aims to explore the feasibility of a randomised trial of a pedometer-based intervention, using step-count goals, recruiting patients from primary care.MethodPatients, aged 35–75, attending four practices in socioeconomically deprived areas, were invited to complete a General Practice PA Questionnaire during routine consultations. Health professionals invited ‘inactive’ individuals to a pedometer-based intervention and were randomly allocated to group 1 (prescribed a self-determined goal) or group 2 (prescribed a specific goal of 2500 steps/day above baseline). Both groups kept step-count diaries and received telephone follow-up at 1, 2, 6 and 11 weeks. Step counts were reassessed after 12 weeks.ResultsOf the 2154 patients attending, 192 questionnaires were completed (8.9%). Of these, 83 were classified as ‘inactive’; 41(10 men; 31 women) completed baseline assessments, with the mean age of participants being 51 years. Mean baseline step counts were similar in group 1 (5685, SD 2945) and group 2 (6513, SD 3350). The mean increase in steps/day was greater in groups 1 than 2 ((2602, SD 1957) vs (748, SD 1997) p=0.005).ConclusionsA trial of a pedometer-based intervention using self-determined step counts appears feasible in primary care. Pedometers appear acceptable to women, particularly at a perimenopausal age, when it is important to engage in impact loading activities such as walking to maintain bone mineral density. An increase of 2500 steps/day is achievable for inactive patients, but the effectiveness of different approaches to realistic goal-setting warrants further study.
Measures of exposure to road traffic injury risk
Authors: Santamariña-Rubio Elena , Pérez Katherine , Olabarria Marta , Novoa Ana M 
Published: February 2013

ObjectiveTo compare the risk of road traffic injury calculated using an exposure measure based on people’s mobility, person-hours travelled (person-hours), with the risk obtained using population census, vehicle fleet and vehicle-kilometres travelled.MethodsThe rate of road traffic injury on a working day in Catalonia in 2006 was calculated using the number of people injured from the Register of Accidents and Victims of the National Traffic Authority and as denominator: person-hours travelled, from the 2006 Daily Mobility Survey of Catalonia; population census and vehicle fleet, from the National Statistics Institute; and vehicle-kilometres, from the Ministry of Public Works.ResultsCompared with person-hours travelled: population census may underestimate the risk in groups with low mobility; vehicle-kilometres may underestimate the risk in regions with high level of non-motorised mobility and high use of public transport; vehicle fleet may underestimate the risk for collective forms of transport such as buses and for motorcyclists who make many trips but of short duration.ConclusionsMeasures of exposure involving people's mobility should be used in the estimation of road traffic injury risk, instead of vehicle's mobility, population census or vehicle fleet.
Development of a Colon Cancer GEMM-Derived Orthotopic Transplant Model for Drug Discovery and Validation
Authors: Martin Eric S. , Belmont Peter J. , Sinnamon Mark J. , Richard Larissa Georgeon , Yuan Jing , Coffee Erin M. , Roper Jatin , Lee Lydia , Heidari Pedram , Lunt Sophia Y. , Goel Gautam , Ji Xiadong , Xie Zhi , Xie Tao , Lamb John , Weinrich Scott L. , VanArsdale Todd , Bronson Roderick T. , Xavier Ramnik J. , Vander Heiden Matthew G. , Kan Julie L. C. , Mahmood Umar , Hung Kenneth E. 
Published: February 2013

AbstractPurpose: Effective therapies for KRAS-mutant colorectal cancer (CRC) are a critical unmet clinical need. Previously, we described genetically engineered mouse models (GEMM) for sporadic Kras-mutant and non-mutant CRC suitable for preclinical evaluation of experimental therapeutics. To accelerate drug discovery and validation, we sought to derive low-passage cell lines from GEMM Kras-mutant and wild-type tumors for in vitro screening and transplantation into the native colonic environment of immunocompetent mice for in vivo validation.Experimental Design: Cell lines were derived from Kras-mutant and non-mutant GEMM tumors under defined media conditions. Growth kinetics, phosphoproteomes, transcriptomes, drug sensitivity, and metabolism were examined. Cell lines were implanted in mice and monitored for in vivo tumor analysis.Results: Kras-mutant cell lines displayed increased proliferation, mitogen-activated protein kinase signaling, and phosphoinositide-3 kinase signaling. Microarray analysis identified significant overlap with human CRC-related gene signatures, including KRAS-mutant and metastatic CRC. Further analyses revealed enrichment for numerous disease-relevant biologic pathways, including glucose metabolism. Functional assessment in vitro and in vivo validated this finding and highlighted the dependence of Kras-mutant CRC on oncogenic signaling and on aerobic glycolysis.Conclusions: We have successfully characterized a novel GEMM-derived orthotopic transplant model of human KRAS-mutant CRC. This approach combines in vitro screening capability using low-passage cell lines that recapitulate human CRC and potential for rapid in vivo validation using cell line-derived tumors that develop in the colonic microenvironment of immunocompetent animals. Taken together, this platform is a clear advancement in preclinical CRC models for comprehensive drug discovery and validation efforts. Clin Cancer Res; 19(11); 2929–40. ©2013 AACR.
Inhibition of BET Bromodomain Targets Genetically Diverse Glioblastoma
Authors: Cheng Zhixiang , Gong Yuanying , Ma Yufang , Lu Kaihua , Lu Xiang , Pierce Larry A. , Thompson Reid C. , Muller Susanne , Knapp Stefan , Wang Jialiang 
Published: February 2013

Abstract
Purpose: Glioblastoma is refractory to conventional therapies. The bromodomain and extraterminal domain (BET) proteins are epigenetic readers that selectively bind to acetylated lysine residues on histone tails. These proteins recently emerged as important therapeutic targets in NUT midline carcinoma and several types of hematopoietic cancers. In this study, the therapeutic potential of a novel BET bromodomain inhibitor, JQ1, was assessed in a panel of genetically heterogeneous glioblastoma samples.
Experimental Design: The antineoplastic effects of JQ1 were shown using ex vivo cultures derived from primary glioblastoma xenograft lines and surgical specimens of different genetic background. The in vivo efficacy was assessed in orthotopic glioblastoma tumors.
Results: We showed that JQ1 induced marked G1 cell-cycle arrest and apoptosis, which was phenocopied by knockdown of individual BET family members. JQ1 treatment resulted in significant changes in expression of genes that play important roles in glioblastoma such as c-Myc, p21CIP1/WAF1, hTERT, Bcl-2, and Bcl-xL. Unlike the observations in some hematopoietic cancer cell lines, exogenous c-Myc did not significantly protect glioblastoma cells against JQ1. In contrast, ectopically expressed Bcl-xL partially rescued cells from JQ1-induced apoptosis, and knockdown of p21CIP1/WAF1 attenuated JQ1-induced cell-cycle arrest. Cells genetically engineered for Akt hyperactivation or p53/Rb inactivation did not compromise JQ1 efficacy, suggesting that these frequently mutated signaling pathways may not confer resistance to JQ1. Furthermore, JQ1 significantly repressed growth of orthotopic glioblastoma tumors.
Conclusion: Our results suggest potentially broad therapeutic use of BET bromodomain inhibitors for treating genetically diverse glioblastoma tumors. Clin Cancer Res; 19(7); 1748–59. ©2013 AACR.
Glioblastoma Resistance to Anti-VEGF Therapy: Has the Challenge Been MET?
Authors: McCarty Joseph H. 
Published: February 2013

Abstract
In glioblastoma cells the receptor tyrosine kinase c-Met is upregulated in response to bevacizumab and plays an important role in promoting invasion and tumor recurrence. These data support novel links between VEGF-A and hepatocyte growth factor and suggest that c-Met and its signaling effectors may be effective targets for anti-invasive therapies. Clin Cancer Res; 19(7); 1631–3. ©2013 AACR.
Effects of Mineralocorticoid Receptor Antagonists on the Risk of Sudden Cardiac Death in Patients With Left Ventricular Systolic Dysfunction
Authors: Bapoje Srinivas R. , Bahia Amit , Hokanson John E. , Peterson Pamela N. , Heidenreich Paul A. , Lindenfeld JoAnn , Allen Larry A. , Masoudi Frederick A. 
Published: February 2013

Background—
Sudden cardiac death (SCD) is an important cause of death in patients with left ventricular systolic dysfunction. Mineralocorticoid receptor antagonists (MRAs) may attenuate this risk. The objective of this meta-analysis was to assess the impact of MRAs on SCD in patients with left ventricular systolic dysfunction.

Methods and Results—

We systematically searched PubMed, EMBASE, Cochrane, and other databases through March 30, 2012, without language restrictions. We included trials that enrolled patients with left ventricular ejection fraction of ≤45%, randomized subjects to MRAs versus control and reported outcomes on SCD, total and cardiovascular mortality. Eight published trials that enrolled 11 875 patients met inclusion criteria. Of these, 6 reported data on SCD and cardiovascular mortality, and 7 reported data on total mortality. No heterogeneity was observed among the trials. Patients treated with MRAs had 23% lower odds of experiencing SCD compared with controls (odds ratio, 0.77; 95% confidence interval, 0.66–0.89;
P
=0.001). Similar reductions were observed in cardiovascular (0.75; 95% confidence interval, 0.68–0.84;
P
<0.001) and total mortality (odds ratio, 0.74; 95% confidence interval, 0.63–0.86;
P
<0.001). Although publication bias was observed, the results did not change after a trim and fill test, suggesting that the impact of this bias was likely insignificant.

Conclusions
—MRAs reduce the risk of SCD in patients with left ventricular systolic dysfunction. Comparative effectiveness studies of MRAs on SCD in usual care as well as studies evaluating the efficacy of other therapies to prevent SCD in patients receiving optimal MRA therapy are needed to guide clinical decision-making.
Chronic Manifestation of Postreperfusion Intramyocardial Hemorrhage as Regional Iron Deposition
Authors: Kali Avinash , Kumar Andreas , Cokic Ivan , Tang Richard L.Q. , Tsaftaris Sotirios A. , Friedrich Matthias G. , Dharmakumar Rohan 
Published: February 2013

Background—
Intramyocardial hemorrhage frequently accompanies large reperfused myocardial infarctions. However, its influence on the makeup and the ensuing effect on the infarcted tissue during the chronic phase remain unexplored.

Methods and Results—

Patients (n=15; 3 women), recruited after successful percutaneous coronary intervention for first segment–elevation myocardial infarction, underwent cardiovascular magnetic resonance imaging on day 3 and month 6 after percutaneous coronary intervention. Patients with hemorrhagic (Hemo+) infarctions, as determined by T2* cardiovascular magnetic resonance on day 3 (n=11), showed persistent T2* losses colocalized with scar tissue on the follow-up scans, suggesting chronic iron deposition. T2* values of Hemo+ territories were significantly higher than nonhemorrhagic (Hemo−) and remote territories (
P
<0.001); however, T2* values of nonhemorrhagic (Hemo−) and remote territories were not different (
P
=0.51). Canines (n=20) subjected to ischemia-reperfusion injury (n=14) underwent cardiovascular magnetic resonance on days 3 and 56 after ischemia-reperfusion injury. Similarly, sham-operated animals (Shams; n=3) were imaged using cardiovascular magnetic resonance at similar time points. Subsequently, hearts were explanted and imaged ex vivo, and samples of Hemo+, Hemo−, remote, and Sham myocardium were isolated and stained. The extent of iron deposition ([Fe]) within each sample was measured using mass spectrometry. Hemo+ infarcts showed significant T2* losses compared with the other (control) groups (
P
<0.001), and Perls stain confirmed localized iron deposition. Mean [Fe] of Hemo+ was nearly an order of magnitude greater than that of the control groups (
P
<0.001), but no significant differences were observed among the control groups. A strong linear relationship was observed between log(T2*) and −log([Fe]);
R
2
=0.7 and
P
<0.001. The monoclonal antibody Mac387 stains, along with Perls stains, showed preferential localization of newly recruited macrophages at the site of chronic iron deposition.

Conclusions—
Hemorrhagic myocardial infarction can lead to iron depositions within the infarct zones, which can be a source of prolonged inflammatory burden in the chronic phase of myocardial infarction.
Statins Reduce Neurologic Injury in Asymptomatic Carotid Endarterectomy Patients
Authors: Heyer Eric J. , Mergeche Joanna L. , Bruce Samuel S. , Ward Justin T. , Stern Yaakov , Anastasian Zirka H. , Quest Donald O. , Solomon Robert A. , Todd George J. , Benvenisty Alan I. , McKinsey James F. , Nowygrod Roman , Morrissey Nicholas J. , Connolly E. Sander 
Published: February 2013

Background and Purpose—
Statins are neuroprotective in a variety of experimental models of cerebral injury. We sought to determine whether patients taking statins before asymptomatic carotid endarterectomy exhibit a lower incidence of neurological injury (clinical stroke and cognitive dysfunction).

Methods—
A total of 328 patients with asymptomatic carotid stenosis scheduled for elective carotid endarterectomy consented to participate in this observational study of perioperative neurological injury.

Results—

Patients taking statins had a lower incidence of clinical stroke (0.0% vs 3.1%;
P
=0.02) and cognitive dysfunction (11.0% vs 20.2%;
P
=0.03). In a multivariate regression model, statin use was significantly associated with decreased odds of cognitive dysfunction (odds ratio, 0.51 [95% CI, 0.27–0.96];
P
=0.04).

Conclusions—
Preoperative statin use was associated with less neurological injury after asymptomatic carotid endarterectomy. These observations suggest that it may be possible to further reduce the perioperative morbidity of carotid endarterectomy.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00597883