bluuebunny/crossref_metadata_2025_split huggingface dataset:
OmpK26, a Novel Porin Associated with Carbapenem Resistance in Klebsiella pneumoniae
Authors: García-Sureda Laura , Doménech-Sánchez Antonio , Barbier Mariette , Juan Carlos , Gascó Joan , Albertí Sebastián 
Published: August 2011

ABSTRACT

Clinical isolates of
Klebsiella pneumoniae
resistant to carbapenems are being isolated with increasing frequency. Loss of the expression of the major nonspecific porins OmpK35/36 is a frequent feature in these isolates. In this study, we looked for porins that could compensate for the loss of the major porins in carbapenem-resistant organisms. Comparison of the outer membrane proteins from two
K. pneumoniae
clinical isogenic isolates that are susceptible (KpCS-1) and resistant (KpCR-1) to carbapenems revealed the absence of OmpK35/36 and the presence of a new 26-kDa protein in the resistant isolate. An identical result was obtained when another pair of isogenic isolates that are homoresistant (Kpn-3) and heteroresistant (Kpn-17) to carbapenems were compared. Mass spectrometry and DNA sequencing analysis demonstrated that this new protein, designated OmpK26, is a small monomeric oligogalacturonate-specific porin that belongs to the KdgM family of porins. Insertion-duplication mutagenesis of the OmpK26 coding gene,
yjhA
, in the carbapenem-resistant, porin-deficient isolate KpCR-1 caused the expression of OmpK36 and the reversion to the carbapenem-susceptible phenotype, suggesting that OmpK26 is indispensable for KpCR-1 to lose OmpK36 and become resistant to these antibiotics. Moreover, loss of the major porin and expression of OmpK26 reduced
in vitro
fitness and attenuated virulence in a murine model of acute systemic infection. Altogether, these results indicate that expression of the oligogalacturonate-specific porin OmpK26 compensates for the absence of OmpK35/36 and allows carbapenem resistance in
K. pneumoniae
but cannot restore the fitness of the microorganism.
Endocytosis-Mediated Vacuolar Accumulation of the Human ApoE Apolipoprotein-Derived ApoEdpL-W Antimicrobial Peptide Contributes to Its Antifungal Activity in Candida albicans
Authors: Rossignol Tristan , Kelly Bridie , Dobson Curtis , d'Enfert Christophe 
Published: August 2011

ABSTRACT

The 18-amino-acid cationic, tryptophan-rich ApoEdpL-W peptide derived from human ApoE apolipoprotein was shown to have antifungal activity against pathogenic yeasts of the
Candida
genus (except
C. glabrata
). ApoEdpL-W was active against planktonic cells and early-stage biofilms but less active against mature biofilms, possibly because of its affinity for extracellular matrix beta-glucans. Moreover, ApoEdpL-W absorbed to medically relevant materials partially prevented the formation of biofilms on these materials. The exposure of
C. albicans
cells to sublethal doses of ApoEdpL-W triggered a transcriptional response reminiscent of that associated with the inactivation of the
MYO5
gene required for endocytosis as well as the upregulation of amino acid transporter genes. A fluorescent derivative of ApoEdpL-W accumulated at the cytoplasmic membrane and subsequently was translocated to the vacuole. Strikingly, the inactivation of
MYO5
or addition of latrunculin, an inhibitor of endocytosis, prevented the vacuolar accumulation of fluorescein-labeled ApoEdpL-W and reduced the antifungal activity of ApoEdpL-W. This, together with the insensitivity of ApoEdpL-W to alterations in membrane fluidity and high salt, suggested that the ApoEdpL-W mode of action was dependent upon vacuolar targeting and differed significantly from that of other antifungal peptides, such as Histatin-5 and Magainin 2.
Bacteriophages Carrying Antibiotic Resistance Genes in Fecal Waste from Cattle, Pigs, and Poultry
Authors: Colomer-Lluch Marta , Imamovic Lejla , Jofre Juan , Muniesa Maite 
Published: August 2011

ABSTRACT

This study evaluates the occurrence of bacteriophages carrying antibiotic resistance genes in animal environments.
bla
TEM
,
bla
CTX-M
(clusters 1 and 9), and
mecA
were quantified by quantitative PCR in 71 phage DNA samples from pigs, poultry, and cattle fecal wastes. Densities of 3 to 4 log
10
gene copies (GC) of
bla
TEM
, 2 to 3 log
10
GC of
bla
CTX-M
, and 1 to 3 log
10
GC of
mecA
per milliliter or gram of sample were detected, suggesting that bacteriophages can be environmental vectors for the horizontal transfer of antibiotic resistance genes.
Virological Response after Short-Term CCR5 Antagonist Exposure in HIV-Infected Patients: Frequency of Subjects with Virological Response and Associated Factors
Authors: Ruiz-Mateos Ezequiel , González-Serna Alejandro , Genebat Miguel , Machmach Kawthar , Vidal Francesc , Muñoz-Fernández Ángeles , Ferrando-Martinez Sara , Leal Manuel 
Published: August 2011

ABSTRACT

The virological response after an 8-day maraviroc monotherapy has been proposed to be an alternative method to determine whether an CCR5 antagonist should be prescribed to HIV-infected patients. The frequency of patients eligible for a combined antiretroviral therapy which includes maraviroc on the basis of the result of this clinical test is not well-known at the moment. In the same way, clinical and immunovirological factors associated with the virological response after antagonist exposure need to be determined. Ninety consecutive HIV-infected patients were exposed to an 8-day maraviroc monotherapy. The virological response was considered positive if either a reduction of ≥1-log
10
HIV RNA copies/ml or an undetectable viral load (<40 HIV RNA copies/ml) was achieved. CXCR4- and CCR5-tropic virus levels were determined by using patients' viral isolates and multiple rounds of infection of indicator cell lines (U87-CXCR4 and U87-CCR5). The frequency of patients with a positive virological response was 72.2% (94.7% and 66.2% for treatment-naïve and pretreated patients, respectively). The positive response rates dramatically decreased in patients with lower CD4
+
T-cell counts. The CXCR4-tropic virus level was the only variable independently associated with the virological response after short-term maraviroc exposure. Lower CD4
+
T-cell strata were associated with higher CXCR4-tropic virus levels. These results support the suggestion that CCR5 antagonists should be an early treatment option before the expansion of CXCR4-tropic strains.
Design and Evaluation of Primaquine-Artemisinin Hybrids as a Multistage Antimalarial Strategy
Authors: Capela Rita , Cabal Ghislain G. , Rosenthal Philip J. , Gut Jiri , Mota Maria M. , Moreira Rui , Lopes Francisca , Prudêncio Miguel 
Published: August 2011

ABSTRACT

It is widely accepted that the struggle against malaria depends on the development of new strategies to fight infection. The “magic bullet” thought to be necessary to reach eradication should not only provide treatment for all
Plasmodium
spp. that infect human red blood cells but should also eliminate the replicative and dormant liver forms of the parasite. Moreover, these goals should ideally be achieved by using different mechanisms of action so as to avoid the development of resistance. To that end, two hybrid molecules with covalently linked primaquine and artemisinin moieties were synthesized, and their effectiveness against the liver and blood stages of infection was compared
in vitro
and
in vivo
with those of the parent compounds. Both hybrids displayed enhanced
in vitro
activities, relative to those of the parent compounds, against
Plasmodium berghei
liver stages. Both compounds were about as potent as artemisinin against cultured
Plasmodium falciparum
(50% inhibitory concentration [IC
50
], ∼10 nM). When used to treat a murine
P. berghei
infection, one of the molecules displayed better efficacy than an equimolar mixture of the parent pharmacophores, leading to improved cure and survival rates. These results reveal a novel approach to the design and evaluation of antimalarials based on the covalent combination of molecules acting on different stages of the parasite life cycle.
Tricomponent Immunopotentiating System as a Novel Molecular Design Strategy for Malaria Vaccine Development
Authors: Miyata Takeshi , Harakuni Tetsuya , Tsuboi Takafumi , Sattabongkot Jetsumon , Ikehara Ayumu , Tachibana Mayumi , Torii Motomi , Matsuzaki Goro , Arakawa Takeshi 
Published: August 2011

ABSTRACTThe creation of subunit vaccines to prevent malaria infection has been hampered by the intrinsically weak immunogenicity of the recombinant antigens. We have developed a novel strategy to increase immune responses by creating genetic fusion proteins to target specific antigen-presenting cells (APCs). The fusion complex was composed of three physically linked molecular entities: (i) a vaccine antigen, (ii) a multimeric α-helical coiled-coil core, and (iii) an APC-targeting ligand linked to the core via a flexible linker. The vaccine efficacy of the tricomponent complex was evaluated using an ookinete surface protein ofPlasmodium vivax, Pvs25, and merozoite surface protein-1 ofPlasmodium yoelii. Immunization of mice with the tricomponent complex induced a robust antibody response and conferred substantial levels ofP. vivaxtransmission blockade as evaluated by a membrane feed assay, as well as protection from lethalP. yoeliiinfection. The observed effect was strongly dependent on the presence of all three components physically integrated as a fusion complex. This system, designated the tricomponent immunopotentiating system (TIPS), onto which any recombinant protein antigens or nonproteinaceous substances could be loaded, may be a promising strategy for devising subunit vaccines or adjuvants against various infectious diseases, including malaria.
Population Dynamics and Niche Distribution of Uropathogenic Escherichia coli during Acute and Chronic Urinary Tract Infection
Authors: Schwartz Drew J. , Chen Swaine L. , Hultgren Scott J. , Seed Patrick C. 
Published: August 2011

ABSTRACT

Urinary tract infections (UTIs) have complex dynamics, with uropathogenic
Escherichia coli
(UPEC), the major causative agent, capable of colonization from the urethra to the kidneys in both extracellular and intracellular niches while also producing chronic persistent infections and frequent recurrent disease. In mouse and human bladders, UPEC invades the superficial epithelium, and some bacteria enter the cytoplasm to rapidly replicate into intracellular bacterial communities (IBCs) comprised of ∼10
4
bacteria each. Through IBC formation, UPEC expands in numbers while subverting aspects of the innate immune response. Within 12 h of murine bladder infection, half of the bacteria are intracellular, with 3 to 700 IBCs formed. Using mixed infections with green fluorescent protein (GFP) and wild-type (WT) UPEC, we discovered that each IBC is clonally derived from a single bacterium. Genetically tagged UPEC and a multiplex PCR assay were employed to investigate the distribution of UPEC throughout urinary tract niches over time. In the first 24 h postinfection (hpi), the fraction of tags dramatically decreased in the bladder and kidney, while the number of CFU increased. The percentage of tags detected at 6 hpi correlated to the number of IBCs produced, which closely matched a calculated multinomial distribution based on IBC clonality. The fraction of tags remaining thereafter depended on UTI outcome, which ranged from resolution of infection with or without quiescent intracellular reservoirs (QIRs) to the development of chronic cystitis as defined by persistent bacteriuria. Significantly more tags remained in mice that developed chronic cystitis, arguing that during the acute stages of infection, a higher number of IBCs precedes chronic cystitis than precedes QIR formation.
Comparative Genomics ofesxGenes from Clinical Isolates of Mycobacterium tuberculosis Provides Evidence for Gene Conversion and Epitope Variation
Authors: Uplekar Swapna , Heym Beate , Friocourt Véronique , Rougemont Jacques , Cole Stewart T. 
Published: August 2011

ABSTRACTThe 23-membered Esx protein family is involved in the host-pathogen interactions ofMycobacterium tuberculosis. These secreted proteins are among the most immunodominant antigens recognized by the human immune system and have thus been used to develop vaccines and immunodiagnostic tests for tuberculosis (TB). Gene pairs for 10 Esx proteins are contained in the ESX-1 to ESX-5 loci, encoding type VII secretion systems. A subset of Esx proteins can be further classified into the Mtb9.9, QILSS, and TB10.4 subfamilies. To survey genetic diversity in the Esx family and its potential for antigenic variation, we sequenced allesxgenes from 108 clinical isolates ofM. tuberculosisfrom different clades by using a targeted approach. A total of 109 unique single nucleotide polymorphisms (SNPs) were observed, and 59 of these were nonsynonymous. Some of the resultant amino acid substitutions affect known Esx epitopes, including two in the EsxB (CFP-10) and EsxH (TB10.4) antigens. Assessment of the SNP distribution across the Esx proteins revealed high genetic variability, especially in the Mtb9.9 and QILSS subfamilies, and more conservation in the ESX-1 to ESX-4 loci. Comparison of the DNA sequences of variableesxgenes provided clear evidence for recombination events between different genes in the same strain, some of which are predicted to truncate the corresponding protein. Many of these polymorphisms escape detection by ultrahigh-throughput sequencing using short sequence reads, as such approaches cannot distinguish between closely related genes. Theesxgene family is dynamic, and sequence changes likely lead to immune variation.
Neutrophils Produce Interleukin 17A (IL-17A) in a Dectin-1- and IL-23-Dependent Manner during Invasive Fungal Infection
Authors: Werner Jessica L. , Gessner Melissa A. , Lilly Lauren M. , Nelson Michael P. , Metz Allison E. , Horn Dawn , Dunaway Chad W. , Deshane Jessy , Chaplin David D. , Weaver Casey T. , Brown Gordon D. , Steele Chad 
Published: August 2011

ABSTRACTWe have previously reported that compromised interleukin 17A (IL-17A) production in the lungs increased susceptibility to infection with the invasive fungal pathogenAspergillus fumigatus. Here we have shown that culturing lung cells fromA. fumigatus-challenged miceex vivodemonstrated Dectin-1-dependent IL-17A production. In this system, neutralization of IL-23 but not IL-6, IL-1β, or IL-18 resulted in attenuated IL-17A production.Il23mRNA expression was found to be lower in lung cells fromA. fumigatus-challenged Dectin-1-deficient mice, whereas bone marrow-derived dendritic cells from Dectin-1-deficient mice failed to produce IL-23 in response toA. fumigatusin vitro. Addition of recombinant IL-23 augmented IL-17A production by wild-type (WT) and Dectin-1-deficient lung cells, although the addition of IL-6 or IL-1β did not augment the effect of IL-23. Intracellular cytokine staining of lung cells revealed lower levels of CD11b+IL-17A+and Ly-6G+IL-17A+cells inA. fumigatus-challenged Dectin-1-deficient mice. Ly-6G+neutrophils purified from the lungs ofA. fumigatus-challenged Dectin-1-deficient mice displayed lowerIl17amRNA expression but surprisingly had intactRorcandRoramRNA expression. We further demonstrated that Ly-6G+neutrophils required the presence of myeloid cells for IL-17A production. Finally, uponin vitrostimulation withA. fumigatus, thioglycolate-elicited peritoneal neutrophils were positive for intracellular IL-17A expression and produced IL-17A in a Dectin-1- and IL-23-dependent manner. In summary, Dectin-1-dependent IL-17A production in the lungs during invasive fungal infection is mediated in part by CD11b+Ly-6G+neutrophils in an IL-23-dependent manner.
Sedentary behaviour interventions in young people: a meta-analysis
Authors: Biddle Stuart JH , O'Connell Sophie , Braithwaite Rock E 
Published: August 2011

BackgroundThere is increasing concern about the time young people spend in sedentary behaviour (‘sitting time’), especially with the development of attractive home-based electronic entertainment. This may have deleterious health effects.PurposeTo ascertain, through a meta-analytic review, whether interventions targeted at reducing sedentary behaviours in young people are successful.MethodERIC, MedLine, PsychInfo, SportDiscus and the Cochrane Library databases were searched up to 2010. Titles and abstracts of identified papers were examined against inclusion criteria. Included papers were coded by three researchers.Results17 papers, including 17 independent samples (N=4976), met the inclusion criteria and were analysed. There was a small but significant effect in favour of sedentary behaviour reduction for intervention groups (Hedges' g = − 0.192; SE = 0.056; 95% CI = −0.303 to −0.082; p = 0.001). Moderator analyses produced no significant between-moderator results for any of the intervention or study characteristics, although trends were evident.ConclusionBehaviour change interventions targeting reductions in sedentary behaviour have been shown to be successful, although effects are small. More needs to be known about how best to optimise intervention effects.
Automated Volumetric Growth Plate Measurement Using Magnetic Resonance Imaging for Monitoring Skeletal Toxicity in Children Treated on Investigational Drug Trials
Authors: Kim AeRang , Dombi Eva , Solomon Jeffrey , Fox Elizabeth , Balis Frank M. , Widemann Brigitte C. 
Published: August 2011

Abstract
Purpose: Targeted anticancer agents have been reported to have side effects on the skeletal system such as thickening of the epiphyseal growth plate in preclinical models of juvenile, but not mature, animals. Careful evaluation of skeletal toxicity in the clinical development of targeted therapies for children is required. We validated a novel method to measure the growth plate volume using MRI.
Experimental Design: A semiautomated method of volumetric growth plate measurement was developed on the basis of the differences of pixel intensity of the growth plate from surrounding bone on T1 sagittal MRI. Two observers measured the femoral growth plate volume and thickness on three different days using 20 pediatric knee MRIs obtained at the NIH. Five subjects had two knee MRIs obtained on the same day to evaluate intrasubject reproducibility.
Results: Volumetric analysis showed low intraobserver variability, with the coefficient of variation for the two observers ranging from 0.2% to 6.1%. Interobserver correlation was 0.99, and good concordance was shown with a mean volume difference of −1.8 mm3. One-dimensional measurements had poorer intra and interobserver consistency. No statistically significant differences in volumetric measurements were observed between the two scans done on the same day in five subjects (P = 0.5).
Conclusions: MRI volumetric growth plate measurement is a reproducible and sensitive method to evaluate meaningful growth plate volume changes over time. This tool, along with close monitoring of height and laboratory evaluations for bone metabolism, may be used to evaluate potential bone and growth toxicities of children enrolled in trials of investigational drugs. Clin Cancer Res; 17(18); 5982–90. ©2011 AACR.
A Polymorphic −844T/C in FasL Promoter Predicts Survival and Relapse in Non–Small Cell Lung Cancer
Authors: Sung Wen-Wei , Wang Yao-Chen , Cheng Ya-Wen , Lee Ming-Ching , Yeh Kun-Tu , Wang Lee , Wang John , Chen Chih-Yi , Lee Huei 
Published: August 2011

Abstract
Purpose: Fas ligand (FasL) −844T/C polymorphism (rs763110) has a demonstrated association with lung cancer risk. FasL −844CC with higher FasL expression has been suggested to contribute to tumor progression via immune escape. However, the impact of FasL −844T/C polymorphism on the clinical outcome of non–small cell lung cancer (NSCLC) remains to be identified.
Experimental Design: A total of 385 adjacent normal lung tissues from patients with NSCLC were collected to determine FasL −844T/C polymorphism by PCR-based restriction fragment length polymorphism. FasL mRNA and protein expression in lung tumors were evaluated by real-time PCR and immunohistochemistry. The prognostic value of FasL −844T/C polymorphism on survival and relapse was determined by Kaplan–Meier analysis and Cox proportional hazards models.
Results: The FasL −844CC genotype had higher prevalence in those with advanced tumors than in those with early tumors (P = 0.008). In addition, patients with the FasL −844CC genotype were more prone to tumor relapse than those with the FasL −844TT+TC genotype (62.1% vs. 37.9%, P = 0.001). Multivariate Cox regression analysis showed that patients with the FasL −844CC genotype had poorer survival in terms of overall survival (OS) and relapse-free survival (RFS) than those with the FasL −844TT+TC genotype (24.1 vs. 42.8 months for OS, HR = 1.455, P = 0.004; 15.4 vs. 31.4 months for RFS, HR = 1.710, P &lt; 0.001).
Conclusions: FasL −844T/C polymorphism may predict survival and relapse in NSCLC. We suggest that FasL may be a molecular target for immunotherapeutic interventions to improve the clinical outcome of patients with NSCLC. This finding should be validated by another investigative group. Clin Cancer Res; 17(18); 5991–9. ©2011 AACR.
Dose Response Between Physical Activity and Risk of Coronary Heart Disease
Authors: Sattelmair Jacob , Pertman Jeremy , Ding Eric L. , Kohl Harold W. , Haskell William , Lee I-Min 
Published: August 2011

Background
No reviews have quantified the specific amounts of physical activity required for lower risks of coronary heart disease when assessing the dose-response relation. Instead, previous reviews have used qualitative estimates such as low, moderate, and high physical activity.

Methods and Results

We performed an aggregate data meta-analysis of epidemiological studies investigating physical activity and primary prevention of CHD. We included prospective cohort studies published in English since 1995. After reviewing 3194 abstracts, we included 33 studies. We used random-effects generalized least squares spline models for trend estimation to derive pooled dose-response estimates. Among the 33 studies, 9 allowed quantitative estimates of leisure-time physical activity. Individuals who engaged in the equivalent of 150 min/wk of moderate-intensity leisure-time physical activity (minimum amount, 2008 US federal guidelines) had a 14% lower coronary heart disease risk (relative risk, 0.86; 95% confidence interval, 0.77 to 0.96) compared with those reporting no leisure-time physical activity. Those engaging in the equivalent of 300 min/wk of moderate-intensity leisure-time physical activity (2008 US federal guidelines for additional benefits) had a 20% (relative risk, 0.80; 95% confidence interval, 0.74 to 0.88) lower risk. At higher levels of physical activity, relative risks were modestly lower. People who were physically active at levels lower than the minimum recommended amount also had significantly lower risk of coronary heart disease. There was a significant interaction by sex (
P
=0.03); the association was stronger among women than men.

Conclusions
These findings provide quantitative data supporting US physical activity guidelines that stipulate that “some physical activity is better than none” and “additional benefits occur with more physical activity.”