bluuebunny/crossref_metadata_2025_split huggingface dataset:
Candida albicans Flu1-Mediated Efflux of Salivary Histatin 5 Reduces Its Cytosolic Concentration and Fungicidal Activity
Authors: Li Rui , Kumar Rohitashw , Tati Swetha , Puri Sumant , Edgerton Mira 
Published: February 2013

ABSTRACT

Histatin 5 (Hst 5) is a salivary human antimicrobial peptide that is toxic to the opportunistic yeast
Candida albicans
. Fungicidal activity of Hst 5 requires intracellular translocation and accumulation to a threshold concentration for it to disrupt cellular processes. Previously, we observed that total cytosolic levels of Hst 5 were gradually reduced from intact cells, suggesting that
C. albicans
possesses a transport mechanism for efflux of Hst 5. Since we identified
C. albicans
polyamine transporters responsible for Hst 5 uptake, we hypothesized that one or more polyamine efflux transporters may be involved in the efflux of Hst 5.
C. albicans FLU1
and
TPO2
were found to be the closest homologs of
Saccharomyces cerevisiae TPO1
, which encodes a major spermidine efflux transporter, indicating that the products of these two genes may be involved in efflux of Hst 5. We found that
flu1
Δ/Δ cells, but not
tpo2
Δ/Δ cells, had significant reductions in their rates of Hst 5 efflux and had significantly higher cytoplasmic Hst 5 and Hst 5 susceptibilities than did the wild type. We also found that
flu1
Δ/Δ cells had reduced biofilm formation compared to wild-type cells in the presence of Hst 5. Transcriptional levels of
FLU1
were not altered over the course of treatment with Hst 5; therefore, Hst 5 is not likely to induce
FLU1
gene overexpression as a potential mechanism of resistance. Thus, Flu1, but not Tpo2, mediates efflux of Hst 5 and is responsible for reduction of its toxicity in
C. albicans
.
Antimicrobial Activity of Ceftaroline-Avibactam Tested against Clinical Isolates Collected from U.S. Medical Centers in 2010-2011
Authors: Sader Helio S. , Flamm Robert K. , Jones Ronald N. 
Published: February 2013

ABSTRACT

Ceftaroline-avibactam and comparator agents were tested by the broth microdilution method against 20,089 isolates consecutively collected in 2010 and 2011 from 75 U.S. medical centers. Ceftaroline-avibactam was active against
Enterobacteriaceae
(4,908 strains; MIC
90
, 0.25 μg/ml; highest MIC, 4 μg/ml), including meropenem-nonsusceptible
Klebsiella
spp. and ceftazidime-nonsusceptible
Enterobacter cloacae
strains (MIC
90
, 1 μg/ml for both). Ceftaroline-avibactam was also active against ceftriaxone-nonsusceptible
Streptococcus pneumoniae
(MIC
90
, 0.25 μg/ml) and methicillin-resistant
Staphylococcus aureus
(MIC
90
, 1 μg/ml).
Drug Repurposing Screen Reveals FDA-Approved Inhibitors of Human HMG-CoA Reductase and Isoprenoid Synthesis That Block Cryptosporidium parvum Growth
Authors: Bessoff Kovi , Sateriale Adam , Lee K. Kyungae , Huston Christopher D. 
Published: February 2013

ABSTRACT

Cryptosporidiosis, a diarrheal disease usually caused by
Cryptosporidium parvum
or
Cryptosporidium hominis
in humans, can result in fulminant diarrhea and death in AIDS patients and chronic infection and stunting in children. Nitazoxanide, the current standard of care, has limited efficacy in children and is no more effective than placebo in patients with advanced AIDS. Unfortunately, the lack of financial incentives and the technical difficulties associated with working with
Cryptosporidium
parasites have crippled efforts to develop effective treatments. In order to address these obstacles, we developed and validated (Z′ score = 0.21 to 0.47) a cell-based high-throughput assay and screened a library of drug repurposing candidates (the NIH Clinical Collections), with the hopes of identifying safe, FDA-approved drugs to treat cryptosporidiosis. Our screen yielded 21 compounds with confirmed activity against
C. parvum
growth at concentrations of <10 μM, many of which had well-defined mechanisms of action, making them useful tools to study basic biology in addition to being potential therapeutics. Additional work, including structure-activity relationship studies, identified the human 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase inhibitor itavastatin as a potent inhibitor of
C. parvum
growth (50% inhibitory concentration [IC
50
] = 0.62 μM). Bioinformatic analysis of the
Cryptosporidium
genomes indicated that the parasites lack all known enzymes required for the synthesis of isoprenoid precursors. Additionally, itavastatin-induced growth inhibition of
C. parvum
was partially reversed by the addition of exogenous isopentenyl pyrophosphate, suggesting that itavastatin reduces
Cryptosporidium
growth via on-target inhibition of host HMG-CoA reductase and that the parasite is dependent on the host cell for synthesis of isoprenoid precursors.
Promoter Polymorphisms in the ATP Binding Cassette Transporter Gene Influence Production of Cell-Derived Microparticles and Are Highly Associated with Susceptibility to Severe Malaria in Humans
Authors: Sahu Upasana , Mohapatra Biranchi N. , Kar Shantanu K. , Ranjit Manoranjan 
Published: February 2013

ABSTRACT

Microparticle (MP) efflux is known to be mediated by the ABCA1 protein, and the plasma level of these cell-derived MPs is elevated considerably during human malarial infection. Therefore, two polymorphisms at positions −477 and −320 in the promoter of the ABCA1 gene were genotyped and tested for association with the plasma MP level in four groups of malaria patients segregated according to the clinical severity, i.e., cerebral malaria (CM), multiorgan dysfunction (MOD), noncerebral severe malaria, and uncomplicated malaria (UM). The TruCount tube-based flow cytometric method was used for the exact quantification of different cell-derived MPs in patients. Polymorphisms in the ABCA1 gene promoter were analyzed by use of the PCR/two-primer-pair method, followed by restriction fragment length polymorphism, in 428 malaria patients. The level of circulating plasma MPs was significantly higher in febrile patients with
Plasmodium falciparum
infection, especially in CM patients compared to healthy individuals. The homozygous wild-type −477 and −320 genotype was observed to be significantly higher in patients with severe malaria. These patients also showed marked increases in the plasma MP numbers compared to UM patients. We report here for the first time an association of ABCA1 promoter polymorphisms with susceptibility to severe malaria, especially to CM and MOD, indicating the protective effect of the mutant variant of the polymorphism. We hypothesize that the −477T and −320G polymorphisms affect the downregulation of MP efflux and may be a predictor of organ complication during
P. falciparum
malarial infections.
5-Lipoxygenase Activity Increases Susceptibility to Experimental Paracoccidioides brasiliensis Infection
Authors: Tristão Fabrine Sales Massafera , Rocha Fernanda Agostini , Moreira Ana Paula , Cunha Fernando Queiroz , Rossi Marcos Antonio , Silva João Santana 
Published: February 2013

ABSTRACT

Paracoccidioidomycosis (PCM) is a systemic mycosis caused by the thermodimorphic fungus
Paracoccidioides brasiliensis
. Leukotrienes and lipoxins are lipid mediators produced after 5-lipoxygenase (5-LO) activation that exhibit pro- and anti-inflammatory roles, respectively. Here, we have investigated the contribution of 5-LO enzymatic activity in PCM using an experimental model of
P. brasiliensis
infection. B6.129 wild-type (B6.129) and 5-LO-deficient (5-LO
−/−
) mice were intravenously inoculated with a virulent strain of
P. brasiliensis
(Pb18), and the survival rate of the infected mice was investigated on different days after yeast infection. 5-LO
−/−
mice exhibited an increased survival rate associated with a decreased number of CFU. The resistance of 5-LO
−/−
during PCM was associated with augmented nitric oxide (NO) production and the formation of compact granulomas. In addition, the absence of 5-LO was associated with a diminished number of CD4
+
CD25
+
regulatory T cells, higher levels of gamma interferon and interleukin-12, and increased T-bet (a T-box transcription factor that directs Th1 lineage commitment) mRNA levels in the lungs. Taken together, our results show for the first time that 5-LO enzymatic activity increases susceptibility to
P. brasiliensis
, suggesting that this pathway may be a potential target for therapeutic intervention during PCM.
Validation of requirements for hybrid systems
Authors: Cimatti Alessandro , Roveri Marco , Susi Angelo , Tonetta Stefano 
Published: February 2013

Flaws in requirements may have unacceptable consequences in the development of safety-critical applications. Formal approaches may help with a deep analysis that takes care of the precise semantics of the requirements. However, the proposed solutions often disregard the problem of integrating the formalization with the analysis, and the underlying logical framework lacks either expressive power, or automation.
We propose a new, comprehensive approach for the validation of functional requirements of hybrid systems, where discrete components and continuous components are tightly intertwined. The proposed solution allows to tackle problems of conversion from informal to formal, traceability, automation, user acceptance, and scalability.
We build on a new language, othello which is expressive enough to represent various domains of interest, yet allowing efficient procedures for checking the satisfiability. Around this, we propose a structured methodology where: informal requirements are fragmented and categorized according to their role; each fragment is formalized based on its category; specialized formal analysis techniques, optimized for requirements analysis, are finally applied.
The approach was the basis of an industrial project aiming at the validation of the European Train Control System (ETCS) requirements specification. During the project a realistic subset of the ETCS specification was formalized and analyzed. The approach was positively assessed by domain experts.
A Single Nucleotide Polymorphism in Inflammatory Gene RNASEL Predicts Outcome after Radiation Therapy for Localized Prostate Cancer
Authors: Schoenfeld Jonathan D. , Margalit Danielle N. , Kasperzyk Julie L. , Shui Irene M. , Rider Jennifer R. , Epstein Mara M. , Meisner Allison , Kenfield Stacey A. , Martin Neil E. , Nguyen Paul L. , Kantoff Philip W. , Giovannucci Edward L. , Stampfer Meir J. , Mucci Lorelei A. 
Published: February 2013

Abstract
Purpose: To study associations between single nucleotide polymorphisms (SNP) in Ribonuclease L (RNASEL), a gene implicated in inflammation and prostate cancer risk, and outcomes after radiation therapy.
Experimental Design: We followed participants in the prospective US Health Professionals Follow-Up Study treated with radiation therapy for early-stage prostate cancer. Three SNPs were genotyped based on previously determined functional and biological significance. We used multivariable Cox proportional hazards models to assess per-allele associations with the primary outcome defined as time to a composite endpoint including development of lethal prostate cancer or biochemical recurrence.
Results: We followed 434 patients treated with radiation therapy for a median of 9 years. On multivariate analysis, the rs12757998 variant allele was associated with significantly decreased risk of the composite endpoint [HR: 0.65; 95% confidence interval (CI), 0.45–0.94%; P = 0.02] driven by decreased biochemical recurrence (HR: 0.60; 95% CI, 0.40–0.89%; P = 0.01) and men treated with external beam (HR: 0.58; 95% CI, 0.36–0.93%; P = 0.02). In contrast, in 516 men from the same cohort treated with radical prostatectomy, we found no significant impact of this variant on outcome. Furthermore, the rs12757998 variant allele significantly modified the association between androgen deprivation therapy and outcomes after radiation therapy (p-interaction = 0.02).
Conclusion: We show an association between RNASEL SNP rs12757998 and outcome after radiation therapy for prostate cancer. This SNP is associated with increased circulating C-reactive protein and interleukin-6, suggesting a potential role for inflammation in the response to radiation. If validated, genetic predictors of outcome may help inform prostate cancer management. Clin Cancer Res; 19(6); 1612–9. ©2013 AACR.
18F-Fluorodeoxyglucose Positron Emission Tomography in the Management of Patients with Thymic Epithelial Tumors
Authors: Thomas Anish , Mena Esther , Kurdziel Karen , Venzon David , Khozin Sean , Berman Arlene W. , Choyke Peter , Szabo Eva , Rajan Arun , Giaccone Giuseppe 
Published: February 2013

Abstract
Purpose: There are limited data regarding the role of 18F-fluorodeoxyglucose positron emission tomography ([18F]-FDG PET) imaging in management of patients with thymic epithelial tumors (TET). The primary objective of this study was to assess the usefulness of early [18F]-FDG PET to monitor treatment efficacy and its correlation with Response Evaluation Criteria in Solid Tumors (RECIST) in patients with TETs.
Experimental Design: [18F]-FDG PET/computed tomographic (CT) scans were conducted at baseline and after 6 weeks of treatment in patients enrolled in two phase II and one phase I/II clinical trials. On the basis of data from other solid tumors, metabolic response was defined as a reduction of [18F]-FDG uptake by more than 30% as assessed by average standardized uptake values (SUV) of up to five most metabolically active lesions.
Results: Fifty-six patients with unresectable Masaoka stage III or IV TETs were included. There was a close correlation between early metabolic response and subsequent best response using RECIST (P &lt; 0.0001–0.0003): sensitivity and specificity for prediction of best response were 95% and 100%, respectively. Metabolic responders had significantly longer progression-free survival (median, 11.5 vs. 4.6 months; P = 0.044) and a trend toward longer overall survival (median, 31.8 vs. 18.4 months; P = 0.14) than nonresponders. [18F]-FDG uptake was significantly higher in thymic carcinoma than in thymoma (P = 0.0004–0.0010).
Conclusion: In patients with advanced TETs, early metabolic response closely correlates with outcome of therapy. [18F]-FDG PET may be used to monitor treatment efficacy and assess histologic differences in patients with advanced TETs. Clin Cancer Res; 19(6); 1487–93. ©2013 AACR.
Next-Generation Medicine: Combining BCR-ABL and Hedgehog-Targeted Therapies
Authors: Dao Kim-Hien T. , Tyner Jeffrey W. 
Published: February 2013

Abstract
Disease relapse remains a major cause of death in patients with BCR-ABL–positive leukemia despite advances in treatment with kinase inhibitors. Significant efforts are underway to target pathways that maintain leukemia stem cells. Targeting these pathways holds promise for definitive leukemia eradication or improvement of the effectiveness of currently available therapies. Clin Cancer Res; 19(6); 1309–11. ©2013 AACR.
The Encoding/Retrieval Flip: Interactions between Memory Performance and Memory Stage and Relationship to Intrinsic Cortical Networks
Authors: Huijbers Willem , Schultz Aaron P. , Vannini Patrizia , McLaren Donald G. , Wigman Sarah E. , Ward Andrew M. , Hedden Trey , Sperling Reisa A. 
Published: February 2013

Abstract
fMRI studies have linked the posteromedial cortex to episodic learning (encoding) and remembering (retrieval) processes. The posteromedial cortex is considered part of the default network and tends to deactivate during encoding but activate during retrieval, a pattern known as the encoding/retrieval flip. Yet, the exact relationship between the neural correlates of memory performance (hit/miss) and memory stage (encoding/retrieval) and the extent of overlap with intrinsic cortical networks remains to be elucidated. Using task-based fMRI, we isolated the pattern of activity associated with memory performance, memory stage, and the interaction between both. Using resting-state fMRI, we identified which intrinsic large-scale functional networks overlapped with regions showing task-induced effects. Our results demonstrated an effect of successful memory performance in regions associated with the control network and an effect of unsuccessful memory performance in the ventral attention network. We found an effect of memory retrieval in brain regions that span the default and control networks. Finally, we found an interaction between memory performance and memory stage in brain regions associated with the default network, including the posteromedial cortex, posterior parietal cortex, and parahippocampal cortex. We discuss these findings in relation to the encoding/retrieval flip. In general, the findings demonstrate that task-induced effects cut across intrinsic cortical networks. Furthermore, regions within the default network display functional dissociations, and this may have implications for the neural underpinnings of age-related memory disorders.
The Contributions of Sensory Dominance and Attentional Bias to Cross-modal Enhancement of Visual Cortex Excitability
Authors: Romei Vincenzo , Murray Micah M. , Cappe Céline , Thut Gregor 
Published: February 2013

Abstract
Approaching or looming sounds (L-sounds) have been shown to selectively increase visual cortex excitability [Romei, V., Murray, M. M., Cappe, C., & Thut, G. Preperceptual and stimulus-selective enhancement of low-level human visual cortex excitability by sounds. Current Biology, 19, 1799–1805, 2009]. These cross-modal effects start at an early, preperceptual stage of sound processing and persist with increasing sound duration. Here, we identified individual factors contributing to cross-modal effects on visual cortex excitability and studied the persistence of effects after sound offset. To this end, we probed the impact of different L-sound velocities on phosphene perception postsound as a function of individual auditory versus visual preference/dominance using single-pulse TMS over the occipital pole. We found that the boosting of phosphene perception by L-sounds continued for several tens of milliseconds after the end of the L-sound and was temporally sensitive to different L-sound profiles (velocities). In addition, we found that this depended on an individual's preferred sensory modality (auditory vs. visual) as determined through a divided attention task (attentional preference), but not on their simple threshold detection level per sensory modality. Whereas individuals with “visual preference” showed enhanced phosphene perception irrespective of L-sound velocity, those with “auditory preference” showed differential peaks in phosphene perception whose delays after sound-offset followed the different L-sound velocity profiles. These novel findings suggest that looming signals modulate visual cortex excitability beyond sound duration possibly to support prompt identification and reaction to potentially dangerous approaching objects. The observed interindividual differences favor the idea that unlike early effects this late L-sound impact on visual cortex excitability is influenced by cross-modal attentional mechanisms rather than low-level sensory processes.
A Study on the Effect of Nudging on Long-Term Boundary Layer Profiles of Wind and Weibull Distribution Parameters in a Rural Coastal Area
Authors: Gryning S.-E. , Batchvarova E. , Floors R. 
Published: February 2013

AbstractBy use of 1 yr of measurements performed with a wind lidar up to 600-m height, in combination with a tall meteorological tower, the impact of nudging on the simulated wind profile at a flat coastal site (Høvsøre) in western Denmark using the Advanced Research version of the Weather Research and Forecasting model (WRF) is studied. It was found that the mean wind speed, the wind direction change with height, and the wind power density profiles are underestimated with the configuration of WRF used and that the impact of nudging on the simulated mean values was minor. Nudging was found to reduce the scatter between the simulated and measured wind speeds, expressed by the root-mean-square error, by about 20% between altitudes of 100 and 500 m. The root-mean-square error was nearly constant with height for the nudged case (~2.2 m s−1) and slightly increased with height for the nonnudged one, reaching 2.8 m s−1 at 300 and 500 m. In studying the long-term wind speed variability with the Weibull distribution, it was found that nudging had a minor effect on the scale parameter profile, which is closely connected to the mean wind speed. Improvement by nudging was seen on the profile of the shape parameter. Without nudging, the shape parameter was underestimated at all heights; with nudging, the agreement was good up to about 100 m and above that height the shape parameter was underestimated.
Resveratrol Decreases Noise‐Induced Cyclooxygenase‐2 Expression in the Rat Cochlea
Authors: Seidman Michael D. , Tang Wenxue , Bai Venkatesh Uma , Ahmad Nadir , Jiang Hao , Media Joseph , Patel Nimisha , Rubin Cory J. , Standring Robert T. 
Published: February 2013

ObjectiveOur previous studies have demonstrated the efficacy of resveratrol, a grape constituent noted for its antioxidant and anti‐inflammatory properties, in reducing temporary threshold shifts and decreasing cochlear hair cell damage following noise exposure. This study was designed to identify the potential protective mechanism of resveratrol by measuring its effect on cyclooxygenase‐2 (COX‐2) protein expression and reactive oxygen species (ROS) formation following noise exposure.Study DesignControlled animal intervention study.SettingOtology Laboratory, Henry Ford Health System.Subjects and MethodsTwenty‐two healthy male Fischer 344 rats (2‐3 months old) were exposed to acoustic trauma of variable duration with or without intervention. An additional 20 healthy male rats were used to study COX‐2 expression at different time points during and following treatment of 24 hours of noise exposure. Cochlear harvest was performed at various time intervals for measurement of COX‐2 protein expression via Western blot analysis and immunostaining. Peripheral blood was also obtained for ROS analysis using flow cytometry.ResultsAcoustic trauma exposure resulted in a progressive up‐regulation of COX‐2 protein expression, commencing at 8 hours and peaking at 32 hours. Similarly, ROS production increased after noise exposure. However, treatment with resveratrol reduced noise‐induced COX‐2 expression as well as ROS formation in the blood as compared with the controls.ConclusionCOX‐2 levels are induced dramatically following noise exposure. This increased expression may be a potential mechanism of noise‐induced hearing loss (NIHL) and a possible mechanism of resveratrol's ability to mitigate NIHL by its ability to reduce COX‐2 expression.