bluuebunny/crossref_metadata_2025_split huggingface dataset:
Staphylococcus aureus Induces Hypoxia and Cellular Damage in Porcine Dermal Explants
Authors: Lone Abdul G. , Atci Erhan , Renslow Ryan , Beyenal Haluk , Noh Susan , Fransson Boel , Abu-Lail Nehal , Park Jeong-Jin , Gang David R. , Call Douglas R. 
Published: April 2015

ABSTRACT

We developed a porcine dermal explant model to determine the extent to which
Staphylococcus aureus
biofilm communities deplete oxygen, change pH, and produce damage in underlying tissue. Microelectrode measurements demonstrated that dissolved oxygen (DO) in biofilm-free dermal tissue was 4.45 ± 1.17 mg/liter, while DO levels for biofilm-infected tissue declined sharply from the surface, with no measurable oxygen detectable in the underlying dermal tissue. Magnetic resonance imaging demonstrated that biofilm-free dermal tissue had a significantly lower relative effective diffusion coefficient (0.26 ± 0.09 to 0.30 ± 0.12) than biofilm-infected dermal tissue (0.40 ± 0.12 to 0.48 ± 0.12;
P
< 0.0001). Thus, the difference in DO level was attributable to biofilm-induced oxygen demand rather than changes in oxygen diffusivity. Microelectrode measures showed that pH within biofilm-infected explants was more alkaline than in biofilm-free explants (8.0 ± 0.17 versus 7.5 ± 0.15, respectively;
P
< 0.002). Cellular and nuclear details were lost in the infected explants, consistent with cell death. Quantitative label-free shotgun proteomics demonstrated that both proapoptotic programmed cell death protein 5 and antiapoptotic macrophage migration inhibitory factor accumulated in the infected-explant spent medium, compared with uninfected-explant spent media (1,351-fold and 58-fold, respectively), consistent with the cooccurrence of apoptosis and necrosis in the explants. Biofilm-origin proteins reflected an extracellular matrix-adapted lifestyle of
S. aureus. S. aureus
biofilms deplete oxygen, increase pH, and induce cell death, all factors that contribute to impede wound healing.
Secretion of Flagellar Proteins by the Pseudomonas aeruginosa Type III Secretion-Injectisome System
Authors: Ince Dilek , Sutterwala Fayyaz S. , Yahr Timothy L. 
Published: April 2015

ABSTRACT

The opportunistic pathogen
Pseudomonas aeruginosa
utilizes an injectisome-type III secretion system (injectisome-T3SS) to elicit cytotoxicity toward epithelial cells and macrophages. Macrophage killing results from the cytotoxic properties of the translocated effector proteins (ExoS, ExoT, ExoU, and ExoY) and inflammasome-mediated induction of pyroptosis. Inflammasome activation can occur following Nlrc4-mediated recognition of cytosolic translocated flagellin (FliC). In the present study, we demonstrate that FliC is a secretion substrate of both the injectisome- and flagellum-associated T3SSs. Molecular analyses indicate that the first 20 amino-terminal residues of FliC are sufficient for secretion by the injectisome-T3SS and that the first 100 residues are sufficient for translocation of FliC into host cells. Although maximal inflammasome activation requires FliC, activation can also occur in the absence of FliC. This prompted us to examine whether other flagellar components might also be translocated into cells to elicit inflammasome activation. Indeed, we find that the flagellar cap (FliD), hook-associated (FlgK and FlgL), hook (FlgE), and rod (FlgE) proteins are secretion substrates of the injectisome-T3SS. None of these proteins, however, result in increased inflammasome activation when they are overexpressed in a
fliC
mutant and appear to be translocated into host cells. While a role in inflammasome activation has been excluded, these data raise the possibility that flagellar components, which are highly conserved between different bacterial species, trigger other specific host responses from the extracellular milieu or contribute to the pathogenesis of
P. aeruginosa
.

IMPORTANCE
The inflammasome is a host defense mechanism that recognizes invading bacteria and triggers an inflammatory immune response. The opportunistic pathogen
P. aeruginosa
produces both inflammasome agonists and antagonists. In this study, we demonstrate that overexpression of an agonist suppresses the activity of an antagonist, thereby resulting in inflammasome activation. Since the relative expression levels of agonists and antagonists likely vary between strains, these differences could be important predictors of whether a particular
P. aeruginosa
strain elicits inflammasome activation.
CysB Negatively Affects the Transcription of
pqsR
and Pseudomonas Quinolone Signal Production in Pseudomonas aeruginosa
Authors: Farrow John M. , Hudson L. Lynn , Wells Greg , Coleman James P. , Pesci Everett C. 
Published: April 2015

ABSTRACT

Pseudomonas aeruginosa
is a Gram-negative bacterium that is ubiquitous in the environment, and it is an opportunistic pathogen that can infect a variety of hosts, including humans. During the process of infection,
P. aeruginosa
coordinates the expression of numerous virulence factors through the production of multiple cell-to-cell signaling molecules. The production of these signaling molecules is linked through a regulatory network, with the signal
N
-(3-oxododecanoyl) homoserine lactone and its receptor LasR controlling the induction of a second acyl-homoserine lactone signal and the
Pseudomonas
quinolone signal (PQS). LasR-mediated control of PQS occurs partly by activating the transcription of
pqsR
, a gene that encodes the PQS receptor and is necessary for PQS production. We show that LasR interacts with a single binding site in the
pqsR
promoter region and that it does not influence the transcription of the divergently transcribed gene,
nadA
. Using DNA affinity chromatography, we identified additional proteins that interact with the
pqsR-nadA
intergenic region. These include the H-NS family members MvaT and MvaU, and CysB, a transcriptional regulator that controls sulfur uptake and cysteine biosynthesis. We show that CysB interacts with the
pqsR
promoter and that CysB represses
pqsR
transcription and PQS production. Additionally, we provide evidence that CysB can interfere with the activation of
pqsR
transcription by LasR. However, as seen with other CysB-regulated genes,
pqsR
expression was not differentially regulated in response to cysteine levels. These findings demonstrate a novel role for CysB in influencing cell-to-cell signal production by
P. aeruginosa
.

IMPORTANCE
The production of PQS and other 4-hydroxy-2-alkylquinolone (HAQs) compounds is a key component of the
P. aeruginosa
cell-to-cell signaling network, impacts multiple physiological functions, and is required for virulence. PqsR directly regulates the genes necessary for HAQ production, but little is known about the regulation of
pqsR
. We identified CysB as a novel regulator of
pqsR
and PQS production, but, unlike other CysB-controlled genes, it does not appear to regulate
pqsR
in response to cysteine. This implies that CysB functions as both a cysteine-responsive and cysteine-unresponsive regulator in
P. aeruginosa
.
Patient Outcomes According to Adherence to Treatment Guidelines for Rhythm Control of Atrial Fibrillation
Authors: Qin Dingxin , Leef George , Alam Mian Bilal , Rattan Rohit , Munir Mohamad Bilal , Patel Divyang , Khattak Furqan , Vaghasia Nishit , Adelstein Evan , Jain Sandeep K. , Saba Samir 
Published: April 2015

Background

Although guidelines for antiarrhythmic drug therapy in atrial fibrillation (
AF
) were published in 2006, it remains uncertain whether adherence to these guidelines affects patient outcomes.

Methods and Results

We retrospectively evaluated the records of 5976 consecutive
AF
patients who were prescribed at least 1 antiarrhythmic drug between 2006 and 2013. Patients with 1 or more prescribed antiarrhythmic drugs that did not comply with guideline recommendations comprised the non–guideline‐directed group (=2920); the remainder constituted the guideline‐directed group (=3056). Time to events was assessed using the survival analysis method and adjusted for covariates using Cox regression. Rates of adherence to the guidelines increased significantly with a higher degree of prescriber specialization in arrhythmias (49%, 55%, and 60% for primary care physicians, general cardiologists, and cardiac electrophysiologists, respectively,
P
=0.001) for the first prescribed antiarrhythmic drug. Compared to the non–guideline‐directed group, the guideline‐directed group had higher rates of heart failure, but lower baseline
CHADS
2‐
VAS
c scores (
P
<0.001) and lower rates of coronary artery disease, valvular disease, hypertension, hyperlipidemia, pulmonary disease, and renal insufficiency (
P
<0.05 for all). During 45±26 months follow‐up, the guideline‐directed group had a lower risk of
AF
recurrence (hazard ratio=0.86, 95%
CI
=0.80 to 0.93), fewer hospital admissions for
AF
(hazard ratio=0.87, 95%
CI
=0.79 to 0.97), and fewer procedures for recurrent
AF
, including electrical cardioversion, pacemaker implantation, and atrioventricular nodal ablation (
P
<0.01 for all). The mortality and stroke risks were similar between the groups.

Conclusions

Adherence to published guidelines in the antiarrhythmic management of
AF
is associated with improved patient outcomes.
Posttonsillectomy Weight Loss in Adults
Authors: Rozycki Stefan , Gessler Eric M. 
Published: April 2015

ObjectiveTo analyze and determine the incidence and severity of weight loss in adult tonsillectomies.Study DesignCase series with chart review.SettingAdult tonsillectomy is performed for a variety of indications. Anecdotally, patients report a 10‐ to 15‐pound weight loss in the postoperative period; however, no supporting research has been documented. The pediatric population has a well‐documented weight gain postoperatively.SubjectsIn total, 138 adults (aged 18‐40 years) receiving tonsillectomy at Naval Medical Center Portsmouth (NMCP) between 2008 and 2013.MethodsA retrospective study was performed using an S3 surgery scheduling system search of all adult tonsillectomies at NMCP between 2008 and 2013. A subsequent electronic medical record search (AHLTA) of preoperative and postoperative weights and demographics was performed.ResultsData analysis revealed a significant difference found between preoperative and postoperative weight across all age groups (4.77 pounds, P <. 005). Analysis of variance was performed to determine if there is a significant difference between these age and body mass index (BMI) groups. The highest amount of weight loss was observed in the oldest population group (5.72 pounds in subjects aged >40 years, 4.95 pounds in 31‐ to 40‐year‐olds, and 5.44 pounds in 20‐ to 30‐year‐olds, P =. 03). Age comparisons were statistically significant. There was no statistically significant association between BMI and postoperative weight loss.ConclusionsThese results indicate that there is evidence of a roughly 5‐pound weight loss in the postoperative period following tonsillectomy in adults with subsequent return to baseline weight after roughly 5 months. These findings are significant since this could lead to further research into changes in obesity‐associated disease.
Simulation-Based Inquiry Learning and Computer Modeling
Authors: Mulder Yvonne G. , Lazonder Ard W. , de Jong Ton 
Published: April 2015

Background.Inquiry learning environments increasingly incorporate simulation and modeling facilities. Students acquire knowledge through systematic experimentation with the simulations and express that knowledge in runnable computer models. Aim. As inquiry and modeling activities are new and demanding for students, support for learning is needed. This article reports three experimental studies that examine how students’ inquiry and modeling activities can be supported. Need for support. Study 1 was an empirical assessment of students’ support needs. It compared a group of domain novices to two more knowledgeable reference groups in order to determine the novices’ support needs. Model progression and worked examples. In Studies 2 and 3, the need for support was addressed by model progression (gradually increasing task complexity) and worked-out examples, examining the effect of those interventions on students’ performance and learning. Results suggest positive effects due to both increasing model complexity and providing worked examples that show what the activities in each model progression phase entail and how they should be performed. Implications. The pattern of results across the three studies are discussed with regard to students’ use of available resources, influence of prior knowledge, and the relationship between performance and learning.
The clinical and functional significance of c-Met in breast cancer: a review
Authors: Ho-Yen Colan M , Jones J Louise , Kermorgant Stephanie 
Published: April 2015

Abstractc-Met is a receptor tyrosine kinase that upon binding of its ligand, hepatocyte growth factor (HGF), activates downstream pathways with diverse cellular functions that are important in organ development and cancer progression. Anomalous c-Met signalling has been described in a variety of cancer types, and the receptor is regarded as a novel therapeutic target. In breast cancer there is a need to develop new treatments, particularly for the aggressive subtypes such as triple-negative and basal-like cancer, which currently lack targeted therapy. Over the last two decades, much has been learnt about the functional role of c-Met signalling in different models of breast development and cancer. This work has been complemented by clinical studies, establishing the prognostic significance of c-Met in tissue samples of breast cancer. While the clinical trials of anti-c-Met therapy in advanced breast cancer progress, there is a need to review the existing evidence so that the potential of these treatments can be better appreciated. The aim of this article is to examine the role of HGF/c-Met signalling in in vitro and in vivo models of breast cancer, to describe the mechanisms of aberrant c-Met signalling in human tissues, and to give a brief overview of the anti-c-Met therapies currently being evaluated in breast cancer patients. We will show that the HGF/c-Met pathway is associated with breast cancer progression and suggest that there is a firm basis for continued development of anti-c-Met treatment, particularly for patients with basal-like and triple-negative breast cancer.
Targeting PTEN-defined breast cancers with a one-two punch
Authors: Maggi Leonard B , Weber Jason D 
Published: April 2015

AbstractWith tremendous advances in sequencing and analysis in recent years, a wealth of genetic information has become available to identify and classify breast cancer into five main subtypes - luminal A, luminal B, claudin-low, human epidermal growth factor receptor 2-enriched, and basal-like. Current treatment decisions are often based on these classifications, and while more beneficial than any single treatment for all breast cancers, targeted therapeutics have exhibited limited success with most of the subtypes. Luminal B breast cancers are associated with early relapse following endocrine therapy and often exhibit a poor prognosis that is similar to that of the aggressive basal-like breast cancers. Identifying genetic components that contribute to the luminal B endocrine resistant phenotype has become imperative. To this end, numerous groups have identified activation of the phosphatidylinositol 3-kinase (PI3K) pathway as a common recurring event in luminal B cancers with poor outcome. Examining the pathways downstream of PI3K, Fu and colleagues have recreated a human model of the luminal B subtype of breast cancer. The authors were able to reduce expression of phosphatase and tensin homolog (PTEN), the negative regulator of PI3K, using inducible short hairpin RNAs. By varying the expression of PTEN, the authors effectively conferred endocrine resistance and recapitulated the luminal B gene expression signature. Using this system in vitro and in vivo, they then tested the ability of selective kinase inhibitors downstream of PI3K to enhance current endocrine therapies. A combination of fulvestrant, which blocks ligand-dependent and -independent estrogen receptor signaling, with protein kinase B inhibition was found to overcome endocrine resistance. These findings squarely place PTEN expression levels at the nexus of luminal B breast cancers and indicates that patients with PTEN-low estrogen receptor-positive tumors might benefit from combined endocrine and PI3K pathway therapies.
Synthesis, crystal structures and docking studies of 2,7-diphenyl-1,4-diazepan-5-one derivatives
Authors: Velusamy Maheshwaran , Sreenivasan Sethuvasan , Kandasamy Ravichandran , Subbu Ponnuswamy , Paramasivam Sugumar , Mondikalipudur Nanjappagounder Ponnuswamy 
Published: April 2015

Abstract

Background
1,4-Diazepine derivatives are the seven membered, nitrogen containing heterocyclic ring systems possessing a wide range of therapeutic applications. 1,4-Diazepines attracted the attention of chemists and druggists due to their biological and medicinal properties, such as antimicrobial, anti-HIV and anticancer activities. Herein, we report the preparation, crystal structure determined by X-ray crystallographic methods and docking of the molecules with the potential target protein NS5B RNA polymerase.

Results
The crystal structures and conformational studies of 1,4-diazepine [t-3, t-6-dimethyl-r-2,c-7-diphenyl-1,4-diazepan-5-one(DIAZ1)] and its nitroso derivative [t-3, t-6-dimethyl-1-nitroso-r-2,c-7-diphenyl-1,4-diazepan-5-one(DIAZ2)] are reported. The analyses of the molecules reveal that the seven membered diazepine ring systems adopt chair and boat conformations in compounds DIAZ1 & DIAZ2, respectively. In DIAZ2, the oxygen O2A is disordered over two positions with the refined occupancies of 0.792(7): 0.208(7) in the nitroso group. In both DIAZ1 & DIAZ2, the symmetry related molecules form a hetero/homo-dimer through N-H…O hydrogen bonds.

Conclusion
In this study, the crystal structures of two new 1,4-diazepines, namely t-3, t-6-dimethyl-r-2,c-7-diphenyl-1,4-diazepan-5-one and t-3, t-6-dimethyl-1-nitroso-r-2,c-7-diphenyl-1,4-diazepan-5-one were synthesized and characterized by X-ray crystallographic methods. The docking studies show that the compounds inhibit at the active site of the target protein and can be utilized as potential drug molecules. In both the compounds, N-H…O hydrogen bonds lead to dimer formation. In DIAZ2, additionally a couple of C-H…O interactions are noted between the molecules.
Physically motivated global alignment method for electron tomography
Authors: Sanders Toby , Prange Micah , Akatay Cem , Binev Peter 
Published: April 2015

AbstractElectron tomography is widely used for nanoscale determination of 3-D structures in many areas of science. Determining the 3-D structure of a sample from electron tomography involves three major steps: acquisition of sequence of 2-D projection images of the sample with the electron microscope, alignment of the images to a common coordinate system, and 3-D reconstruction and segmentation of the sample from the aligned image data. The resolution of the 3-D reconstruction is directly influenced by the accuracy of the alignment, and therefore, it is crucial to have a robust and dependable alignment method. In this paper, we develop a new alignment method which avoids the use of markers and instead traces the computed paths of many identifiable ‘local’ center-of-mass points as the sample is rotated. Compared with traditional correlation schemes, the alignment method presented here is resistant to cumulative error observed from correlation techniques, has very rigorous mathematical justification, and is very robust since many points and paths are used, all of which inevitably improves the quality of the reconstruction and confidence in the scientific results.
A large-scale field study in eastern Siberia using novel time-domain electromagnetic technology
Authors: Davydycheva Sofia , Kaminsky Alexander , Rykhlinski Nikolai , Yakovlev Andrei 
Published: April 2015

We evaluated the results of a large-scale commercial project that illustrated the capabilities of advanced time-domain electromagnetic (TDEM) technologies powered with integrated interpretation of geologic and geophysical data. To study the hydrocarbon prospectivity of a field in Eastern Siberia, we developed a survey design, and then acquired, processed, and interpreted the TDEM data from 30 profiles (total length 772 km) covering an area of approximately [Formula: see text]. The data were acquired using the conventional TDEM and a novel high-resolution version of TDEM, the focused-source electromagnetic method. We described the geologic framework, data acquisition methodologies, and key results obtained using integrated TDEM, seismic, and well-logging data. The interpretation was used to select well locations for additional exploratory drilling. Postsurvey drilling supported our interpretation. The presented case study demonstrates the value of TDEM in the exploration workflow.
Outcomes of Patients With Chronic Lymphocytic Leukemia and Richter's Transformation After Transplantation Failure
Authors: Rozovski Uri , Benjamini Ohad , Jain Preetesh , Thompson Philip A. , Wierda William G. , O'Brien Susan , Burger Jan A. , Ferrajoli Alessandra , Faderl Stefan , Shpall Elizabeth , Hosing Chitra , Khouri Issa F. , Champlin Richard , Keating Michael J. , Estrov Zeev 
Published: April 2015

Purpose Allogeneic stem-cell transplantation (SCT) induces long-term remission in a fraction of patients with high-risk chronic lymphocytic leukemia (CLL) or Richter's transformation (RT). Our purpose was to determine the outcomes of patients whose disease progressed after allogeneic SCT. Patients and Methods We retrospectively analyzed the outcomes of 72 patients (52 with CLL and 20 with RT) who underwent allogeneic SCT between 1998 and 2011 and had documented progression after transplantation. Twenty-two (31%) never had a response, and 50 (69%) had a response but experienced relapse after a median of 7 months (range, 2 to 85 months). Forty-eight patients who were receiving or were candidates to receive post-SCT cell-based therapies were not included in this analysis. Results The median age at time of transplantation was 58 years (range, 30 to 72 years). Sixty-two patients (86%) received more than two treatment regimens and 37 (51%) received more than three treatment regimens before SCT. Sixty-six patients (92%) had active disease at the time of transplantation. The 2- and 5-year survival rates were 67% and 38% (patients with CLL) and 36% and 0% (patients with RT). The patients who developed acute or chronic graft-versus-host disease had a longer overall survival (OS; P = .05). In a multivariable analysis, RT or low hemoglobin at the time of SCT predicted shorter OS. Chronic graft-versus-host disease and an initial response to SCT predicted longer OS. Conclusion Patients with CLL in whom allogeneic SCT fails may have a response to and benefit from salvage therapies, and their prognosis is relatively good.