bluuebunny/crossref_metadata_2025 huggingface dataset:
Protein Acetylation and Acetyl Coenzyme A Metabolism in Budding Yeast
Authors: Galdieri Luciano , Zhang Tiantian , Rogerson Daniella , Lleshi Rron , Vancura Ales
Published: October 2014

Cells sense and appropriately respond to the physical conditions and availability of nutrients in their environment. This sensing of the environment and consequent cellular responses are orchestrated by a multitude of signaling pathways and typically involve changes in transcription and metabolism. Recent discoveries suggest that the signaling and transcription machineries are regulated by signals which are derived from metabolism and reflect the metabolic state of the cell. Acetyl coenzyme A (CoA) is a key metabolite that links metabolism with signaling, chromatin structure, and transcription. Acetyl-CoA is produced by glycolysis as well as other catabolic pathways and used as a substrate for the citric acid cycle and as a precursor in synthesis of fatty acids and steroids and in other anabolic pathways. This central position in metabolism endows acetyl-CoA with an important regulatory role. Acetyl-CoA serves as a substrate for lysine acetyltransferases (KATs), which catalyze the transfer of acetyl groups to the epsilon-amino groups of lysines in histones and many other proteins. Fluctuations in the concentration of acetyl-CoA, reflecting the metabolic state of the cell, are translated into dynamic protein acetylations that regulate a variety of cell functions, including transcription, replication, DNA repair, cell cycle progression, and aging. This review highlights the synthesis and homeostasis of acetyl-CoA and the regulation of transcriptional and signaling machineries in yeast by acetylation.
Ppg1, a PP2A-Type Protein Phosphatase, Controls Filament Extension and Virulence in Candida albicans
Authors: Albataineh Mohammad T. , Lazzell Anna , Lopez-Ribot Jose L. , Kadosh David
Published: October 2014

Candida albicans
, a major human fungal pathogen, is the primary cause of invasive candidiasis in a wide array of immunocompromised patients.
C. albicans
virulence requires the ability to undergo a reversible morphological transition from yeast to filaments in response to a variety of host environmental cues. These cues are sensed by the pathogen and activate multiple signal transduction pathways to induce filamentation. Reversible phosphorylation events are critical for regulation of many of these pathways. While a variety of protein kinases are known to function as components of
C. albicans
filamentous growth signal transduction pathways, considerably little is known about the role of phosphatases. Here we demonstrate that
PPG1
, encoding a putative type 2A-related protein phosphatase, is important for
C. albicans
filament extension, invasion, and virulence in a mouse model of systemic candidiasis.
PPG1
is also important for downregulation of
NRG1
, a key transcriptional repressor of
C. albicans
filamentous growth, and is shown to affect the expression of several filament-specific target genes. An epistasis analysis suggests that
PPG1
controls
C. albicans
filamentation via the cyclic AMP-protein kinase A (cAMP-PKA) signaling pathway. We demonstrate that Ppg1 possesses phosphatase activity and that a
ppg1
catalytic mutant shows nearly equivalent filamentation, invasion, and virulence defects compared to those of a
ppg1
Δ/Δ strain. Overall, our results suggest that phosphatases, such as Ppg1, play critical roles in controlling and fine-tuning
C. albicans
filament extension and virulence as well as signal transduction pathways, transcriptional regulators, and target genes associated with these processes.
Depression screening via a smartphone app: cross-country user characteristics and feasibility
Authors: BinDhim Nasser F , Shaman Ahmed M , Trevena Lyndal , Basyouni Mada H , Pont Lisa G , Alhawassi Tariq M
Published: October 2014

Background and objective Smartphone applications (apps) have the potential to be valuable self-help interventions for depression screening. However, information about their feasibility and effectiveness and the characteristics of app users is limited. The aim of this study is to explore the uptake, utilization, and characteristics of voluntary users of an app for depression screening.

Methods This was a cross-sectional study of a free depression screening smartphone app that contains the demographics, patient health questionnaire (PHQ-9), brief anxiety test, personalized recommendation based on the participant's results, and links to depression-relevant websites. The free app was released globally via Apple's App Store. Participants aged 18 and older downloaded the study app and were recruited passively between September 2012 and January 2013.

Findings 8241 participants from 66 countries had downloaded the app, with a response rate of 73.9%. While one quarter of the participants had a previous diagnosis of depression, the prevalence of participants with a higher risk of depression was 82.5% and 66.8% at PHQ-9 cut-off 11 and cut-off 15, respectively. Many of the participants had one or more physical comorbid conditions and suicidal ideation. The cut-off 11 (OR: 1.4; 95% CI 1.2 to 1.6), previous depression diagnosis (OR: 1.3; 95% CI1.2 to 1.5), and postgraduate educational level (OR: 1.2; 95% CI 1.0 to 1.5) were associated with completing the PHQ-9 questionnaire more than once.

Conclusions Smartphone apps can be used to deliver a screening tool for depression across a large number of countries. Apps have the potential to play a significant role in disease screening, self-management, monitoring, and health education, particularly among younger adults.
Completeness, accuracy, and computability of National Quality Forum-specified eMeasures
Authors: Amster Andy , Jentzsch Joseph , Pasupuleti Ham , Subramanian K G
Published: October 2014

Objective To analyze the completeness, computability, and accuracy of specifications for five National Quality Forum-specified (NQF) eMeasures spanning ambulatory, post-discharge, and emergency care within a comprehensive, integrated electronic health record (EHR) environment.

Materials and methods To evaluate completeness, we assessed eMeasure logic, data elements, and value sets. To evaluate computability, we assessed the translation of eMeasure algorithms to programmable logic constructs and the availability of EHR data elements to implement specified data criteria, using a de-identified clinical data set from Kaiser Permanente Northwest. To assess accuracy, we compared eMeasure results with those obtained independently by existing audited chart abstraction methods used for external and internal reporting.

Results One measure specification was incomplete; missing applicable LOINC codes rendered it non-computable. For three of four computable measures, data availability issues occurred; the literal specification guidance for a data element differed from the physical implementation of the data element in the EHR. In two cases, cross-referencing specified data elements to EHR equivalents allowed variably accurate measure computation. Substantial data availability issues occurred for one of the four computable measures, producing highly inaccurate results.

Discussion Existing clinical workflows, documentation, and coding in the EHR were significant barriers to implementing eMeasures as specified. Implementation requires redesigning business or clinical practices and, for one measure, systemic EHR modifications, including clinical text search capabilities.

Conclusions Five NQF eMeasures fell short of being machine-consumable specifications. Both clinical domain and technological expertise are required to implement manually intensive steps from data mapping to text mining to EHR-specific eMeasure implementation.
Organizational strategies for promoting patient and provider uptake of personal health records
Authors: Wells Susan , Rozenblum Ronen , Park Andrea , Dunn Marie , Bates David W
Published: October 2014

Objective To investigate organizational strategies to promote personal health records (PHRs) adoption with a focus on patients with chronic disease.

Methods Using semi-structured interviews and a web-based survey, we sampled US health delivery organizations which had implemented PHRs for at least 12 months, were recognized as PHR innovators, and had scored highly in national patient satisfaction surveys. Respondents had lead positions for clinical information systems or high-risk population management. Using grounded theory approach, thematic categories were derived from interviews and coupled with data from the survey.

Results Interviews were conducted with 30 informants from 16 identified organizations. Organizational strategies were directed towards raising patient awareness via multimedia communications, and provider acceptance and uptake. Strategies for providers were grouped into six main themes: organizational vision, governance and policies, work process redesign, staff training, information technology (IT) support, and monitoring and incentives. Successful organizations actively communicated their vision, engaged leaders at all levels, had clear governance, planning, and protocols, set targets, and celebrated achievement. The most effective strategy for patient uptake was through health professional encouragement. No specific outreach efforts targeted patients with chronic disease. Registration and PHR activity was routinely measured but without reference to a denominator population or high risk subpopulations.

Discussion and conclusion Successful PHR implementation represents a social change and operational project catalyzed by a technical solution. The key to clinician acceptance is making their work easier. However, organizations will likely not achieve the value they want from PHRs unless they target specific populations and monitor their uptake.
Real-life evaluation of European and American high-risk strategies for primary prevention of cardiovascular disease in patients with first myocardial infarction
Authors: Mortensen Martin B , Falk Erling
Published: October 2014

Objective

To determine the detection rate (sensitivity) of the high-risk strategy recommended in the European Society of Cardiology (ESC) and National Institute for Health and Care Excellence (NICE/UK) and American College of Cardiology/American Heart Association (ACC/AHA) guidelines on cardiovascular disease (CVD) prevention. In particular, to evaluate the ability to ensure statin therapy to contemporary Europeans destined for a first myocardial infarction (MI).

Design

393 consecutive statin-naïve, CVD-free patients without diabetes hospitalised for a first MI, 247 of whom were 40–75 years of age. We assumed they had undergone a health check the day before their MI and estimated the predicted risk.

Primary outcome

Sensitivity of the risk-based eligibility for primary prevention with statins recommended by the guidelines.

Results

All recommended risk scores rank-ordered patients similarly, but the sensitivity of the cut point above which statin therapy should be considered differed substantially. In younger patients (age 40–60), 62% of men and 13% of women qualified for statin therapy by ACC/AHA criteria, compared with only 2% of men and no women using the ESC criteria recommended for most non-Eastern European countries. In those 60–75 years of age, the ACC/AHA guidelines captured all men and 85% of women, compared with 12% and 2%, respectively, using the new ESC guideline. This guideline restricted the eligibility for primary prevention with statins substantially by reclassifying many European countries from ‘high-risk’ to ‘low-risk’, whereas the eligibility was expanded in the ACC/AHA and the new NICE/UK guidelines by lowering the decision threshold.

Conclusions

The 2012 ESC guidelines differ substantially from the 2013 ACC/AHA and 2014 NICE/UK guidelines in ability to secure statin therapy to those destined for a first MI. A great opportunity for primary prevention with statins remains unexploited in Europe.
Health impact assessment of air pollution in Valladolid, Spain
Authors: Cárdaba Arranz Mario , Muñoz Moreno María Fe , Armentia Medina Alicia , Alonso Capitán Margarita , Carreras Vaquer Fernando , Almaraz Gómez Ana
Published: October 2014

Objective

To estimate the attributable and targeted avoidable deaths (ADs; TADs) of outdoor air pollution by ambient particulate matter (PM10), PM2.5and O3according to specific WHO methodology.

Design

Health impact assessment.

Setting

City of Valladolid, Spain (around 300 000 residents).

Data sources

Demographics; mortality; pollutant concentrations collected 1999–2008.

Main outcome measures

Attributable fractions; ADs and TADs per year for 1999–2008.

Results

Higher TADs estimates (shown here) were obtained when assuming as ‘target’ concentrations WHO Air Quality Guidelines instead of Directive 2008/50/EC. ADs are considered relative to pollutant background levels. All-cause mortality associated to PM10(all ages): 52 ADs (95% CI 39 to 64); 31 TADs (95% CI 24 to 39).All-cause mortality associated to PM10(<5 years): 0 ADs (95% CI 0 to 1); 0 TADs (95% CI 0 to 1). All-cause mortality associated to PM2.5(>30 years): 326 ADs (95% CI 217 to 422); 231 TADs (95% CI 153 to 301). Cardiopulmonary and lung cancer mortality associated to PM2.5(>30 years):

▸ Cardiopulmonary: 186 ADs (95% CI 74 to 280); 94 TADs (95% CI 36 to 148).

▸ Lung cancer : 51 ADs (95% CI 21 to 73); 27 TADs (95% CI 10 to 41).All-cause, respiratory and cardiovascular mortality associated to O3(all ages):

▸ All-cause: 52ADs (95% CI 25 to 77) ; 31 TADs (95% CI 15 to 45).

▸ Respiratory: 5ADs (95% CI −2 to 13) ; 3 TADs (95% CI −1 to 8).

▸ Cardiovascular: 30 ADs (95% CI 8 to 51) ; 17 TADs (95% CI 5 to 30).

Negative estimates which should be read as zero were obtained when pollutant concentrations were below counterfactuals or assumed risk coefficients were below one.

Conclusions

Our estimates suggest a not negligible negative impact on mortality of outdoor air pollution. The implementation of WHO methodology provides critical information to distinguish an improvement range in air pollution control.
Day-to-day variability in cardiorespiratory responses to hypoxic cycle exercise
Authors: MacNutt Meaghan J. , Peters Carli M. , Chan Catherine , Moore Jason , Shum Serena , Sheel A. William
Published: October 2014

Repeatedly performing exercise in hypoxia could elicit an independent training response and become an unintended co-intervention. The primary purposes of this study were to determine if hypoxic exercise responses changed across repeated testing and to assess the day-to-day variability of commonly used measures of cardiorespiratory and metabolic responses to hypoxic exercise. Healthy young males (aged 23 ± 2 years) with a maximal O2 consumption of 50.7 ± 4.7 mL·kg−1·min−1 performed 5 trials (H1 to H5) over a 2-week period in hypoxia (fraction of inspired oxygen = 0.13). Participants completed 3-min stages at 20%, 40%, 60%, and 10% of individual peak power. With increasing cycle exercise intensity there were increases in minute ventilation, O2 consumption, CO2 production, respiratory exchange ratio, heart rate (HR), blood lactate concentration, and ratings of perceived exertion for legs and respiratory system along with a reduction in oxyhaemoglobin saturation (%SpO2) (all p < 0.001). There were no systematic changes from H1 to H5 (p > 0.05). Most measures were highly repeatable across testing sessions with the coefficient of variation (CV) averaging ≤10% of the mean value in all variables except O2 consumption (17%), CO2 production (11%) and blood lactate concentration (17%). For HR and %SpO2 the CV was <5%. The exercise protocol did not elicit a training response when repeated 5 times during a 2-week period and the variability of exercise responses was low. We conclude that this protocol allows detection of small changes in cardiorespiratory responses to hypoxic exercise that might occur during exposure to hypoxia.
Holocene climate variability and change; a data-based review
Authors: Wanner H. , Mercolli L. , Grosjean M. , Ritz S. P.
Published: October 2014

The Holocene Thermal Maximum with peak temperatures prior to 7 ka BP is mostly accentuated in the Northern Hemisphere, still visible in the Southern Hemisphere and possibly did not exist in the tropics. Between this period and the modern warming a remarkable negative temperature trend occurred in the Northern Hemisphere, which was probably the effect of a decreasing orbital-induced insolation during the boreal summer. On average the Northern Hemisphere humidity–precipitation records do not show any significant trend. A mechanistic explanation for the multi-decadal- to century-scale Holocene cold relapses, which mainly occurred in the Atlantic–European regions, exists for only the early Holocene cooling events, which are probably the result of a collapse of the meridional overturning circulation owing to freshwater outbursts from the Laurentide ice sheet. Possibly, the late Holocene cold events after
c
. 4 ka BP are influenced by the covarying influence of major tropical volcanic eruptions and Grand Solar Minima.
The New Siberian Islands and evidence for the continuation of the Uralides, Arctic Russia
Authors: Pease Victoria L. , Kuzmichev Alexander B. , Danukalova Maria K.
Published: October 2014

U–Pb detrital zircon results from New Siberian Islands sandstones illuminate the long-lived controversy regarding the continuation of the Uralian orogen into the Arctic region. A dominant age peak of
c
. 285 Ma from Permian sandstone requires proximal derivation from Taimyr’s Carboniferous–Permian granites, thought to reflect syn- to post-tectonic Uralian magmatism. The provenance of Devonian sandstone has Baltica affinities. The data record a dramatic change in provenance between Devonian and Permian time, from Baltica to a mixed Baltica + Uralian source. Our results confirm that the Uralian foreland basin extended from Taimyr to the New Siberian Islands.

Supplementary material:

Sample co-ordinates, sediment petrography and heavy mineral analysis, U–Pb data tables and description of analytical methods associated with detrital zircon and granite analyses are available at
http://www.geolsoc.org.uk/SUP18784
.
Platelets, acting in part via P-selectin, mediate cytomegalovirus-induced microvascular dysfunction
Authors: Khoretonenko Mikhail V. , Brunson Jerry L. , Senchenkov Evgeny , Leskov Igor L. , Marks Christian R. , Stokes Karen Y.
Published: October 2014

Cytomegalovirus (CMV) infects a majority of the population worldwide. It has been implicated in cardiovascular disease, induces microvascular dysfunction, and synergizes with hypercholesterolemia to promote leukocyte and platelet recruitment in venules. Although platelets and platelet-associated P-selectin contribute to cardiovascular disease inflammation, their role in CMV-induced vascular responses is unknown. We assessed the role of platelets in CMV-induced microvascular dysfunction by depleting platelets and developing bone marrow chimeric mice deficient in platelet P-selectin. Wild-type and chimeric mice received mock or murine (m)CMV intraperitoneally. Five weeks later, some mice were switched to a high-cholesterol diet (HC) to investigate the synergism between mCMV and HC. Arteriolar vasodilation and recruitment of leukocytes and donor platelets in venules were measured at 11wk. mCMV with or without HC caused significant endothelial dysfunction in arterioles. Platelet depletion restored normal vasodilation in mCMV-HC but not mCMV-ND mice, whereas protection was seen in both groups for platelet P-selectin chimeras. Only mCMV + HC elevated leukocyte and platelet recruitment in venules. Leukocyte adhesion was reduced to mock levels by acute platelet depletion but was only partially decreased in platelet P-selectin chimeras. Platelets from mCMV-HC mice and, to a lesser extent, mCMV-ND but not mock-HC mice showed significant adhesion in mCMV-HC recipients. Our findings implicate a role for platelets, acting through P-selectin, in CMV-induced arteriolar dysfunction and suggest that the addition of HC leads to a platelet-dependent, inflammatory infiltrate that is only partly platelet P-selectin dependent. CMV appeared to have a stronger activating influence than HC on platelets and may represent an additional therapeutic target in vulnerable patients.
The SIRT1 activator SRT1720 reverses vascular endothelial dysfunction, excessive superoxide production, and inflammation with aging in mice
Authors: Gano Lindsey B. , Donato Anthony J. , Pasha Hamza M. , Hearon Christopher M. , Sindler Amy L. , Seals Douglas R.
Published: October 2014

Reductions in arterial SIRT1 expression and activity with aging are linked to vascular endothelial dysfunction. We tested the hypothesis that the specific SIRT1 activator SRT1720 improves endothelial function [endothelium-dependent dilation (EDD)] in old mice. Young (4–9 mo) and old (29–32 mo) male B6D2F1 mice treated with SRT1720 (100 mg/kg body wt) or vehicle for 4 wk were studied with a group of young controls. Compared with the young controls, aortic SIRT1 expression and activity were reduced ( P < 0.05) and EDD was impaired (83 ± 2 vs. 96 ± 1%; P < 0.01) in old vehicle-treated animals. SRT1720 normalized SIRT1 expression/activity in old mice and restored EDD (95 ± 1%) by enhancing cyclooxygenase (COX)-2-mediated dilation and protein expression in the absence of changes in nitric oxide bioavailability. Aortic superoxide production and expression of NADPH oxidase 4 (NOX4) were increased in old vehicle mice ( P < 0.05), and ex vivo administration of the superoxide scavenger TEMPOL restored EDD in that group. SRT1720 normalized aortic superoxide production in old mice, without altering NOX4 and abolished the improvement in EDD with TEMPOL, while selectively increasing aortic antioxidant enzymes. Aortic nuclear factor-κB (NF-κB) activity and tumor necrosis factor-α (TNF-α) were increased in old vehicle mice ( P < 0.05), whereas SRT1720 normalized NF-κB activation and reduced TNF-α in old animals. SIRT1 activation with SRT1720 ameliorates vascular endothelial dysfunction with aging in mice by enhancing COX-2 signaling and reducing oxidative stress and inflammation. Specific activation of SIRT1 is a promising therapeutic strategy for age-related endothelial dysfunction in humans.
A longitudinal comparison of hemodynamics and intraluminal thrombus deposition in abdominal aortic aneurysms
Authors: Arzani Amirhossein , Suh Ga-Young , Dalman Ronald L. , Shadden Shawn C.
Published: October 2014

Abdominal aortic aneurysm (AAA) is often accompanied by in traluminal thrombus (ILT), which complicates AAA progression and risk of rupture. Patient-specific computational fluid dynamics modeling of 10 small human AAA was performed to investigate relations between hemodynamics and ILT progression. The patients were imaged using magnetic resonance twice in a 2- to 3-yr interval. Wall content data were obtained by a planar T1-weighted fast spin echo black-blood scan, which enabled quantification of thrombus thickness at midaneurysm location during baseline and followup. Computational simulations with patient-specific geometry and boundary conditions were performed to quantify the hemodynamic parameters of time-averaged wall shear stress (TAWSS), oscillatory shear index (OSI), and mean exposure time at baseline. Spatially resolved quantifications of the change in ILT thickness were compared with the different hemodynamic parameters. Regions of low OSI had the strongest correlation with ILT growth and demonstrated a statistically significant correlation coefficient. Prominent regions of high OSI (>0.4) and low TAWSS (<1 dyn/cm2) did not appear to coincide with locations of thrombus deposition.
Emerging molecular phenotypes of asthma
Authors: Ray Anuradha , Oriss Timothy B. , Wenzel Sally E.
Published: October 2014

Although asthma has long been considered a heterogeneous disease, attempts to define subgroups of asthma have been limited. In recent years, both clinical and statistical approaches have been utilized to better merge clinical characteristics, biology, and genetics. These combined characteristics have been used to define phenotypes of asthma, the observable characteristics of a patient determined by the interaction of genes and environment. Identification of consistent clinical phenotypes has now been reported across studies. Now the addition of various 'omics and identification of specific molecular pathways have moved the concept of clinical phenotypes toward the concept of molecular phenotypes. The importance of these molecular phenotypes is being confirmed through the integration of molecularly targeted biological therapies. Thus the global term asthma is poised to become obsolete, being replaced by terms that more specifically identify the pathology associated with the disease.
Cigarette smoke extract affects mitochondrial function in alveolar epithelial cells
Authors: Ballweg Korbinian , Mutze Kathrin , Königshoff Melanie , Eickelberg Oliver , Meiners Silke
Published: October 2014

Cigarette smoke is the main risk factor for chronic obstructive pulmonary disease (COPD). Exposure of cells to cigarette smoke induces an initial adaptive cellular stress response involving increased oxidative stress and induction of inflammatory signaling pathways. Exposure of mitochondria to cellular stress alters their fusion/fission dynamics. Whereas mild stress induces a prosurvival response termed stress-induced mitochondrial hyperfusion, severe stress results in mitochondrial fragmentation and mitophagy. In the present study, we analyzed the mitochondrial response to mild and nontoxic doses of cigarette smoke extract (CSE) in alveolar epithelial cells. We characterized mitochondrial morphology, expression of mitochondrial fusion and fission genes, markers of mitochondrial proteostasis, as well as mitochondrial functions such as membrane potential and oxygen consumption. Murine lung epithelial (MLE)12 and primary mouse alveolar epithelial cells revealed pronounced mitochondrial hyperfusion upon treatment with CSE, accompanied by increased expression of the mitochondrial fusion protein mitofusin 2 and increased metabolic activity. We did not observe any alterations in mitochondrial proteostasis, i.e., induction of the mitochondrial unfolded protein response or mitophagy. Therefore, our data indicate an adaptive prosurvival response of mitochondria of alveolar epithelial cells to nontoxic concentrations of CSE. A hyperfused mitochondrial network, however, renders the cell more vulnerable to additional stress, such as sustained cigarette smoke exposure. As such, cigarette smoke-induced mitochondrial hyperfusion, although part of a beneficial adaptive stress response in the first place, may contribute to the pathogenesis of COPD.
HER2 activation results in β-catenin-dependent changes in pulmonary epithelial permeability
Authors: Finigan James H. , Vasu Vihas T. , Thaikoottathil Jyoti V. , Mishra Rangnath , Shatat Mohammad A. , Mason Robert J. , Kern Jeffrey A.
Published: October 2014

The receptor tyrosine kinase human epidermal growth factor receptor-2 (HER2) is known to regulate pulmonary epithelial barrier function; however, the mechanisms behind this effect remain unidentified. We hypothesized that HER2 signaling alters the epithelial barrier through an interaction with the adherens junction (AJ) protein β-catenin, leading to dissolution of the AJ. In quiescent pulmonary epithelial cells, HER2 and β-catenin colocalized along the lateral intercellular junction. HER2 activation by the ligand neuregulin-1 was associated with tyrosine phosphorylation of β-catenin, dissociation of β-catenin from E-cadherin, and decreased E-cadherin-mediated cell adhesion. All effects were blocked with the HER2 inhibitor lapatinib. β-Catenin knockdown using shRNA significantly attenuated neuregulin-1-induced decreases in pulmonary epithelial resistance in vitro. Our data indicate that HER2 interacts with β-catenin, leading to dissolution of the AJ, decreased cell-cell adhesion, and disruption of the pulmonary epithelial barrier.
Chronic intrauterine pulmonary hypertension increases main pulmonary artery stiffness and adventitial remodeling in fetal sheep
Authors: Dodson R. Blair , Morgan Matthew R. , Galambos Csaba , Hunter Kendall S. , Abman Steven H.
Published: October 2014

Persistent pulmonary hypertension of the newborn (PPHN) is a clinical syndrome that is characterized by high pulmonary vascular resistance due to changes in lung vascular growth, structure, and tone. PPHN has been primarily considered as a disease of the small pulmonary arteries (PA), but proximal vascular stiffness has been shown to be an important predictor of morbidity and mortality in other diseases associated with pulmonary hypertension (PH). The objective of this study is to characterize main PA (MPA) stiffness in experimental PPHN and to determine the relationship of altered biomechanics of the MPA with changes in extracellular matrix (ECM) content and orientation of collagen and elastin fibers. MPAs were isolated from control and PPHN fetal sheep model and were tested by planar biaxial testing to measure stiffness in circumferential and axial vessel orientations. Test specimens were fixed for histological assessments of the vascular wall ECM constituents collagen and elastin. MPAs from PPHN sheep had increased mechanical stiffness ( P < 0.05) and altered ECM remodeling compared with control MPA. A constitutive mathematical model and histology demonstrated that PPHN vessels have a smaller contribution of elastin and a greater role for collagen fiber engagement compared with the control arteries. We conclude that exposure to chronic hemodynamic stress in late-gestation fetal sheep increases proximal PA stiffness and alters ECM remodeling. We speculate that proximal PA stiffness further contributes to increased right ventricular impedance in experimental PPHN, which contributes to abnormal transition of the pulmonary circulation at birth.
Analysis of 1,115 Patients Tested for MET Amplification and Therapy Response in the MD Anderson Phase I Clinic
Authors: Jardim Denis L.F. , Tang Chad , Gagliato Debora De Melo , Falchook Gerald S. , Hess Kenneth , Janku Filip , Fu Siqing , Wheler Jennifer J. , Zinner Ralph G. , Naing Aung , Tsimberidou Apostolia M. , Holla Vijaykumar , Li Marylin M. , Roy-Chowdhuri Sinchita , Luthra Raja , Salgia Ravi , Kurzrock Razelle , Meric-Bernstam Funda , Hong David S.
Published: October 2014

Purpose: This study aimed to assess MET amplification among different cancers, association with clinical factors and genetic aberrations and targeted therapy response modifications.

Experimental Design: From May 2010 to November 2012, samples from patients with advanced tumors referred to the MD Anderson Phase I Clinic were analyzed for MET gene amplification by FISH. Patient demographic, histologic characteristics, molecular characteristics, and outcomes in phase I protocols were compared per MET amplification status.

Results: Of 1,115 patients, 29 (2.6%) had MET amplification. The highest prevalence was in adrenal (2 of 13; 15%) and renal (4 of 28; 14%) tumors, followed by gastroesophageal (6%), breast (5%), and ovarian cancers (4%). MET amplification was associated with adenocarcinomas (P = 0.007), high-grade tumors (P = 0.003), more sites of metastasis, higher BRAF mutation, and PTEN loss (all P < 0.05). Median overall survival was 7.23 and 8.62 months for patients with and without a MET amplification, respectively (HR = 1.12; 95% confidence intervals, 0.83–1.85; P = 0.29). Among the 20 patients with MET amplification treated on a phase I protocol, 4 (20%) achieved a partial response with greatest response rate on agents targeting angiogenesis (3 of 6, 50%). No patient treated with a c-MET inhibitor (0 of 7) achieved an objective response.

Conclusion: MET amplification was detected in 2.6% of patients with solid tumors and was associated with adenocarcinomas, high-grade histology, and higher metastatic burden. Concomitant alterations in additional pathways (BRAF mutation and PTEN loss) and variable responses on targeted therapies, including c-MET inhibitors, suggest that further studies are needed to target this population. Clin Cancer Res; 20(24); 6336–45. ©2014 AACR.
Applications of ImmunoPET: Using 124I-Anti-PSCA A11 Minibody for Imaging Disease Progression and Response to Therapy in Mouse Xenograft Models of Prostate Cancer
Authors: Knowles Scott M. , Tavaré Richard , Zettlitz Kirstin A. , Rochefort Matthew M. , Salazar Felix B. , Jiang Ziyue Karen , Reiter Robert E. , Wu Anna M.
Published: October 2014

Purpose: Prostate stem cell antigen (PSCA) is highly expressed in local prostate cancers and prostate cancer bone metastases and its expression correlates with androgen receptor activation and a poor prognosis. In this study, we investigate the potential clinical applications of immunoPET with the anti-PSCA A11 minibody, an antibody fragment optimized for use as an imaging agent. We compare A11 minibody immunoPET to 18F-Fluoride PET bone scans for detecting prostate cancer bone tumors and evaluate the ability of the A11 minibody to image tumor response to androgen deprivation.

Experimental Design: Osteoblastic, PSCA-expressing, LAPC-9 intratibial xenografts were imaged with serial 124I-anti-PSCA A11 minibody immunoPET and 18F-Fluoride bone scans. Mice bearing LAPC-9 subcutaneous xenografts were treated with either vehicle or MDV-3100 and imaged with A11 minibody immunoPET/CT scans pre- and posttreatment. Ex vivo flow cytometry measured the change in PSCA expression in response to androgen deprivation.

Results: A11 minibody demonstrated improved sensitivity and specificity over 18F-Fluoride bone scans for detecting LAPC-9 intratibial xenografts at all time points. LAPC-9 subcutaneous xenografts showed downregulation of PSCA when treated with MDV-3100 which A11 minibody immunoPET was able to detect in vivo.

Conclusions: A11 minibody immunoPET has the potential to improve the sensitivity and specificity of clinical prostate cancer metastasis detection over bone scans, which are the current clinical standard-of-care. A11 minibody immunoPET additionally has the potential to image the activity of the androgen signaling axis in vivo which may help evaluate the clinical response to androgen deprivation and the development of castration resistance. Clin Cancer Res; 20(24); 6367–78. ©2014 AACR.
Interaction Between Neuronal Nitric Oxide Synthase Signaling and Temperature Influences Sarcoplasmic Reticulum Calcium Leak
Authors: Dulce Raul A. , Mayo Vera , Rangel Erika B. , Balkan Wayne , Hare Joshua M.
Published: October 2014

Rationale:

Although nitric oxide (NO) signaling modulates cardiac function and excitation–contraction coupling, opposing results because of inconsistent experimental conditions, particularly with respect to temperature, confound the ability to elucidate NO signaling pathways. Here, we show that temperature significantly modulates NO effects.

Objective:

To test the hypothesis that temperature profoundly affects nitroso–redox equilibrium, thereby affecting sarcoplasmic reticulum (SR) calcium (Ca
2+
) leak.

Methods and Results:

We measured SR Ca
2+
leak in cardiomyocytes from wild-type (WT), NO/redox imbalance (neuronal nitric oxide synthase–deficient mice-1 [NOS1
−/−
]), and hyper
S
-nitrosoglutathione reductase–deficient (GSNOR
−/−
) mice. In WT cardiomyocytes, SR Ca
2+
leak increased because temperature decreased from 37°C to 23°C, whereas in NOS1
−/−
cells, the leak suddenly increased when the temperature surpassed 30°C. GSNOR
−/−
cardiomyocytes exhibited low leak throughout the temperature range. Exogenously added NO had a biphasic effect on NOS1
−/−
cardiomyocytes; reducing leak at 37°C but increasing it at subphysiological temperatures. Oxypurinol and Tempol diminished the leak in NOS1
−/−
cardiomyocytes. Cooling from 37°C to 23°C increased reactive oxygen species generation in WT but decreased it in NOS1
−/−
cardiomyocytes. Oxypurinol further reduced reactive oxygen species generation. At 23°C in WT cells, leak was decreased by tetrahydrobiopterin, an essential NOS cofactor. Cooling significantly increased SR Ca
2+
content in NOS1
−/−
cells but had no effect in WT or GSNOR
−/−
.

Conclusions:

Ca
2+
leak and temperature are normally inversely proportional, whereas NOS1 deficiency reverses this effect, increasing leak and elevating reactive oxygen species production because temperature increases. Reduced denitrosylation (GSNOR deficiency) eliminates the temperature dependence of leak. Thus, temperature regulates the balance between NO and reactive oxygen species which in turn has a major effect on SR Ca
2+
.
An occupation-based video feedback intervention for improving self-awareness: Protocol and rationale
Authors: Schmidt Julia , Fleming Jennifer , Ownsworth Tamara , Lannin Natasha A.
Published: October 2014

Background.

Impaired self-awareness can limit rehabilitation outcomes for people with traumatic brain injury (TBI). Video feedback on occupational performance has been found to improve self-awareness after TBI when delivered according to specific principles.

Purpose.

The purpose of this article is to describe an occupation-based video feedback intervention found to be effective in a randomized controlled trial to assist with translation into clinical practice.

Key Issues.

The intervention uses therapist-mediated video feedback on clients’ occupational performance, aiming to facilitate self-reflection on performance and improve self-awareness. This paper describes the theoretical background, intervention principles, and protocol of the intervention.

Implications.

Therapists can use video feedback intervention, incorporating the principles in this article, to improve people’s intellectual awareness and ability to recognize and correct errors during task performance after TBI without a negative impact on emotional status.
All Alliances Are Multilateral
Authors: Fordham Benjamin , Poast Paul
Published: October 2014

Alliance formation is a multilateral process. The vast majority of alliance relations are created via multilateral alliances. Moreover, leaders assess the alliance as a whole, not just each prospective partner. Any alliance could have three or more members, so one must understand not just why third parties were included in multilateral alliances, but why they were excluded from bilateral alliances. Unfortunately, current research treats alliance formation as a bilateral process: it theorizes about bilateral alliances and tests hypotheses using dyadic research designs. Reconceptualizing all alliances as originating from a multilateral process reveals that a long-neglected theory, William Riker’s size principle, illuminates the role of power in alliance formation. Using k-adic data to analyze multilateral processes, we find strong support for Riker’s claim about minimum winning coalitions in world politics. Our argument and findings, by highlighting how a fundamental state behavior like alliance formation follows a multilateral process, suggest rethinking much of international relations research.
Regional Water Cooperation
Authors: Ovodenko Alexander
Published: October 2014

Shared water has prompted some neighboring countries to form integrated regional institutions and rules. Other neighboring countries have maintained less cooperative policies in managing shared water. When do governments achieve integrated management of regional water? How do they overcome barriers to integrated cooperation? This article contends that the structure of interdependence, not the number of states bordering the water, encourages different international policies. It analyzes original panel data on the agreement histories of seventy-six rivers, lakes, and seas. It also examines the role of selective incentives in promoting mutual water management. Fundamentally, the number of states with access to the water does not determine the fate of water management. Strategies for overcoming divergent preferences can be applied across situations. The key is to provide selective incentives when states are asymmetrically interdependent in using the water, to alter national preferences. Selective incentives are particularly important when few states share the water.
Three-dimensional launch simulation and active cooling analysis of a single-shot electromagnetic railgun
Authors: Zhao Han , Souza Jeferson A , Ordonez Juan C
Published: October 2014

An electromagnetic railgun is one of the applications of electromagnetic launchers, which are devices used to accelerate projectiles to velocities exceeding those attained with conventional propelling systems. A magnetic field is generated when current flows through two conductive rails connected by a moving armature. The current that passes through the rails exerts an electromagnetic force on the armature and causes it to accelerate to high speeds. In this work, a three-dimensional transient model for the thermal and electromagnetic solutions of the launch process is presented. The model accounts for the determination of the current and temperature profiles inside the rails, the projectile movement, and the cooling process after the first launch. Focus is given to the thermal management where five different arrangements, one without cooling and four that include cooling channels, are studied. A 10 to 50 K reduction in the peak temperature was obtained with the inclusion of cooling channels when compared to the no-cooling-channel case. It was also shown that the position and size of these channels can be optimized in order to reduce this peak temperature.
Tourism Blogging Motivations
Authors: Wu Mao-Ying , Pearce Philip L.
Published: October 2014

Chinese tourists, who are increasingly traveling out of Asia independently, need trustworthy and readily available information sources. This study explores the motives of Chinese tourists who have invested considerable time (mostly more than a week) in creating information-rich, influential, and interactive online travel blogs—effectively creating personalized little “Lonely Planets” that serve these growing information needs. This study assesses the demographic characteristics of the “Lonely Planets” creators, the features of their blogging behavior, and the motivations for the involvement. It reveals six motive categories: “positive self-enhancement through online social connection,” “altruism: being helpful to fellow travelers,” “social status issues,” “personal status and achievement,” “self-documentation and sharing,” and “hedonic enjoyment of blogging.” Superficially, these motivations seem to be similar with previous Western studies of blogging behavior, but significant contextual and cultural issues exist and are explained. Management implications and future research arising from the current study are provided.
Grassroots Labor Organizations in Metropolitan Buenos Aires, 2003–2007
Authors: Scolnik Fernando
Published: October 2014

During the 1990s, the Argentine working class was hard-hit by the neoliberal offensive, which reversed many of the gains previously won. The decade saw a serious degradation of living conditions and an increase in inequality as a consequence of unemployment and precarious work. After the economic crisis of 2001, labor unions were strengthened by a decline in unemployment and the reactivation of collective bargaining. At the same time, the crisis generated a questioning of the traditional union leadership and the emergence of grassroots organizations (internal committees and bodies of delegates) that introduced democratic decision making to the workplace in accordance with developments at the time in the community assemblies, movements of unemployed workers, and recovered factories. During Néstor Kirchner’s presidency, these organizations led union struggles that had a strong political and social impact and even achieved coordination among themselves outside of the organic labor union groups.

Durante la década de 1990, la clase obrera argentina fue muy impactada por la ofensiva neoliberal que revocó muchas de las ganancias previamente obtenidas. La década fue testigo de una degradación grave de las condiciones de vida y un aumento en la desigualdad como consecuencia del desempleo y el trabajo precario. Tras la crisis económica de 2001, los sindicatos fueron reforzados por una disminución del desempleo y la reactivación de la negociación colectiva. Al mismo tiempo, la crisis generó un cuestionamiento de la dirigencia sindical tradicional y el surgimiento de organizaciones de base (comités y cuerpos de delegados) que introdujo la toma de decisiones democrática a los lugares de trabajo en función de los acontecimientos de ese entonces en las asambleas comunitarias, movimientos de trabajadores desempleados, y las fábricas recuperadas. Durante la presidencia de Néstor Kirchner, estas organizaciones condujeron luchas sindicales que tuvieron un fuerte impacto político y social, e incluso lograron coordinación entre sí fuera de los grupos sindicales orgánicos.
Positive Expectations Encourage Generalization From a Positive Intergroup Interaction to Outgroup Attitudes
Authors: Deegan Matthew P. , Hehman Eric , Gaertner Samuel L. , Dovidio John F.
Published: October 2014

The current research reveals that while positive expectations about an anticipated intergroup interaction encourage generalization of positive contact to outgroup attitudes, negative expectations restrict the effects of contact on outgroup attitudes. In Study 1, when Blacks and Whites interacted with positive expectations, interaction quality predicted outgroup attitudes to a greater degree than when groups interacted with negative expectations. When expectations (Studies 2 and 3) and the actual interaction quality (Study 4) were manipulated orthogonally, negative expectations about the interaction predicted negative outgroup attitudes, regardless of actual interaction quality. By contrast, participants holding positive expectations who experienced a positive interaction expressed positive outgroup attitudes, whereas when they experienced a negative interaction, they expressed outgroup attitudes as negative as those with negative expectations. Across all four studies, positive expectations encouraged developing outgroup attitudes consistent with interaction quality.
Justice and capabilities in the postcolony
Authors: Graham Greg
Published: October 2014

This article explores briefly the practical as well as theoretical issues that arise when Amartya Sen’s evaluation of justice through the capabilities afforded citizens in a society is applied to postcolonies like Jamaica and South Africa. It argues that the application of the capabilities approach to the circumstances of the postcolony gives rise to the need for an expansion of its purview as the informational focus of Sen’s theory of justice. This is so because of the manner in which domestic as well as external forces and interests function so as to limit in particular the material conditions necessary for freedom and self-actualization in the postcolony. As examples the article engages briefly with the way in which multinationals and multilateral lending agencies in pursuit of their interests have adverse impact upon capabilities in Jamaica and South Africa, affecting in turn the quality of material life, as well as that of democratic governance in both states. In doing so it broaches the important issue of the failure to engage thoroughly with the reality of the limited maneuverability, both at the domestic and also the international levels, that issues from the role of the developing state in the global political economy (as peripheries for the extraction of raw materials, according to Immanuel Wallerstein’s World Systems Theory), which I think haunts the utilization of the capabilities approach to understanding justice and development in the postcolony.