BMPR-II deficiency elicits pro-proliferative and anti-apoptotic responses through the activation of TGFbeta-TAK1-MAPK pathways in PAH

Pulmonary arterial hypertension (PAH) is a cardiovascular disorder associated with enhanced proliferation and suppressed apoptosis of pulmonary arterial smooth muscle cells (PASMCs). Heterozygous mutations in the type II receptor for bone morphogenetic protein (BMPR2) underlie the majority of the inherited and familial forms of PAH. The transforming growth factor beta (TGFbeta) pathway is activated in both human and experimental models of PAH. However, how these factors exert pro-proliferative and anti-apoptotic responses in PAH remains unclear. Using mouse primary PASMCs derived from knock-in mice, we demonstrated that BMPR-II dysfunction promotes the activation of small mothers against decapentaplegia-independent mitogen-activated protein kinase (MAPK) pathways via TGFbeta-associated kinase 1 (TAK1), resulting in a pro-proliferative and anti-apoptotic response. Inhibition of the TAK1-MAPK axis rescues abnormal proliferation and apoptosis in these cells. In both hypoxia and monocrotaline-induced PAH rat models, which display reduced levels of bmpr2 transcripts, this study further indicates that the TGFbeta-MAPK axis is activated in lungs following elevation of both expression and phosphorylation of the TAK1 protein. In ex vivo cell-based assays, TAK1 inhibits BMP-responsive reporter activity and interacts with BMPR-II receptor. In the presence of pathogenic BMPR2 mutations observed in PAH patients, this interaction is greatly reduced. Taken together, these data suggest dysfunctional BMPR-II responsiveness intensifies TGFbeta-TAK1-MAPK signalling and thus alters the ratio of apoptosis to proliferation. This axis may be a potential therapeutic target in PAH

Marine pelagic ecosystems: the West Antarctic Peninsula

The marine ecosystem of the West Antarctic Peninsula (WAP) extends from the Bellingshausen Sea to the northern tip of the peninsula and from the mostly glaciated coast across the continental shelf to the shelf break in the west. The glacially sculpted coastline along the peninsula is highly convoluted and characterized by deep embayments that are often interconnected by channels that facilitate transport of heat and nutrients into the shelf domain. The ecosystem is divided into three subregions, the continental slope, shelf and coastal regions, each with unique ocean dynamics, water mass and biological distributions. The WAP shelf lies within the Antarctic Sea Ice Zone (SIZ) and like other SIZs, the WAP system is very productive, supporting large stocks of marine mammals, birds and the Antarctic krill, Euphausia superba. Ecosystem dynamics is dominated by the seasonal and interannual variation in sea ice extent and retreat. The Antarctic Peninsula is one among the most rapidly warming regions on Earth, having experienced a 28C increase in the annual mean temperature and a 68C rise in the mean winter temperature since 1950. Delivery of heat from the Antarctic Circumpolar Current has increased significantly in the past decade, sufficient to drive to a 0.68C warming of the upper 300 m of shelf water. In the past 50 years and continuing in the twenty-first century, the warm, moist maritime climate of the northern WAP has been migrating south, displacing the once dominant cold, dry continental Antarctic climate and causing multi-level responses in the marine ecosystem. Ecosystem responses to the regional warming include increased heat transport, decreased sea ice extent and duration, local declines in icedependent Ade´lie penguins, increase in ice-tolerant gentoo and chinstrap penguins, alterations in phytoplankton and zooplankton community composition and changes in krill recruitment, abundance and availability to predators. The climate/ecological gradients extending along theWAPand the presence of monitoring systems, field stations and long-term research programmes make the region an invaluable observatory of climate change and marine ecosystem response

Measurement of the Bottom-Strange Meson Mixing Phase in the Full CDF Data Set

We report a measurement of the bottom-strange meson mixing phase \beta_s using the time evolution of B0_s -> J/\psi (->\mu+\mu-) \phi (-> K+ K-) decays in which the quark-flavor content of the bottom-strange meson is identified at production. This measurement uses the full data set of proton-antiproton collisions at sqrt(s)= 1.96 TeV collected by the Collider Detector experiment at the Fermilab Tevatron, corresponding to 9.6 fb-1 of integrated luminosity. We report confidence regions in the two-dimensional space of \beta_s and the B0_s decay-width difference \Delta\Gamma_s, and measure \beta_s in [-\pi/2, -1.51] U [-0.06, 0.30] U [1.26, \pi/2] at the 68% confidence level, in agreement with the standard model expectation. Assuming the standard model value of \beta_s, we also determine \Delta\Gamma_s = 0.068 +- 0.026 (stat) +- 0.009 (syst) ps-1 and the mean B0_s lifetime, \tau_s = 1.528 +- 0.019 (stat) +- 0.009 (syst) ps, which are consistent and competitive with determinations by other experiments.Comment: 8 pages, 2 figures, Phys. Rev. Lett 109, 171802 (2012

Learning from multimedia and hypermedia

Computer-based multimedia and hypermedia resources (e.g., the world wide web) have become one of the primary sources of academic information for a majority of pupils and students. In line with this expansion in the field of education, the scientific study of learning from multimedia and hypermedia has become a very active field of research. In this chapter we provide a short overview with regard to research on learning with multimedia and hypermedia. In two review sections, we describe the educational benefits of multiple representations and of learner control, as these are the two defining characteristics of hypermedia. In a third review section we describe recent scientific trends in the field of multimedia/hypermedia learning. In all three review sections we will point to relevant European work on multimedia/hypermedia carried out within the last 5 years, and often carried out within the Kaleidoscope Network of Excellence. According to the interdisciplinary nature of the field this work might come not only from psychology, but also from technology or pedagogy. Comparing the different research activities on multimedia and hypermedia that have dominated the international scientific discourse in the last decade reveals some important differences. Most important, a gap seems to exist between researchers mainly interested in a “serious” educational use of multimedia/ hypermedia and researchers mainly interested in “serious” experimental research on learning with multimedia/hypermedia. Recent discussions about the pros and cons of “design-based research” or “use-inspired basic research” can be seen as a direct consequence of an increasing awareness of the tensions within these two different cultures of research on education

Do personality traits moderate the manifestation of type 2 diabetes genetic risk?

AbstractObjective. To test whether personality traits moderate type 2 diabetes (T2D) genetic risk. Methods. Using a large community-dwelling sample (n=837, Mage=69.59±0.85years, 49% males) we fitted a series of linear regression models predicting glycated haemoglobin (HbA1c) from T2D polygenic risk — aggregation of small individual effects of a large number of single nucleotide polymorphisms (SNPs) — and five personality traits. We tested the main effects of personality traits and their interactions with T2D polygenic risk score, controlling for age and sex. The models in the final set were adjusted for cognitive ability, highest educational qualification, and occupational class. Results. Lower levels of openness were associated with heightened levels of HbA1c (β=−0.014, p=.032). There was a significant interaction between T2D polygenic risk score and agreeableness: lower agreeableness was related to a stronger association between T2D polygenic risk and HbA1c (β=−0.08, p=.021). In the model adjusted for cognitive ability, the main effect of openness was not significant (β=−0.08, p=.057). The interaction between agreeableness and T2D polygenic risk was still present after controlling for cognitive ability and socioeconomic status indicators, and the interaction between conscientiousness and polygenic risk score was also significant: lower conscientiousness was associated with a stronger association between T2D polygenic risk and HbA1c levels (β=0.09, p=.04). Conclusions. Personality may be associated with markers of diabetes, and may moderate the expression of its genetic risk

Association of C-reactive protein with bacterial and respiratory syncytial virus-associated pneumonia among children aged <5 years in the PERCH study

Background. Lack of a gold standard for identifying bacterial and viral etiologies of pneumonia has limited evaluation of C-reactive protein (CRP) for identifying bacterial pneumonia. We evaluated the sensitivity and specificity of CRP for identifying bacterial vs respiratory syncytial virus (RSV) pneumonia in the Pneumonia Etiology Research for Child Health (PERCH) multicenter case-control study. Methods. We measured serum CRP levels in cases with World Health Organization-defined severe or very severe pneumonia and a subset of community controls. We evaluated the sensitivity and specificity of elevated CRP for "confirmed" bacterial pneumonia (positive blood culture or positive lung aspirate or pleural fluid culture or polymerase chain reaction [PCR]) compared to "RSV pneumonia" (nasopharyngeal/oropharyngeal or induced sputum PCR-positive without confirmed/suspected bacterial pneumonia). Receiver operating characteristic (ROC) curves were constructed to assess the performance of elevated CRP in distinguishing these cases. Results. Among 601 human immunodeficiency virus (HIV)-negative tested controls, 3% had CRP ≥40 mg/L. Among 119 HIVnegative cases with confirmed bacterial pneumonia, 77% had CRP ≥40 mg/L compared with 17% of 556 RSV pneumonia cases. The ROC analysis produced an area under the curve of 0.87, indicating very good discrimination; a cut-point of 37.1 mg/L best discriminated confirmed bacterial pneumonia (sensitivity 77%) from RSV pneumonia (specificity 82%). CRP ≥100 mg/L substantially improved specificity over CRP ≥40 mg/L, though at a loss to sensitivity. Conclusions. Elevated CRP was positively associated with confirmed bacterial pneumonia and negatively associated with RSV pneumonia in PERCH. CRP may be useful for distinguishing bacterial from RSV-associated pneumonia, although its role in discriminating against other respiratory viral-associated pneumonia needs further study