An Exploratory Investigation of Stakeholders\u27 Perceptions of Political Leaders\u27 Behavior and Outcomes

This was an exploratory and descriptive study on stakeholders’ perceptions of political leaders’ behavior and outcomes. A purposeful sample comprised of 471 respondents whom were highly engaged in the political process was conducted on five distinct stakeholder groups, consisting of government employees, elected officials, union-building trades, business professionals, and college students. Two emergent results were identified: political party affiliation was a major indicator of stakeholder differences, and the inversion of agency theory. Contributing factors of the inversion of agency theory whereby a political agent begins to acts as a principle have led the researcher to develop the Corrupt-Unethical Behavior (CUB) model. Future research would focus more on the salient differences between political party affiliations rather than differences between stakeholder groups

An Exploratory Investigation of Stakeholders\u27 Perceptions of Political Leaders\u27 Behavior and Outcomes

This was an exploratory and descriptive study on stakeholders’ perceptions of political leaders’ behavior and outcomes. A purposeful sample comprised of 471 respondents whom were highly engaged in the political process was conducted on five distinct stakeholder groups, consisting of government employees, elected officials, union-building trades, business professionals, and college students. Two emergent results were identified: political party affiliation was a major indicator of stakeholder differences, and the inversion of agency theory. Contributing factors of the inversion of agency theory whereby a political agent begins to acts as a principle have led the researcher to develop the Corrupt-Unethical Behavior (CUB) model. Future research would focus more on the salient differences between political party affiliations rather than differences between stakeholder groups

A talin mutant that impairs talin-integrin binding in platelets decelerates αIIbβ3 activation without pathological bleeding

Tight regulation of integrin affinity is critical for hemostasis. A final step of integrin activation is talin binding to 2 sites within the integrin β cytoplasmic domain. Binding of talin to a membrane-distal NPxY sequence facilitates a second, weaker interaction of talin with an integrin membrane-proximal region (MPR) that is critical for integrin activation. To test the functional significance of these distinct interactions on platelet function in vivo, we generated knock-in mice expressing talin1 mutants with impaired capacity to interact with the β3 integrin MPR (L325R) or NPLY sequence (W359A). Both talin1(L325R) and talin1(W359A) mice were protected from experimental thrombosis. Talin1(L325R) mice, but not talin(W359A) mice, exhibited a severe bleeding phenotype. Activation of αIIbβ3 was completely blocked in talin1(L325R) platelets, whereas activation was reduced by approximately 50% in talin1(W359A) platelets. Quantitative biochemical measurements detected talin1(W359A) binding to β3 integrin, albeit with a 2.9-fold lower affinity than wild-type talin1. The rate of αIIbβ3 activation was slower in talin1(W359A) platelets, which consequently delayed aggregation under static conditions and reduced thrombus formation under physiological flow conditions. Together our data indicate that reduction of talin-β3 integrin binding affinity results in decelerated αIIbβ3 integrin activation and protection from arterial thrombosis without pathological bleeding

Mice Expressing Low Levels of CalDAG-GEFI Exhibit Markedly Impaired Platelet Activation With Minor Impact on HemostasisHighlights

OBJECTIVE: The tight regulation of platelet adhesiveness, mediated by the αIIbβ3 integrin, is critical for hemostasis and prevention of thrombosis. We recently demonstrated that integrin affinity in platelets is controlled by the guanine nucleotide exchange factor, CalDAG-GEFI (CD-GEFI), and its target, RAP1. In this study, we investigated whether low-level expression of CD-GEFI leads to protection from thrombosis without pathological bleeding in mice. APPROACH AND RESULTS: Cdg1(low) mice were generated by knockin of human CD-GEFI cDNA into the mouse Cdg1 locus. CD-GEFI expression in platelets from Cdg1(low) mice was reduced by ≈90% when compared with controls. Activation of RAP1 and αIIbβ3 was abolished at low agonist concentrations and partially inhibited at high agonist concentrations in Cdg1(low) platelets. Consistently, the aggregation response of Cdg1(low) platelets was weaker than that of wild-type platelets, but more efficient than that observed in Cdg1(-/-) platelets. Importantly, Cdg1(low) mice were strongly protected from arterial and immune complex-mediated thrombosis, with only minimal impact on primary hemostasis. CONCLUSIONS: Together, our studies suggest the partial inhibition of CD-GEFI function as a powerful new approach to safely prevent thrombotic complications

Joint spatiotemporal models to predict seabird densities at sea

Introduction: Seabirds are abundant, conspicuous members of marine ecosystems worldwide. Synthesis of distribution data compiled over time is required to address regional management issues and understand ecosystem change. Major challenges when estimating seabird densities at sea arise from variability in dispersion of the birds, sampling effort over time and space, and differences in bird detection rates associated with survey vessel type. Methods: Using a novel approach for modeling seabirds at sea, we applied joint dynamic species distribution models (JDSDM) with a vector-autoregressive spatiotemporal framework to survey data collected over nearly five decades and archived in the North Pacific Pelagic Seabird Database. We produced monthly gridded density predictions and abundance estimates for 8 species groups (77% of all birds observed) within Cook Inlet, Alaska. JDSDMs included habitat covariates to inform density predictions in unsampled areas and accounted for changes in observed densities due to differing survey methods and decadal-scale variation in ocean conditions. Results: The best fit model provided a high level of explanatory power (86% of deviance explained). Abundance estimates were reasonably precise, and consistent with limited historical studies. Modeled densities identified seasonal variability in abundance with peak numbers of all species groups in July or August. Seabirds were largely absent from the study region in either fall (e.g., murrelets) or spring (e.g., puffins) months, or both periods (shearwaters). Discussion: Our results indicated that pelagic shearwaters (Ardenna spp.) and tufted puffin (Fratercula cirrhata) have declined over the past four decades and these taxa warrant further investigation into underlying mechanisms explaining these trends. JDSDMs provide a useful tool to estimate seabird distribution and seasonal trends that will facilitate risk assessments and planning in areas affected by human activities such as oil and gas development, shipping, and offshore wind and renewable energy

Cost-Effectiveness Analysis of Efforts to Reduce Risk of Type 2 Diabetes and Cardiovascular Disease in Southwestern Pennsylvania, 2005-2007

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2938403/pdf/PCD75A109.pd

The Phosphatidylinositol 3,4,5-trisphosphate (PI(3,4,5)P 3 ) Binder Rasa3 Regulates Phosphoinositide 3-kinase (PI3K)-dependent Integrin α IIb β 3 Outside-in Signaling

The class I PI3K family of lipid kinases plays an important role in integrin αIIbβ3 function, thereby supporting thrombus growth and consolidation. Here, we identify Ras/Rap1GAP Rasa3 (GAP1IP4BP) as a major phosphatidylinositol 3,4,5-trisphosphate-binding protein in human platelets and a key regulator of integrin αIIbβ3 outside-in signaling. We demonstrate that cytosolic Rasa3 translocates to the plasma membrane in a PI3K-dependent manner upon activation of human platelets. Expression of wild-type Rasa3 in integrin αIIbβ3-expressing CHO cells blocked Rap1 activity and integrin αIIbβ3-mediated spreading on fibrinogen. In contrast, Rap1GAP-deficient (P489V) and Ras/Rap1GAP-deficient (R371Q) Rasa3 had no effect. We furthermore show that two Rasa3 mutants (H794L and G125V), which are expressed in different mouse models of thrombocytopenia, lack both Ras and Rap1GAP activity and do not affect integrin αIIbβ3-mediated spreading of CHO cells on fibrinogen. Platelets from thrombocytopenic mice expressing GAP-deficient Rasa3 (H794L) show increased spreading on fibrinogen, which in contrast to wild-type platelets is insensitive to PI3K inhibitors. Together, these results support an important role for Rasa3 in PI3K-dependent integrin αIIbβ3-mediated outside-in signaling and cell spreading

Urgent referral for suspected CNS cancer: which clinical features are associated with a positive predictive value of 3 % or more?

Background Urgent referral for suspected central nervous system (CNS) cancer is recommended, but little analysis of the referral criteria diagnostic performance has been conducted. New 2015 NICE guidance recommends direct brain imaging for patients with symptoms with positive predictive values (PPV) of 3 %, but further guidance is needed. Methods A 12-month retrospective evaluation of 393 patients referred under previous 2005 NICE 2-week rule criteria was conducted. Analysis was based on the three groups of symptoms forming the referral criteria, (1) CNS symptoms, (2) recent onset headaches, (3) rapidly progressive subacute focal deficit/cognitive/behavioural/personality change. Comparison was made with neuroimaging findings. Results Twelve (3.1 %) of 383 patients who attended clinic had CNS cancer suggesting the combination of clinical judgement and application of 2005 criteria matched the 2015 guideline’s PPV threshold. PPVs for the three groups of symptoms were (1) 4.1 % (95 % CIs 2.0 to 7.4 %), (2) 1.2 % (0.1 to 4.3 %) and (3) 3.7 % (0.1 to 19.0 %). Sensitivities were (1) 83.3 % (95 % CIs 51.6 to 97.9 %), (2) 16.7 % (2.1 to 48.4 %), and (3) 8.3 % (0.2 to 38.5 %); specificities were (1) 37.2 % (32.3 to 42.3 %), (2) 55.5 % (50.3 to 60.7 %) and (3) 93.0 % (89.9 to 95.4 %). Of 288 patients who underwent neuroimaging, 59 (20.5 %) had incidental findings, most commonly cerebrovascular disease. Conclusions The 2015 guidance is less prescriptive than previous criteria making clinical judgement more important. CNS symptoms had greatest sensitivity, while PPVs for CNS symptoms and rapidly progressive subacute deficit/cognitive/behavioural/personality change were closest to 3 %. Recent onset headaches had the lowest sensitivity and PPV