Drug repurposing screen identifies Foxo1-dependent angiopoietin-2 regulation in sepsis

Objective: The recent withdrawal of a targeted sepsis therapy has diminished pharmaceutical enthusiasm for developing novel drugs for the treatment of sepsis. Angiopoietin-2 is an endothelial-derived protein that potentiates vascular inflammation and leakage and may be involved in sepsis pathogenesis. We screened approved compounds for putative inhibitors of angiopoietin-2 production and investigated underlying molecular mechanisms. Design: Laboratory and animal research plus prospective placebo-controlled randomized controlled trial (NCT00529139) and retrospective analysis (NCT00676897). Setting: Research laboratories of Hannover Medical School and Harvard Medical School. Patients: Septic patients/C57Bl/6 mice and human endothelial cells. Interventions: Food and Drug Administration-approved library screening. Measurements and Main Results: In a cell-based screen of more than 650 Food and Drug Administration-approved compounds, we identified multiple members of the 3-hydroxy-3-methyl-glutaryl-CoA reductase inhibitor drug class (referred to as statins) that suppressed angiopoietin-2. Simvastatin inhibited 3-hydroxy-3-methyl-glutaryl-CoA reductase, which in turn activated PI3K-kinase. Downstream of this signaling, PI3K-dependent phosphorylation of the transcription factor Foxo1 at key amino acids inhibited its ability to shuttle to the nucleus and bind cis-elements in the angiopoietin-2 promoter. In septic mice, transient inhibition of angiopoietin-2 expression by liposomal siRNA in vivo improved absolute survival by 50%. Simvastatin had a similar effect, but the combination of angiopoietin-2 siRNA and simvastatin showed no additive benefit. To verify the link between statins and angiopoietin-2 in humans, we performed a pilot matched case-control study and a small randomized placebo-controlled trial demonstrating beneficial effects on angiopoietin-2. Conclusions: 3-hydroxy-3-methyl-glutaryl-CoA reductase inhibitors may operate through a novel Foxo1-angiopoietin-2 mechanism to suppress de novo production of angiopoietin-2 and thereby ameliorate manifestations of sepsis. Given angiopoietin-2's dual role as a biomarker and candidate disease mediator, early serum angiopoietin-2 measurement may serve as a stratification tool for future trials of drugs targeting vascular leakage.

Dissidents with an innovation cause? Non-institutionalized actors’ online social knowledge sharing, solution-finding tensions and technology management innovation

Purpose – Traditionally, most studies focus on institutionalized management-driven actors to understand technology management innovation. The purpose of this paper is to argue that there is a need for research to study the nature and role of dissident non-institutionalized actors’ (i.e. outsourced web designers and rapid application software developers). The authors propose that through online social knowledge sharing, non-institutionalized actors’ solution-finding tensions enable technology management innovation. Design/methodology/approach – A synthesis of the literature and an analysis of the data (21 interviews) provided insights in three areas of solution-finding tensions enabling management innovation. The authors frame the analysis on the peripherally deviant work and the nature of the ways that dissident non-institutionalized actors deviate from their clients (understood as the firm) original contracted objectives. Findings – The findings provide insights into the productive role of solution-finding tensions in enabling opportunities for management service innovation. Furthermore, deviant practices that leverage non-institutionalized actors’ online social knowledge to fulfill customers’ requirements are not interpreted negatively, but as a positive willingness to proactively explore alternative paths. Research limitations/implications – The findings demonstrate the importance of dissident non-institutionalized actors in technology management innovation. However, this work is based on a single country (USA) and additional research is needed to validate and generalize the findings in other cultural and institutional settings. Originality/value – This paper provides new insights into the perceptions of dissident non-institutionalized actors in the practice of IT managerial decision making. The work departs from, but also extends, the previous literature, demonstrating that peripherally deviant work in solution-finding practice creates tensions, enabling management innovation between IT providers and users.

Governance in foreign policy-making in Germany and Poland and Polish-German relations:the role of non-state actors

This thesis examines the influence of non-state actors on Polish-German relations by considering foreign policy-making towards Poland in Germany and vice versa. The approach chosen for this thesis is interdisciplinary and takes into consideration literature from domestic politics (Area Studies), Foreign Policy Analysis and International Relations (IR). The thesis argues that IR, by purely looking into the quality of inter-state relations, too often treats these relations as a result of policies emanating from the relevant governments, without considering the policies’ background. Therefore, the thesis argues that it is necessary to engage with the domestic factors which might explain where foreign policies come from. It points out that non-state actors influence governments’ choices by supplying resources, and by cooperating or competing with the government on an issue at stake. In order to determine the degree of influence that non-state actors can have on foreign policymaking two variables are examined: the institutionalisation of the state relations in question; and the domestic structures of the relevant states. Specifically, the thesis examines the institutionalisation of Polish-German relations, and examines Germany’s and Poland’s domestic structures and their effect on the two states’ foreign policy-making in general. Thereafter, the thesis uses case studies in order to unravel the influence of non-state actors on specific foreign policies. Three case studies are examined in detail: (i) Poland’s EU accession negotiations with regard to the free movement of capital chapter of the acquis communautaire; (ii) Germany’s EU 2004 Eastern Enlargement negotiations with regard to the free movement of workers chapter of the acquis communautaire; and (iii) Germany’s decision to establsh a permanent exhibition in Berlin that will depict the expulsions of millions of Germans from the East following WWII.

Environmental governance in a contested state:the influence of European Union and other external actors on energy sector regulation in Kosovo

This article examines environmental governance in Kosovo, with a particular focus on the energy sector. The article considers the degree to which the emerging model of environmental governance is characterised by hierarchical and non-hierarchical modes of coordination. We examine the roles of a number of domestic institutions and actors – ministries, agencies, and regulatory bodies– and the influence of external actors, including the EU, the US, and Serbia. The EU is building Kosovo’s own hierarchical governance capacity by strengthening domestic institutions, whilst the US focuses primarily on market liberalization, whilst simultaneously supporting EU efforts. Moreover, environmental policy change is not wholly or predominantly driven by domestic actors, which can partly be attributed to Kosovo’s limited domestic sovereignty. We conclude that the emerging model of environmental governance in Kosovo is characterized by a weak hierarchy, partly as a result of external actor involvement, which disincentivises the government from responding to domestic non-state actor pressure.

Validity and reliability of the Spanish version of Caregiver Abuse Screen (CASE)

Detection of elder abuse risk is a critical issue because a lot of cases remain hidden. Screening tools can be used to detect elder abuse. However, few tools have been developed for use with caregivers. The purpose was to develop a translation and adaptation of a Spanish version of the Caregiver Abuse Screen (CASE) and to assess its validity and reliability. The CASE was then used with 211 primary caregivers. Validity and reliability were evaluated, as well as the factorial structure of the instrument. This version showed good psychometric properties. It was found to have strong internal consistency and split-half reliability as well as allowing for a good replication of the original factorial structure. Additionally, several variables related to elder abuse were linked to the CASE such as depression, burden, frequency, and reactions to problem behaviors. The version developed showed sufficient validity and reliability and could be considered as a suitable instrument to assess risks of elder abuse in a Spanish-speaking context.

Networked governance and the regulation of expression on the Internet:the blurring of the role of public and private actors as content regulators

This editorial provides an overview of the themes of network governance and content regulation that are expanded upon in the subsequent articles, identifying key issues and concerns that are prevalent in the literature in this field. In particular, this text considers governance not as an Internet-specific phenomenon, but as a global phenomenon, identifying and discussing literature pertaining to governance both online and offline, and providing examples of theories that seek to explain these forms of governance. Focusing on the interaction between public and private actors in content regulation, this editorial highlights that content regulation is a complex and contested issue that cannot be separated from its social and cultural contexts, and provides an overview of the articles contained.

Memory conformity: Actors and bystanders

This dissertation explored memory conformity effects on people who interacted with a confederate and of bystanders to that interaction. Two studies were carried out. Study 1 was conducted in the field. A male confederate approached a group of people at the beach and had a brief interaction. About a minute later a research assistant approached the group and administered a target-absent lineup to each person in the group. Analyses revealed that memory conformity occurred during the lineup task. Bystanders were twice as likely to conform as those who interacted with the confederate. Study 2 was carried out in a laboratory under controlled conditions. Participants were exposed to two events during their time in the laboratory. In one event, participants were shown a brief video with no determinate roles assigned. In the other event participants were randomly assigned to interact with a confederate (actor condition) or to witness that interaction (bystander condition). Participants were given memory tests on both events to understand the effects of participant role (actor vs. bystander) on memory conformity. Participants answered second to all questions, following a confederate acting as a participant, who disseminated misinformation on critical questions. Analyses revealed no significant differences in memory conformity between actors and bystanders during the movie memory task. However, differences were found for the interaction memory task such that bystanders conformed more than actors on two of four critical questions. Bystanders also conformed more than actors during a lineup identification task. The results of these studies suggest that the role a person plays in an interaction affects how susceptible they are to information from a co-witness. Theoretical and applied implications are discussed. First, the results are explained through the use of two models of memory. Second, recommendations are made for forensic investigators.

On-screen pre-deblurring of digital images using the wavefront aberration function of the human eye to improve computer access for the visually impaired

Traditional Optics has provided ways to compensate some common visual limitations (up to second order visual impairments) through spectacles or contact lenses. Recent developments in wavefront science make it possible to obtain an accurate model of the Point Spread Function (PSF) of the human eye. Through what is known as the "Wavefront Aberration Function" of the human eye, exact knowledge of the optical aberration of the human eye is possible, allowing a mathematical model of the PSF to be obtained. This model could be used to pre-compensate (inverse-filter) the images displayed on computer screens in order to counter the distortion in the user's eye. This project takes advantage of the fact that the wavefront aberration function, commonly expressed as a Zernike polynomial, can be generated from the ophthalmic prescription used to fit spectacles to a person. This allows the pre-compensation, or onscreen deblurring, to be done for various visual impairments, up to second order (commonly known as myopia, hyperopia, or astigmatism). The technique proposed towards that goal and results obtained using a lens, for which the PSF is known, that is introduced into the visual path of subjects without visual impairment will be presented. In addition to substituting the effect of spectacles or contact lenses in correcting the loworder visual limitations of the viewer, the significance of this approach is that it has the potential to address higher-order abnormalities in the eye, currently not correctable by simple means.

Women actors demonstrate against theatre school

General note: Title and date provided by Bettye Lane.

Type of actors, objects of exchange, type of original transactions in the coverage of corruption

In the following analysis we deal with only specific corruption cases within our seven-country sample for content analysis (France, Hungary, Italy, Latvia, Romania, Slovakia, and the UK). Only 5,212 relevant articles dealt with such cases within the total sample (12,742). We focus here on providing a descriptive comparative analysis of the actors, types of transactions and country specifics. The second part of the analysis describes the actors involved in the corrupt transactions, while in the third section we deal with the object of exchange in corrupt transactions. The fourth section focuses on the type of transaction which is linked to the corruption. Finally, a summary of the results of our preliminary findings is provided.

Silent screen: book review.

Book Review. Kevin Rockett, Irish film censorship: a cultural journey from silent cinema to internet pornography (Dublin, 2004) and Mary Corcoran and Mark O'Brien (eds), Political censorship and the democratic state: the Irish broadcasting ban (Dublin, 2005)

Diversity, difference and nation: indigenous peoples on screen in Mexico

This paper draws on constructivist theories of identity that regard the self as, paradoxically, coming into existence through interaction with the other, to investigate the discursive formation of indigenous people in the forging of Mexican national identity. The aim of the essay is to show how difference has been managed and deployed in the establishment of national Mexican identities from independence until the present. This is done with reference to visual culture and film and illustrated with examples from the ‘Golden Age’ as well as ‘the New Mexican Cinema’.