Enacting accountability under populist pressures: theorizing the relationship between anti-elite rhetoric and public accountability

While populism challenges the pluralism and technocratic expertise on which public bureaucracies are based, extant scholarship has overlooked its effects on accountability processes. In particular, it neglects the impact of anti-elite rhetoric, characterized by what can be regarded as “emotionalized blame attribution,” on the thinking and behavior of accountability actors. Responding to this gap, this article examines the impact of this distinctive form of populist rhetoric on accountability relationships within the bureaucratic state. It identifies three “stages” whereby these populist pressures challenge accountability relationships, threaten the reputation of accountability actors, and result in alternative accountability practices. In doing so, the article provides a roadmap for assessing the impact of anti-elite rhetoric on accountability actions

Bat 1: Estimate of bat populations at the southern North Sea : Supporting note to ZDV report no. 2016.031 Migration bats at the southern North Sea

To close the knowledge gap described above, or better said in order to make a start to overcome this crucial lack of insight into (sub)population sizes, RWS commissioned the Bats_1 study as part of the Wind op Zee Ecological Programma (Wozep; in English: Wind at Sea Ecological Programme), a multi-annual research programme initiated in view of the realisation of new offshore wind farms under the SER agreement (2013). Aim of the Bat_1 desk study is to estimate the extent to which (sub)populations of Nathusius’ Pipistrelle and possibly other relevant bat species, expressed in terms of numbers of individuals, use migration routes across the southern North Sea (SNS)1. This information is of great importance to be able to make better estimates of what the Potential Biological Removal (PBR) values are of Nathusius’ Pipistrelle and possibly other bat species, knowing that these values depend on the size of the (sub)populations to be considered

Exocytosis of Weibel–Palade bodies: how to unpack a vascular emergency kit

Summary: The blood vessel wall has a number of self-healing properties, enabling it to minimize blood loss and prevent or overcome infections in the event of vascular trauma. Endothelial cells prepackage a cocktail of hemostatic, inflammatory and angiogenic mediators in their unique secretory organelles, the Weibel–Palade bodies (WPBs), which can be immediately released on demand. Secretion of their contents into the vascular lumen through a process called exocytosis enables the endothelium to actively participate in the arrest of bleeding and to slow down and direct leukocytes to areas of inflammation. Owing to their remarkable elongated morphology and their secretory contents, which span the entire size spectrum of small chemokines all the way up to ultralarge von Willebrand factor multimers, WPBs constitute an ideal model system for studying the molecular mechanisms of secretory organelle biogenesis, exocytosis, and content expulsion. Recent studies have now shown that, during exocytosis, WPBs can undergo several distinct modes of fusion, and can utilize fundamentally different mechanisms to expel their contents. In this article, we discuss recent advances in our understanding of the composition of the WPB exocytotic machinery and how, because of its configuration, it is able to support WPB release in its various forms

The Weibel-Palade Body Localized SNARE (Soluble NSF Attachment Protein Receptor) Syntaxin-3 Modulates Von Willebrand Factor Secretion From Endothelial Cells

Objective Endothelial cells store von Willebrand factor (VWF) in rod-shaped secretory organelles, called Weibel-Palade bodies (WPBs). WPB exocytosis is coordinated by a complex network of Rab GTPases, Rab-effectors and SNARE proteins. We have previously identified STXBP1 as the link between the Rab27A-Slp4-a complex on WPBs and the SNARE proteins syntaxin-2 and -3. In this study we investigate the function of syntaxin-3 in VWF secretion. Approach and Results In human umbilical vein endothelial cells (HUVECs) and in blood outgrowth endothelial cells (BOECs) from healthy controls endogenous syntaxin-3 immunolocalized to WPBs. A detailed analysis of BOECs isolated from a patient with variant microvillus inclusion disease (MVID), carrying a homozygous mutation in STX3 (STX3-/-), showed a loss of syntaxin-3 protein and absence of WPB-associated syntaxin-3 immunoreactivity. Ultrastructural analysis revealed no detectable differences in morphology or prevalence of immature or mature WPBs in control versus STX3-/- BOECs. VWF multimer analysis showed normal patterns in plasma of the MVID patient, and media from STX3-/- BOECs, together indicating WPB formation and maturation are unaffected by absence of syntaxin-3. However, a defect in basal as well as Ca2+ - and cAMP-mediated VWF secretion was found in the STX3-/- BOECs. We also show that syntaxin-3 interacts with the WPB-associated SNARE protein VAMP8. Conclusions Our data reveal syntaxin-3 as a novel WPB-associated SNARE protein that controls WPB exocytosis

New development: Breaking out or hanging on? Internal audit in government

Public audit is in transition. On the one hand, professional organizations claim it is time ‘to break out’ and develop new roles for auditors that ‘add more value’. On the other hand, critics are concerned about public sector accountability deficits necessitating more control and urging auditors to hold on to their traditional role. This article discusses tensions and relevance between these positions and their implications for auditing in government. The article will help policy-makers in their strategic decision-making on the role and focus of internal audit in government

Alternative trafficking of Weibel-Palade body proteins in CRISPR/Cas9-engineered von Willebrand factor-deficient blood outgrowth endothelial cells

Background: Synthesis of the hemostatic protein von Willebrand factor (VWF) drives formation of endothelial storage organelles called Weibel‐Palade bodies (WPBs). In the absence of VWF, angiogenic and inflammatory mediators that are costored in WPBs are subject to alternative trafficking routes. In patients with von Willebrand disease (VWD), partial or complete absence of VWF/WPBs may lead to additional bleeding complications, such as angiodysplasia. Studies addressing the role of VWF using VWD patient–derived blood outgrowth endothelial cells (BOECs) have reported conflicting results due to the intrinsic heterogeneity of patient‐derived BOECs. Objective: To generate a VWF‐deficient endothelial cell model using clustered regularly interspaced short palindromic repeats (CRISPR) genome engineering of blood outgrowth endothelial cells. Methods: We used CRISPR/CRISPR‐associated protein 9 editing in single‐donor cord blood–derived BOECs (cbBOECs) to generate clonal VWF−/− cbBOECs. Clones were selected using high‐throughput screening, VWF mutations were validated by sequencing, and cells were phenotypically characterized. Results: Two VWF−/− BOEC clones were obtained and were entirely devoid of WPBs, while their overall cell morphology was unaltered. Several WPB proteins, including CD63, syntaxin‐3 and the cargo proteins angiopoietin (Ang)‐2, interleukin (IL)‐6, and IL‐8 showed alternative trafficking and secretion in the absence of VWF. Interestingly, Ang‐2 was relocated to the cell periphery and colocalized with Tie‐2. Conclusions: CRISPR editing of VWF provides a robust method to create VWF‐ deficient BOECs that can be directly compared to their wild‐type counterparts. Results obtained with our model system confirmed alternative trafficking of several WPB proteins in the absence of VWF and support the theory that increased Ang‐2/Tie‐2 interaction contributes to angiogenic abnormalities in VWD patients

Between mediatisation and politicisation: The changing role and position of Whitehall press officers in the age of political spin

Despite widespread critiques of ‘political spin’, the way governments engage with the mass media has attracted relatively little empirical attention. There is a small but growing body of research into bureaucracies’ responses to mediatisation from within which have identified tensions between bureaucratic and party political values, but this has not included the United Kingdom. There are concerns that the traditional dividing line between government information and political propaganda has come under increasing pressure as a higher premium is placed on persuasion by both journalists and politicians battling for public attention in an increasingly competitive market. Within Whitehall, the arrival of Labour in 1997 after 18 years in opposition was a watershed for UK government communications, allowing the government to reconfigure its official information service in line with the party political imperative to deploy strategic communications as a defence against increasingly invasive media scrutiny. Public relations, in government as elsewhere, has grown in scale, scope and status, becoming institutionalised and normalised within state bureaucracies, but how has this affected the role, status and influence of the civil servants who conduct media management? Within the system of executive self-regulation of government publicity that is characteristic of Whitehall, government press officers must negotiate a difficult path between the need to inform citizens about the government’s programme, and demands by ministers to deploy privileged information to secure and maintain personal and party advantage in the struggle for power. Taking 1997 as a turning point, and through the voices of the actors who negotiate government news – mainly press officers, but also journalists and special advisers – this article examines the changing role and position of Whitehall press officers in what has become known as the age of political spin, finding that profound and lasting change in the rules of engagement has taken place and is continuing

Associations of Polymorphisms in the Peroxisome Proliferator-Activated Receptor Gamma Coactivator-1 Alpha Gene With Subsequent Coronary Heart Disease: An Individual-Level Meta-Analysis

Background: The knowledge of factors influencing disease progression in patients with established coronary heart disease (CHD) is still relatively limited. One potential pathway is related to peroxisome proliferator–activated receptor gamma coactivator-1 alpha (PPARGC1A), a transcription factor linked to energy metabolism which may play a role in the heart function. Thus, its associations with subsequent CHD events remain unclear. We aimed to investigate the effect of three different SNPs in the PPARGC1A gene on the risk of subsequent CHD in a population with established CHD. Methods: We employed an individual-level meta-analysis using 23 studies from the GENetIcs of sUbSequent Coronary Heart Disease (GENIUS-CHD) consortium, which included participants (n = 80,900) with either acute coronary syndrome, stable CHD, or a mixture of both at baseline. Three variants in the PPARGC1A gene (rs8192678, G482S; rs7672915, intron 2; and rs3755863, T528T) were tested for their associations with subsequent events during the follow-up using a Cox proportional hazards model adjusted for age and sex. The primary outcome was subsequent CHD death or myocardial infarction (CHD death/myocardial infarction). Stratified analyses of the participant or study characteristics as well as additional analyses for secondary outcomes of specific cardiovascular disease diagnoses and all-cause death were also performed. Results: Meta-analysis revealed no significant association between any of the three variants in the PPARGC1A gene and the primary outcome of CHD death/myocardial infarction among those with established CHD at baseline: rs8192678, hazard ratio (HR): 1.01, 95% confidence interval (CI) 0.98–1.05 and rs7672915, HR: 0.97, 95% CI 0.94–1.00; rs3755863, HR: 1.02, 95% CI 0.99–1.06. Similarly, no significant associations were observed for any of the secondary outcomes. The results from stratified analyses showed null results, except for significant inverse associations between rs7672915 (intron 2) and the primary outcome among 1) individuals aged ≥65, 2) individuals with renal impairment, and 3) antiplatelet users. Conclusion: We found no clear associations between polymorphisms in the PPARGC1A gene and subsequent CHD events in patients with established CHD at baseline

Llama-Derived Single Domain Antibodies to Build Multivalent, Superpotent and Broadened Neutralizing Anti-Viral Molecules

For efficient prevention of viral infections and cross protection, simultaneous targeting of multiple viral epitopes is a powerful strategy. Llama heavy chain antibody fragments (VHH) against the trimeric envelope proteins of Respiratory Syncytial Virus (Fusion protein), Rabies virus (Glycoprotein) and H5N1 Influenza (Hemagglutinin 5) were selected from llama derived immune libraries by phage display. Neutralizing VHH recognizing different epitopes in the receptor binding sites on the spikes with affinities in the low nanomolar range were identified for all the three viruses by viral neutralization assays. By fusion of VHH with variable linker lengths, multimeric constructs were made that improved neutralization potencies up to 4,000-fold for RSV, 1,500-fold for Rabies virus and 75-fold for Influenza H5N1. The potencies of the VHH constructs were similar or better than best performing monoclonal antibodies. The cross protection capacity against different viral strains was also improved for all three viruses, both by multivalent (two or three identical VHH) and biparatopic (two different VHH) constructs. By combining a VHH neutralizing RSV subtype A, but not subtype B with a poorly neutralizing VHH with high affinity for subtype B, a biparatopic construct was made with low nanomolar neutralizing potency against both subtypes. Trivalent anti-H5N1 VHH neutralized both Influenza H5N1 clade1 and 2 in a pseudotype assay and was very potent in neutralizing the NIBRG-14 Influenza H5N1 strain with IC50 of 9 picomolar. Bivalent and biparatopic constructs against Rabies virus cross neutralized both 10 different Genotype 1 strains and Genotype 5. The results show that multimerization of VHH fragments targeting multiple epitopes on a viral trimeric spike protein is a powerful tool for anti-viral therapy to achieve "best-in-class" and broader neutralization capacity

Associations of Polymorphisms in the Peroxisome Proliferator-Activated Receptor Gamma Coactivator-1 Alpha Gene With Subsequent Coronary Heart Disease : An Individual-Level Meta-Analysis

Background: The knowledge of factors influencing disease progression in patients with established coronary heart disease (CHD) is still relatively limited. One potential pathway is related to peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PPARGC1A), a transcription factor linked to energy metabolism which may play a role in the heart function. Thus, its associations with subsequent CHD events remain unclear. We aimed to investigate the effect of three different SNPs in the PPARGC1A gene on the risk of subsequent CHD in a population with established CHD.Methods: We employed an individual-level meta-analysis using 23 studies from the GENetIcs of sUbSequent Coronary Heart Disease (GENIUS-CHD) consortium, which included participants (n = 80,900) with either acute coronary syndrome, stable CHD, or a mixture of both at baseline. Three variants in the PPARGC1A gene (rs8192678, G482S; rs7672915, intron 2; and rs3755863, T528T) were tested for their associations with subsequent events during the follow-up using a Cox proportional hazards model adjusted for age and sex. The primary outcome was subsequent CHD death or myocardial infarction (CHD death/myocardial infarction). Stratified analyses of the participant or study characteristics as well as additional analyses for secondary outcomes of specific cardiovascular disease diagnoses and all-cause death were also performed.Results: Meta-analysis revealed no significant association between any of the three variants in the PPARGC1A gene and the primary outcome of CHD death/myocardial infarction among those with established CHD at baseline: rs8192678, hazard ratio (HR): 1.01, 95% confidence interval (CI) 0.98-1.05 and rs7672915, HR: 0.97, 95% CI 0.94-1.00; rs3755863, HR: 1.02, 95% CI 0.99-1.06. Similarly, no significant associations were observed for any of the secondary outcomes. The results from stratified analyses showed null results, except for significant inverse associations between rs7672915 (intron 2) and the primary outcome among 1) individuals aged >= 65, 2) individuals with renal impairment, and 3) antiplatelet users.Conclusion: We found no clear associations between polymorphisms in the PPARGC1A gene and subsequent CHD events in patients with established CHD at baseline.Peer reviewe