Responsible mission governance:An integrative framework and research agenda

Governance lies at the heart of instigating, steering, and creating the conditions for mission-oriented transitions that potentially help resolve some of our grand societal challenges. In doing so, policymakers will need to navigate both epistemic and normative considerations to develop, implement, and evaluate missions responsibly. A number of scholars have therefore expressed the need for a better conceptualization of responsible mission governance as a procedural approach, particularly with the aim of coping with the complexity, uncertainty, and contestation that render these wicked problems intractable. In this paper we develop an integrative framework for responsible mission governance by taking wickedness dimensions as our entry point. Accordingly, we argue that responsible mission governance should integrate various complementary governance responsibilities (e.g., reflexivity) and modes (e.g., reflexive governance) that potentially improve the effectiveness and desirability of missions.</p

Reinforcement Learning by Guided Safe Exploration

Safety is critical to broadening the application of reinforcement learning (RL). Often, we train RL agents in a controlled environment, such as a laboratory, before deploying them in the real world. However, the real-world target task might be unknown prior to deployment. Reward-free RL trains an agent without the reward to adapt quickly once the reward is revealed. We consider the constrained reward-free setting, where an agent (the guide) learns to explore safely without the reward signal. This agent is trained in a controlled environment, which allows unsafe interactions and still provides the safety signal. After the target task is revealed, safety violations are not allowed anymore. Thus, the guide is leveraged to compose a safe behaviour policy. Drawing from transfer learning, we also regularize a target policy (the student) towards the guide while the student is unreliable and gradually eliminate the influence of the guide as training progresses. The empirical analysis shows that this method can achieve safe transfer learning and helps the student solve the target task faster.Comment: Accecpted at ECAI 202

Влияние параметров одномассной системы с упругими ограничителями на характер ее колебаний

У статті розглянуто одномасну систему з пружними обмежувачами. Побудовано області існування різних режимів коливань системи, а також визначено вплив параметрів системи на межі цих областей.A one-mass system with elastic constraints is studied. Areas of existing of different oscillation modes are built. Also an influence of system parameters on limits of these areas is determined

How the carrying capacity of the Wadden Sea regulates the number of wintering waders at Banc d’Arguin

Omdat veel van de in Afrika overwinterende steltlopers gebruik maken van de Waddenzee als opvetstation, zou de voedselsituatie in de Waddenzee wel eensvan invloed kunnen zijn op het aantal in Afrika overwinterende steltlopers. Om dit te onderzoeken wordt in dit artikel gekeken naar Kanoeten en hun voedsel, inde Wad denzee en op de Banc d’Arguin, vroeger en nu, daarbij gebruikmakend van de rigoureuze veranderingen die de laatste jaren in de Waddenzee hebben plaats gehad.The number of Red Knots Calidris canutus wintering at the Banc d'Arguin, Mauritania, has declined over the last two decades. The fact that food densities in this relatively undisturbed ecosystem have increased suggests that the reason for the declining Knot abundance needs to be sought elsewhere along the flyway. With the Wadden Sea acting as a major stopover site for Red Knots wintering at the Banc d'Arguin (at least in spring), we hypothesize that the declining food stocks in the Wadden Sea are responsible for the reduced number of Red Knots wintering in Mauritania. Speculating further, we bring up the idea that the declining Red Knot population has led to reduced predation pressure on the bivalve stocks at the Banc d'Arguin, which may be the reason why food densities in Mauritania have gone up. Others have brought up an alternative, but non-mutually exclusive, hypothesis explaining this increase by an increased algal production. With production rates in individual shellfish presumably being under strong density-dependent control, the reduced predation hypothesis (in contrast to the alternative hypothesis) predicts lower per capita shellfish production rates nowadays than two decades ago.</p

Daily interruption of sedation in critically ill children: Study protocol for a randomized controlled trial

Background: In adult patients who are critically ill and mechanically ventilated, daily interruption of sedation (DSI) is an effective method of improving sedation management, resulting in a decrease of the duration of mechanical ventilation, the length of stay in the intensive care unit (ICU) and the length of stay in the hospital. It is a safe and effective approach and is common practice in adult ICUs. For critically ill children it is unknown if DSI is effective and feasible. The aim of this multicenter randomized controlled trial is to evaluate the safety and

Hypoxic oligodendrocyte precursor cell-derived VEGFA is associated with blood–brain barrier impairment

Abstract Cerebral small vessel disease is characterised by decreased cerebral blood flow and blood–brain barrier impairments which play a key role in the development of white matter lesions. We hypothesised that cerebral hypoperfusion causes local hypoxia, affecting oligodendrocyte precursor cell—endothelial cell signalling leading to blood–brain barrier dysfunction as an early mechanism for the development of white matter lesions. Bilateral carotid artery stenosis was used as a mouse model for cerebral hypoperfusion. Pimonidazole, a hypoxic cell marker, was injected prior to humane sacrifice at day 7. Myelin content, vascular density, blood–brain barrier leakages, and hypoxic cell density were quantified. Primary mouse oligodendrocyte precursor cells were exposed to hypoxia and RNA sequencing was performed. Vegfa gene expression and protein secretion was examined in an oligodendrocyte precursor cell line exposed to hypoxia. Additionally, human blood plasma VEGFA levels were measured and correlated to blood–brain barrier permeability in normal-appearing white matter and white matter lesions of cerebral small vessel disease patients and controls. Cerebral blood flow was reduced in the stenosis mice, with an increase in hypoxic cell number and blood–brain barrier leakages in the cortical areas but no changes in myelin content or vascular density. Vegfa upregulation was identified in hypoxic oligodendrocyte precursor cells, which was mediated via Hif1α and Epas1. In humans, VEGFA plasma levels were increased in patients versus controls. VEGFA plasma levels were associated with increased blood–brain barrier permeability in normal appearing white matter of patients. Cerebral hypoperfusion mediates hypoxia induced VEGFA expression in oligodendrocyte precursor cells through Hif1α/Epas1 signalling. VEGFA could in turn increase BBB permeability. In humans, increased VEGFA plasma levels in cerebral small vessel disease patients were associated with increased blood–brain barrier permeability in the normal appearing white matter. Our results support a role of VEGFA expression in cerebral hypoperfusion as seen in cerebral small vessel disease

Structural basis for CRISPR RNA-guided DNA recognition by Cascade

The CRISPR (clustered regularly interspaced short palindromic repeats) immune system in prokaryotes uses small guide RNAs to neutralize invading viruses and plasmids. In Escherichia coli, immunity depends on a ribonucleoprotein complex called Cascade. Here we present the composition and low-resolution structure of Cascade and show how it recognizes double-stranded DNA (dsDNA) targets in a sequence-specific manner. Cascade is a 405-kDa complex comprising five functionally essential CRISPR-associated (Cas) proteins (CasA1B2C6D1E1) and a 61-nucleotide CRISPR RNA (crRNA) with 5′-hydroxyl and 2′,3′-cyclic phosphate termini. The crRNA guides Cascade to dsDNA target sequences by forming base pairs with the complementary DNA strand while displacing the noncomplementary strand to form an R-loop. Cascade recognizes target DNA without consuming ATP, which suggests that continuous invader DNA surveillance takes place without energy investment. The structure of Cascade shows an unusual seahorse shape that undergoes conformational changes when it binds target DNA.

COVID-19 vaccination in patients with immune thrombocytopenia

Immune thrombocytopenia (ITP) is an acquired autoimmune disorder characterized by low platelet count and increased bleeding risk. COVID-19 vaccination has been described as risk factor for de novo ITP, but the effects of COVID-19 vaccination in patients with ITP are unknown. Our aims were to investigate the effects of COVID-19 vaccination in ITP patients on platelet count, bleeding complications and ITP exacerbation (any of: ≥50% decline in platelet count; or nadir platelet count 20% decrease from baseline; or use of rescue therapy). Platelet counts of ITP patients and healthy controls were collected immediately before, 1 and 4 weeks after first and second vaccination. Linear mixed-effects modelling was applied to analyze platelet counts over time. We included 218 ITP patients (50.9% female, mean age 55 years and median platelet count of 106x109/L) and 200 healthy controls (60.0% female, mean age 58 years and median platelet count of 256x109/L). Platelet counts decreased by 6.3% after vaccination. We observed no difference in decrease between the groups. Thirty ITP patients (13.8%, 95%CI 9.5%-19.1%) had an exacerbation and 5 (2.2%, 95%CI 0.7%-5.3%) suffered from a bleeding event. Risk factors for ITP exacerbation were platelet count <50x109/L (OR 5.3, 95%CI 2.1-13.7), ITP treatment at time of vaccination (OR 3.4, 95%CI 1.5-8.0) and age (OR 0.96 per year, 95%CI 0.94-0.99). Our study highlights safety of COVID-19 vaccination in ITP patients and importance of close monitoring platelet counts in a subgroup of ITP patients. ITP patients with exacerbation responded well on therapy

PET and MRI for the evaluation of regional myocardial perfusion and wall thickening after myocardial infarction

Deterioration of left ventricular (LV) function after myocardial infarction (MI) is a major cause of heart failure. Myocardial perfusion performance may play an important role in deterioration or improvement in LV function after MI. The aim of this study was to evaluate the myocardial perfusion reserve (MPR) and stress perfusion in deteriorating and non-deteriorating LV segments in patients after MI by PET and MRI, respectively. Regional wall thickening of 352 segments in 22 patients was assessed at 4 and 24 months after MI by cardiac MRI. PET was performed to evaluate MPR and adenosine stress N-13-ammonia perfusion 24 months after MI. Segments were divided into four groups according to deterioration or improvement in wall thickening. Normal functional segments at 4 months after MI that remained stable had a significantly higher mean MPR and mean stress perfusion PET value than deteriorated segments (p < 0.001). Furthermore, dysfunctional segments that improved had a significantly higher mean stress perfusion PET value than dysfunctional segments that remained dysfunctional (p < 0.001). This study demonstrated the additional value of myocardial perfusion assessment in relation to the functional integrity of the injured myocardium. Segmental functional LV improvement after MI was associated with better regional myocardial perfusion characteristics. Furthermore, the amount of wall thickening reduction was associated with regional myocardial perfusion abnormalities in patients after MI