Continuous millisecond conformational cycle of a DEAH box helicase reveals control of domain motions by atomic-scale transitions

Helicases are motor enzymes found in every living organism and viruses, where they maintain the stability of the genome and control against false recombination. The DEAH-box helicase Prp43 plays a crucial role in pre-mRNA splicing in unicellular organisms by translocating single-stranded RNA. The molecular mechanisms and conformational transitions of helicases are not understood at the atomic level. We present a complete conformational cycle of RNA translocation by Prp43 in atomic detail based on molecular dynamics simulations. To enable the sampling of such complex transition on the millisecond timescale, we combined two enhanced sampling techniques, namely simulated tempering and adaptive sampling guided by crystallographic data. During RNA translocation, the center-of-mass motions of the RecAlike domains followed the established inchworm model, whereas the domains crawled along the RNA in a caterpillar-like movement, suggesting an inchworm/caterpillar model. However, this crawling required a complex sequence of atomic-scale transitions involving the release of an arginine finger from the ATP pocket, stepping of the hook-loop and hook-turn motifs along the RNA backbone, and several others. These findings highlight that large-scale domain dynamics may be controlled by complex sequences of atomic-scale transitions

Problem Analysis and Focus of EdTech Hub’s Work: Technology in Education in Low- and Middle-Income Countries

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Reducing work pressure and IT problems and facilitating IT integration and audit & feedback help adherence to perioperative safety guidelines: a survey among 95 perioperative professionals

Background: To improve perioperative patient safety, guidelines for the preoperative, peroperative, andpostoperative phase were introduced in the Netherlands between 2010 and 2013. To help the implementation ofthese guidelines, we aimed to get a better understanding of the barriers and drivers of perioperative guidelineadherence and to explore what can be learned for future implementation projects in complex organizations.Methods: We developed a questionnaire survey based on the theoretical framework of Van Sluisveld et al. forclassifying barriers and facilitators. The questionnaire contained 57 statements derived from (a) an instrument formeasuring determinants of innovations by the Dutch Organization for Applied Scientific Research, (b) interviewswith quality and safety policy officers and perioperative professionals, and (c) a publication of Cabana et al. Thetarget group consisted of 232 perioperative professionals in nine hospitals. In addition to rating the statements on afive-point Likert scale (which were classified into the seven categories of the framework: factors relating to theintervention, society, implementation, organization, professional, patients, and social factors), respondents wereinvited to rank their three most important barriers in a separate, extra open-ended question.Results: Ninety-five professionals (41%) completed the questionnaire. Fifteen statements (26%) were considered tobe barriers, relating to social factors (N = 5), the organization (N = 4), the professional (N = 4), the patient (N = 1),and the intervention (N = 1). An integrated information system was considered an important facilitator (70.4%) aswell as audit and feedback (41.8%). The Barriers Top-3 question resulted in 75 different barriers in nearly allcategories. The most frequently reported barriers were as follows: time pressure (16% of the total number ofbarriers), emergency patients (8%), inefficient IT structure (4%), and workload (3%).Conclusions: We identified a wide range of barriers that are believed to hinder the use of the perioperative safetyguidelines, while an integrated information system and local data collection and feedback will also be necessary toengage perioperative teams. These barriers need to be locally prioritized and addressed by tailored implementationstrategies. These results may also be of relevance for guideline implementation in general in complex organizations.Trial registration: Dutch Trial Registry: NTR3568.Keywords: Guideline adherence, Implementation, Implementation barriers, Implementation facilitators, Patientsafety, Perioperative car

The funhouse mirror: the I in personalised healthcare

Precision Medicine is driven by the idea that the rapidly increasing range of relatively cheap and efficient self-tracking devices make it feasible to collect multiple kinds of phenotypic data. Advocates of N = 1 research emphasize the countless opportunities personal data provide for optimizing individual health. At the same time, using biomarker data for lifestyle interventions has shown to entail complex challenges. In this paper, we argue that researchers in the field of precision medicine need to address the performative dimension of collecting data. We propose the fun-house mirror as a metaphor for the use of personal health data; each health data source yields a particular type of image that can be regarded as a ‘data mirror’ that is by definition specific and skewed. This requires competence on the part of individuals to adequately interpret the images thus provided

Carbon regulation and pathways for institutional transition in market-led housing systems : a case study of English housebuilders and zero carbon housing policy

In this paper, we argue that current research on carbon regulation neglects the complex interactions of institutional norms and market behaviour that characterise responses to regulatory change. We draw on empirical research undertaken with English housebuilders and housing market stakeholders to examine how transitional pathways towards a low-carbon housing future might be advanced and consider the implications of such for carbon regulation and low-carbon economies. Our core proposition is that carbon regulation research can no longer ignore the impact of institutionally constituted market behaviour in shaping pathways and transitions towards low-carbon futures

From Utopia to Science: Challenges of Personalised Genomics Information for Health Management and Health Enhancement

From 1900 onwards, scientists and novelists have explored the contours of a future society based on the use of “anthropotechnologies” (techniques applicable to human beings for the purpose of performance enhancement ranging from training and education to genome-based biotechnologies). Gradually but steadily, the technologies involved migrated from (science) fiction into scholarly publications, and from “utopia” (or “dystopia”) into science. Building on seminal ideas borrowed from Nietzsche, Peter Sloterdijk has outlined the challenges inherent in this development. Since time immemorial, and at least since the days of Plato’s Academy, human beings have been interested in possibilities for (physical or mental) performance enhancement. We are constantly trying to improve ourselves, both collectively and individually, for better or for worse. At present, however, new genomics-based technologies are opening up new avenues for self-amelioration. Developments in research facilities using animal models may to a certain extent be seen as expeditions into our own future. Are we able to address the bioethical and biopolitical issues awaiting us? After analyzing and assessing Sloterdijk’s views, attention will shift to a concrete domain of application, namely sport genomics. For various reasons, top athletes are likely to play the role of genomics pioneers by using personalized genomics information to adjust diet, life-style, training schedules and doping intake to the strengths and weaknesses of their personalized genome information. Thus, sport genomics may be regarded as a test bed where the contours of genomics-based self-management are tried out

Increased adherence to perioperative safety guidelines associated with improved patient safety outcomes:a stepped-wedge, cluster-randomised multicentre trial

Background: National Dutch guidelines have been introduced to improve suboptimal perioperative care. A multifaceted implementation programme (IMPlementatie Richtlijnen Operatieve VEiligheid [IMPROVE]) has been developed to support hospitals in applying these guidelines. This study evaluated the effectiveness of IMPROVE on guideline adherence and the association between guideline adherence and patient safety. Methods: Nine hospitals participated in this unblinded, superiority, stepped-wedge, cluster RCT in patients with major noncardiac surgery (mortality risk >= 1%). IMPROVE consisted of educational activities, audit and feedback, reminders, organisational, team-directed, and patient-mediated activities. The primary outcome of the study was guideline adherence measured by nine patient safety indicators on the process (stop moments from the composite STOP bundle, and timely administration of antibiotics) and on the structure of perioperative care. Secondary safety outcomes included in-hospital complications, postoperative wound infections, mortality, length of hospital stay, and unplanned care. Results: Data were analysed for 1934 patients. The IMPROVE programme improved one stop moment: 'discharge from recovery room' (+16%; 95% confidence interval [CI], 9-23%). This stop moment was related to decreased mortality (-3%; 95% CI, -4% to -1%), fewer complications (-8%; 95% CI, -13% to -3%), and fewer unscheduled transfers to the ICU (-6%; 95% CI, -9% to -3%). IMPROVE negatively affected one other stop moment - 'discharge from the hospital' - possibly because of the limited resources of hospitals to improve all stop moments together. Conclusions: Mixed implementation effects of IMPROVE were found. We found some positive associations between guideline adherence and patient safety (i.e. mortality, complications, and unscheduled transfers to the ICU) except for the timely administration of antibiotics