University of Applied Sciences Utrecht

Automated structure validation was introduced in chemical crystallography about 12 years ago as a tool to assist practitioners with the exponential growth in crystal structure analyses. Validation has since evolved into an easy-to-use checkCIF/PLATON web-based IUCr service. The result of a crystal structure determination has to be supplied as a CIF-formatted computer-readable file. The checking software tests the data in the CIF for completeness, quality and consistency. In addition, the reported structure is checked for incomplete analysis, errors in the analysis and relevant issues to be verified. A validation report is generated in the form of a list of ALERTS on the issues to be corrected, checked or commented on. Structure validation has largely eliminated obvious problems with structure reports published in IUCr journals, such as refinement in a space group of too low symmetry. This paper reports on the current status of structure validation and possible future extensions.

More than 1.4 billion people depend on water from the Indus, Ganges, Brahmaputra, Yangtze, and Yellow rivers. Upstream snow and ice reserves of these basins, important in sustaining seasonal water availability, are likely to be affected substantially by climate change, but to what extent is yet unclear. Here, we show that meltwater is extremely important in the Indus basin and important for the Brahmaputra basin, but plays only a modest role for the Ganges, Yangtze, and Yellow rivers. A huge difference also exists between basins in the extent to which climate change is predicted to affect water availability and food security. The Brahmaputra and Indus basins are most susceptible to reductions of flow, threatening the food security of an estimated 60 million people.

Extracellular vesicles (EVs), through their complex cargo, can reflect the state of their cell of origin and change the functions and phenotypes of other cells. These features indicate strong biomarker and therapeutic potential and have generated broad interest, as evidenced by the steady year-on-year increase in the numbers of scientific publications about EVs. Important advances have been made in EV metrology and in understanding and applying EV biology. However, hurdles remain to realising the potential of EVs in domains ranging from basic biology to clinical applications due to challenges in EV nomenclature, separation from non-vesicular extracellular particles, characterisation and functional studies. To address the challenges and opportunities in this rapidly evolving field, the International Society for Extracellular Vesicles (ISEV) updates its 'Minimal Information for Studies of Extracellular Vesicles', which was first published in 2014 and then in 2018 as MISEV2014 and MISEV2018, respectively. The goal of the current document, MISEV2023, is to provide researchers with an updated snapshot of available approaches and their advantages and limitations for production, separation and characterisation of EVs from multiple sources, including cell culture, body fluids and solid tissues. In addition to presenting the latest state of the art in basic principles of EV research, this document also covers advanced techniques and approaches that are currently expanding the boundaries of the field. MISEV2023 also includes new sections on EV release and uptake and a brief discussion of in vivo approaches to study EVs. Compiling feedback from ISEV expert task forces and more than 1000 researchers, this document conveys the current state of EV research to facilitate robust scientific discoveries and move the field forward even more rapidly.

Secreted membrane-enclosed vesicles, collectively called extracellular vesicles (EVs), which include exosomes, ectosomes, microvesicles, microparticles, apoptotic bodies and other EV subsets, encompass a very rapidly growing scientific field in biology and medicine. Importantly, it is currently technically challenging to obtain a totally pure EV fraction free from non-vesicular components for functional studies, and therefore there is a need to establish guidelines for analyses of these vesicles and reporting of scientific studies on EV biology. Here, the International Society for Extracellular Vesicles (ISEV) provides researchers with a minimal set of biochemical, biophysical and functional standards that should be used to attribute any specific biological cargo or functions to EVs.

Abstract: It has been argued that the EU suffers from serious accountability deficits. But how can we establish the existence of accountability deficits? This article tries to get to grips with the appealing but elusive concept of accountability by asking three types of questions. First a conceptual one: what exactly is meant by accountability? In this article the concept of accountability is used in a rather narrow sense: a relationship between an actor and a forum, in which the actor has an obligation to explain and to justify his or her conduct, the forum can pose questions and pass judgement, and the actor may face consequences. The second question is analytical: what types of accountability are involved? A series of dimensions of accountability are discerned that can be used to describe the various accountability relations and arrangements that can be found in the different domains of European governance. The third question is evaluative: how should we assess these accountability arrangements? The article provides three evaluative perspectives: a democratic, a constitutional and a learning perspective. Each of these perspectives may produce different types of accountability deficits.

Amazon forests are a key but poorly understood component of the global carbon cycle. If, as anticipated, they dry this century, they might accelerate climate change through carbon losses and changed surface energy balances. We used records from multiple long-term monitoring plots across Amazonia to assess forest responses to the intense 2005 drought, a possible analog of future events. Affected forest lost biomass, reversing a large long-term carbon sink, with the greatest impacts observed where the dry season was unusually intense. Relative to pre-2005 conditions, forest subjected to a 100-millimeter increase in water deficit lost 5.3 megagrams of aboveground biomass of carbon per hectare. The drought had a total biomass carbon impact of 1.2 to 1.6 petagrams (1.2 x 10(15) to 1.6 x 10(15) grams). Amazon forests therefore appear vulnerable to increasing moisture stress, with the potential for large carbon losses to exert feedback on climate change.

Gaining insights into the structural determinants of protein-protein interactions holds the key for a deeper understanding of biological functions, diseases and development of therapeutics. An important aspect of this is the ability to accurately predict the binding strength for a given protein-protein complex. Here we present PROtein binDIng enerGY prediction (PRODIGY), a web server to predict the binding affinity of protein-protein complexes from their 3D structure. The PRODIGY server implements our simple but highly effective predictive model based on intermolecular contacts and properties derived from non-interface surface. AVAILABILITY AND IMPLEMENTATION: PRODIGY is freely available at: http://milou.science.uu.nl/services/PRODIGY CONTACT: a.m.j.j.bonvin@uu.nl, a.vangone@uu.nl.

BACKGROUND: Misconceptions about ADHD stigmatize affected people, reduce credibility of providers, and prevent/delay treatment. To challenge misconceptions, we curated findings with strong evidence base. METHODS: We reviewed studies with more than 2000 participants or meta-analyses from five or more studies or 2000 or more participants. We excluded meta-analyses that did not assess publication bias, except for meta-analyses of prevalence. For network meta-analyses we required comparison adjusted funnel plots. We excluded treatment studies with waiting-list or treatment as usual controls. From this literature, we extracted evidence-based assertions about the disorder. RESULTS: We generated 208 empirically supported statements about ADHD. The status of the included statements as empirically supported is approved by 80 authors from 27 countries and 6 continents. The contents of the manuscript are endorsed by 366 people who have read this document and agree with its contents. CONCLUSIONS: Many findings in ADHD are supported by meta-analysis. These allow for firm statements about the nature, course, outcome causes, and treatments for disorders that are useful for reducing misconceptions and stigma.

Glaciers distinct from the Greenland and Antarctic Ice Sheets are losing large amounts of water to the world's oceans. However, estimates of their contribution to sea level rise disagree. We provide a consensus estimate by standardizing existing, and creating new, mass-budget estimates from satellite gravimetry and altimetry and from local glaciological records. In many regions, local measurements are more negative than satellite-based estimates. All regions lost mass during 2003-2009, with the largest losses from Arctic Canada, Alaska, coastal Greenland, the southern Andes, and high-mountain Asia, but there was little loss from glaciers in Antarctica. Over this period, the global mass budget was -259 ± 28 gigatons per year, equivalent to the combined loss from both ice sheets and accounting for 29 ± 13% of the observed sea level rise.

Abstract We assess evidence relevant to Earth's equilibrium climate sensitivity per doubling of atmospheric CO 2 , characterized by an effective sensitivity S . This evidence includes feedback process understanding, the historical climate record, and the paleoclimate record. An S value lower than 2 K is difficult to reconcile with any of the three lines of evidence. The amount of cooling during the Last Glacial Maximum provides strong evidence against values of S greater than 4.5 K. Other lines of evidence in combination also show that this is relatively unlikely. We use a Bayesian approach to produce a probability density function (PDF) for S given all the evidence, including tests of robustness to difficult‐to‐quantify uncertainties and different priors. The 66% range is 2.6–3.9 K for our Baseline calculation and remains within 2.3–4.5 K under the robustness tests; corresponding 5–95% ranges are 2.3–4.7 K, bounded by 2.0–5.7 K (although such high‐confidence ranges should be regarded more cautiously). This indicates a stronger constraint on S than reported in past assessments, by lifting the low end of the range. This narrowing occurs because the three lines of evidence agree and are judged to be largely independent and because of greater confidence in understanding feedback processes and in combining evidence. We identify promising avenues for further narrowing the range in S , in particular using comprehensive models and process understanding to address limitations in the traditional forcing‐feedback paradigm for interpreting past changes.

BACKGROUND: Physical therapy (PT) is one of the key disciplines in interdisciplinary stroke rehabilitation. The aim of this systematic review was to provide an update of the evidence for stroke rehabilitation interventions in the domain of PT. METHODS AND FINDINGS: Randomized controlled trials (RCTs) regarding PT in stroke rehabilitation were retrieved through a systematic search. Outcomes were classified according to the ICF. RCTs with a low risk of bias were quantitatively analyzed. Differences between phases poststroke were explored in subgroup analyses. A best evidence synthesis was performed for neurological treatment approaches. The search yielded 467 RCTs (N = 25373; median PEDro score 6 [IQR 5-7]), identifying 53 interventions. No adverse events were reported. Strong evidence was found for significant positive effects of 13 interventions related to gait, 11 interventions related to arm-hand activities, 1 intervention for ADL, and 3 interventions for physical fitness. Summary Effect Sizes (SESs) ranged from 0.17 (95%CI 0.03-0.70; I(2) = 0%) for therapeutic positioning of the paretic arm to 2.47 (95%CI 0.84-4.11; I(2) = 77%) for training of sitting balance. There is strong evidence that a higher dose of practice is better, with SESs ranging from 0.21 (95%CI 0.02-0.39; I(2) = 6%) for motor function of the paretic arm to 0.61 (95%CI 0.41-0.82; I(2) = 41%) for muscle strength of the paretic leg. Subgroup analyses yielded significant differences with respect to timing poststroke for 10 interventions. Neurological treatment approaches to training of body functions and activities showed equal or unfavorable effects when compared to other training interventions. Main limitations of the present review are not using individual patient data for meta-analyses and absence of correction for multiple testing. CONCLUSIONS: There is strong evidence for PT interventions favoring intensive high repetitive task-oriented and task-specific training in all phases poststroke. Effects are mostly restricted to the actually trained functions and activities. Suggestions for prioritizing PT stroke research are given.

The Mediterranean Intensive Oxidant Study, performed in the summer of 2001, uncovered air pollution layers from the surface to an altitude of 15 kilometers. In the boundary layer, air pollution standards are exceeded throughout the region, caused by West and East European pollution from the north. Aerosol particles also reduce solar radiation penetration to the surface, which can suppress precipitation. In the middle troposphere, Asian and to a lesser extent North American pollution is transported from the west. Additional Asian pollution from the east, transported from the monsoon in the upper troposphere, crosses the Mediterranean tropopause, which pollutes the lower stratosphere at middle latitudes.

BACKGROUND: Physical activity is beneficial for healthy ageing. It may also help maintain good cognitive function in older age. Aerobic activity improves cardiovascular fitness, but it is not known whether this sort of fitness is necessary for improved cognitive function. Studies in which activity, fitness and cognition are reported in the same individuals could help to resolve this question. OBJECTIVES: To assess the effectiveness of physical activity, aimed at improving cardiorespiratory fitness, on cognitive function in older people without known cognitive impairment. SEARCH STRATEGY: We searched MEDLINE, EMBASE, PEDro, SPORTDiscus, PsycINFO, CINAHL, Cochrane Controlled Trials Register (CENTRAL), Dissertation abstracts international and ongoing trials registers on 15 December 2005 with no language restrictions. SELECTION CRITERIA: All published randomised controlled trials comparing aerobic physical activity programmes with any other intervention or no intervention with participants older than 55 years of age were eligible for inclusion. DATA COLLECTION AND ANALYSIS: Eleven RCTs fulfilling the inclusion criteria are included in this review. Two reviewers independently extracted the data from these included studies. MAIN RESULTS: Eight out of 11 studies reported that aerobic exercise interventions resulted in increased cardiorespiratory fitness of the intervention group (an improvement on the maximum oxygen uptake test which is considered to be the single best indicator of the cardiorespiratory system) of approximately 14% and this improvement coincided with improvements in cognitive capacity. The largest effects on cognitive function were found on motor function and auditory attention (effect sizes of 1.17 and 0.50 respectively). Moderate effects were observed for cognitive speed (speed at which information is processed; effect size 0.26) and visual attention (effect size 0.26). AUTHORS' CONCLUSIONS: There is evidence that aerobic physical activities which improve cardiorespiratory fitness are beneficial for cognitive function in healthy older adults, with effects observed for motor function, cognitive speed, auditory and visual attention. However, the majority of comparisons yielded no significant results. The data are insufficient to show that the improvements in cognitive function which can be attributed to physical exercise are due to improvements in cardiovascular fitness, although the temporal association suggests that this might be the case. Larger studies are still required to confirm whether the aerobic training component is necessary, or whether the same can be achieved with any type of physical exercise. At the same time, it would be informative to understand why some cognitive functions seem to improve with (aerobic) physical exercise while other functions seem to be insensitive to physical exercise. Clinicians and scientists in the field of neuropsychology should seek mutual agreement on a smaller battery of cognitive tests to use, in order to render research on cognition clinically relevant and transparent and heighten the reproducibility of results for future research.

ISSN:0959-6658

X-ray computed tomography (CT) can reveal the internal details of objects in three dimensions non-destructively. In this Primer, we outline the basic principles of CT and describe the ways in which a CT scan can be acquired using X-ray tubes and synchrotron sources, including the different possible contrast modes that can be exploited. We explain the process of computationally reconstructing three-dimensional (3D) images from 2D radiographs and how to segment the 3D images for subsequent visualization and quantification. Whereas CT is widely used in medical and heavy industrial contexts at relatively low resolutions, here we focus on the application of higher resolution X-ray CT across science and engineering. We consider the application of X-ray CT to study subjects across the materials, metrology and manufacturing, engineering, food, biological, geological and palaeontological sciences. We examine how CT can be used to follow the structural evolution of materials in three dimensions in real time or in a time-lapse manner, for example to follow materials manufacturing or the in-service behaviour and degradation of manufactured components. Finally, we consider the potential for radiation damage and common sources of imaging artefacts, discuss reproducibility issues and consider future advances and opportunities. This Primer on X-ray computed tomography explores the different experimental configurations for three-dimensional data acquisition as well as the fundamentals of three-dimensional data reconstruction, segmentation and analysis with examples across the physical and life sciences.

Plant defenses against pathogens and insects are regulated differentially by cross-communicating signaling pathways in which salicylic acid (SA), jasmonic acid (JA), and ethylene (ET) play key roles. To understand how plants integrate pathogen- and insect-induced signals into specific defense responses, we monitored the dynamics of SA, JA, and ET signaling in Arabidopsis after attack by a set of microbial pathogens and herbivorous insects with different modes of attack. Arabidopsis plants were exposed to a pathogenic leaf bacterium (Pseudomonas syringae pv. tomato), a pathogenic leaf fungus (Alternaria brassicicola), tissue-chewing caterpillars (Pieris rapae), cell-content-feeding thrips (Frankliniella occidentalis), or phloem-feeding aphids (Myzus persicae). Monitoring the signal signature in each plant-attacker combination showed that the kinetics of SA, JA, and ET production varies greatly in both quantity and timing. Analysis of global gene expression profiles demonstrated that the signal signature characteristic of each Arabidopsis-attacker combination is orchestrated into a surprisingly complex set of transcriptional alterations in which, in all cases, stress-related genes are overrepresented. Comparison of the transcript profiles revealed that consistent changes induced by pathogens and insects with very different modes of attack can show considerable overlap. Of all consistent changes induced by A. brassicicola, Pieris rapae, and E occidentalis, more than 50% also were induced consistently by P. syringae. Notably, although these four attackers all stimulated JA biosynthesis, the majority of the changes in JA-responsive gene expression were attacker specific. All together, our study shows that SA, JA, and ET play a primary role in the orchestration of the plant's defense response, but other regulatory mechanisms, such as pathway cross-talk or additional attacker-induced signals, eventually shape the highly complex attacker-specific defense response.

The RCP2.6 emission and concentration pathway is representative of the literature on mitigation scenarios aiming to limit the increase of global mean temperature to 2°C. These scenarios form the low end of the scenario literature in terms of emissions and radiative forcing. They often show negative emissions from energy use in the second half of the 21st century. The RCP2.6 scenario is shown to be technically feasible in the IMAGE integrated assessment modeling framework from a medium emission baseline scenario, assuming full participation of all countries. Cumulative emissions of greenhouse gases from 2010 to 2100 need to be reduced by 70% compared to a baseline scenario, requiring substantial changes in energy use and emissions of non-CO2 gases. These measures (specifically the use of bio-energy and reforestation measures) also have clear consequences for global land use. Based on the RCP2.6 scenario, recommendations for further research on low emission scenarios have been formulated. These include the response of the climate system to a radiative forcing peak, the ability of society to achieve the required emission reduction rates given political and social inertia and the possibilities to further reduce emissions of non-CO2 gases.

A Geologic Time Scale (GTS2004) is presented that integrates currently available stratigraphic and geochronologic information. Key features of the new scale are outlined, how it was constructed, and how it can be further improved. The accompanying International Stratigraphic Chart, issued under auspices of the International Commission on Stratigraphy (ICS), shows the current chronostratigraphic scale and ages with estimates of uncertainty for all stage boundaries. Special reference is made to the Precambrian part of the time scale, which is coming of age in terms of detail, and to the Neogene portion, which has attained an ultra-high-precision absolute-age calibration.

The use of information and communication technology (ICT) is rapidly changing the structure of a number of large, executive public agencies. They used to be machine bureaucracies in which street‐level officials exercised ample administrative discretion in dealing with individual clients. In some realms, the street‐level bureaucrats have vanished. Instead of street‐level bureaucracies, they have become system‐level bureaucracies. System analysts and software designers are the key actors in these executive agencies. This article explores the implications of this transformation from the perspective of the constitutional state. Thanks to ICT, the implementation of the law has virtually been perfected. However, some new issues rise: What about the discretionary power of the system‐level bureaucrats? How can we guarantee due process and fairness in difficult cases? The article ends with several institutional innovations that may help to embed these system‐level bureaucracies in the constitutional state.

Plants generate effective responses to infection by recognizing both conserved and variable pathogen-encoded molecules. Pathogens deploy virulence effector proteins into host cells, where they interact physically with host proteins to modulate defense. We generated an interaction network of plant-pathogen effectors from two pathogens spanning the eukaryote-eubacteria divergence, three classes of Arabidopsis immune system proteins, and ~8000 other Arabidopsis proteins. We noted convergence of effectors onto highly interconnected host proteins and indirect, rather than direct, connections between effectors and plant immune receptors. We demonstrated plant immune system functions for 15 of 17 tested host proteins that interact with effectors from both pathogens. Thus, pathogens from different kingdoms deploy independently evolved virulence proteins that interact with a limited set of highly connected cellular hubs to facilitate their diverse life-cycle strategies.