Technical Note: On the Production and Accuracy of CNC-Manufactured Hydraulic Scale Models

This Technical Note addresses the workflow for the production of hydraulic scale models using a Computer Numerically Controlled (CNC) production technique and investigates the possibilities to accurately reproduce topographical roughness features. Focusing on the construction of three scale models of unlined rock blasted tunnels, their accuracy is evaluated based on the comparison of differences between scaled prototype point clouds obtained by terrestrial laser scanning, spatially filtered meshes that served as input for the milling of the models, and digital twins of the constructed models that were created by Structure from Motion photogrammetry. The direct comparison between the point clouds and meshes as well as the comparison of derived statistical parameters show that the models could be reproduced with a high degree of accuracy. Observed deviations between the point clouds of the milled models and the milling meshes, as well as the scaled original point cloud, are identified and discussed in light of the production technique and the accuracy of the applied methods for the comparison

Bringing science and pragmatism together a tiered approach for modelling toxicological impacts in LCA

Goal, Scope and Background: The EU 5th framework project OMNIITOX will develop models calculating characterisation factors for assessing the potential toxic impacts of chemicals within the framework of LCA. These models will become accessible through a web-based information system. The key objective of the OMNIITOX project is to increase the coverage of substances by such models. In order to reach this objective, simpler models which need less but available data, will have to be developed while maintaining scientific quality. Methods. Experience within the OMNIITOX project has taught that data availability and quality are crucial issues for calculating characterisation factors. Data availability determines whether calculating characterisation factors is possible at all, whereas data quality determines to what extent the resulting characterisation factors are reliable. Today, there is insufficient knowledge and/or resources to have high data availability as well as high data quality and high model quality at the same time. Results: The OMNIITOX project is developing two inter-related models in order to be able to provide LCA impact assessment characterisation factors for toxic releases for as broad a range of chemicals as possible: 1) A base model representing a state-of-the-art multimedia model and 2) a simple model derived from the base model using statistical tools. Discussion. A preliminary decision tree for using the OMNIITOX information system (IS) is presented. The decision tree aims to illustrate how the OMNIITOX IS can assist an LCA practitioner in finding or deriving characterisation factors for use in life cycle impact assessment of toxic releases. Conclusions and Outlook: Data availability and quality are crucial issues when calculating characterisation factors for the toxicity impact categories. The OMNIITOX project is developing a tiered model approach for this. It is foreseen that a first version of the base model will be ready in late summer of 2004, whereas a first version of the simple base model is expected a few months late

Directional dependency of flow resistance in an unlined rock blasted hydropower tunnel

The dependency of the friction factor on the flow direction was investigated experimentally in a milled scale model of an unlined rock blasted tunnel under pressurized flow conditions by reversing the flow direction. The experimental data were used to highlight the significance of anisotropic roughness structures and variations in the cross-sectional area on the flow resistance. It is hypothesized that local sudden expansions of the cross-sectional area, which are followed by gradual contractions, contribute significantly to the directional dependency of the friction factor due to potential flow separation. For the reversed case, i.e. when sudden large-scale contractions were followed by gradual expansions, 15% lower friction factors were observed. The results were also used to highlight the scale dependency of these topographical features, the dependency of the friction factor from the tunnel driving direction, and to show the need for the development of methods that can be used to parameterize the directional dependency of hydraulic roughness and friction factors

Plasmodium falciparum Heterochromatin Protein 1 Marks Genomic Loci Linked to Phenotypic Variation of Exported Virulence Factors

Epigenetic processes are the main conductors of phenotypic variation in eukaryotes. The malaria parasite Plasmodium falciparum employs antigenic variation of the major surface antigen PfEMP1, encoded by 60 var genes, to evade acquired immune responses. Antigenic variation of PfEMP1 occurs through in situ switches in mono-allelic var gene transcription, which is PfSIR2-dependent and associated with the presence of repressive H3K9me3 marks at silenced loci. Here, we show that P. falciparum heterochromatin protein 1 (PfHP1) binds specifically to H3K9me3 but not to other repressive histone methyl marks. Based on nuclear fractionation and detailed immuno-localization assays, PfHP1 constitutes a major component of heterochromatin in perinuclear chromosome end clusters. High-resolution genome-wide chromatin immuno-precipitation demonstrates the striking association of PfHP1 with virulence gene arrays in subtelomeric and chromosome-internal islands and a high correlation with previously mapped H3K9me3 marks. These include not only var genes, but also the majority of P. falciparum lineage-specific gene families coding for exported proteins involved in host–parasite interactions. In addition, we identified a number of PfHP1-bound genes that were not enriched in H3K9me3, many of which code for proteins expressed during invasion or at different life cycle stages. Interestingly, PfHP1 is absent from centromeric regions, implying important differences in centromere biology between P. falciparum and its human host. Over-expression of PfHP1 results in an enhancement of variegated expression and highlights the presence of well-defined heterochromatic boundaries. In summary, we identify PfHP1 as a major effector of virulence gene silencing and phenotypic variation. Our results are instrumental for our understanding of this widely used survival strategy in unicellular pathogens

Targeting class I histone deacetylase 2 in MYC amplified group 3 medulloblastoma

Introduction: Medulloblastoma (MB) is the most frequent malignant brain tumor in children. Four subgroups with distinct genetic, epigenetic and clinical characteristics have been identified. Survival remains particularly poor in patients with Group 3 tumors harbouring a MYC amplification. We herein explore the molecular mechanisms and translational implications of class I histone deacetylase (HDAC) inhibition in MYC driven MBs. Material and Methods: Expression of HDACs in primary MB subgroups was compared to normal brain tissue. A panel of MB cell lines, including Group 3 MYC amplified cell lines, were used as model systems. Cells were treated with HDAC inhibitors (HDACi) selectively targeting class I or IIa HDACs. Depletion of HDAC2 was performed. Intracellular HDAC activity, cellular viability, metabolic activity, caspase activity, cell cycle progression, RNA and protein expression were analyzed. Results: HDAC2 was found to be overexpressed in MB subgroups with poor prognosis (SHH, Group 3 and Group 4) compared to normal brain and the WNT subgroup. Inhibition of the enzymatic activity of the class I HDACs reduced metabolic activity, cell number, and viability in contrast to inhibition of class IIa HDACs. Increased sensitivity to HDACi was specifically observed in MYC amplified cells. Depletion of HDAC2 increased H4 acetylation and induced cell death. Simulation of clinical pharmacokinetics showed time-dependent on target activity that correlated with binding kinetics of HDACi compounds. Conclusions: We conclude that HDAC2 is a valid drug target in patients with MYC amplified MB. HDACi should cover HDAC2 in their inhibitory profile and timing and dosing regimen in clinical trials should take binding kinetics of compounds into consideration

Towards a UK co-operative for the advancement of quantum technology

The meeting was the fourth in DSTL's series of community meetings and had a Systems Engineering theme – recognising the increasing importance of this topic for many in the Quantum Technology (QT) community. There is a growing recognition that, although there are significant research challenges associated with realising the commercial and societal benefits anticipated from quantum technologies, there are also other challenges which concern the physical, commercial, societal and regulatory environments into which these new technologies will be integrated. Similar difficulties have been faced and overcome by the information and communications industry. One of the striking characteristics of this sector over the past 20 years has been the speed at which advances in semiconductor technology have been exploited by industry. Each new generation of semiconductor devices has led to new system designs and to new user capabilities which represented a major advance upon the systems and capabilities that came before them. However, to achieve this required a large number of different components and tools to become available at the right time, and at an affordable price. The routine achievement of this is evidence of how companies and institutions within the sector have been able to communicate effectively and establish a high level of collaboration, whilst still maintaining intense competition at the product level. QT is very different to the semiconductor industry. While a number of target applications exist the discipline is very much in its infancy. At one end of the spectrum, there are some applications in communications and sensors that are relatively close to market, and, at the other end, there are some applications in computing and simulation that are still far from market. Many choices of enabling technologies and materials have yet to be fixed, and there is, as yet, very little first-hand experience of the problems that will arise when companies seek to establish repeatable manufacture of quantum components and systems. What can we learn from the International Technology Roadmap for Semiconductors (ITRS) that might benefit the Quantum Technology community? Generating an additional quantum roadmap would merely duplicate previous work – but establishing a small number of cross-community working groups might be a way to assist UK industry to gain a competitive edge in the application of quantum technologies, without duplicating the existing activities by other bodies such as InnovateUK, British Standards Institution (BSI), European Telecommunications Standards Institute (ETSI), Defence Science and Technology Laboratory (Dstl) etc. This document reports on discussions held at the meeting around this question and, leveraging this input, seeks to provide clear and appropriate recommendations to the UK QT community

Direct and plant community mediated effects of management intensity on annual nutrient leaching risk in temperate grasslands

Grassland management intensity influences nutrient cycling both directly, by changing nutrient inputs and outputs from the ecosystem, and indirectly, by altering the nutrient content, and the diversity and functional composition of plant and microbial communities. However, the relative importance of these direct and indirect processes for the leaching of multiple nutrients is poorly studied. We measured the annual leaching of nitrate, ammonium, phosphate and sulphate at a depth of 10 cm in 150 temperate managed grasslands using a resin method. Using Structural Equation Modeling, we distinguished between various direct and indirect effects of management intensity (i.e. grazing and fertilization) on nutrient leaching. We found that management intensity was positively associated with nitrate, ammonium and phosphate leaching risk both directly (i.e. via increased nutrient inputs) and indirectly, by changing the stoichiometry of soils, plants and microbes. In contrast, sulphate leaching risk was negatively associated with management intensity, presumably due to increased outputs with mowing and grazing. In addition, management intensification shifted plant communities towards an exploitative functional composition (characterized by high tissue turnover rates) and, thus, further promoted the leaching risk of inorganic nitrogen. Plant species richness was associated with lower inorganic nitrogen leaching risk, but most of its effects were mediated by stoichiometry and plant community functional traits. Maintaining and restoring diverse plant communities may therefore mitigate the increased leaching risk that management intensity imposes upon grasslands

Single cell sequencing reveals endothelial plasticity with transient mesenchymal activation after myocardial infarction.

Endothelial cells play a critical role in the adaptation of tissues to injury. Tissue ischemia induced by infarction leads to profound changes in endothelial cell functions and can induce transition to a mesenchymal state. Here we explore the kinetics and individual cellular responses of endothelial cells after myocardial infarction by using single cell RNA sequencing. This study demonstrates a time dependent switch in endothelial cell proliferation and inflammation associated with transient changes in metabolic gene signatures. Trajectory analysis reveals that the majority of endothelial cells 3 to 7 days after myocardial infarction acquire a transient state, characterized by mesenchymal gene expression, which returns to baseline 14 days after injury. Lineage tracing, using the Cdh5-CreERT2;mT/mG mice followed by single cell RNA sequencing, confirms the transient mesenchymal transition and reveals additional hypoxic and inflammatory signatures of endothelial cells during early and late states after injury. These data suggest that endothelial cells undergo a transient mes-enchymal activation concomitant with a metabolic adaptation within the first days after myocardial infarction but do not acquire a long-term mesenchymal fate. This mesenchymal activation may facilitate endothelial cell migration and clonal expansion to regenerate the vascular network

Ergebnisse und Implikationen aus dem Modellversuch zum Handel mit Flächenzertifikaten

Die Flächeninanspruchnahme liegt im Vierjahresdurchschnitt der Jahre 2011 bis 2014 mit 69 Hektar pro Tag immer noch mehr als doppelt so hoch wie von der Bundesregierung vor 14 Jahren in der nationalen Nachhaltigkeitsstrategie festgelegt. Vor dem Hintergrund des 30-Hektar-Zieles hat die Bundesregierung in den Koalitionsverträgen der 17. und 18. Legislaturperiode vereinbart, gemeinsam mit den Städten und Gemeinden den kommunalen Handel mit Flächenzertifikaten in einem Modellversuch zu erproben. Der vom Umweltbundesamt beauftragte Modellversuch wurde als Planspiel durchgeführt. Kernstück des Planspiels war ein praxisnahes kontrolliertes Feldexperiment, an dem sich 87 Kommunen beteiligten. In diesem Feldexperiment simulierten die teilnehmenden Kommunen für eigene, real geplante Baugebiete den Flächenzertifikatehandel über einen Zeitraum von 15 Jahren (2014-2028) mittels einer Online-Plattform. Die Ergebnisse zeigen, dass ein Flächenhandelssystem in der Lage ist, die Flächenneuinanspruchnahme effektiv zu verringern. Flächensparziele lassen sich zudem im Verbund aus Planung und flexibler Mengensteuerung effizient erreichen. Die Kommunen konnten die überörtlichen Mengenvorgaben durch den Kauf und Verkauf von Zertifikaten flexibel vor Ort umsetzen. Insgesamt belegen die Ergebnisse, dass ein Flächenhandelssystem geeignet ist, eine nachhaltige Siedlungsentwicklung zu fördern und Kommunalfinanzen zu entlasten

Characterisation of Cdkl5transcript isoforms in rat

CDKL5 deficiency is a severe neurological disorder caused by mutations in the X-linked Cyclin-Dependent Kinase-Like 5 gene (CDKL5). The predominant human CDKL5 brain isoform is a 9.7 kb transcript comprised of 18 exons with a large 6.6 kb 3′-untranslated region (UTR). Mammalian models of CDKL5 disorder are currently limited to mouse, and little is known about Cdkl5 in other organisms used to model neurodevelopmental disorders, such as rat. In this study we characterise, both bioinformatically and experimentally, the rat Cdkl5 gene structure and its associated transcript isoforms. New exonic regions, splice sites and UTRs are described, confirming the presence of four distinct transcript isoforms. The predominant isoform in the brain, which we name rCdkl5_1, is orthologous to the human hCDKL5_1 and mouse mCdkl5_1 isoforms and is the most highly expressed isoform across all brain regions tested. This updated gene model of Cdkl5 in rat provides a framework for studies into its protein products and provides a reference for the development of molecular therapies for testing in rat models of CDKL5 disorder