A communication protocol for interactively controlling software tools

We present a protocol for interactively using software tools in a loosely coupled tool environment. Such an environment can assist the user in doing tasks that require the use of multiple tools. For example, it can invoke tools on certain input, set processing parameters, await task completion and have tools communicate the resulting output. It can also keep track of files produced by tools and prevent tools from reading and writing to the same file at the same time. The protocol serves as an interface between the tools and a central tool manager. Generally, the manager controls the tools and forms an interface to a human user. The protocol is used to connect our tool manager SQuADT to a variety of tools, hereby allowing these tools to be used on all major software platforms

Generic programming in the mCRL2 toolset

The mCRL2 tool set [GKM+08] is a tool set for verification and validation of concurrent processes, based on process algebra speci??cations. The mCRL2 language is based on the Algebra of Communicating Processes (ACP), which is extended to include data and time. This paper reports on experiences with generic programming in C++ as applied in the implementation of the tool set. C++ concepts, a type system for templates [RS06], form a key ingredient of this style of programming. Using concept definitions, requirements on template types can be defined that are type checked during compile time. The main benefits for the mCRL2 tool set are uniform and exible interfaces that operate on well-defined types, and a signi??cant increase in code reuse. The use of concepts also promotes the writing of code that corresponds closely to pseudo code, since the chosen concepts correspond naturally with domain specific concepts. This will be illustrated by a simple use case, namely substitution functions. Generic programming is about generalizing software components, to enable reuse in a wide variety of situations. In C++, generic programming is enabled using templates. C++ concepts are proposed as a means to type check template types. A concept is a set of requirements (valid expressions, associated types, semantic invariants, complexity guarantees, and so on) that a type must fulfill to be correctly used as an argument in a call to a generic algorithm, see [RS06]. Language support for concepts has been proposed [GJS+06] for the next version of the C++ standard, C++0x. Concepts will be used to make the specification of the C++ standard library more complete and precise. A derivative of the GNU C++ compiler [Gre08] already implements language support for concepts. In the mCRL2 tool set we have used a portable library for concept checking. Most uses of generic programming in general, and more specifically the use of concepts, that are described in the literature treat the construction of data structures and algorithms that operate on these, see e.g. [GL05]

Recreatief gebruik van water : achtergronddocument bij Natuurbalans 2008

Voor de rol van water is onderscheid gemaakt tussen zogenaamde kleine wateren en grote wateren. Kleine wateren als beekjes, vennen en sloten zijn een onderdeel van het landschap en hebben als zodanig invloed op de aantrekkelijkheid en de beleving. Grote wateren zijn dominant in het landschap en daardoor bepalend voor de aantrekkelijkheid en de beleving daarvan. Water vergroot de levendigheid van en de variatie in het landschap. Aspecten van water met een positieve invloed op de waardering van landschap, zijn een vloeiend en natuurlijk verloop van oevers, de openheid van het water en de mate waarin het waterlandschap is te voorspellen aan de hand van de rest van het landschap. Tweederde van de Nederlanders vindt water mooier als er geen menselijke sporen zichtbaar zijn. De meeste mensen zien horizonvervuiling als een van de belangrijkste bedreigingen voor het landscha

Antibody-mediated delivery of viral epitopes to redirect EBV-specific CD8+ T-cell immunity towards cancer cells

Antibody-mediated delivery of immunogenic epitopes to redirect virus-specific CD8+ T-cells towards cancer cells is an emerging and promising new therapeutic strategy. These so-called antibody-epitope conjugates (AECs) rely on the proteolytic release of the epitopes close to the tumor surface for presentation by HLA class I molecules to eventually redirect and activate virus-specific CD8+ T-cells towards tumor cells. We fused the immunogenic EBV-BRLF1 epitope preceded by a protease cleavage site to the C-terminus of the heavy and/or light chains of cetuximab and trastuzumab. We evaluated these AECs and found that, even though all AECs were able to redirect the EBV-specific T-cells, AECs with an epitope fused to the C-terminus of the heavy chain resulted in higher levels of T-cell activation compared to AECs with the same epitope fused to the light chain of an antibody. We observed that all AECs were depending on the presence of the antibody target, that the level of T-cell activation correlated with expression levels of the antibody target, and that our AECs could efficiently deliver the BRLF1 epitope to cancer cell lines from different origins (breast, ovarian, lung, and cervical cancer and a multiple myeloma). Moreover, in vivo, the AECs efficiently reduced tumor burden and increased the overall survival, which was prolonged even further in combination with immune checkpoint blockade. We demonstrate the potential of these genetically fused AECs to redirect the potent EBV-specific T-cells towards cancer in vitro and in vivo. Immunobiology of allogeneic stem cell transplantation and immunotherapy of hematological disease

Comparison of methods generating antibody-epitope conjugates for targeting cancer with virus-specific T cells

Therapeutic antibody-epitope conjugates (AECs) are promising new modalities to deliver immunogenic epitopes and redirect virus-specific T-cell activity to cancer cells. Nevertheless, many aspects of these antibody conjugates require optimization to increase their efficacy. Here we evaluated different strategies to conjugate an EBV epitope (YVL/A2) preceded by a protease cleavage site to the antibodies cetuximab and trastuzumab. Three approaches were taken: chemical conjugation (i.e. a thiol-maleimide reaction) to reduced cysteine side chains, heavy chain C-terminal enzymatic conjugation using sortase A, and genetic fusions, to the heavy chain (HC) C-terminus. All three conjugates were capable of T-cell activation and target-cell killing via proteolytic release of the EBV epitope and expression of the antibody target was a requirement for T-cell activation. Moreover, AECs generated with a second immunogenic epitope derived from CMV (NLV/A2) were able to deliver and redirect CMV specific T-cells, in which the amino sequence of the attached peptide appeared to influence the efficiency of epitope delivery. Therefore, screening of multiple protease cleavage sites and epitopes attached to the antibody is necessary. Taken together, our data demonstrated that multiple AECs could sensitize cancer cells to virus-specific T cells.Bio-organic Synthesi

Diastolic delta best predicts paravalvular regurgitation after transcatheter aortic valve replacement as assessed by cardiac magnetic resonance: the APPOSE trial

Aims: Paravalvular regurgitation (PVR) is a common complication after transcatheter aortic valve replacement (TAVR) that poses an increased risk of rehospitalization for heart failure and mortality. The aim of this study was to assess the accuracy of haemodynamic indices to predict relevant PVR. Methods and results: In this prospective single-centre clinical trial, four haemodynamic indices of PVR measured during TAVR were assessed for their correlation with gold standard cardiac magnetic resonance (CMR)-derived regurgitant fraction (CMR-RF) at 1 month follow-up: diastolic delta (DD), heart rate-adjusted diastolic delta (HR-DD), aortic regurgitation index (ARI), and aortic regurgitation index ratio (ARI ratio). These haemodynamic indices were analysed for their ability to predict relevant PVR (defined as CMR-RF > 20%) using receiver operating characteristic (ROC) curves with corresponding area under the ROC curves (AUCs). A total of 77 patients were included and had CMR performed 41 ± 14 days after TAVR. Mean CMR-RF was 12.4 ± 9.3%. Fifteen (19.5%) patients had CMR-RF > 20%. DD had the best correlation with CMR-RF and the highest AUC to predict relevant PVR (0.82; 95% CI, 0.72-0.92), followed by HR-DD (AUC 0.78; 95% CI, 0.67-0.89), ARI (AUC 0.78; 95% CI, 0.66-0.89), and ARI ratio (AUC 0.65; 95% CI, 0.49-0.81). The optimal cut-off value for DD was 32 mmHg, with sensitivity of 69% and specificity of 77% in predicting relevant PVR. Conclusion: DD measured during TAVR best predicts relevant PVR. Correction for heart rate (HR-DD) or systolic blood pressure (ARI, ARI ratio) did not improve this predictive value

Fermentative production of isobutene

Isobutene (2-methylpropene) is one of those chemicals for which bio-based production might replace the petrochemical production in the future. Currently, more than 10 million metric tons of isobutene are produced on a yearly basis. Even though bio-based production might also be achieved through chemocatalytic or thermochemical methods, this review focuses on fermentative routes from sugars. Although biological isobutene formation is known since the 1970s, extensive metabolic engineering is required to achieve economically viable yields and productivities. Two recent metabolic engineering developments may enable anaerobic production close to the theoretical stoichiometry of 1isobutene + 2CO2 + 2H2O per mol of glucose. One relies on the conversion of 3-hydroxyisovalerate to isobutene as a side activity of mevalonate diphosphate decarboxylase and the other on isobutanol dehydration as a side activity of engineered oleate hydratase. The latter resembles the fermentative production of isobutanol followed by isobutanol recovery and chemocatalytic dehydration. The advantage of a completely biological route is that not isobutanol, but instead gaseous isobutene is recovered from the fermenter together with CO2. The low aqueous solubility of isobutene might also minimize product toxicity to the microorganisms. Although developments are at their infancy, the potential of a large scale fermentative isobutene production process is assessed. The production costs estimate is 0.9 € kg−1, which is reasonably competitive. About 70% of the production costs will be due to the costs of lignocellulose hydrolysate, which seems to be a preferred feedstock