Simplified Monopalmitoyl Toll-like Receptor 2 Ligand Mini-UPam for Self-Adjuvanting Neoantigen-Based Synthetic Cancer Vaccines

Synthetic vaccines, based on antigenic peptides that comprise MHC−I and MHC-II T-cell epitopes expressed by tumors, show great promise for the immunotherapy of cancer. For optimal immunogenicity, the synthetic peptides (SPs) should be adjuvanted with suitable immunostimulatory additives. Previously, we have shown that improved immunogenicity in vivo is obtained with vaccine modalities in which an SP is covalently connected to an adjuvanting moiety, typically a ligand to Toll-like receptor 2 (TLR2). SPs were covalently attached to UPam, which is a derivative of the classic TLR2 ligand Pam₃CysSK₄. A disadvantage of the triply palmitoylated UPam is its high lipophilicity, which precludes universal adoption of this adjuvant for covalent modification of various antigenic peptides as it renders the synthetic vaccine insoluble in several cases. Here, we report a novel conjugatable TLR2 ligand, mini-UPam, which contains only one palmitoyl chain, rather than three, and therefore has less impact on the solubility and other physicochemical properties of a synthetic peptide. In this study, we used SPs that contain the clinically relevant neoepitopes identified in a melanoma patient who completely recovered after T-cell therapy. Homogeneous mini-UPam-SP conjugates have been prepared in good yields by stepwise solid-phase synthesis that employed a mini-UPam building block pre-prepared in solution and the standard set of Fmoc-amino acids. The immunogenicity of the novel mini-UPam-SP conjugates was demonstrated by using the cancer patient's T-cells.     

Low‐Temperature Chemical Synthesis of High‐Purity Diacylglycerols (DAG) from Monoacylglycerols (MAG)

A chemical method was developed for low‐temperature synthesis of DAG from MAG followed by an easy purification procedure in order to obtain high‐purity DAG. Solvent‐assisted and solvent‐free reaction conditions were used, combined with different catalysts (sodium methoxide, p‐toluenesulfonic acid, methanesulfonic acid, and sulfuric acid). All reactions were performed at 35 and 70 °C. By increasing both acidity and polarity of the catalyst the equilibrium shifts towards the formation of DAG. When using sulfuric acid in solvent‐assisted condition at 70 °C, 88 % conversion was obtained after 20 min of reaction (77 % w/w DAG in the reaction mixture after evaporation of the solvent). After purifying by means of column chromatography, 96 % pure DAG were obtained. The overall yield of DAG was 81 %.     

银河桥 荷兰皮尔墨伦德

正荷兰Melkweg大桥,俗称"银河桥",横跨Noord-hollandsch运河,连接皮尔默伦德市历史中心区与西南地区不断发展的Weidevenne区。银河桥的建造是运河及其周边地区总体发展规划的第一阶段。"设计团队旨在打造一个具有特定标志的新区,以作为新旧两个中心城区之间的连系纽带。"银河桥,由NEXT建筑事务所设计建造。最引人注目的部分是一个巨大的拱形桥,水平面之上高达12米,与Melkweg路连绵延伸为一     

A comparative assessment of local municipal food policy integration in the Netherlands

ABSTRACT

Local governments around the world increasingly engage in food governance, aiming to address food system challenges such as obesity, food waste, or food insecurity. However, the extent to which municipalities have actually integrated food across their policies remains unknown. This study addresses this question by conducting a medium-n systematic content analysis of local food policy outputs of 31 Dutch municipalities. Policy outputs were coded for the food goals and instruments adopted by local governments. Our analysis shows that most municipalities integrate food to a limited extent only, predominantly addressing health and local food production or consumption. Furthermore, municipalities seem hesitant to use coercive instruments and predominantly employ informative and organizational instruments. Nonetheless, a small number of municipalities have developed more holistic approaches to address food challenges. These cities may prove to be a leading group in the development of system-based approaches in Dutch local food policy.     

Social learning for adaptive delta management: Tidal River Management in the Bangladesh Delta

ABSTRACT

The article analyzes Tidal River Management in Bangladesh from a social learning perspective. Four cases were investigated using participatory assessment. Knowledge acquisition through transformations in the Tidal River Management process was explored as an intended learning outcome. The study finds that social learning occurred more prominently at the individual stakeholder level and less at the collective level. For Tidal River Management to be responsive and sustainable, especially in times of increased uncertainty and climate vulnerability, more attention needs to be paid to coordination and facilitation of multi-level learning that includes all stakeholders.     

Reconstruction of defects of the trachea

The trachea has a complex anatomy to fulfill its tasks. Its unique fibro-cartilaginous structure maintains an open conduit during respiration, and provides vertical elasticity for deglutition, mobility of the neck and speech. Blood vessels pierce the intercartilaginous ligaments to perfuse the ciliated epithelium, which ensures effective mucociliary clearance. Removal of a tracheal segment affected by benign or malignant disease requires airtight restoration of the continuity of the tube. When direct approximation of both tracheal ends is no longer feasible, a reconstruction is needed. This may occur in recurrent short-segment defects in a scarred environment, or in defects comprising more than half the length of the trachea. The resulting gap must be filled with vascularized tissue that restores the mucosal lining and supports the semi-rigid, semi-flexible framework of the trachea. For long-segment or circular defects, restoration of this unique biomechanical profile becomes even more important. Due to the inherent difficulty of creating such a tube, a tracheostomy or palliative stenting are often preferred over permanent reconstruction. To significantly improve and sustain quality of life of these patients, surgeons proposed innovative strategies for complex tracheal repair. In this review, we provide an overview of current clinical applications of tracheal repair using autologous and allogenic tissues. We look at recent advances in the field of tissue engineering, and the areas for improvement of these first human applications. Lastly, we highlight the focus of our research, in an effort to contribute to the development of optimized tracheal reconstructive techniques.     

Statistical reasoning in diagnostic problem-solving—The case of flow-rate measurements

There are various methods for measuring flow rates in rivers, but all of them have practical issues and challenges. A period of exceptionally high water levels revealed substantial discrepancies between two measurement setups in the same waterway. Finding a causal explanation of the discrepancies was important, as the problem might have ramifications for other flow-rate measurement setups as well. Finding the causes of problems is called diagnostic problem-solving. We applied a branch-and-prune strategy, in which we worked with a hierarchy of hypotheses, and used statistical analysis as well as domain knowledge to rule out options. We were able to narrow down the potential explanations to one main suspect and an alternative explanation. Based on the analysis, we discuss the role of statistical techniques in diagnostic problem-solving and reasoning patterns that make the application of statistics powerful. The contribution to theory in statistics is not in the individual techniques but in their application and integration in a coherent sequence of studies – a reasoning strategy.