H3.3K27M mutation is not a suitable target for immunotherapy in HLA-A2(+) patients with diffuse midline glioma

Diffuse midline glioma is the leading cause of solid cancer-related deaths in children with very limited treatment options. A majority of the tumors carry a point mutation in the histone 3 variant (H3.3) creating a potential HLA-A*02:01 binding epitope (H3.3K27M(26-35)). Here, we isolated an H3.3K27M-specific T cell receptor (TCR) from transgenic mice expressing a diverse human TCR repertoire. Despite a high functional avidity of H3.3K27M-specific T cells, we were not able to achieve recognition of cells naturally expressing the H3.3K27M mutation, even when overexpressed as a transgene. Similar results were obtained with T cells expressing the published TCR 1H5 against the same epitope. CRISPR/Cas9 editing was used to exclude interference by endogenous TCRs in donor T cells. Overall, our data provide strong evidence that the H3.3K27M mutation is not a suitable target for cancer immunotherapy, most likely due to insufficient epitope processing and/or amount to be recognized by HLA-A*02:01 restricted CD8(+) T cells

Hybrid Control Techniques for Switched-Mode DC-DC Converters, Part I: The Step-Down Topology

Several recent techniques from hybrid and optimal control are evaluated on a power electronics benchmark problem. The benchmark involves a number of practically interesting operating scenarios for a fixed-frequency synchronous step-down dc-dc converter. The specifications are defined such that good performance only can be obtained if the switched and nonlinear nature of the problem is respected during the design phase.</p

In vitro proteasome processing of neo-splicetopes does not predict their presentation in vivo

Proteasome catalyzed peptide splicing (PCPS) of cancer-driving antigens could generate attractive neoepitopes to be targeted by TCR-based adoptive T cell therapy. Based on a spliced peptide prediction algorithm TCRs were generated against putative KRAS(G12V) and RAC2(P29L) derived neo-splicetopes with high HLA-A*02:01 binding affinity. TCRs generated in mice with a diverse human TCR repertoire specifically recognized the respective target peptides with high efficacy. However, we failed to detect any neo-splicetope specific T cell response when testing the in vivo neo-splicetope generation and obtained no experimental evidence that the putative KRAS(G12V)- and RAC2(P29L)-derived neo-splicetopes were naturally processed and presented. Furthermore, only the putative RAC2(P29L)-derived neo-splicetopes was generated by in vitro PCPS. The experiments pose severe questions on the notion that available algorithms or the in vitro PCPS reaction reliably simulate in vivo splicing and argue against the general applicability of an algorithm-driven 'reverse immunology' pipeline for the identification of cancer-specific neo-splicetopes

A Cell-Centred CVD-MPFA Finite Volume Method for Two-Phase Fluid Flow Problems with Capillary Heterogeneity and Discontinuity

A novel finite-volume method is presented for porous media flow simulation that is applicable to discontinuous capillary pressure fields. The method crucially retains the optimal single of freedom per control-volume being developed within the flux-continuous control-volume distributed multi-point flux approximation (CVD-MPFA) framework (Edwards and Rogers in Comput Geosci 02(04):259–290, 1998; Friis et al. in SIAM J Sci Comput 31(02):1192–1220, 2008) . The new methods enable critical subsurface flow processes involving oil and gas trapping to be correctly resolved on structured and unstructured grids. The results demonstrate the ability of the method to resolve flow with oil/gas trapping in the presence of a discontinuous capillary pressure field for diagonal and full-tensor permeability fields. In addition to an upwind approximation for the saturation equation flux, the importance of upwinding on capillary pressure flux via a novel hybrid formulation is demonstrated

Tissue culture of ornamental cacti

Cacti species are plants that are well adapted to growing in arid and semiarid regions where the main problem is water availability. Cacti have developed a series of adaptations to cope with water scarcity, such as reduced leaf surface via morphological modifications including spines, cereous cuticles, extended root systems and stem tissue modifications to increase water storage, and crassulacean acid metabolism to reduce transpiration and water loss. Furthermore, seeds of these plants very often exhibit dormancy, a phenomenon that helps to prevent germination when the availability of water is reduced. In general, cactus species exhibit a low growth rate that makes their rapid propagation difficult. Cacti are much appreciated as ornamental plants due to their great variety and diversity of forms and their beautiful short-life flowers; however, due to difficulties in propagating them rapidly to meet market demand, they are very often over-collected in their natural habitats, which leads to numerous species being threatened, endangered or becoming extinct. Therefore, plant tissue culture techniques may facilitate their propagation over a shorter time period than conventional techniques used for commercial purposes; or may help to recover populations of endangered or threatened species for their re-introduction in the wild; or may also be of value to the preservation and conservation of the genetic resources of this important family. Herein we present the state-of-the-art of tissue culture techniques used for ornamental cacti and selected suggestions for solving a number of the problems faced by members of the Cactaceae family

Online adaptive space vector modulation

In this paper, we present a new modulation method for multilevel three-phase inverters, called online adaptive space vector modulation (oaSVM). The task of a modulator is to reconstruct the desired voltage υ* from the available discrete voltage vectors that correspond to the inverter switch positions. State-of-the-art SVM chooses three voltage vectors that form the closest triangle containing υ*. On the other hand, oaSVM explores every possible triangle that contains υ* and selects the three voltage vectors such that the trade-off between inverter switching losses and load current total harmonic distortion (THD) is improved. Inverter switching constraints and neutral-point voltage balancing are also included. The resulting mixed-integer optimization problem is solved using a branch and bound method. Through MATLAB-simulations, the loss-THD trade-off between SVM and oaSVM will be compared and we show that oaSVM can improve the inverter's efficiency

How to screen for problematic cannabis use in population surveys. An Evaluation of the Cannabis Use Disorders Identification Test (CUDIT) in a Swiss sample of adolescents and young adults

BACKGROUND/AIMS: Cannabis use is a growing challenge for public health, calling for adequate instruments to identify problematic consumption patterns. The Cannabis Use Disorders Identification Test (CUDIT) is a 10-item questionnaire used for screening cannabis abuse and dependency. The present study evaluated that screening instrument. METHODS: In a representative population sample of 5,025 Swiss adolescents and young adults, 593 current cannabis users replied to the CUDIT. Internal consistency was examined by means of Cronbach's alpha and confirmatory factor analysis. In addition, the CUDIT was compared to accepted concepts of problematic cannabis use (e.g. using cannabis and driving). ROC analyses were used to test the CUDIT's discriminative ability and to determine an appropriate cut-off. RESULTS: Two items ('injuries' and 'hours being stoned') had loadings below 0.5 on the unidimensional construct and correlated lower than 0.4 with the total CUDIT score. All concepts of problematic cannabis use were related to CUDIT scores. An ideal cut-off between six and eight points was found. CONCLUSIONS: Although the CUDIT seems to be a promising instrument to identify problematic cannabis use, there is a need to revise some of its items

Online adaptive space vector modulation

In this paper, we present a new modulation method for multilevel three-phase inverters, called online adaptive space vector modulation (oaSVM). The task of a modulator is to reconstruct the desired voltage υ* from the available discrete voltage vectors that correspond to the inverter switch positions. State-of-the-art SVM chooses three voltage vectors that form the closest triangle containing υ*. On the other hand, oaSVM explores every possible triangle that contains υ* and selects the three voltage vectors such that the trade-off between inverter switching losses and load current total harmonic distortion (THD) is improved. Inverter switching constraints and neutral-point voltage balancing are also included. The resulting mixed-integer optimization problem is solved using a branch and bound method. Through MATLAB-simulations, the loss-THD trade-off between SVM and oaSVM will be compared and we show that oaSVM can improve the inverter's efficiency