The human cytomegalovirus-encoded G protein- coupled receptor UL33 exhibits oncomodulatory properties

Herpesviruses can rewire cellular signaling in host cells by expressing viral G protein- coupled receptors (GPCRs). These viral receptors exhibit homology to human chemokine receptors, but some display constitutive activity and promiscuous G protein coupling. Human cytomegalovirus (HCMV) has been detected in multiple cancers, including glioblastoma, and its genome encodes four GPCRs. One of these receptors, US28, is expressed in glioblastoma and possesses constitutive activity and oncomodulatory properties. UL33, another HCMV-encoded GPCR, also displays constitutive signaling via Gαq, Gαi, and Gαs proteins. However, little is known about the nature and functional effects of UL33-driven signaling. Here, we assessed UL33's signaling repertoire and oncomodulatory potential. UL33 activated multiple proliferative, angiogenic, and inflammatory signaling pathways in HEK293T and U251 glioblastoma cells. Notably, upon infection, UL33 contributed to HCMV-mediated STAT3 activation. Moreover, UL33 increased spheroid growth in vitro and accelerated tumor growth in different in vivo tumor models, including an orthotopic glioblastoma xenograft model. UL33-mediated signaling was similar to that stimulated by US28; however, UL33-induced tumor growth was delayed. Additionally, the spatiotemporal expression of the two receptors only partially overlapped in HCMV-infected glioblastoma cells. In conclusion, our results unveil that UL33 has broad signaling capacity and provide mechanistic insight into its functional effects. UL33, like US28, exhibits oncomodulatory properties, elicited via constitutive activation of multiple signaling pathways. UL33 and US28 might contribute to HCMV's oncomodulatory effects through complementing and converging cellular signaling, and hence UL33 may represent a promising drug target in HCMV-associated malignancies

NEXT: Generating tailored ERP applications from ontological enterprise models

Tailoring Enterprise Resource Planning (ERP) software to the needs of the enterprise still is a technical endeavor, often requiring the (de)activation of modules, modification of configuration files or even execution of database queries. Considering the large body of work on Enterprise Modeling and Model-Driven Software Engineering, this is remarkable: Ideally, one models one’s own enterprise and, at the press of a button, ERP software tailored to the needs of the modeled enterprise is generated. In this paper, we introduce NEXT, a novel model-driven software generation approach being developed with precisely this goal in mind. It uses the expressive power of ontological enterprise models (OEMs) to generate ERP cloud applications. An OEM only describes the real-world phenomena essential to the enterprise, using terms and customizations specific to the enterprise. We present our considerations during development of the OEM modeling language, which is designed to capture the specifics of enterprise phenomena in a way that technical details can be derived from it. We expect NEXT to drastically shorten the time-to-market of ERP software, from months–years to hours–days

Functional disparities among BCL-2 members in tonsillar and leukemic B-cell subsets assessed by BH3-mimetic profiling

For successful treatment of malignant B-cells it is crucial to understand intrinsic survival requirements in relation to their normal progenitors. Long-lived humoral immunity as well as most B-cell malignancies, originate in the germinal center (GC). Murine GC B-cells depend on pro-survival protein MCL-1, but not BCL-XL. In contrast, naive and memory B-cells depend on BCL-2, but not BCL-XL or MCL-1. For human B-cell subsets, the functional relationships among BCL-2 members are unclear, and also if and how they shift after malignant transformation. We here dissect these aspects in human tonsil and primary leukemia (CLL) cells by single and combined treatment with novel, highly specific BH3-mimetics. We found that MCL-1 expression in GC B-cells is regulated post-translationally and its importance is highlighted by preferential binding to pro-apoptotic BIM. In contrast, BCL-XL is transcriptionally induced and binds solely to weak sensitizer BIK, potentially explaining why BCL-XL is not required for GC B-cell survival. Using novel BH3-mimetics, we found that naive and memory B-cells depend on BCL-2, GC cells predominantly on MCL-1, whereas plasma cells need both BCL-XL and MCL-1 for survival. CLL cells switch from highly sensitive for BCL-2 inhibition to resistant after CD40-stimulation. However, combined inhibition of BCL-2, plus BCL-XL or MCL-1 effectively kills these cells, thus exposing a weakness that may be therapeutically useful. These general principles offer important clues for designing treatment strategies for B-cell malignancie

Higher order cycling skills among 11 to 13-year-old cyclists and relationships with cycling experience, risky behaviour, crashes and self-assessed skill

Introduction In the Netherlands, young cyclists are extremely vulnerable in traffic, which may partly be due to their still under-developed higher order cycling skill. So far, knowledge on their actual level of skill is lacking. Using a computerized test battery mimicking real life risky traffic conditions, this study assessed the level of higher order cycling skill in children 11 and 12 years of age and tested the hypothesis that these skills show caveats. Furthermore, factors potentially influencing the development and impact of these skills were studied, such as cycling experience, risky road behaviour, crash involvement, and self-assessed skill. Method A total of 335 students (49% female) completed computerized tests on hazard perception, gap acceptance, blind spot strategies, and priority decisions in traffic, and completed questionnaires on cycling experience, risky cycling behaviour, crashes, and self-assessment of cycling skill. Results On the hazard perception test, a third of the participants missed at least half of the number of hazards. They made errors in about 50% of the priority decisions, accepted critical gaps when crossing the road, and conversely rejected safe gaps, only 1% of the participants identified all blind spots of a truck correctly, while 69% made unsafe decisions when interacting with trucks in traffic scenarios. Overall, in complex traffic situations performance was worse than in simple ones. The hypothesis of lack of skills was therefore accepted. However, the study failed to demonstrate consistent relationships between subtest performance and cycling experience, risky behaviour, crashes, and self-assessed skill, which weakens the theoretical assumptions concerning the subtests. Conclusions The results suggest that children at the end of primary school are still lacking elementary skills for safe cycling, calling for measures to accelerate skill development. Practical Applications Test batteries are essential tools for systematically monitoring skill development in cyclists, evaluating education programmes, and for guiding the development of effective road safety education. The next step is the validation of such batteries

Combined ibrutinib and venetoclax treatment vs single agents in the TCL1 mouse model of chronic lymphocytic leukemia

The covalent inhibitor of Bruton’s tyrosine kinase ibrutinib and the specific Bcl-2 inhibitor venetoclax are both highly efficacious single-agent drugs in the treatment of chronic lymphocytic leukemia (CLL). Based on their complementary modes of action, ibrutinib and venetoclax are hypothesized to act in a synergistic fashion. Currently, it is unclear whether combined treatment is indeed superior to continuous single-agent treatment and what mechanisms underlie the resistance to combination treatment. In addition, the effects of such treatment on the skewed T-cell compartment characteristic of CLL are as yet unknown. In the murine Em-TCL1 adoptive transfer model resembling aggressive CLL, we found that combined treatment resulted in the deepest responses, with the longest duration related to a combination of decreased proliferation and increased induction of apoptosis. In addition, alterations in T-cell subsets were most prominent after combination treatment, with increased naive cells and reduced effector memory cells. Remarkably, effects of single agents but also combination treatment were eventually interrupted by relapse, and we found downregulation of BIM expression as a plausible cause of acquired drug resistance. Nevertheless, in this murine model, the combination of venetoclax and ibrutinib has increased efficacy over single agents, accompanied by a restoration of the T-cell compartment

NEXT: Generating Tailored ERP Applications from Ontological Enterprise Models

Part 1: Regular PapersInternational audienceTailoring Enterprise Resource Planning (ERP) software to the needs of the enterprise still is a technical endeavor, often requiring the (de)activation of modules, modification of configuration files or even execution of database queries. Considering the large body of work on Enterprise Modeling and Model-Driven Software Engineering, this is remarkable: Ideally, one models one’s own enterprise and, at the press of a button, ERP software tailored to the needs of the modeled enterprise is generated. In this paper, we introduce NEXT, a novel model-driven software generation approach being developed with precisely this goal in mind. It uses the expressive power of ontological enterprise models (OEMs) to generate ERP cloud applications. An OEM only describes the real-world phenomena essential to the enterprise, using terms and customizations specific to the enterprise. We present our considerations during development of the OEM modeling language, which is designed to capture the specifics of enterprise phenomena in a way that technical details can be derived from it. We expect NEXT to drastically shorten the time-to-market of ERP software, from months–years to hours–days