Sensing of endogenous nucleic acids by ZBP1 induces keratinocyte necroptosis and skin inflammation

Aberrant detection of endogenous nucleic acids by the immune system can cause inflammatory disease. The scaffold function of the signaling kinase RIPK1 limits spontaneous activation of the nucleic acid sensor ZBP1. Consequently, loss of RIPK1 in keratinocytes induces ZBP1-dependent necroptosis and skin inflammation. Whether nucleic acid sensing is required to activate ZBP1 in RIPK1-deficient conditions and which immune pathways are associated with skin disease remained open questions. Using knock-in mice with disrupted ZBP1 nucleic acid–binding activity, we report that sensing of endogenous nucleic acids by ZBP1 is critical in driving skin pathology characterized by antiviral and IL-17 immune responses. Inducing ZBP1 expression by interferons triggers necroptosis in RIPK1-deficient keratinocytes, and epidermis-specific deletion of MLKL prevents disease, demonstrating that cell-intrinsic events cause inflammation. These findings indicate that dysregulated sensing of endogenous nucleic acid by ZBP1 can drive inflammation and may contribute to the pathogenesis of IL-17–driven inflammatory skin conditions such as psoriasis

Oncolytic virus-induced cell death and immunity: a match made in heaven?

Our understanding of the mechanisms responsible for cancer development has increased enormously over the last decades. However, for many cancers, this has not been translated into a significant improvement in overall survival, and overall mortality remains high. Treatment for many malignancies remains based on surgery, chemotherapy, and radiotherapy. Significant progress has been made toward the development of more specific, more potent, and less invasive treatment modalities, but such targeted therapies remain the exception for most cancers. Thus, cancer therapies based on a different mechanism of action should be explored. The immune system plays an important role in keeping tumor growth at bay. However, in many cases, these responses are not strong enough to keep tumor growth under control. Thus, immunotherapy aims to boost the immune system to suppress tumor growth efficiently. This has been demonstrated by the recent successes of immune checkpoint therapy in several cancers. Oncolytic viruses (OVs) are another exciting class of immunotherapy agent. As well as replicating selectively within and killing tumor cells, OVs are able to elicit potent anti-tumor immune responses. Therapeutic vaccination with OVs, also referred to as cancer virotherapy, can thus be tailored to elicit vigorous cellular immune responses and even target individual malignancies in a personalized manner. In this review, we will describe the intricate link among oncolytic virotherapy, tumor immunology, and immunogenic cell death (ICD) and discuss ways to harness optimally their potential for future cancer therapy

Characterization of the Bond between Textile Reinforced Cement and Extruded Polystyrene by Shear Tests

Loadbearing sandwich panels used as wall elements are a promising development since they combine structural and energy efficiency. Composite behaviour needs to be ensured so that the sandwich panel works as one element under a flexural load (meaning that the shear forces due to bending are transferred from one face to the other). To assure this full composite behaviour, an investigation of the bond strength between the faces and the core of the sandwich panel is necessary. Therefore, two different bond test set-ups were performed on sandwich panels with Textile Reinforced Cement (TRC) faces and an Extruded Polystyrene (XPS) insulating foam core. The two bond test set-ups were compared and revealed that one of the set-ups showed a combination of bond and shear failure of the core so that a clear conclusion on the bond strength couldn’t be obtained. The second set-up showed clear bond failure and gave a good estimation of the bond strength between TRC and XPS

Repeated Loading of Cement Composite Sandwich Beams

Using large lightweight prefabricated sandwich panels offers great possibilities for the renovation of existing dwellings. By facilitating the installation process it reduces the total renovation time to a couple of days. During their life-time, these panels will be subjected to wind loading, equivalent to a repeated loading. The effect of this loading condition on the structural behavior of the sandwich panels was verified experimentally. Four-point bending tests were conducted, both static and cyclic. Results showed that the subjection to different loading-unloading cycles resulted in a residual deformation and a decreased stiffness. After being subjected to a repeated loading, the residual ultimate capacity was lowered with 30%

Fatigue Behaviour of Textile Reinforced Cementitious Composites and Their Application in Sandwich Elements

Using large lightweight insulating sandwich panels with cement composite faces offers great possibilities for the renovation of existing dwellings. During their lifetime, these panels are subjected to wind loading, which is equivalent to a repeated loading. To guarantee the structural performance of these panels during their entire lifetime, it is necessary to quantify the impact of these loading conditions on the long term. The fatigue behaviour was, therefore, examined in this paper both at the material level of the faces and at the element level as well. plain textile reinforced cementitious composite (TRC) specimens were subjected to 100,000 loading cycles by means of a uniaxial tensile test, while sandwich beams were loaded 100.000 times with a four-point bending test. Results show that the residual behaviour is strongly dependent on the occurrence of cracks. The formation of cracks leads to a reduction of the initial stiffness. The ultimate strength is only affected in a minor way by the preloading history

Thermomechanical Behavior of Textile Reinforced Cementitious Composites Subjected to Fire

The mechanical behavior of textile reinforced cementitious composites (TRC) has been a topic of wide investigation during the past 30 years. However, most of the investigation is focused on the behavior under ambient temperatures, while only a few studies about the behavior under high temperatures have been conducted thus far. This paper focused on the thermomechanical behavior of TRC after exposure to fire and the residual capacity was examined. The parameters that were considered were the fiber material, the thickness of the concrete cover, the moisture content and the temperature of exposure. The specimens were exposed to fire only from one side and the residual strength was measured by means of flexural capacity. The results showed that the critical factor that affects the residual strength was the coating of the textiles and the law of the coating mass loss with respect to temperature. The effect of the other parameters was not quantified. The degradation of the compressive strength of TRC was quantified with respect to temperature. It was also concluded that a highly asymmetrical design scheme might lead to premature failure

Validation of a Numerical Bending Model for Sandwich Beams with Textile-Reinforced Cement Faces by Means of Digital Image Correlation

Sandwich panels with textile-reinforced cement (TRC) faces merge both structural and insulating performance into one lightweight construction element. To design with sandwich panels, predictive numerical models need to be thoroughly validated, in order to use them with high confidence and reliability. Numerical bending models established in literature have been validated by means of local displacement measurements, but are missing a full surface strain validation. Therefore, four-point bending tests monitored by a digital image correlation system were compared with a numerical bending model, leading to a thorough validation of that numerical model. Monitoring with a digital image correlation (DIC) system gave a highly detailed image of behaviour during bending and the strains in the different materials of the sandwich panel. The measured strains validated the numerical model predictions of, amongst others, the multiple cracking of the TRC tensile face and the shear deformation of the core

Oncolytic Herpes Simplex Virus Type 1 Induces Immunogenic Cell Death Resulting in Maturation of BDCA-1+ Myeloid Dendritic Cells

Recently, a paradigm shift has been established for oncolytic viruses (OVs) as it was shown that the immune system plays an important role in the specific killing of tumor cells by OVs. OVs have the intrinsic capacity to provide the right signals to trigger anti-tumor immune responses, on the one hand by delivering virus-derived innate signals and on the other hand by inducing immunogenic cell death (ICD), which is accompanied by the release of various damage-associated molecules from infected tumor cells. Here, we determined the ICD-inducing capacity of Talimogene laherparepvec (T-VEC), a herpes simplex virus type 1 based OV, and benchmarked this to other previously described ICD (e.g., doxorubicin) and non-ICD inducing agents (cisplatin). Furthermore, we studied the capability of T-VEC to induce the maturation of human BDCA-1+ myeloid dendritic cells (myDCs). We found that T-VEC treatment exerts direct and indirect anti-tumor effects as it induces tumor cell death that coincides with the release of hallmark mediators of ICD, while simultaneously contributing to the maturation of BDCA-1+ myDCs. These results unequivocally cement OVs in the category of cancer immunotherapy