CDK9-mediated phosphorylation controls the interaction of TIP60 with the transcriptional machinery.

The acetyltransferase TIP60 is regulated by phosphorylation, and we have previously shown that phosphorylation of TIP60 on S86 by GSK-3 promotes p53-mediated induction of the BCL-2 protein PUMA. TIP60 phosphorylation by GSK-3 requires a priming phosphorylation on S90, and here, we identify CDK9 as a TIP60S90 kinase. We demonstrate that a phosphorylation-deficient mutant, TIP60S90A, exhibits reduced interaction with chromatin, histone 3 and RNA Pol II, while its association with the TIP60 complex subunit EPC1 is not affected. Consistently, we find a diminished association of TIP60S90A with the MYC gene. We show that cells expressing TIP60S90A, but also TIP60S86A, which retains S90 phosphorylation, exhibit reduced histone 4 acetylation and proliferation. Thus, our data indicate that, during transcription, phosphorylation of TIP60 at two sites has different regulatory effects on TIP60, whereby S90 phosphorylation controls association with the transcription machinery, and S86 phosphorylation is regulating TIP60 HAT activity.

Abstraction and simulation of EV battery systems-resilience engineering by biological transformation.

While the demand for electric vehicles (EVs) is continuously growing, safety issues still remain, specifically related to fire hazards. This research aims to improve the resilience of battery systems in EVs by transferring concepts found in biology to a bioinspired battery system. Due to the complexity of modern battery systems, the biological concepts cannot be applied directly. A simplified simulation battery system for EVs is modelled, which contains the essential battery components necessary to understand both, software and battery dynamics. This is used as a baseline model to study the effects of typical heat-related disturbances. Subsequently, this simulation model is modified to demonstrate the transfer of biological concepts underlying specifically the hypersensitization and vasospasm mechanisms related to wound healing, and to test the effects of disturbances and alterations comparable to damages caused by vehicle accidents. As a battery system's mass and volume should not be increased by additional hardware, the biological concepts target the interaction within, and the composition of, the system, while leaving single components relatively unchanged. It is found that small bioinspired alterations to the battery system can have significant impacts on their vulnerability to common hazards.

Biological transformation-battery protection inspired by wound healing.

One of the major challenges for electric vehicle safety and mobility is the development of battery protection mechanisms that are able to cope with irregular and unpredictable heating of the battery unit. Biological protection mechanisms are considered to be one of the most effective and resilient mechanisms due to their ability to react dynamically and adaptively to unpredictable disturbances. Consequently, biological systems can be viewed as models for high resiliency that provide inspiration for tackling issues such as excessive resource consumption or low technical resilience. This study demonstrates the improvement of the safety of an electric vehicle battery system inspired by wound healing and pain reflex response, which are among the most important protective mechanisms of the human body system. In particular, the individual mechanisms are systematically characterized, their underlying principles identified and transferred to a simulated battery system using a novel attribute-based method. As a result, the detection of irregular heating is improved and cooling of the battery system is more efficient. Further, this example can be used to explain how protective mechanisms that contribute to the resilience of biological systems can be abstracted and transferred to different technical systems.

Preclinical Testing Oncolytic Vaccinia Virus Strain GLV-5b451 Expressing an Anti-VEGF Single-Chain Antibody for Canine Cancer Therapy.

Virotherapy on the basis of oncolytic vaccinia virus (VACV) strains is a novel approach for canine cancer therapy. Here we describe, for the first time, the characterization and the use of VACV strain GLV-5b451 expressing the anti-vascular endothelial growth factor (VEGF) single-chain antibody (scAb) GLAF-2 as therapeutic agent against different canine cancers. Cell culture data demonstrated that GLV-5b451 efficiently infected and destroyed all four tested canine cancer cell lines including: mammary carcinoma (MTH52c), mammary adenoma (ZMTH3), prostate carcinoma (CT1258), and soft tissue sarcoma (STSA-1). The GLV-5b451 virus-mediated production of GLAF-2 antibody was observed in all four cancer cell lines. In addition, this antibody specifically recognized canine VEGF. Finally, in canine soft tissue sarcoma (CSTS) xenografted mice, a single systemic administration of GLV-5b451 was found to be safe and led to anti-tumor effects resulting in the significant reduction and substantial long-term inhibition of tumor growth. A CD31-based immuno-staining showed significantly decreased neo-angiogenesis in GLV-5b451-treated tumors compared to the controls. In summary, these findings indicate that GLV-5b451 has potential for use as a therapeutic agent in the treatment of CSTS.