TAK1 kinase switches cell fate from apoptosis to necrosis following TNF stimulation

TNF activates three distinct intracellular signaling cascades leading to cell survival, caspase-8–mediated apoptosis, or receptor interacting protein kinase 3 (RIPK3)–dependent necrosis, also called necroptosis. Depending on the cellular context, one of these pathways is activated upon TNF challenge. When caspase-8 is activated, it drives the apoptosis cascade and blocks RIPK3-dependent necrosis. Here we report the biological event switching to activate necrosis over apoptosis. TAK1 kinase is normally transiently activated upon TNF stimulation. We found that prolonged and hyperactivation of TAK1 induced phosphorylation and activation of RIPK3, leading to necrosis without caspase activation. In addition, we also demonstrated that activation of RIPK1 and RIPK3 promoted TAK1 activation, suggesting a positive feedforward loop of RIPK1, RIPK3, and TAK1. Conversely, ablation of TAK1 caused caspase-dependent apoptosis, in which Ripk3 deletion did not block cell death either in vivo or in vitro. Our results reveal that TAK1 activation drives RIPK3-dependent necrosis and inhibits apoptosis. TAK1 acts as a switch between apoptosis and necrosis.     

Skill-Specific Changes in Somatosensory Nogo Potentials in Baseball Players

Athletic training is known to induce neuroplastic alterations in specific somatosensory circuits, which are reflected by changes in somatosensory evoked potentials and event-related potentials. The aim of this study was to clarify whether specific athletic training also affects somatosensory Nogo potentials related to the inhibition of movements. The Nogo potentials were recorded at nine cortical electrode positions (Fz, Cz, Pz, F3, F4, C3, C4, P3 and P4) in 12 baseball players (baseball group) and in 12 athletes in sports, such as track and field events and swimming, that do not require response inhibition, such as batting for training or performance (sports group). The Nogo potentials and Go/Nogo reaction times (Go/Nogo RTs) were measured under a somatosensory Go/Nogo paradigm in which subjects were instructed to rapidly push a button in response to stimulus presentation. The Nogo potentials were obtained by subtracting the Go trial from the Nogo trial. The peak Nogo-N2 was significantly shorter in the baseball group than that in the sports group. In addition, the amplitude of Nogo-N2 in the frontal area was significantly larger in the baseball group than that in the sports group. There was a significant positive correlation between the latency of Nogo-N2 and Go/Nogo RT. Moreover, there were significant correlations between the Go/Nogo RT and both the amplitude of Nogo-N2 and Nogo-P3 (i.e., amplitude of the Nogo-potentials increases with shorter RT). Specific athletic training regimens may induce neuroplastic alterations in sensorimotor inhibitory processes.     

Generation of a purely clonal defective interfering influenza virus

Defective interfering (DI) influenza viruses carry a large deletion in a gene segment that interferes with the replication of infectious virus; thus, such viruses have potential for antiviral therapy. However, because DI viruses cannot replicate autonomously without the aid of an infectious helper virus, clonal DI virus stocks that are not contaminated with helper virus have not yet been generated. To overcome this problem, we used reverse genetics to generate a clonal DI virus with a PB2 DI gene, amplified the clonal DI virus using a cell line stably expressing the PB2 protein, and confirmed its ability to interfere with infectious virus replication in vitro. Thus, our approach is suitable for obtaining purely clonal DI viruses, will contribute to the understanding of DI virus interference mechanisms and can be used to develop DI virus‐based antivirals.     

Three types of mouse peptidylarginine deiminase: characterization and tissue distribution.

Three types of mouse peptidylarginine deiminase were separated by DEAE-Sephacel ion-exchange column chromatography, and we propose designating them peptidylarginine deiminase type I, II, and III according to the order of elution. The type II enzyme was widely distributed in various tissues including the skeletal muscle, whereas the type I enzyme was localized in the epidermis and uterus, and the type III enzyme was detected in the epidermis and hair follicles. These enzymes were distinguished by their molecular weights and substrate specificity. The molecular weights were estimated to be approximately 54,000 (type I) and 100,000 (type II and III) by Sephacryl S-200 gel filtration column chromatography. On SDS-PAGE the type II and III enzymes gave Mr = 81,000 and Mr = 76,000, respectively. Among the substrates tested, the type I enzyme showed highest activity toward BZ-L-Arg-NH2, type II toward BZ-L-Arg-O-Et, and type III toward protamine. Western blot analysis showed that antibodies against the type II enzyme were immuno-crossreactive to the type III enzyme.     

Human Pluripotent Stem Cell-Derived Tumor Model Uncovers the Embryonic Stem Cell Signature as a Key Driver in Atypical Teratoid/Rhabdoid Tumor

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