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Event-driven figure-ground organisation model for the humanoid robot iCub
A distributed task allocation approach for multi-UAV persistent monitoring in dynamic environments
EccDNA atlas in male mice reveals features protecting genes against transcription-induced eccDNA formation
Body mass index and head circumference growth charts for the United Arab Emirates-the UAEMCGS 2 study
Phage parasites targeting phage homologous recombinases provide antiviral immunity
Abstract Bacteria often carry multiple genes encoding anti-phage defense systems, clustered in defense islands and phage satellites. Various unrelated anti-phage defense systems target phage-encoded homologous recombinases (HRs) through unclear mechanisms. Here, we show that the phage satellite SaPI2, which does not encode orthodox anti-phage defense systems, provides antiviral immunity mediated by Stl2, the SaPI2-encoded transcriptional repressor. Stl2 targets and inhibits phage-encoded HRs, including Sak and Sak4, two HRs from the Rad52-like and Rad51-like superfamilies. Remarkably, apo Stl2 forms a collar of dimers oligomerizing as closed rings and as filaments, mimicking the quaternary structure of its targets. Stl2 decorates both Sak rings and Sak4 filaments. The oligomerization of Stl2 as a collar of dimers is necessary for its inhibitory activity both in vitro and in vivo. Our results shed light on the mechanisms underlying antiviral immunity against phages carrying divergent HRs.
Association between adverse childhood experiences with chronic kidney diseases in middle-aged and older adults in mainland China
Activation of CAMK2 by pseudokinase PEAK1 represents a targetable pathway in triple negative breast cancer
Abstract The PEAK family of pseudokinases, comprising PEAK1-3, play oncogenic roles in several poor prognosis human cancers, including triple negative breast cancer (TNBC). However, therapeutic targeting of pseudokinases is challenging due to their lack of catalytic activity. To address this, we screen for PEAK1 effectors and identify calcium/calmodulin-dependent protein kinase 2 (CAMK2)D and CAMK2G. PEAK1 promotes CAMK2 activation in TNBC cells via PLCγ1/Ca 2+ signalling and direct binding to CAMK2. In turn, CAMK2 phosphorylates PEAK1 to enhance association with PEAK2, which is critical for PEAK1 oncogenic signalling. To achieve pharmacologic targeting of PEAK1/CAMK2, we repurpose RA306, a second generation CAMK2 inhibitor. RA306 inhibits PEAK1-enhanced migration and invasion of TNBC cells in vitro and significantly attenuates TNBC xenograft growth and metastasis in a manner mirrored by PEAK1 ablation. Overall, these studies establish PEAK1 as a critical cell signalling nexus that integrates Ca 2+ and tyrosine kinase signals and identify CAMK2 as a therapeutically ‘actionable’ target downstream of PEAK1.