Developmental partitioning of SYK and ZAP70 prevents autoimmunity and cancer

Even though SYK and ZAP70 kinases share high sequence homology and serve analogous functions, their expression in B and T cells is strictly segregated throughout evolution. Here, we identified aberrant ZAP70 expression as a common feature in a broad range of B cell malignancies. We validated SYK as the kinase that sets the thresholds for negative selection of autoreactive and premalignant clones. When aberrantly expressed in B cells, ZAP70 competes with SYK at the BCR signalosome and redirects SYK from negative selection to tonic PI3K signaling, thereby promoting B cell survival. In genetic mouse models for B-ALL and B-CLL, conditional expression of Zap70 accelerated disease onset, while genetic deletion impaired malignant transformation. Inducible activation of Zap70 during B cell development compromised negative selection of autoreactive B cells, resulting in pervasive autoantibody production. Strict segregation of the two kinases is critical for normal B cell selection and represents a central safeguard against the development of autoimmune disease and B cell malignancies.acceptedVersionPeer reviewe

Perception of Autonomy and the Role of Experience within the Maritime Industry

The seafaring occupation will soon evolve as human operators transition to a more supervisory role for autonomous systems onboard. Therefore, gaining a greater understanding of the mindset that officers have towards the world of autonomy will aid the maritime industry by developing a baseline for future navigational training. This paper examines the perceptions and attitudes of 100 navigational seafaring participants of varying navigational ranks and levels of seagoing experience. The aim of the study was to identify the perceptions and self-conscious trust that current seafarers have towards automated and future autonomous systems. Participants were issued a situational judgement test comprising of three questions, allowing them to assess and respond to a hazardous scenario. The results of the study found that seafarers are receptive towards the introduction of autonomous shipping. Furthermore, the participants showed an awareness of what autonomous shipping would mean for the maritime industry. However, concerns remain about the responsibility and safety of the vessel in the event of the introduction of an unmanned vessel. Moreover, when comparing opinions and trust levels among the cohort of ranks, it was found that participants of a higher rank had a similar outlook towards autonomy to that of the less experienced groups

BioSITe: A Method for Direct Detection and Quantitation of Site-Specific Biotinylation

Biotin-based labeling strategies are widely employed to study protein-protein interactions, subcellular proteomes and post-translational modifications, as well as, used in drug discovery. While the high affinity of streptavidin for biotin greatly facilitates the capture of biotinylated proteins, it still presents a challenge, as currently employed, for the recovery of biotinylated peptides. Here we describe a strategy designated Biotinylation Site Identification Technology (BioSITe) for the capture of biotinylated peptides for LC–MS/MS analyses. We demonstrate the utility of BioSITe when applied to proximity-dependent labeling methods, APEX and BioID, as well as biotin-based click chemistry strategies for identifying O-GlcNAc-modified sites. We demonstrate the use of isotopically labeled biotin for quantitative BioSITe experiments that simplify differential interactome analysis and obviate the need for metabolic labeling strategies such as SILAC. Our data also highlight the potential value of site-specific biotinylation in providing spatial and topological information about proteins and protein complexes. Overall, we anticipate that BioSITe will replace the conventional methods in studies where detection of biotinylation sites is important