Box Handling in the Loading and Unloading of Vans

The handling of 2,306 boxes being loaded or unloaded from vans onto or from 4-wheeled trolleys by 31 handlers in a warehouse were characterized. Handling was videotaped and characterized through an analysis grid completed by three trained observers. The following execution parameters were observed: nature of the exertion applied by the upper limbs, plane and direction of the exertion, resulting displacement of the box, grip, use of the lower limbs and the back. Results show that execution parameters used by handlers vary considerably from those usually recommended or studied. For example, symmetric grips were rarely used (4%). The grip was modified during the handling of half the boxes. Significant knee flexion was rarely observed (3% of exertions). Each box was moved by applying an average o f . 3.5 different exertions. Exertions were mostly applied in a plane parallel to the shoulders; they were rarely executed in a strict sagittal plane (11%). The implication of these observations are discussed

Charting the molecular network of the drug target Bcr-Abl

The tyrosine kinase Bcr-Abl causes chronic myeloid leukemia and is the cognate target of tyrosine kinase inhibitors like imatinib. We have charted the protein–protein interaction network of Bcr-Abl by a 2-pronged approach. Using a monoclonal antibody we have first purified endogenous Bcr-Abl protein complexes from the CML K562 cell line and characterized the set of most tightly-associated interactors by MS. Nine interactors were subsequently subjected to tandem affinity purifications/MS analysis to obtain a molecular interaction network of some hundred cellular proteins. The resulting network revealed a high degree of interconnection of 7 “core” components around Bcr-Abl (Grb2, Shc1, Crk-I, c-Cbl, p85, Sts-1, and SHIP-2), and their links to different signaling pathways. Quantitative proteomics analysis showed that tyrosine kinase inhibitors lead to a disruption of this network. Certain components still appear to interact with Bcr-Abl in a phosphotyrosine-independent manner. We propose that Bcr-Abl and other drug targets, rather than being considered as single polypeptides, can be considered as complex protein assemblies that remodel upon drug action

Structure and Dynamics of the HIV‑1 Frameshift Element RNA

The HIV-1 ribosomal frameshift element is highly structured, regulates translation of all virally encoded enzymes, and is a promising therapeutic target. The prior model for this motif contains two helices separated by a three-nucleotide bulge. Modifications to this model were suggested by SHAPE chemical probing of an entire HIV-1 RNA genome. Novel features of the SHAPE-directed model include alternate helical conformations and a larger, more complex structure. These structural elements also support the presence of a secondary frameshift site within the frameshift domain. Here, we use oligonucleotide-directed structure perturbation, probing in the presence of formamide, and in-virion experiments to examine these models. Our data support a model in which the frameshift domain is anchored by a stable helix outside the conventional domain. Less stable helices within the domain can switch from the SHAPE-predicted to the two-helix conformation. Translational frameshifting assays with frameshift domain mutants support a functional role for the interactions predicted by and specific to the SHAPE-directed model. These results reveal that the HIV-1 frameshift domain is a complex, dynamic structure and underscore the importance of analyzing folding in the context of full-length RNAs