Leukemia-Associated Mutations in Nucleophosmin Alter Recognition by CRM1: Molecular Basis of Aberrant Transport

Nucleophosmin (NPM) is a nucleocytoplasmic shuttling protein, normally enriched in nucleoli, that performs several activities related to cell growth. NPM mutations are characteristic of a subtype of acute myeloid leukemia (AML), where mutant NPM seems to play an oncogenic role. AML-associated NPM mutants exhibit altered subcellular traffic, being aberrantly located in the cytoplasm of leukoblasts. Exacerbated export of AML variants of NPM is mediated by the nuclear export receptor CRM1, and due, in part, to a mutationally acquired novel nuclear export signal (NES). To gain insight on the molecular basis of NPM transport in physiological and pathological conditions, we have evaluated the export efficiency of NPM in cells, and present new data indicating that, in normal conditions, wild type NPM is weakly exported by CRM1. On the other hand, we have found that AML-associated NPM mutants efficiently form complexes with CRM1HA (a mutant CRM1 with higher affinity for NESs), and we have quantitatively analyzed CRM1HA interaction with the NES motifs of these mutants, using fluorescence anisotropy and isothermal titration calorimetry. We have observed that the affinity of CRM1HA for these NESs is similar, which may help to explain the transport properties of the mutants. We also describe NPM recognition by the import machinery. Our combined cellular and biophysical studies shed further light on the determinants of NPM traffic, and how it is dramatically altered by AML-related mutations.

Dealing with the Effects of Sensor Displacement in Wearable Activity Recognition

Most wearable activity recognition systems assume a predefined sensor deployment that remains unchanged during runtime. However, this assumption does not reflect real-life conditions. During the normal use of such systems, users may place the sensors in a position different from the predefined sensor placement. Also, sensors may move from their original location to a different one, due to a loose attachment. Activity recognition systems trained on activity patterns characteristic of a given sensor deployment may likely fail due to sensor displacements. In this work, we innovatively explore the effects of sensor displacement induced by both the intentional misplacement of sensors and self-placement by the user. The effects of sensor displacement are analyzed for standard activity recognition techniques, as well as for an alternate robust sensor fusion method proposed in a previous work. While classical recognition models show little tolerance to sensor displacement, the proposed method is proven to have notable capabilities to assimilate the changes introduced in the sensor position due to self-placement and provides considerable improvements for large misplacements.