How close to a pendulum is human upper limb movement during walking?

The aim of this work was to investigate how close to pendulum-like behaviour the periodic motion of the human upper limb (or upper extremity) is, during normal walking at a comfortable speed of locomotion. Twenty-five healthy young persons (males and females) participated in the experiment. Biomechanical testing was undertaken (mass and centre of mass of each segment of the total upper extremity). Participants were walking on a treadmill with a standardised velocity of 1.1 ms(-1) (comfortable speed for all of them). A video analysis system with Silicon software was used to measure the different angles of the arm and forearm. The theoretical period of motion and maximal angular velocity were computed for the centre of mass of the total upper limb from the measured phases of the arm swing and associated positional potential energies. Actual measured periods of motion, in comparison, represented a level of similarity to a lightly damped simple pendulum. Using this assumption, the "damping factor" was calculated from the ratio between theoretical and measured values. A vast majority of people exhibited an actual angular velocity exceeding the expected theoretical angular velocity calculated for a virtual pendulum of similar mass and length characteristics. This may be due to muscle forces that are contributing to the motion of the upper limb during walking rather than simple gravity force acting alone. The observed positional potential energy of the dominant limb was greater than that of the non-dominant limb for the vast majority of participants.

Fe65 and X11beta co-localize with and compete for binding to the amyloid precursor protein.

The Fe65s and X11s are two families of adaptor proteins that bind to the Alzheimer's disease amyloid precursor protein (APP). Although both the X11s and Fe65s bind to similar regions of APP, they have opposing effects on Abeta production and hence may represent novel therapeutic targets. However, there is no evidence that the Fe65s and X11s are present within the same cell type or cell compartment and are thus capable of competing for binding to APP. Here we show that in neurones and transfected cells, APP, Fe65 and X11beta show overlapping subcellular distributions. Furthermore, we demonstrate that Fe65 and X11beta compete for binding to APP.

X11 alpha and x11 beta interact with presenilin-1 via their PDZ domains.

X11 alpha and X11 beta are two neuronal adaptor proteins that interact with the Alzheimer's disease amyloid precursor protein (APP). X11 alpha and X11 beta stabilise APP and inhibit production of proteolytic APP fragments including the A beta peptide that is deposited in the brains of Alzheimer's disease patients. The mechanisms by which X11 alpha and X11 beta modulate APP processing are not clear but one possibility is that they influence the activity of the secretases that cleave APP to give rise to A beta. Presenilin-1 is required for gamma-secretase activity and here we demonstrate that both X11 alpha and X11 beta interact with presenilin-1. X11/presenilin-1 binding is via two X11 PDZ domains and sequences within the carboxy-terminus of presenilin-1. We also demonstrate that both X11 alpha and X11 beta mediate the formation of complexes between APP and presenilin-1. These results suggest that the X11 regulation of APP processing is controlled, at least in part, via their interactions with APP and presenilin-1.

Phosphorylation of thr(668) in the cytoplasmic domain of the Alzheimer's disease amyloid precursor protein by stress-activated protein kinase 1b (Jun N-terminal kinase-3).

Threonine(668) (thr(668)) within the carboxy-terminus of the Alzheimer's disease amyloid precursor protein (APP) is a known in vivo phosphorylation site. Phosphorylation of APPthr(668) is believed to regulate APP function and metabolism. Thr(668) precedes a proline, which suggests that it is targeted for phosphorylation by proline-directed kinase(s). We have investigated the ability of four major neuronally active proline-directed kinases, cyclin dependent protein kinase-5, glycogen synthase kinase-3 beta, p42 mitogen-activated protein kinase and stress-activated protein kinase-1b, to phosphorylate APPthr(668) and report here that SAPK1b induces robust phosphorylation of this site both in vitro and in vivo. This finding provides a molecular framework to link cellular stresses with APP metabolism in both normal and disease states.

The neuronal adaptor protein X11alpha interacts with the copper chaperone for SOD1 and regulates SOD1 activity.

The neuronal adaptor protein X11alpha participates in the formation of multiprotein complexes and intracellular trafficking. It contains a series of discrete protein-protein interaction domains including two contiguous C-terminal PDZ domains. We used the yeast two-hybrid system to screen for proteins that interact with the PDZ domains of human X11alpha, and we isolated a clone encoding domains II and III of the copper chaperone for Cu,Zn-superoxide dismutase-1 (CCS). The X11alpha/CCS interaction was confirmed in coimmunoprecipitation studies plus glutathione S-transferase fusion protein pull-down assays and was shown to be mediated via PDZ2 of X11alpha and a sequence within the carboxyl terminus of domain III of CCS. CCS delivers the copper cofactor to the antioxidant superoxide dismutase-1 (SOD1) enzyme and is required for its activity. Overexpression of X11alpha inhibited SOD1 activity in transfected Chinese hamster ovary cells which suggests that X11alpha binding to CCS is inhibitory to SOD1 activation. X11alpha also interacts with another copper-binding protein found in neurons, the Alzheimer's disease amyloid precursor protein. Thus, X11alpha may participate in copper homeostasis within neurons.