Developing a systems and informatics based approach to lifestyle monitoring within eHealth:part I - technology and data management

Lifestyle monitoring forms a subset of telecare in which data derived from sensors located in the home is used to identify variations in behaviour which are indicative of a change in care needs. Key to this is the performance of the sensors themselves and the way in which the information from multiple sources is integrated within the decision making process. The paper therefore considers the functions of the key sensors currently deployed and places their operation within the context of a proposed multi-level system structure which takes due cognisance of the requisite informatics framework

N<i>e</i>XOS – the design, development and evaluation of a rehabilitation system for the lower limbs

Recent years have seen the development of a number of automated and semi-automated systems to support for physiotherapy and rehabilitation. These deploy a range of technologies from highly complex purpose built systems to approaches based around the use of industrial robots operating either individually or in combination for applications ranging from stroke to mobility enhancement. The NeXOS project set out to investigate an approach to the rehabilitation of the lower limbs in a way which brought together expertise in engineering design and mechatronics with specilists in rehabilitation and physiotherapy. The resulting system has resulted in a prototype of a system which is capable in operating in a number of modes from fully independent to providing direct support to a physiotherapist during manipulation of the limb. Designed around a low cost approach for an implementation ultimately capable of use in a patients home using web-baased strategies for communication with their support team, the prototype NeXOS system has validated the adoption of an integrated approach to its development. The paper considers this design and development process and provides the results from the initial tests with physiotherapists to establish the operational basis for clinical implementation

Phosphorylation by Akt within the ST loop of AMPK-α1 down-regulates its activation in tumour cells

The insulin/IGF-1 (insulin-like growth factor 1)-activated protein kinase Akt (also known as protein kinase B) phosphorylates Ser(487) in the ‘ST loop’ (serine/threonine-rich loop) within the C-terminal domain of AMPK-α1 (AMP-activated protein kinase-α1), leading to inhibition of phosphorylation by upstream kinases at the activating site, Thr(172). Surprisingly, the equivalent site on AMPK-α2, Ser(491), is not an Akt target and is modified instead by autophosphorylation. Stimulation of HEK (human embryonic kidney)-293 cells with IGF-1 caused reduced subsequent Thr(172) phosphorylation and activation of AMPK-α1 in response to the activator A769662 and the Ca(2+) ionophore A23187, effects we show to be dependent on Akt activation and Ser(487) phosphorylation. Consistent with this, in three PTEN (phosphatase and tensin homologue deleted on chromosome 10)-null tumour cell lines (in which the lipid phosphatase PTEN that normally restrains the Akt pathway is absent and Akt is thus hyperactivated), AMPK was resistant to activation by A769662. However, full AMPK activation could be restored by pharmacological inhibition of Akt, or by re-expression of active PTEN. We also show that inhibition of Thr(172) phosphorylation is due to interaction of the phosphorylated ST loop with basic side chains within the αC-helix of the kinase domain. Our findings reveal that a previously unrecognized effect of hyperactivation of Akt in tumour cells is to restrain activation of the LKB1 (liver kinase B1)–AMPK pathway, which would otherwise inhibit cell growth and proliferation

CBS domains form energy-sensing modules whose binding of adenosine ligands is disrupted by disease mutations

CBS domains are defined as sequence motifs that occur in several different proteins in all kingdoms of life. Although thought to be regulatory, their exact functions have been unknown. However, their importance was underlined by findings that mutations in conserved residues within them cause a variety of human hereditary diseases, including (with the gene mutated in parentheses): Wolff-Parkinson-White syndrome (γ2 subunit of AMP-activated protein kinase); retinitis pigmentosa (IMP dehydrogenase-1); congenital myotonia, idiopathic generalized epilepsy, hypercalciuric nephrolithiasis, and classic Bartter syndrome (CLC chloride channel family members); and homocystinuria (cystathionine β-synthase). AMP-activated protein kinase is a sensor of cellular energy status that is activated by AMP and inhibited by ATP, but the location of the regulatory nucleotide-binding sites (which are prime targets for drugs to treat obesity and diabetes) was not characterized. We now show that tandem pairs of CBS domains from AMP-activated protein kinase, IMP dehydrogenase-2, the chloride channel CLC2, and cystathionine β-synthase bind AMP, ATP, or S-adenosyl methionine,while mutations that cause hereditary diseases impair this binding. This shows that tandem pairs of CBS domains act, in most cases, as sensors of cellular energy status and, as such, represent a newly identified class of binding domain for adenosine derivatives

AMP Is a True Physiological Regulator of AMP-Activated Protein Kinase by Both Allosteric Activation and Enhancing Net Phosphorylation

SummaryWhile allosteric activation of AMPK is triggered only by AMP, binding of both ADP and AMP has been reported to promote phosphorylation and inhibit dephosphorylation at Thr172. Because cellular concentrations of ADP and ATP are higher than AMP, it has been proposed that ADP is the physiological signal that promotes phosphorylation and that allosteric activation is not significant in vivo. However, we report that: AMP is 10-fold more potent than ADP in inhibiting Thr172 dephosphorylation; only AMP enhances LKB1-induced Thr172 phosphorylation; and AMP can cause >10-fold allosteric activation even at concentrations 1–2 orders of magnitude lower than ATP. We also provide evidence that allosteric activation by AMP can cause increased phosphorylation of acetyl-CoA carboxylase in intact cells under conditions in which there is no change in Thr172 phosphorylation. Thus, AMP is a true physiological regulator of AMPK, and allosteric regulation is an important component of the overall activation mechanism

Athena: A New Code for Astrophysical MHD

A new code for astrophysical magnetohydrodynamics (MHD) is described. The code has been designed to be easily extensible for use with static and adaptive mesh refinement. It combines higher-order Godunov methods with the constrained transport (CT) technique to enforce the divergence-free constraint on the magnetic field. Discretization is based on cell-centered volume-averages for mass, momentum, and energy, and face-centered area-averages for the magnetic field. Novel features of the algorithm include (1) a consistent framework for computing the time- and edge-averaged electric fields used by CT to evolve the magnetic field from the time- and area-averaged Godunov fluxes, (2) the extension to MHD of spatial reconstruction schemes that involve a dimensionally-split time advance, and (3) the extension to MHD of two different dimensionally-unsplit integration methods. Implementation of the algorithm in both C and Fortran95 is detailed, including strategies for parallelization using domain decomposition. Results from a test suite which includes problems in one-, two-, and three-dimensions for both hydrodynamics and MHD are given, not only to demonstrate the fidelity of the algorithms, but also to enable comparisons to other methods. The source code is freely available for download on the web.Comment: 61 pages, 36 figures. accepted by ApJ

Regulation of the energy sensor AMP-activated protein kinase by antigen receptor and Ca2+ in T lymphocytes

The adenosine monophosphate (AMP)–activated protein kinase (AMPK) has a crucial role in maintaining cellular energy homeostasis. This study shows that human and mouse T lymphocytes express AMPKα1 and that this is rapidly activated in response to triggering of the T cell antigen receptor (TCR). TCR stimulation of AMPK was dependent on the adaptors LAT and SLP76 and could be mimicked by the elevation of intracellular Ca2+ with Ca2+ ionophores or thapsigargin. AMPK activation was also induced by energy stress and depletion of cellular adenosine triphosphate (ATP). However, TCR and Ca2+ stimulation of AMPK required the activity of Ca2+–calmodulin-dependent protein kinase kinases (CaMKKs), whereas AMPK activation induced by increased AMP/ATP ratios did not. These experiments reveal two distinct pathways for the regulation of AMPK in T lymphocytes. The role of AMPK is to promote ATP conservation and production. The rapid activation of AMPK in response to Ca2+ signaling in T lymphocytes thus reveals that TCR triggering is linked to an evolutionally conserved serine kinase that regulates energy metabolism. Moreover, AMPK does not just react to cellular energy depletion but also anticipates it

Methotrexate promotes glucose uptake and lipid oxidation in skeletal muscle via AMPK activation

Methotrexate (MTX) is a widely used anticancer and antirheumatic drug that has been postulated to protect against metabolic risk factors associated with type 2 diabetes, although the mechanism remains unknown. MTX inhibits 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/inosine monophosphate cyclohydrolase (ATIC) and thereby slows the metabolism of 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranosyl-5′-monophosphate (ZMP) and its precursor AICAR, which is a pharmacological AMPK activator. We explored whether MTX promotes AMPK activation in cultured myotubes and isolated skeletal muscle. We found MTX markedly reduced the threshold for AICAR-induced AMPK activation and potentiated glucose uptake and lipid oxidation. Gene silencing of the MTX target ATIC activated AMPK and stimulated lipid oxidation in cultured myotubes. Furthermore, MTX activated AMPK in wild-type HEK-293 cells. These effects were abolished in skeletal muscle lacking the muscle-specific, ZMP-sensitive AMPK-γ3 subunit and in HEK-293 cells expressing a ZMP-insensitive mutant AMPK-γ2 subunit. Collectively, our findings underscore a role for AMPK as a direct molecular link between MTX and energy metabolism in skeletal muscle. Cotherapy with AICAR and MTX could represent a novel strategy to treat metabolic disorders and overcome current limitations of AICAR monotherapy.</jats:p