Valuing capabilities in later life

This research report examines, from the perspective of the Brotherhood’s aged service users, what they value in life, what enables them to live fulfilled and meaningful lives, and what Brotherhood aged services can contribute to this. With its accent on freedoms, opportunities and human rights, the capability approach provides a conceptual framework in which to consider a new model of aged services in which will enhance older adults’ human rights and capabilities, especially for those who have been disadvantaged, and ensure that their views continue to inform and shape ageing policies, services and models of practice. The central concern of the capability approach, first articulated by Amartya Sen (1979) and developed by Martha Nussbaum within a social justice and human rights framework, is the opportunities people have for being and doing what, for them, constitutes a good life. Taking this as the starting point, this research represents the first part of a larger study which will examine what users of Brotherhood aged services value in life, what capabilities they aspire to, how current services enhance capabilities and how the capability approach might be integrated into service provision. Image: Report Cove

Detection of Event-Related Spectral Changes in Electrocorticograms

The University of Michigan Direct Brain Interface (UM-DBI) project seeks to detect voluntarily produced electrocortical activity (ECoG) related to actual or imagined movements in humans as the basis for a DBI. In past work we have used cross-correlation based template matching (CCTM) as the method for detecting event-related potentials (ERPs). That approach ignores event-related spectral changes in the ECoG signal. This paper discusses model-based signal detection methods that exploit event-related spectral changes. In particular we propose a quadratic detector based on a two-class hypothesis test with different covariances for the two classes. The covariance matrices are generated by fitting autoregressive (AR) models to training data. Preliminary results show that the quadratic detector yields more channels with good detection performance than the CCTM method, particularly when we impose constraints on detection delay.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/85984/1/Fessler209.pd

Tumor necrosis factor receptor I blockade shows that TNF-dependent and independent mechanisms synergise in TNF receptor associated periodic syndrome

TNF receptor associated periodic syndrome (TRAPS) is an autoinflammatory disease involving recurrent episodes of fever and inflammation. It is associated with autosomal dominant mutations in TNF receptor superfamily 1A gene localised to exons encoding the ectodomain of the p55 TNF receptor, TNF receptor-1 (TNFR1). The aim of this study was to investigate the role of cell surface TNFR1 in TRAPS, and the contribution of TNF-dependent and TNF-independent mechanisms to the production of cytokines. HEK-293 and SK-HEP-1 cell lines were stably transfected with WT or TRAPS-associated variants of human TNF receptor superfamily 1A gene. An anti-TNFR1 single domain antibody (dAb), and an anti-TNFR1 mAb, bound to cell surface WT and variant TNFR1s. In HEK-293 cells transfected with death domain-inactivated (R347A) TNFR1, and in SK-HEP-1 cells transfected with normal (full-length) TNFR1, cytokine production stimulated in the absence of exogenous TNF by the presence of certain TNFR1 variants was not inhibited by the anti-TNFR1 dAb. In SK-Hep-1 cells, specific TRAPS mutations increased the level of cytokine response to TNF, compared to WT, and this augmented cytokine production was suppressed by the anti-TNFR1 dAb. Thus, TRAPS-associated variants of TNFR1 enhance cytokine production by a TNF-independent mechanism and by sensitising cells to a TNF-dependent stimulation. The TNF-dependent mechanism requires cell surface expression of TNFR1, as this is blocked by TNFR1-specific dAb

It Seemed Like a Good Idea at the Time

We often learn of successful pedagogical experiments, but we seldom hear of the the ones that failed. For this special session we solicited submissions from the SIGCSE membership, selected the best from among these, and will have presentations at the session by the selected authors. Our contributions describe pedagogical approaches that seemed to be good ideas but turned out as failures. At the session, contributors will describe their pedagogical experiment, the rationale for the experiment, evidence of failure, and lessons learned

Integer polyhedra for program analysis

Polyhedra are widely used in model checking and abstract interpretation. Polyhedral analysis is effective when the relationships between variables are linear, but suffers from imprecision when it is necessary to take into account the integrality of the represented space. Imprecision also arises when non-linear constraints occur. Moreover, in terms of tractability, even a space defined by linear constraints can become unmanageable owing to the excessive number of inequalities. Thus it is useful to identify those inequalities whose omission has least impact on the represented space. This paper shows how these issues can be addressed in a novel way by growing the integer hull of the space and approximating the number of integral points within a bounded polyhedron

Quantum error mitigation

For quantum computers to successfully solve real-world problems, it is necessary to tackle the challenge of noise: the errors that occur in elementary physical components due to unwanted or imperfect interactions. The theory of quantum fault tolerance can provide an answer in the long term, but in the coming era of noisy intermediate-scale quantum machines one must seek to mitigate errors rather than completely eliminate them. This review surveys the diverse methods that have been proposed for quantum error mitigation, assesses their in-principle efficacy, and describes the hardware demonstrations achieved to date. Commonalities and limitations among the methods are identified, while mention is made of how mitigation methods can be chosen according to the primary type of noise present, including algorithmic errors. Open problems in the field are identified, and the prospects for realizing mitigation-based devices that can deliver a quantum advantage with an impact on science and business are discussed

Telephone-delivered cognitive-behavioral therapy for pain management among older military veterans: a randomized trial.

This study investigated the effectiveness of telephone-delivered cognitive-behavioral therapy (T-CBT) in the management of chronic pain with older military veterans enrolled in VA primary-care clinics. We conducted a randomized clinical trial comparing T-CBT with telephone-delivered pain education (T-EDU). A total of 98 military veterans with chronic pain were enrolled in the study and randomized into one of two treatment conditions. Study participants were recruited from primary-care clinics at an urban VA medical center and affiliated VA community-based outpatient clinics (CBOCs). Pain management outcomes were measured at midtreatment (10 weeks), posttreatment (20 weeks), 3-month follow-up (32 weeks), and 6-month follow-up (46 weeks). No significant differences were found between the two treatment groups on any of the outcome measures. Both treatment groups reported small but significant increases in level of physical and mental health, and reductions in pain and depressive symptoms. Improvements in all primary outcome measures were mediated by reductions in catastrophizing. Telephone-delivered CBT and EDU warrant further study as easily accessible interventions for rural-living older individuals with chronic pain

Expectancies regarding the interaction between smoking and substance use in alcohol-dependent smokers in early recovery.

The purpose of this study was to investigate expectancies regarding the interaction between cigarette smoking and use of alcohol among alcohol-dependent smokers in early recovery, using the Nicotine and Other Substances Interaction Expectancies Questionnaire (NOSIE). Participants were 162 veterans, 97% male, with a mean age of 50 years, enrolled in a clinical trial aimed at determining the efficacy of an intensive smoking cessation intervention versus usual care. At baseline, participants were assessed on measures of smoking behavior, abstinence thoughts about alcohol and tobacco use, symptoms of depression, and smoking-substance use interaction expectancies. In addition, biologically verified abstinence from tobacco and alcohol was assessed at 26 weeks. Participants reported that they expected smoking to have less of an impact on substance use than substance use has on smoking (p < .001). Severity of depressive symptoms was significantly associated with the expectancy that smoking provides a way of coping with the urge to use other substances (p < .01). The expectation that smoking increases substance urges/use was predictive of prospectively measured and biologically verified abstinence from smoking at 26 weeks (p < .03). The results add to our knowledge of smoking-substance use interaction expectancies among alcohol-dependent smokers in early recovery and will inform the development of more effective counseling interventions for concurrent alcohol and tobacco use disorders

Allosteric modulation of AURKA kinase activity by a small-molecule inhibitor of its protein-protein interaction with TPX2.

The essential mitotic kinase Aurora A (AURKA) is controlled during cell cycle progression via two distinct mechanisms. Following activation loop autophosphorylation early in mitosis when it localizes to centrosomes, AURKA is allosterically activated on the mitotic spindle via binding to the microtubule-associated protein, TPX2. Here, we report the discovery of AurkinA, a novel chemical inhibitor of the AURKA-TPX2 interaction, which acts via an unexpected structural mechanism to inhibit AURKA activity and mitotic localization. In crystal structures, AurkinA binds to a hydrophobic pocket (the 'Y pocket') that normally accommodates a conserved Tyr-Ser-Tyr motif from TPX2, blocking the AURKA-TPX2 interaction. AurkinA binding to the Y- pocket induces structural changes in AURKA that inhibit catalytic activity in vitro and in cells, without affecting ATP binding to the active site, defining a novel mechanism of allosteric inhibition. Consistent with this mechanism, cells exposed to AurkinA mislocalise AURKA from mitotic spindle microtubules. Thus, our findings provide fresh insight into the catalytic mechanism of AURKA, and identify a key structural feature as the target for a new class of dual-mode AURKA inhibitors, with implications for the chemical biology and selective therapeutic targeting of structurally related kinases.We are grateful for the access and support at beamlines i02, i03 and i04-1 at Diamond Light Source at Harwell, UK (proposal MX9007 and MX9537) and at beamline Proxima1 at the SOLEIL Synchrotron, Gif-sur-Yvette, France. We are grateful for access and support from the X-ray and biophysics facilities (Dept. of Biochemistry) and the screening/imaging facility (MRC Cancer Unit). M.J. was supported by a Cancer Research UK studentship held in the labs of DS and ARV, PS and MR by a Wellcome Trust Strategic Award to ARV and MH, and DJH, BH, AJN and GM by grants from the UK Medical Research Council to ARV.This is the final version of the article. It first appeared from Nature Publishing Group via http://dx.doi.org/10.1038/srep2852

A pro-inflammatory signalome is constitutively activated by C33Y mutant TNF receptor 1 in TNF receptor-associated periodic syndrome (TRAPS)

Mutations in TNFRSF1A encoding TNF receptor 1 (TNFR1) cause the autosomal dominant TNF receptor-associated periodic syndrome (TRAPS): a systemic autoinflammatory disorder. Misfolding, intracellular aggregation, and ligand-independent signaling by mutant TNFR1 are central to disease pathophysiology. Our aim was to understand the extent of signaling pathway perturbation in TRAPS. A prototypic mutant TNFR1 (C33Y), and wild-type TNFR1 (WT), were expressed at near physiological levels in an SK-Hep-1 cell model. TNFR1-associated signaling pathway intermediates were examined in this model, and in PBMCs from C33Y TRAPS patients and healthy controls. In C33Y-TNFR1-expressing SK-Hep-1 cells and TRAPS patients' PBMCs, a subtle, constitutive upregulation of a wide spectrum of signaling intermediates and their phosphorylated forms was observed; these were associated with a proinflammatory/antiapoptotic phenotype. In TRAPS patients' PBMCs, this upregulation of proinflammatory signaling pathways was observed irrespective of concurrent treatment with glucocorticoids, anakinra or etanercept, and the absence of overt clinical symptoms at the time that the blood samples were taken. This study reveals the pleiotropic effect of a TRAPS-associated mutant form of TNFR1 on inflammatory signaling pathways (a proinflammatory signalome), which is consistent with the variable and limited efficacy of cytokine-blocking therapies in TRAPS. It highlights new potential target pathways for therapeutic intervention