Computational exploration of α-lactone rearrangements and the cyclic halonium zwitterion from bromination of acrylate anion in water: implicit vs. explicit solvation

In memory of Jonathan Williams, a valued colleague of incisive intellect (and regarded by undergraduates as ‘the better-looking Prof. Williams’ in the Department). Bromomethyloxiranone has a much larger repertoire of molecular acrobatics than previously recognised: conformational isomerism, degenerate rearrangement that exchanges O atoms in the α-lactone ring, and epimerisation, all of which occur with lower barriers than dyotropic rearrangement to the more stable β-lactone. DFT calculations (B3LYP/6-31 + G∗) with implicit solvation (PCM) by water predict the cyclic bromonium zwitterion (formally derived from addition of Br + to acrylate anion) to be a transition structure but QM/MM simulations, combining the same DFT method with explicit solvation by many MM water molecules and using molecular dynamics to obtain free-energy profiles and surfaces, reconfirms the status of the cyclic bromonium as an intermediate. </p

Muscle-related traits in cattle: The role of the myostatin gene in the South Devon breed

In this paper, we examined the effects of an 11-bp mutation within the GDF-8 gene, originally identified in Belgian Blue cattle, in the South Devon breed. The mutation was found at moderate frequency (0.37) in the South Devon population. We quantified the effects of this mutation on growth, body composition and calving traits in South Devon cattle. We found that the mutation significantly increased muscle score and calving difficulty and decreased fat depth. The mutation did not significantly affect weight at 200 and 400 days or muscle depth. Its effect on muscle score and fat depth was additive while its effect on calving difficulty was recessive. The mutation accounted for a significant proportion of the phenotypic variance in muscle score and calving difficulty. There was an economic benefit of the mutation for this data set, however, calculations were sensitive to changes in the parameter values. Additional data would be required to refine these calculations

The Challenges of Multimorbidity from the Patient Perspective

BACKGROUND Although multiple co-occurring chronic illnesses within the same individual are increasingly common, few studies have examined the challenges of multimorbidity from the patient perspective. OBJECTIVE The aim of this study is to examine the self-management learning needs and willingness to see non-physician providers of patients with multimorbidity compared to patients with single chronic illnesses. DESIGN. This research is designed as a cross-sectional survey. PARTICIPANTS Based upon ICD-9 codes, patients from a single VHA healthcare system were stratified into multimorbidity clusters or groups with a single chronic illness from the corresponding cluster. Nonproportional sampling was used to randomly select 720 patients. MEASUREMENTS Demographic characteristics, functional status, number of contacts with healthcare providers, components of primary care, self-management learning needs, and willingness to see nonphysician providers. RESULTS Four hundred twenty-two patients returned surveys. A higher percentage of multimorbidity patients compared to single morbidity patients were "definitely" willing to learn all 22 self-management skills, of these only 2 were not significant. Compared to patients with single morbidity, a significantly higher percentage of patients with multimorbidity also reported that they were "definitely" willing to see 6 of 11 non-physician healthcare providers. CONCLUSIONS Self-management learning needs of multimorbidity patients are extensive, and their preferences are consistent with team-based primary care. Alternative methods of providing support and chronic illness care may be needed to meet the needs of these complex patients.US Department of Veterans Affairs (01-110, 02-197); Agency for Healthcare Research and Quality (K08 HS013008-02

A solid-state process for formation of boron nitride nanotubes

The formation of boron nitride (BN) nanotubes via a solid-state process is demonstrated. The nanotubes are produced by first ball-milling hexagonal BN powder to generate highly disordered or amorphous nanostructures, followed by annealing at temperatures up to 1300 °C. The annealing leads to the nucleation and growth of hexagonal BN nanotubes of both cylindrical and bamboo-like morphology. Unlike previous mechanisms for nanotube formation, the reordering and solid-state growth process of our nanotubes does not involve deposition from the vapor phase nor chemical reaction

Identification of substrates for the Epac1-inducible E3 ubiquitin ligase component SOCS3

It is now accepted that there is a link between obesity and several diseases such as cardiovascular disease (CVD), diabetes, rheumatoid arthritis (RA), and atherosclerosis with the common initiating factor in pathogenesis being a state of low grade, chronic inflammation. This state, characterised by elevated levels of pro-inflammatory cytokines such as interleukin (IL) 6, leads to sustained activation of inflammatory signalling pathways such as the Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway and subsequently pathogenesis. Suppressor of cytokine signalling (SOCS) 3 is inducible by several stimuli including IL6 and 3'-5'-cyclic adenosine monophosphate (cAMP), and via these routes has been demonstrated to terminate IL6 signalling thus quenching JAK/STAT signalling and an inflammatory response. While SOCS3 was primarily characterised as a competitive inhibitor of intracellular signalling, it also functions as specificity factor for an elongin-cullin-SOCS (ECS)-type E3 ubiquitin ligase. In this role, it has been demonstrated to direct ubiquitin-mediated proteasomal degradation of several substrates and lysosomal routing. However, the full spectrum of SOCS3-dependently ubiquitinated substrates is unknown. Given that JAK/STAT signalling is critical in the development of chronic inflammatory disorders, delineating the role of SOCS3 as an E3 ligase might be therapeutically beneficial. However, given the broad range of SOCS3 stimuli, the availability of certain SOCS3 substrates might be conditional on the route of SOCS3 induction. Using a global proteomics approach, this study aimed to identify SOCS3-dependently ubiquitinated substrates in response to cAMP and thus elaborate on the already well-established role of cAMP in inflammation. Differentially stable isotope labelling of amino acids in cell culture (SILAC)-labelled, tandem affinity purified ubiquitinomes of wild type (WT) murine embryonic fibroblasts (MEFs) and SOCS3-/- MEFs, each expressing epitope-tagged forms of ubiquitin, were compared using mass spectrometry (MS) following cAMP-mediated SOCS3 induction. Using this approach, proteins modified by SOCS3 with the epitope-tagged form of ubiquitin should be enriched in WT MEFs but not SOCS3-/- MEFs. MaxQuant analysis of raw mass spectromeric data identified several candidate SOCS3 substrates. Of these, SOCS3 was found to interact with PTRF/cavin-1, a regulator of caveolae formation and stability. Other substrates were tested but with limited success. Co-immunoprecipitation studies showed that SOCS3 could precipitate cavin-1 however the interaction was reduced following the inhibition of protein tyrosine phosphatases (PTPs) using sodium orthovanadate and hydrogen peroxide. This was surprising since all known SOCS3 substrates are tyrosine-phosphorylated prior to interacting with SOCS3 via its Src-homology (SH) 2 domain. Consistent with this finding, SOCS3 did not interact with known cavin-1 tyrosine-phosphorylated peptides spotted on a peptide array. However, a full-length cavin-1 peptide array spotted with non-tyrosine-phosphorylated peptides showed specific interactions at multiple sites. It is proposed that this interaction might influence the localisation and stability of either protein. While SOCS3 was demonstrated to impact cavin-1 ubiquitination, the mechanism by which it does so or the functional consequence is still not clear. Immunoprecipitation of cavin-1 following the introduction of SOCS3 was accompanied by a shift in the polyubiquitin signal from a high molecular weight, seen with cavin-1 alone, to a low molecular weight. Furthermore, an enhanced K48-polyubiquitin signal was detectable in this low molecular weight fraction, which was focused around the molecular weight of cavin-1. It is not known if this ubiquitin signal is SOCS3-dependent. In conclusion, the project has identified and validated a novel substrate of SOCS3. However, the mechanism by which SOCS3 regulates cavin-1 ubiquitination or the biological function of the interaction is currently unknown

Reviews

Reviews of Collective bargaining in industrialised market economics, Appraising and exploring organisations London, Delivering the goods, a history of the Transport Workers' Union in New South Wales 1888-1986, Democracy and control in the workplace, Training contractors for results: a guide for trainers and training managers and Training entrepreneurs for small business creation, lessons from experienc

Long-term effectiveness and cost-effectiveness of cognitive behavioural therapy as an adjunct to pharmacotherapy for treatment-resistant depression in primary care: follow-up of the CoBalT randomised controlled trial

Background: Cognitive behavioural therapy (CBT) is an effective treatment for people whose depression has not responded to antidepressants. However, the long-term outcome is unknown. In a long-term follow-up of the CoBalT trial, we examined the clinical and cost-effectiveness of cognitive behavioural therapy as an adjunct to usual care that included medication over 3–5 years in primary care patients with treatment-resistant depression. Methods: CoBalT was a randomised controlled trial done across 73 general practices in three UK centres. CoBalT recruited patients aged 18–75 years who had adhered to antidepressants for at least 6 weeks and had substantial depressive symptoms (Beck Depression Inventory [BDI-II] score ≥14 and met ICD-10 depression criteria). Participants were randomly assigned using a computer generated code, to receive either usual care or CBT in addition to usual care. Patients eligible for the long-term follow-up were those who had not withdrawn by the 12 month follow-up and had given their consent to being re-contacted. Those willing to participate were asked to return the postal questionnaire to the research team. One postal reminder was sent and non-responders were contacted by telephone to complete a brief questionnaire. Data were also collected from general practitioner notes. Follow-up took place at a variable interval after randomisation (3–5 years). The primary outcome was self-report of depressive symptoms assessed by BDI-II score (range 0–63), analysed by intention to treat. Cost-utility analysis compared health and social care costs with quality-adjusted life-years (QALYs). This study is registered with isrctn.com, number ISRCTN38231611. Findings: Between Nov 4, 2008, and Sept 30, 2010, 469 eligible participants were randomised into the CoBalT study. Of these, 248 individuals completed a long-term follow-up questionnaire and provided data for the primary outcome (136 in the intervention group vs 112 in the usual care group). At follow-up (median 45·5 months [IQR 42·5–51·1]), the intervention group had a mean BDI-II score of 19·2 (SD 13·8) compared with a mean BDI-II score of 23·4 (SD 13·2) for the usual care group (repeated measures analysis over the 46 months: difference in means −4·7 [95% CI −6·4 to −3·0, p&lt;0·001]). Follow-up was, on average, 40 months after therapy ended. The average annual cost of trial CBT per participant was £343 (SD 129). The incremental cost-effectiveness ratio was £5374 per QALY gain. This represented a 92% probability of being cost effective at the National Institute for Health and Care Excellence QALY threshold of £20 000. Interpretation: CBT as an adjunct to usual care that includes antidepressants is clinically effective and cost effective over the long-term for individuals whose depression has not responded to pharmacotherapy. In view of this robust evidence of long-term effectiveness and the fact that the intervention represented good value-for-money, clinicians should discuss referral for CBT with all those for whom antidepressants are not effective

Production of metal-free diamond nanoparticles

In this paper, the controlled production of high-quality metal-free diamond nanoparticles is demonstrated. Milling with tempered steel is shown to leave behind iron oxide contamination which is difficult to remove. Milling with SiN alleviates this issue but generates more nondiamond carbon. Thus, the choice of milling materials is critically determined by the acceptable contaminants in the ultimate application. The removal of metal impurities, present in all commercially available nanoparticles, will open new possibilities toward the production of customized diamond nanoparticles, covering the most demanding quantum applications

Interactive Voice Response-An Innovative Approach to Post-Stroke Depression Self-Management Support

Automated interactive voice response (IVR) call systems can provide systematic monitoring and self-management support to depressed patients, but it is unknown if stroke patients are able and willing to engage in IVR interactions. We sought to assess the feasibility and acceptability of IVR as an adjunct to post-stroke depression follow-up care. The CarePartner program is a mobile health program designed to optimize depression self-management, facilitate social support from a caregiver, and strengthen connections between stroke survivors and primary care providers (PCPs). Ischemic stroke patients and an informal caregiver, if available, were recruited during the patient's acute stroke hospitalization or follow-up appointment. The CarePartner program was activated in patients with depressive symptoms during their stroke hospitalization or follow-up. The 3-month intervention consisted of weekly IVR calls monitoring both depressive symptoms and medication adherence along with tailored suggestions for depressive symptom self-management. After each completed IVR call, informal caregivers were automatically updated, and, if needed, the subject's PCP was notified. Of the 56 stroke patients who enrolled, depressive symptoms were identified in 13 (23 %) subjects. Subjects completed 74 % of the weekly IVR assessments. A total of six subjects did not complete the outcome assessment, including two non-study-related deaths. PCPs were notified five times, including two times for suicidal ideation and three times for medication non-adherence. Stroke patients with depressive symptoms were able to engage in an IVR call system. Future studies are needed to explore the efficacy of an IVR approach for post-stroke self-management and monitoring of stroke-related outcomes