Mechanistic analysis of an asymmetric palladium-catalyzed conjugate addition of arylboronic acids to β-substituted cyclic enones.

An asymmetric palladium-catalyzed conjugate addition reaction of arylboronic acids to enone substrates was investigated mechanistically. Desorption electrospray ionization coupled to mass spectrometry was used to identify intermediates of the catalytic cycle and delineate differences in substrate reactivity. Our findings provide evidence for the catalytic cycle proceeding through formation of an arylpalladium(II) cation, subsequent formation of an arylpalladium-enone complex, and, ultimately, formation of the new C-C bond. Reaction monitoring in both positive and negative ion modes revealed that 4-iodophenylboronic acid formed a relatively stable trimeric species under the reaction conditions

Effect of Immobilisation on Neuromuscular Function In Vivo in Humans: A Systematic Review

This is the final version. Available on open access from Springer Verlag via the DOI in this recordData Availability Statement: Data and materials are available on request from the corresponding author.Background: Muscle strength loss following immobilisation has been predominantly attributed to rapid muscle atrophy. However, this cannot fully explain the magnitude of muscle strength loss, so changes in neuromuscular function (NMF) may be involved. Objectives: We systematically reviewed literature that quantified changes in muscle strength, size and NMF following periods of limb immobilisation in vivo in humans. Methods: Studies were identified following systematic searches, assessed for inclusion, data extracted and quality appraised by two reviewers. Data were tabulated and reported narratively. Results: Forty eligible studies were included, 22 immobilised lower and 18 immobilised upper limbs. Limb immobilisation ranged from 12 h to 56 days. Isometric muscle strength and muscle size declined following immobilisation; however, change magnitude was greater for strength than size. Evoked resting twitch force decreased for lower but increased for upper limbs. Rate of force development either remained unchanged or slowed for lower and typically slowed for upper limbs. Twitch relaxation rate slowed for both lower and upper limbs. Central motor drive typically decreased for both locations, while electromyography amplitude during maximum voluntary contractions decreased for the lower and presented mixed findings for the upper limbs. Trends imply faster rates of NMF loss relative to size earlier in immobilisation periods for all outcomes. Conclusions: Limb immobilisation results in non-uniform loss of isometric muscle strength, size and NMF over time. Different outcomes between upper and lower limbs could be attributed to higher degrees of central neural control of upper limb musculature. Future research should focus on muscle function losses and mechanisms following acute immobilisation. Registration: PROSPERO reference: CRD42016033692

Correction to: Effect of Immobilisation on Neuromuscular Function In Vivo in Humans: A Systematic Review

The following sections 3.5.1 to 3.5.3.2, which previously read

Proportional/non-proportional constant/variable amplitude multiaxial notch fatigue: cyclic plasticity, non-zero mean stresses, and critical distance/plane

This paper deals with the formulation and experimental validation of a novel fatigue lifetime estimation technique suitable for assessing the extent of damage in notched metallic materials subjected to in‐service proportional/nonproportional constant/variable amplitude multiaxial load histories. The methodology being formulated makes use of the Modified Manson‐Coffin Curve Method, the Shear Strain–Maximum Variance Method, and the elasto‐plastic Theory of Critical Distances, with the latter theory being applied in the form of the Point Method. The accuracy and reliability of our novel fatigue lifetime estimation technique were checked against a large number of experimental results we generated by testing, under proportional/nonproportional constant/variable amplitude axial‐torsional loading, V‐notched cylindrical specimens made of unalloyed medium‐carbon steel En8 (080M40). Specific experimental trials were run to investigate also the effect of non‐zero mean stresses as well as of different frequencies between the axial and torsional stress/strain components. This systematic validation exercise allowed us to demonstrate that our novel multiaxial fatigue assessment methodology is remarkably accurate, with the estimates falling within an error factor of 2. By modelling the cyclic elasto‐plastic behaviour of metals explicitly, the design methodology being formulated and validated in the present paper offers a complete solution to the problem of estimating multiaxial fatigue lifetime of notched metallic materials, with this holding true independently of sharpness of the stress/strain raiser and complexity of the load history

Effect of Immobilisation on Neuromuscular Function In Vivo in Humans: A Systematic Review

BACKGROUND: Muscle strength loss following immobilisation has been predominantly attributed to rapid muscle atrophy. However, this cannot fully explain the magnitude of muscle strength loss, so changes in neuromuscular function (NMF) may be involved. OBJECTIVES: We systematically reviewed literature that quantified changes in muscle strength, size and NMF following periods of limb immobilisation in vivo in humans. METHODS: Studies were identified following systematic searches, assessed for inclusion, data extracted and quality appraised by two reviewers. Data were tabulated and reported narratively. RESULTS: Forty eligible studies were included, 22 immobilised lower and 18 immobilised upper limbs. Limb immobilisation ranged from 12 h to 56 days. Isometric muscle strength and muscle size declined following immobilisation; however, change magnitude was greater for strength than size. Evoked resting twitch force decreased for lower but increased for upper limbs. Rate of force development either remained unchanged or slowed for lower and typically slowed for upper limbs. Twitch relaxation rate slowed for both lower and upper limbs. Central motor drive typically decreased for both locations, while electromyography amplitude during maximum voluntary contractions decreased for the lower and presented mixed findings for the upper limbs. Trends imply faster rates of NMF loss relative to size earlier in immobilisation periods for all outcomes. CONCLUSIONS: Limb immobilisation results in non-uniform loss of isometric muscle strength, size and NMF over time. Different outcomes between upper and lower limbs could be attributed to higher degrees of central neural control of upper limb musculature. Future research should focus on muscle function losses and mechanisms following acute immobilisation. REGISTRATION: PROSPERO reference: CRD42016033692

A transformative translational change programme to introduce genomics into healthcare: a complexity and implementation science study protocol

INTRODUCTION: Translating scientific advances in genomic medicine into evidence-based clinical practice is challenging. Studying the natural translation of genomics into 'early-adopting' health system sectors is essential. We will (a) examine 29 health systems (Australian and Melbourne Genomics Health Alliance flagships) integrating genomics into practice and (b) combine this learning to co-design and test an evidence-based generalisable toolkit for translating genomics into healthcare. METHODS AND ANALYSIS: Twenty-nine flagships integrating genomics into clinical settings are studied as complex adaptive systems to understand emergent and self-organising behaviours among inter-related actors and processes. The Effectiveness-Implementation Hybrid approach is applied to gather information on the delivery and potential for real-world implementation. Stages '1' and '2a' (representing hybrid model 1) are the focus of this protocol. The Translation Science to Population Impact (TSci Impact) framework is used to study policy decisions and service provision, and the Theoretical Domains Framework (TDF) is used to understand individual level behavioural change; both frameworks are applied across stages 1 and 2a. Stage 1 synthesises interview data from 32 participants involved in developing the genomics clinical practice systems and approaches across five 'demonstration-phase' (early adopter) flagships. In stage 2a, stakeholders are providing quantitative and qualitative data on process mapping, clinical audits, uptake and sustainability (TSci Impact), and psychosocial and environmental determinants of change (TDF). Findings will be synthesised before codesigning an intervention toolkit to facilitate implementation of genomic testing. Study methods to simultaneously test the comparative effectiveness of genomic testing and the implementation toolkit (stage 2b), and the refined implementation toolkit while simply observing the genomics intervention (stage 3) are summarised. ETHICS AND DISSEMINATION: Ethical approval has been granted. The results will be disseminated in academic forums and used to refine interventions to translate genomics evidence into healthcare. Non-traditional academic dissemination methods (eg, change in guidelines or government policy) will also be employed

Phases of one dimensional large N gauge theory in a 1/D expansion

We consider large N Yang Mills theory with D adjoint scalar fields in d dimensions for d=0 or 1. We show the existence of a non-trivial saddle point of the functional integral at large D which is characterized by a mass gap for the adjoint scalars. We integrate out the adjoint scalars in a 1/D expansion around the saddle point. In case of one dimension which is regarded as a circle, this procedure leads to an effective action for the Wilson line. We find an analogue of the confinement/deconfinement transition which consists of a second order phase transition from a uniform to a non-uniform eigenvalue distribution of the Wilson line, closely followed by a Gross-Witten-Wadia transition where a gap develops in the eigenvalue distribution. The phase transition can be regarded as a continuation of a Gregory-Laflamme transition. Our methods involve large values of the dimensionless 'tHooft coupling. The analysis in this paper is quantitatively supported by earlier numerical work for D=9.Comment: 27 pages + 21 pages of Appendix; 8 figures, v2:some comments are added in sec.4.3, minor corrections, one reference added, v3: minor corrections, one reference added, version to be published in JHE

International Consensus on Differential Diagnosis and Management of Patients With Danon Disease: JACC State-of-the-Art Review

Danon disease is a rare X-linked autophagic vacuolar cardioskeletal myopathy associated with severe heart failure that can be accompanied with extracardiac neurologic, skeletal, and ophthalmologic manifestations. It is caused by loss of function variants in the LAMP2 gene and is among the most severe and penetrant of the genetic cardiomyopathies. Most patients with Danon disease will experience symptomatic heart failure. Male individuals generally present earlier than women and die of either heart failure or arrhythmia or receive a heart transplant by the third decade of life. Herein, the authors review the differential diagnosis of Danon disease, diagnostic criteria, natural history, management recommendations, and recent advances in treatment of this increasingly recognized and extremely morbid cardiomyopathy

Tumour-derived alkaline phosphatase regulates tumour growth, epithelial plasticity and disease-free survival in metastatic prostate cancer

BACKGROUND: Recent evidence suggests that bone-related parameters are the main prognostic factors for overall survival in advanced prostate cancer (PCa), with elevated circulating levels of alkaline phosphatase (ALP) thought to reflect the dysregulated bone formation accompanying distant metastases. We have identified that PCa cells express ALPL, the gene that encodes for tissue nonspecific ALP, and hypothesised that tumour-derived ALPL may contribute to disease progression. METHODS: Functional effects of ALPL inhibition were investigated in metastatic PCa cell lines. ALPL gene expression was analysed from published PCa data sets, and correlated with disease-free survival and metastasis. RESULTS: ALPL expression was increased in PCa cells from metastatic sites. A reduction in tumour-derived ALPL expression or ALP activity increased cell death, mesenchymal-to-epithelial transition and reduced migration. Alkaline phosphatase activity was decreased by the EMT repressor Snail. In men with PCa, tumour-derived ALPL correlated with EMT markers, and high ALPL expression was associated with a significant reduction in disease-free survival. CONCLUSIONS: Our studies reveal the function of tumour-derived ALPL in regulating cell death and epithelial plasticity, and demonstrate a strong association between ALPL expression in PCa cells and metastasis or disease-free survival, thus identifying tumour-derived ALPL as a major contributor to the pathogenesis of PCa progression.British Journal of Cancer advance online publication, 22 December 2016; doi:10.1038/bjc.2016.402 www.bjcancer.com

Serotonin tranporter methylation and response to cognitive behaviour therapy in children with anxiety disorders

Anxiety disorders that are the most commonly occurring psychiatric disorders in childhood, are associated with a range of social and educational impairments and often continue into adulthood. Cognitive behaviour therapy (CBT) is an effective treatment option for the majority of cases, although up to 35-45% of children do not achieve remission. Recent research suggests that some genetic variants may be associated with a more beneficial response to psychological therapy. Epigenetic mechanisms such as DNA methylation work at the interface between genetic and environmental influences. Furthermore, epigenetic alterations at the serotonin transporter (SERT) promoter region have been associated with environmental influences such as stressful life experiences. In this study, we measured DNA methylation upstream of SERT in 116 children with an anxiety disorder, before and after receiving CBT. Change during treatment in percentage DNA methylation was significantly different in treatment responders vs nonresponders. This effect was driven by one CpG site in particular, at which responders increased in methylation, whereas nonresponders showed a decrease in DNA methylation. This is the first study to demonstrate differences in SERT methylation change in association with response to a purely psychological therapy. These findings confirm that biological changes occur alongside changes in symptomatology following a psychological therapy such as CBT