Enzymatic synthesis of L-pipecolic acid and L-proline

This article does not have an abstract

An Automated Approach to Instrumenting the Up-on-the-Toes Test(s)

YesNormal ankle function provides a key contribution to everyday activities, particularly step/stair ascent and descent, where many falls occur. The rising to up-on-the-toes (UTT) 30 second test (UTT-30) is used in the clinical assessment of ankle muscle strength/function and endurance and is typically assessed by an observer counting the UTT movement completed. The aims of this study are: (i) to determine whether inertial measurement units (IMUs) provide valid assessment of the UTT-30 by comparing IMU-derived metrics with those from a force-platform (FP), and (ii) to de-scribe how IMUs can be used to provide valid assessment of the movement dynamics/stability when performing a single UTT movement that is held for 5 s (UTT-stand). Twenty adults (26.2 ± 7.7 years) performed a UTT-30 and a UTT-stand on a force-platform with IMUs attached to each foot and the lumbar spine. We evaluate the agreement/association between IMU measures and measures de-termined from the FP. For UTT-30, IMU analysis of peaks in plantarflexion velocity and in FP’s centre of pressure (CoP) velocity was used to identify each repeated UTT movement and provided an objective means to discount any UTT movements that were not completed ‘fully’. UTT movements that were deemed to have not been completed ‘fully’ were those that yielded peak plantarflexion and CoP velocity values during the period of rising to up-on-the-toes that were below 1 SD of each participant’s mean peak rising velocity across their repeated UTT. The number of UTT movements detected by the IMU approach (23.5) agreed with the number determined by the FP (23.6), and each approach determined the same number of ‘fully’ completed movements (IMU, 19.9; FP, 19.7). For UTT-stand, IMU-derived movement dynamics/postural stability were moderately-to-strongly correlated with measures derived from the FP. Our findings highlight that the use of IMUs can provide valid assessment of UTT test(s)

Use of ‘wearables’ to assess the Up-on-the-toes test

YesThe mechanical output at the ankle provides key contribution to everyday activities, particularly step/stair ascent and descent. Age-related decline in ankle functioning can lead to an increased risk of falls on steps and stairs. The rising up-on-the-toes (UTT) 30-second test (UTT-30) is used in the clinical assessment of ankle muscle strength/function and endurance; the main outcome being how many repetitive UTT movements are completed. This preliminary study describes how inertial measurement units (IMUs) can be used to assess the UTT-30. Twenty adults (26.2 ± 7.7 years) performed a UTT-30 at a comfortable speed, with IMUs attached to the dorsal aspect of each foot. Use of IMUs’ angular velocity signal to detect the peak plantarflexion angular velocity (p-fAngVelpeak) associated with each repeated UTT movement indicated the number of UTT movements attempted by each participant. Any UTT movements that were performed with a p-fAngVelpeak 2SD below the mean were deemed to have not been completed over a sufficiently ‘full’ range. Findings highlight that use of IMUs can provide valid assessment of the UTT 30-second test. Their use detected the same number of attempted UTT movements as that observed by a researcher (average difference, -0.1 CI, -0.2 – 0.1), and on average 97.6 ± 3.1% of these movements were deemed to have been completed ‘fully’. We discuss the limitations of our approach for identifying the movements not completed fully, and how assessing the consistency in the magnitude of the repeated p-fAngVelpeak could be undertaken and what this would indicate about UTT-30 performance

Structure-guided design and optimization of small molecules targeting the protein-protein interaction between the von hippel-lindau (VHL) E3 ubiquitin ligase and the hypoxia inducible factor (HIF) alpha subunit with in vitro nanomolar affinities

E3 ubiquitin ligases are attractive targets in the ubiquitin-proteasome system, however, the development of small-molecule ligands has been rewarded with limited success. The von Hippel-Lindau protein (pVHL) is the substrate recognition subunit of the VHL E3 ligase that targets HIF-1α for degradation. We recently reported inhibitors of the pVHL:HIF-1α interaction, however they exhibited moderate potency. Herein, we report the design and optimization, guided by X-ray crystal structures, of a ligand series with nanomolar binding affinities

Dystrophin Gene Mutation Location and the Risk of Cognitive Impairment in Duchenne Muscular Dystrophy

Contains fulltext : 88828.pdf (publisher's version ) (Open Access)BACKGROUND: A significant component of the variation in cognitive disability that is observed in Duchenne muscular dystrophy (DMD) is known to be under genetic regulation. In this study we report correlations between standardised measures of intelligence and mutational class, mutation size, mutation location and the involvement of dystrophin isoforms. METHODS AND RESULTS: Sixty two male subjects were recruited as part of a study of the cognitive spectrum in boys with DMD conducted at the Sydney Children's Hospital (SCH). All 62 children received neuropsychological testing from a single clinical psychologist and had a defined dystrophin gene (DMD) mutation; including DMD gene deletions, duplications and DNA point mutations. Full Scale Intelligence Quotients (FSIQ) in unrelated subjects with the same mutation were found to be highly correlated (r = 0.83, p = 0.0008), in contrast to results in previous publications. In 58 cases (94%) it was possible to definitively assign a mutation as affecting one or more dystrophin isoforms. A strong association between the risk of cognitive disability and the involvement of groups of DMD isoforms was found. In particular, improvements in the correlation of FSIQ with mutation location were identified when a new classification system for mutations affecting the Dp140 isoform was implemented. SIGNIFICANCE: These data represent one of the largest studies of FSIQ and mutational data in DMD patients and is among the first to report on a DMD cohort which has had both comprehensive mutational analysis and FSIQ testing through a single referral centre. The correlation between FSIQ results with the location of the dystrophin gene mutation suggests that the risk of cognitive deficit is a result of the cumulative loss of central nervous system (CNS) expressed dystrophin isoforms, and that correct classification of isoform involvement results in improved estimates of risk

Beyond synthesis: Augmenting systematic review procedures with practical principles to optimise impact and uptake in educational policy and practice

Whilst systematic reviews, meta-analyses and other forms of synthesis are often constructed as sitting proudly atop the hierarchy of research evidence, their limited impact on educational policy and practice has been criticised. In this article, we analyse why systematic reviews do not benefit users of evidence more consistently and suggest how review teams can optimise the impact of their work. We introduce the Beyond Synthesis Impact Chain (BSIC), an integrated framework of practical strategies for enhancing the impact of systematic reviews. Focusing upon examples from health professions education, we propose that review teams can optimise the impact of their work by employing strategies that 1) focus on practical problems and mindful planning in collaboration with users; 2) ensure reviews are relevant and syntheses reflexively account for users’ needs; and 3) couch reports in terms that resonate with users’ needs and increase access through targeted and strategic dissemination. We argue that combining practical principles with robust and transparent procedures can purposefully account for impact, and foster the uptake of review evidence in educational policy and practice. For systematic review teams, this paper offers strategies for enhancing the practical utility and potential impact of systematic reviews and other forms of synthesis

X-linked myotubular myopathy associated with an MTM1 variant in a Maine coon cat.

OBJECTIVE: Describe the clinical course and diagnostic and genetic findings in a cat with X-linked myotubular myopathy. CASE SUMMARY: A 7-month-old male Maine coon was evaluated for progressively worsening gait abnormalities and generalized weakness. Neurolocalization was to the neuromuscular system. Genetic testing for spinal muscular atrophy (LIX1) was negative. Given the progressive nature and suspected poor long-term prognosis, the owners elected euthanasia. Histopathology of skeletal muscle obtained post-mortem disclosed numerous rounded atrophic or hypotrophic fibers with internal nuclei or central basophilic staining. Using oxidative reactions mediated by cytochrome C oxidase and succinic dehydrogenase, scattered myofibers were observed to have central dark staining structures and a ring-like appearance. Given the cats age and clinical history, a congenital myopathy was considered most likely, with the central nuclei and ring-like changes consistent with either centronuclear or myotubular myopathy. Whole genome sequencing identified an underlying missense variant in myotubularin 1 (MTM1), a known candidate gene for X-linked myotubular myopathy. NEW OR UNIQUE INFORMATION PROVIDED: This case is the first report of X-linked myotubular myopathy in a cat with an MTM1 missense mutation. Maine coon cat breeders may consider screening for this variant to prevent production of affected cats and to eradicate the variant from the breeding population

Variable response to phosphorus mitigation measures across the nutrient transfer continuum in a dairy grassland catchment

peer-reviewedPhosphorus (P) loss from soils to water can be a major pressure on freshwater quality and dairy farming, with higher animal stocking rates, may lead to potentially greater nutrient source pressures. In many countries with intensive agriculture, regulation of P management aims to minimise these losses. This study examined the P transfer continuum, from source to impact, in a dairy-dominated, highly stocked, grassland catchment with free-draining soils over three years. The aim was to measure the effects of P source management and regulation on P transfer across the nutrient transfer continuum and subsequent water quality and agro-economic impacts. Reduced P source pressure was indicated by: (a) lower average farm-gate P balances (2.4 kg ha−1 yr−1), higher P use efficiencies (89%) and lower inorganic fertilizer P use (5.2 kg ha−1 yr−1) relative to previous studies; (b) almost no recorded P application during the winter closed period, when applications were prohibited, to avoid incidental transfers; and (c) decreased proportions of soils with excessive P concentrations (32–24%). Concurrently, production and profitability remained comparable with the top 10% of dairy farmers nationally with milk outputs of 14,585 l ha−1, and gross margins of € 3130 ha−1. Whilst there was some indication of a response in P delivery in surface water with declines in quick flow and interflow pathway P concentrations during the winter closed period for P application, delayed baseflows in the wetter third year resulted in elevated P concentrations for long durations and there were no clear trends of improving stream biological quality. This suggests a variable response to policy measures between P source pressure and delivery/impact where the strength of any observable trend is greater closer to the source end of the nutrient transfer continuum and a time lag occurs at the other end. Policy monitoring and assessment efforts will need to be cognisant of this

A study of the norcaradiene-cycloheptatriene equilibrium in a series of azulenones by NMR spectroscopy; the impact of substitution on the position of equilibrium

A systematic investigation of the influence of substitution at positions C-2 and C-3 on the azulenone skeleton, based on NMR characterisation, is discussed with particular focus on the impact of the steric and electronic characteristics of substituents on the position of the norcaradiene-cycloheptatriene (NCD-CHT) equilibrium. Variable temperature (VT) NMR studies, undertaken to enable the resolution of signals for the equilibrating valence tautomers revealed, in addition, interesting shifts in the equilibrium

Minimal residual disease prior to allogeneic hematopoietic cell transplantation in acute myeloid leukemia: a meta-analysis

Minimal residual disease prior to allogeneic hematopoietic cell transplantation has been associated with increased risk of relapse and death in patients with acute myeloid leukemia, but detection methodologies and results vary widely. We performed a systematic review and meta-analysis evaluating the prognostic role of minimal residual disease detected by polymerase chain reaction or multiparametric flow cytometry before transplant. We identified 19 articles published between January 2005 and June 2016 and extracted hazard ratios for leukemia-free survival, overall survival, and cumulative incidences of relapse and non-relapse mortality. Pre-transplant minimal residual disease was associated with worse leukemia-free survival (HR=2.76 [1.90-4.00]), overall survival (HR=2.36 [1.73-3.22]), and cumulative incidence of relapse (HR=3.65 [2.53-5.27]), but not non-relapse mortality (HR=1.12 [0.81-1.55]). These associations held regardless of detection method, conditioning intensity, and patient age. Adverse cytogenetics was not an independent risk factor for death or relapse. There was more heterogeneity among studies using flow cytometry-based than WT1 polymerase chain reaction-based detection (I(2)=75.1% vs. <0.1% for leukemia-free survival, 67.8% vs. <0.1% for overall survival, and 22.1% vs. <0.1% for cumulative incidence of relapse). These results demonstrate a strong relationship between pre-transplant minimal residual disease and post-transplant relapse and survival. Outcome heterogeneity among studies using flow-based methods may underscore site-specific methodological differences or differences in test performance and interpretation