312 research outputs found
First down, Goal to Go: Enforcing the NFL\u27s Salary Cap Using the Implied Covenant of Good Faith and Fair Dealing
Global CNS gene transfer for a childhood neurogenetic enzyme deficiency: Canavan disease.
The neurogenetic prototypic disease on which we chose to test our gene therapy strategy is Canavan disease (CD). CD is an autosomal recessive leukodystrophy associated with spongiform degeneration of the brain. At present the disease is uniformly fatal in affected probands. CD is characterized by mutations in the aspartoacylase (ASPA) gene, resulting in loss of enzyme activity. In this review, recent evidence is summarized on the etiology and possible treatments for CD. In particular, we discuss two gene delivery systems representing recent advances in both viral and liposome technology: a novel cationic liposome-polymer-DNA (LPD) complex, DCChol/DOPE-protamine, as well as recombinant adeno-associated virus (AAV) vectors
A Pilot Study on the Effects of Exercise on Depression Symptoms Using Levels of Neurotransmitters and EEG as Markers
Context: The prescribing of exercise by physicians has become a popular practice, yet the effectiveness of exercise on symptoms of depression is difficult to determine due to a lack of randomized controlled trials with clinical populations. Reports also indicate that only a small percentage of physicians advise their patients regarding exercise and confusion still exists as to how much and what types are best. Aims: To understand the mechanisms that make exercise a viable treatment in depression. Settings and Design: This study employed a six‑week, two group, single‑level trial, pre‑ and posttest design using self‑report of symptoms, blood levels of serotonin, dopamine, epinephrine, and norepinephrine, and frontal slow wave EEG activity as markers. This study was registered with clinicaltrials.gov. ID# NCT02023281. Subjects and Methods: Eleven participants with a diagnosis of depression between the ages of 18 and 65 were enrolled from March 2013 through May 2013. Baseline and post‑intervention measures consisted of the Beck Depression Inventory‑II, blood serum levels of serotonin, catecholamines (epinephrine, norepinephrine, and dopamine), and mean alpha frequency. Statistical Analysis Used: A series of independent t‑tests for each dependent variable was conducted. Results: Independent t‑tests reveal significant between‑group differences in depression scores (P = 0.005, d = 2.23); F7 activity (P = 0.012, d = 1.92); and F8 activity (P = 0.04, d = 1.52). Conclusions: The results of this pilot study show that even mild to very moderate levels of exercise 2‑3 times per week consisting of alternating days of aerobic and strength resistance training can be effective in reducing symptoms of depression giving physicians concrete information for their patients on the prescription of exercise
Efficacy of a compulsory homework programme for increasing physical activity and improving nutrition in children: A cluster randomised controlled trial
Background: Most physical activity interventions in children focus on the school setting; however, children typically engage in more sedentary activities and spend more time eating when at home. The primary aim of this cluster randomised controlled trial was to investigate the effects of a compulsory, health-related homework programme on physical activity, dietary patterns, and body size in primary school-aged children. Methods: A total of 675 children aged 7-10 years from 16 New Zealand primary schools participated in the Healthy Homework study. Schools were randomised into intervention and control groups (1:1 allocation). Intervention schools implemented an 8-week applied homework and in-class teaching module designed to increase physical activity and improve dietary patterns. Physical activity was the primary outcome measure, and was assessed using two sealed pedometers that monitored school- and home-based activity separately. Secondary outcome measures included screen-based sedentary time and selected dietary patterns assessed via parental proxy questionnaire. In addition, height, weight, and waist circumference were measured to obtain body mass index (BMI) and waist-to-height ratio (WHtR). All measurements were taken at baseline (T0), immediately post-intervention (T1), and 6-months post-intervention (T2). Changes in outcome measures over time were estimated using generalised linear mixed models (GLMMs) that adjusted for fixed (group, age, sex, group x time) and random (subjects nested within schools) effects. Intervention effects were also quantified using GLMMs adjusted for baseline values. Results: Significant intervention effects were observed for weekday physical activity at home (T1 [P < 0.001] and T2 [P = 0.019]), weekend physical activity (T1 [P < 0.001] and T2 [P < 0.001]), BMI (T2 only [P = 0.020]) and fruit consumption (T1 only [P = 0.036]). Additional analyses revealed that the greatest improvements in physical activity occurred in children from the most socioeconomically deprived schools. No consistent effects on sedentary time, WHtR, or other dietary patterns were observed. Conclusions: A compulsory health-related homework programme resulted in substantial and consistent increases in children's physical activity - particularly outside of school and on weekends - with limited effects on body size and fruit consumption. Overall, our findings support the integration of compulsory home-focused strategies for improving health behaviours into primary education curricula. Trial registration: Australian New Zealand Clinical Trials Registry, ACTRN12618000590268. Registered 17 April 2018. © 2019 The Author(s)
Development of Patient-specific AAV Vectors After Neutralizing Antibody Selection for Enhanced Muscle Gene Transfer
A major hindrance in gene therapy trials with adeno-associated virus (AAV) vectors is the presence of neutralizing antibodies (NAbs) that inhibit AAV transduction. In this study, we used directed evolution techniques in vitro and in mouse muscle to select novel NAb escape AAV chimeric capsid mutants in the presence of individual patient serum. AAV mutants isolated in vitro escaped broad patient-specific NAb activity but had poor transduction ability in vivo. AAV mutants isolated in vivo had enhanced NAb evasion from cognate serum and had high muscle transduction ability. More importantly, structural modeling identified a 100 amino acid motif from AAV6 in variable region (VR) III that confers this enhanced muscle tropism. In addition, a predominantly AAV8 capsid beta barrel template with a specific preference for AAV1/AAV9 in VR VII located at threefold symmetry axis facilitates NAb escape. Our data strongly support that chimeric AAV capsids composed of modular and nonoverlapping domains from various serotypes are capable of evading patient-specific NAbs and have enhanced muscle transduction
Ectrodactyly and lethal pulmonary acinar dysplasia associated with homozygous FGFR2 mutations identified by exome sequencing
First published: 11 July 2016Abstract not availableChristopher P. Barnett, Nathalie J. Nataren, Manuela Klingler-Hoffmann, Quenten Schwarz, Chan-Eng Chong, Young K. Lee, Damien L. Bruno, Jill Lipsett, Andrew J. McPhee, Andreas W. Schreiber, Jinghua Feng, Christopher N. Hahn, and Hamish S. Scot
Polymeric peptide pigments with sequence-encoded properties
Melanins are a family of heterogeneous polymeric pigments that provide ultraviolet (UV) light protection, structural support, coloration, and free radical scavenging. Formed by oxidative oligomerization of catecholic small molecules, the physical properties of melanins are influenced by covalent and noncovalent disorder. We report the use of tyrosine-containing tripeptides as tunable precursors for polymeric pigments. In these structures, phenols are presented in a (supra-)molecular context dictated by the positions of the amino acids in the peptide sequence. Oxidative polymerization can be tuned in a sequence-dependent manner, resulting in peptide sequence–encoded properties such as UV absorbance, morphology, coloration, and electrochemical properties over a considerable range. Short peptides have low barriers to application and can be easily scaled, suggesting near-term applications in cosmetics and biomedicine
Recommended from our members
Effects of keels on ice bottom turbulence exchange
The effects of ice keels on the upper ocean are examined using a combination of
turbulence measurements and output from a large-eddy simulation (LES) model. Two
cases are examined, one during the winter when the under-ice boundary layer is relatively
deep (~20 m) and near the freezing point and a second during the summer when the ice is
melting and the boundary layer consists of a shallow (~0.5 m), highly stratified fresh
layer. In the winter case, measurements show that flow disruption by a 10-m-deep keel
causes enhanced vertical mixing, increasing the heat flux from a background value of
~5 W m^(-2) to values averaging ~25 W m^(-2). Simulations using the LES model are in good
agreement with the measurements and indicate that the keel generates a turbulent wake
region extending hundreds of meters downstream from the keel. Elevated heat fluxes
in the wake region are generated by increased entrainment of warmer water from beneath
the mixed layer. Simulations of summer cases demonstrate that shallow keels (~0.5 m)
generate strong turbulence that is able to rapidly mix the fresh layer in the lee of keels.
However, this effect decreases quickly as the fresh layer accelerates to match the ice
velocity. Deeper keels (1 m) follow a similar pattern but generate more mixing as the fresh
layer is forced under the keel. Simulated ice melt heat fluxes are similar to estimates
made from ice balance measurements taken during the Surface Heat Budget of the
Arctic Ocean summer field program
- …