Cytotoxic Aggregation and Amyloid Formation by the Myostatin Precursor Protein

Myostatin, a negative regulator of muscle growth, has been implicated in sporadic inclusion body myositis (sIBM). sIBM is the most common age-related muscle-wastage disease with a pathogenesis similar to that of amyloid disorders such as Alzheimer's and Parkinson's diseases. Myostatin precursor protein (MstnPP) has been shown to associate with large molecular weight filamentous inclusions containing the Alzheimer's amyloid beta peptide in sIBM tissue, and MstnPP is upregulated following ER stress. The mechanism for how MstnPP contributes to disease pathogenesis is unknown. Here, we show for the first time that MstnPP is capable of forming amyloid fibrils in vitro. When MstnPP-containing Escherichia coli inclusion bodies are refolded and purified, a proportion of MstnPP spontaneously misfolds into amyloid-like aggregates as characterised by electron microscopy and binding of the amyloid-specific dye thioflavin T. When subjected to a slightly acidic pH and elevated temperature, the aggregates form straight and unbranched amyloid fibrils 15 nm in diameter and also exhibit higher order amyloid structures. Circular dichroism spectroscopy reveals that the amyloid fibrils are dominated by β-sheet and that their formation occurs via a conformational change that occurs at a physiologically relevant temperature. Importantly, MstnPP aggregates and protofibrils have a negative effect on the viability of myoblasts. These novel results show that the myostatin precursor protein is capable of forming amyloid structures in vitro with implications for a role in sIBM pathogenesis

Spatial structure of boreal woodland caribou populations in northwest Canada

Local population units (LPUs) were delineated in Canada’s recovery strategy for threatened boreal woodland caribou (Rangifer tarandus caribou). Population viability analyses central to contemporary integrated risk assessments of LPUs implicitly assume geographic closure. Several LPUs in northwest Canada, however, were in part delineated by geopolitical boundaries and/or included large areas in the absence of evidence of more finely resolved population spatial structure. We pooled >1.2 million locations from >1200 GPS or VHF-collared caribou from northeast British Columbia, northwest Alberta and southwestern Northwest Territories. Bayesian cluster analysis generated 10 alternative candidate LPUs based on a spatial cluster graph of the extent of pairwise co-occurrence of collared caribou. Up to four groups may be artifacts in as yet under-sampled areas. Four were mapped LPUs that were conserved (Prophet, Parker, Chinchaga and Red Earth).  One small group between Parker and Snake-Sahtaneh known locally as the “Fort Nelson core,” and outside any mapped LPU, was also conserved. Finally, one large group, at >136000 km2, spanned all three jurisdictions and subsumed all of six delineated LPUs (Maxhamish, Snake-Sahtaneh, Calendar, Bistcho, Yates, Caribou Mountains) and part of southern Northwest Territories. These results suggest less geographic closure of LPUs than those currently delineated, but further analyses will be required to better reconcile various sources of knowledge about local population structure in this region.  &nbsp

MUSE observations of the optical nebula surrounding the central compact object in the Vela Junior Supernova Remnant

Central Compact Objects (CCOs), neutron stars found near the centre of some Supernova Remnants (SNRs), have been almost exclusively studied in X-rays and are thought to lack the wind nebulae typically seen around young, rotation-powered pulsars. We present the first, spatially-resolved, morphological and spectroscopic study of the optical nebula observed at the location of CXOU J085201.4-461753, the CCO in the heart of the Vela Junior SNR. It is currently the only Galactic CCO with a spatially coincident nebula detected at optical wavelengths, whose exact nature remains uncertain. New MUSE integral field spectroscopy data confirm that the nebula, shaped like a smooth blob extending 8" in diameter, is dominated by [N II]$\lambda\lambda$6548,6583 emission. The data reveals a distinct and previously unobserved morphology of the H$\alpha$ emission, exhibiting an arc-like shape reminiscent of a bow shock nebula. We observe a significantly strong [N II] emission relative to H$\alpha$, with the [N II]$\lambda\lambda$6548,6583 up to 34 times the intensity of the H$\alpha$ emission within the optical nebula environment. Notably, the [N II] and H$\alpha$ structures are not spatially coincident, with the [N II] nebula concentrated to the south of the CCO and delimited by the H$\alpha$ arc-like structure. We detect additional emission in [N I], He I, [S II], [Ar III], [Fe II], and [S III]. We discuss our findings in the light of a photoionization or Wolf-Rayet nebula, pointing to a very massive progenitor and further suggesting that very massive stars do not necessarily make black holes.Comment: 11 pages, 7 figures, 2 tables; Accepted for publication in MNRA

Words Volume 2 2009-2011

https://openspace.dmacc.edu/words/1001/thumbnail.jp

A randomized trial to monitor the efficacy and effectiveness by QT-NASBA of artemether-lumefantrine versus dihydroartemisinin-piperaquine for treatment and transmission control of uncomplicated Plasmodium falciparum malaria in western Kenya

<p>Abstract</p> <p>Background</p> <p>Many countries have implemented artemisinin-based combination therapy (ACT) for the first-line treatment of malaria. Although many studies have been performed on efficacy and tolerability of the combination arthemeter-lumefantrine (AL) or dihydroartemisinin-piperaquine (DP), less is known of the effect of these drugs on gametocyte development, which is an important issue in malaria control.</p> <p>Methods and results</p> <p>In this two-arm randomized controlled trial, 146 children were treated with either AL or DP. Both groups received directly observed therapy and were followed for 28 days after treatment. Blood samples were analysed with microscopy and NASBA. In comparison with microscopy NASBA detected much more gametocyte positive individuals. Moreover, NASBA showed a significant difference in gametocyte clearance in favour of AL compared to DP. The decline of parasitaemia was slower and persistence or development of gametocytes was significantly higher and longer at day 3, 7 and 14 in the DP group but after 28 days no difference could be observed between both treatment arms.</p> <p>Conclusion</p> <p>Although practical considerations could favour the use of one drug over another, the effect on gametocytogenesis should also be taken into account and studied further using molecular tools like NASBA. This also applies when a new drug is introduced.</p> <p>Trial registration</p> <p>Current controlled trials ISRCTN36463274</p

The relationship between sensory sensitivity and autistic traits in the general population.

Individuals with Autism Spectrum Disorders (ASDs) tend to have sensory processing difficulties (Baranek et al. in J Child Psychol Psychiatry 47:591–601, 2006). These difficulties include over- and under-responsiveness to sensory stimuli, and problems modulating sensory input (Ben-Sasson et al. in J Autism Dev Disorders 39:1–11, 2009). As those with ASD exist at the extreme end of a continuum of autistic traits that is also evident in the general population, we investigated the link between ASD and sensory sensitivity in the general population by administering two questionnaires online to 212 adult participants. Results showed a highly significant positive correlation (r = .775, p &#60; .001) between number of autistic traits and the frequency of sensory processing problems. These data suggest a strong link between sensory processing and autistic traits in the general population, which in turn potentially implicates sensory processing problems in social interaction difficulties

Longitudinal stability of temperamental exuberance and social-emotional outcomes in early childhood

The goals of the current study were to investigate the stability of temperamental exuberance across infancy and toddlerhood and to examine the associations between exuberance and social-emotional outcomes in early childhood. The sample consisted of 291 4-month-olds followed at 9, 24, and 36 months and again at 5 years of age. Behavioral measures of exuberance were collected at 9, 24, and 36 months. At 36 months, frontal electroencephalogram (EEG) asymmetry was assessed. At 5 years, maternal reports of temperament and behavior problems were collected, as were observational measures of social behavior during an interaction with an unfamiliar peer in the laboratory. Latent profile analysis revealed a high, stable exuberance profile that was associated with greater ratings of 5-year externalizing behavior and surgency, as well as observed disruptive behavior and social competence with unfamiliar peers. These associations were particularly true for children who displayed left frontal EEG asymmetry. Multiple factors supported an approach bias for exuberant temperament but did not differentiate between adaptive and maladaptive social-emotional outcomes at 5 years of age