Site-specific perturbations of alpha-synuclein fibril structure by the Parkinson's disease associated mutations A53T and E46K.

PMCID: PMC3591419This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Parkinson's disease (PD) is pathologically characterized by the presence of Lewy bodies (LBs) in dopaminergic neurons of the substantia nigra. These intracellular inclusions are largely composed of misfolded α-synuclein (AS), a neuronal protein that is abundant in the vertebrate brain. Point mutations in AS are associated with rare, early-onset forms of PD, although aggregation of the wild-type (WT) protein is observed in the more common sporadic forms of the disease. Here, we employed multidimensional solid-state NMR experiments to assess A53T and E46K mutant fibrils, in comparison to our recent description of WT AS fibrils. We made de novo chemical shift assignments for the mutants, and used these chemical shifts to empirically determine secondary structures. We observe significant perturbations in secondary structure throughout the fibril core for the E46K fibril, while the A53T fibril exhibits more localized perturbations near the mutation site. Overall, these results demonstrate that the secondary structure of A53T has some small differences from the WT and the secondary structure of E46K has significant differences, which may alter the overall structural arrangement of the fibrils

About females and males: continuity and discontinuity in flies

Through the decades of relentless and dedicated studies in Drosophila melanogaster, the pathway that governs sexual development has been elucidated in great detail and has become a paradigm in understanding fundamental cell-fate decisions. However, recent phylogenetic studies show that the molecular strategy used in Drosophila deviates in some important aspects from those found in other dipteran flies and suggest that the Drosophila pathway is likely to be a derivative of a simpler and more common principle. In this essay, I will discuss the evolutionary plasticity of the sex-determining pathway based on studies in the common housefly, Musca domestica. Diversification appears to primarily arise from subtle differences in the regulation of the key switch gene transformer at the top of the pathway. On the basis of these findings I propose a new idea on how the Drosophila pathway may have evolved from a more archetypal system such as in M. domestica. In essence, the arrival of an X counting mechanism mediated by Sex-lethal to compensate for X linked gene dose differences set the stage for an intimate coupling of the two pathways. Its precedent recruitment to the dosage compensation pathway allowed for an intervention in the regulation of transformer where it gradually and eventually' completely substituted for a need of transformer autoregulation

Persistent Lipophilic Environmental Chemicals and Endometriosis: The ENDO Study

Background: An equivocal literature exists regarding the relation between persistent organochlorine pollutants (POPs) and endometriosis in women, with differences attributed to methodologies

Genome of the house fly, <i>Musca domestica</i> L., a global vector of diseases with adaptations to a septic environment

Background: Adult house flies, Musca domestica L., are mechanical vectors of more than 100 devastating diseases that have severe consequences for human and animal health. House fly larvae play a vital role as decomposers of animal wastes, and thus live in intimate association with many animal pathogens. Results: We have sequenced and analyzed the genome of the house fly using DNA from female flies. The sequenced genome is 691 Mb. Compared with Drosophila melanogaster, the genome contains a rich resource of shared and novel protein coding genes, a significantly higher amount of repetitive elements, and substantial increases in copy number and diversity of both the recognition and effector components of the immune system, consistent with life in a pathogen-rich environment. There are 146 P450 genes, plus 11 pseudogenes, in M. domestica, representing a significant increase relative to D. melanogaster and suggesting the presence of enhanced detoxification in house flies. Relative to D. melanogaster, M. domestica has also evolved an expanded repertoire of chemoreceptors and odorant binding proteins, many associated with gustation. Conclusions: This represents the first genome sequence of an insect that lives in intimate association with abundant animal pathogens. The house fly genome provides a rich resource for enabling work on innovative methods of insect control, for understanding the mechanisms of insecticide resistance, genetic adaptation to high pathogen loads, and for exploring the basic biology of this important pest. The genome of this species will also serve as a close out-group to Drosophila in comparative genomic studies

Transformative Pedagogies for Sustainable Development

Transformative pedagogies for sustainable development encourage learners to change the direction of development that seems to be inevitable by enhancing their awareness, understanding of complexities, empathy, compassion and empowermentPeer reviewe

Body mass index, adiposity rebound and early feeding in a longitudinal cohort (Raine study)

Objective: This study examined the influence of type and duration of infant feeding on adiposity rebound and the tracking of body mass index (BMI) from birth to 14 years. Methods: A sample of 1330 individuals over eight follows-ups was drawn from the Western Australian Pregnancy Cohort (Raine) Study. Trajectories of BMI from birth to adolescence using linear mixed model (LMM) analysis investigated the influence of age breastfeeding stopped and age other milk introduced (binomial 4-month cut-point). A sub-sample of LMM predicted BMI was used to determine BMI and age at nadir for early infant feeding groups. Results: Chi square analysis between early feeding and weight status (normal weight, overweight and obese) groups found a significant difference between age breastfeeding stopped (p Conclusions: Early infant feeding was important in the timing and BMI at adiposity rebound. The relationship between infant feeding and BMI remained up to age 14 years. Although confounding factors cannot be excluded, these findings support the importance of exclusive breastfeeding for longer than four months as a protective behaviour against the development of adolescent obesity

A Review of Flight-Initiation Distances and their Application to Managing Disturbance to Australian Birds

Disturbance – the response of birds to a stimulus such as the presence of a person – is considered a conservation threat for some Australian birds. The distance at which a bird flees from perceived danger is defined as the flight-initiation distance (FID), and could be used to designate separation distances between birds and stimuli that might cause disturbance. We review the known FIDs for Australian birds, and report FIDs for 250 species. Most FIDs are from south-eastern Australia, and almost all refer to a single walker as the stimulus. Several prominent factors correlated with FID are discussed (e.g. body mass and the distance at which an approach begins). FIDs have not been used extensively in the management of disturbance, for a variety of reasons including lack and inaccessibility of available data. We call for standardised data collection and greater application of available data to the management of disturbance