Drosophila melanogaster in the Study of Human Neurodegeneration

Human neurodegenerative diseases are devastating illnesses that predominantly affect elderly people. The majority of the diseases are associated with pathogenic oligomers from misfolded proteins, eventually causing the formation of aggregates and the progressive loss of neurons in the brain and nervous system. Several of these proteinopathies are sporadic and the cause of pathogenesis remains elusive. Heritable forms are associated with genetic defects, suggesting that the affected protein is causally related to disease formation and/or progression. The limitations of human genetics, however, make it necessary to use model systems to analyse affected genes and pathways in more detail. During the last two decades, research using the genetically amenable fruitfly has established Drosophila melanogaster as a valuable model system in the study of human neurodegeneration. These studies offer reliable models for Alzheimer’s, Parkinson’s, and motor neuron diseases, as well as models for trinucleotide repeat expansion diseases, including ataxias and Huntington’s disease. As a result of these studies, several signalling pathways including phosphatidylinositol 3-kinase (PI3K)/Akt and target of rapamycin (TOR), c-Jun N-terminal kinase (JNK) and bone morphogenetic protein (BMP) signalling, have been shown to be deregulated in models of proteinopathies, suggesting that two or more initiating events may trigger disease formation in an age-related manner. Moreover, these studies also demonstrate that the fruitfly can be used to screen chemical compounds for their potential to prevent or ameliorate the disease, which in turn can directly guide clinical research and the development of novel therapeutic strategies for the treatment of human neurodegenerative diseases

Introduction to ‘Homology and convergence in nervous system evolution’

The origin of brains and central nervous systems (CNSs) is thought to have occurred before the Palaeozoic era 540 Ma. Yet in the absence of tangible evidence, there has been continued debate whether today's brains and nervous systems derive from one ancestral origin or whether similarities among them are due to convergent evolution. With the advent of molecular developmental genetics and genomics, it has become clear that homology is a concept that applies not only to morphologies, but also to genes, developmental processes, as well as to behaviours. Comparative studies in phyla ranging from annelids and arthropods to mammals are providing evidence that corresponding developmental genetic mechanisms act not only in dorso–ventral and anterior–posterior axis specification but also in segmentation, neurogenesis, axogenesis and eye/photoreceptor cell formation that appear to be conserved throughout the animal kingdom. These data are supported by recent studies which identified Mid-Cambrian fossils with preserved soft body parts that present segmental arrangements in brains typical of modern arthropods, and similarly organized brain centres and circuits across phyla that may reflect genealogical correspondence and control similar behavioural manifestations. Moreover, congruence between genetic and geological fossil records support the notion that by the ‘Cambrian explosion’ arthropods and chordates shared similarities in brain and nervous system organization. However, these similarities are strikingly absent in several sister- and outgroups of arthropods and chordates which raises several questions, foremost among them: what kind of natural laws and mechanisms underlie the convergent evolution of such similarities? And, vice versa: what are the selection pressures and genetic mechanisms underlying the possible loss or reduction of brains and CNSs in multiple lineages during the course of evolution? These questions were addressed at a Royal Society meeting to discuss homology and convergence in nervous system evolution. By integrating knowledge ranging from evolutionary theory and palaeontology to comparative developmental genetics and phylogenomics, the meeting covered disparities in nervous system origins as well as correspondences of neural circuit organization and behaviours, all of which allow evidence-based debates for and against the proposition that the nervous systems and brains of animals might derive from a common ancestor

The Dopaminergic System in the Aging Brain of Drosophila

Drosophila models of Parkinson's disease are characterized by two principal phenotypes: the specific loss of dopaminergic (DA) neurons in the aging brain and defects in motor behavior. However, an age-related analysis of these baseline parameters in wildtype Drosophila is lacking. Here we analyzed the DA system and motor behavior in aging Drosophila. DA neurons in the adult brain can be grouped into bilateral symmetric clusters, each comprising a stereotypical number of cells. Analysis of TH > mCD8::GFP and cell type-specific MARCM clones revealed that DA neurons show cluster-specific, stereotypical projection patterns with terminal arborization in target regions that represent distinct functional areas of the adult brain. Target areas include the mushroom bodies, involved in memory formation and motivation, and the central complex, involved in the control of motor behavior, indicating that similar to the mammalian brain, DA neurons in the fly brain are involved in the regulation of specific behaviors. Behavioral analysis revealed that Drosophila show an age-related decline in startle-induced locomotion and negative geotaxis. Motion tracking however, revealed that walking activity, and exploration behavior, but not centrophobism increase at late stages of life. Analysis of TH > Dcr2, mCD8::GFP revealed a specific effect of Dcr2 expression on walking activity but not on exploratory or centrophobic behavior, indicating that the siRNA pathway may modulate distinct DA behaviors in Drosophila. Moreover, DA neurons were maintained between early- and late life, as quantified by TH > mCD8::GFP and anti-TH labeling, indicating that adult onset, age-related degeneration of DA neurons does not occur in the aging brain of Drosophila. Taken together, our data establish baseline parameters in Drosophila for the study of Parkinson's disease as well as other disorders affecting DA neurons and movement control

Ground state of a large number of particles on a frozen topography

Problems consisting in finding the ground state of particles interacting with a given potential constrained to move on a particular geometry are surprisingly difficult. Explicit solutions have been found for small numbers of particles by the use of numerical methods in some particular cases such as particles on a sphere and to a much lesser extent on a torus. In this paper we propose a general solution to the problem in the opposite limit of a very large number of particles M by expressing the energy as an expansion in M whose coefficients can be minimized by a geometrical ansatz. The solution is remarkably universal with respect to the geometry and the interaction potential. Explicit solutions for the sphere and the torus are provided. The paper concludes with several predictions that could be verified by further theoretical or numerical work.Comment: 9 pages, 9 figures, LaTeX fil

Crowdsourced network measurements: Benefits and best practices

Network measurements are of high importance both for the operation of networks and for the design and evaluation of new management mechanisms. Therefore, several approaches exist for running network measurements, ranging from analyzing live traffic traces from campus or Internet Service Provider (ISP) networks to performing active measurements on distributed testbeds, e.g., PlanetLab, or involving volunteers. However, each method falls short, offering only a partial view of the network. For instance, the scope of passive traffic traces is limited to an ISP’s network and customers’ habits, whereas active measurements might be biased by the population or node location involved. To complement these techniques, we propose to use (commercial) crowdsourcing platforms for network measurements. They permit a controllable, diverse and realistic view of the Internet and provide better control than do measurements with voluntary participants. In this study, we compare crowdsourcing with traditional measurement techniques, describe possible pitfalls and limitations, and present best practices to overcome these issues. The contribution of this paper is a guideline for researchers to understand when and how to exploit crowdsourcing for network measurements

Buried dislocation networks designed to organize the growth of III-V semiconductor nanostructures

We first report a detailed transmission electron microscopy study of dislocation networks (DNs) formed at shallowly buried interfaces obtained by bonding two GaAs crystals between which we establish in a controlled manner a twist and a tilt around a k110l direction. For large enough twists, the DN consists of a twodimensional network of screw dislocations accommodating mainly the twist and of a one-dimensional network of mixed dislocations accommodating mainly the tilt. We show that in addition the mixed dislocations accommodate part of the twist and we observe and explain slight unexpected disorientations of the screw dislocations with respect to the k110l directions. By performing a quantitative analysis of the whole DN, we propose a coherent interpretation of these observations which also provides data inaccessible by direct experiments. When the twist is small enough, one screw subnetwork vanishes. The surface strain field induced by such DNs has been used to pilot the lateral ordering of GaAs and InGaAs nanostructures during metal-organic vapor phase epitaxy. We prove that the dimensions and orientations of the nanostructures are correlated with those of the cells of the underlying DN and explain how the interface dislocation structure governs the formation of the nanostructures

Hydrodynamical Models of Outflow Collimation in YSOs

We explore the physics of time-dependent hydrodynamic collimation of jets from Young Stellar Objects (YSOs). Using parameters appropriate to YSOs we have carried out high resolution hydrodynamic simulations modeling the interaction of a central wind with an environment characterized by a moderate opening angle toroidal density distribution. The results show that the the wind/environment interaction produces strongly collimated supersonic jets. The jet is composed of shocked wind gas. Using analytical models of wind blown bubble evolution we show that the scenario studied here should be applicable to YSOs and can, in principle, initiate collimation on the correct scales (R ~ 100 AU). The simulations reveal a number of time-dependent non-linear features not anticipated in previous analytical studies including: a prolate wind shock; a chimney of cold swept-up ambient material dragged into the bubble cavity; a plug of dense material between the jet and bow shocks. We find that the collimation of the jet occurs through both de Laval nozzles and focusing of the wind via the prolate wind shock. Using an analytical model for shock focusing we demonstrate that a prolate wind shock can, by itself, produce highly collimated supersonic jets.Comment: Accepted by ApJ, 31 pages with 12 figures (3 JPEG's) now included, using aasms.sty, Also available in postscript via a gzipped tar file at ftp://s1.msi.umn.edu/pub/afrank/SFIC1/SFIC.tar.g