A strategy for designing inhibitors of alpha-synuclein aggregation and toxicity as a novel treatment for Parkinson's disease and related disorders.

Convergent biochemical and genetic evidence suggests that the formation of alpha-synuclein (alpha-syn) protein deposits is an important and, probably, seminal step in the development of Parkinson's disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy (MSA). It has been reported that transgenic animals overexpressing human alpha-syn develop lesions similar to those found in the brain in PD, together with a progressive loss of dopaminergic cells and associated abnormalities of motor function. Inhibiting and/or reversing alpha-syn self-aggregation could, therefore, provide a novel approach to treating the underlying cause of these diseases. We synthesized a library of overlapping 7-mer peptides spanning the entire alpha-syn sequence, and identified amino acid residues 64-100 of alpha-syn as the binding region responsible for its self-association. Modified short peptides containing alpha-syn amino acid sequences from part of this binding region (residues 69-72), named alpha-syn inhibitors (ASI), were found to interact with full-length alpha-syn and block its assembly into both early oligomers and mature amyloid-like fibrils. We also developed a cell-permeable inhibitor of alpha-syn aggregation (ASID), using the polyarginine peptide delivery system. This ASID peptide was able to inhibit the DNA damage induced by Fe(II) in neuronal cells transfected with alpha-syn(A53T), a familial PD-associated mutation. ASI peptides without this delivery system did not reverse levels of Fe(II)-induced DNA damage. Furthermore, the ASID peptide increased (P

The periodic variations of a white-light flare observed with ULTRACAM

High time resolution observations of a white-light flare on the active star EQ PegB show evidence of intensity variations with a period of ≈10 s. The period drifts to longer values during the decay phase of the flare. If the oscillation is interpreted as an impulsively-excited, standing-acoustic wave in a flare loop, the period implies a loop length of ≈3.4 Mm and ≈6.8 Mm for the case of the fundamental mode and the second harmonic, respectively. However, the small loop lengths imply a very high modulation depth making the acoustic interpretation unlikely. A more realistic interpretation may be that of a fast-MHD wave, with the modulation of the emission being due to the magnetic field. Alternatively, the variations could be due to a series of reconnection events. The periodic signature may then arise as a result of the lateral separation of individual flare loops or current sheets with oscillatory dynamics (i.e., periodic reconnection).

White-light oscillations during a flare on II Peg

We analyse the intensity oscillations observed in the gradual phase of a white-light flare on the RS CV n binary II Peg. Fast Fourier Transform power spectra and Wavelet analysis reveal a period of 220 s. The reliability of the oscillation is tested using several criteria. Oscillating coronal loop models are used to derive physical parameters such as temperature, electron density and magnetic field strength associated with the coronal loop. The derived parameters are consistent with the near-simultaneous X-ray observations of the flare. There is no evidence for oscillations in the quiescent state of the binary.

Absence of aquaporin-4 expression in lesions of neuromyelitis optica but increased expression in multiple sclerosis lesions and normal-appearing white matter.

Aquaporin-4 (AQP4) has recently been implicated in the pathogenesis of neuromyelitis optica(NMO) where it has been identifed as the first defined autoantigen pertinent to an infammatory demyelinating disorder of the human CNS. Furthermore, a recent case report has shown a lack of AQP4 expression in the spinal cord lesions of NMO. However, the pattern of AQP4 expression in multiple sclerosis (MS) tissues has not been well-defned. In the present investigation we have confirmed a lack of expression of AQP4 in optic and spinal cord lesions in NMO which contrasted sharply with the increased levels of AQP4 expression seen in MS lesions. Furthermore a detailed immunohistochemical and semi-quantitative analysis is used to describe the expression pattern of AQP4 on well-characterized tissue microarray samples of MS and control white matter. Anatomically AQP4 was more highly expressed in all categories of MS tissue compared to normal control tissues with the most abundant expression in active lesions. Within active lesions AQP4 expression was significantly correlated with expression of the pro-infammatory cytokine osteopontin. At the cellular level dual-labelling immunofluoresence demonstrated that increased expression of AQP4 was most pronounced at the astrocytic endfeet but was also associated with the cell bodies of astrocytes in the tissue parenchyma. The finding of increased AQP4 expression in MS lesions in contrast to the lack of expression in NMO lesions may suggest different mechanisms of initiation and progression between the two disease states.

Novel frenatins from the skin of the Australasian Giant White-lipped tree frog, Litoria infrafrenata: cloning of precursor cDNAs and identification in defensive skin secretion.

The Australasian anuran amphibian genus Litoria, contains many phenotypically-diverse species as a result of radial evolution of an ancestral species into different biotopes much in the manner of the indigenous marsupial mammals. In common with members of the Central/South American genus Phyllomedusa, their specialized skin granular glands are factories for the production of a plethora of biologically-active peptides. Here we report a more detailed study of those present in the defensive skin secretion of the Australasian giant white-lipped tree frog, Litoria infrafrenata, and, for the first time, we have identified three novel frenatins by deduction of primary structures from cDNAs that were cloned from a library constructed from lyophilized skin secretion using a recently-developed technique. All open-reading frames consisted of a putative signal peptide and an acidic pro-region followed by a single copy of a frenatin peptide. Processed peptides corresponding in molecular mass to the deduced molecular masses of frenatins (named 1.1, 3, 3.1 and 4.1) were identified in the same secretion sample using HPLC and mass spectroscopy. The application of this technique thus permits parallel peptidomic and transcriptomic analyzes on the same lyophilized skin secretion sample circumventing sacrifice of specimens from endangered herpetofauna.