3,122 research outputs found

    Analysis of Toxic Amyloid Fibril Interactions at Natively Derived Membranes by Ellipsometry

    Get PDF
    There is an ongoing debate regarding the culprits of cytotoxicity associated with amyloid disorders. Although small pre-fibrillar amyloid oligomers have been implicated as the primary toxic species, the fibrillar amyloid material itself can also induce cytotoxicity. To investigate membrane disruption and cytotoxic effects associated with intact and fragmented fibrils, the novel in situ spectroscopic technique of Total Internal Reflection Ellipsometry (TIRE) was used. Fibril lipid interactions were monitored using natively derived whole cell membranes as a model of the in vivo environment. We show that fragmented fibrils have an increased ability to disrupt these natively derived membranes by causing a loss of material from the deposited surface when compared with unfragmented fibrils. This effect was corroborated by observations of membrane disruption in live cells, and by dye release assay using synthetic liposomes. Through these studies we demonstrate the use of TIRE for the analysis of protein-lipid interactions on natively derived lipid surfaces, and provide an explanation on how amyloid fibrils can cause a toxic gain of function, while entangled amyloid plaques exert minimal biological activity

    Squelched Galaxies and Dark Halos

    Get PDF
    There is accumulating evidence that the faint end of the galaxy luminosity function might be very different in different locations. The luminosity function might be rising in rich clusters and flat or declining in regions of low density. If galaxies form according to the model of hierarchical clustering then there should be many small halos compared to the number of big halos. If this theory is valid then there must be a mechanism that eliminates at least the visible component of galaxies in low density regions. A plausible mechanism is photoionization of the intergalactic medium at a time before the epoch that most dwarf galaxies form in low density regions but after the epoch of formation for similar systems that ultimately end up in rich clusters. The dynamical timescales are found to accommodate this hypothesis in a flat universe with Omega_m < 0.4. If small halos exist but simply cannot be located because they have never become the sites of significant star formation, they still might have dynamical manifestations. These manifestations are hard to identify in normal groups of galaxies because small halos do not make a significant contribution to the global mass budget. However, it could be entertained that there are clusters of halos where there are only small systems, clusters that are at the low mass end of the hierarchical tree. There may be places where only a few small galaxies managed to form, enough for us to identify and use as test probes of the potential. It turns out that such environments might be common. Four probable groups of dwarfs are identified within 5 Mpc and the assumption they are gravitationally bound suggests M/L_B ~ 300 - 1200 M_sun/L_sun, 6 +/- factor 2 times higher than typical values for groups with luminous galaxies.Comment: Accepted ApJ 569, (April 20), 2002, 12 pages, 6 figures, 1 tabl

    An algorithm for the direct reconstruction of the dark matter correlation function from weak lensing and galaxy clustering

    Full text link
    The clustering of matter on cosmological scales is an essential probe for studying the physical origin and composition of our Universe. To date, most of the direct studies have focused on shear-shear weak lensing correlations, but it is also possible to extract the dark matter clustering by combining galaxy-clustering and galaxy-galaxy-lensing measurements. In this study we develop a method that can constrain the dark matter correlation function from galaxy clustering and galaxy-galaxy-lensing measurements, by focusing on the correlation coefficient between the galaxy and matter overdensity fields. To generate a mock galaxy catalogue for testing purposes, we use the Halo Occupation Distribution approach applied to a large ensemble of N-body simulations to model pre-existing SDSS Luminous Red Galaxy sample observations. Using this mock catalogue, we show that a direct comparison between the excess surface mass density measured by lensing and its corresponding galaxy clustering quantity is not optimal. We develop a new statistic that suppresses the small-scale contributions to these observations and show that this new statistic leads to a cross-correlation coefficient that is within a few percent of unity down to 5 Mpc/h. Furthermore, the residual incoherence between the galaxy and matter fields can be explained using a theoretical model for scale-dependent bias, giving us a final estimator that is unbiased to within 1%. We also perform a comprehensive study of other physical effects that can affect the analysis, such as redshift space distortions and differences in radial windows between galaxy clustering and weak lensing observations. We apply the method to a range of cosmological models and show the viability of our new statistic to distinguish between cosmological models.Comment: 23 pages, 14 figures, accepted by PRD; minor changes to V1, 1 new figure, more detailed discussion of the covariance of the new ADSD statisti

    Tear Fluid Pharmacokinetics Following Oral Prednisone Administration in Dogs With and Without Conjunctivitis

    Get PDF
    Purpose: To describe the pharmacokinetics (PK) of prednisone and prednisolone in tear fluid of dogs receiving oral prednisone at anti-inflammatory to immunosuppressive doses and to assess the impact of induced conjunctivitis on lacrimal drug levels. Methods: Six healthy Beagle dogs were administered 4 courses of prednisone at 0.5, 1.0, 2.0, and 4.0 mg/kg given orally once a day for 5 days. At steady state, topical histamine was applied to induce mild (1 mg/mL) or severe (375 mg/mL) conjunctivitis in 1 eye of each dog and tear samples were collected from both eyes at selected times. Prednisone and prednisolone were quantified in tears by liquid chromatography-mass spectrometry. Results: Lacrimal prednisone and prednisolone concentrations ranged from 2 to 523 ng/mL and 5 to 191 ng/mL, respectively. Drug concentrations were overall greater in dogs receiving higher doses of prednisone, but were not correlated with tear flow rate. Eyes with conjunctivitis often had larger amounts of prednisone and prednisolone in tear fluid compared to control eyes (up to +64%), but differences were not statistically significant. Significantly greater, but clinically insignificant, levels of prednisolone were found in eyes with severe versus mild conjunctivitis for oral prednisone doses ≥1.0 mg/kg. Conclusions: Disruption of the blood–tear barrier with conjunctivitis did not significantly affect drug levels in tears. Based on drug PK in tears, oral prednisone is likely safe for the management of reflex uveitis and ocular surface diseases. However, further prospective trials using systemic corticotherapy in diseased animals are warranted to confirm findings from this preclinical study

    Onset of experimental severe cardiac fibrosis is mediated by overexpression of angiotensin-converting enzyme 2

    Get PDF
    Angiotensin-converting enzyme (ACE) 2 is a recently identified homologue of ACE. There is great interest in the therapeutic benefit for ACE2 overexpression in the heart. However, the role of ACE2 in the regulation of cardiac structure and function, as well as maintenance of systemic blood pressure, remains poorly understood. In cell culture, ACE2 overexpression led to markedly increased myocyte volume, assessed in primary rabbit myocytes. To assess ACE2 function in vivo, we used a recombinant adeno-associated virus 6 delivery system to provide 11-week overexpression of ACE2 in the myocardium of stroke-prone spontaneously hypertensive rats. ACE2, as well as the ACE inhibitor enalapril, significantly reduced systolic blood pressure. However, in the heart, ACE2 overexpression resulted in cardiac fibrosis, as assessed by histological analysis with concomitant deficits in ejection fraction and fractional shortening measured by echocardiography. Furthermore, global gene expression profiling demonstrated the activation of profibrotic pathways in the heart mediated by ACE2 gene delivery. This study demonstrates that sustained overexpression of ACE2 in the heart in vivo leads to the onset of severe fibrosis

    The Orthologue of Sjögren's Syndrome Nuclear Autoantigen 1 (SSNA1) in Trypanosoma brucei Is an Immunogenic Self-Assembling Molecule

    Get PDF
    Primary Sjögren's Syndrome (PSS) is a highly prevalent autoimmune disease, typically manifesting as lymphocytic infiltration of the exocrine glands leading to chronically impaired lacrimal and salivary secretion. Sjögren's Syndrome nuclear autoantigen 1 (SSNA1 or NA14) is a major specific target for autoantibodies in PSS but the precise function and clinical relevance of this protein are largely unknown. Orthologues of the gene are absent from many of the commonly used model organisms but are present in Chlamyodomonas reinhardtii (in which it has been termed DIP13) and most protozoa. We report the functional characterisation of the orthologue of SSNA1 in the kinetoplastid parasite, Trypanosoma brucei. Both TbDIP13 and human SSNA1 are small coiled-coil proteins which are predicted to be remote homologues of the actin-binding protein tropomyosin. We use comparative proteomic methods to identify potential interacting partners of TbDIP13. We also show evidence that TbDIP13 is able to self-assemble into fibril-like structures both in vitro and in vivo, a property which may contribute to its immunogenicity. Endogenous TbDIP13 partially co-localises with acetylated α-tubulin in the insect procyclic stage of the parasite. However, deletion of the DIP13 gene in cultured bloodstream and procyclic stages of T. brucei has little effect on parasite growth or morphology, indicating either a degree of functional redundancy or a function in an alternative stage of the parasite life cycle
    corecore