Stochastic Modelling Approach to the Incubation Time of Prionic Diseases

Transmissible spongiform encephalopathies like the bovine spongiform encephalopathy (BSE) and the Creutzfeldt-Jakob disease (CJD) in humans are neurodegenerative diseases for which prions are the attributed pathogenic agents. A widely accepted theory assumes that prion replication is due to a direct interaction between the pathologic (PrPsc) form and the host encoded (PrPc) conformation, in a kind of an autocatalytic process. Here we show that the overall features of the incubation time of prion diseases are readily obtained if the prion reaction is described by a simple mean-field model. An analytical expression for the incubation time distribution then follows by associating the rate constant to a stochastic variable log normally distributed. The incubation time distribution is then also shown to be log normal and fits the observed BSE data very well. The basic ideas of the theoretical model are then incorporated in a cellular automata model. The computer simulation results yield the correct BSE incubation time distribution at low densities of the host encoded protein

On the Spectral Evolution of Cool, Helium-Atmosphere White Dwarfs: Detailed Spectroscopic and Photometric Analysis of DZ Stars

We present a detailed analysis of a large spectroscopic and photometric sample of DZ white dwarfs based on our latest model atmosphere calculations. We revise the atmospheric parameters of the trigonometric parallax sample of Bergeron, Leggett, & Ruiz (12 stars) and analyze 147 new DZ white dwarfs discovered in the Sloan Digital Sky Survey. The inclusion of metals and hydrogen in our model atmosphere calculations leads to different atmospheric parameters than those derived from pure helium models. Calcium abundances are found in the range from log (Ca/He) = -12 to -8. We also find that fits of the coolest objects show peculiarities, suggesting that our physical models may not correctly describe the conditions of high atmospheric pressure encountered in the coolest DZ stars. We find that the mean mass of the 11 DZ stars with trigonometric parallaxes, = 0.63 Mo, is significantly lower than that obtained from pure helium models, = 0.78 Mo, and in much better agreement with the mean mass of other types of white dwarfs. We determine hydrogen abundances for 27% of the DZ stars in our sample, while only upper limits are obtained for objects with low signal-to-noise ratio spectroscopic data. We confirm with a high level of confidence that the accretion rate of hydrogen is at least two orders of magnitude smaller than that of metals (and up to five in some cases) to be compatible with the observations. We find a correlation between the hydrogen abundance and the effective temperature, suggesting for the first time empirical evidence of a lower temperature boundary for the hydrogen screening mechanism. Finally, we speculate on the possibility that the DZA white dwarfs could be the result of the convective mixing of thin hydrogen-rich atmospheres with the underlying helium convection zone.Comment: 67 pages, 32 figures, accepted for publication in Ap

Shadoo (Sprn) and prion disease incubation time in mice

Prion diseases are transmissible neurodegenerative disorders of mammalian species and include scrapie, bovine spongiform encephalopathy (BSE), and variant Creutzfeldt-Jakob disease (vCJD). The prion protein (PrP) plays a key role in the disease, with coding polymorphism in both human and mouse influencing disease susceptibility and incubation time, respectively. Other genes are also thought to be important and a plausible candidate is Sprn, which encodes the PrP-like protein Shadoo (Sho). Sho is expressed in the adult central nervous system and exhibits neuroprotective activity reminiscent of PrP in an in vitro assay. To investigate the role of Sprn in prion disease incubation time we sequenced the open reading frame (ORF) in a diverse panel of mice and saw little variation except in strains derived from wild-trapped mice. Sequencing the untranslated regions revealed polymorphisms that allowed us to carry out an association study of incubation period in the Northport heterogeneous stock of mice inoculated with Chandler/RML prions. We also examined the expression level of Sprn mRNA in the brains of normal and prion-infected mice and saw no correlation with either genotype or incubation time. We therefore conclude that Sprn does not play a major role in prion disease incubation time in these strains of mice

Plant extracts as potential control agents of Black Sigatoka in banana

Aqueous extracts of Cinnamomum zeylanicum, Capsicum annuum and Azadirachta indica were tested for efficacy for management of Pseudocercospora fijiensis in banana (Musa spp.) when applied as foliar sprays. Extracts of C. annuum and A.indica demonstrated fungicidal effects in vitro, without showing phytotoxic effects. The two extracts protected tissue culture banana plantlets of cultivar Musakala to a similar degree as the traditional fungicide difenoconazole. Extracts of A. indica and C. annuum (0.3 g/ml) reduced Black Sigatoka severity by 69.3% and 65.6%, respectively, and were thus comparable to the fungicide difenoconazole (72.7%). Soil drenching of the extracts did not significantly reduce Black Sigatoka severity. In planta effects of the extracts mainly consisted of delayed symptom appearance and reduced lesion number. Symptom development was dependent on extract concentration and days between extract application and inoculation. Effect of the tested extracts on height of plants and new leaves was not significant. Collectively, our data suggest that A. indica and C. annuum have interesting and unique properties as plant protection agents against Pseudocercospora fijiensis, but further research is needed to investigate their efficacy

HECTD2 Is Associated with Susceptibility to Mouse and Human Prion Disease

Prion diseases are fatal transmissible neurodegenerative disorders, which include Scrapie, Bovine Spongiform Encephalopathy (BSE), Creutzfeldt-Jakob Disease (CJD), and kuru. They are characterised by a prolonged clinically silent incubation period, variation in which is determined by many factors, including genetic background. We have used a heterogeneous stock of mice to identify Hectd2, an E3 ubiquitin ligase, as a quantitative trait gene for prion disease incubation time in mice. Further, we report an association between HECTD2 haplotypes and susceptibility to the acquired human prion diseases, vCJD and kuru. We report a genotype-associated differential expression of Hectd2 mRNA in mouse brains and human lymphocytes and a significant up-regulation of transcript in mice at the terminal stage of prion disease. Although the substrate of HECTD2 is unknown, these data highlight the importance of proteosome-directed protein degradation in neurodegeneration. This is the first demonstration of a mouse quantitative trait gene that also influences susceptibility to human prion diseases. Characterisation of such genes is key to understanding human risk and the molecular basis of incubation periods

Isolation of Proteinase K-Sensitive Prions Using Pronase E and Phosphotungstic Acid

Disease-related prion protein, PrPSc, is classically distinguished from its normal cellular precursor, PrPC, by its detergent insolubility and partial resistance to proteolysis. Molecular diagnosis of prion disease typically relies upon detection of protease-resistant fragments of PrPSc using proteinase K, however it is now apparent that the majority of disease-related PrP and indeed prion infectivity may be destroyed by this treatment. Here we report that digestion of RML prion-infected mouse brain with pronase E, followed by precipitation with sodium phosphotungstic acid, eliminates the large majority of brain proteins, including PrPC, while preserving >70% of infectious prion titre. This procedure now allows characterization of proteinase K-sensitive prions and investigation of their clinical relevance in human and animal prion disease without being confounded by contaminating PrPC

Substructure revealed by RR Lyraes in SDSS Stripe 82

We present an analysis of the substructure revealed by 407 RR Lyraes in Sloan Digital Sky Survey (SDSS) Stripe 82. Period estimates are determined to high accuracy using a string-length method. A subset of 178 RR Lyraes with spectrally derived metallicities are employed to derive metallicity-period-amplitude relations, which are then used to find metallicities and distances for the entire sample. The RR Lyraes lie between 5 and 115 kpc from the Galactic center. They are divided into subsets of 316 RRab types and 91 RRc types based on their period, colour and metallicity. The density distribution is not smooth, but dominated by clumps and substructure. Samples of 55 and 237 RR Lyraes associated with the Sagittarius Stream and the Hercules-Aquila Cloud respectively are identified. Hence, ~ 70 % of the RR Lyraes in Stripe 82 belong to known substructure. There is a sharp break in the density distribution at Galactocentric radii of 40 kpc, reflecting the fact that the dominant substructure in Stripe 82 - the Hercules-Aquila Cloud and the Sagittarius Stream - lies within 40 kpc. In fact, almost 60 % of all the RR Lyraes in Stripe 82 are associated with the Hercules-Aquila Cloud alone, which emphasises its pre-eminence. Additionally, evidence of a new and distant substructure - the Pisces Overdensity - is found, consisting of 28 faint RR Lyraes centered on Galactic coordinates (80 deg, -55 deg) and with distances of ~ 80 kpc. The total stellar mass in the Pisces Overdensity is ~10000 solar masses and its metallicity is [Fe/H] ~ -1.5.Comment: 15 pages, submitted to MNRA

An Initial Survey of White Dwarfs in the Sloan Digital Sky Survey

An initial assessment is made of white dwarf and hot subdwarf stars observed in the Sloan Digital Sky Survey. In a small area of sky (190 square degrees), observed much like the full survey will be, 269 white dwarfs and 56 hot subdwarfs are identified spectroscopically where only 44 white dwarfs and 5 hot subdwarfs were known previously. Most are ordinary DA (hydrogen atmosphere) and DB (helium) types. In addition, in the full survey to date, a number of WDs have been found with uncommon spectral types. Among these are blue DQ stars displaying lines of atomic carbon; red DQ stars showing molecular bands of C_2 with a wide variety of strengths; DZ stars where Ca and occasionally Mg, Na, and/or Fe lines are detected; and magnetic WDs with a wide range of magnetic field strengths in DA, DB, DQ, and (probably) DZ spectral types. Photometry alone allows identification of stars hotter than 12000 K, and the density of these stars for 15<g<20 is found to be ~2.2 deg^{-2} at Galactic latitudes 29-62 deg. Spectra are obtained for roughly half of these hot stars. The spectra show that, for 15<g<17, 40% of hot stars are WDs and the fraction of WDs rises to ~90% at g=20. The remainder are hot sdB and sdO stars.Comment: Accepted for AJ; 43 pages, including 12 figures and 5 table

Amyloid-β nanotubes are associated with prion protein-dependent synaptotoxicity

Growing evidence suggests water-soluble, non-fibrillar forms of amyloid-β protein (Aβ) have important roles in Alzheimer’s disease with toxicities mimicked by synthetic Aβ1–42. However, no defined toxic structures acting via specific receptors have been identified and roles of proposed receptors, such as prion protein (PrP), remain controversial. Here we quantify binding to PrP of Aβ1–42 after different durations of aggregation. We show PrP-binding and PrP-dependent inhibition of long-term potentiation (LTP) correlate with the presence of protofibrils. Globular oligomers bind less avidly to PrP and do not inhibit LTP, whereas fibrils inhibit LTP in a PrP-independent manner. That only certain transient Aβ assemblies cause PrP-dependent toxicity explains conflicting reports regarding the involvement of PrP in Aβ-induced impairments. We show that these protofibrils contain a defined nanotubular structure with a previously unidentified triple helical conformation. Blocking the formation of Aβ nanotubes or their interaction with PrP might have a role in treatment of Alzheimer’s disease