Idiopathic Brainstem Neuronal Chromatolysis (IBNC): a novel prion protein related disorder of cattle?

<p>Abstract</p> <p>Background</p> <p>The epidemic form of Bovine Spongiform Encephalopathy (BSE) is generally considered to have been caused by a single prion strain but at least two strain variants of cattle prion disorders have recently been recognized. An additional neurodegenerative condition, idiopathic brainstem neuronal chromatolysis and hippocampal sclerosis (IBNC), a rare neurological disease of adult cattle, was also recognised in a sub-set of cattle submitted under the BSE Orders in which lesions of BSE were absent. Between the years of 1988 and 1991 IBNC occurred in Scotland with an incidence of 7 cases per 100,000 beef suckler cows over the age of 6 years.</p> <p>Results</p> <p>When the brains of 15 IBNC cases were each tested by immunohistochemistry, all showed abnormal labelling for prion protein (PrP). Immunohistological labelling for PrP was also present in the retina of a single case available for examination. The pattern of PrP labelling in brain is distinct from that seen in other ruminant prion diseases and is absent from brains with other inflammatory conditions and from normal control brains. Brains of IBNC cattle do not reveal abnormal PrP isoforms when tested by the commercial BioRad or Idexx test kits and do not reveal PrP^reswhen tested by Western blotting using stringent proteinase digestion methods. However, some weakly protease resistant isoforms of PrP may be detected when tissues are examined using mild proteinase digestion techniques.</p> <p>Conclusion</p> <p>The study shows that a distinctive neurological disorder of cattle, which has some clinical similarities to BSE, is associated with abnormal PrP labelling in brain but the pathology and biochemistry of IBNC are distinct from BSE. The study is important either because it raises the possibility of a significant increase in the scope of prion disease or because it demonstrates that widespread and consistent PrP alterations may not be confined to prion diseases. Further studies, including transmission experiments, are needed to establish whether IBNC is a condition in which prion protein is abnormally regulated or it is yet a further example of an infectious cattle prion disease.</p

La importancia de diseñar instrumentos eficaces para evaluar la habilidad oral en el Idioma Inglés/The importance of designing effective tools for assessing oral proficiency in the English Language

Es vital diseñar y utilizar instrumentos eficaces para entrenar y evaluar la habilidad oral en la enseñanza del idioma Inglés, particularmente si esta preparación tiene como meta final lograr un capital humano que tenga como competencia laboral el uso adecuado de una lengua extranjera. Esto es, sin dudas, un problema actual. Este artículo tiene como objetivo revisar el marco teórico en el que se sustentan estos diseños, analizar ejemplos negativos y proponer instrumentos de evaluación que han sido diseñados y validados en la práctica en un contexto laboral turístico

Piccolo modulation of Synapsin1a dynamics regulates synaptic vesicle exocytosis

Active zones are specialized regions of the presynaptic plasma membrane designed for the efficient and repetitive release of neurotransmitter via synaptic vesicle (SV) exocytosis. Piccolo is a high molecular weight component of the active zone that is hypothesized to participate both in active zone formation and the scaffolding of key molecules involved in SV recycling. In this study, we use interference RNAs to eliminate Piccolo expression from cultured hippocampal neurons to assess its involvement in synapse formation and function. Our data show that Piccolo is not required for glutamatergic synapse formation but does influence presynaptic function by negatively regulating SV exocytosis. Mechanistically, this regulation appears to be calmodulin kinase II–dependent and mediated through the modulation of Synapsin1a dynamics. This function is not shared by the highly homologous protein Bassoon, which indicates that Piccolo has a unique role in coupling the mobilization of SVs in the reserve pool to events within the active zone

Poloxomer 188 Has a Deleterious Effect on Dystrophic Skeletal Muscle Function

Duchenne muscular dystrophy (DMD) is an X-linked, fatal muscle wasting disease for which there is currently no cure and limited palliative treatments. Poloxomer 188 (P188) is a tri-block copolymer that has been proposed as a potential treatment for cardiomyopathy in DMD patients. Despite the reported beneficial effects of P188 on dystrophic cardiac muscle function, the effects of P188 on dystrophic skeletal muscle function are relatively unknown. Mdx mice were injected intraperitoneally with 460 mg/kg or 30 mg/kg P188 dissolved in saline, or saline alone (control). The effect of single-dose and 2-week daily treatment was assessed using a muscle function test on the Tibialis Anterior (TA) muscle in situ in anaesthetised mice. The test comprises a warm up, measurement of the force-frequency relationship and a series of eccentric contractions with a 10% stretch that have previously been shown to cause a drop in maximum force in mdx mice. After 2 weeks of P188 treatment at either 30 or 460 mg/kg/day the drop in maximum force produced following eccentric contractions was significantly greater than that seen in saline treated control mice (P = 0.0001). Two week P188 treatment at either dose did not significantly change the force-frequency relationship or maximum isometric specific force produced by the TA muscle. In conclusion P188 treatment increases susceptibility to contraction-induced injury following eccentric contractions in dystrophic skeletal muscle and hence its suitability as a potential therapeutic for DMD should be reconsidered

Longitudinal two-photon imaging in somatosensory cortex of behaving mice reveals dendritic spine formation enhancement by subchronic administration of low-dose ketamine

Ketamine, a well-known anesthetic, has recently attracted renewed attention as a fast-acting antidepressant. A single dose of ketamine induces rapid synaptogenesis, which may underlie its antidepressant effect. To test whether repeated exposure to ketamine triggers sustained synaptogenesis, we administered a sub-anesthetic dose of ketamine (10 mg/kg i.p.) once-daily for 5 days, and repeatedly imaged dendritic spines of the YFP-expressing pyramidal neurons in somatosensory cortex of awake female mice using in vivo two-photon microscopy. We found that the spine formation rate became significantly higher at 72-132 h after the first ketamine injection (but not at 6-24 h), while the rate of elimination of pre-existing spines remained unchanged. In contrast to the net gain of spines observed in ketamine-treated mice, the vehicle-injected control mice exhibited a net loss typical for young-adult animals undergoing synapse pruning. Ketamine-induced spinogenesis was correlated with increased PSD-95 and phosphorylated actin, consistent with formation of new synapses. Moreover, structural synaptic plasticity caused by ketamine was paralleled by a significant improvement in the nest building behavioral assay. Taken together, our data show that subchronic low-dose ketamine induces a sustained shift towards spine formation.Peer reviewe

The Gray Needle: Large Grains in the HD 15115 Debris Disk from LBT/PISCES/Ks and LBTI/LMIRcam/L' Adaptive Optics Imaging

We present diffraction-limited \ks band and \lprime adaptive optics images of the edge-on debris disk around the nearby F2 star HD 15115, obtained with a single 8.4 m primary mirror at the Large Binocular Telescope. At \ks band the disk is detected at signal-to-noise per resolution element (SNRE) \about 3-8 from \about 1-2\fasec 5 (45-113 AU) on the western side, and from \about 1.2-2\fasec 1 (63-90 AU) on the east. At \lprime the disk is detected at SNRE \about 2.5 from \about 1-1\fasec 45 (45-90 AU) on both sides, implying more symmetric disk structure at 3.8 \microns . At both wavelengths the disk has a bow-like shape and is offset from the star to the north by a few AU. A surface brightness asymmetry exists between the two sides of the disk at \ks band, but not at \lprime . The surface brightness at \ks band declines inside 1\asec (\about 45 AU), which may be indicative of a gap in the disk near 1\asec. The \ks - \lprime disk color, after removal of the stellar color, is mostly grey for both sides of the disk. This suggests that scattered light is coming from large dust grains, with 3-10 \microns -sized grains on the east side and 1-10 \microns dust grains on the west. This may suggest that the west side is composed of smaller dust grains than the east side, which would support the interpretation that the disk is being dynamically affected by interactions with the local interstellar medium.Comment: Apj-accepted March 27 2012; minor correction

First Light LBT AO Images of HR 8799 bcde at 1.65 and 3.3 Microns: New Discrepancies between Young Planets and Old Brown Dwarfs

As the only directly imaged multiple planet system, HR 8799 provides a unique opportunity to study the physical properties of several planets in parallel. In this paper, we image all four of the HR 8799 planets at H-band and 3.3 microns with the new LBT adaptive optics system, PISCES, and LBTI/LMIRCam. Our images offer an unprecedented view of the system, allowing us to obtain H and 3.3$ micron photometry of the innermost planet (for the first time) and put strong upper-limits on the presence of a hypothetical fifth companion. We find that all four planets are unexpectedly bright at 3.3 microns compared to the equilibrium chemistry models used for field brown dwarfs, which predict that planets should be faint at 3.3 microns due to CH4 opacity. We attempt to model the planets with thick-cloudy, non-equilibrium chemistry atmospheres, but find that removing CH4 to fit the 3.3 micron photometry increases the predicted L' (3.8 microns) flux enough that it is inconsistent with observations. In an effort to fit the SED of the HR 8799 planets, we construct mixtures of cloudy atmospheres, which are intended to represent planets covered by clouds of varying opacity. In this scenario, regions with low opacity look hot and bright, while regions with high opacity look faint, similar to the patchy cloud structures on Jupiter and L/T transition brown-dwarfs. Our mixed cloud models reproduce all of the available data, but self-consistent models are still necessary to demonstrate their viability.Comment: Accepted to Ap

Improving Risk Regulation

Confronted with the challenge of improving regulatory performance, many governments in the world are looking for ways to better manage risks, in particular those risks that develop in complex systems, with stakeholders from various sectors, and that are marked by uncertainty. This report includes five authored pieces about: The contribution of transnational private regulation to revisiting risk regulation (Scott), Emerging strategies to manage system-level risks: an examination of private sector, government and non-governmental organization initiative (Yosie), Potential scope and challenges of behaviourally informed regulation (Renn and Florin), and Managing uncertainty in drug development and use, by enhancing adaptability and flexibility in pharmaceuticals regulation (Oye et al.)

Regulating levels of the neuromodulator D-serine in human brain: structural insight into pLG72 and D-amino acid oxidase interaction

The human flavoenzyme D-amino acid oxidase (hDAAO) degrades the NMDA-receptor modulator D-serine in the brain. Whereas hDAAO has been extensively characterized, little is known about its main modulator pLG72, a small protein encoded by the primate-specific gene G72 that has been associated with schizophrenia susceptibility. pLG72 interacts with neosynthesized hDAAO, promoting its inactivation and degradation. In this work we used low-resolution techniques to characterize the surface topology of the hDAAO-pLG72 complex. By using limited proteolysis coupled to mass spectrometry we could map the exposed regions in the two proteins after complex formation and highlighted an increased sensitivity to proteolysis of hDAAO in complex with pLG72. Cross-linking experiments by using bis(sulfosuccinimidyl)suberate identified the single covalent bond between T182 in hDAAO and K62 in pLG72. In order to validate the designed mode of interaction, three pLG72 variants incrementally truncated at the C-terminus, in addition to a form lacking the 71 N-terminal residues, were produced. All variants were dimeric, folded, and interacted with hDAAO. The strongest decrease in affinity for hDAAO (as well as for the hydrophobic drug chlorpromazine) was apparent for the N-terminally deleted pLG7272-153 form, which lacked K62. On the other hand, eliminating the disordered C-terminal tail yielded a more stable pLG72 protein, improved the binding to hDAAO, although giving lower enzyme inhibition. Elucidation of the mode of hDAAO-pLG72 interaction now makes it possible to design novel molecules that, by targeting the protein complex, can be therapeutically advantageous for diseases related to impairment in D-serine metabolism. This article is protected by copyright. All rights reserved

Associations between Polycyclic Aromatic Hydrocarbon–Related Exposures and p53 Mutations in Breast Tumors

Background: Previous studies have suggested that polycyclic aromatic hydrocarbons (PAHs) may be associated with breast cancer. However, the carcinogenicity of PAHs on the human breast remains unclear. Certain carcinogens may be associated with specific mutation patterns in the p53 tumor suppressor gene, thereby contributing information about disease etiology. Objectives: We hypothesized that associations of PAH-related exposures with breast cancer would differ according to tumor p53 mutation status, effect, type, and number. Methods: We examined this possibility in a population-based case–control study using polytomous logistic regression. As previously reported, 151 p53 mutations among 859 tumors were identified using Surveyor nuclease and confirmed by sequencing. Results: We found that participants with p53 mutations were less likely to be exposed to PAHs (assessed by smoking status in 859 cases and 1,556 controls, grilled/smoked meat intake in 822 cases and 1,475 controls, and PAH–DNA adducts in peripheral mononuclear cells in 487 cases and 941 controls) than participants without p53 mutations. For example, active and passive smoking was associated with p53 mutation–negative [odds ratio (OR) = 1.55; 95% confidence interval (CI), 1.11–2.15] but not p53 mutation–positive (OR = 0.77; 95% CI, 0.43–1.38) cancer (ratio of the ORs = 0.50, p < 0.05). However, frameshift mutations, mutation number, G:C→A:T transitions at CpG sites, and insertions/deletions were consistently elevated among exposed subjects. Conclusions: These findings suggest that PAHs may be associated with specific breast tumor p53 mutation subgroups rather than with overall p53 mutations and may also be related to breast cancer through mechanisms other than p53 mutation