Prion degradation pathways: Potential for therapeutic intervention

Prion diseases are fatal neurodegenerative disorders. Pathology is closely linked to the misfolding of native cellular PrP(C) into the disease-associated form PrP(Sc) that accumulates in the brain as disease progresses. Although treatments have yet to be developed, strategies aimed at stimulating the degradation of PrP(Sc) have shown efficacy in experimental models of prion disease. Here, we describe the cellular pathways that mediate PrP(Sc) degradation and review possible targets for therapeutic intervention. This article is part of a Special Issue entitled 'Neuronal Protein'

Detrended Fluctuation analysis of Bach's Inventions and Sinfonias pitches

Detrended Fluctuation Analysis (DFA), suitable for the analysis of nonstationary time series, is used to investigate power law in some of the Bach's pitches series. Using DFA method, which also is a well-established method for the detection of long-range correlations, frequency series of Bach's pitches have been analyzed. In this view we find same Hurts exponents in the range (0.7-0.8) in his Inventions and sinfonia.Comment: 5 pages, 4 figure

Gene suppression approaches to neurodegeneration

Gene suppression approaches have emerged over the last 20 years as a novel therapeutic approach for the treatment of neurodegenerative diseases. These include RNA interference and anti-sense oligonucleotides, both of which act at the post-transcriptional level, and genome-editing techniques, which aim to repair the responsible mutant gene. All serve to inhibit the expression of disease-causing proteins, leading to the potential prevention or even reversal of the disease phenotype. In this review we summarise the main developments in gene suppression strategies, using examples from Huntington’s disease and other inherited causes of neurodegeneration, and explore how these might illuminate a path to tackle other proteinopathy-associated dementias in the future

Idea of negation and contrary progression in Blake

This thesis consists of two parts. The first pert is a detailed study of The Marriage of Heaven and Hell in the context of Swedenborg's Heaven and Hell and the social background of the eighteenth century. It has five chapters, in the first of which an attempt has been made to sketch an outline of social cohditions and relationship in eighteenth century England. There are two reasons for doing this. First, Blake's writings reflect his contemporary social conditions an class conflict. When he attacks Swedenborg, Newton and Locke, for example, he is indeed attacking as most radical and romantic writers did, the whole social order that they formed and represented. From the evidence thus obtained one may conclue that Blake's Marriage of Heaven and Hell and Swedenborg's' Heaven and Hell must be studied in this social context. 'Heaven' and 'Hell' are not abstract terms. They represent social conditions. 'Heaven' represents the rich and propertied or higher clerical class epitomised by Swedenborg in conflict with 'Hell' which represents the poor and working class epitomised by Blake. Those who are in 'Heaven' are called Angels, and those in 'Hell' Devils. Secondly, Heaven and Hell and The Marriage of Heaven and Hell reflect two contrasting philosophies, two types of social outlook and literature in defence of two opposing interests. Chapter Two shows first that The Marriage of Heaven and Hell is essentially written as moral criticism of Swedenborg's social system, that 'The Argument' in The Marragae refers to Swedenborg's Heaven and Hell and that Rintrah represents Swedenborg as a passive and fallen character who punishes the 'just' man in himself and people in 'Hell'

On the Viability of Minimal Neutrinophilic Two-Higgs-Doublet Models

We study the constraints that electroweak precision data can impose, after the discovery of the Higgs boson by the LHC, on neutrinophilic two-Higgs-doublet models which comprise one extra $SU(2)\times U(1)$ doublet and a new symmetry, namely a spontaneously broken $\mathbb{Z}_2$ or a softly broken global $U(1)$. In these models the extra Higgs doublet, via its very small vacuum expectation value, is the sole responsible for neutrino masses. We find that the model with a $\mathbb{Z}_2$ symmetry is basically ruled out by electroweak precision data, even if the model is slightly extended to include extra right-handed neutrinos, due to the presence of a very light scalar. While the other model is still perfectly viable, the parameter space is considerably constrained by current data, specially by the $T$ parameter. In particular, the new charged and neutral scalars must have very similar masses.Comment: 22 pages, 3 figures, references and comments added, conclusions unchanged, matches version to appear in JHE

Signature change from Schutz's canonical quantum cosmology and its classical analogue

We study the signature change in a perfect fluid Friedmann-Robertson-Walker quantum cosmological model. In this work the Schutz's variational formalism is applied to recover the notion of time. This gives rise to a Schrodinger-Wheeler-DeWitt equation with arbitrary ordering for the scale factor. We use the eigenfunctions in order to construct wave packets and evaluate the time-dependent expectation value of the scale factor which coincides with the ontological interpretation. We show that these solutions exhibit signature transitions from a finite Euclidean to a Lorentzian domain. Moreover, such models are equivalent to a classical system where, besides the perfect fluid, a repulsive fluid is present.Comment: 15 pages, 4 figures, to appear in PR

Mutant Huntingtin Does Not Affect the Intrinsic Phenotype of Human Huntington's Disease T Lymphocytes

Huntington's disease is a fatal neurodegenerative condition caused by a CAG repeat expansion in the huntingtin gene. The peripheral innate immune system is dysregulated in Huntington's disease and may contribute to its pathogenesis. However, it is not clear whether or to what extent the adaptive immune system is also involved. Here, we carry out the first comprehensive investigation of human ex vivo T lymphocytes in Huntington's disease, focusing on the frequency of a range of T lymphocyte subsets, as well as analysis of proliferation, cytokine production and gene transcription. In contrast to the innate immune system, the intrinsic phenotype of T lymphocytes does not appear to be affected by the presence of mutant huntingtin, with Huntington's disease T lymphocytes exhibiting no significant functional differences compared to control cells. The transcriptional profile of T lymphocytes also does not appear to be significantly affected, suggesting that peripheral immune dysfunction in Huntington's disease is likely to be mediated primarily by the innate rather than the adaptive immune system. This study increases our understanding of the effects of Huntington's disease on peripheral tissues, while further demonstrating the differential effects of the mutant protein on different but related cell types. Finally, this study suggests that the potential use of novel therapeutics aimed at modulating the Huntington's disease innate immune system should not be extended to include the adaptive immune system

Simultaneous conduction and valence band quantisation in ultra-shallow, high density doping profiles in semiconductors

We demonstrate simultaneous quantisation of conduction band (CB) and valence band (VB) states in silicon using ultra-shallow, high density, phosphorus doping profiles (so-called Si:P $\delta$-layers). We show that, in addition to the well known quantisation of CB states within the dopant plane, the confinement of VB-derived states between the sub-surface P dopant layer and the Si surface gives rise to a simultaneous quantisation of VB states in this narrow region. We also show that the VB quantisation can be explained using a simple particle-in-a-box model, and that the number and energy separation of the quantised VB states depend on the depth of the P dopant layer beneath the Si surface. Since the quantised CB states do not show a strong dependence on the dopant depth (but rather on the dopant density), it is straightforward to exhibit control over the properties of the quantised CB and VB states independently of each other by choosing the dopant density and depth accordingly, thus offering new possibilities for engineering quantum matter.Comment: 5 pages, 2 figures and supplementary materia

Calculation of molecular g-tensors by sampling spin orientations of generalised Hartree-Fock states

The variational inclusion of spin-orbit coupling in self-consistent field (SCF) calculations requires a generalised two-component framework, which permits the single-determinant wave function to completely break spin symmetry. The individual components of the molecular g-tensor are commonly obtained from separate SCF solutions that align the magnetic moment along one of the three principal tensor axes. However, this strategy raises the question if energy differences between solutions are relevant, or how convergence is achieved if the principal axis system is not determined by molecular symmetry. The present work resolves these issues by a simple two-step procedure akin to the generator coordinate method (GCM). First, a few generalised Hartree Fock (GHF) solutions are converged, applying, where needed, a constraint to the orientation of the magnetic-moment or spin vector. Then, superpositions of GHF determinants are formed through non-orthogonal configuration interaction. This procedure yields a Kramers doublet for the calculation of the complete g-tensor. Alternatively, for systems with weak spin-orbit effects, diagonalisation in a basis spanned by spin rotations of a single GHF determinant affords qualitatively correct g-tensors by eliminating errors related to spin contamination. For small first-row molecules, these approaches are evaluated against experimental data and full configuration interaction results. It is further demonstrated for two systems (a fictitious tetrahedral CH4+ species, and a CuF4(2-) complex) that a GCM strategy, in contrast to alternative mean-field methods, can correctly describe the spin-orbit splitting of orbitally-degenerate ground states, which causes large g-shifts and may lead to negative g-values.Comment: 33 pages, 5 figur

Classical and quantum spinor cosmology with signature change

We study the classical and quantum cosmology of a universe in which the matter source is a massive Dirac spinor field and consider cases where such fields are either free or self-interacting. We focus attention on the spatially flat Robertson-Walker cosmology and classify the solutions of the Einstein-Dirac system in the case of zero, negative and positive cosmological constant $\Lambda$. For $\Lambda<0$, these solutions exhibit signature transitions from a Euclidean to a Lorentzian domain. In the case of massless spinor fields it is found that signature changing solutions do not exist when the field is free while in the case of a self-interacting spinor field such solutions may exist. The resulting quantum cosmology and the corresponding Wheeler-DeWitt equation are also studied for both free and self interacting spinor fields and closed form expressions for the wavefunction of the universe are presented. These solutions suggest a quantization rule for the energy.Comment: 13 pages, 4 figure