Genome-wide association study of behavioural and psychiatric features in human prion disease.

Prion diseases are rare neurodegenerative conditions causing highly variable clinical syndromes, which often include prominent neuropsychiatric symptoms. We have recently carried out a clinical study of behavioural and psychiatric symptoms in a large prospective cohort of patients with prion disease in the United Kingdom, allowing us to operationalise specific behavioural/psychiatric phenotypes as traits in human prion disease. Here, we report exploratory genome-wide association analysis on 170 of these patients and 5200 UK controls, looking for single-nucleotide polymorphisms (SNPs) associated with three behavioural/psychiatric phenotypes in the context of prion disease. We also specifically examined a selection of candidate SNPs that have shown genome-wide association with psychiatric conditions in previously published studies, and the codon 129 polymorphism of the prion protein gene, which is known to modify various aspects of the phenotype of prion disease. No SNPs reached genome-wide significance, and there was no evidence of altered burden of known psychiatric risk alleles in relevant prion cases. SNPs showing suggestive evidence of association (P<10(-5)) included several lying near genes previously implicated in association studies of other psychiatric and neurodegenerative diseases. These include ANK3, SORL1 and a region of chromosome 6p containing several genes implicated in schizophrenia and bipolar disorder. We would encourage others to acquire phenotype data in independent cohorts of patients with prion disease as well as other neurodegenerative and neuropsychiatric conditions, to allow meta-analysis that may shed clearer light on the biological basis of these complex disease manifestations, and the diseases themselves

Role of SUMO-1 and SUMO Interacting Motifs in Rhesus TRIM5α-mediated Restriction

Background TRIM5α is a member of the tripartite motif family of proteins that restricts retroviral infection in a species-specific manner. The restriction requires an interaction between the viral capsid lattice and the B30.2/SPRY domain of TRIM5α. Previously, we determined that two SUMO interacting motifs (SIMs) present in the B30.2/SPRY domain of human TRIM5α (huTRIM5α) were important for the restriction of N-tropic Murine Leukemia Virus. Here, we examined whether SUMO expression and the SIM1 and SIM2 motifs in rhesus monkey TRIM5α (rhTRIM5α) are similarly important for Human Immunodeficiency Type 1 (HIV-) restriction. Results We found that mutation of SIM1 and SIM2 of rhTRIM5α abolished the restriction of HIV-1 virus. Further, knockdown of SUMO-1 in rhTRIM5α expressing cells abolished restriction of HIV-1. These results may be due, in part, to the ability of SUMO-1 to stabilize rhTRIM5α protein expression, as SUMO-1 knockdown increased rhTRIM5α turnover and the mutations in SIM1 and SIM2 led to more rapid degradation than the wild type protein. The NF-κB signaling ability of rhTRIM5α was also attenuated by SUMO-1 knockdown. Finally, upon inhibition of CRM1-dependent nuclear export with Leptomycin B (LMB), wild type rhTRIM5α localized to SUMO-1 bodies in the nucleus, while the SIM1 and SIM2 mutants did not localize to SUMO-1. Conclusions Our results suggest that the rhTRIM5α B30.2/SPRY domain is not only important for the recognition of the HIV-1 CA, but it is also important for its association with SUMO-1 or SUMO-1 modified proteins. These interactions help to maintain TRIM5α protein levels and its nuclear localization into specific nuclear bodies

Pointwise consistency of the kriging predictor with known mean and covariance functions

This paper deals with several issues related to the pointwise consistency of the kriging predictor when the mean and the covariance functions are known. These questions are of general importance in the context of computer experiments. The analysis is based on the properties of approximations in reproducing kernel Hilbert spaces. We fix an erroneous claim of Yakowitz and Szidarovszky (J. Multivariate Analysis, 1985) that the kriging predictor is pointwise consistent for all continuous sample paths under some assumptions.Comment: Submitted to mODa9 (the Model-Oriented Data Analysis and Optimum Design Conference), 14th-19th June 2010, Bertinoro, Ital

Factors Affecting the Improvement of District Heating. Case Studies of Estonia and Serbia

© 2020 Pavel Rušeljuk et al., published by Sciendo 2020. Factors affecting both the Estonian and Serbian district heating improvement are analysed, including geographical and climate factors, as well as economic and legal factors. This analysis is added by evaluation of main technical and economic parameters related to the district heating networks from the case studies (Estonian Narva city and Serbian Kragujevac district heating). This analysis uncovered the weakest points of Kragujevac district heating and explain why district heating is not considered as sustainable and environmentally friendly heating option

IL-33/ST2 axis in innate and acquired immunity to tumors

Interleukin-33, a ligand for ST2/T1, has an important role in allergy, autoimmunity and inflammation. The role of IL-33/ST2 axis in cancer is not elucidated. Using metastatic breast cancer model we provide evidence that lack of ST2 signaling led to reduced tumor growth and metastasis and enhanced anti-tumor immunity

Numerical solution to the hermitian Yang-Mills equation on the Fermat quintic

We develop an iterative method for finding solutions to the hermitian Yang-Mills equation on stable holomorphic vector bundles, following ideas recently developed by Donaldson. As illustrations, we construct numerically the hermitian Einstein metrics on the tangent bundle and a rank three vector bundle on P^2. In addition, we find a hermitian Yang-Mills connection on a stable rank three vector bundle on the Fermat quintic.Comment: 25 pages, 2 figure

The nature of the different zero-temperature phases in discrete two-dimensional spin glasses: Entropy, universality, chaos and cascades in the renormalization group flow

The properties of discrete two-dimensional spin glasses depend strongly on the way the zero-temperature limit is taken. We discuss this phenomenon in the context of the Migdal-Kadanoff renormalization group. We see, in particular, how these properties are connected with the presence of a cascade of fixed points in the renormalization group flow. Of particular interest are two unstable fixed points that correspond to two different spin-glass phases at zero temperature. We discuss how these phenomena are related with the presence of entropy fluctuations and temperature chaos, and universality in this model.Comment: 14 pages, 5 figures, 2 table

Subextensive singularity in the 2D ±J\pm J Ising spin glass

The statistics of low energy states of the 2D Ising spin glass with +1 and -1 bonds are studied for $L \times L$ square lattices with $L \le 48$, and $p$ = 0.5, where $p$ is the fraction of negative bonds, using periodic and/or antiperiodic boundary conditions. The behavior of the density of states near the ground state energy is analyzed as a function of $L$, in order to obtain the low temperature behavior of the model. For large finite $L$ there is a range of $T$ in which the heat capacity is proportional to $T^{5.33 \pm 0.12}$. The range of $T$ in which this behavior occurs scales slowly to $T = 0$ as $L$ increases. Similar results are found for $p$ = 0.25. Our results indicate that this model probably obeys the ordinary hyperscaling relation $d \nu = 2 - \alpha$, even though $T_c = 0$. The existence of the subextensive behavior is attributed to long-range correlations between zero-energy domain walls, and evidence of such correlations is presented.Comment: 13 pages, 7 figures; final version, to appear in J. Stat. Phy