Phenotypic heterogeneity and genetic modification of P102L inherited prion disease in an international series

The largest kindred with inherited prion disease P102L, historically Gerstmann-Sträussler-Scheinker syndrome, originates from central England, with émigrés now resident in various parts of the English-speaking world. We have collected data from 84 patients in the large UK kindred and numerous small unrelated pedigrees to investigate phenotypic heterogeneity and modifying factors. This collection represents by far the largest series of P102L patients so far reported. Microsatellite and genealogical analyses of eight separate European kindreds support multiple distinct mutational events at a cytosine-phosphate diester-guanidine dinucleotide mutation hot spot. All of the smaller P102L kindreds were linked to polymorphic human prion protein gene codon 129M and were not connected by genealogy or microsatellite haplotype background to the large kindred or each other. While many present with classical Gerstmann-Sträussler-Scheinker syndrome, a slowly progressive cerebellar ataxia with later onset cognitive impairment, there is remarkable heterogeneity. A subset of patients present with prominent cognitive and psychiatric features and some have met diagnostic criteria for sporadic Creutzfeldt-Jakob disease. We show that polymorphic human prion protein gene codon 129 modifies age at onset: the earliest eight clinical onsets were all MM homozygotes and overall age at onset was 7 years earlier for MM compared with MV heterozygotes (P = 0.02). Unexpectedly, apolipoprotein E4 carriers have a delayed age of onset by 10 years (P = 0.02). We found a preponderance of female patients compared with males (54 females versus 30 males, P = 0.01), which probably relates to ascertainment bias. However, these modifiers had no impact on a semi-quantitative pathological phenotype in 10 autopsied patients. These data allow an appreciation of the range of clinical phenotype, modern imaging and molecular investigation and should inform genetic counselling of at-risk individuals, with the identification of two genetic modifiers

Catching NGC4051 in the low state with XMM-Newton

The Narrow Line Seyfert 1 galaxy NGC4051 shows unusual low flux states, lasting several months, when the 2-10 keV X-ray spectrum becomes unusually hard (photon index<1) while the spectrum at lower X-ray energies is dominated by a large soft excess. A Chandra TOO of the low state has shown that the soft excess and hard components are variable and well-correlated. The variability of the hard component rules out an origin in a distant reflector. Here we present results from a recent XMM-Newton TOO of NGC4051 in the low state, which allows a much more detailed examination of the nature of the hard and soft spectral components in the low state. We demonstrate that the spectral shape in the low state is consistent with the extrapolation of the spectral pivoting observed at higher fluxes. The XMM-Newton data also reveals the warm absorbing gas in emission, as the drop in the primary continuum flux unmasks prominent emission lines from a range of ion species.Comment: 4 pages, 4 figures. Proc. of the meeting: "The Restless High-Energy Universe" (Amsterdam, The Netherlands), E.P.J. van den Heuvel, J.J.M. in 't Zand, and R.A.M.J. Wijers Ed

A Cross-Match of 2MASS and SDSS: Newly-Found L and T Dwarfs and an Estimate of the Space Densitfy of T Dwarfs

We report new L and T dwarfs found in a cross-match of the SDSS Data Release 1 and 2MASS. Our simultaneous search of the two databases effectively allows us to relax the criteria for object detection in either survey and to explore the combined databases to a greater completeness level. We find two new T dwarfs in addition to the 13 already known in the SDSS DR1 footprint. We also identify 22 new candidate and bona-fide L dwarfs, including a new young L2 dwarf and a peculiar L2 dwarf with unusually blue near-IR colors: potentially the result of mildly sub-solar metallicity. These discoveries underscore the utility of simultaneous database cross-correlation in searching for rare objects. Our cross-match completes the census of T dwarfs within the joint SDSS and 2MASS flux limits to the 97% level. Hence, we are able to accurately infer the space density of T dwarfs. We employ Monte Carlo tools to simulate the observed population of SDSS DR1 T dwarfs with 2MASS counterparts and find that the space density of T0-T8 dwarf systems is 0.0070 (-0.0030; +0.0032) per cubic parsec (95% confidence interval), i.e., about one per 140 cubic parsecs. Compared to predictions for the T dwarf space density that depend on various assumptions for the sub-stellar mass function, this result is most consistent with models that assume a flat sub-stellar mass function dN/dM ~ M^0. No >T8 dwarfs were discovered in the present cross-match, though less than one was expected in the limited area (2099 sq. degrees) of SDSS DR1.Comment: To appear in ApJ, Feb 10, 2008 issue. 37 pages, including 12 figures and 14 table

The Blazar Sequence: Validity and Predictions

The "blazar sequence" posits that the most powerful BL Lacertae objects and flat-spectrum radio quasars should have relatively small synchrotron peak frequencies, nu_peak, and that the least powerful such objects should have the highest nu_peak values. This would have strong implications for our understanding of jet formation and physics and the possible detection of powerful, moderately high-redshift TeV blazars. I review the validity of the blazar sequence by using the results of very recent surveys and compare its detailed predictions against observational data. I find that the blazar sequence in its simplest form is ruled out. However, powerful flat-spectrum radio quasars appear not to reach the nu_peak typical of BL Lacs. This could indeed be related to some sort of sequence, although it cannot be excluded that it is instead due to a selection effect.Comment: 9 pages, 4 figures, invited talk at the Workshop "The Multi-messenger approach to high energy gamma-ray sources", Barcelona, Spain, July 4-7, 2006, to appear in the proceeding

The distance to the Galactic Centre based on Population-II Cepheids and RR Lyrae stars

Context: The distance to the Galactic Centre (GC) is of importance for the distance scale in the Universe. The value derived by Eisenhauer et al. (2005) of 7.62 +- 0.32 kpc based on the orbit of one star around the central black hole is shorter than most other distance estimates based on a variety of different methods. Aim: To establish an independent distance to the GC with high accuracy. To this end Population-II Cepheids are used that have been discovered in the OGLE-II and III surveys. Method: Thirty-nine Pop-II Cepheids have been monitored on 4 nights spanning 14 days. Light curves have been fitted using the known periods from the OGLE data to determine the mean K-band magnitude. It so happens that 37 RR Lyrae stars are in the field-of-views and mean K-band magnitudes are derived for this sample as well. Results: The period-luminosity relation of Pop-II Cepheids in the K-band is determined, and the derived slope of -2.24 +- 0.14 is consistent with the value derived by Matsunaga et al. (2006). Fixing the slope to their more accurate value results in a zero point, and implies a distance modulus to the GC of 14.51 +- 0.12, with an additional systematic uncertainty of 0.07 mag. Similarly, from the RR Lyrae K-band PL-relation we derive a value of 14.48 +- 0.17 (random) +- 0.07 (syst.). The two independent determinations are averaged to find 14.50 +- 0.10 (random) +- 0.07 (syst.), or 7.94 +- 0.37 +- 0.26 kpc.Comment: A&A accepte

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

General Foreword JSSE 66

This issue (n° 66) of the Journal of the Short Story in English is a double-volume featuring a general section as well as a special section devoted to studies of the Affect and the Short Story and Cycle, the latter under the guest editorship of Paul Ardoin and Fiona McWilliam. We thank them as well as Robert Luscher, specialist of the short-story sequence and guest consultant for this special section, for their active involvement in contributing to research on the short story in English. Contents of the general section: Donna White: Is There a Doctor in the House? Rudyard Kipling’s Private Message to Arthur Conan Doyle in “The House Surgeon” Daniela Janes: Liminality and the Epiphanic Spectrum in Joyce’s Dubliners and Mistry’s Tales from Firozsha Baag Thomas O’Grady: The Geography of the Imagination: Benedict Kiely’s Dubliners Timothy K. Nixon: Immigration, Ethnicity, and Race in Alice Dunbar-Nelson’s “Tony’s Wife” Brian Jansen: “Betch you’ bootsh!”: Jewish Humour, Jewish Identity, and Yiddish Literary Traditions in Abraham Cahan’s Yekl Yair Solan: Housebreakers and Peeping Toms: Voyeurism in John Cheever’s Early Suburban Storie

Variants of PLCXD3 are not associated with variant or sporadic Creutzfeldt-Jakob disease in a large international study

BACKGROUND: Human prion diseases are relentlessly progressive neurodegenerative disorders which include sporadic Creutzfeldt-Jakob disease (sCJD) and variant CJD (vCJD). Aside from variants of the prion protein gene (PRNP) replicated association at genome-wide levels of significance has proven elusive. A recent association study identified variants in or near to the PLCXD3 gene locus as strong disease risk factors in multiple human prion diseases. This study claimed the first non-PRNP locus to be highly significantly associated with prion disease in genomic studies. METHODS: A sub-study of a genome-wide association study with imputation aiming to replicate the finding at PLCXD3 including 129 vCJD and 2500 sCJD samples. Whole exome sequencing to identify rare coding variants of PLCXD3. RESULTS: Imputation of relevant polymorphisms was accurate based on wet genotyping of a sample. We found no supportive evidence that PLCXD3 variants are associated with disease. CONCLUSION: The marked discordance in vCJD genotype frequencies between studies, despite extensive overlap in vCJD cases, and the finding of Hardy-Weinberg disequilibrium in the original study, suggests possible reasons for the discrepancies between studies