Using Narrow Band Photometry to Detect Young Brown Dwarfs in IC348

We report the discovery of a population of young brown dwarf candidates in the open star cluster IC348 and the development of a new spectroscopic classification technique using narrow band photometry. Observations were made using FLITECAM, the First Light Camera for SOFIA, at the 3-m Shane Telescope at Lick Observatory. FLITECAM is a new 1-5 micron camera with an 8 arcmin field of view. Custom narrow band filters were developed to detect absorption features of water vapor (at 1.495 microns) and methane (at 1.66 microns) characteristic of brown dwarfs. These filters enable spectral classification of stars and brown dwarfs without spectroscopy. FLITECAM's narrow and broadband photometry was verified by examining the color-color and color-magnitude characteristics of stars whose spectral type and reddening was known from previous surveys. Using our narrow band filter photometry method, it was possible to identify an object measured with a signal-to-noise ratio of 20 or better to within +/-3 spectral class subtypes for late-type stars. With this technique, very deep images of the central region of IC348 (H ~ 20.0) have identified 18 sources as possible L or T dwarf candidates. Out of these 18, we expect that between 3 - 6 of these objects are statistically likely to be background stars, with the remainder being true low-mass members of the cluster. If confirmed as cluster members then these are very low-mass objects (~5 Mjupiter). We also describe how two additional narrow band filters can improve the contrast between M, L, and T dwarfs as well as provide a means to determine the reddening of an individual object.Comment: 43 pages, 17 figures. Accepted for publication in the Astrophysical Journal 27 June 200

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

Patterns of Resource Use by a Drosophilid (Diptera) Leaf Miner on a Native Crucifer

Distribution and damage of Scaptomyza nigrita Wheeler on its host (bittercress, Cardamine cordifolia A. Gray), a native perennial crucifer, were examined over two growing seasons in relation to leaf position. Concentrations of defensive compounds (glucosinolates) and of nutritive compounds (total nitrogen, free amino acids, soluble carbohydrates) were also examined. The fly-host plant relationship was studied in sun and shade habitats at two sites. Oviposition and leaf-mining damage were concentrated on the lower central leaves of a stem in both habitats. These mature leaves have lower glucosinolate concentrations than new leaves. Adult densities and larval feeding damage were consistently and significantly greater on plants in the sun than on those in the shade. Higher S. nigrita densities in the sun habitat and slightly higher soluble carbohydrate concentrations in sun leaves at the beginning of the growing season, rather than variation in defensive glucosinolate levels, are the most likely mechanisms determining higher levels of leaf mining on host plants in the sun habitat

\u3ci\u3eScaptomyza nigrita\u3c/i\u3e Wheeler (Diptera: Drosophilidae), a Leaf Miner of the Native Crucifer, \u3ci\u3eCardamine cordifolia\u3c/i\u3e A. Gray (Bittercress)

The biology of Scaptomyza nigrita on its host plant, a native crucifer (Bittercress) in the Rocky Mountains, is described. Development of each stage in the life history was studied both in the field and in the laboratory. This is the first documentation of a host for S. nigrita. We examined the activity of adult flies in two adjacent habitats, sun and adjacent willow shade. Adult flies were more abundant on bittercress plants in sun-exposed versus in shaded areas, and were most active from mid-day to late afternoon. Female flies were significantly larger than male flies, but there were no differences in size of adults between the two habitats. Larval damage to bittercress is generally much greater on plants in sunny areas than on those in the shade, possibly due to the increased activity of ovipositing flies in sun-exposed areas

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

Chronic wasting disease prions are not transmissible to transgenic mice overexpressing human prion protein

Chronic wasting disease (CWD) is a prion disease that affects free-ranging and captive cervids, including mule deer, white-tailed deer, Rocky Mountain elk and moose. CWD-infected cervids have been reported in 14 USA states, two Canadian provinces and in South Korea. The possibility of a zoonotic transmission of CWD prions via diet is of particular concern in North America where hunting of cervids is a popular sport. To investigate the potential public health risks posed by CWD prions, we have investigated whether intracerebral inoculation of brain and spinal cord from CWD-infected mule deer transmits prion infection to transgenic mice overexpressing human prion protein with methionine or valine at polymorphic residue 129. These transgenic mice have been utilized in extensive transmission studies of human and animal prion disease and are susceptible to BSE and vCJD prions, allowing comparison with CWD. Here, we show that these mice proved entirely resistant to infection with mule deer CWD prions arguing that the transmission barrier associated with this prion strain/host combination is greater than that observed with classical BSE prions. However, it is possible that CWD may be caused by multiple prion strains. Further studies will be required to evaluate the transmission properties of distinct cervid prion strains as they are characterized

Imaging and CSF analyses effectively distinguish CJD from its mimics

OBJECTIVE: To review clinical and investigation findings in patients referred to a specialist prion clinic who were suspected to have sporadic Creutzfeldt-Jakob disease (sCJD) and yet were found to have an alternative final diagnosis. METHODS: Review the clinical findings and investigations in 214 patients enrolled into the UK National Prion Monitoring Cohort Study between October 2008 and November 2015 who had postmortem confirmed sCJD and compare these features with 50 patients referred over the same period who had an alternative final diagnosis (CJD mimics). RESULTS: Patients with an alternative diagnosis and those with sCJD were of similar age, sex and frequency of dementia but CJD mimics had a longer clinical history. Myoclonus, rigidity and hallucinations were more frequent in patients with sCJD but these features were not helpful in classifying individual patients. Alzheimer's disease, dementia with Lewy bodies and genetic neurodegenerative disorders were alternative diagnoses in more than half of the CJD mimic cases, and 10% had an immune-mediated encephalopathy; lymphoma, hepatic encephalopathy and progressive multifocal leukoencephalopathy were seen more than once. Diffusion-weighted MRI was the most useful readily available test to classify cases correctly (92% CJD, 2% CJD mimics). The CSF cell count, 14-3-3 protein detection and S100B were of limited value. A positive CSF RT-QuIC test, introduced during the course of the study, was found in 89% of tested CJD cases and 0% CJD mimics. CONCLUSION: The combination of diffusion-weighted MRI analysis and CSF RT-QuIC allowed a perfect classification of sCJD versus its mimics in this study

An extended XMM-Newton observation of the Seyfert galaxy NGC 4051. II. Soft X-ray emission from a limb-brightened shell of post-shock gas

An extended XMM-Newton observation of the Seyfert I galaxy NGC 4051 in 2009 revealed a complex absorption spectrum, with a wide range of outflow velocities and ionisation states.The main velocity and ionisation structure was interpreted in Paper I in terms of a decelerating, recombining flow resulting from the shocking of a still higher velocity wind colliding with the ISM or slower moving ejecta. The high sensitivity of the XMM-Newton observation also revealed a number of broad emission lines, all showing evidence of self-absorption near the line cores. The line profiles are found here to be consistent with emission from a limb-brightened shell of post-shock gas building up ahead of the contact discontinuity. While the broad emission lines remain quasi-constant as the continuum flux changes by an order of magnitude, recombination continua of several H- and He-like ions are found to vary in response to the continuum, providing an important key to scaling the ionised flow.Comment: Accepted for publication in MNRA

Preclinical detection of infectivity and disease-specific PrP in blood throughout the incubation period of prion disease.

Variant Creutzfeldt-Jakob disease (vCJD) is a fatal neurodegenerative disorder characterised by accumulation of pathological isoforms of the prion protein, PrP. Although cases of clinical vCJD are rare, there is evidence there may be tens of thousands of infectious carriers in the United Kingdom alone. This raises concern about the potential for perpetuation of infection via medical procedures, in particular transfusion of contaminated blood products. Accurate biochemical detection of prion infection is crucial to mitigate risk and we have previously reported a blood assay for vCJD. This assay is sensitive for abnormal PrP conformers at the earliest stages of preclinical prion disease in mice and precedes the maximum infectious titre in blood. Not only does this support the possibility of screening asymptomatic individuals, it will also facilitate the elucidation of the complex relationship that exists between the ensemble of abnormal PrP conformers present in blood and the relationship to infectivity

Diagnosing Sporadic Creutzfeldt-Jakob Disease by the Detection of Abnormal Prion Protein in Patient Urine

IMPORTANCE: Creutzfeldt-Jakob disease (CJD) is a fatal neurodegenerative disorder associated with the accumulation of infectious abnormal prion protein through a mechanism of templated misfolding. A recent report has described the detection of abnormal prion protein in the urine of patients with variant CJD (vCJD) using protein misfolding by cyclic amplification, which was apparently absent in the more common sporadic form of CJD (sCJD). A noninvasive diagnostic test could improve early diagnosis of sCJD and, by screening donations, mitigate the potential risks of prion transmission through human urine–derived pharmaceuticals. Here, we describe the adaptation of the direct detection assay, developed originally as a blood test for vCJD, for the detection of disease-associated prion protein in urine samples from patients with sCJD. OBJECTIVE: To determine the feasibility of sCJD diagnosis by adaptation of an established vCJD diagnostic blood test to urine. DESIGN, SETTINGS AND PARTICIPANTS: This retrospective, cross-sectional study included anonymized urine samples from healthy nonneurological control individuals (n = 91), patients with non-prion neurodegenerative diseases (n = 34), and patients with prion disease (n = 37) of which 20 had sCJD. Urine samples obtained during the Medical Research Council PRION-1 Trial, the National Prion Monitoring Cohort Study, and/or referred to the National Prion Clinic or Dementia Research Centre at the National Hospital for Neurology and Neurosurgery in the United Kingdom. MAIN OUTCOMES AND MEASURES: Presence of sCJD infection determined by an assay that captures, enriches, and detects disease-associated prion protein isoforms. RESULTS: A total of 162 samples were analyzed, composed of 91 normal control individuals (51 male, 33 female, and 7 not recorded), 34 neurological disease control individuals (19 male and 15 female), and 37 with prion disease (22 male and 15 female). The assay’s specificity for prion disease was 100% (95% CI, 97%-100%), with no false-positive reactions from 125 control individuals, including 34 from a range of neurodegenerative diseases. In contrast to a previous study, which used a different method, sensitivity to vCJD infection was low (7.7%; 95% CI, 0.2%-36%), with only 1 of 13 patients with positive test results, while sensitivity to sCJD was unexpectedly high at 40% (95% CI, 19%-64%). CONCLUSIONS AND RELEVANCE: We determined 40% of sCJD urine sample results as positive. To our knowledge, this is the first demonstration of an assay that can detect sCJD infection in urine or any target analyte outside of the central nervous system. Urine detection could allow the development of rapid, molecular diagnostics for sCJD and has implications for other neurodegenerative diseases where disease-related assemblies of misfolded proteins might also be present in urine