277 research outputs found

    Caprine PRNP polymorphisms N146S and Q222K are associated with proteolytic cleavage of PrPC

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    Abstract Expression of the cellular prion protein (PrPC) is crucial for the development of prion diseases. Amino acid changes in PrPC or a reduced amount of PrPC may modulate disease resistance. The relative abundance of C1, a natural α-cleavage fragment of PrPC, was previously found to be associated with a resistant PRNP genotype in sheep. Goats are another small ruminant where classical scrapie susceptibility is under strong genetic control. In this study, we assessed PrPC in goats for the existence of similar associations between PrPC fragments and genotype. Brain tissue homogenates from scrapie-free goats with wild type PRNP or polymorphisms (I142M, H143R, N146S, or Q222K) were deglycosylated prior to immunoblot for assessment of the relative abundance of the C1 fragment of PrPC. The presence of K222 or S146 alleles demonstrated significantly different relative levels of C1 compared to that observed in wild type goats, which suggests that the genotype association with C1 is neither unique to sheep nor exclusive to the ovine Q171R dimorphism

    The impact of the Art Therapy Large Group, an educational tool in the training of art therapists, on post-qualification professional practice

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    This article reports the findings of a Likert scale survey that was sent to past graduates of the MA Art Psychotherapy, Goldsmiths, University of London asking them about the relevance of their experience in the Art Therapy Large Group (ATLG) to their subsequent employment as art therapists or work in another capacity. The ATLG comprises all the students and staff in a psychodynamically based experiential group that meets six times during the year. Survey questions were drawn from previously devised theory and related to learning relevant to the workplace and the development of professional identity. Though there was a low response rate (20%), there were some significant findings, namely that graduates found the ATLG to be helpful in their work, whether this was art therapy or non-art therapy work, and that those who had studied part-time were much more positive about the applicability of their learning in the group to their work than those who had studied full-time. The findings suggest that the ATLG has a particular role in meeting key performance indicators in professional regulation and teaching and in quality assurance and employability policies in higher education. Finally, the potential for the use of the ATLG beyond the university in the public, private and voluntary sectors is suggested

    Asymptotics and local constancy of characters of p-adic groups

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    In this paper we study quantitative aspects of trace characters Θπ\Theta_\pi of reductive pp-adic groups when the representation π\pi varies. Our approach is based on the local constancy of characters and we survey some other related results. We formulate a conjecture on the behavior of Θπ\Theta_\pi relative to the formal degree of π\pi, which we are able to prove in the case where π\pi is a tame supercuspidal. The proof builds on J.-K.~Yu's construction and the structure of Moy-Prasad subgroups.Comment: Proceedings of Simons symposium on the trace formul

    Tissue-specific calibration of extracellular matrix material properties by transforming growth factor-beta and Runx2 in bone is required for hearing

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    Publisher version: http://www.nature.com/embor/journal/v11/n10/full/embor2010135.htmlDA - 20100917 IS - 1469-3178 (Electronic) IS - 1469-221X (Linking) LA - ENG PT - JOURNAL ARTICLEDA - 20100917 IS - 1469-3178 (Electronic) IS - 1469-221X (Linking) LA - ENG PT - JOURNAL ARTICLEDA - 20100917 IS - 1469-3178 (Electronic) IS - 1469-221X (Linking) LA - ENG PT - JOURNAL ARTICLEPhysical cues, such as extracellular matrix stiffness, direct cell differentiation and support tissue-specific function. Perturbation of these cues underlies diverse pathologies, including osteoarthritis, cardiovascular disease and cancer. However, the molecular mechanisms that establish tissue-specific material properties and link them to healthy tissue function are unknown. We show that Runx2, a key lineage-specific transcription factor, regulates the material properties of bone matrix through the same transforming growth factor-beta (TGFbeta)-responsive pathway that controls osteoblast differentiation. Deregulated TGFbeta or Runx2 function compromises the distinctly hard cochlear bone matrix and causes hearing loss, as seen in human cleidocranial dysplasia. In Runx2(+/-) mice, inhibition of TGFbeta signalling rescues both the material properties of the defective matrix, and hearing. This study elucidates the unknown cause of hearing loss in cleidocranial dysplasia, and demonstrates that a molecular pathway controlling cell differentiation also defines material properties of extracellular matrix. Furthermore, our results suggest that the careful regulation of these properties is essential for healthy tissue functio

    AAV9-mediated SMN gene therapy rescues cardiac desmin but not lamin A/C and elastin dysregulation in Smn2B/- spinal muscular atrophy mice

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    This work was supported by Great Ormond Street Hospital Charity (GOSH) and SPARKS Children’s Medical Research Charity (Grant No. V5018 to H.R.F.). M.B. acknowledges general financial support from SMA Angels Charity, SMA UK, Muscular Dystrophy UK, Action Medical Research, Academy of Medical Sciences and Association Française contre les Myopathies for SMA research in her laboratory. H.K.S. and T.H.G. acknowledge support from the Euan MacDonald Centre for Motor Neuron Disease Research and SMA Europe. E.M.C. was partially funded by a scholarship from Royal Holloway University of London. R.J.Y.-M. acknowledges general financial support from SMA UK (formerly The SMA Trust), through the UK SMA Research Consortium, for SMA research in his laboratory.Structural, functional and molecular cardiac defects have been reported in spinal muscular atrophy (SMA) patients and mouse models. Previous quantitative proteomics analyses demonstrated widespread molecular defects in the severe Taiwanese SMA mouse model. Whether such changes are conserved across different mouse models, including less severe forms of the disease, has yet to be established. Here, using the same high-resolution proteomics approach in the less-severe Smn2B/− SMA mouse model, 277 proteins were found to be differentially abundant at a symptomatic timepoint (post-natal day (P) 18), 50 of which were similarly dysregulated in severe Taiwanese SMA mice. Bioinformatics analysis linked many of the differentially abundant proteins to cardiovascular development and function, with intermediate filaments highlighted as an enriched cellular compartment in both datasets. Lamin A/C was increased in the cardiac tissue, whereas another intermediate filament protein, desmin, was reduced. The extracellular matrix (ECM) protein, elastin, was also robustly decreased in the heart of Smn2B/− mice. AAV9-SMN1-mediated gene therapy rectified low levels of survival motor neuron protein and restored desmin levels in heart tissues of Smn2B/− mice. In contrast, AAV9-SMN1 therapy failed to correct lamin A/C or elastin levels. Intermediate filament proteins and the ECM have key roles in cardiac function and their dysregulation may explain cardiac impairment in SMA, especially since mutations in genes encoding these proteins cause other diseases with cardiac aberration. Cardiac pathology may need to be considered in the long-term care of SMA patients, as it is unclear whether currently available treatments can fully rescue peripheral pathology in SMA.Publisher PDFPeer reviewe

    An Infrared Coronagraphic Survey for Substellar Companions

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    We have used the F160W filter (1.4-1.8 um) and the coronagraph on the Near-InfraRed Camera and Multi-Object Spectrometer (NICMOS) on the Hubble Space Telescope (HST) to survey 45 single stars with a median age of 0.15 Gyr, an average distance of 30 pc, and an average H-magnitude of 7 mag. For the median age we were capable of detecting a 30 M_Jup companion at separations between 15 and 200 AU. A 5 M_Jup object could have been detected at 30 AU around 36% of our primaries. For several of our targets that were less than 30 Myr old, the lower mass limit was as low as a Jupiter mass, well into the high mass planet region. Results of the entire survey include the proper motion verification of five low-mass stellar companions, two brown dwarfs (HR7329B and TWA5B) and one possible brown dwarf binary (Gl 577B/C).Comment: 11 figures, accepted by A

    Aptamer-based multiplexed proteomic technology for biomarker discovery

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    Interrogation of the human proteome in a highly multiplexed and efficient manner remains a coveted and challenging goal in biology. We present a new aptamer-based proteomic technology for biomarker discovery capable of simultaneously measuring thousands of proteins from small sample volumes (15 [mu]L of serum or plasma). Our current assay allows us to measure ~800 proteins with very low limits of detection (1 pM average), 7 logs of overall dynamic range, and 5% average coefficient of variation. This technology is enabled by a new generation of aptamers that contain chemically modified nucleotides, which greatly expand the physicochemical diversity of the large randomized nucleic acid libraries from which the aptamers are selected. Proteins in complex matrices such as plasma are measured with a process that transforms a signature of protein concentrations into a corresponding DNA aptamer concentration signature, which is then quantified with a DNA microarray. In essence, our assay takes advantage of the dual nature of aptamers as both folded binding entities with defined shapes and unique sequences recognizable by specific hybridization probes. To demonstrate the utility of our proteomics biomarker discovery technology, we applied it to a clinical study of chronic kidney disease (CKD). We identified two well known CKD biomarkers as well as an additional 58 potential CKD biomarkers. These results demonstrate the potential utility of our technology to discover unique protein signatures characteristic of various disease states. More generally, we describe a versatile and powerful tool that allows large-scale comparison of proteome profiles among discrete populations. This unbiased and highly multiplexed search engine will enable the discovery of novel biomarkers in a manner that is unencumbered by our incomplete knowledge of biology, thereby helping to advance the next generation of evidence-based medicine

    Limbic-predominant age-related TDP-43 encephalopathy (LATE): consensus working group report.

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    We describe a recently recognized disease entity, limbic-predominant age-related TDP-43 encephalopathy (LATE). LATE neuropathological change (LATE-NC) is defined by a stereotypical TDP-43 proteinopathy in older adults, with or without coexisting hippocampal sclerosis pathology. LATE-NC is a common TDP-43 proteinopathy, associated with an amnestic dementia syndrome that mimicked Alzheimer's-type dementia in retrospective autopsy studies. LATE is distinguished from frontotemporal lobar degeneration with TDP-43 pathology based on its epidemiology (LATE generally affects older subjects), and relatively restricted neuroanatomical distribution of TDP-43 proteinopathy. In community-based autopsy cohorts, ∼25% of brains had sufficient burden of LATE-NC to be associated with discernible cognitive impairment. Many subjects with LATE-NC have comorbid brain pathologies, often including amyloid-β plaques and tauopathy. Given that the 'oldest-old' are at greatest risk for LATE-NC, and subjects of advanced age constitute a rapidly growing demographic group in many countries, LATE has an expanding but under-recognized impact on public health. For these reasons, a working group was convened to develop diagnostic criteria for LATE, aiming both to stimulate research and to promote awareness of this pathway to dementia. We report consensus-based recommendations including guidelines for diagnosis and staging of LATE-NC. For routine autopsy workup of LATE-NC, an anatomically-based preliminary staging scheme is proposed with TDP-43 immunohistochemistry on tissue from three brain areas, reflecting a hierarchical pattern of brain involvement: amygdala, hippocampus, and middle frontal gyrus. LATE-NC appears to affect the medial temporal lobe structures preferentially, but other areas also are impacted. Neuroimaging studies demonstrated that subjects with LATE-NC also had atrophy in the medial temporal lobes, frontal cortex, and other brain regions. Genetic studies have thus far indicated five genes with risk alleles for LATE-NC: GRN, TMEM106B, ABCC9, KCNMB2, and APOE. The discovery of these genetic risk variants indicate that LATE shares pathogenetic mechanisms with both frontotemporal lobar degeneration and Alzheimer's disease, but also suggests disease-specific underlying mechanisms. Large gaps remain in our understanding of LATE. For advances in prevention, diagnosis, and treatment, there is an urgent need for research focused on LATE, including in vitro and animal models. An obstacle to clinical progress is lack of diagnostic tools, such as biofluid or neuroimaging biomarkers, for ante-mortem detection of LATE. Development of a disease biomarker would augment observational studies seeking to further define the risk factors, natural history, and clinical features of LATE, as well as eventual subject recruitment for targeted therapies in clinical trials.Sally Hunter and Carol Brayne are supported by funding from the National Institute for Health Research, Senior Investigator Award, awarded to Carol Brayne. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care. Sally Hunter is supported by the Addenbrooke’s Charitable Trust, the Paul G. Allen Family Foundation and Alzheimer’s Research, UK. Suvi Hokkanen was supported by Alzheimer’s Research, UK

    Limbic-Predominant Age-Related TDP-43 Encephalopathy (LATE): Consensus Working Group Report

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    We describe a recently recognized disease entity, limbic-predominant age-related TDP-43 encephalopathy (LATE). LATE neuropathological change (LATE-NC) is defined by a stereotypical TDP-43 proteinopathy in older adults, with or without coexisting hippocampal sclerosis pathology. LATE-NC is a common TDP-43 proteinopathy, associated with an amnestic dementia syndrome that mimicked Alzheimer’s-type dementia in retrospective autopsy studies. LATE is distinguished from frontotemporal lobar degeneration with TDP-43 pathology based on its epidemiology (LATE generally affects older subjects), and relatively restricted neuroanatomical distribution of TDP-43 proteinopathy. In community-based autopsy cohorts, ∼25% of brains had sufficient burden of LATE-NC to be associated with discernible cognitive impairment. Many subjects with LATE-NC have comorbid brain pathologies, often including amyloid-β plaques and tauopathy. Given that the ‘oldest-old’ are at greatest risk for LATE-NC, and subjects of advanced age constitute a rapidly growing demographic group in many countries, LATE has an expanding but under-recognized impact on public health. For these reasons, a working group was convened to develop diagnostic criteria for LATE, aiming both to stimulate research and to promote awareness of this pathway to dementia. We report consensus-based recommendations including guidelines for diagnosis and staging of LATE-NC. For routine autopsy workup of LATE-NC, an anatomically-based preliminary staging scheme is proposed with TDP-43 immunohistochemistry on tissue from three brain areas, reflecting a hierarchical pattern of brain involvement: amygdala, hippocampus, and middle frontal gyrus. LATE-NC appears to affect the medial temporal lobe structures preferentially, but other areas also are impacted. Neuroimaging studies demonstrated that subjects with LATE-NC also had atrophy in the medial temporal lobes, frontal cortex, and other brain regions. Genetic studies have thus far indicated five genes with risk alleles for LATE-NC: GRN, TMEM106B, ABCC9, KCNMB2, and APOE. The discovery of these genetic risk variants indicate that LATE shares pathogenetic mechanisms with both frontotemporal lobar degeneration and Alzheimer’s disease, but also suggests disease-specific underlying mechanisms. Large gaps remain in our understanding of LATE. For advances in prevention, diagnosis, and treatment, there is an urgent need for research focused on LATE, including in vitro and animal models. An obstacle to clinical progress is lack of diagnostic tools, such as biofluid or neuroimaging biomarkers, for ante-mortem detection of LATE. Development of a disease biomarker would augment observational studies seeking to further define the risk factors, natural history, and clinical features of LATE, as well as eventual subject recruitment for targeted therapies in clinical trials

    Effectiveness of an Intervention to Increase Construction Workers' Use of Hearing Protection

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    In this project we tested the effectiveness of a theory-based intervention (video, pamphlets, and guided practice session) to increase the use of hearing protection devices (HPDs) among Midwestern construction workers and a national group of plumber/pipefitter trainers. Posttest measures were collected 10--12 months following this intervention. Pender's Health Promotion Model (1987) provided the conceptual basis for development of the training program. A total of 837 highnoise- exposed workers were included in the analysis: 652 regional Midwestern construction workers and 185 national plumber/pipefitter trainers. Effectiveness of the intervention was determined through the sequence of analyses recommended by Braver and Braver (1988) for the Solomon Four-Group Design. Analysis of variance and covariance of postintervention use and intention to use HPDs and a meta-analytic test were done. These analyses indicated that the intervention significantly increased use of HPDs but had no effect on intention to use HPDs in the future. Pretesting had no effect on use. Actual or potential applications of this research include guidance in the development of successful theorybased interventions to increase use of HPDs.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/68025/2/10.1518_001872099779610969.pd
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