Neuropathologic basis of frontotemporal dementia in progressive supranuclear palsy.

BackgroundProgressive supranuclear palsy (PSP) is a neurodegenerative disorder characterized by neuronal loss in the extrapyramidal system with pathologic accumulation of tau in neurons and glia. The most common clinical presentation of PSP, referred to as Richardson syndrome, is that of atypical parkinsonism with vertical gaze palsy, axial rigidity, and frequent falls. Although cognitive deficits in PSP are often ascribed to subcortical dysfunction, a subset of patients has dementia with behavioral features similar to the behavioral variant of frontotemporal dementia. In this study we aimed to identify the clinical and pathological characteristics of PSP presenting with frontotemporal dementia.MethodsIn this study, we compared clinical and pathologic characteristics of 31 patients with PSP with Richardson syndrome with 15 patients with PSP with frontotemporal dementia. For pathological analysis, we used semiquantitative methods to assess neuronal and glial lesions with tau immunohistochemistry, as well image analysis of tau burden using digital microscopic methods.ResultsWe found greater frontal and temporal neocortical neuronal tau pathology in PSP with frontotemporal dementia compared with PSP with Richardson syndrome. White matter tau pathology was also greater in PSP with frontotemporal dementia than PSP with Richardson syndrome. Genetic and demographic factors were not associated with atypical distribution of tau pathology in PSP with frontotemporal dementia.ConclusionsThe results confirm the subset of cognitive-predominant PSP mimicking frontotemporal dementia in PSP. PSP with frontotemporal dementia has distinct clinical features that differ from PSP with Richardson syndrome, as well as differences in distribution and density of tau pathology. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society

Opportunities for Competency Support of Virginia Cooperative Extension Professionals at the Colleague Stage

This study focused on the professional development needs of Cooperative Extension agents and specialists with between four and seven years of experience, placing them roughly within the colleague career stage. Data were collected through focus groups and validated through member checking and the use of a modified World Café approach. A research team collaborated, increasing the reliability of the findings through intentional reflection in the development of the findings. Areas of competency strength and weakness vary for agents and specialists, and specific topic areas within competencies vary. While many of the emergent competencies identified in this study fit within the competency framework of Harder et al. (2011) and previous competency studies, more specific topic areas were identified. However, the top priorities identified for professional development focus included communication, educational design, leadership, and budget and fiscal management. Attention to these areas can increase the ability of these professionals to work more effectively and productively. Providing professional development in areas of need for both agents and specialists can support the development of collegiality within the Extension organization. Supporting professionals in this stage of their career growth will position them well for advancing to additional career stages within Cooperative Extension

Contemporary geomorphological activity throughout the proglacial area of an alpine catchment

Quantification of contemporary geomorphological activity is a fundamental prerequisite for predicting the effects of future earth surface process and landscape development changes. However, there is a lack of high-resolution spatial and temporal data on geomorphological activity within alpine catchments, which are especially sensitive to climate change, human impacts and which are amongst the most dynamic landscapes on Earth. This study used data from repeated laser scanning to identify and quantify the distribution of contemporary sediment sources and the intensity of geomorphological activity within the lower part of a glaciated alpine catchment; Ödenwinkelkees, central Austria. Spatially, geomorphological activity was discriminated by substrate class. Activity decreased in both areal extent and intensity with distance from the glacier, becoming progressively more restricted to the fluvially-dominated valley floor. Temporally, geomorphological activity was identified on annual, seasonal, weekly and daily timescales. Activity became more extensive with increasing study duration but more intense over shorter timescales, thereby demonstrating the importance of temporary storage of sediment within the catchment. The mean volume of material moved within the proglacial zone was 4400m.yr, which suggests a net surface lowering of 34mm.yr in this part of the catchment. We extrapolate a minimum of 4.8mm.yr net surface lowering across the whole catchment. These surface lowering values are approximately twice those calculated elsewhere from contemporary measurements of suspended sediment flux, and of rates calculated from the geological record, perhaps because we measure total geomorphological activity within the catchment rather than overall efflux of material. Repeated geomorphological surveying therefore appears to mitigate the problems of hydrological studies underestimating sediment fluxes on decadal-annual time-scales. Further development of the approach outlined in this study will enable the quantification of geomorphological activity, alpine terrain stability and persistence of landforms

Novel mutations in TARDBP (TDP-43) in patients with familial amyotrophic lateral sclerosis.

The TAR DNA-binding protein 43 (TDP-43) has been identified as the major disease protein in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitin inclusions (FTLD-U), defining a novel class of neurodegenerative conditions: the TDP-43 proteinopathies. The first pathogenic mutations in the gene encoding TDP-43 (TARDBP) were recently reported in familial and sporadic ALS patients, supporting a direct role for TDP-43 in neurodegeneration. In this study, we report the identification and functional analyses of two novel and one known mutation in TARDBP that we identified as a result of extensive mutation analyses in a cohort of 296 patients with variable neurodegenerative diseases associated with TDP-43 histopathology. Three different heterozygous missense mutations in exon 6 of TARDBP (p.M337V, p.N345K, and p.I383V) were identified in the analysis of 92 familial ALS patients (3.3%), while no mutations were detected in 24 patients with sporadic ALS or 180 patients with other TDP-43-positive neurodegenerative diseases. The presence of p.M337V, p.N345K, and p.I383V was excluded in 825 controls and 652 additional sporadic ALS patients. All three mutations affect highly conserved amino acid residues in the C-terminal part of TDP-43 known to be involved in protein-protein interactions. Biochemical analysis of TDP-43 in ALS patient cell lines revealed a substantial increase in caspase cleaved fragments, including the approximately 25 kDa fragment, compared to control cell lines. Our findings support TARDBP mutations as a cause of ALS. Based on the specific C-terminal location of the mutations and the accumulation of a smaller C-terminal fragment, we speculate that TARDBP mutations may cause a toxic gain of function through novel protein interactions or intracellular accumulation of TDP-43 fragments leading to apoptosis

Contemporary Tendencies in Mediation

Editors: Humberto dalla Bernardina de Pinho, Juliana Loss de AndradePresentation / Humberto Dalla Bernardina de Pinho, Juliana Loss de Andrade. -- Mediation in England / Neil Andrews. -- Un Reto para la Mediación: el Diseño de su Código Deontológico / Nuria Belloso Martín. -- Alternative Dispute Resolution and Aboriginal-Crown Reconciliation in Canada / Roshan Danesh, Jessica Dickson. -- A False ‘Prince Charming’ Keeps ‘Sleeping Beauty’ in a Coma: On Voluntary Mediation Being the True Oxymoron of Dispute Resolution Policy / Giuseppe De Palo. -- Programa de Derivación Judicial en Puerto Rico Desde la Perspectiva de la Mediación / Jacqueline N. Font-Guzmán. -- Mediation in Switzerland / Isabelle Hering. -- Reconocimiento y eficacia de los acuerdos de mediación mercantil internacional / Juliana Loss de Andrade. -- The Uses of Mediation / Lela P. Love, Joseph B. Stulberg. -- Multi-Dimensional Mediation / Paul E. Mason. -- “Italy Is Doing It – Should We Be?” Civil and Commercial Mediation in Italy / Giovanni Matteucci. -- Limites dos Meios Alternativos de Conflito / José Marinho Paulo Junior. -- New Perspectives of Civil and Commercial Mediation in Brazil / Humberto Dalla Bernardina de Pinho. -- Practical Impacts of Theoretical Lenses / Elton Simoes, Andrea Maia. -- Development and Resistance in South Europe Justice Systems to Restorative Justice / Helena Soleto Muño

Potential climatic transitions with profound impact on Europe

We discuss potential transitions of six climatic subsystems with large-scale impact on Europe, sometimes denoted as tipping elements. These are the ice sheets on Greenland and West Antarctica, the Atlantic thermohaline circulation, Arctic sea ice, Alpine glaciers and northern hemisphere stratospheric ozone. Each system is represented by co-authors actively publishing in the corresponding field. For each subsystem we summarize the mechanism of a potential transition in a warmer climate along with its impact on Europe and assess the likelihood for such a transition based on published scientific literature. As a summary, the ‘tipping’ potential for each system is provided as a function of global mean temperature increase which required some subjective interpretation of scientific facts by the authors and should be considered as a snapshot of our current understanding. <br/

ALS/FTD Mutation-Induced Phase Transition of FUS Liquid Droplets and Reversible Hydrogels into Irreversible Hydrogels Impairs RNP Granule Function.

The mechanisms by which mutations in FUS and other RNA binding proteins cause ALS and FTD remain controversial. We propose a model in which low-complexity (LC) domains of FUS drive its physiologically reversible assembly into membrane-free, liquid droplet and hydrogel-like structures. ALS/FTD mutations in LC or non-LC domains induce further phase transition into poorly soluble fibrillar hydrogels distinct from conventional amyloids. These assemblies are necessary and sufficient for neurotoxicity in a C. elegans model of FUS-dependent neurodegeneration. They trap other ribonucleoprotein (RNP) granule components and disrupt RNP granule function. One consequence is impairment of new protein synthesis by cytoplasmic RNP granules in axon terminals, where RNP granules regulate local RNA metabolism and translation. Nuclear FUS granules may be similarly affected. Inhibiting formation of these fibrillar hydrogel assemblies mitigates neurotoxicity and suggests a potential therapeutic strategy that may also be applicable to ALS/FTD associated with mutations in other RNA binding proteins.Supported by Canadian Institutes of Health Research (PEF, PStGH), Alzheimer Society of Ontario (PEF, PStGH), Wellcome Trust (PStGH, MEV, CFK, GSK, DR, CEH), Medical Research Council (PStGH, MEV, CFK, GSK), National Institutes of Health Research, Alzheimer Research UK (CFK, GSK), Gates Cambridge Scholarship (JQL), Engineering and Physical Sciences Research Council (CFK, GSK), European Research Council Starting Grant RIBOMYLOME_309545 (GGT), European Research Council under the European Union's Seventh Framework Programme (FP/2007-2013) / ERC Grant Agreement no. 322817 (CEH), and National Institute of Neurological Disorders and Stroke R01 NS07377 (NAS). The authors thank Tom Cech and Roy Parker for helpful discussions.This is the final version of the article. It was first available from Elsevier via http://dx.doi.org/10.1016/j.neuron.2015.10.03

Towards nationally curated data archives for clinical radiology image analysis at scale: Learnings from national data collection in response to a pandemic

The prevalence of the coronavirus SARS-CoV-2 disease has resulted in the unprecedented collection of health data to support research. Historically, coordinating the collation of such datasets on a national scale has been challenging to execute for several reasons, including issues with data privacy, the lack of data reporting standards, interoperable technologies, and distribution methods. The coronavirus SARS-CoV-2 disease pandemic has highlighted the importance of collaboration between government bodies, healthcare institutions, academic researchers and commercial companies in overcoming these issues during times of urgency. The National COVID-19 Chest Imaging Database, led by NHSX, British Society of Thoracic Imaging, Royal Surrey NHS Foundation Trust and Faculty, is an example of such a national initiative. Here, we summarise the experiences and challenges of setting up the National COVID-19 Chest Imaging Database, and the implications for future ambitions of national data curation in medical imaging to advance the safe adoption of artificial intelligence in healthcare

Hundreds of variants clustered in genomic loci and biological pathways affect human height

Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P < 0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy