Genome-wide survival study identifies a novel synaptic locus and polygenic score for cognitive progression in Parkinson's disease

A key driver of patients' well-being and clinical trials for Parkinson's disease (PD) is the course that the disease takes over time (progression and prognosis). To assess how genetic variation influences the progression of PD over time to dementia, a major determinant for quality of life, we performed a longitudinal genome-wide survival study of 11.2 million variants in 3,821 patients with PD over 31,053 visits. We discover RIMS2 as a progression locus and confirm this in a replicate population (hazard ratio (HR) = 4.77, P = 2.78 x 10(-11)), identify suggestive evidence for TMEM108 (HR = 2.86, P = 2.09 x 10(-8)) and WWOX (HR = 2.12, P = 2.37 x 10(-8)) as progression loci, and confirm associations for GBA (HR = 1.93, P = 0.0002) and APOE (HR = 1.48, P = 0.001). Polygenic progression scores exhibit a substantial aggregate association with dementia risk, while polygenic susceptibility scores are not predictive. This study identifies a novel synaptic locus and polygenic score for cognitive disease progression in PD and proposes diverging genetic architectures of progression and susceptibility.A genome-wide survival study identifies variants at RIMS2 associated with progression of Parkinson's disease to dementia and highlights divergence in the genetic architecture of disease onset and progression.Neurological Motor Disorder

New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

Highly-parallelized simulation of a pixelated LArTPC on a GPU

The rapid development of general-purpose computing on graphics processing units (GPGPU) is allowing the implementation of highly-parallelized Monte Carlo simulation chains for particle physics experiments. This technique is particularly suitable for the simulation of a pixelated charge readout for time projection chambers, given the large number of channels that this technology employs. Here we present the first implementation of a full microphysical simulator of a liquid argon time projection chamber (LArTPC) equipped with light readout and pixelated charge readout, developed for the DUNE Near Detector. The software is implemented with an end-to-end set of GPU-optimized algorithms. The algorithms have been written in Python and translated into CUDA kernels using Numba, a just-in-time compiler for a subset of Python and NumPy instructions. The GPU implementation achieves a speed up of four orders of magnitude compared with the equivalent CPU version. The simulation of the current induced on 10^3 pixels takes around 1 ms on the GPU, compared with approximately 10 s on the CPU. The results of the simulation are compared against data from a pixel-readout LArTPC prototype

Criterios zoot?cnicos de conservaci?n y utilizaci?n de ganado criollo (Reyna) en fincas lecheras o de doble prop?sito, en el tr?pico seco de Nicaragua

Tesis (M. Sc) -- CATIE, Turrialba (Costa Rica), 1993Con el prop?sito de establecer criterios de conservaci?n de ganado Criollo (Reyna) fueron caracterizadas fincas lecheras o de doble prop?sito distribuidas en los municipios de Tola, Potos?, Masatepe, Tipitapa y Muy-muy en el tr?pico seco de Nicaragua. Los resultados obtenidos en la E1 indican la posibilidad de utilizaci?n estrat?gica e integrada de los recursos existentes. Por otro lado, los resultados de la E2 muestran que el Criollo Reyna posee niveles productivos y reproductivos, biol?gica y ecol?gicamente aceptables y la existencia de variabilidad gen?tica para algunas caracter?sticas, justifican su conservaci?n con miras en su utilizaci?n potencial en los sistemas de Producci?n bovina de bajo nivel tecnol?gico, particularmente de doble prop?sito en el tr?pico seco de Nicaragu

Fast, Quality, Segmentation of Large Volumes -- Isoperimetric Distance Trees

For many medical segmentation tasks, the contrast along most of the boundary of the target object is high, allowing simple thresholding or region growing approaches to provide nearly sufficient solutions for the task. However, the regions recovered by these techniques frequently leak through bottlenecks in which the contrast is low or nonexistent. We propose a new approach based on a novel speed-up of the isoperimetric algorithm [1] that can solve the problem of leaks through a bottleneck. The speed enhancement converts the isoperimetric segmentation algorithm to a fast, linear-time computation by using a tree representation as the underlying graph instead of a standard lattice structure. In this paper, we show how to create an appropriate tree substrate for the segmentation problem and how to use this structure to perform a lineartime computation of the isoperimetric algorithm. This approach is shown to overcome common problems with watershed-based techniques and to provide fast, high-quality results on large datasets

Specifically neuropathic Gaucher's mutations accelerate cognitive decline in Parkinson's

Neurological Motor Disorder