Multiancestry analysis of the HLA locus in Alzheimer’s and Parkinson’s diseases uncovers a shared adaptive immune response mediated by HLA-DRB1*04 subtypes

Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson’s disease (PD) and Alzheimer’s disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1*04:07, and intermediary with HLA-DRB1*04:01 and HLA-DRB1*04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased Aβ42. Protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1*04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues

Online Resource Management in a Multiprocessor with a Network on Chip

We propose an online resource allocation solution for multiprocessor systems-on-chip, that executes several real-time, streaming media jobs simultaneously. The system consists of up to 24 processors connected by an Æthereal [7] Network-on-Chip (NoC) of 4 to 12 routers. A job is a set of processing tasks connected by FIFO channels. Each job can be independently started or stopped by the user. Each job is annotated with resource budgets per computation task and communication channel which have been computed at compile-time. When a job is requested to start, resources that meet the required resource budgets have to be found. Because it is done online, allocation must be done with low-complexity algorithms. We do the allocation in two-steps. First, tasks are assigned to virtual tiles (VTs), while trying to minimise the total number of VTs and the total bandwidth used. In the second step, these VTs are mapped to real tiles, and network bandwidth allocation and routing are performed simultaneously. We show with simulations that introducing randomisation in the processing order yields a significant improvement in the percentage of mapping succdesses. In combination, these techniques allow 95 % of the processor resources to be allocated while handling a large number of job arrivals and departures

Foundations of Peer-to-Peer Reputation

Successful classification of good or bad behavior in the digital domain is limited to central governance, as can be seen with trading platforms, search engines and news feeds. We explore and consolidate existing work on decentralized reputation systems to form a common denominator for what makes a reputation system successful when applied without a centralized reputation authority, formalized in 7 axioms and 3 postulates. Reputation must start from nothing and always reward performed work, respectively lowering and increasing as work is consumed and performed. However, it is impossible for nodes to perform work in a purely synchronous attackproof work model and real systems must necessarily employ relaxations to such a work model. We show how the relaxations of performing parallel work, allowing unconsumed work and seeding well-known identities with work satisfy our model. Our formalizations allow constraint driven design of decentralized reputation mechanisms.Distributed System

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

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