6 research outputs found
Dementia Revealed: Novel Chromosome 6 Locus for Late-Onset Alzheimer Disease Provides Genetic Evidence for Folate-Pathway Abnormalities
Genome-wide association studies (GWAS) of late-onset Alzheimer disease (LOAD) have consistently observed strong evidence of association with polymorphisms in APOE. However, until recently, variants at few other loci with statistically significant associations have replicated across studies. The present study combines data on 483,399 single nucleotide polymorphisms (SNPs) from a previously reported GWAS of 492 LOAD cases and 496 controls and from an independent set of 439 LOAD cases and 608 controls to strengthen power to identify novel genetic association signals. Associations exceeding the experiment-wide significance threshold () were replicated in an additional 1,338 cases and 2,003 controls. As expected, these analyses unequivocally confirmed APOE's risk effect (rs2075650, ). Additionally, the SNP rs11754661 at 151.2 Mb of chromosome 6q25.1 in the gene MTHFD1L (which encodes the methylenetetrahydrofolate dehydrogenase (NADP+ dependent) 1-like protein) was significantly associated with LOAD (; Bonferroni-corrected P = 0.022). Subsequent genotyping of SNPs in high linkage disequilibrium () with rs11754661 identified statistically significant associations in multiple SNPs (rs803424, P = 0.016; rs2073067, P = 0.03; rs2072064, P = 0.035), reducing the likelihood of association due to genotyping error. In the replication case-control set, we observed an association of rs11754661 in the same direction as the previous association at P = 0.002 ( in combined analysis of discovery and replication sets), with associations of similar statistical significance at several adjacent SNPs (rs17349743, P = 0.005; rs803422, P = 0.004). In summary, we observed and replicated a novel statistically significant association in MTHFD1L, a gene involved in the tetrahydrofolate synthesis pathway. This finding is noteworthy, as MTHFD1L may play a role in the generation of methionine from homocysteine and influence homocysteine-related pathways and as levels of homocysteine are a significant risk factor for LOAD development
Theory of Constraints Thinking Processes: A Copy Shop Case Application
ABSTRACT This paper illustrates an application of a portion of Eliyahu M. Goldratt's Thinking Processes, a set of tools that are part of his Theory of Constraints body of knowledge, by using them to examine the operational problems encountered by a local franchise unit of a large copy shop chain and to posit solutions. The problems noted by the local franchise unit were mapped into a Current Reality Tree, a diagramming process used to reveal the singular root cause of observed problems. That diagram deduced the problems were caused by the fact that the local unit had not embraced the corporation's recent repositioning strategy into its own activities, decisions and requests. The root cause was then, in turn, used as the basis to create an Evaporating Cloud, a diagramming process that reveals the logical conflicts interfering with root cause removal. The Evaporating Cloud deduced that the local franchise unit had not embraced the repositioning strategy because it believed that if it did so, the division of its resources would cause it to achieve neither short-term goals nor the repositioning strategy. An Evaporating Cloud also facilitates the generation of possible actions to resolve the conflicts and it was used to do so. Several secondary recommendations for improvement in efficiency were also made, based on the direct observation of routine operations while collecting the requisite information to conduct the Thinking Process analysis