A Design Process Centric Application of State Space Modeling as a Function of Communications and Cognitive Skills Assessments.

Humans have a reliable basic probabilistic intuition. We utilize our probabilistic intuition in many day-to-day activities such as driving. In fact any interaction that occurs in the presence of other independent actors requires some probabilistic assessment. While we are good at sorting between rare and common events, determining if these events are statistical significant is always subject to scrutiny. Quite often the bounds of statistical significance are at ends with the ‘common sense’ expectation. While our probabilistic intuition is good for first moment effects such as driving a car, throwing a football and understanding simplistic mathematical models, our probabilistic intuition fails when we need to evaluate secondary effects such as high speed turns, playing golf or understanding complex mathematical models. When our probabilistic intuition is challenged misinterpretation of results and skewed perspectives of possible outcomes will occur. The work presented in this dissertation provides a mathematical formulation that will provide a guide to when our probabilistic intuition will be challenged. This dissertation will discuss the development of the Process Failure Estimation Technique (ProFET). A multitude of potential team parameters could have been selected, interpersonal communication effectiveness and cognitive skill assessments seemed the most obvious first steps. This is due to the prolific discussion on communication and the general acceptance of the cognitive testing as an indicator of performance potential. The teams skill set must be variable with respect to time in order to accomplish the required objectives of each phase of the design process. ProFET develops a metric for the design process that is sensitive to the team composition and structure. This metric is applied to a domain that is traditionally devoid of objective scoring. With the use of ProFET more informed decisions on team structure and composition can be made at critical junctions of the design process. Specifically, ProFET looks at how variability propagates through the design activities as opposed to attempting to quantify the actual values of design activities, which is the focus of the majority of other design research.PhDNaval Architecture and Marine EngineeringUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/116679/1/jdstrick_1.pd

APOE-ε4 synergizes with sleep disruption to accelerate Aβ deposition and Aβ-associated tau seeding and spreading

Alzheimer\u27s disease (AD) is the most common cause of dementia. The APOE-ε4 allele of the apolipoprotein E (APOE) gene is the strongest genetic risk factor for late-onset AD. The APOE genotype modulates the effect of sleep disruption on AD risk, suggesting a possible link between apoE and sleep in AD pathogenesis, which is relatively unexplored. We hypothesized that apoE modifies Aβ deposition and Aβ plaque-associated tau seeding and spreading in the form of neuritic plaque-tau (NP-tau) pathology in response to chronic sleep deprivation (SD) in an apoE isoform-dependent fashion. To test this hypothesis, we used APPPS1 mice expressing human APOE-ε3 or -ε4 with or without AD-tau injection. We found that SD in APPPS1 mice significantly increased Aβ deposition and peri-plaque NP-tau pathology in the presence of APOE4 but not APOE3. SD in APPPS1 mice significantly decreased microglial clustering around plaques and aquaporin-4 (AQP4) polarization around blood vessels in the presence of APOE4 but not APOE3. We also found that sleep-deprived APPPS1:E4 mice injected with AD-tau had significantly altered sleep behaviors compared with APPPS1:E3 mice. These findings suggest that the APOE-ε4 genotype is a critical modifier in the development of AD pathology in response to SD

Cholesterol 25-hydroxylase mediates neuroinflammation and neurodegeneration in a mouse model of tauopathy

Alzheimer\u27s disease (AD) is characterized by amyloid plaques and neurofibrillary tangles, in addition to neuroinflammation and changes in brain lipid metabolism. 25-Hydroxycholesterol (25-HC), a known modulator of both inflammation and lipid metabolism, is produced by cholesterol 25-hydroxylase encoded by Ch25h expressed as a disease-associated microglia signature gene. However, whether Ch25h influences tau-mediated neuroinflammation and neurodegeneration is unknown. Here, we show that in the absence of Ch25h and the resultant reduction in 25-HC, there is strikingly reduced age-dependent neurodegeneration and neuroinflammation in the hippocampus and entorhinal/piriform cortex of PS19 mice, which express the P301S mutant human tau transgene. Transcriptomic analyses of bulk hippocampal tissue and single nuclei revealed that Ch25h deficiency in PS19 mice strongly suppressed proinflammatory signaling in microglia. Our results suggest a key role for Ch25h/25-HC in potentiating proinflammatory signaling to promote tau-mediated neurodegeneration. Ch25h may represent a novel therapeutic target for primary tauopathies, AD, and other neuroinflammatory diseases

Genomic Adaptations to Salinity Resist Gene Flow in the Evolution of Floridian Watersnakes

The migration-selection balance often governs the evolution of lineages, and speciation with gene flow is now considered common across the tree of life. Ecological speciation is a process that can facilitate divergence despite gene flow due to strong selective pressures caused by ecological differences; however, the exact traits under selection are often unknown. The transition from freshwater to saltwater habitats provides strong selection targeting traits with osmoregulatory function. Several lineages of North American watersnakes (Nerodia spp.) are known to occur in saltwater habitat and represent a useful system for studying speciation by providing an opportunity to investigate gene flow and evaluate how species boundaries are maintained or degraded. We use double digest restriction-site associated DNA sequencing to characterize the migration-selection balance and test for evidence of ecological divergence within the Nerodia fasciata-clarkii complex in Florida. We find evidence of high intraspecific gene flow with a pattern of isolation-by-distance underlying subspecific lineages. However, we identify genetic structure indicative of reduced gene flow between inland and coastal lineages suggesting divergence due to isolation-by-environment. This pattern is consistent with observed environmental differences where the amount of admixture decreases with increased salinity. Furthermore, we identify significantly enriched terms related to osmoregulatory function among a set of candidate loci, including several genes that have been previously implicated in adaptation to salinity stress. Collectively, our results demonstrate that ecological differences, likely driven by salinity, cause strong divergent selection which promotes divergence in the N. fasciata-clarkii complex despite significant gene flow

The James Webb Space Telescope Mission

Twenty-six years ago a small committee report, building on earlier studies, expounded a compelling and poetic vision for the future of astronomy, calling for an infrared-optimized space telescope with an aperture of at least $4m$. With the support of their governments in the US, Europe, and Canada, 20,000 people realized that vision as the $6.5m$ James Webb Space Telescope. A generation of astronomers will celebrate their accomplishments for the life of the mission, potentially as long as 20 years, and beyond. This report and the scientific discoveries that follow are extended thank-you notes to the 20,000 team members. The telescope is working perfectly, with much better image quality than expected. In this and accompanying papers, we give a brief history, describe the observatory, outline its objectives and current observing program, and discuss the inventions and people who made it possible. We cite detailed reports on the design and the measured performance on orbit.Comment: Accepted by PASP for the special issue on The James Webb Space Telescope Overview, 29 pages, 4 figure

Pathological chemotherapy response score is prognostic in tubo-ovarian high-grade serous carcinoma: A systematic review and meta-analysis of individual patient data

There is a need to develop and validate biomarkers for treatment response and survival in tubo-ovarian high-grade serous carcinoma (HGSC). The chemotherapy response score (CRS) stratifies patients into complete/near-complete (CRS3), partial (CRS2), and no/minimal (CRS1) response after neoadjuvant chemotherapy (NACT). Our aim was to review current evidence to determine whether the CRS is prognostic in women with tubo-ovarian HGSC treated with NACT.This article is freely available via Open Access. Click on the Publisher URL to access the full-text via the publisher's site

Correction to: A nonsynonymous mutation in PLCG2 reduces the risk of Alzheimer’s disease, dementia with Lewy bodies and frontotemporal dementia, and increases the likelihood of longevity

The IPDGC (The International Parkinson Disease Genomics Consortium) and EADB (Alzheimer Disease European DNA biobank) are listed correctly as an author to the article, however, they were incorrectly listed more than once

Correction to: A nonsynonymous mutation in PLCG2 reduces the risk of Alzheimer’s disease, dementia with Lewy bodies and frontotemporal dementia, and increases the likelihood of longevity

The IPDGC (The International Parkinson Disease Genomics Consortium) and EADB (Alzheimer Disease European DNA biobank) are listed correctly as an author to the article, however, they were incorrectly listed more than once

Responses to environmental variability by herbivorous insects and their natural enemies within a bioenergy crop, Miscanthus x giganteus.

Precision agriculture (PA) is the application of management decisions based on identifying, quantifying, and responding to space-time variability. However, knowledge of crop pest responses to within-field environmental variability, and the spatial distribution of their natural enemies, is limited. Quantitative methods providing insights on how pest-predator relationships vary within fields are potentially important tools. In this study, phloem feeders and their natural enemies, were observed over two years across 81 locations within a field of the perennial feedstock grass in Georgia, USA. Geographically weighted regression (GWR) was used to spatially correlate their abundance with environmental factors. Variables included distance to forest edge, Normalized Difference of Vegetation Index (NDVI), slope, aspect, elevation, soil particle size distribution, and weather values. GWR methods were compared with generalized linear regression methods that do not account for spatial information. Non-spatial models indicated positive relationships between phloem-feeder abundance and wind speed, but negative relationships between elevation, proportions of silt and sand, and NDVI. With data partitioned into three seasonal groups, terrain and soil variables remained significant, and natural enemies and spiders became relevant. Results from GWR indicated that magnitudes and directions of responses varied within the field, and that relationships differed among seasons. Strong negative relationships between response and explanatory factors occurred: with NDVI during mid-season; with percent silt, during mid-, and late seasons; and with spider abundance during early and late seasons. In GWR models, slope, elevation, and aspect were mostly positive indicating further that associations with elevation depended on whether models incorporated spatial information or not. By using spatially explicit models, the analysis provided a complex, nuanced understanding of within-field relationships between phloem feeders and environmental covariates. This approach provides an opportunity to learn about the variability within agricultural fields and, with further analysis, has potential to inform and improve PA and habitat management decisions