A Multiancestral Genome-Wide Exome Array Study of Alzheimer Disease, Frontotemporal Dementia, and Progressive Supranuclear Palsy

Importance Previous studies have indicated a heritable component of the etiology of neurodegenerative diseases such as Alzheimer disease (AD), frontotemporal dementia (FTD), and progressive supranuclear palsy (PSP). However, few have examined the contribution of low-frequency coding variants on a genome-wide level. Objective To identify low-frequency coding variants that affect susceptibility to AD, FTD, and PSP. Design, Setting, and Participants We used the Illumina HumanExome BeadChip array to genotype a large number of variants (most of which are low-frequency coding variants) in a cohort of patients with neurodegenerative disease (224 with AD, 168 with FTD, and 48 with PSP) and in 224 control individuals without dementia enrolled between 2005-2012 from multiple centers participating in the Genetic Investigation in Frontotemporal Dementia and Alzheimer’s Disease (GIFT) Study. An additional multiancestral replication cohort of 240 patients with AD and 240 controls without dementia was used to validate suggestive findings. Variant-level association testing and gene-based testing were performed. Main Outcomes and Measures Statistical association of genetic variants with clinical diagnosis of AD, FTD, and PSP. Results Genetic variants typed by the exome array explained 44%, 53%, and 57% of the total phenotypic variance of AD, FTD, and PSP, respectively. An association with the known AD gene ABCA7 was replicated in several ancestries (discovery P = .0049, European P = .041, African American P = .043, and Asian P = .027), suggesting that exonic variants within this gene modify AD susceptibility. In addition, 2 suggestive candidate genes, DYSF (P = 5.53 × 10−5) and PAXIP1 (P = 2.26 × 10−4), were highlighted in patients with AD and differentially expressed in AD brain. Corroborating evidence from other exome array studies and gene expression data points toward potential involvement of these genes in the pathogenesis of AD. Conclusions and Relevance Low-frequency coding variants with intermediate effect size may account for a significant fraction of the genetic susceptibility to AD and FTD. Furthermore, we found evidence that coding variants in the known susceptibility gene ABCA7, as well as candidate genes DYSF and PAXIP1, confer risk for AD

Changing foreign policy: the Obama Administration’s decision to oust Mubarak

This paper analyses the decision of the Obama administration to redirect its foreign policy towards Egypt in the wake of the Arab Spring. It attempts to highlight the issue of how governments deal with decision-making at times of crisis, and under which circumstances they take critical decisions that lead to major shifts in their foreign policy track record. It focuses on the process that led to a reassessment of US (United States) foreign policy, shifting from decades of support to the autocratic regime of Hosni Mubarak, towards backing his ouster. Specifically, the paper attempts to assess to what extent the decision to withdraw US support from a longstanding state-leader and ally in the Middle East can be seen as a foreign policy change (FPC). A relevant research question this paper pursues is: how can the withdrawal of US support to a regime considered as an ally be considered, in itself, as a radical FPC

Lung Squamous Cell Carcinoma mRNA Expression Subtypes Are Reproducible, Clinically Important, and Correspond to Normal Cell Types

Lung squamous cell carcinoma (SCC) is clinically and genetically heterogeneous and current diagnostic practices do not adequately substratify this heterogeneity. A robust, biologically-based SCC subclassification may describe this variability and lead to more precise patient prognosis and management. We sought to determine if SCC mRNA expression subtypes exist, are reproducible across multiple patient cohorts, and are clinically relevant

Differential Pathogenesis of Lung Adenocarcinoma Subtypes Involving Sequence Mutations, Copy Number, Chromosomal Instability, and Methylation

Lung adenocarcinoma (LAD) has extreme genetic variation among patients, which is currently not well understood, limiting progress in therapy development and research. LAD intrinsic molecular subtypes are a validated stratification of naturally-occurring gene expression patterns and encompass different functional pathways and patient outcomes. Patients may have incurred different mutations and alterations that led to the different subtypes. We hypothesized that the LAD molecular subtypes co-occur with distinct mutations and alterations in patient tumors.The LAD molecular subtypes (Bronchioid, Magnoid, and Squamoid) were tested for association with gene mutations and DNA copy number alterations using statistical methods and published cohorts (n = 504). A novel validation (n = 116) cohort was assayed and interrogated to confirm subtype-alteration associations. Gene mutation rates (EGFR, KRAS, STK11, TP53), chromosomal instability, regional copy number, and genomewide DNA methylation were significantly different among tumors of the molecular subtypes. Secondary analyses compared subtypes by integrated alterations and patient outcomes. Tumors having integrated alterations in the same gene associated with the subtypes, e.g. mutation, deletion and underexpression of STK11 with Magnoid, and mutation, amplification, and overexpression of EGFR with Bronchioid. The subtypes also associated with tumors having concurrent mutant genes, such as KRAS-STK11 with Magnoid. Patient overall survival, cisplatin plus vinorelbine therapy response and predicted gefitinib sensitivity were significantly different among the subtypes.The lung adenocarcinoma intrinsic molecular subtypes co-occur with grossly distinct genomic alterations and with patient therapy response. These results advance the understanding of lung adenocarcinoma etiology and nominate patient subgroups for future evaluation of treatment response

The United States COVID-19 Forecast Hub dataset

Academic researchers, government agencies, industry groups, and individuals have produced forecasts at an unprecedented scale during the COVID-19 pandemic. To leverage these forecasts, the United States Centers for Disease Control and Prevention (CDC) partnered with an academic research lab at the University of Massachusetts Amherst to create the US COVID-19 Forecast Hub. Launched in April 2020, the Forecast Hub is a dataset with point and probabilistic forecasts of incident cases, incident hospitalizations, incident deaths, and cumulative deaths due to COVID-19 at county, state, and national, levels in the United States. Included forecasts represent a variety of modeling approaches, data sources, and assumptions regarding the spread of COVID-19. The goal of this dataset is to establish a standardized and comparable set of short-term forecasts from modeling teams. These data can be used to develop ensemble models, communicate forecasts to the public, create visualizations, compare models, and inform policies regarding COVID-19 mitigation. These open-source data are available via download from GitHub, through an online API, and through R packages

Impact of intra- versus inter-annual snow depth variation on water relations and photosynthesis for two Great Basin Desert shrubs

Snowfall provides the majority of soil water in certain ecosystems of North America. We tested the hypothesis that snow depth variation affects soil water content, which in turn drives water potential (Ψ) and photosynthesis, over 10 years for two widespread shrubs of the western USA. Stem Ψ (Ψ stem) and photosynthetic gas exchange [stomatal conductance to water vapor (g s), and CO2 assimilation (A)] were measured in mid-June each year from 2004 to 2013 for Artemisia tridentata var. vaseyana (Asteraceae) and Purshia tridentata (Rosaceae). Snow fences were used to create increased or decreased snow depth plots. Snow depth on +snow plots was about twice that of ambient plots in most years, and 20 % lower on -snow plots, consistent with several down-scaled climate model projections. Maximal soil water content at 40- and 100-cm depths was correlated with February snow depth. For both species, multivariate ANOVA (MANOVA) showed that Ψ stem, g s, and A were significantly affected by intra-annual variation in snow depth. Within years, MANOVA showed that only A was significantly affected by spatial snow depth treatments for A. tridentata, and Ψ stem was significantly affected by snow depth for P. tridentata. Results show that stem water relations and photosynthetic gas exchange for these two cold desert shrub species in mid-June were more affected by inter-annual variation in snow depth by comparison to within-year spatial variation in snow depth. The results highlight the potential importance of changes in inter-annual variation in snowfall for future shrub photosynthesis in the western Great Basin Desert

Reinventing foreign aid for inclusive and sustainable development: a survey

This survey essay reviews over 200 papers in arguing that in order to achieve sustainable and inclusive development, foreign aid should not orient developing countries towards industrialisation in the perspective of Kuznets but in the view of Piketty. Abandoning the former’s view that inequality will fall with progress in industrialisation and placing more emphasis on inequality in foreign aid policy will lead to more sustainable development outcomes. Inter alia: mitigate short-term poverty; address concerns of burgeoning population growth; train recipient governments on inclusive development; fight corruption and mismanagement and; avoid the shortfalls of celebrated Kuznets’ conjectures. We discuss how the essay addresses post-2015 development challenges and provide foreign aid policy instruments with which discussed objectives can be achieved. In summary, the essay provides useful policy measures to avoid past pitfalls. ‘Output may be growing, and yet the mass of the people may be becoming poorer’ (Lewis, 1955). ‘Lewis led all developing countries to water, proverbially speaking, some African countries have so far chosen not to drink’ (Amavilah, 2014). Piketty (2014) has led all developing countries to the stream again and a challenging policy syndrome of our time is how foreign aid can help them to drink