High-Resolution Genome-Wide Single Nucleotide Polymorphism Mapping in Acute Myeloid Leukaemia

PhDInvestigation of the genetics of acute myeloid leukaemia (AML) has revealed the underlying basis of the disease and led to targets for therapy. High-resolution single nucleotide polymorphism (SNP) arrays detected regions of loss of heterozygosity and DNA copy number changes, augmenting the results of conventional cytogenetic analysis in AML. Fifteen out of 72 (20%) primary AML samples exhibited large regions of homozygosity that could not be accounted for by visible chromosomal abnormalities in the karyotype. Further analysis confirmed that these patterns were due to partial uniparental disomy (UPD). Remission marrow was available from five patients showing UPD in their leukemias, and in all cases the homozygosity was found to be restricted to the diagnostic leukemic clone. These cryptic nonrandom chromosomal abnormalities are characteristic of mitotic recombination. In 7 of 13 cases with UPD, concurrent homozygous mutations were identified at four distinct loci (WTI, FLT3, CEBPA, and RUNXI). This implies that mutation precedes mitotic recombination which acts as a "second hit" responsible for removal of the remaining wild-type allele. Clonal evolution from heterozygous to homozygous mutations by mitotic recombination would provide a mechanism for relapse of AML. Analysis of 27 paired diagnostic and relapsed AML samples demonstrated newly acquired segmental UPDs at relapse in 11 AML samples (40%). Six were segmental UPDs of chromosome 13q, which led to a change from heterozygosity to homozygosity for internal tandem duplication of FLT3. Three further AML samples had evidence of acquired segmental UPD of 13q in a subclone of the relapsed leukemia. One patient acquired segmental UPD of 19q which led to homozygosity for a CEBPA mutation 207 C-'T. Finally, a single AML patient acquired segmental UPD of chromosome 4q, for which the candidate gene is unknown. In conclusion, the acquisition of segmental UPD and the resulting homozygous mutation is a common event associated with relapse of AML

Comparative Analysis of Plastid Genomes Using Pangenome Research ToolKit (PGR-TK)

Plastid genomes (plastomes) of angiosperms are of great interest among biologists. High-throughput sequencing is making many such genomes accessible, increasing the need for tools to perform rapid comparative analysis. This exploratory analysis investigates whether the Pangenome Research Tool Kit (PGR-TK) is suitable for analyzing plastomes. After determining the optimal parameters for this tool on plastomes, we use it to compare sequences from each of the genera - Magnolia, Solanum, Fragaria and Cotoneaster, as well as a combined set from 20 rosid genera. PGR-TK recognizes large-scale plastome structures, such as the inverted repeats, among combined sequences from distant rosid families. If the plastid genomes are rotated to the same starting point, it also correctly groups different species from the same genus together in a generated cladogram. The visual approach of PGR-TK provides insights into genome evolution without requiring gene annotations.Comment: 15 pages, 4 figure

Mapping & decoding cortical engagement during motor imagery, mental arithmetic, and silent word generation using MEG

Accurate quantification of cortical engagement during mental imagery tasks remains a challenging brain-imaging problem with immediate relevance to developing brain–computer interfaces. We analyzed magnetoencephalography (MEG) data from 18 individuals completing cued motor imagery, mental arithmetic, and silent word generation tasks. Participants imagined movements of both hands (HANDS) and both feet (FEET), subtracted two numbers (SUB), and silently generated words (WORD). The task-related cortical engagement was inferred from beta band (17–25 Hz) power decrements estimated using a frequency-resolved beamforming method. In the hands and feet motor imagery tasks, beta power consistently decreased in premotor and motor areas. In the word and subtraction tasks, beta-power decrements showed engagements in language and arithmetic processing within the temporal, parietal, and inferior frontal regions. A support vector machine classification of beta power decrements yielded high accuracy rates of 74 and 68% for classifying motor-imagery (HANDS vs. FEET) and cognitive (WORD vs. SUB) tasks, respectively. From the motor-versus-nonmotor contrasts, excellent accuracy rates of 85 and 80% were observed for hands-versus-word and hands-versus-sub, respectively. A multivariate Gaussian-process classifier provided an accuracy rate of 60% for the four-way (HANDS-FEET-WORD-SUB) classification problem. Individual task performance was revealed by within-subject correlations of beta-decrements. Beta-power decrements are helpful metrics for mapping and decoding cortical engagement during mental processes in the absence of sensory stimuli or overt behavioral outputs. Markers derived based on beta decrements may be suitable for rehabilitation purposes, to characterize motor or cognitive impairments, or to treat patients recovering from a cerebral stroke

Spotting 2-D Atomic Layers on Aluminum Nitride Thin Films

The availability of large-area substrates imposes an important constraint on the technological and commercial realization of devices made of layered materials. Aluminum nitride films on silicon are shown to be promising candidate materials as large-area substrates for such devices. Herein, the optical contrast of exemplar 2D layers - MoS2and graphene - on AlN films has been investigated as a necessary first step to realize devices on these substrates. Significant contrast enhancements are predicted and observed on AlN films compared to conventional SiO2films. Quantitative estimates of experimental contrast using reflectance spectroscopy show very good agreement with predicted values.Comment: 17 pages, 8 figures, supplementary informatio

A Complete Spectroscopic Survey of the Milky Way satellite Segue 1: Dark matter content, stellar membership and binary properties from a Bayesian analysis

We introduce a comprehensive analysis of multi-epoch stellar line-of-sight velocities to determine the intrinsic velocity dispersion of the ultrafaint satellites of the Milky Way. Our method includes a simultaneous Bayesian analysis of both membership probabilities and the contribution of binary orbital motion to the observed velocity dispersion within a 14-parameter likelihood. We apply our method to the Segue 1 dwarf galaxy and conclude that Segue 1 is a dark-matter-dominated galaxy at high probability with an intrinsic velocity dispersion of 3.7^{+1.4}_{-1.1} km/sec. The dark matter halo required to produce this dispersion must have an average density of 2.5^{+4.1}_{-1.9} solar mass/pc^3 within a sphere that encloses half the galaxy's stellar luminosity. This is the highest measured density of dark matter in the Local Group. Our results show that a significant fraction of the stars in Segue 1 may be binaries with the most probable mean period close to 10 years, but also consistent with the 180 year mean period seen in the solar vicinity at about 1 sigma. Despite this binary population, the possibility that Segue 1 is a bound star cluster with the observed velocity dispersion arising from the orbital motion of binary stars is disfavored by the multi-epoch stellar velocity data at greater than 99% C.L. Finally, our treatment yields a projected (two-dimensional) half-light radius for the stellar profile of Segue 1 of 28^{+5}_{-4} pc, in excellent agreement with photometric measurements.Comment: 15 pages, 19 figure

Impacts of climate change on hydrology, water quality and crop productivity in the Ohio-Tennessee River Basin

Nonpoint source pollution from agriculture is the main source of nitrogen and phosphorus in the stream systems of the Corn Belt region in the Midwestern US. The eastern part of this region is comprised of the Ohio-Tennessee River Basin (OTRB), which is considered a key contributing area for water pollution and the Northern Gulf of Mexico hypoxic zone. A point of crucial importance in this basin is therefore how intensive corn-based cropping systems for food and fuel production can be sustainable and coexist with a healthy water environment, not only under existing climate but also under climate change conditions in the future. To address this issue, a OTRB integrated modeling system has been built with a greatly refined 12-digit subbasin structure based on the Soil and Water Assessment Tool (SWAT) water quality model, which is capable of estimating landscape and in-stream water and pollutant yields in response to a wide array of alternative cropping and/or management strategies and climatic conditions. The effects of three agricultural management scenarios on crop production and pollutant loads exported from the crop land of the OTRB to streams and rivers were evaluated: (1) expansion of continuous corn across the entire basin, (2) adoption of no-till on all corn and soybean fields in the region, (3) implementation of a winter cover crop within the baseline rotations. The effects of each management scenario were evaluated both for current climate and projected mid-century (2046-2065) climates from seven global circulation models (GCMs). In both present and future climates each management scenario resulted in reduced erosion and nutrient loadings to surface water bodies compared to the baseline agricultural management, with cover crops causing the highest water pollution reduction. Corn and soybean yields in the region were negligibly influenced from the agricultural management scenarios. On the other hand, both water quality and crop yield numbers under climate change deviated considerably for all seven GCMs compared to the baseline climate. Future climates from all GCMs led to decreased corn and soybean yields by up to 20% on a mean annual basis, while water quality alterations were either positive or negative depending on the GCM. The study highlights the loss of productivity in the eastern Corn Belt under climate change, the need to consider a range of GCMs when assessing impacts of climate change, and the value of SWAT as a tool to analyze the effects of climate change on parameters of interest at the basin scale

Identification of Glycopeptides as Posttranslationally Modified Neoantigens in Leukemia

Abstract Leukemias are highly immunogenic, but they have a low mutational load, providing few mutated peptide targets. Thus, the identification of alternative neoantigens is a pressing need. Here, we identify 36 MHC class I–associated peptide antigens with O-linked β-N-acetylglucosamine (O-GlcNAc) modifications as candidate neoantigens, using three experimental approaches. Thirteen of these peptides were also detected with disaccharide units on the same residues and two contain either mono- and/or di-methylated arginine residues. A subset were linked with key cancer pathways, and these peptides were shared across all of the leukemia patient samples tested (5/5). Seven of the O-GlcNAc peptides were synthesized and five (71%) were shown to be associated with multifunctional memory T-cell responses in healthy donors. An O-GlcNAc-specific T-cell line specifically killed autologous cells pulsed with the modified peptide, but not the equivalent unmodified peptide. Therefore, these posttranslationally modified neoantigens provide logical targets for cancer immunotherapy. Cancer Immunol Res; 5(5); 376–84. ©2017 AACR.</jats:p

The potential clinical utility of Whole Genome Sequencing for patients with cancer:evaluation of a regional implementation of the 100,000 Genomes Project

Background: The 100,000 Genomes Project established infrastructure for Whole Genome Sequencing (WGS) in the United Kingdom. Methods: A retrospective study of cancer patients recruited to the 100,000 Genomes Project by the West Midlands Genomics Medicine Centre, evaluating clinical relevance of results. Results: After excluding samples with no sequencing data (1678/4851; 34.6%), 3166 sample sets (germline and somatic) from 3067 participants were sequenced. Results of 1256 participants (41.0%) were interpreted (excluding participants who died (308/3067; 10.0%) or were clinically excluded (1503/3067; 49.0%)). Of these, 323 (25.7%) had no variants in genes which may alter management (Domain 1 genes). Of the remaining 933 participants, 552 (59.2%) had clinical recommendations made (718 recommendations in total). These included therapeutic recommendations (377/933; 40.4%), such as clinical trial, unlicensed or licensed therapies or high TMB recommendations, and germline variants warranting clinical genetics review (85/933; 9.1%). At the last follow up, 20.2% of all recommendations were followed (145/718). However, only a small proportion of therapeutic recommendations were followed (5.1%, 25/491). Conclusions: The 100,000 Genomes Project has established infrastructure and regional experience to support personalised cancer care. The majority of those with successful sequencing had actionable variants. Ensuring GTAB recommendations are followed will maximise benefits for patients

LUMINATE: linking agricultural land use, local water quality and Gulf of Mexico hypoxia

In this paper, we discuss the importance of developing integrated assessment models to support the design and implementation of policies to address water quality problems associated with agricultural pollution. We describe a new modelling system, LUMINATE, which links land use decisions made at the field scale in the Upper Mississippi, Ohio and Tennessee Basins through both environmental and hydrological components to downstream water quality effects and hypoxia in the Gulf of Mexico. This modelling system can be used to analyse detailed policy scenarios identifying the costs of the policies and their resulting benefits for improved local and regional water quality. We demonstrate the model\u27s capabilities with a simple scenario where cover crops are incentivised with green payments over a large expanse of the watershed