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The use of ionising radiation (IR) for medical diagnosis and treatment procedures has had a major impact on the survival of paediatric patients. Although the benefits of these techniques lead to efficient health care, evaluation of potential associated long-term health effects is required. HARMONIC aims to better understand the increased risk of cancer and non-cancer effects after exposure to medical IR in children with cancer treated with modern external beam radiotherapy (EBRT) – radiation energy in MeV range – and in children with cardiac defects diagnosed and treated with cardiac fluoroscopy procedures (CFP) – radiation energy in keV range. The project investigates, among survivors of paediatric cancer, potential endocrine dysfunction, cardiovascular and neurovascular damage, health-related quality of life and second (and subsequent) primary cancer (SPC). The cardiac component builds a pooled cohort of approximately 90 000 paediatric patients who underwent CFP during childhood and adolescence to investigate cancer risk following exposure to IR and explore the potential effects of conditions predisposing to cancer. HARMONIC develops software tools to allow dose reconstruction in both EBRT and CFP to enable epidemiological investigations and future optimisation of treatments. With the creation of a biobank of blood and saliva samples, HARMONIC aims to provide a mechanistic understanding of radiation-induced adverse health effects and identify potential biomarkers that can predict these effects.

The United States Constitution is the bedrock upon which government and society rest, yet its precepts remain generally unfamiliar to contemporary college students. Considering the extent of its impact and the misinformation regarding its purpose, content, efficacy, and limits, the authors provide suggestions for civic learning based on this seminal document. While all American educational institutions receiving federal funding must celebrate the U.S. Constitution each year on or near September 17th, research suggests that comprehensive and integrative instruction is scarce. Citing a lack of formal Constitution Day programming among honors colleges, the authors present a multi-modal framework for honors students to conduct research, stimulate critical thinking, showcase their findings, and engage in civic dialogues. Historical underpinnings of Constitution Day legislation are provided, and curricular guidelines are included.

BackgroundHalyomorpha halys (Stål), the brown marmorated stink bug, is a highly invasive insect species due in part to its exceptionally high levels of polyphagy. This species is also a nuisance due to overwintering in human-made structures. It has caused significant agricultural losses in recent years along the Atlantic seaboard of North America and in continental Europe. Genomic resources will assist with determining the molecular basis for this species' feeding and habitat traits, defining potential targets for pest management strategies.ResultsAnalysis of the 1.15-Gb draft genome assembly has identified a wide variety of genetic elements underpinning the biological characteristics of this formidable pest species, encompassing the roles of sensory functions, digestion, immunity, detoxification and development, all of which likely support H. halys' capacity for invasiveness. Many of the genes identified herein have potential for biomolecular pesticide applications.ConclusionsAvailability of the H. halys genome sequence will be useful for the development of environmentally friendly biomolecular pesticides to be applied in concert with more traditional, synthetic chemical-based controls.

Most ways of predicting flow resistance in shallow rivers with a partial or complete cover of coarse sediment use a bed‐sediment grain diameter as a roughness length scale. However, beds with the same grain size distribution differ in roughness and flow resistance depending on how the larger grains are arranged, the nature of any bedforms and the possible complications of bedrock or rough banks. This has led to interest in predicting flow resistance using metrics of the topographic roughness of the bed. Some researchers have used the standard deviation of bed elevation as a roughness length scale. An alternative for channels containing boulders is to regard the bed as an array of large roughness elements. Fluvial research to date using these two approaches is limited and inconclusive. We review potentially relevant findings from the much more extensive literature in boundary‐layer meteorology and various branches of engineering and note links between the distribution‐statistics and element‐array approaches. The skewness of the elevation distribution is widely seen as important but it is unclear how best to use it for flow prediction. Other open questions include the scale dependence of topographic metrics, and what type of flow resistance equation to use them in. Calibration and testing of new prediction methods require flow data from reaches with known roughness statistics. This need should be met partly by measurements at field sites or in flume models of them, but also by flume experiments and numerical simulations using synthetic roughness. [ABSTRACT FROM AUTHOR]

To determine the breadth and underpinning of changes in immunocyte gene expression due to genetic variation in mice, we performed, as part of the Immunological Genome Project, gene expression profiling for CD4(+) T cells and neutrophils purified from 39 inbred strains of the Mouse Phenome Database. Considering both cell types, a large number of transcripts showed significant variation across the inbred strains, with 22% of the transcriptome varying by 2-fold or more. These included 119 loci with apparent complete loss of function, where the corresponding transcript was not expressed in some of the strains, representing a useful resource of "natural knockouts." We identified 1222 cis-expression quantitative trait loci (cis-eQTL) that control some of this variation. Most (60%) cis-eQTLs were shared between T cells and neutrophils, but a significant portion uniquely impacted one of the cell types, suggesting cell type-specific regulatory mechanisms. Using a conditional regression algorithm, we predicted regulatory interactions between transcription factors and potential targets, and we demonstrated that these predictions overlap with regulatory interactions inferred from transcriptional changes during immunocyte differentiation. Finally, comparison of these and parallel data from CD4(+) T cells of healthy humans demonstrated intriguing similarities in variability of a gene's expression: the most variable genes tended to be the same in both species, and there was an overlap in genes subject to strong cis-acting genetic variants. We speculate that this "conservation of variation" reflects a differential constraint on intraspecies variation in expression levels of different genes, either through lower pressure for some genes, or by favoring variability for others.

Precipitation is the most important driver of the hydrological cycle, but it is challenging to estimate it over large scales from satellites and models. Here, we assessed the performance of six global and quasi-global high-resolution precipitation datasets (European Centre for Medium-Range Weather Forecasts (ECMWF) Reanalysis version 5 (ERA5), Climate Hazards group Infrared Precipitation with Stations version 2.0 (CHIRPS), Multi-Source Weighted-Ensemble Precipitation version 2.80 (MSWEP), TerraClimate (TERRA), Climate Prediction Centre Unified version 1.0 (CPCU), and Precipitation Estimation from Remotely Sensed Information using Artificial Neural Networks-Cloud Classification System-Climate Data Record (PERSIANN-CCS-CDR, hereafter PERCCDR) for hydrological modelling globally and quasi-globally. We forced the WBMsed global hydrological model with the precipitation datasets to simulate river discharge from 1983 to 2019 and evaluated the predicted discharge against 1825 hydrological stations worldwide, using a range of statistical methods. The results show large differences in the accuracy of discharge predictions when using different precipitation input datasets. Based on evaluation at annual, monthly, and daily timescales, MSWEP followed by ERA5 demonstrated a higher correlation (CC) and Kling–Gupta efficiency (KGE) than other datasets for more than 50 % of the stations, whilst ERA5 was the second-highest-performing dataset, and it showed the highest error and bias for about 20 % of the stations. PERCCDR is the least-well-performing dataset, with a bias of up to 99 % and a normalised root mean square error of up to 247 %. PERCCDR only show a higher KGE and CC than the other products for less than 10 % of the stations. Even though MSWEP provided the highest performance overall, our analysis reveals high spatial variability, meaning that it is important to consider other datasets in areas where MSWEP showed a lower performance. The results of this study provide guidance on the selection of precipitation datasets for modelling river discharge for a basin, region, or climatic zone as there is no single best precipitation dataset globally. Finally, the large discrepancy in the performance of the datasets in different parts of the world highlights the need to improve global precipitation data products. [ABSTRACT FROM AUTHOR]

Alternative splicing (AS) allows increased diversity and orthogonal regulation of the transcriptional products of mammalian genomes. To assess the distribution and variation of alternative splicing across cell lineages of the immune system, we comprehensively analyzed RNA sequencing and microarray data generated by the Immunological Genome Project Consortium. AS is pervasive: 60% of genes showed frequent AS isoforms in T or B lymphocytes, with 7,599 previously unreported isoforms. Distinct cell specificity was observed, with differential exon skipping in 5% of genes otherwise coexpressed in both B and T cells. The distribution of isoforms was mostly all or none, suggesting on/off switching as a frequent mode of AS regulation in lymphocytes. From the identification of differential exon use in the microarray data, clustering of exon inclusion/exclusion patterns across all Immunological Genome Project cell types showed that ∼70% of AS exons are distributed along a common pattern linked to lineage differentiation and cell cycling. Other AS events distinguished myeloid from lymphoid cells or affected only a small set of exons without clear lineage specificity (e.g., Ptprc). Computational analysis predicted specific associations between AS exons and splicing regulators, which were verified by detection of the hnRPLL/Ptprc connection.

The differentiation of αβT cells from thymic precursors is a complex process essential for adaptive immunity. Here we exploited the breadth of expression data sets from the Immunological Genome Project to analyze how the differentiation of thymic precursors gives rise to mature T cell transcriptomes. We found that early T cell commitment was driven by unexpectedly gradual changes. In contrast, transit through the CD4(+)CD8(+) stage involved a global shutdown of housekeeping genes that is rare among cells of the immune system and correlated tightly with expression of the transcription factor c-Myc. Selection driven by major histocompatibility complex (MHC) molecules promoted a large-scale transcriptional reactivation. We identified distinct signatures that marked cells destined for positive selection versus apoptotic deletion. Differences in the expression of unexpectedly few genes accompanied commitment to the CD4(+) or CD8(+) lineage, a similarity that carried through to peripheral T cells and their activation, demonstrated by mass cytometry phosphoproteomics. The transcripts newly identified as encoding candidate mediators of key transitions help define the 'known unknowns' of thymocyte differentiation.

The differentiation of hematopoietic stem cells into cells of the immune system has been studied extensively in mammals, but the transcriptional circuitry that controls it is still only partially understood. Here, the Immunological Genome Project gene-expression profiles across mouse immune lineages allowed us to systematically analyze these circuits. To analyze this data set we developed Ontogenet, an algorithm for reconstructing lineage-specific regulation from gene-expression profiles across lineages. Using Ontogenet, we found differentiation stage-specific regulators of mouse hematopoiesis and identified many known hematopoietic regulators and 175 previously unknown candidate regulators, as well as their target genes and the cell types in which they act. Among the previously unknown regulators, we emphasize the role of ETV5 in the differentiation of γδ T cells. As the transcriptional programs of human and mouse cells are highly conserved, it is likely that many lessons learned from the mouse model apply to humans.

Concussions are a brain injury that affects the athlete on and off the playing field. The aim of our investigation was to give PE teachers another strategy to use in addition to the recommended approaches set forth by national organizations to convey the message to adolescents regarding the negative effects of concussion. Using the website www.mlssoccer.com, we evaluated the performance measures of MLS players. We compared career performance measures of a control group to the career performance measures of a concussed group, compared career performance measures per position, and compared career performance measures occurring prior to concussion onset to performance measures obtained after concussion occurrence for the concussed group. Of the 2,214 listed players, 288 were eligible for the study. From our sample, 34% sustained a concussion while competing in MLS and 66% were placed in the control group (nonconcussed). In a comparison of the control to the concussed group, total number of shots decreased per season for the concussed group. When the performance measures of both groups were compared by position, midfielders had fewer shots per season, and total shots on goal per season had a trend toward statistical significance. In the comparison of games measures before and after concussion, the total number of seasons and the average games played, total minutes, and shots on goal all decreased per season after concussion occurrence. Concussions negatively affected performance measures of MLS players. PE teachers can use this data to engage with their students about the importance of preventing concussions., With the larger societal recognition that concussions are causing health problems, the Centers for Disease Control and Prevention (CDC) initiated a campaign to bring awareness to this issue. To do [...]