A Combinatorial Approach of Ionomics, Quantitative Trait Locus Mapping, and Transcriptome Analysis to Characterize Element Homeostasis in Maize

In plant systems, genetic and biochemical pathways impact uptake of elements from the soil. These environment-sensitive pathways often act in the root tissue to impact element concentrations throughout the plant. In order to characterize element regulation as well as apply ionomics to understand plant adaptation, perspectives are needed from multiple tissues and environments and from approaches that take interactions between elements into account. The work described in this thesis includes multi-environment and multi-tissue experiments that connect variation in genetic sequence, and in gene expression, with variation in element accumulation. The associations found here include those that are sensitive to environment, reflecting the complex environmental influence on the ionome, as well as those that exhibit consistent effects across different environments. A variety of statistical tools were employed to model genetic by environment interactions and test methodologies that can be applied to future studies of the ionome with more in-depth environmental data. Genetic loci with strong effects on elements across environments were further explored using root-based gene expression data, which identified candidate genes and gene networks underlying element accumulation. Additional research on these candidate genes has the potential to improve our understanding of the genetic basis of homeostatic processes that involve the ionome, as well as isolate targets for genetic modification or selective breeding that can enhance nutritional content and adaptive capacity of crops

Modeling the growth of stylolites in sedimentary rocks

[1] Stylolites are ubiquitous pressure solution seams found in sedimentary rocks. Their morphology is shown to follow two self-affine regimes. Analyzing the scaling properties of their height over their average direction shows that (1) at small scale, they are self-affine surfaces with a Hurst exponent around 1, and (2) at large scale, they follow another self-affine scaling with Hurst exponent around 0.5. In the present paper, we show theoretically the influence of the main principal stress and the local geometry of the stylolitic interface on the dissolution reaction rate. We compute how it is affected by the deviation between the principal stress axis and the local interface between the rock and the soft material in the stylolite. The free energy entering in the dissolution reaction kinetics is expressed from the surface energy term and via integration from the stress perturbations due to these local misalignments. The resulting model shows the interface evolution at different stress conditions. In the stylolitic case, i.e., when the main principal stress is normal to the interface, two different stabilizing terms dominate at small and large scales which are linked respectively to the surface energy and to the elastic interactions. Integrating the presence of small-scale heterogeneities related to the rock properties of the grains in the model leads to the formulation of a Langevin equation predicting the dynamic evolution of the surface. This equation leads to saturated surfaces obeying the two observed scaling laws. Analytical and numerical analysis of this surface evolution model shows that the crossover length separating both scaling regimes depends directly on the applied far-field stress magnitude. This method gives the basis for the development of a paleostress magnitude marker. We apply the computation of this marker, i.e., the morphological analysis, on a stylolite found in the Dogger limestone layer located in the neighborhood of the ANDRA Underground Research Laboratory at Bure (eastern France). The results are consistent with the two scaling regimes expected, and the practical determination of the major principal paleostress, from the estimation of a crossover length, is illustrated on this example

The management of acute venous thromboembolism in clinical practice. Results from the European PREFER in VTE Registry

Venous thromboembolism (VTE) is a significant cause of morbidity and mortality in Europe. Data from real-world registries are necessary, as clinical trials do not represent the full spectrum of VTE patients seen in clinical practice. We aimed to document the epidemiology, management and outcomes of VTE using data from a large, observational database. PREFER in VTE was an international, non-interventional disease registry conducted between January 2013 and July 2015 in primary and secondary care across seven European countries. Consecutive patients with acute VTE were documented and followed up over 12 months. PREFER in VTE included 3,455 patients with a mean age of 60.8 ± 17.0 years. Overall, 53.0 % were male. The majority of patients were assessed in the hospital setting as inpatients or outpatients (78.5 %). The diagnosis was deep-vein thrombosis (DVT) in 59.5 % and pulmonary embolism (PE) in 40.5 %. The most common comorbidities were the various types of cardiovascular disease (excluding hypertension; 45.5 %), hypertension (42.3 %) and dyslipidaemia (21.1 %). Following the index VTE, a large proportion of patients received initial therapy with heparin (73.2 %), almost half received a vitamin K antagonist (48.7 %) and nearly a quarter received a DOAC (24.5 %). Almost a quarter of all presentations were for recurrent VTE, with >80 % of previous episodes having occurred more than 12 months prior to baseline. In conclusion, PREFER in VTE has provided contemporary insights into VTE patients and their real-world management, including their baseline characteristics, risk factors, disease history, symptoms and signs, initial therapy and outcomes

Multivariate analysis reveals environmental and genetic determinants of element covariation in the maize grain ionome

Abstract The integrated responses of biological systems to genetic and environmental variation result in substantial covariance in multiple phenotypes. The resultant pleiotropy, environmental effects, and genotype‐by‐environmental interactions (GxE) are foundational to our understanding of biology and genetics. Yet, the treatment of correlated characters, and the identification of the genes encoding functions that generate this covariance, has lagged. As a test case for analyzing the genetic basis underlying multiple correlated traits, we analyzed maize kernel ionomes from Intermated B73 x Mo17 (IBM) recombinant inbred populations grown in 10 environments. Plants obtain elements from the soil through genetic and biochemical pathways responsive to physiological state and environment. Most perturbations affect multiple elements which leads the ionome, the full complement of mineral nutrients in an organism, to vary as an integrated network rather than a set of distinct single elements. We compared quantitative trait loci (QTL) determining single‐element variation to QTL that predict variation in principal components (PCs) of multiple‐element covariance. Single‐element and multivariate approaches detected partially overlapping sets of loci. QTL influencing trait covariation were detected at loci that were not found by mapping single‐element traits. Moreover, this approach permitted testing environmental components of trait covariance, and identified multi‐element traits that were determined by both genetic and environmental factors as well as genotype‐by‐environment interactions. Growth environment had a profound effect on the elemental profiles and multi‐element phenotypes were significantly correlated with specific environmental variables

The Interaction of Genotype and Environment Determines Variation in the Maize Kernel Ionome

Plants obtain soil-resident elements that support growth and metabolism from the water-flow facilitated by transpiration and active transport processes. The availability of elements in the environment interacts with the genetic capacity of organisms to modulate element uptake through plastic adaptive responses, such as homeostasis. These interactions should cause the elemental contents of plants to vary such that the effects of genetic polymorphisms will be dramatically dependent on the environment in which the plant is grown. To investigate genotype by environment interactions underlying elemental accumulation, we analyzed levels of elements in maize kernels of the Intermated B73 × Mo17 (IBM) recombinant inbred population grown in 10 different environments, spanning a total of six locations and five different years. In analyses conducted separately for each environment, we identified a total of 79 quantitative trait loci (QTL) controlling seed elemental accumulation. While a set of these QTL was found in multiple environments, the majority were specific to a single environment, suggesting the presence of genetic by environment interactions. To specifically identify and quantify QTL by environment interactions (QEIs), we implemented two methods: linear modeling with environmental covariates, and QTL analysis on trait differences between growouts. With these approaches, we found several instances of QEI, indicating that elemental profiles are highly heritable, interrelated, and responsive to the environment

The management of acute venous thromboembolism in clinical practice - study rationale and protocol of the European PREFER in VTE Registry

Background: Venous thromboembolism (VTE) is a major health problem, with over one million events every year in Europe. However, there is a paucity of data on the current management in real life, including factors influencing treatment pathways, patient satisfaction, quality of life (QoL), and utilization of health care resources and the corresponding costs. The PREFER in VTE registry has been designed to address this and to understand medical care and needs as well as potential gaps for improvement. Methods/design: The PREFER in VTE registry was a prospective, observational, multicenter study conducted in seven European countries including Austria, France Germany, Italy, Spain, Switzerland, and the UK to assess the characteristics and the management of patients with VTE, the use of health care resources, and to provide data to estimate the costs for 12 months treatment following a first-time and/or recurrent VTE diagnosed in hospitals or specialized or primary care centers. In addition, existing anticoagulant treatment patterns, patient pathways, clinical outcomes, treatment satisfaction, and health related QoL were documented. The centers were chosen to reflect the care environment in which patients with VTE are managed in each of the participating countries. Patients were eligible to be enrolled into the registry if they were at least 18 years old, had a symptomatic, objectively confirmed first time or recurrent acute VTE defined as either distal or proximal deep vein thrombosis, pulmonary embolism or both. After the baseline visit at the time of the acute VTE event, further follow-up documentations occurred at 1, 3, 6 and 12 months. Follow-up data was collected by either routinely scheduled visits or by telephone calls. Results: Overall, 381 centers participated, which enrolled 3,545 patients during an observational period of 1 year. Conclusion: The PREFER in VTE registry will provide valuable insights into the characteristics of patients with VTE and their acute and mid-term management, as well as into drug utilization and the use of health care resources in acute first-time and/or recurrent VTE across Europe in clinical practice. Trial registration: Registered in DRKS register, ID number: DRKS0000479

The management of patients with venous thromboembolism in Italy: insights from the PREFER in VTE registry

Venous thromboembolism (VTE) is the third most common cardiovascular disease. Real-life data on the clinical presentation, risk factors, diagnosis, and treatment of VTE in Italy and Europe are required to optimize the management of this disease. The PREFER in VTE registry, a prospective non-interventional real-life study, was designed to assess clinical characteristics and management of patients with VTE, use of health care resources, and on-treatment patient quality of life. Eligible consecutive patients with objectively diagnosed VTE were enrolled in the registry and followed up for 12 months. Between January and December 2013, 816 Italian and 1027 patients from 6 European countries other than Italy (European patients) were enrolled in the registry, and followed up until December 2014. Italian patients were the oldest (mean age 65.7 years) among the European patients. The Italian patients with a history of cancer were 24.6 % of whom 63.2 % had an active cancer (18.2 and 57.0 %, respectively, in Europe). Parenteral heparin was given, as initial treatment, in 73.8 % of Italian patients (66.4 % in Europe); VKA in combination with other treatments in 45.8 % (34.7 % in Europe); and VKA as the only anticoagulant treatment in 24.4 % (17.2 % in Europe). Of the Italian patients, 43.2 and 90.6 % of patients were hospitalized for deep vein thrombosis and pulmonary embolism, respectively; 65.4 % were admitted to the hospital through the emergency department. Following a real world approach, PREFER in VTE shows that the Italian patients, among and compared to the European patients, are the oldest, have a history of cancer more commonly, receive an initial treatment with heparin more commonly, and are more commonly hospitalized, particularly if affected by PE