GWAS meta-analysis of over 29,000 people with epilepsy identifies 26 risk loci and subtype-specific genetic architecture

Epilepsy is a highly heritable disorder affecting over 50 million people worldwide, of which about one-third are resistant to current treatments. Here we report a multi-ancestry genome-wide association study including 29,944 cases, stratified into three broad categories and seven subtypes of epilepsy, and 52,538 controls. We identify 26 genome-wide significant loci, 19 of which are specific to genetic generalized epilepsy (GGE). We implicate 29 likely causal genes underlying these 26 loci. SNP-based heritability analyses show that common variants explain between 39.6% and 90% of genetic risk for GGE and its subtypes. Subtype analysis revealed markedly different genetic architectures between focal and generalized epilepsies. Gene-set analyses of GGE signals implicate synaptic processes in both excitatory and inhibitory neurons in the brain. Prioritized candidate genes overlap with monogenic epilepsy genes and with targets of current antiseizure medications. Finally, we leverage our results to identify alternate drugs with predicted efficacy if repurposed for epilepsy treatment

Travel burden and clinical presentation of retinoblastoma: analysis of 1024 patients from 43 African countries and 518 patients from 40 European countries

BACKGROUND: The travel distance from home to a treatment centre, which may impact the stage at diagnosis, has not been investigated for retinoblastoma, the most common childhood eye cancer. We aimed to investigate the travel burden and its impact on clinical presentation in a large sample of patients with retinoblastoma from Africa and Europe. METHODS: A cross-sectional analysis including 518 treatment-naïve patients with retinoblastoma residing in 40 European countries and 1024 treatment-naïve patients with retinoblastoma residing in 43 African countries. RESULTS: Capture rate was 42.2% of expected patients from Africa and 108.8% from Europe. African patients were older (95% CI -12.4 to -5.4, p<0.001), had fewer cases of familial retinoblastoma (95% CI 2.0 to 5.3, p<0.001) and presented with more advanced disease (95% CI 6.0 to 9.8, p<0.001); 43.4% and 15.4% of Africans had extraocular retinoblastoma and distant metastasis at the time of diagnosis, respectively, compared to 2.9% and 1.0% of the Europeans. To reach a retinoblastoma centre, European patients travelled 421.8 km compared to Africans who travelled 185.7 km (p<0.001). On regression analysis, lower-national income level, African residence and older age (p<0.001), but not travel distance (p=0.19), were risk factors for advanced disease. CONCLUSIONS: Fewer than half the expected number of patients with retinoblastoma presented to African referral centres in 2017, suggesting poor awareness or other barriers to access. Despite the relatively shorter distance travelled by African patients, they presented with later-stage disease. Health education about retinoblastoma is needed for carers and health workers in Africa in order to increase capture rate and promote early referral

Carbon nanomaterials in agriculture: A critical review

There has been great interest in the use of carbon nano-materials (CNMs) in agriculture. However, the existing literature reveals mixed effects from CNM exposure on plants, ranging from enhanced crop yield to acute cytotoxicity and genetic alteration. These seemingly inconsistent research-outcomes, taken with the current technological limitations for in situ CNM detection, present significant hurdles to the wide scale use of CNMs in agriculture. The objective of this review is to evaluate the current literature, including studies with both positive and negative effects of different CNMs (e.g., carbon nano-tubes, fullerenes, carbon nanoparticles, and carbon nano-horns, among others) on terrestrial plants and associated soil-dwelling microbes. The effects of CNMs on the uptake of various co-contaminants will also be discussed. Last, we highlight critical knowledge gaps, including the need for more soil-based investigations under environmentally relevant conditions. In addition, efforts need to be focused on better understanding of the underlying mechanism of CNM-plant interactions

Co-exposure of imidacloprid and nanoparticle Ag or CeO2 to Cucurbita pepo (zucchini): Contaminant bioaccumulation and translocation

The use of engineered nanomaterial (ENMs) has increased dramatically and the possible interaction of these materials with soil-borne organic co-contaminants is largely unknown. Imidacloprid (IMDA) is a neonicotinoid insecticide and one of the most widely used pesticides in the United States and significant concerns have risen due to unknown role of these insecticides in pollinator decline. As such, understanding ENM interactions with these agrochemicals is important. In this study, the bioaccumulation, translocation, and toxicity of IMDA (10 mg/kg) to Cucurbita pepo L (zucchini) was evaluated upon simultaneous exposure to CeO2 or Ag in bulk (CeBulk or AgBulk) or nanoparticle (CeNP or AgNP) form at 100mg/kg under soil-grown conditions. Additionally, expression analysis of seven genes (related to stress, photosynthesis, and elemental transport) previously identified as putative biomarkers of nanoparticle (NPs) exposure in zucchini was also performed. Total IMDA and metabolites accumulation in plant root and aerial tissues (shoot-stem and leaf, flower, and stamen) was equivalent to controls (soil with IMDA minus NPs) in both CeO2 exposures. However, co-exposure to AgBulk and AgNP significantly suppressed IMDA accumulation in zucchini aerial tissues by 30% and 33%, respectively. The Ag and Ce concentration in aerial tissues exposed to NPs alone were 85.4% and 79.2%, re- spectively, higher than plants co-exposed to NPs with IMDA. The expression level of the seven genes studied shows that the response mechanisms of zucchini to IMDA and NPs are different. Moreover, no synergistic effects were observed in gene expression upon IMDA-NPs co-exposure. These findings show that ENMs may not only affect the bioavailability and translocation of currently used pesticides but that the reverse is true as well; these interactions should be considered when assessing the exposure and risk of these materials in the environment

Improved Many-Objective Optimization Algorithms for the 3D Indoor Deployment Problem

International audienceCompared with the two-dimensional deployment, the three-dimensional deployment of sensor networks is more challenging. We studied the problem of 3D repositioning of sensor nodes in wireless sensor networks. We aim essentially to add a set of nodes to the initial architecture. The positions of the added nodes are determined by the proposed algorithms while optimizing a set of objectives. In this paper, we suggest two main contributions. The first one is an analysis contribution where the modelling of the problem is given and a set of modifications is incorporated on the tested multi-objective evolutionary algorithms to resolve the issues encountered when resolving many-objective problems. These modifications concern essentially an adaptive mutation and recombination operators with neighbourhood mating restrictions, the use of a multiple scalarizing functions concept and the incorporation of the reduction in dimensionality. The second contribution is an application one, where an experimental study on real testbeds is detailed to test the behaviour of the enhanced algorithms on a real-world context. Experimental tests followed by numerical results prove the efficiency of the proposed modifications against original algorithms

Weathering in soil increases nanoparticle CuO bioaccumulation within a terrestrial food chain

<p>This study evaluates the bioaccumulation of unweathered (U) and weathered (W) CuO in NP, bulk and ionic form (0–400 mg/kg) by lettuce exposed for 70 d in soil co-contaminated with field incurred chlordane. To evaluate CuO trophic transfer, leaves were fed to crickets (<i>Acheta domestica</i>) for 15 d, followed by insect feeding to lizards (<i>Anolis carolinensis</i>). Upon weathering, the root Cu content of the NP treatment increased 214% (327 ± 59.1 mg/kg) over unaged treatment. Cu root content decreased in bulk and ionic treatments from 70–130 mg/kg to 13–26 mg/kg upon aging in soil. Micro X-ray fluorescence (μ-XRF) analysis of W-NP-exposed roots showed a homogenous distribution of Cu (and Ca) in the tissues. Additionally, micro X-ray absorption near-edge (μ-XANES) analysis of W-NP-exposed roots showed near complete transformation of CuO to Cu (I)-sulfur and oxide complexes in the tissues, whereas in unweathered treatment, most root Cu remained as CuO. The expression level of nine genes involved in Cu transport shows that the mechanisms of CuO NPs (and bulk) response/accumulation are different than ionic Cu. The chlordane accumulation by lettuce upon co-exposure to CuO NPs significantly increased upon weathering. Conversely, bulk and ionic exposures decreased pesticide accumulation by plant upon weathering. The Cu cricket fecal content from U-NP-exposed insects was significantly greater than the bulk or ion treatments, suggesting a higher initial NP accumulation followed by significantly greater elimination during depuration. In the lizard, Cu content in the intestine, body and head did not differ as a function of weathering. This study demonstrates that CuO NPs may undergo transformation processes in soil upon weathering that subsequently impact NPs availability in terrestrial food chains.</p

Molecular Response of Crop Plants to Engineered Nanomaterials

Functional toxicology has enabled the identification of genes involved in conferring tolerance and sensitivity to engineered nanomaterial (ENM) exposure in the model plant Arabidopsis thaliana (L.) Heynh. Several genes were found to be involved in metabolic functions, stress response, transport, protein synthesis, and DNA repair. Consequently, analysis of physiological parameters, metal content (through ICP-MS quantification), and gene expression (by RT-qPCR) of A. thaliana orthologue genes were performed across different plant species of agronomic interest to highlight putative biomarkers of exposure and effect related to ENMs. This approach led to the identification of molecular markers in Solanum lycopersicum L. and Cucurbita pepo L. (tomato and zucchini) that might not only indicate exposure to ENMs (CuO, CeO₂, and La₂O₃) but also provide mechanistic insight into response to these materials. Through Gene Ontology (GO) analysis, the target genes were mapped in complex interatomic networks representing molecular pathways, cellular components, and biological processes involved in ENM response. The transcriptional response of 38 (out of 204) candidate genes studied varied according to particle type, size, and plant species. Importantly, some of the genes studied showed potential as biomarkers of ENM exposure and effect and may be useful for risk assessment in foods and in the environment