Use of geochemical signatures, including rare earth elements, in mosses and lichens to assess spatial integration and the influence of forest environment

In order to assess the influence of local environment and spatial integration of Trace Metals (TM) by biomonitors, Al, As, Cd, Cr, Cs, Cu, Fe, Mn, Ni, Pb, Sb, Sn, V and Zn and some rare earth element (REE) concentrations have been measured in lichens and mosses collected in three French forest sites located in three distinct mountainous areas, as well as in the local soil and bedrock, and in both bulk deposition (BD) and throughfall (TF). Similar enrichment factors (EF) were calculated using lichens and mosses and local bedrock for most elements, except for Cs, Mn, Ni, Pb, and Cu which were significantly (KW, p < 0.05) more enriched in mosses. Similar REE ratios were measured in soils, bedrock, lichens and mosses at each study sites, indicating a regional integration of atmospheric deposition by both biomonitors. Both TM signature and REE composition of mosses revealed that this biomonitor is highly influenced by throughfall composition, and reflect atmospheric deposition interaction with the forest canopy. This explained the higher enrichment measured in mosses for elements which concentration in deposition were influenced by the canopy, either due to leaching (Mn), direct uptake (Ni), or dry deposition dissolution (Pb, Cu, Cs)

A generic framework for context-sensitive analysis of modular programs

Context-sensitive analysis provides information which is potentially more accurate than that provided by context-free analysis. Such information can then be applied in order to validate/debug the program and/or to specialize the program obtaining important improvements. Unfortunately, context-sensitive analysis of modular programs poses important theoretical and practical problems. One solution, used in several proposals, is to resort to context-free analysis. Other proposals do address context-sensitive analysis, but are only applicable when the description domain used satisfies rather restrictive properties. In this paper, we argüe that a general framework for context-sensitive analysis of modular programs, Le., one that allows using all the domains which have proved useful in practice in the non-modular setting, is indeed feasible and very useful. Driven by our experience in the design and implementation of analysis and specialization techniques in the context of CiaoPP, the Ciao system preprocessor, in this paper we discuss a number of design goals for context-sensitive analysis of modular programs as well as the problems which arise in trying to meet these goals. We also provide a high-level description of a framework for analysis of modular programs which does substantially meet these objectives. This framework is generic in that it can be instantiated in different ways in order to adapt to different contexts. Finally, the behavior of the different instantiations w.r.t. the design goals that motivate our work is also discussed

Identification of novel APOB mutations by targeted next-generation sequencing for the molecular diagnosis of familial hypobetalipoproteinemia

International audienceFamilial hypobetalipoproteinemia (FHBL) is a co-dominant disorder characterized by decreased plasma levels of LDL-cholesterol and apolipoprotein B (ApoB). Currently, genetic diagnosis in FHBL relies largely on Sanger sequencing to identify APOB and PCSK9 gene mutations and on western blotting to detect truncated ApoB species

SCN5A mutations and the role of genetic background in the pathophysiology of Brugada syndrome.

International audienceBACKGROUND: Mutations in SCN5A are identified in approximately 20% to 30% of probands affected by Brugada syndrome (BrS). However, in familial studies, the relationship between SCN5A mutations and BrS remains poorly understood. The aim of this study was to investigate the association of SCN5A mutations and BrS in a group of large genotyped families. METHODS AND RESULTS: Families were included if at least 5 family members were carriers of the SCN5A mutation, which was identified in the proband. Thirteen large families composed of 115 mutation carriers were studied. The signature type I ECG was present in 54 mutation carriers (BrS-ECG+; 47%). In 5 families, we found 8 individuals affected by BrS but with a negative genotype (mutation-negative BrS-ECG+). Among these 8 mutation-negative BrS-ECG+ individuals, 3, belonging to 3 different families, had a spontaneous type I ECG, whereas 5 had a type I ECG only after the administration of sodium channel blockers. One of these 8 individuals had also experienced syncope. Mutation carriers had, on average, longer PR and QRS intervals than noncarriers, demonstrating that these mutations exerted functional effects. CONCLUSIONS: Our results suggest that SCN5A mutations are not directly causal to the occurrence of a BrS-ECG+ and that genetic background may play a powerful role in the pathophysiology of BrS. These findings add further complexity to concepts regarding the causes of BrS, and are consistent with the emerging notion that the pathophysiology of BrS includes various elements beyond mutant sodium channels

Variable Nav1.5 Protein Expression from the Wild-Type Allele Correlates with the Penetrance of Cardiac Conduction Disease in the Scn5a+/− Mouse Model

BACKGROUND: Loss-of-function mutations in SCN5A, the gene encoding Na(v)1.5 Na+ channel, are associated with inherited cardiac conduction defects and Brugada syndrome, which both exhibit variable phenotypic penetrance of conduction defects. We investigated the mechanisms of this heterogeneity in a mouse model with heterozygous targeted disruption of Scn5a (Scn5a(+/-) mice) and compared our results to those obtained in patients with loss-of-function mutations in SCN5A. METHODOLOGY/PRINCIPAL FINDINGS: Based on ECG, 10-week-old Scn5a(+/-) mice were divided into 2 subgroups, one displaying severe ventricular conduction defects (QRS interval>18 ms) and one a mild phenotype (QRS53 weeks), ajmaline effect was larger in the severely affected subgroup. These data matched the clinical observations on patients with SCN5A loss-of-function mutations with either severe or mild conduction defects. Ventricular tachycardia developed in 5/10 old severely affected Scn5a(+/-) mice but not in mildly affected ones. Correspondingly, symptomatic SCN5A-mutated Brugada patients had more severe conduction defects than asymptomatic patients. Old severely affected Scn5a(+/-) mice but not mildly affected ones showed extensive cardiac fibrosis. Mildly affected Scn5a(+/-) mice had similar Na(v)1.5 mRNA but higher Na(v)1.5 protein expression, and moderately larger I(Na) current than severely affected Scn5a(+/-) mice. As a consequence, action potential upstroke velocity was more decreased in severely affected Scn5a(+/-) mice than in mildly affected ones. CONCLUSIONS: Scn5a(+/-) mice show similar phenotypic heterogeneity as SCN5A-mutated patients. In Scn5a(+/-) mice, phenotype severity correlates with wild-type Na(v)1.5 protein expression

Different genes interact with particulate matter and tobacco smoke exposure in affecting lung function decline in the general population

BACKGROUND: Oxidative stress related genes modify the effects of ambient air pollution or tobacco smoking on lung function decline. The impact of interactions might be substantial, but previous studies mostly focused on main effects of single genes. OBJECTIVES: We studied the interaction of both exposures with a broad set of oxidative-stress related candidate genes and pathways on lung function decline and contrasted interactions between exposures. METHODS: For 12679 single nucleotide polymorphisms (SNPs), change in forced expiratory volume in one second (FEV(1)), FEV(1) over forced vital capacity (FEV(1)/FVC), and mean forced expiratory flow between 25 and 75% of the FVC (FEF(25-75)) was regressed on interval exposure to particulate matter >10 microm in diameter (PM10) or packyears smoked (a), additive SNP effects (b), and interaction terms between (a) and (b) in 669 adults with GWAS data. Interaction p-values for 152 genes and 14 pathways were calculated by the adaptive rank truncation product (ARTP) method, and compared between exposures. Interaction effect sizes were contrasted for the strongest SNPs of nominally significant genes (p(interaction)>0.05). Replication was attempted for SNPs with MAF<10% in 3320 SAPALDIA participants without GWAS. RESULTS: On the SNP-level, rs2035268 in gene SNCA accelerated FEV(1)/FVC decline by 3.8% (p(interaction) = 2.5x10(-6)), and rs12190800 in PARK2 attenuated FEV1 decline by 95.1 ml p(interaction) = 9.7x10(-8)) over 11 years, while interacting with PM10. Genes and pathways nominally interacting with PM10 and packyears exposure differed substantially. Gene CRISP2 presented a significant interaction with PM10 (p(interaction) = 3.0x10(-4)) on FEV(1)/FVC decline. Pathway interactions were weak. Replications for the strongest SNPs in PARK2 and CRISP2 were not successful. CONCLUSIONS: Consistent with a stratified response to increasing oxidative stress, different genes and pathways potentially mediate PM10 and tobac smoke effects on lung function decline. Ignoring environmental exposures would miss these patterns, but achieving sufficient sample size and comparability across study samples is challengin

Absence of triadin, a protein of the calcium release complex, is responsible for cardiac arrhythmia with sudden death in human

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmogenic disease so far related to mutations in the cardiac ryanodine receptor (RYR2) or the cardiac calsequestrin (CASQ2) genes. Because mutations in RYR2 or in CASQ2 are not retrieved in all CPVT cases, we searched for mutations in the physiological protein partners of RyR2 and CSQ2 in a large cohort of CPVT patients with no detected mutation in these two genes. Based on a candidate gene approach, we focused our investigations on triadin and junctin, two proteins that link RyR2 and CSQ2. Mutations in the triadin (TRDN) and in the junctin (ASPH) genes were searched in a cohort of 97 CPVT patients. We identified three mutations in triadin which cosegregated with the disease on a recessive mode of transmission in two families, but no mutation was found in junctin. Two TRDN mutations, a 4 bp deletion and a nonsense mutation, resulted in premature stop codons; the third mutation, a p.T59R missense mutation, was further studied. Expression of the p.T59R mutant in COS-7 cells resulted in intracellular retention and degradation of the mutant protein. This was confirmed after in vivo expression of the mutant triadin in triadin knock-out mice by viral transduction. In this work, we identified TRDN as a new gene responsible for an autosomal recessive form of CPVT. The mutations identified in the two families lead to the absence of the protein, thereby demonstrating the importance of triadin for the normal function of the cardiac calcium release complex in humans