Deficient Cholesterol Esterification in Plasma of apoc2 Knockout Zebrafish and Familial Chylomicronemia Patients.

Hypertriglyceridemia is an independent risk factor for cardiovascular disease. Apolipoprotein C-II (APOC2) is an obligatory cofactor for lipoprotein lipase (LPL), the major enzyme catalyzing plasma triglyceride hydrolysis. We have created an apoc2 knockout zebrafish model, which mimics the familial chylomicronemia syndrome (FCS) in human patients with a defect in the APOC2 or LPL gene. In this study, we measured plasma levels of free cholesterol (FC) and cholesterol esters (CE) and found that apoc2 mutant zebrafish have a significantly higher FC to CE ratio (FC/CE), when compared to the wild type. Feeding apoc2 mutant zebrafish a low-fat diet reduced triglyceride levels but not the FC/CE ratio. In situ hybridization and qPCR results demonstrated that the hepatic expression of lecithin-cholesterol acyltransferase (lcat), the enzyme responsible for esterifying plasma FC to CE, and of apolipoprotein A-I, a major protein component of HDL, were dramatically decreased in apoc2 mutants. Furthermore, the FC/CE ratio was significantly increased in the whole plasma and in a chylomicron-depleted fraction of human FCS patients. The FCS plasma LCAT activity was significantly lower than that of healthy controls. In summary, this study, using a zebrafish model and human patient samples, reports for the first time the defect in plasma cholesterol esterification associated with LPL deficiency

Development of non-linear guidance algorithms for asteroids close-proximity operations

In this paper, we discuss non-linear methodologies that can be employed to devise real-time algorithms suitable for guidance and control of spacecrafts during asteroid close-proximity operations. Combination of optimal and sliding control theory provide the theoretical framework for the development of guidance laws that generates thrust commands as function of the estimated spacecraft state. Using a Lyapunov second theorem one can design non-linear guidance laws that are proven to be globally stable against unknown perturbations with known upper bound. Such algorithms can be employed for autonomous targeting of points of the asteroid surface (soft landing , Touch-And-Go (TAG) maneuvers). Here, we theoretically derived and tested the Optimal Sliding Guidance (OSG) for close-proximity operations. The guidance algorithm has its root in the generalized ZEM/ZEV feedback guidance and its mathematical equations are naturally derived by a proper definition of a sliding surface as function of Zero-Effort-Miss and Zero-Effort-Velocity. Thus, the sliding surface allows a natural augmentation of the energy-optimalguidance via a sliding mode that ensures global stability for the proposed algorithm. A set of Monte Carlo simulations in realistic environment are executed to assess the guidance performance in typical operational scenarios found during asteroids close-proximity operations. OSG is shown to satisfy stringent requirements for asteroid pinpoint landing and sampling accuracy

Prenatal exposure to maternal cigarette smoking, amygdala volume, and fat intake in adolescence

Context : Prenatal exposure to maternal cigarette smoking is a well-established risk factor for obesity, but the underlying mechanisms are not known. Preference for fatty foods, regulated in part by the brain reward system, may contribute to the development of obesity. Objective : To examine whether prenatal exposure to maternal cigarette smoking is associated with enhanced fat intake and risk for obesity, and whether these associations may be related to subtle structural variations in brain regions involved in reward processing. Design : Cross-sectional study of a population-based cohort. Setting : The Saguenay Youth Study, Quebec, Canada. Participants : A total of 378 adolescents (aged 13 to 19 years; Tanner stage 4 and 5 of sexual maturation), half of whom were exposed prenatally to maternal cigarette smoking (mean [SD], 11.1 [6.8] cigarettes/d). Main Outcome Measures : Fat intake was assessed with a 24-hour food recall (percentage of energy intake consumed as fat). Body adiposity was measured with anthropometry and multifrequency bioimpedance. Volumes of key brain structures involved in reward processing, namely the amygdala, nucleus accumbens, and orbitofrontal cortex, were measured with magnetic resonance imaging. Results : Exposed vs nonexposed subjects exhibited a higher total body fat (by approximately 1.7 kg; P = .009) and fat intake (by 2.7%; P = .001). They also exhibited a lower volume of the amygdala (by 95 mm3; P < .001) but not of the other 2 brain structures. Consistent with its possible role in limiting fat intake, amygdala volume correlated inversely with fat intake (r = −0.15; P = .006). Conclusions : Prenatal exposure to maternal cigarette smoking may promote obesity by enhancing dietary preference for fat, and this effect may be mediated in part through subtle structural variations in the amygdala

The neXtProt knowledgebase on human proteins: current status

neXtProt (http://www.nextprot.org) is a human protein-centric knowledgebase developed at the SIB Swiss Institute of Bioinformatics. Focused solely on human proteins, neXtProt aims to provide a state of the art resource for the representation of human biology by capturing a wide range of data, precise annotations, fully traceable data provenance and a web interface which enables researchers to find and view information in a comprehensive manner. Since the introductory neXtProt publication, significant advances have been made on three main aspects: the representation of proteomics data, an extended representation of human variants and the development of an advanced search capability built around semantic technologies. These changes are presented in the current neXtProt updat

Recyclage agricole des déchets organiques dans les sols tropicaux (île de la Réunion) : quel impact sur les transferts d'éléments traces métalliques?

Face à l'augmentation de la production de déchets dans les régions ultra périphériques insulaires comme La Réunion, il est demandé aux décideurs politiques et aux scientifiques de proposer des solutions de valorisation pérennes. Le recyclage agricole est une de ces solutions. Elle suppose, cependant, une bonne appréciation des impacts environnementaux de cette pratique. La présence en quantité élevée à l'état naturel d'éléments traces métalliques (ETM) dans les sols de La Réunion soulève un problème spécifique : l'épandage de déchets organiques ne risque-t-il pas de conduire à des transferts des ETM des sols vers les nappes et les cultures ? En milieu tropical, les éléments pour répondre à cette question manquent. Dans le cadre de ce projet, nous avons évalué l'impact de l'épandage de déchets organiques sur la spéciation et le transfert des ETM présents dans les sols réunionnais. Il s'est agit de : (i) déterminer la spéciation des ETM des sols de La Réunion et son évolution suite à l'apport de déchets organiques puis (ii) de quantifier la mobilité des ETM entre les différents compartiments : sol, plante et eau. Pour cela, trois sols, naturellement riches en ETM, ont été sélectionnés afin de représenter la diversité des conditions pédologiques rencontrées à l'échelle de l'île de La Réunion ainsi que deux déchets organiques (compost de déchet vert et lisier de porc) avec des teneurs en ETM contrastées. L'ensemble des résultats qui concernent la spéciation des ETM dans les sols sont cohérents quelle que soit la méthode utilisée (chimique ou spectroscopique). En effet, ils permettent de montrer que malgré les concentrations élevées en ETM des sols étudiés, les ETM ne sont pas ou peu mobiles et biodisponibles. Malgré des évolutions importantes des propriétés physico-chimiques liées à l'apport de déchets organiques (acidification et augmentation de la salinité), nous n'avons pas détecté d'augmentation de la fraction échangeable des ETM au cours des incubations. Autrement dit, la minéralisation de la MO des déchets organiques ne se traduit pas par le relargage d'une quantité d'ETM significative, ou, si ce phénomène a lieu, les ETM sont rapidement piégés par les phases minérales ou organiques présentes dans le sol. Les expériences conduites en colonnes de sol ou in situ sur des parcelles expérimentales donnent des résultats concordants : l'épandage de lisier de porc se traduit par une accumulation de Cu et Zn dans les premiers centimètres du sol et nous n'avons enregistré aucune mobilité des ETM présents dans les sols. (Résumé d'auteur

Loss of neuronal potassium/chloride cotransporter 3 (KCC3) is responsible for the degenerative phenotype in a conditional mouse model of hereditary motor and sensory neuropathy associated with agenesis of the corpus callosum

Disruption of the potassium/chloride cotransporter 3 (KCC3), encoded by the SLC12A6 gene, causes hereditary motor and sensory neuropathy associated with agenesis of the corpus callosum (HMSN/ACC), a neurodevelopmental and neurodegenerative disorder affecting both the peripheral nervous system and CNS. However, the precise role of KCC3 in the maintenance of ion homeostasis in the nervous system and the pathogenic mechanisms leading to HMSN/ACC remain unclear. We established two Slc12a6 Cre/LoxP transgenic mouse lines expressing C-terminal truncated KCC3 in either a neuron-specific or ubiquitous fashion. Our results suggest that neuronal KCC3 expression is crucial for axon volume control. We also demonstrate that the neuropathic features of HMSN/ACC are predominantly due to a neuronal KCC3 deficit, while the auditory impairment is due to loss of non-neuronal KCC3 expression. Furthermore, we demonstrate that KCC3 plays an essential role in inflammatory pain pathways. Finally, we observed hypoplasia of the corpus callosum in both mouse mutants and a marked decrease in axonal tracts serving the auditory cortex in only the general deletion mutant. Together, these results establish KCC3 as an important player in both central and peripheral nervous system maintenance

Development of a real-time immuno-PCR assay for the quantification of environmental contaminants

This thesis outlines the development of two universal real-time immuno-PCR (RT-iPCR) assays for application in agriculture. The first RT-iPCR was developed for the sensitive quantification of 17β-estradiol in water. Using a universal iPCR method and polyclonal antibodies, 17β-estradiol was accurately quantified at concentrations ranging from 1 pg mL-1 to 10 μg mL-1, with a limit of detection of 0.7 pg mL-1. The RT-iPCR assay provided an 800-fold increase in sensitivity as well as an expanded working range compared to the corresponding enzyme-linked immunosorbent assay. Antibodies were swapped with antibodies specific to P. brassicae for the quantification of clubroot resting spores using the same RT-iPCR assay. P. brassicae resting spores were quantified in the range of 50 to 10 000 spores, with a detection limit of 29 spores. Both RT-iPCR showed equal or improved sensitivity compared to other published analytical methods, with expanded linear working ranges and high-throughput capabilities.Agriculture and Agri-Foods Canad

Identification of a BRCA2-Specific modifier locus at 6p24 related to breast cancer risk

Common genetic variants contribute to the observed variation in breast cancer risk for BRCA2 mutation carriers; those known to date have all been found through population-based genome-wide association studies (GWAS). To comprehensively identify breast cancer risk modifying loci for BRCA2 mutation carriers, we conducted a deep replication of an ongoing GWAS discovery study. Using the ranked P-values of the breast cancer associations with the imputed genotype of 1.4 M SNPs, 19,029 SNPs were selected and designed for inclusion on a custom Illumina array that included a total of 211,155 SNPs as part of a multi-consortial project. DNA samples from 3,881 breast cancer affected and 4,330 unaffected BRCA2 mutation carriers from 47 studies belonging to the Consortium of Investigators of Modifiers of BRCA1/2 were genotyped and available for analysis. We replicated previously reported breast cancer susceptibility alleles in these BRCA2 mutation carriers and for several regions (including FGFR2, MAP3K1, CDKN2A/B, and PTHLH) identified SNPs that have stronger evidence of association than those previously published. We also identified a novel susceptibility allele at 6p24 that was inversely associated with risk in BRCA2 mutation carriers (rs9348512; per allele HR = 0.85, 95% CI 0.80-0.90, P = 3.9×10−8). This SNP was not associated with breast cancer risk either in the general population or in BRCA1 mutation carriers. The locus lies within a region containing TFAP2A, which encodes a transcriptional activation protein that interacts with several tumor suppressor genes. This report identifies the first breast cancer risk locus specific to a BRCA2 mutation background. This comprehensive update of novel and previously reported breast cancer susceptibility loci contributes to the establishment of a panel of SNPs that modify breast cancer risk in BRCA2 mutation carriers. This panel may have clinical utility for women with BRCA2 mutations weighing options for medical prevention of breast cancer