Integrated transcriptional profiling and linkage analysis for identification of genes underlying disease

Integration of genome-wide expression profiling with linkage analysis is a new approach to identifying genes underlying complex traits. We applied this approach to the regulation of gene expression in the BXH/HXB panel of rat recombinant inbred strains, one of the largest available rodent recombinant inbred panels and a leading resource for genetic analysis of the highly prevalent metabolic syndrome. In two tissues important to the pathogenesis of the metabolic syndrome, we mapped cis- and trans-regulatory control elements for expression of thousands of genes across the genome. Many of the most highly linked expression quantitative trait loci are regulated in cis, are inherited essentially as monogenic traits and are good candidate genes for previously mapped physiological quantitative trait loci in the rat. By comparative mapping we generated a data set of 73 candidate genes for hypertension that merit testing in human populations. Mining of this publicly available data set is expected to lead to new insights into the genes and regulatory pathways underlying the extensive range of metabolic and cardiovascular disease phenotypes that segregate in these recombinant inbred strains.     

Influence of vitamin A on experimental atherosclerosis in rabbits

Résumé La vitamine A a eu un effet hypocholestérimique modéré (7 à 43%) sur des lapins nourris de 0.2% cholestérol. La gravité de l'athérosclérose moyenne fut réduite de 31% dans la crosse aortique, et de 61% dans l'aorte abdominale. L'administration de vitamine A aux lapins nourris de cholésterol a réduit les niveaux de sérum -glucuronidase d'une manière significative, il est donc possible que cette vitamine ait une influence stabilisatrice sur le lysosome.     

Haem homeostasis is regulated by the conserved and concerted functions of HRG-1 proteins

Haems are metalloporphyrins that serve as prosthetic groups for various biological processes including respiration, gas sensing, xenobiotic detoxification, cell differentiation, circadian clock control, metabolic reprogramming and microRNA processing. With a few exceptions, haem is synthesized by a multistep biosynthetic pathway comprising defined intermediates that are highly conserved throughout evolution. Despite our extensive knowledge of haem biosynthesis and degradation, the cellular pathways and molecules that mediate intracellular haem trafficking are unknown. The experimental setback in identifying haem trafficking pathways has been the inability to dissociate the highly regulated cellular synthesis and degradation of haem from intracellular trafficking events. Caenorhabditis elegans and related helminths are natural haem auxotrophs that acquire environmental haem for incorporation into haemoproteins, which have vertebrate orthologues. Here we show, by exploiting this auxotrophy to identify HRG-1 proteins in C. elegans, that these proteins are essential for haem homeostasis and normal development in worms and vertebrates. Depletion of hrg-1, or its paralogue hrg-4, in worms results in the disruption of organismal haem sensing and an abnormal response to haem analogues. HRG-1 and HRG-4 are previously unknown transmembrane proteins, which reside in distinct intracellular compartments. Transient knockdown of hrg-1 in zebrafish leads to hydrocephalus, yolk tube malformations and, most strikingly, profound defects in erythropoiesis-phenotypes that are fully rescued by worm HRG-1. Human and worm proteins localize together, and bind and transport haem, thus establishing an evolutionarily conserved function for HRG-1. These findings reveal conserved pathways for cellular haem trafficking in animals that define the model for eukaryotic haem transport. Thus, uncovering the mechanisms of haem transport in C. elegans may provide insights into human disorders of haem metabolism and reveal new drug targets for developing anthelminthics to combat worm infestations.     

Common variants at 6q22 and 17q21 are associated with intracranial volume

During aging, intracranial volume remains unchanged and represents maximally attained brain size, while various interacting biological phenomena lead to brain volume loss. Consequently, intracranial volume and brain volume in late life reflect different genetic influences. Our genome-wide association study (GWAS) in 8,175 community-dwelling elderly persons did not reveal any associations at genome-wide significance (P < 5 × 10(-8)) for brain volume. In contrast, intracranial volume was significantly associated with two loci: rs4273712 (P = 3.4 × 10(-11)), a known height-associated locus on chromosome 6q22, and rs9915547 (P = 1.5 × 10(-12)), localized to the inversion on chromosome 17q21. We replicated the associations of these loci with intracranial volume in a separate sample of 1,752 elderly persons (P = 1.1 × 10(-3) for 6q22 and 1.2 × 10(-3) for 17q21). Furthermore, we also found suggestive associations of the 17q21 locus with head circumference in 10,768 children (mean age of 14.5 months). Our data identify two loci associated with head size, with the inversion at 17q21 also likely to be involved in attaining maximal brain size.     

CCDC39 is required for assembly of inner dynein arms and the dynein regulatory complex and for normal ciliary motility in humans and dogs

Primary ciliary dyskinesia (PCD) is an inherited disorder characterized by recurrent infections of the upper and lower respiratory tract, reduced fertility in males and situs inversus in about 50% of affected individuals (Kartagener syndrome). It is caused by motility defects in the respiratory cilia that are responsible for airway clearance, the flagella that propel sperm cells and the nodal monocilia that determine left-right asymmetry. Recessive mutations that cause PCD have been identified in genes encoding components of the outer dynein arms, radial spokes and cytoplasmic pre-assembly factors of axonemal dyneins, but these mutations account for only about 50% of cases of PCD. We exploited the unique properties of dog populations to positionally clone a new PCD gene, CCDC39. We found that loss-of-function mutations in the human ortholog underlie a substantial fraction of PCD cases with axonemal disorganization and abnormal ciliary beating. Functional analyses indicated that CCDC39 localizes to ciliary axonemes and is essential for assembly of inner dynein arms and the dynein regulatory complex.     

C-terminal truncations in human 3'-5' DNA exonuclease TREX1 cause autosomal dominant retinal vasculopathy with cerebral leukodystrophy

Autosomal dominant retinal vasculopathy with cerebral leukodystrophy is a microvascular endotheliopathy with middle-age onset. In nine families, we identified heterozygous C-terminal frameshift mutations in TREX1, which encodes a 3'-5' exonuclease. These truncated proteins retain exonuclease activity but lose normal perinuclear localization. These data have implications for the maintenance of vascular integrity in the degenerative cerebral microangiopathies leading to stroke and dementias.     

Measurement Preconditions Systemic Action: The Case of Integral Low-Carbon Country and Sustainable Development Indicators

Sustainable development (SD) belongs to objectives of social responsibility (SR), including the ‘integral low-carbon societies’, as an objective and effort. This article presents the concept of low-carbon Slovenia and indicators of sustainable development (SDI) in Croatia and Slovenia that help in measurement efforts. Indicators reflect the national sets of SDI, developed recently; one focuses on EU and comparison with other regions in the world. Key challenges include (1) making a low-carbon country reality, (2) comparability and aggregation variability of SDI determined by SD policies; (3) SR, as a contribution to, and framework of, sustainability, as a requisitely holistic approach to current problems, based on ethics of interdependence of humans and other nature.     

A survey and assessment of the rare vascular plants of the Idaho National Engineering Laboratory site

A two-year study of the rare vascular plants of the Idaho National Engineering Laboratory generated new data on the abundance, distribution, and habitat features of eight taxa presently under review at either the federal or state level, or recently proposed for such review. Astragalus ceramicus Sheld. var. apus Barneby is common on the INEL and adjacent areas and will be recommended for removal from further consideration at the federal level and placed on Idaho's Federal Watch List. Coryphanta missouriensis (Sweet) Britt. & Rose is common throughout east central Idaho, but will be recommended for retainment on the State Watch List. Gymnosteris nudicaulis (H. & A.) Greene and Oxytheca dendroidea Nutt. are also recommended for retention on the State Watch List. Four taxa not previously known to occur in Idaho or not known from the southeastern part of the state ( Astragalus gilviflorus Sheld., Astragalus kentrophyta Gray var. jessiae (Peck) Barneby, Gilia polycladon Torr., and Lesquerella kingii S. Wats. var. cobrensis Roll. & Shaw) were encountered and evaluated with reference to current or potential threats, and are recommended for placement on Idaho's State Watch List. &nbsp;&nbsp;&nbsp;     

Real coded genetic algorithm for stochastic hydrothermal generation scheduling

The intent of this paper is to schedule short-term hydrothermal system probabilistically considering stochastic operating cost curves for thermal power generation units and uncertainties in load demand and reservoir water inflows. Therefore, the stochastic multi-objective hydrothermal generation scheduling problem is formulated with explicit recognition of uncertainties in the system production cost coefficients and system load, which are treated as random variable. Fuzzy methodology has been exploited for solving a decision making problem involving multiplicity of objectives and selection criterion for best compromised solution. A real-coded genetic algorithm with arithmetic-average-bound-blend crossover and wavelet mutation operator is applied to solve short-term variable-head hydrothermal scheduling problem. Initial feasible solution has been obtained by implementing the random heuristic search. The search is performed within the operating generation limits. Equality constraints that satisfy the demand during each time interval are considered by introducing a slack thermal generating unit for each time interval. Whereas the equality constraint which satisfies the consumption of available water to its full extent for the whole scheduling period is considered by introducing slack hydro generating unit for a particular time interval. Operating limit violation by slack hydro and slack thermal generating unit is taken care using exterior penalty method. The effectiveness of the proposed method is demonstrated on two sample systems.