Drastic reduction in the luminal Ca2+ -binding proteins calsequestrin and sarcalumenin in dystrophin-deficient cardiac muscle

Luminal Ca2+ -binding proteins play a central role in mediating between Ca2+ -uptake and Ca2+ -release during the excitation-contraction-relaxation cycle in muscle fibres. In the most commonly inherited neuromuscular disorder, Duchenne muscular dystrophy (DMD), the reduced expression of key Ca2+ -binding proteins causes abnormal Ca2+ -buffering in the sarcoplasmic reticulum (SR) of skeletal muscle. The heart is also affected in dystrophinopathies, as manifested by the pathological replacement of cardiac fibres by connective and fatty tissue. We therefore investigated whether similar changes occur in the abundance of luminal Ca2+ -regulatory elements in dystrophin-deficient cardiac fibres. Two-dimensional immunoblotting of total cardiac extracts was employed to unequivocally determine potential changes in the expression levels of SR components. Interestingly, the expression of the histidine-rich Ca2+ -binding protein was increased in the dystrophic heart. In contrast, the major Ca2+ -reservoir protein of the terminal cisternae, calsequestrin (CSQ), and the Ca2+ -shuttle and ion-binding protein of the longitudinal tubules, sarcalumenin, were drastically reduced in cardiac mdx fibres. This result agrees with the recently reported decrease in the Ca2+ -release channel and Ca2+ -ATPase in the mdx heart. Abnormal Ca2+ -handling appears to play a major role in the molecular pathogenesis of the cardiac involvement in X-linked muscular dystrophy.     

Sequencing and analysis of an Irish human genome

Background

Recent studies generating complete human sequences from Asian, African and European subgroups have revealed population-specific variation and disease susceptibility loci. Here, choosing a DNA sample from a population of interest due to its relative geographical isolation and genetic impact on further populations, we extend the above studies through the generation of 11-fold coverage of the first Irish human genome sequence.

Results

Using sequence data from a branch of the European ancestral tree as yet unsequenced, we identify variants that may be specific to this population. Through comparisons with HapMap and previous genetic association studies, we identified novel disease-associated variants, including a novel nonsense variant putatively associated with inflammatory bowel disease. We describe a novel method for improving SNP calling accuracy at low genome coverage using haplotype information. This analysis has implications for future re-sequencing studies and validates the imputation of Irish haplotypes using data from the current Human Genome Diversity Cell Line Panel (HGDP-CEPH). Finally, we identify gene duplication events as constituting significant targets of recent positive selection in the human lineage.

Conclusions

Our findings show that there remains utility in generating whole genome sequences to illustrate both general principles and reveal specific instances of human biology. With increasing access to low cost sequencing we would predict that even armed with the resources of a small research group a number of similar initiatives geared towards answering specific biological questions will emerge.     

Control of Reproductive Floral Organ Identity Specification in Arabidopsis by the C Function Regulator AGAMOUS

The floral organ identity factor AGAMOUS (AG) is a key regulator of Arabidopsis thaliana flower development, where it is involved in the formation of the reproductive floral organs as well as in the control of meristem determinacy. To obtain insights into how AG specifies organ fate, we determined the genes and processes acting downstream of this C function regulator during early flower development and distinguished between direct and indirect effects. To this end, we combined genome-wide localization studies, gene perturbation experiments, and computational analyses. Our results demonstrate that AG controls flower development to a large extent by controlling the expression of other genes with regulatory functions, which are involved in mediating a plethora of different developmental processes. One aspect of this function is the suppression of the leaf development program in emerging floral primordia. Using trichome initiation as an example, we demonstrate that AG inhibits an important aspect of leaf development through the direct control of key regulatory genes. A comparison of the gene expression programs controlled by AG and the B function regulators APETALA3 and PISTILLATA, respectively, showed that while they control many developmental processes in conjunction, they also have marked antagonistic, as well as independent activities.     

Refinement of the chromosome 5p locus for craniometaphyseal dysplasia

Craniometaphyseal dysplasia--Jackson type (CMDJ) is an autosomal dominant bone dysplasia with hyperostosis and sclerosis of the skull and abnormal modelling of the metaphyses. In a large German pedigree, a locus for CMDJ has been mapped previously to the short arm of chromosome 5 (5p15.2-p14.1), defining a 19-cM disease interval between markers D5S2004 and D5S502. Analysis of a large Australian pedigree together with a second German family confirms linkage to the same region. Obligate recombinations in the new families and confirmation of a supposed recombination in the previously reported German kindred have enabled us to narrow the critical region down to approximately 4 cM between markers D5S1987 and D5S1991.     

ICI 182,780 has agonistic effects and synergizes with estradiol-17 beta in fish liver, but not in testis

Background  

ICI 182,780 (ICI) belongs to a new class of antiestrogens developed to be pure estrogen antagonists and, in addition to its therapeutic use, it has been used to knock-out estrogen and estrogen receptor (ER) actions in several mammalian species. In the present study, the effects and mechanism of action of ICI were investigated in the teleost fish, sea bream (Sparus auratus).     

Can lantana seeds be utilized in lamb rations?

Lantana seeds contain 70.6 g crude protein, 12.8 g ether extract, 103.1 g crude fibre, 761.0 g nitrogen-free extract, 52.5 g total ash, 8.4 g calcium and 2.5 g phosphorus/kg dry matter. The replacement, by lantana seeds, of 200 g maize/kg of concentrate mixture for lambs was studied in two experiments lasting 3–4 months. The crude protein concentration in the lantana ration was lower than in the maize, and significantly (P<0.01) so in the second experiment. In the first experiment, the digestibility and intakes of dietary crude protein (DCP) and total dietary nitrogen (TDN) of the lantana group were not significantly lower. In the second experiment, dry matter and crude protein digestibility and intakes of DCP and TDN of the lantana group were significantly (P<0.01) lower than the maize group. Even after adjustment for mean protein concentration in the diets, the intakes of DCP (P<0.01) and TDN (P<0.05) in the lantana group were significantly lower. In a repeat metabolic trial also, the adjusted intakes of both DCP and TDN (P<0.01) of the lantana group were significantly lower. In spite of the depression in feed utilization, the biochemical and haematological parameters of the blood of animals in the lantana group were within the normal range. The apparent non-toxicity of lantana seeds to lambs over long-term feeding trials calls for further work on their possible utilization as a feed ingredient.