Ciguatera fish poisoning in the Pacific Islands (1998 to 2008)

Background

Ciguatera is a type of fish poisoning that occurs throughout the tropics, particularly in vulnerable island communities such as the developing Pacific Island Countries and Territories (PICTs). After consuming ciguatoxin-contaminated fish, people report a range of acute neurologic, gastrointestinal, and cardiac symptoms, with some experiencing chronic neurologic symptoms lasting weeks to months. Unfortunately, the true extent of illness and its impact on human communities and ecosystem health are still poorly understood.

Methods

A questionnaire was emailed to the Health and Fisheries Authorities of the PICTs to quantify the extent of ciguatera. The data were analyzed using t-test, incidence rate ratios, ranked correlation, and regression analysis.

Results

There were 39,677 reported cases from 17 PICTs, with a mean annual incidence of 194 cases per 100,000 people across the region from 1998–2008 compared to the reported annual incidence of 104/100,000 from 1973–1983. There has been a 60% increase in the annual incidence of ciguatera between the two time periods based on PICTs that reported for both time periods. Taking into account under-reporting, in the last 35 years an estimated 500,000 Pacific islanders might have suffered from ciguatera.

Conclusions

This level of incidence exceeds prior ciguatera estimates locally and globally, and raises the status of ciguatera to an acute and chronic illness with major public health significance. To address this significant public health problem, which is expected to increase in parallel with environmental change, well-funded multidisciplinary research teams are needed to translate research advances into practical management solutions.     

Molecular and Structural Characterization of Barley Vernalization Genes

Vernalization, the requirement of a period of low temperature to induce transition from the vegetative to reproductive state, is an evolutionarily and economically important trait in the Triticeae. The genetic basis of vernalization in cultivated barley (Hordeum vulgare subsp. vulgare) can be defined using the two-locus VRN-H1/VRN-H2 model. We analyzed the allelic characteristics of HvBM5A, the candidate gene for VRN-H1, from ten cultivated barley accessions and one wild progenitor accession (subsp. spontaneum), representing the three barley growth habits – winter, facultative, and spring. We present multiple lines of evidence, including sequence, linkage map location, and expression, that support HvBM5A being VRN-H1. While the predicted polypeptides from different growth habits are identical, spring accessions contain a deletion in the first intron of HvBM5A that may be important for regulation. While spring HvBM5A alleles are typified by the intron-localized deletion, in some cases, the promoter may also determine the allele type. The presence/absence of the tightly linked ZCCT-H gene family members on chromosome 4H perfectly correlates with growth habit and we conclude that one of the three ZCCT-H genes is VRN-H2. The VRN-H2 locus is present in winter genotypes and deleted from the facultative and spring genotypes analyzed in this study, suggesting the facultative growth habit (cold tolerant, vernalization unresponsive) is a result of deletion of the VRN-H2 locus and presence of a winter HvBM5A allele. All reported barley vernalization QTLs can be explained by the two-locus VRN-H1/VRN-H2 model based on the presence/absence of VRN-H2 and a winter vs. spring HvBM5A allele. Electronic Supplementary Material Electronic Supplementary material is available for this article at and accessible for authorised users.     

Digital biology: an emerging and promising discipline

This article examines the role of computation and quantitative methods in modern biomedical research to identify emerging scientific, technical, policy and organizational trends. It identifies common concerns and practices in the emerging community of computationally-oriented bio-scientists by reviewing a national symposium, Digital Biology: the Emerging Paradigm, held at the National Institutes of Health in Bethesda, Maryland, November 6th and 7th 2003. This meeting showed how biomedical computing promises scientific breakthroughs that will yield significant health benefits. Three key areas that define the emerging discipline of digital biology are: scientific data integration, multi-scale modeling and networked science. Each area faces unique technical challenges and information policy issues that must be addressed as the field matures. Here we summarize the emergent challenges and offer suggestions to academia, industry and government on how best to expand the role of computation in their scientific activities.     

Most nuclear systemic autoantigens are extremely disordered proteins: implications for the etiology of systemic autoimmunity

Patients with systemic autoimmune diseases usually produce high levels of antibodies to self-antigens (autoantigens). The repertoire of common autoantigens is remarkably limited, yet no readily understandable shared thread links these apparently diverse proteins. Using computer prediction algorithms, we have found that most nuclear systemic autoantigens are predicted to contain long regions of extreme structural disorder. Such disordered regions would generally make poor B cell epitopes and are predicted to be under-represented as potential T cell epitopes. Consideration of the potential role of protein disorder may give novel insights into the possible role of molecular mimicry in the pathogenesis of autoimmunity. The recognition of extreme autoantigen protein disorder has led us to an explicit model of epitope spreading that explains many of the paradoxical aspects of autoimmunity – in particular, the difficulty in identifying autoantigen-specific helper T cells that might collaborate with the B cells activated in systemic autoimmunity. The model also explains the experimentally observed breakdown of major histocompatibility complex (MHC) class specificity in peptides associated with the MHC II proteins of activated autoimmune B cells, and sheds light on the selection of particular T cell epitopes in autoimmunity. Finally, the model helps to rationalize the relative rarity of clinically significant autoimmunity despite the prevalence of low specificity/low avidity autoantibodies in normal individuals.     

Vps29 has a phosphoesterase fold that acts as a protein interaction scaffold for retromer assembly

The retromer complex is responsible for the retrieval of mannose 6-phosphate receptors from the endosomal system to the Golgi. Here we present the crystal structure of the mammalian retromer subunit mVps29 and show that it has structural similarity to divalent metal-containing phosphoesterases. mVps29 can coordinate metals in a similar manner but has no detectable phosphoesterase activity in vitro, suggesting a unique specificity or function. The mVps29 and mVps26 subunits bind independently to mVps35 and together form a high-affinity heterotrimeric subcomplex. Mutagenesis reveals the structural basis for the interaction of mVps29 with mVps35 and subsequent association with endosomal membranes in vivo. A conserved hydrophobic surface distinct from the primary Vps35p binding site mediates assembly of the Vps29p-Vps26p-Vps35p subcomplex with sorting nexins in yeast, and mutation of either site results in a defect in retromer-dependent membrane trafficking.     

S3-12, Adipophilin, and TIP47 package lipid in adipocytes

Animals have evolved mechanisms to maintain circulating nutrient levels when energy demands exceed feeding opportunities. Mammals store most of their energy as triacylglycerol in the perilipin-coated lipid droplets of adipocytes. How newly synthesized triacylglycerol is delivered to perilipin-coated lipid droplets is poorly understood. Perilipin is a member of the evolutionarily related family of PAT proteins (Perilipin, Adipophilin, TIP47), which is defined by sequence similarity and association with lipid droplets. We previously showed that S3-12, which is also a member of this family, associates with a separate pool of lipid droplets that emerge when triacylglycerol storage is driven by adding oleate to the culture medium of adipocytes. Our current data extend these findings to demonstrate that nascent lipid droplets emerge with a coat composed of S3-12, TIP47, and adipophilin. After 100 min of oleate treatment, the nascent lipid droplets are more heterogeneous: S3-12 and TIP47 coat smaller, peripheral droplets and adipophilin coats a more medial population of droplets. Fractionation of untreated and oleate-treated adipocytes shows oleate-dependent redistribution of TIP47 and adipophilin from cytosolic fractions to the lipid droplet fraction. Inhibition of protein synthesis with cycloheximide does not block the oleate-induced formation of the nascent lipid droplets, nor does it prevent TAG accumulation. We suggest that the non-lipid droplet pools of S3-12, adipophilin, and TIP47 constitute a ready reservoir of coat proteins to permit rapid packaging of newly synthesized triacylglycerol and to maximize energy storage during nutrient excess.     

Common genetic and environmental effects on lipid phenotypes: the HERITAGE family study

OBJECTIVE: Despite the well known genetic component influencing plasma lipid-lipoprotein levels and the observed correlations among these traits, little is known about pleiotropic heritable determinants among them. Our aim is to investigate pair-wise polygenic and environmental correlations among lipid-lipoprotein levels at baseline and in response to regular exercise in Whites and Blacks. METHODS: Common pair-wise genetic and environmental correlations among levels of total cholesterol (TC), LDL-C, ApoB, HDL-C (also HDL2-C and HDL3-C), triglycerides (TG, HDL-TG and LDL-TG) and ApoA-1 were investigated at baseline and again after a 20-week endurance exercise program using a variance-components-decomposition. RESULTS: With a few exceptions, all lipid phenotypes were heritable at baseline and for training responses in Blacks and Whites. Strong to high genetic and environmental correlations (0.4 < rho(g) < 0.7) were observed for the majority of the baseline pair-wise traits. For training responses, many of the same patterns were noted, although fewer genetic correlations were significant as compared to the baseline results. CONCLUSIONS: Results suggest that the observed phenotypic correlations among many of these traits may be due to in part to pleiotropic genes, in particular between LDL-C and ApoB and between TG and HDL-C. This shared genetic architecture should be considered in follow-up gene finding studies.     

Interaction of calmodulin with the phosphofructokinase target sequence

Ca4.calmodulin (Ca4.CaM) inhibits the glycolytic enzyme phosphofructokinase, by preventing formation of its active tetramer. Fluorescence titrations show that the affinity of complex formation of Ca4.CaM with the key 21-residue target peptide increases 1000-fold from pH 9.0 to 4.8, suggesting the involvement of histidine and carboxylic acid residues. 1H NMR pH titration indicates a marked increase in pKa of the peptide histidine on complex formation and HSQC spectra show related pH-dependent changes in the conformation of the complex. This unusually strong sensitivity of a CaM-target complex to pH suggests a potential functional role for Ca4.CaM in regulation of the glycolytic pathway.