Combinatorial Roles of Heparan Sulfate Proteoglycans and Heparan Sulfates in Caenorhabditis elegans Neural Development

Heparan sulfate proteoglycans (HSPGs) play critical roles in the development and adult physiology of all metazoan organisms. Most of the known molecular interactions of HSPGs are attributed to the structurally highly complex heparan sulfate (HS) glycans. However, whether a specific HSPG (such as syndecan) contains HS modifications that differ from another HSPG (such as glypican) has remained largely unresolved. Here, a neural model in C. elegans is used to demonstrate for the first time the relationship between specific HSPGs and HS modifications in a defined biological process in vivo. HSPGs are critical for the migration of hermaphrodite specific neurons (HSNs) as genetic elimination of multiple HSPGs leads to 80% defect of HSN migration. The effects of genetic elimination of HSPGs are additive, suggesting that multiple HSPGs, present in the migrating neuron and in the matrix, act in parallel to support neuron migration. Genetic analyses suggest that syndecan/sdn-1 and HS 6-O-sulfotransferase, hst-6, function in a linear signaling pathway and glypican/lon-2 and HS 2-O-sulfotransferase, hst-2, function together in a pathway that is parallel to sdn-1 and hst-6. These results suggest core protein specific HS modifications that are critical for HSN migration. In C. elegans, the core protein specificity of distinct HS modifications may be in part regulated at the level of tissue specific expression of genes encoding for HSPGs and HS modifying enzymes. Genetic analysis reveals that there is a delicate balance of HS modifications and eliminating one HS modifying enzyme in a compromised genetic background leads to significant changes in the overall phenotype. These findings are of importance with the view of HS as a critical regulator of cell signaling in normal development and disease

Discovering joint associations between disease and gene pairs with a novel similarity test

Genes in a functional pathway can have complex interactions. A gene might activate or suppress another gene, so it is of interest to test joint associations of gene pairs. To simultaneously detect the joint association between disease and two genes (or two chromosomal regions), we propose a new test with the use of genomic similarities. Our test is designed to detect epistasis in the absence of main effects, main effects in the absence of epistasis, or the presence of both main effects and epistasis. Results: The simulation results show that our similarity test with the matching measure is more powerful than the Pearson's chi(2) test when the disease mutants were introduced at common haplotypes, but is less powerful when the disease mutants were introduced at rare haplotypes. Our similarity tests with the counting measures are more sensitive to marker informativity and linkage disequilibrium patterns, and thus are often inferior to the similarity test with the matching measure and the Pearson 's chi(2) test. Conclusions: In detecting joint associations between disease and gene pairs, our similarity test is a complementary method to the Pearson's chi(2) test

Otitis media in young Aboriginal children from remote communities in Northern and Central Australia: a cross-sectional survey

BACKGROUND: Middle ear disease (otitis media) is common and frequently severe in Australian Aboriginal children. There have not been any recent large-scale surveys using clear definitions and a standardised middle ear assessment. The aim of the study was to determine the prevalence of middle ear disease (otitis media) in a high-risk population of young Aboriginal children from remote communities in Northern and Central Australia. METHODS: 709 Aboriginal children aged 6–30 months living in 29 communities from 4 health regions participated in the study between May and November 2001. Otitis media (OM) and perforation of the tympanic membrane (TM) were diagnosed by tympanometry, pneumatic otoscopy, and video-otoscopy. We used otoscopic criteria (bulging TM or recent perforation) to diagnose acute otitis media. RESULTS: 914 children were eligible to participate in the study and 709 were assessed (78%). Otitis media affected nearly all children (91%, 95%CI 88, 94). Overall prevalence estimates adjusted for clustering by community were: 10% (95%CI 8, 12) for unilateral otitis media with effusion (OME); 31% (95%CI 27, 34) for bilateral OME; 26% (95%CI 23, 30) for acute otitis media without perforation (AOM/woP); 7% (95%CI 4, 9) for AOM with perforation (AOM/wiP); 2% (95%CI 1, 3) for dry perforation; and 15% (95%CI 11, 19) for chronic suppurative otitis media (CSOM). The perforation prevalence ranged from 0–60% between communities and from 19–33% between regions. Perforations of the tympanic membrane affected 40% of children in their first 18 months of life. These were not always persistent. CONCLUSION: Overall, 1 in every 2 children examined had otoscopic signs consistent with suppurative ear disease and 1 in 4 children had a perforated tympanic membrane. Some of the children with intact tympanic membranes had experienced a perforation that healed before the survey. In this high-risk population, high rates of tympanic perforation were associated with high rates of bulging of the tympanic membrane

Genetic and Cellular Characterization of Caenorhabditis elegans Mutants Abnormal in the Regulation of Many Phase II Enzymes

Background: The phase II detoxification enzymes execute a major protective role against xenobiotics as well as endogenous toxicants. To understand how xenobiotics regulate phase II enzyme expression, acrylamide was selected as a model xenobiotic chemical, as it induces a large number and a variety of phase II enzymes, including numerous glutathione S-transferases (GSTs) in Caenorhabditis elegans. Methodology/Principal Findings: To begin dissecting genetically xenobiotics response pathways (xrep), 24 independent mutants of C. elegans that exhibited abnormal GST expression or regulation against acrylamide were isolated by screening about 3.5610 5 genomes of gst::gfp transgenic strains mutagenized with ethyl methanesulfonate (EMS). Complementation testing assigned the mutants to four different genes, named xrep-1,-2,-3, and-4. One of the genes, xrep-1, encodes WDR-23, a nematode homologue of WD repeat-containing protein WDR23. Loss-of-function mutations in xrep-1 mutants resulted in constitutive expression of many GSTs and other phase II enzymes in the absence of acrylamide, and the wild-type xrep-1 allele carried on a DNA construct successfully cured the mutant phenotype of the constitutive enzyme expression. Conclusions/Significance: Genetic and cellular characterization of xrep-1 mutants suggest that a large number of GSTs and other phase II enzymes induced by acrylamide are under negative regulation by XREP-1 (WDR-23), which is likely to be a functional equivalent of mammalian Keap1 and a regulator of SKN-1, a C. elegans analogue of cap-n-collar Nrf2 (nuclea

Juvenile Greylag Geese (Anser anser) Discriminate between Individual Siblings

Social species that maintain individualised relationships with certain others despite continuous changes in age, reproductive status and dominance rank between group members ought to be capable of individual recognition. Tests of “true” individual recognition, where an individual recognises unique features of another, are rare, however. Often kinship and/or familiarity suffice to explain dyadic interactions. The complex relationships within a greylag goose flock suggest that they should be able to recognise individuals irrespective of familiarity or kinship. We tested whether six-week-old hand-raised greylags can discriminate between two of their siblings. We developed a new experimental protocol, in which geese were trained to associate social siblings with geometrical symbols. Subsequently, focals were presented with two geometrical symbols in the presence of a sibling associated with one of the symbols. Significant choice of the geometrical symbol associated with the target present indicated that focals were able to distinguish between individual targets. Greylag goslings successfully learned this association-discrimination task, regardless of genetic relatedness or sex of the sibling targets. Social relationships within a goose flock thus may indeed be based on recognition of unique features of individual conspecifics

The Things You Do:Internal Models of Others' Expected Behaviour Guide Action Observation

Predictions allow humans to manage uncertainties within social interactions. Here, we investigate how explicit and implicit person models-how different people behave in different situations-shape these predictions. In a novel action identification task, participants judged whether actors interacted with or withdrew from objects. In two experiments, we manipulated, unbeknownst to participants, the two actors action likelihoods across situations, such that one actor typically interacted with one object and withdrew from the other, while the other actor showed the opposite behaviour. In Experiment 2, participants additionally received explicit information about the two individuals that either matched or mismatched their actual behaviours. The data revealed direct but dissociable effects of both kinds of person information on action identification. Implicit action likelihoods affected response times, speeding up the identification of typical relative to atypical actions, irrespective of the explicit knowledge about the individual's behaviour. Explicit person knowledge, in contrast, affected error rates, causing participants to respond according to expectations instead of observed behaviour, even when they were aware that the explicit information might not be valid. Together, the data show that internal models of others' behaviour are routinely re-activated during action observation. They provide first evidence of a person-specific social anticipation system, which predicts forthcoming actions from both explicit information and an individuals' prior behaviour in a situation. These data link action observation to recent models of predictive coding in the non-social domain where similar dissociations between implicit effects on stimulus identification and explicit behavioural wagers have been reported

Full-Exon Resequencing Reveals Toll-Like Receptor Variants Contribute to Human Susceptibility to Tuberculosis Disease

Tuberculosis (TB) is the leading cause of death worldwide due to an infectious agent. Data have accumulated over decades suggesting that variability in human susceptibility to TB disease has a genetic component. Toll-like receptors (TLRs) play a critical role in initiating the innate immune response to many pathogens in mouse models, but little is known about their role in human infections. Human TLRs have been reported to recognize mycobacterial antigens and initiate an immune response. We tested the hypothesis that amino acid-altering polymorphisms in five TLRs were associated with susceptibility to TB disease using a population-based case-control study with 1,312 adult TB patients and controls. Full-coding region sequencing of the five TLR genes in all 1,312 subjects yielded a data set in excess of 16 Mb. Rare nonsynonymous polymorphisms in TLR6-TLR1-TLR10 were significantly overrepresented among African-American TB cases compared with ethnically-matched control subjects. Common nonsynonymous polymorphisms in TLR6-TLR1-TLR10 also were significantly associated with TB disease in certain ethnic groups. Among African Americans, homozygotes for the common-variant haplotype TLR1-248S, TLR1-602I, and TLR6-249S had a significantly increased TB disease risk. A transmission/disequilibrium test on an independent sample found that the TLR1-248S variant was preferentially transmitted to diseased children, thereby confirming disease association. These results are consistent with recent reports implicating TLR1 variants, including TLR1-602, in significantly altered innate immune responses. Also consistent with disease association, rare TLR6 variants were defective in their ability to mediate NF-κB signal transduction in transfected human cells. Taken together, the data suggest that variant TLRs contribute to human susceptibility to TB disease. Extensive full-exon resequencing was critical for revealing new information about the role of TLRs in human-pathogen interactions and the genetic basis of innate immune function