Authentically ambiguous, credibly anonymous: Perceptually reframing the personal narrative towards effective persuasion in aggressive human rights contexts

Testing the strategies of discourse and materiality, this practice-based and practice-led research experiments with how anonymous storytelling by vulnerable communities, like that of the sexual minorities and their allies in Malaysia, can better speak to their human rights issues without further subjecting them to personal attacks and targetted persecution. The research identifies the critical role of the voice in lending authenticity and credibility to first person narratives; and contextual credibility as a form of credibility which personal stories naturally aspire to achieve with audiences. Adopting a discursive view of persuasion and recognising too that the power of persuasion may in effect lie with those who receive these stories rather than with those who tell them, the insights and knowledge gained from the research informed the development of the field output, Persuasive Storytelling by Vulnerable Communities in Aggressive Contexts: A Human Rights Communication Framework.

Incorporation of human recombinant tropoelastin into silk fibroin membranes with the view to repairing Bruch’s membrane

Bombyx mori silk fibroin membranes provide a potential delivery vehicle for both cells and extracellular matrix (ECM) components into diseased or injured tissues. We have previously demonstrated the feasibility of growing retinal pigment epithelial cells (RPE) on fibroin membranes with the view to repairing the retina of patients afflicted with age-related macular degeneration (AMD). The goal of the present study was to investigate the feasibility of incorporating the ECM component elastin, in the form of human recombinant tropoelastin, into these same membranes. Two basic strategies were explored: (1) membranes prepared from blended solutions of fibroin and tropoelastin; and (2) layered constructs prepared from sequentially cast solutions of fibroin, tropoelastin, and fibroin. Optimal conditions for RPE attachment were achieved using a tropoelastin-fibroin blend ratio of 10 to 90 parts by weight. Retention of tropoelastin within the blend and layered constructs was confirmed by immunolabelling and Fourier-transform infrared spectroscopy (FTIR). In the layered constructs, the bulk of tropoelastin was apparently absorbed into the initially cast fibroin layer. Blend membranes displayed higher elastic modulus, percentage elongation, and tensile strength (p < 0.01) when compared to the layered constructs. RPE cell response to fibroin membranes was not affected by the presence of tropoelastin. These findings support the potential use of fibroin membranes for the co-delivery of RPE cells and tropoelastin.

Genome-wide association study identifies a variant in HDAC9 associated with large vessel ischemic stroke

Genetic factors have been implicated in stroke risk, but few replicated associations have been reported. We conducted a genome-wide association study (GWAS) for ischemic stroke and its subtypes in 3,548 affected individuals and 5,972 controls, all of European ancestry. Replication of potential signals was performed in 5,859 affected individuals and 6,281 controls. We replicated previous associations for cardioembolic stroke near PITX2 and ZFHX3 and for large vessel stroke at a 9p21 locus. We identified a new association for large vessel stroke within HDAC9 (encoding histone deacetylase 9) on chromosome 7p21.1 (including further replication in an additional 735 affected individuals and 28,583 controls) (rs11984041; combined P = 1.87 × 10 -11; odds ratio (OR) = 1.42, 95% confidence interval (CI) = 1.28-1.57). All four loci exhibited evidence for heterogeneity of effect across the stroke subtypes, with some and possibly all affecting risk for only one subtype. This suggests distinct genetic architectures for different stroke subtypes.

Genome-wide association study using extreme truncate selection identifies novel genes affecting bone mineral density and fracture risk

Osteoporotic fracture is a major cause of morbidity and mortality worldwide. Low bone mineral density (BMD) is a major predisposing factor to fracture and is known to be highly heritable. Site-, gender-, and age-specific genetic effects on BMD are thought to be significant, but have largely not been considered in the design of genome-wide association studies (GWAS) of BMD to date. We report here a GWAS using a novel study design focusing on women of a specific age (postmenopausal women, age 55-85 years), with either extreme high or low hip BMD (age- and gender-adjusted BMD z-scores of +1.5 to +4.0, n = 1055, or -4.0 to -1.5, n = 900), with replication in cohorts of women drawn from the general population (n = 20,898). The study replicates 21 of 26 known BMD-associated genes. Additionally, we report suggestive association of a further six new genetic associations in or around the genes CLCN7, GALNT3, IBSP, LTBP3, RSPO3, and SOX4, with replication in two independent datasets. A novel mouse model with a loss-of-function mutation in GALNT3 is also reported, which has high bone mass, supporting the involvement of this gene in BMD determination. In addition to identifying further genes associated with BMD, this study confirms the efficiency of extreme-truncate selection designs for quantitative trait association studies. © 2011 Duncan et al.

Revisiting the Task-Capability interface model for incorporating human factors into car-following models

Human factors such as distraction, fatigue, alcohol and drug use are generally ignored in car-following (CF) models. Such ignorance overestimates driver capability and leads to most CF models’ inability in realistically explaining human driving behaviors. This paper proposes a novel car-following modeling framework by introducing the difficulty of driving task measured as the dynamic interaction between driving task demand and driver capability. Task difficulty is formulated based on the famous Task Capability Interface (TCI) model, which explains the motivations behind driver’s decision making. The proposed method is applied to enhance two popular CF models: Gipps’ model and IDM, and named as TDGipps and TDIDM respectively. The behavioral soundness of TDGipps and TDIDM are discussed and their stabilities are analyzed. Moreover, the enhanced models are calibrated with the vehicle trajectory data, and validated to explain both regular and human factor influenced CF behavior (which is distraction caused by hand-held mobile phone conversation in this paper). Both the models show better performance than their predecessors, especially in presence of human factors.

The IFITM5 mutation c.-14C > T results in an elongated transcript expressed in human bone; And causes varying phenotypic severity of osteogenesis imperfecta type V

Background The genetic mutation resulting in osteogenesis imperfecta (OI) type V was recently characterised as a single point mutation (c.-14C > T) in the 5' untranslated region (UTR) of IFITM5, a gene encoding a transmembrane protein with expression restricted to skeletal tissue. This mutation creates an alternative start codon and has been shown in a eukaryotic cell line to result in a longer variant of IFITM5, but its expression has not previously been demonstrated in bone from a patient with OI type V. Methods Sanger sequencing of the IFITM5 5' UTR was performed in our cohort of subjects with a clinical diagnosis of OI type V. Clinical data was collated from referring clinicians. RNA was extracted from a bone sample from one patient and Sanger sequenced to determine expression of wild-type and mutant IFITM5. Results: All nine subjects with OI type V were heterozygous for the c.-14C > T IFITM5 mutation. Clinically, there was heterogeneity in phenotype, particularly in the manifestation of bone fragility amongst subjects. Both wild-type and mutant IFITM5 mRNA transcripts were present in bone. Conclusions The c.-14C > T IFITM5 mutation does not result in an RNA-null allele but is expressed in bone. Individuals with identical mutations in IFITM5 have highly variable phenotypic expression, even within the same family.

Whole-genome screening in ankylosing spondylitis: Evidence of non-MHC genetic-susceptibility loci

Ankylosing spondylitis (AS) is a common inflammatory arthritis predominantly affecting the axial skeleton. Susceptibility to the disease is thought to be oligogenic. To identify the genes involved, we have performed a genomewide scan in 185 families containing 255 affected sibling pairs. Two-point and multipoint nonparametric linkage analysis was performed. Regions were identified showing "suggestive" or stronger linkage with the disease on chromosomes 1p, 2q, 6p, 9q, 10q, 16q, and 19q. The MHC locus was identified as encoding the greatest component of susceptibility, with an overall LOD score of 15.6. The strongest non-MHC linkage lies on chromosome 16q (overall LOD score 4.7). These results strongly support the presence of non-MHC genetic-susceptibility factors in AS and point to their likely locations.

The interleukin 1 gene cluster contains a major susceptibility locus for ankylosing spondylitis

Ankylosing spondylitis (AS) is a common and highly heritable inflammatory arthropathy. Although the gene HLA-B27 is almost essential for the inheritance of the condition, it alone is not sufficient to explain the pattern of familial recurrence of the disease. We have previously demonstrated suggestive linkage of AS to chromosome 2q13, a region containing the interleukin 1 (IL-1) family gene cluster, which includes several strong candidates for involvement in the disease. In the current study, we describe strong association and transmission of IL-1 family gene cluster single-nucleotide polymorphisms and haplotypes with AS.

Autosomal dominant familial calcium pyrophosphate dihydrate deposition disease is caused by mutation in the transmembrane protein ANKH

Familial autosomal dominant calcium pyrophosphate dihydrate (CPPD) chondrocalcinosis has previously been mapped to chromosome 5pl5. We have identified a mutation in the ANKH gene that segregates with the disease in a family with this condition. ANKH encodes a putative transmembrane inorganic pyrophosphate (PPi) transport channel. We postulate that loss of function of ANKH causes elevated extracellular PPi levels, predisposing to CPPD crystal deposition.

Replication of association of IL1 gene complex members with ankylosing spondylitis in Taiwanese Chinese

Objective: To test the association of interleukin 1 (IL1) gene family members with ankylosing spondylitis (AS), previously reported in Europid subjects, in an ethnically remote population. Methods: 200 Taiwanese Chinese AS patients and 200 ethnically matched healthy controls were genotyped for five single nucleotide polymorphisms (SNPs) and the IL1RN.VNTR, markers previously associated with AS. Allele, genotype, and haplotype frequencies were compared between cases and controls. Results: Association of alleles and genotypes of the markers IL1F10.3, IL1RN.4, and IL1RN.VNTR was observed with AS (p<0.05). Haplotypes of pairs of these markers and of the markers IL1RN.6/1 and IL1RN.6/2 were also significantly associated with AS. The strongest associations observed were with the marker IL1RN.4, and with the two-marker haplotype IL1RN.4-IL1RN.VNTR (both p = 0.004). Strong linkage disequilibrium was observed between all marker pairs except those involving IL1B-511 (D′ 0.4 to 0.9, p<0.01). Conclusions: The IL1 gene cluster is associated with AS in Taiwanese Chinese. This finding provides strong statistical support that the previously observed association of this gene cluster with AS is a true positive finding.

The chromosome 16q region associated with ankylosing spondylitis includes the candidate gene tumour necrosis factor receptor type 1-associated death domain (TRADD)

Objective: To replicate and refine the reported association of ankylosing spondylitis (AS) with two nonsynonymous single nucleotide polymorphisms (nsSNPs) on chromosome 16q22.1. Methods: Firstly, 730 independent UK patients with AS were genotyped for rs9939768 and rs6979 and allele frequencies were compared with 2879 previously typed historic disease controls. Secondly, the two data sets were combined in meta-analyses. Finally, 5 tagging SNPs, located between rs9939768 and rs6979, were analysed in 1604 cases and 1020 controls. Results: The association of rs6979 with AS was replicated, p=0.03, OR=1.14 (95% CI 1.01 to 1.28), and a trend for association with rs9939768 detected, p=0.06, OR=1.25 (95% CI 0.99 to 1.57). Meta-analyses revealed association of both SNPs with AS, p=0.0008, OR=1.31 (95% CI 1.12 to 1.54) and p=0.0009, OR=1.15 (95% CI 1.06 to 1.23) for rs9939768 and rs6979, respectively. New associations with rs9033 and rs868213 (p=0.00002, OR=1.23 (95% CI 1.12 to 1.36) and p=0.00002 OR=1.45 (95% CI 1.22 to 1.72), respectively, were identified. Conclusions: The region on chromosome 16 that has been replicated in the present work is interesting as the highly plausible candidate gene, tumour necrosis factor receptor type 1 (TNFR1)-associated death domain (TRADD), is located between rs9033 and rs868213. It will require additional work to identify the primary genetic association(s) with AS.

Identification of major loci controlling clinical manifestations of ankylosing spondylitis

Objective. To identify genomic regions linked with determinants of age at symptom onset, disease activity, and functional impairment in ankylosing spondylitis (AS). Methods. A whole genome linkage scan was performed in 188 affected sibling pair families with 454 affected individuals. Traits assessed were age at symptom onset, disease activity assessed by the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), and functional impairment assessed by the Bath Ankylosing Spondylitis Functional Index (BASFI). Parametric and nonparametric quantitative linkage analysis was performed using parameters defined in a previous segregation study. Results. Heritabilities of the traits studied in this data set were as follows: BASDAI 0.49 (P = 0.0001, 95% confidence interval [95% CI] 0.23-0.75), BASFI 0.76 (P = 10-7, 95% CI 0.49-1.0), and age at symptom onset 0.33 (P = 0.005, 95% CI 0.04-0.62). No linkage was observed between the major histocompatibility complex (MHC) and any of the traits studied (logarithm of odds [LOD] score <1.0). "Significant" linkage (LOD score 4.0) was observed between a region on chromosome 18p and the BASDAI. Age at symptom onset showed "suggestive" linkage to chromosome 11p (LOD score 3.3). Maximum linkage with the BASFI was seen at chromosome 2q (LOD score 2.9). Conclusion. In contrast to the genetic determinants of susceptibility to AS, clinical manifestations of the disease measured by the BASDAI, BASFI, and age at symptom onset are largely determined by a small number of genes not encoded within the MHC.

A genome-wide screen for susceptibility loci in ankylosing spondylitis

Objective. To localize the regions containing genes that determine susceptibility to ankylosing spondylitis (AS). Methods. One hundred five white British families with 121 affected sibling pairs with AS were recruited, largely from the Royal National Hospital for Rheumatic Diseases AS database. A genome-wide linkage screen was undertaken using 254 highly polymorphic microsatellite markers from the Medical Research Council (UK) (MRC) set. The major histocompatibility complex (MHC) region was studied more intensively using 5 microsatellites lying within the HLA class III region and HLA-DRB1 typing. The Analyze package was used for 2-point analysis, and GeneHunter for multipoint analysis. Results. When only the MRC set was considered, 11 markers in 7 regions achieved a P value of ≤0.01. The maximum logarithm of odds score obtained was 3.8 (P = 1.4 x 10-5) using marker D6S273, which lies in the HLA class III region. A further marker used in mapping of the MHC class III region achieved a LOD score of 8.1 (P = 1 x 10-9). Nine of 118 affected sibling pairs (7.6%) did not share parental haplotypes identical by descent across the MHC, suggesting that only 31% of the susceptibility to AS is coded by genes linked to the MHC. The maximum non-MHC LOD score obtained was 2.6 (P = 0.0003) for marker D16S422. Conclusion. The results of this study confirm the strong linkage of the MHC with AS, and provide suggestive evidence regarding the presence and location of non-MHC genes influencing susceptibility to the disease.

Whole-genome linkage analysis of rheumatoid arthritis susceptibility loci in 252 affected sibling pairs in the United Kingdom

Objective. To undertake a systematic wholegenome screen to identify regions exhibiting genetic linkage to rheumatoid arthritis (RA). Methods. Two hundred fifty-two RA-affected sibling pairs from 182 UK families were genotyped using 365 highly informative microsatellite markers. Microsatellite genotyping was performed using fluorescent polymerase chain reaction primers and semiautomated DNA sequencing technology. Linkage analysis was undertaken using MAPMAKER/SIBS for single-point and multipoint analysis. Results. Significant linkage (maximum logarithm of odds score 4.7 [P = 0.000003] at marker D6S276, 1 cM from HLA-DRB1) was identified around the major histocompatibility complex (MHC) region on chromosome 6. Suggestive linkage (P < 7.4 × 10-4) was identified on chromosome 6q by single- and multipoint analysis. Ten other sites of nominal linkage (P < 0.05) were identified on chromosomes 3p, 4q, 7p, 2 regions of 10q, 2 regions of 14q, 16p, 21q, and Xq by single-point analysis and on 3 sites (1q, 14q, and 14q) by multipoint analysis. Conclusion. Linkage to the MHC region was confirmed. Eleven non-HLA regions demonstrated evidence of suggestive or nominal linkage, but none reached the genome-wide threshold for significant linkage (P = 2.2 × 10-5). Results of previous genome screens have suggested that 6 of these regions may be involved in RA susceptibility.

Dissection of class III major histocompatibility complex haplotypes associated with rheumatoid arthritis

Objective. We have previously identified a single-nucleotide polymorphism (SNP) haplotype involving the lymphotoxin α (LTA) and tumor necrosis factor (TNF) loci (termed haplotype LTA-TNF2) on chromosome 6 that shows differential association with rheumatoid arthritis (RA) on HLA-DRB1*0404 and *0401 haplotypes, suggesting the presence of additional non-HLA-DRB1 RA susceptibility genes on these haplotypes. To refine this association, we performed a case-control association study using both SNPs and microsatellite markers in haplotypes matched either for HLA-DRB1*0404 or for HLA-DRB1*0401. Methods. Fourteen SNPs lying between HLA-DRB1 and LTA were genotyped in 87 DRB1*04-positive families. High-density microsatellite typing was performed using 24 markers spanning 2,500 kb centered around the TNF gene in 305 DRB1*0401 or *0404 cases and 400 DRB1*0401 or *0404 controls. Single-marker, 2-marker, and 3-marker minihaplotypes were constructed and their frequencies compared between the DRB1*0401 and DRB1*0404 matched case and control haplotypes. Results. Marked preservation of major histocompatibility complex haplotypes was seen, with chromosomes carrying LTA-TNF2 and either DRB1*0401 or DRB1*0404 both carrying an identical SNP haplotype across the 1-Mb region between TNF and HLA-DRB1. Using microsatellite markers, we observed two 3-marker minihaplotypes that were significantly overrepresented in the DRB1*0404 case haplotypes (P = 0.00024 and P = 0.00097). Conclusion. The presence of a single extended SNP haplotype between LTA-TNF2 and both DRB1*0401 and DRB1*0404 is evidence against this region harboring the genetic effects in linkage disequillbrium with LTA-TNF2. Two RA-associated haplotypes on the background of DRB1*0404 were identified in a 126-kb region surrounding and centromeric to the TNF locus.