Resequencing and fine-mapping of the chromosome 12q13-14 locus associated with multiple sclerosis refines the number of implicated genes

Multiple sclerosis (MS) is a common chronic inflammatory disease of the central nervous system. Susceptibility to the disease is affected by both environmental and genetic factors. Genetic factors include haplotypes in the histocompatibility complex (MHC) and over 50 non-MHC loci reported by genome-wide association studies. Amongst these, we previously reported polymorphisms in chromosome 12q13-14 with a protective effect in individuals of European descent. This locus spans 288 kb and contains 17 genes, including several candidate genes which have potentially significant pathogenic and therapeutic implications. In this study, we aimed to fine-map this locus. We have implemented a two-phase study: a variant discovery phase where we have used next-generation sequencing and two target-enrichment strategies [long-range polymerase chain reaction (PCR) and Nimblegen's solution phase hybridization capture] in pools of 25 samples; and a genotyping phase where we genotyped 712 variants in 3577 healthy controls and 3269 MS patients. This study confirmed the association (rs2069502, P = 9.9 × 10−11, OR = 0.787) and narrowed down the locus of association to an 86.5 kb region. Although the study was unable to pinpoint the key-associated variant, we have identified a 42 (genotyped and imputed) single-nucleotide polymorphism haplotype block likely to harbour the causal variant. No evidence of association at previously reported low-frequency variants in CYP27B1 was observed. As part of the study we compared variant discovery performance using two target-enrichment strategies. We concluded that our pools enriched with Nimblegen's solution phase hybridization capture had better sensitivity to detect true variants than the pools enriched with long-range PCR, whilst specificity was better in the long-range PCR-enriched pools compared with solution phase hybridization capture enriched pools; this result has important implications for the design of future fine-mapping studies.

Low formalin concentrations induce fine-tuned responses that are sex and age-dependent : a developmental study

The formalin test is increasingly applied as a model of inflammatory pain using high formalin concentrations (5–15%). However, little is known about the effects of low formalin concentrations on related behavioural responses. To examine this, rat pups were subjected to various concentrations of formalin at four developmental stages: 7, 13, 22, and 82 days of age. At postnatal day (PND) 7, sex differences in flinching but not licking responses were observed with 0.5% formalin evoking higher flinching in males than in females. A dose response was evident in that 0.5% formalin also produced higher licking responses compared to 0.3% or 0.4% formalin. At PND 13, a concentration of 0.8% formalin evoked a biphasic response. At PND 22, a concentration of 1.1% evoked higher flinching and licking responses during the late phase (10–30 min) in both males and females. During the early phase (0–5 min), 1.1% evoked higher licking responses compared to 0.9% or 1% formalin. 1.1% formalin produced a biphasic response that was not evident with 0.9 or 1%. At PND 82, rats displayed a biphasic pattern in response to three formalin concentrations (1.25%, 1.75% and 2.25%) with the presence of an interphase for both 1.75% and 2.25% but not for 1.25%. These data suggest that low formalin concentrations induce fine-tuned responses that are not apparent with the high formalin concentration commonly used in the formalin test. These data also show that the developing nociceptive system is very sensitive to subtle changes in formalin concentrations.

Investigations of the physical and chemical properties of ambient fine particles in urban schools

This thesis reports a comprehensive study on the physical and chemical properties of airborne particles in Brisbane, especially around schools. The sources and potential toxicity of the particles were identified, enabling an assessment of the contributing factors to children's exposure at school. The results from this thesis give a quantitative estimate of the range of airborne particles that children are exposed to at urban schools with different traffic conditions.

Fine tuning of elasticity via crosslinking collagen-based materials to mediate mechanotransduction and stability using corona treatment

The common goal of tissue engineering is to develop substitutes that can closely mimic the structure of extracellular matrix (ECM). However, similarly important is the intensive material properties which have often been overlooked, in particular, for soft tissues that are not to bear load assumingly. The mechanostructural properties determine not only the structural stability of biomaterials but also their physiological functionality by directing cellular activity and regulating cell fate decision. The aim here is to emphasize that cells could sense intensive material properties like elasticity and reside, proliferate, migrate and differentiate accordinglyno matter if the construct is from a natural source like cartilage, skin etc. or of synthetic one. Meanwhile, the very objective of this work is to provide a tunable scheme for manipulating the elasticity of collagen-based constructs to be used to demonstrate how to engineer cell behavior and regulate mechanotransduction. Articular cartilage was chosen as it represents one of the most complex hierarchical arrangements of collagen meshwork in both connective tissues and ECM-like biomaterials. Corona discharge treatment was used to produce constructs with varying density of crosslinked collagen and stiffness accordingly. The results demonstrated that elastic modulus increased up to 33% for samples treated up to one minute as crosslink density was found to increase with exposure time. According to the thermal analysis, longer exposure to corona increased crosslink density as the denaturation enthalpy increased. However the spectroscopy results suggested that despite the stabilization of the collagen structure the integrity of the triple helical structure remained intact. The in vitro superficial culture of heterologous chondrocytes also determined that the corona treatment can modulate migration with increased focal adhesion of cells due to enhanced stiffness, without cytotoxicity effects, and providing the basis for reinforcing three-dimensional collagen-based biomaterials in order to direct cell function and mediate mechanotransduction.

Visible light photocatalysts for synthesis of fine organic chemicals on supported nanostructures

This thesis is focus on developing new photocatalysts for synthesis of fine organic chemicals on supported nanostructures. These photocatalysts can facilitate reactions by using visible light, moderate temperature and atmospheric pressure which is suitable for a sustainable, green and eco-friendly modern chemical industry. Both Semiconductor Photocatalyst and Noble Metal Photocatalysts are designed to facilitate the homocouplings reaction of imine generation by amines.

A stochastic thermostat algorithm for coarse-grained thermomechanical modeling of large-scale soft matters : theory and application to microfilaments

As all-atom molecular dynamics method is limited by its enormous computational cost, various coarse-grained strategies have been developed to extend the length scale of soft matters in the modeling of mechanical behaviors. However, the classical thermostat algorithm in highly coarse-grained molecular dynamics method would underestimate the thermodynamic behaviors of soft matters (e.g. microfilaments in cells), which can weaken the ability of materials to overcome local energy traps in granular modeling. Based on all-atom molecular dynamics modeling of microfilament fragments (G-actin clusters), a new stochastic thermostat algorithm is developed to retain the representation of thermodynamic properties of microfilaments at extra coarse-grained level. The accuracy of this stochastic thermostat algorithm is validated by all-atom MD simulation. This new stochastic thermostat algorithm provides an efficient way to investigate the thermomechanical properties of large-scale soft matters.

Feral pig populations are structured at fine spatial scales in tropical Queensland, Australia

Feral pigs occur throughout tropical far north Queensland, Australia and are a significant threat to biodiversity and World Heritage values, agriculture and are a vector of infectious diseases. One of the constraints on long-lasting, local eradication of feral pigs is the process of reinvasion into recently controlled areas. This study examined the population genetic structure of feral pigs in far north Queensland to identify the extent of movement and the scale at which demographically independent management units exist. Genetic analysis of 328 feral pigs from the Innisfail to Tully region of tropical Queensland was undertaken. Seven microsatellite loci were screened and Bayesian clustering methods used to infer population clusters. Sequence variation at the mitochondrial DNA control region was examined to identify pig breed. Significant population structure was identified in the study area at a scale of 25 to 35 km, corresponding to three demographically independent management units (MUs). Distinct natural or anthropogenic barriers were not found, but environmental features such as topography and land use appear to influence patterns of gene flow. Despite the strong, overall pattern of structure, some feral pigs clearly exhibited ancestry from a MU outside of that from which they were sampled indicating isolated long distance dispersal or translocation events. Furthermore, our results suggest that gene flow is restricted among pigs of domestic Asian and European origin and non-random mating influences management unit boundaries. We conclude that the three MUs identified in this study should be considered as operational units for feral pig control in far north Queensland. Within a MU, coordinated and simultaneous control is required across farms, rainforest areas and National Park Estates to prevent recolonisation from adjacent localities.

Rapid on-site evaluation of fine needle aspiration specimens by cytology scientists : a review of 3032 specimens

Objectives To determine: (1) the accuracy of cytology scientists at assessing specimen adequacy by rapid on-site evaluation (ROSE) at fine needle aspiration (FNA) cytology collections; and (2) whether thyroid FNA with ROSE has lower inadequacy rates than non-attended FNAs. Methods The ROSE of adequacy for 3032 specimens from 17 anatomical sites collected over a 20-month period was compared with the final report assessment of adequacy. ROSE was performed by 19 cytology scientists. The report profile for 1545 thyroid nodules with ROSE was compared with that for 1536 consecutive non-ROSE thyroid FNAs reported by the same cytopathologists during the study period. Results ROSE was adequate in 75% (2276/3032), inadequate in 12% (366/3032) and in 13% (390/3032) no opinion was rendered. Of the 2276 cases assessed as adequate by ROSE, 2268 (99.6%) were finally reported as adequate for assessment; eight specimens had adequacy downgraded on the final report. Fifty eight per cent of cases with a ROSE assessment of inadequate were reported as adequate (212/366), whereas 93% (363/390) with no opinion rendered were reported as adequate. The overall final report adequacy rate for the 3032 specimens was 94% (2843/3032). Confirmation of a ROSE of adequacy at reporting was uniformly high amongst the 19 scientists, ranging from 98% to 100%. The inadequacy rate for thyroid FNAs with ROSE (6%) was significantly (P < 0.0001) lower than for non-ROSE thyroid FNAs (17%). A significantly (P = 0.02) higher proportion of adequate ROSE thyroid specimens was reported with abnormalities, compared with non-ROSE thyroid collections. Conclusions Cytology scientists are highly accurate at determining specimen adequacy at ROSE for a wide range of body sites. ROSE of thyroid FNAs can significantly reduce inadequate reports.

Online fine line : using social media to predict the Big Brother eviction

Reality television, alongside shows such as Q&A – which may be Reality TV in all but name – frequently drives social media conversations about the Australian television industry. Big Brother, currently screening on Channel 9, is consistently among the shows with the highest levels of chatter in that regard. The precise Facebook data is hard to quantify but the Official Big Brother page boasts 805,400 likes and more than 59,000 comments since the start of the series, suggesting it has established a firm presence on that platform too...

Fine-needle aspiration cytology of Merkel cell carcinoma-A review of 69 cases

Background This study reviewed the clinical presentation, cytologic findings and the immunophenotype of 69 Merkel Cell Carcinoma (MCC) cases sampled by FNA. Methods Demographic and clinical data, the cytology findings and results of ancillary testing were reviewed. Results Median patient age was 78 years (37 – 104) with a 1:1.8 female to male ratio. The most common FNA sites sampled included lymph nodes in the neck, the axillary region, the inguinal region and the parotid gland. Most patients had a history of MCC (68%) &/or non-MCC malignancy (70%). The common cytologic pattern was a cellular smear with malignant cells arranged in a dispersed pattern with variable numbers of disorganised groups of cells. Cytoplasm was scant or absent and nuclei showed mild to moderate anisokaryosis, stippled chromatin, inconspicuous nucleoli and nuclear molding. Numerous apoptotic bodies were often present. Cell block samples (28 cases) were usually positive for cytokeratins in a perinuclear dot pattern, including 88% of cases with CK20 positivity. CD56 was the most sensitive (95%) neuroendocrine marker on cell blocks and was also positive with flow cytometry in 9 cases tested. Conclusions MCC is most commonly seen in FNA specimens from the head and neck of elderly patients, often with a history of previous skin lesions. Occasional cases present in younger patients and some may be mistaken for other round blue cell tumors, such as lymphoma. CD 56 may be a useful marker in cell block preparations and in flow cytometric analysis of MCC.

Fine-mapping the HOXB region detects common variants tagging a rare coding allele : evidence for synthetic association in prostate cancer

The HOXB13 gene has been implicated in prostate cancer (PrCa) susceptibility. We performed a high resolution fine-mapping analysis to comprehensively evaluate the association between common genetic variation across the HOXB genetic locus at 17q21 and PrCa risk. This involved genotyping 700 SNPs using a custom Illumina iSelect array (iCOGS) followed by imputation of 3195 SNPs in 20,440 PrCa cases and 21,469 controls in The PRACTICAL consortium. We identified a cluster of highly correlated common variants situated within or closely upstream of HOXB13 that were significantly associated with PrCa risk, described by rs117576373 (OR 1.30, P = 2.62×10(-14)). Additional genotyping, conditional regression and haplotype analyses indicated that the newly identified common variants tag a rare, partially correlated coding variant in the HOXB13 gene (G84E, rs138213197), which has been identified recently as a moderate penetrance PrCa susceptibility allele. The potential for GWAS associations detected through common SNPs to be driven by rare causal variants with higher relative risks has long been proposed; however, to our knowledge this is the first experimental evidence for this phenomenon of synthetic association contributing to cancer susceptibility.

The varied presentation of metastatic melanoma in fine needle aspiration cytology of the breast

Objective To identify cytomorphological patterns of metastatic melanoma (MM) in breast fine needle aspiration (FNA) specimens and highlight the differential diagnoses and features most useful in identifying MM. Methods The clinical, radiological and FNA findings of 16 cases were reviewed. Cytological features evaluated related to cell arrangement, size and shape of cells, nuclear and cytoplasmic features, and the presence or absence of necrosis. Results The series consisted of 14 females and two males, ranging in age from 24 to 83 years (mean = 50 years). A previous history of melanoma was available in 12/16 (75%) cases at the time of FNA reporting; however the clinical/radiological impression in 4/16 cases was of a breast cyst. The cases were classified into six morphological variants: classical (8/16), pseudopapillary (3/16), spindle-cell (1/16), melanin-rich (1/16), pleomorphic (2/16) and lymphoma-like (1/16). The varying patterns raised a wide range of differential diagnoses; however, discohesion, binucleation and granular cytoplasm were the major features seen in 94% of all cases. In 14/16 cases (88%), plasmacytoid cells, prominent nucleoli and cytoplasmic vacuolation were identified. Melanin and multinucleation were detected in 44% of cases and intranuclear cytoplasmic invaginations in 63%. Necrosis was present in more than half of the cases (56%). Conclusion MM should be considered in the differential diagnosis of breast FNA specimens when atypical cells are seen that present as plasmacytoid cells in a dispersed or pseudopapillary pattern, or as spindle, pleomorphic or pigmented cells. These features, combined with clinical history and immunocytochemistry, may assist in correctly identifying MM and directing optimal treatment.

Elemental composition of ambient fine particles in urban schools : sources of children’s exposure

Currently, there is a limited understanding of the sources of ambient fine particles that contribute to the exposure of children at urban schools. Since the size and chemical composition of airborne particle are key parameters for determining the source as well as toxicity, PM1 particles (mass concentration of particles with an aerodynamic diameter less than 1 µm) were collected at 24 urban schools in Brisbane, Australia and their elemental composition determined. Based on the elemental composition four main sources were identified; secondary sulphates, biomass burning, vehicle and industrial emissions. The largest contributing source was industrial emissions and this was considered as the main source of trace elements in the PM1 that children were exposed to at school. PM1 concentrations at the schools were compared to the elemental composition of the PM2.5 particles (mass concentration of particles with an aerodynamic diameter less than 2.5 µm) from a previous study conducted at a suburban and roadside site in Brisbane. This comparison revealed that the more toxic heavy metals (V, Cr, Ni, Cu, Zn and Pb), mostly from vehicle and industrial emissions, were predominantly in the PM1 fraction. Thus, the results from this study points to PM1 as a potentially better particle size fraction for investigating the health effects of airborne particles.

Towards equalisation of the impact of the penal fine : why the wealth of the offender was taken into account

Important changes in the legal regulation of the fine culminated in the implementation of the day‐fine system in many European countries during the twentieth century. These changes resulted from various late nineteenth century rationalities that considered the fine a justifiable punishment. Therefore, they supported extending its application by making it affordable for people on low incomes, which meant imprisonment for fine default could mostly be avoided without undermining the end of punishment. In this paper I investigate the historical development of the penal fine as well as the changing forms of this penalty in Western European criminal systems from the end of the eighteenth century until the late nineteenth century.