'Sink or swim': An evaluation of the clinical characteristics of individuals with high bone mass

Summary High bone mineral density on routine dual energy X-ray absorptiometry (DXA) may indicate an underlying skeletal dysplasia. Two hundred fifty-eight individuals with unexplained high bone mass (HBM), 236 relatives (41% with HBM) and 58 spouses were studied. Cases could not float, had mandible enlargement, extra bone, broad frames, larger shoe sizes and increased body mass index (BMI). HBM cases may harbour an underlying genetic disorder. Introduction High bone mineral density is a sporadic incidental finding on routine DXA scanning of apparently asymptomatic individuals. Such individuals may have an underlying skeletal dysplasia, as seen in LRP5 mutations. We aimed to characterize unexplained HBM and determine the potential for an underlying skeletal dysplasia. Methods Two hundred fifty-eight individuals with unexplained HBM (defined as L1 Z-score ≥ +3.2 plus total hip Z-score ≥ +1.2, or total hip Z-score ≥ +3.2) were recruited from 15 UK centres, by screening 335,115 DXA scans. Unexplained HBM affected 0.181% of DXA scans. Next 236 relatives were recruited of whom 94 (41%) had HBM (defined as L1 Z-score + total hip Z-score ≥ +3.2). Fifty-eight spouses were also recruited together with the unaffected relatives as controls. Phenotypes of cases and controls, obtained from clinical assessment, were compared using random-effects linear and logistic regression models, clustered by family, adjusted for confounders, including age and sex. Results Individuals with unexplained HBM had an excess of sinking when swimming (7.11 [3.65, 13.84], p < 0.001; adjusted odds ratio with 95% confidence interval shown), mandible enlargement (4.16 [2.34, 7.39], p < 0.001), extra bone at tendon/ligament insertions (2.07 [1.13, 3.78], p = 0.018) and broad frame (3.55 [2.12, 5.95], p < 0.001). HBM cases also had a larger shoe size (mean difference 0.4 [0.1, 0.7] UK sizes, p = 0.009) and increased BMI (mean difference 2.2 [1.3, 3.1] kg/m 2, p < 0.001). Conclusion Individuals with unexplained HBM have an excess of clinical characteristics associated with skeletal dysplasia and their relatives are commonly affected, suggesting many may harbour an underlying genetic disorder affecting bone mass.

Modeling of Channel Potential and Subthreshold Slope of Symmetric Double-Gate Transistor

A new physically based classical continuous potential distribution model, particularly considering the channel center, is proposed for a short-channel undoped body symmetrical double-gate transistor. It involves a novel technique for solving the 2-D nonlinear Poisson's equation in a rectangular coordinate system, which makes the model valid from weak to strong inversion regimes and from the channel center to the surface. We demonstrated, using the proposed model, that the channel potential versus gate voltage characteristics for the devices having equal channel lengths but different thicknesses pass through a single common point (termed ``crossover point''). Based on the potential model, a new compact model for the subthreshold swing is formulated. It is shown that for the devices having very high short-channel effects (SCE), the effective subthreshold slope factor is mainly dictated by the potential close to the channel center rather than the surface. SCEs and drain-induced barrier lowering are also assessed using the proposed model and validated against a professional numerical device simulator.

Study of miRNA polymorphisms and their potential association with breast cancer risk in Australian Caucasian populations

This project established a large and well characterised prospective breast cancer DNA biobank and used this biobank to conduct genetic studies in breast cancer. The thesis presented the results of these high-throughput genotyping studies in two separate Australian Caucasian case-control populations and identified association between three novel genetic variants in microRNA genes and breast cancer risk.

The potential role of a late gene expression factor, lef2, from Bombyx mori nuclear polyhedrosis virus in very late gene transcription and DNA replication

Several late gene expression factors (Lefs) have been implicated in fostering high levels of transcription from the very late gene promoters of polyhedrin and p10 from baculoviruses. We cloned and characterized from Bombyx mori nuclear polyhedrosis virus a late gene expression factor (Bmlef2) that encodes a 209-amino-acid protein harboring a Cys-rich C-terminal domain. The temporal transcription profiles of lef2 revealed a 1.2-kb transcript in both delayed early and late periods after virus infection. Transcription start site mapping identified the presence of an aphidicolin-sensitive late transcript arising from a TAAG motif located at -352 nucleotides and an aphidicolin-insensitive early transcript originating from a TTGT motif located 35 nucleotides downstream to a TATA box at -312 nucleotides, with respect to the +1 ATG of lef2. BmLef2 trans-activated very late gene expression from both polyhedrin and p10 promoters in transient expression assays. Internal deletion of the Cys-rich domain from the C-terminal region abolished the transcriptional activation. Inactivation of Lef2 synthesis by antisense lef2 transcripts drastically reduced the very late gene transcription but showed little effect on the expression from immediate early promoter. Decrease in viral DNA synthesis and a reduction in virus titer were observed only when antisense lef2 was expressed under the immediate early (ie-1) promoter. Furthermore, the antisense experiments suggested that lef2 plays a direct role in very late gene transcription.

Crop Classification using Biologically-inspired Techniques with High Resolution Satellite Image

Remote sensing provides a lucid and effective means for crop coverage identification. Crop coverage identification is a very important technique, as it provides vital information on the type and extent of crop cultivated in a particular area. This information has immense potential in the planning for further cultivation activities and for optimal usage of the available fertile land. As the frontiers of space technology advance, the knowledge derived from the satellite data has also grown in sophistication. Further, image classification forms the core of the solution to the crop coverage identification problem. No single classifier can prove to satisfactorily classify all the basic crop cover mapping problems of a cultivated region. We present in this paper the experimental results of multiple classification techniques for the problem of crop cover mapping of a cultivated region. A detailed comparison of the algorithms inspired by social behaviour of insects and conventional statistical method for crop classification is presented in this paper. These include the Maximum Likelihood Classifier (MLC), Particle Swarm Optimisation (PSO) and Ant Colony Optimisation (ACO) techniques. The high resolution satellite image has been used for the experiments.

Damage potential of an introduced biological control agent Agonosoma trilineatum (F.) on bellyache bush (Jatropha gossypiifolia L.)

The seed-feeding jewel bug, Agonosoma trilineatum (F.), is an introduced biological control agent for bellyache bush, Jatropha gossypiifolia L. To quantify the damage potential of this agent, shadehouse experiments were conducted with individual bellyache bush plants exposed to a range of jewel bug densities (0, 6 or 24 jewel bugs/plant). The level of abortion of both immature and mature seed capsules and impacts on seed weight and seed viability were recorded in an initial short-term study. The ability of the jewel bug to survive and cause sustained damage was then investigated by measuring seed production, the survival of adults and nymph density across three 6-month cycles. The level of seed capsule abortion caused by the jewel bug was significantly affected by the maturity status of capsules and the density of insects present. Immature capsules were most susceptible and capsule abortion increased with jewel bug density. Similarly, on average, the insects reduced the viability of bellyache bush seeds by 79% and 89% at low and high densities, respectively. However, sustaining jewel bug populations for prolonged periods proved difficult. Adult survival at the end of three 6-month cycles averaged 11% and associated reductions in viable seed production ranged between 55% and 77%. These results suggest that the jewel bug has the potential to reduce the number of viable seeds entering the soil seed bank provided populations can be established and maintained at sufficiently high densities.

Glucosinolate composition and anti-cancer potential of daikon and radish sprouts

Daikon and radish sprouts contain high levels of glucoraphenin, a glucosinolate which hydrolyses to form sulphoraphene. Sulphoraphene, like sulphoraphane from broccoli, is a potent inducer of phase 2 detoxification enzymes and consequently has potential anti-cancer action. Unlike broccoli however, daikon and radish do not possess epithiospecifier protein, a protein that inhibits conversion of glucosinolates to isothiocyanates, and consequently they may represent more suitable sources of phyto-chemicals with anti-cancer potential. Concentrations of glucoraphenin were highest in the seed, declining exponentially with sprout development. The rate of decline was observed to vary considerably between varieties of daikon and radish, with some varieties maintaining significantly high levels of glucoraphenin. Varieties maintaining a high level of glucoraphenin included 'Cherry Belle' and 'French Breakfast'.

The use of high resolution melting (HRM) to map single nucleotide polymorphism markers linked to a covered smut resistance gene in barley

Using an established genetic map, a single gene conditioning covered smut resistance, Ruh.7H, was mapped to the telomere region of chromosome 7HS in an Alexis/Sloop doubled haploid barley population. The closest marker to Ruh.7H, abg704 was 7.5 cM away. Thirteen loci on the distal end of 7HS with potential to contain single nucleotide polymorphisms (SNPs) were identified by applying a comparative genomics approach using rice sequence data. Of these, one locus produced polymorphic co-dominant bands of different size while two further loci contained SNPs that were identified using the recently developed high resolution melting (HRM) technique. Two of these markers flanked Ruh.7H with the proximal marker located 3.8 cM and the distal marker 2.7 cM away. This is the first report on the application of the HRM technique to SNP detection and to rapid scoring of known cleaved amplified polymorphic sequence (CAPS) markers in plants. This simple, precise post-PCR technique should find widespread use in the fine-mapping of genetic regions of interest in complex cereal and other plant genomes.

A systems evaluation of high-input management using fortified molasses for beef production in Australia's dry tropics

The potential of beef producers to profitably produce 500-kg steers at 2.5 years of age in northern Australia's dry tropics to meet specifications of high-value markets, using a high-input management (HIM) system was examined. HIM included targeted high levels of fortified molasses supplementation, short seasonal mating and the use of growth promotants. Using herds of 300-400 females plus steer progeny at three sites, HIM was compared at a business level to prevailing best-practice, strategic low-input management (SLIM) in which there is a relatively low usage of energy concentrates to supplement pasture intake. The data presented for each breeding-age cohort within management system at each site includes: annual pregnancy rates (range: 14-99%), time of conception, mortalities (range: 0-10%), progeny losses between confirmed pregnancy and weaning (range: 0-29%), and weaning rates (range: 14-92%) over the 2-year observation. Annual changes in weight and relative net worth were calculated for all breeding and non-breeding cohorts. Reasons for outcomes are discussed. Compared with SLIM herds, both weaning weights and annual growth were >= 30 kg higher, enabling 86-100% of HIM steers to exceed 500 kg at 2.5 years of age. Very few contemporary SLIM steers reached this target. HIM was most profitably applied to steers. Where HIM was able to achieve high pregnancy rates in yearlings, its application was recommended in females. Well managed, appropriate HIM systems increased profits by around $15/adult equivalent at prevailing beef and supplement prices. However, a 20% supplement price rise without a commensurate increase in values for young slaughter steers would generally eliminate this advantage. This study demonstrated the complexity of pro. table application of research outcomes to commercial business, even when component research suggests that specific strategies may increase growth and reproductive efficiency and/or be more pro. table. Because of the higher level of management required, higher costs and returns, and higher susceptibility to market changes and disease, HIM systems should only be applied after SLIM systems are well developed. To increase profitability, any strategy must ultimately either increase steer growth and sale values and/or enable a shift to high pregnancy rates in yearling heifers.

Thermal tolerance and potential distribution of Carvalhotingis visenda (Hemiptera: Tingidae), a biological control agent for cat's claw creeper, Macfadyena unguis-cati (Bignoniaceae)

The specialist tingid, Carvalhotingis visenda, is a biological control agent for cat's claw creeper, Macfadyena unguis-cati (Bignoniaceae). Cat's claw creeper is an invasive liana with a wide climatic tolerance, and for biological control to be effective the tingid must survive and develop over a range of temperatures. We evaluated the effect of constant temperatures (0-45°C) on the survival and development of C. visenda. Adults showed tolerance for wider temperature ranges (0-45°C), but oviposition, egg hatching and nymphal development were all affected by both high (>30°C) and low (<20°C) temperatures. Temperatures between 20°C and 30°C are the most favourable for adult survival, oviposition, egg hatching and nymphal development. The ability of adults and nymphs to survive for a few days at high (40°C and 45°C) and low (0°C and 5°C) temperatures suggest that extreme temperature events, which usually occur for short durations (hours) in cat's claw creeper infested regions in Queensland and New South Wales states are not likely to affect the tingid population. The potential number of generations (egg to adult) the tingid can complete in a year in Australia ranged from three to eight, with more generations in Queensland than in New South Wales.

High temperature stability of oxysulfides containing Ce3+ and Y3+ ions

Standard Gibbs energies of formation of oxysulfides of cerium and yttrium from their respective oxedes were determined using solid oxide galvanic cells incorporating calcia-stabilized zirconia as the electrolyte in the temperature range 870–1120 K. The sulfur potential over the electrode containing the oxide and oxysulfide was fixed by a buffer mixture of Ag + Ag2S. A small amount of CaH2 was added to the buffer to generate an equilibrium ratio of H2S and H2 species in a closed system containing the buffer and the electrode. The sulfur potential is transmitted to the electrode via the gas phase. The results can be summarized by the equations 2left angle bracketCeO2right-pointing angle bracket+1/2(S2)→left angle bracketCe2O2Sright-pointing angle bracket+(O2) ΔG°=430600−109·7T(±400)J mol−1 left angle bracketY2O3right-pointing angle bracket+1/2(S2)→left angle bracketY2O2Sright-pointing angle bracket+1/2(O2) ΔG°=114780−1·45T(±200)J mol−1 The values are compared with data reported in the literature. The stability field diagram for the Ce---O---S system has been developed using the results of this study for Ce2O2S and data for other phases from the literature.

Membrane fractionation technologies for high quality mill sugar and value-added by products - an integrated sugar production process concept model.

Membrane filtration technology has been proven to be a technically sound process to improve the quality of clarified cane juice and subsequently to increase the productivity of crystallisation and the quality of sugar production. However, commercial applications have been hindered because the benefits to crystallisation and sugar quality have not outweighed the increased processing costs associated with membrane applications. An 'Integrated Sugar Production Process (ISPP) Concept Model' is proposed to recover more value from the non-sucrose streams generated by membrane processing. Pilot scale membrane fractionation trials confirmed the technical feasibility of separating high-molecular weight, antioxidant and reducing sugar fractions from cane juice in forms suitable for value recovery. It was also found that up to 40% of potassium salts from the juice can be removed by membrane application while removing the similar amount of water with potential energy saving in subsequent evaporation. Application of ISPP would allow sugar industry to co-produce multiple products and high quality mill sugar while eliminating energy intensive refining processes.

Investigations into the potential for mixed cultures of banana prawns Penaeus merguiensis, sea mullet Mugil cephalus and rabbitfish Siganus nebulosus for bioremediation of aquaculture waste

To experimentally investigate the potential of mixed species polycultures for bioremediation of nutrient rich prawn farm effluent, a series of experiments was performed with banana prawns Penaeus (Fenneropenaeus) merguiensis, sea mullet Mugil cephalus and rabbitfish Siganus nebulosus to determine their compatibilities during particular life stages. Rabbitfish demonstrated a high tendency to prey upon banana prawn juveniles when no other food was available. Mullet of various sizes did not appear to prey upon banana prawn postlarvae (PL16) or juveniles in a fed or unfed environment. The study confirms the good potential for mullet and banana prawn polycultures.

Studies on the pro-oxidative properties and neurotoxic potential of Angeli's salt-derived nitroxyl (HNO/NO-)

The biological function of nitric oxide and its oxidized forms has received a great deal of attention over the past two decades. However much less attention has been focused on the reduced nitric oxide, nitroxyl (HNO). Unlike NO, HNO is highly reactive species and thus it needs to be generated by using donor compounds under experimental conditions. Currently there is only one donor available, Angeli s salt, which releases HNO in a controlled fashion under pysiological conditions. Prior studies have shown the pro-oxidative and cytotoxic potential of Angeli s salt compared to NO donors. The high reactivity of HNO with cysteine thiols is considered to form the biochemical basis for its unique properties compared to other nitrogen oxides. Such thiol modification cold result in disturbances of vital cellular functions and subsequently to death of disturbance sensitive cells, such as neurons. Therefore modification of proteins and lipids was studied in vitro and the potential neurotoxicity was studied in vivo by local infusion of Angeli s salt into the rat central nervous system. The results show that under aerobic in vitro conditions, HNO can, subsequent to autoxidation, cause irreversible oxidative modification of proteins and lipids. These effects are not however seen in cell culture or following infusion of Angeli s salt directly into the rat central nervous tissue likely due to presence of lower oxygen and higher thiol concentration. However, due to high reactivity with thiols, HNO can cause irreversible inactivation of cysteine modification sensitive enzymes such as cysteine proteases papain in vitro and cathepsin B in cell culture. Furthermore it was shown that infusion of HNO releasing Angeli s salt into the rat central nervous system causes necrotic cell death and motor dysfunction following infusion into the lumbal intrathecal space. In conclusion, the acute neurotoxic potential of Angeli s salt was shown to be relatively low, but still higher compared to NO donors. HNO was shown to affect numerous cellular processes which could result in neurotoxicity if HNO was produced in vivo.

Studies on Matrix Metalloproteinase (MMP-2, -9 and -14) and β2 Integrin Targeting as Potential Anticancer Therapeutics

Proteolytic enzymes, such as matrix metalloproteinases (MMP), are associated to the progression of several cancers. They degrade extracellular components, which helps tumors to expand and cancer cells to escape from the primary site. Of all MMPs, gelatinases (MMP-2 and -9) and membrane type-1 matrix metalloproteinase (MT1-MMP, MMP-14), in particular, are often associated to more aggressive types of head and neck carcinomas as well as to a poorer outcome in patient survival. Although therapies during the last decades have advanced, the mortality of the disease is still rather high and adjuvant therapies are searched for continuously. MMP-9 and MT1-MMP are also involved in neo-angiogenesis, which is necessary for tumor expansion. For this reason, we have identified synthetic peptides-targeting gelatinases and MT1-MMP, and have also evaluated their anticancer effects in vitro and in vivo. Antigelatinolytic peptides effectively inhibited tongue-carcinoma cell invasion and reduced the growth of xenografted tumors. In tumor samples of mice that were treated with antigelatinolytic peptides, the micro-vessel density was significantly reduced. We also identified a novel MT1-MMP targeting peptide and demonstrated that it exerted anticancer effects against several malignant cell lines in vitro. The effects of MT1-MMP inhibition on tongue-squamous cell carcinomas were evaluated by using xenograft tumors, which it effectively inhibited. Tranexamic acid was also demonstrated to inhibit tongue-squamous cell carcinoma invasion, most probably due to its ability to prevent the plasmin-mediated activation of proMMP-9. Leukocyte β2 integrins are another interesting option when evaluating targets for the therapeutic intervention of inflammatory conditions or malignancies of hematopoietic origin, since β2 integrins are expressed mainly by leukocytes. We identified a novel technique for screening small-molecule libraries against β2 integrins, and by using this technique we identified a novel αMβ2 integrin-binding chemical (IMB-10). IMB-10 significantly enhances leukocyte adhesion and inhibits their motility. We also demonstrated that IMB-10 can be used to inhibit inflammation and lymphoma growth in vivo. Interestingly, IMB-10 also reduced leukocyte tumor infiltration and inhibited tumor invasion.