Selective cleavage of human sex hormone-binding globulin by kallikrein-related peptidases and effects on androgen action in LNCaP prostate cancer cells

Stimulation of the androgen receptor via bioavailable androgens, including testosterone and testosterone metabolites, is a key driver of prostate development and the early stages of prostate cancer. Androgens are hydrophobic and as such require carrier proteins, including sex hormone-binding globulin (SHBG), to enable efficient distribution from sites of biosynthesis to target tissues. The similarly hydrophobic corticosteroids also require a carrier protein whose affinity for steroid is modulated by proteolysis. However, proteolytic mechanisms regulating the SHBG/androgen complex have not been reported. Here, we show that the cancer-associated serine proteases, kallikrein-related peptidase (KLK)4 and KLK14, bind strongly to SHBG in glutathione S-transferase interaction analyses. Further, we demonstrate that active KLK4 and KLK14 cleave human SHBG at unique sites and in an androgen-dependent manner. KLK4 separated androgen-free SHBG into its two laminin G-like (LG) domains that were subsequently proteolytically stable even after prolonged digestion, whereas a catalytically equivalent amount of KLK14 reduced SHBG to small peptide fragments over the same period. Conversely, proteolysis of 5α-dihydrotestosterone (DHT)-bound SHBG was similar for both KLKs and left the steroid binding LG4 domain intact. Characterization of this proteolysis fragment by [(3)H]-labeled DHT binding assays revealed that it retained identical affinity for androgen compared with full-length SHBG (dissociation constant = 1.92 nM). Consistent with this, both full-length SHBG and SHBG-LG4 significantly increased DHT-mediated transcriptional activity of the androgen receptor compared with DHT delivered without carrier protein. Collectively, these data provide the first evidence that SHBG is a target for proteolysis and demonstrate that a stable fragment derived from proteolysis of steroid-bound SHBG retains binding function in vitro.

Finding additional semantic entity information for search engines

Entity-oriented search has become an essential component of modern search engines. It focuses on retrieving a list of entities or information about the specific entities instead of documents. In this paper, we study the problem of finding entity related information, referred to as attribute-value pairs, that play a significant role in searching target entities. We propose a novel decomposition framework combining reduced relations and the discriminative model, Conditional Random Field (CRF), for automatically finding entity-related attribute-value pairs from free text documents. This decomposition framework allows us to locate potential text fragments and identify the hidden semantics, in the form of attribute-value pairs for user queries. Empirical analysis shows that the decomposition framework outperforms pattern-based approaches due to its capability of effective integration of syntactic and semantic features.

Classification of the Johnson Space Center stratospheric dust collection

A review of 291 catalogued particles on the bases of particle size, shape, bulk chemistry, and texture is used to establish a reliable taxonomy. Extraterrestrial materials occur in three defined categories: spheres, aggregates and fragments. Approximately 76% of aggregates are of probable extraterrestrial origin, whereas spheres contain the smallest amount of extraterrestrial material (approx 43%). -B.M.

Large igneous provinces and silicic large igneous provinces : progress in our understanding over the last 25 years

Large Igneous Provinces are exceptional intraplate igneous events throughout Earth’s history. Their significance and potential global impact is related to the total volume of magma intruded and released during these geologically brief events (peak eruptions are often within 1-5 Myrs duration) where millions to tens of millions of cubic kilometers of magma are produced. In some cases, at least 1% of the Earth’s surface has been directly covered in volcanic rock, being equivalent to the size of small continents with comparable crustal thicknesses. Large Igneous Provinces are thus important, albeit episodic episodes of new crust addition. However, most magmatism is basaltic so that contributions to crustal growth will not always be picked up in zircon geochronology studies that better trace major episodes of extension-related silicic magmatism and the silicic Large Igneous Provinces. Much headway has been made on our understanding of these anomalous igneous events over the last 25 years, driving many new ideas and models. This includes their: 1) global spatial and temporal distribution, with a long-term average of one event approximately every 20 Myrs, but a clear clustering of events at times of supercontinent break-up – Large Igneous Provinces are thus an integral part of the Wilson cycle and are becoming an increasingly important tool in reconnecting dispersed continental fragments; 2) compositional diversity that in part reflects their crustal setting of ocean basins, and continental interiors and margins where in the latter setting, LIP magmatism can be silicicdominant; 3) mineral and energy resources with major PGE and precious metal resources being hosted in these provinces, as well as magmatism impacting on the hydrocarbon potential of volcanic basins and rifted margins through enhancing source rock maturation, providing fluid migration pathways, and trap formation; 4) biospheric, hydrospheric and atmospheric impacts, with Large Igneous Provinces now widely regarded as a key trigger mechanism for mass extinctions, although the exact kill mechanism(s) are still being resolved; 5) role in mantle geodynamics and thermal evolution of the Earth, by potentially recording the transport of material from the lower mantle or core-mantle boundary to the Earth's surface and being a fundamental component in whole mantle convection models; and 6) recognition on the inner planets where the lack of plate tectonics and erosional processes and planetary antiquity means that the very earliest record of LIP events during planetary evolution may be better preserved than on Earth.

Comparing child product safety concerns with injury incidents : does the evidence support the response?

Background Efficient effective child product safety (PS) responses require data on hazards, injury severity and injury probability. PS responses in Australia largely rely on reports from manufacturers/retailers, other jurisdictions/regulators, or consumers. The extent to which reactive responses reflect actual child injury priorities is unknown. Aims/Objectives/Purpose This research compared PS issues for children identified using data compiled from PS regulatory data and data compiled from health data sources in Queensland, Australia. Methods PS regulatory documents describing issues affecting children in Queensland in 2008–2009 were compiled and analysed to identify frequent products and hazards. Three health data sources (ED, injury surveillance and hospital data) were analysed to identify frequent products and hazards. Results/Outcomes Projectile toys/squeeze toys were the priority products for PS regulators with these toys having the potential to release small parts presenting choking hazards. However, across all health datasets, falls were the most common mechanism of injury, and several of the products identified were not subject to a PS system response. While some incidents may not require a response, a manual review of injury description text identified child poisonings and burns as common mechanisms of injuries in the health data where there was substantial documentation of product-involvement, yet only 10% of PS system responses focused on these two mechanisms combined. Significance/contribution to the field Regulatory data focused on products that fail compliance checks with ‘potential’ to cause harm, and health data identified actual harm, resulting in different prioritisation of products/mechanisms. Work is needed to better integrate health data into PS responses in Australia.

A case for optimising fracture healing through inverse dynamization

The mechanical conditions in the repair tissues are known to influence the outcome of fracture healing. These mechanical conditions are determined by the stiffness of fixation and limb loading. Experimental studies have shown that there is a range of beneficial fixation stiffness for timely healing and that fixation stiffness that is either too flexible or too stiff impairs callus healing. However, much less is known about how mechanical conditions influence the biological processes that make up the sequence of bone repair and if indeed mechanical stimulation is required at all stages of repair. Secondary bone healing occurs through a sequence of events broadly characterised by inflammation, proliferation, consolidation and remodelling. It is our hypothesis that a change in fixation stiffness from very flexible to stiff can shorten the time to healing relative to constant fixation stiffness. Flexible fixation has the benefit of promoting greater callus formation and needs to be applied during the proliferative stage of repair. The greater callus size helps to stabilize the fragments earlier allowing mineralization to occur faster. Together with stable/rigid fixation applied during the latter stage of repair to ensure mineralization of the callus. The predicted benefits of inverse dynamization are shortened healing in comparison to very flexible fixation and healing time comparable or faster than stable fixation with greater callus stiffness.

Pieces of a city : the art of making speculative cities, bodies, & texts

This practice-led doctorate involved the development of a collection – a bricolage – of interwoven fragments of literary texts and visual imagery explor-ing questions of speculative fiction, urban space and embodiment. As a sup-plement to the creative work, I also developed an exegesis, using a combina-tion of theoretical and contextual analysis combined with critical reflections on my creative process and outputs. An emphasis on issues of creative practice and a sustained investigation into an aesthetics of fragmentation and assem-blage is organised around the concept and methodology of bricolage, the eve-ryday art of ‘making do’. The exegesis also addresses my interest in the city and urban forms of subjectivity and embodiment through the use of a range of theorists, including Michel de Certeau and Elizabeth Grosz.

Carbonate cementation in sandstones of the Plover Formation, North West Shelf, W.A

Ancient sandstones include important reservoirs for hydrocarbons (oil and gas), but, in many cases, their ability to serve as reservoirs is heavily constrained by the effects of carbonate cements on porosity and permeability. This study investigated the controls on distribution and abundance of carbonate cements within the Jurassic Plover Formation, Browse Basin, North West Shelf, Australia. Samples were analysed petrographically with point counting of 59 thin sections and mineralogically with x-ray diffraction from two wells within the Torosa Gas Field. Selected samples were also analysed for stable isotopes of O and C. Sandstones are classified into eleven groups. Most abundant are quartzarenites and then calcareous quartzarenites. Lithology ranged between sandstones consisting of mostly quartz with scant or no carbonate in the form of cement or allochems, to sandstones with as much as 40% carbonate. The major sources of carbonate cement in Torosa 1 and Torosa 4 sandstones were found to be early, shallow marine diagenetic processes (including cementation), followed by calcite cementation and recrystallisation of cements and allochems during redistribution by meteoric waters. Blocky and sparry calcite cements, indicative of meteoric environments on the basis of stable isotope values and palaeotemperature assessment, overprinted the initial shallow marine cement phase in all cases and meteoric cements are dominant. Torosa 4 was influenced more by marine settings than Torosa 1, and thus has the greater potential for calcite cement. The relatively low compaction of calcite-cemented sandstones and the stable isotope data suggest deep burial cementation was not a major factor. Insufficient volcanic rock fragments or authigenic clay content infers alteration of feldspars was not a major source of calcite. Very little feldspar is present, altered or otherwise. Hence, increased alkalinity from feldspar dissolution is not a contributing factor in cement formation. Increased alkalinity from bacterial sulphate reduction in organic–rich fine sediments may have driven limited cementation in some samples. The main definable and significant source of diagenetic marine calcite cement originated from original marine cements and the nearby dissolution of biogenic sources (allochems) at relatively shallow depths. Later diagenetic fluids emplaced minor dolomite, but this cement did not greatly affect the reservoir quality in the samples studied.

Simplifying process model abstraction : techniques for generating model names

The increased adoption of business process management approaches, tools and practices, has led organizations to accumulate large collections of business process models. These collections can easily include hundred to thousand models, especially in the context of multinational corporations or as a result of organizational mergers and acquisitions. A concrete problem is thus how to maintain these large repositories in such a way that their complexity does not hamper their practical usefulness as a means to describe and communicate business operations. This paper proposes a technique to automatically infer suitable names for business process models and fragments thereof. This technique is useful for model abstraction scenarios, as for instance when user-specific views of a repository are required, or as part of a refactoring initiative aimed to simplify the repository’s complexity. The technique is grounded in an adaptation of the theory of meaning to the realm of business process models. We implemented the technique in a prototype tool and conducted an extensive evaluation using three process model collections from practice and a case study involving process modelers with different experience.

Business process variability modeling : A survey

It is common for organizations to maintain multiple variants of a given business process, such as multiple sales processes for different products or multiple bookkeeping processes for different countries. Conventional business process modeling languages do not explicitly support the representation of such families of process variants. This gap triggered significant research efforts over the past decade leading to an array of approaches to business process variability modeling. This survey examines existing approaches in this field based on a common set of criteria and illustrates their key concepts using a running example. The analysis shows that existing approaches are characterized by the fact that they extend a conventional process mod- eling language with constructs that make it able to capture customizable process models. A customizable process model represents a family of process variants in a way that each variant can be derived by adding or deleting fragments according to configuration parameters or according to a domain model. The survey puts into evidence an abundance of customizable process modeling languages, embodying a diverse set of con- structs. In contrast, there is comparatively little tool support for analyzing and constructing customizable process models, as well as a scarcity of empirical evaluations of languages in the field.

Urinary biomolecular indicators of exercise-induced over exertion injury

Poor health and injury represent major obstacles to the future economic security of Australia. The national economic cost of work-related injury is estimated at $57.5 billion p/a. Since exposure to high physical demands is a major risk factor for musculoskeletal injury, monitoring and managing such physical activity levels in workers is a potentially important injury prevention strategy. Current injury monitoring practices are inadequate for the provision of clinically valuable information about the tissue specific responses to physical exertion. Injury of various soft tissue structures can manifest over time through accumulation of micro-trauma. Such micro-trauma has a propensity to increase the risk of acute injuries to soft-tissue structures such as muscle or tendon. As such, the capacity to monitor biomarkers that result from the disruption of these tissues offers a means of assisting the pre-emptive management of subclinical injury prior to acute failure or for evaluation of recovery processes. Here we have adopted an in-vivo exercise induced muscle damage model allowing the application of laboratory controlled conditions to assist in uncovering biochemical indicators associated with soft-tissue trauma and recovery. Importantly, urine was utilised as the diagnostic medium since it is non-invasive to collect, more acceptable to workers and less costly to employers. Moreover, it is our hypothesis that exercise induced tissue degradation products enter the circulation and are subsequently filtered by the kidney and pass through to the urine. To test this hypothesis a range of metabolomic and proteomic discovery-phase techniques were used, along with targeted approaches. Several small molecules relating to tissue damage were identified along with a series of skeletal muscle-specific protein fragments resulting from exercise induced soft-tissue damage. Each of the potential biomolecular markers appeared to be temporally present within urine. Moreover, the regulation of abundance seemed to be associated with functional recovery following the injury. This discovery may have important clinical applications for monitoring of a variety of inflammatory myopathies as well as novel applications in monitoring of the musculoskeletal health status of workers, professional athletes and/or military personnel to reduce the onset of potentially debilitating musculoskeletal injuries within these professions.

Iron nodules in ferric soils of the Fraser Coast, Australia : relicts of laterisation or features of contemporary weathering and pedogenesis?

The genesis of ferruginous nodules and pisoliths in soils and weathering profiles of coastal southern and eastern Australia has long been debated. It is not clear whether iron (Fe) nodules are redox accumulations, residues of Miocene laterite duricrust, or the products of contemporary weathering of Fe-rich sedimentary rocks. This study combines a catchment-wide survey of Fe nodule distribution in Poona Creek catchment (Fraser Coast, Queensland) with detailed investigations of a representative ferric soil profile to show that Fe nodules are derived from Fe-rich sandstones. Where these crop out, they are broken down, transported downslope by colluvial processes, and redeposited. Chemical and physical weathering transforms these eroded rock fragments into non-magnetic Fe nodules. Major features of this transformation include lower hematite/goethite and kaolinite/gibbsite ratios, increased porosity, etching of quartz grains, and development of rounded morphology and a smooth outer cortex. Iron nodules are commonly concentrated in ferric horizons. We show that these horizons form as the result of differential biological mixing of the soil. Bioturbation gradually buries nodules and rock fragments deposited at the surface of the soil, resulting in a largely nodule-free 'biomantle' over a ferric 'stone line'. Maghemite-rich magnetic nodules are a prominent feature of the upper half of the profile. These are most likely formed by the thermal alteration of non-magnetic nodules located at the top of the profile during severe bushfires. They are subsequently redistributed through the soil profile by bioturbation. Iron nodules occurring in the study area are products of contemporary weathering of Fe-rich rock units. They are not laterite duricrust residues nor are they redox accumulations, although redox-controlled dissolution/re-precipitation is an important component of post-depositional modification of these Fe nodules.

Controls on mid-Holocene fringing reef growth and termination in a high latitude, estuarine setting, Wellington Point, Southeast Queensland

Several fringing coral reefs in Moreton Bay, Southeast Queensland, some 300 km south of the Great Barrier Reef (GBR), are set in a relatively high latitude, estuarine environment that is considered marginal for coral growth. Previous work indicated that these marginal reefs, as with many fringing reefs of the inner GBR, ceased accreting in the mid-Holocene. This research presents for the first time data from the subsurface profile of the mid-Holocene fossil reef at Wellington Point comprising U/Th dates of in situ and framework corals, and trace element analysis from the age constrained carbonate fragments. Based on trace element proxies the palaeo-water quality during reef accretion was reconstructed. Results demonstrate that the reef initiated more than 7,000 yr BP during the post glacial transgression, and the initiation progressed to the west as sea level rose. In situ micro-atolls indicate that sea level was at least 1 m above present mean sea level by 6,680 years ago. The reef remained in "catch-up" mode, with a seaward sloping upper surface, until it stopped aggrading abruptly at ca 6,000 yr BP; no lateral progradation occurred. Changes in sediment composition encountered in the cores suggest that after the laterite substrate was covered by the reef, most of the sediment was produced by the carbonate factory with minimal terrigenous influence. Rare earth element, Y and Ba proxies indicate that water quality during reef accretion was similar to oceanic waters, considered suitable for coral growth. A slight decline in water quality on the basis of increased Ba in the later stages of growth may be related to increased riverine input and partial closing up of the bay due to either tidal delta progradation, climatic change and/or slight sea level fall. The age data suggest that termination of reef growth coincided with a slight lowering of sea level, activation of ENSO and consequent increase in seasonality, lowering of temperatures and the constrictions to oceanic flushing. At the cessation of reef accretion the environmental conditions in the western Moreton Bay were changing from open marine to estuarine. The living coral community appears to be similar to the fossil community, but without the branching Acropora spp. that were more common in the fossil reef. In this marginal setting coral growth periods do not always correspond to periods of reef accretion due to insufficient coral abundance. Due to several environmental constraints modern coral growth is insufficient for reef growth. Based on these findings Moreton Bay may be unsuitable as a long term coral refuge for most species currently living in the GBR.

A Bayesian network approach to modelling temporal behaviour of Lyngbya majuscula bloom initiation

Lyngbya majuscula is a cyanobacterium (blue-green algae) occurring naturally in tropical and subtropical coastal areas worldwide. Deception Bay, in Northern Moreton Bay, Queensland, has a history of Lyngbya blooms, and forms a case study for this investigation. The South East Queensland (SEQ) Healthy Waterways Partnership, collaboration between government, industry, research and the community, was formed to address issues affecting the health of the river catchments and waterways of South East Queensland. The Partnership coordinated the Lyngbya Research and Management Program (2005-2007) which culminated in a Coastal Algal Blooms (CAB) Action Plan for harmful and nuisance algal blooms, such as Lyngbya majuscula. This first phase of the project was predominantly of a scientific nature and also facilitated the collection of additional data to better understand Lyngbya blooms. The second phase of this project, SEQ Healthy Waterways Strategy 2007-2012, is now underway to implement the CAB Action Plan and as such is more management focussed. As part of the first phase of the project, a Science model for the initiation of a Lyngbya bloom was built using Bayesian Networks (BN). The structure of the Science Bayesian Network was built by the Lyngbya Science Working Group (LSWG) which was drawn from diverse disciplines. The BN was then quantified with annual data and expert knowledge. Scenario testing confirmed the expected temporal nature of bloom initiation and it was recommended that the next version of the BN be extended to take this into account. Elicitation for this BN thus occurred at three levels: design, quantification and verification. The first level involved construction of the conceptual model itself, definition of the nodes within the model and identification of sources of information to quantify the nodes. The second level included elicitation of expert opinion and representation of this information in a form suitable for inclusion in the BN. The third and final level concerned the specification of scenarios used to verify the model. The second phase of the project provides the opportunity to update the network with the newly collected detailed data obtained during the previous phase of the project. Specifically the temporal nature of Lyngbya blooms is of interest. Management efforts need to be directed to the most vulnerable periods to bloom initiation in the Bay. To model the temporal aspects of Lyngbya we are using Object Oriented Bayesian networks (OOBN) to create ‘time slices’ for each of the periods of interest during the summer. OOBNs provide a framework to simplify knowledge representation and facilitate reuse of nodes and network fragments. An OOBN is more hierarchical than a traditional BN with any sub-network able to contain other sub-networks. Connectivity between OOBNs is an important feature and allows information flow between the time slices. This study demonstrates more sophisticated use of expert information within Bayesian networks, which combine expert knowledge with data (categorized using expert-defined thresholds) within an expert-defined model structure. Based on the results from the verification process the experts are able to target areas requiring greater precision and those exhibiting temporal behaviour. The time slices incorporate the data for that time period for each of the temporal nodes (instead of using the annual data from the previous static Science BN) and include lag effects to allow the effect from one time slice to flow to the next time slice. We demonstrate a concurrent steady increase in the probability of initiation of a Lyngbya bloom and conclude that the inclusion of temporal aspects in the BN model is consistent with the perceptions of Lyngbya behaviour held by the stakeholders. This extended model provides a more accurate representation of the increased risk of algal blooms in the summer months and show that the opinions elicited to inform a static BN can be readily extended to a dynamic OOBN, providing more comprehensive information for decision makers.

Posttranscriptional gene silencing is not compromised in the Arabidopsis CARPEL FACTORY (DICER-LIKE1) mutant, a homolog of dicer-1 from Drosophila

Posttranscriptional silencing (PTGS) in plants, nematodes, Drosophila, and perhaps all eukaryotes operates by sequence-specific degradation or translational inhibition of the target mRNA. These processes are mediated by duplexed RNA. In Drosophila and nematodes, double-stranded (ds)RNA or self-complementary RNA is processed into fragments of approximately 21 nt by Dicer-1 [1, 2]. These small interfering RNAs (siRNAs) serve as guides to target degradation of homologous single-stranded (ss)RNA [1, 3]. In some cases, the approximately 21 nt guide fragments derived from endogenous, imperfectly self-complementary RNAs cause translational inhibition of their target mRNAs, with which they have substantial, but not perfect sequence complementarity [4-6]. These small temporal RNAs (stRNAs) belong to a class of noncoding microRNAs (miRNAs), 20-24 nt in length, that are found in flies, plants, nematodes, and mammals [4, 6-12]. In nematodes, the Dicer-1 enzyme catalyzes the production of both siRNA and stRNA [2, 13-15]. Mutation of the Arabidopsis Dicer-1 homolog, CARPEL FACTORY (CAF), blocks miRNA production [1, 4, 16-18]. Here, we report that the same caf mutant does not block either PTGS or siRNA production induced by self-complementary hairpin RNA. This suggests either that this mutation only impairs miRNA formation or, more interestingly, that plants have two distinct dicer-like enzymes, one for miRNA and another for siRNAi production.