Macrophage inhibitory cytokine-1 (MIC-1/GDF15) slows cancer development but increases metastases in TRAMP prostate cancer prone mice

Macrophage inhibitory cytokine-1 (MIC-1/GDF15), a divergent member of the TGF-β superfamily, is over-expressed by many common cancers including those of the prostate (PCa) and its expression is linked to cancer outcome. We have evaluated the effect of MIC-1/GDF15 overexpression on PCa development and spread in the TRAMP transgenic model of spontaneous prostate cancer. TRAMP mice were crossed with MIC-1/GDF15 overexpressing mice (MIC-1fms) to produce syngeneic TRAMPfmsmic-1 mice. Survival rate, prostate tumor size, histopathological grades and extent of distant organ metastases were compared. Metastasis of TC1-T5, an androgen independent TRAMP cell line that lacks MIC-1/GDF15 expression, was compared by injecting intravenously into MIC-1fms and syngeneic C57BL/6 mice. Whilst TRAMPfmsmic-1 survived on average 7.4 weeks longer, had significantly smaller genitourinary (GU) tumors and lower PCa histopathological grades than TRAMP mice, more of these mice developed distant organ metastases. Additionally, a higher number of TC1-T5 lung tumor colonies were observed in MIC-1fms mice than syngeneic WT C57BL/6 mice. Our studies strongly suggest that MIC-1/GDF15 has complex actions on tumor behavior: it limits local tumor growth but may with advancing disease, promote metastases. As MIC-1/GDF15 is induced by all cancer treatments and metastasis is the major cause of cancer treatment failure and cancer deaths, these results, if applicable to humans, may have a direct impact on patient care.

The cell surface glycoprotein CUB domain-containing protein 1 (CDCP1) contributes to epidermal growth factor receptor-mediated cell migration

Epidermal growth factor (EGF) activation of the EGF receptor (EGFR) is an important mediator of cell migration, and aberrant signaling via this system promotes a number of malignancies including ovarian cancer. We have identified the cell surface glycoprotein CDCP1 as a key regulator of EGF/EGFR-induced cell migration. We show that signaling via EGF/EGFR induces migration of ovarian cancer Caov3 and OVCA420 cells with concomitant up-regulation of CDCP1 mRNA and protein. Consistent with a role in cell migration CDCP1 relocates from cell-cell junctions to punctate structures on filopodia after activation of EGFR. Significantly, disruption of CDCP1 either by silencing or the use of a function blocking antibody efficiently reduces EGF/EGFR-induced cell migration of Caov3 and OVCA420 cells. We also show that up-regulation of CDCP1 is inhibited by pharmacological agents blocking ERK but not Src signaling, indicating that the RAS/RAF/MEK/ERK pathway is required downstream of EGF/EGFR to induce increased expression of CDCP1. Our immunohistochemical analysis of benign, primary, and metastatic serous epithelial ovarian tumors demonstrates that CDCP1 is expressed during progression of this cancer. These data highlight a novel role for CDCP1 in EGF/EGFR-induced cell migration and indicate that targeting of CDCP1 may be a rational approach to inhibit progression of cancers driven by EGFR signaling including those resistant to anti-EGFR drugs because of activating mutations in the RAS/RAF/MEK/ERK pathway.

The Spartan-3E Tutorial 2 : Introduction to using the PicoBlaze Microcontroller Version 1.0

This tutorial is designed to help new users become familiar with using the PicoBlaze microcontroller with the Spartan-3E board. The tutorial gives a brief introduction to the PicoBlaze microcontroller, and then steps through the following: - Writing a small PicoBlaze assembly language (.psm) file, and stepping through the process of assembling the .psm file using KCPSM3; - Writing a top level VHDL module to connect the PicoBlaze microcontroller (KCPSM3 component) and the program ROM, and to connect the required input and output ports; - Connecting the top level module inputs and outputs to the switches, buttons and LEDs on the Spartan-3E board; - Downloading the program to the Spartan-3E board using the Project Navigator software.

Antenatal ureaplasma infection impairs development of the fetal ovine gut in an IL-1-dependent manner

Ureaplasma infection of the amniotic cavity is associated with adverse postnatal intestinal outcomes. We tested whether interleukin-1 (IL-1) signaling underlies intestinal pathology following ureaplasma exposure in fetal sheep. Pregnant ewes received intra-amniotic injections of ureaplasma or culture media for controls at 3, 7, and 14 d before preterm delivery at 124 d gestation (term 150 d). Intra-amniotic injections of recombinant human interleukin IL-1 receptor antagonist (rhIL-1ra) or saline for controls  were given 3 h before and every 2 d after Ureaplasma injection. Ureaplasma exposure caused fetal gut inflammation within 7 d with damaged villus epithelium and gut barrier loss. Proliferation, differentiation, and maturation of enterocytes were significantly reduced after 7 d of ureaplasma exposure, leading to severe villus atrophy at 14 d. Inflammation, impaired development and villus atrophy of the fetal gut was largely prevented by intra-uterine rhIL-1ra treatment. These data form the basis for a clinical understanding of the role of ureaplasma in postnatal intestinal pathologies.

Krüppel-associated box (KRAB)-associated co-repressor (KAP-1) Ser-473 phosphorylation regulates heterochromatin protein 1 (HP1- ) mobilization and DNA repair in heterochromatin

The DNA damage response encompasses a complex series of signaling pathways that function to regulate and facilitate the repair of damaged DNA. Recent studies have shown that the repair of transcriptionally inactive chromatin, named heterochromatin, is dependent upon the phosphorylation of the co-repressor, Krüppel-associated box (KRAB) domain-associated protein (KAP-1), by the ataxia telangiectasia-mutated (ATM) kinase. Co-repressors, such as KAP-1, function to regulate the rigid structure of heterochromatin by recruiting histone-modifying enzymes, such HDAC1/2, SETDB1, and nucleosome-remodeling complexes such as CHD3. Here, we have characterized a phosphorylation site in the HP1-binding domain of KAP-1, Ser-473, which is phosphorylated by the cell cycle checkpoint kinase Chk2. Expression of a nonphosphorylatable S473A mutant conferred cellular sensitivity to DNA-damaging agents and led to defective repair of DNA double-strand breaks in heterochromatin. In addition, cells expressing S473A also displayed defective mobilization of the HP1-β chromodomain protein. The DNA repair defect observed in cells expressing S473A was alleviated by depletion of HP1-β, suggesting that phosphorylation of KAP-1 on Ser-473 promotes the mobilization of HP1-β from heterochromatin and subsequent DNA repair. These results suggest a novel mechanism of KAP-1-mediated chromatin restructuring via Chk2-regulated HP1-β exchange from heterochromatin, promoting DNA repair.

Motorcycle Safety Research Project Interim Summary Report Research Deliverable 1: Investigate and Develop a Pre-learner Motorcycle Licensing Package

Motorcycle trauma is a serious road safety issue in Queensland and throughout Australia. In 2009, Queensland Transport (later Transport and Main Roads or TMR) appointed CARRS-Q to provide a three-year program of Road Safety Research Services for Motorcycle Rider Safety. Funding for this research originated from the Motor Accident Insurance Commission. This program of research was undertaken to produce knowledge to assist TMR to improve motorcycle safety by further strengthening the licensing and training system to make learner riders safer by developing a pre-learner package (Deliverable 1 which is the focus of this report), and by evaluating the Q-Ride CAP program to ensure that it is maximally effective and contributes to the best possible training for new riders (Deliverable 2), which is the focus of this report. Deliverable 3 of the program identified potential new licensing components that will reduce the incidence of risky riding and improve higher-order cognitive skills in new riders. While fatality and injury rates for learner car drivers are typically lower than for those with intermediate licences, this pattern is not found for learner motorcycle riders. Learner riders cannot be supervised as effectively as learner car drivers and errors are more likely to result in injury for learner riders than learner drivers. It is therefore imperative to improve safety for learner riders. Deliverable 1 examines the potential for improving the motorcycle learner and licence scheme by introducing a pre-learner motorcycle licensing and training scheme within Queensland. The tasks undertaken for Deliverable 1 were a literature review, analysis of learner motorcyclist crash and licensing data, and the development of a potential pre-learner motorcycle rider program.

4-Amino-N-(4,6-dimethylpyrimidin-2-yl)benzenesulfonamide--2-nitrobenzoic acid (1/1)

In the asymmetric unit of the title co-crystal, C12H14N4O2S·C7H5NO4, the sulfamethazine and 2-nitrobenzoic acid molecules form a heterodimer through intermolecular amide-carboxylic acid N-HO and carboxylic acid-pyrimidine O-HN hydrogen-bond pairs, giving a cyclic motif [graph set R22(8)]. The dihedral angle between the two aromatic ring systems in the sulfamethazine molecule is 88.96 (18)° and the nitro group of the acid is 50% rotationally disordered. Secondary aniline N-HOsulfone hydrogen-bonding associations give a two-dimensional structure lying parallel to the ab plane.

The effect of Yb addition in bi2sr2ca 1-xybxcu2oy partial melted thick films

To study the phase relations in the Bi-2212 and Yb2O3 system, Bi2Sr2Ca1-xYbxCu 2Oy thick films are prepared by partial melt processing via an intermediate reaction between Bi-2212 and Yb2O3. When Bi-2212 and Yb2O3 are partially melted and then slowly cooled, solid solutions of Bi2Sr2Ca 1-xYbxCu2Oy, form by reactions between liquid and solid phases which contain Yb. Following these reactions, Ca is partially replaced in Bi-2212 matrix and participates in the formation of secondary phases, such as Bi-free, (Ca, Sr)Ox and CaO. Variation of the Bi-2212-Yb2O3 ratios and processing parameters changes the balance between the phases and leads to different Yb:Ca ratios in the Bi-2212 matrix of processed thick films. When the partial melting process is optimized for each sample to minimize the growth of secondary phases, x = 0.42-0.46 for the samples prepared at pO2 = 0.01 atm, x = 0.24-0.29 for the samples prepared at pO2 = 0.21 atm, x = 0.18-0.23 for the samples prepared at pO2 = 0.99 atm are obtained regardless to the starting compositions. It is found that superconducting properties of Bi 2Sr2Ca1-xYbxCu2O y thick films strongly depend on the processing conditions, because the conditions result in different Yb content in the Bi-2212 matrix and the volume fraction of the secondary phases. The highest Tc(0) of 77, 90 and 91 K were obtained for the samples processed at 0.01, 0.21 and 0.99 atm of O2, respectively.

Slid pairs in the initialisation of the A5/1 stream cipher

A5/1 is a shift register based stream cipher which uses a majority clocking rule to update its registers. It is designed to provide privacy for the GSM system. In this paper, we analyse the initialisation process of A5/1. We demonstrate a sliding property of the A5/1 cipher, where every valid internal state is also a legitimate loaded state and multiple key-IV pairs produce phase shifted keystream sequences. We describe a possible ciphertext only attack based on this property.

Anatomical MR imaging of long bones : comparative performance of MRI at 1.5 T and 3 T

The current gold standard for the design of orthopaedic implants is 3D models of long bones obtained using computed tomography (CT). However, high-resolution CT imaging involves high radiation exposure, which limits its use in healthy human volunteers. Magnetic resonance imaging (MRI) is an attractive alternative for the scanning of healthy human volunteers for research purposes. Current limitations of MRI include difficulties of tissue segmentation within joints and long scanning times. In this work, we explore the possibility of overcoming these limitations through the use of MRI scanners operating at a higher field strength. We quantitatively compare the quality of anatomical MR images of long bones obtained at 1.5 T and 3 T and optimise the scanning protocol of 3 T MRI. FLASH images of the right leg of five human volunteers acquired at 1.5 T and 3 T were compared in terms of signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR). The comparison showed a relatively high CNR and SNR at 3 T for most regions of the femur and tibia, with the exception of the distal diaphyseal region of the femur and the mid diaphyseal region of the tibia. This was accompanied by an ~65% increase in the longitudinal spin relaxation time (T1) of the muscle at 3 T compared to 1.5 T. The results suggest that MRI at 3 T may be able to enhance the segmentability and potentially improve the accuracy of 3D anatomical models of long bones, compared to 1.5 T. We discuss how the total imaging times at 3 T can be kept short while maximising the CNR and SNR of the images obtained.

The Spartan-3E tutorial 3 : using the LCD display [version 1.0]

This tutorial is designed to assist users who wish to use the LCD screen on the Spartan-3E board. In this tutorial, the PicoBlaze microcontroller is used to control the LCD. The tutorial is organised into three Parts. In Part A, code is written to display the message "Hello World" on the LCD. Part B demonstrates how to define and display custom characters. Finally, Part C shows how the display can be shifted and flashed. Shifting is done by using a delay in the main PicoBlaze program loop, while flashing is done using the PicoBlaze interrupt. The slider switches can be used to select the shifting direction, and to turn shifting and flashing on and off.

Debts “incurred” by receivers, administrators and liquidators : the case for a harmonised construction of ss 419, 443A and 556(1)(a) of the Corporations Act

This article analyses the inconsistent approaches taken by courts when interpreting provisions of the Corporations Act which address debts or expenses “incurred” by receivers, administrators and liquidators. The article contends for a consistent construction of these provisions which will enable the legislation to operate (as was intended) for the benefit of persons who supply goods, services or labour to companies in external administration. The article explains how and why debts can be “incurred” by insolvency practitioners continuing on pre-existing contracts. Specifically, the article contends for a construction of ss 419 and 443A of the Corporations Act which renders receivers and administrators personally liable for certain entitlements of employees (eg, wages and superannuation contributions) which become due and payable by reason of the decision of a receiver or administrator to continue a pre-existing contract rather than terminate it.

Logan Basin Water Resource Plan : environmental assessment of the southern Moreton Bay islands. Technical Advisory Panel Report: Stage 1.

This report is a technical assessment of the hydrological environment of the southern Moreton Bay islands and follows the terms of reference supplied by the then Queensland Department of Natural Resources and Water. The terms of reference describe stage 1 as a condition assessment and stage 2 as an assessment of the implications of water planning scenarios on future condition. This report is the first stage of a two-stage investigation whose primary purpose is to identify and assess groundwater dependent ecosystems (GDEs) and the groundwater flow regimes necessary to support them. Within this context, the groundwaters themselves are also considered and comment made on their condition. Information provided in this report will inform an amendment to the Logan Basin Water Resource Plan to incorporate the southern Moreton Bay islands. The study area is the water resource plan amendment area, which includes North and South Stradbroke islands and the smaller islands between these and the mainland, including the inhabited smaller rocky islands—namely, Macleay, Russell, Karragarra, Lamb and Coochiemudlo islands. This assessment is largely a desktop study based on existing information, but incorporates some field observations, input from experts in specific areas and community representatives, and the professional experience and knowledge of the authors. This report reviews existing research and information on the southern Moreton Bay area with an emphasis on North Stradbroke Island, as it represents the largest and most regionally significant groundwater resource in southern Moreton Bay. The report provides an assessment of key waterrelated environmental features, their condition and their degree of dependence on groundwater. This report also assesses the condition and status of ecosystems within this region. In addition, the report identifies information gaps, uncertainties and potential impacts; reviews groundwater models that have been developed for North Stradbroke Island; and makes recommendations on monitoring and research needs.

2-(4-Aminobenzenesulfonamido)-4,6-dimetylpyrimidin-1-ium 2-carboxy-4,6-dinitrophenolate

In the structure of the of the phenolate salt of the sulfa drug sulfamethazine with 3,5-dinitrosalicylic acid, C12H15N4O2S+ C7H3N2O7-, the dihedral angle between the pyrimidine and phenyl rings of the cation is 59.70(17)\%. Cation--anion hydrogen-bonding interactions involving pyrimidine N+-H...O(carboxyl) and amine N-H...O(carboxyl) pairs give a cyclic R2/2(8) motif while secondary N-H...O hydrogen bonds between the aniline group and both sulfone and nitro O-atom acceptors give a two-dimensional structure extending along (001).