Identification and characterization of novel proteolytic interactions of prostate cancer-expressed kallikrein-related peptidases, type II transmembrane serine proteases and matrix metalloproteinases

This study investigated interactions of protein-cleaving enzymes (or proteases) that promote prostate cancer progression. It provides the first evidence of a novel regulatory network of protease activity at the surface of cells. The proteases kallikrein-related peptidases 4 and 14, and matrix metalloproteinases 3 and 9 are cleaved at the cell surface by the cell surface proteases hepsin and TMPRSS2. These cleavage events potentially regulate activation of downstream targets of kallikrein 4 and 14 such as cell surface signalling via the protease-activated receptors (PARs) and cell growth-promoting factors such as hepatocyte-growth factor.

Fatal consequences: An analysis of the failed employee voice system at the Bundaberg Hospital

In this paper we discuss the failure of the employee voice system at the Bundaberg Base Hospital (BBH) in Australia. Surgeon Jayant Patel was arrested over the deaths of patients on whom he operated when he was the director of surgery at the hospital. Our interest is in the reasons the established employee voice mechanisms failed when employees attempted to bring serious issues to the attention of managers. Our data is based on an analysis of the sworn testimonies of participants who participated in two inquiries concerning these events. An analysis of the events with a particular focus on the failings of the voice system is presented. We ask the following: how and why did the voice systems in the case of the BBH fail?

Identification of a BRCA1-mRNA splicing complex required for efficient DNA repair and maintenance of genomic stability

Mutations within BRCA1 predispose carriers to a high risk of breast and ovarian cancers. BRCA1 functions to maintain genomic stability through the assembly of multiple protein complexes involved in DNA repair, cell-cycle arrest, and transcriptional regulation. Here, we report the identification of a DNA damage-induced BRCA1 protein complex containing BCLAF1 and other key components of the mRNA-splicing machinery. In response to DNA damage, this complex regulates pre-mRNA splicing of a number of genes involved in DNA damage signaling and repair, thereby promoting the stability of these transcripts/proteins. Further, we show that abrogation of this complex results in sensitivity to DNA damage, defective DNA repair, and genomic instability. Interestingly, mutations in a number of proteins found within this complex have been identified in numerous cancer types. These data suggest that regulation of splicing by the BRCA1-mRNA splicing complex plays an important role in the cellular response to DNA damage.

Global, regional, and national comparative risk assessment of 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks in 188 countries, 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013

Background The Global Burden of Disease, Injuries, and Risk Factor study 2013 (GBD 2013) is the first of a series of annual updates of the GBD. Risk factor quantification, particularly of modifiable risk factors, can help to identify emerging threats to population health and opportunities for prevention. The GBD 2013 provides a timely opportunity to update the comparative risk assessment with new data for exposure, relative risks, and evidence on the appropriate counterfactual risk distribution. Methods Attributable deaths, years of life lost, years lived with disability, and disability-adjusted life-years (DALYs) have been estimated for 79 risks or clusters of risks using the GBD 2010 methods. Risk–outcome pairs meeting explicit evidence criteria were assessed for 188 countries for the period 1990–2013 by age and sex using three inputs: risk exposure, relative risks, and the theoretical minimum risk exposure level (TMREL). Risks are organised into a hierarchy with blocks of behavioural, environmental and occupational, and metabolic risks at the first level of the hierarchy. The next level in the hierarchy includes nine clusters of related risks and two individual risks, with more detail provided at levels 3 and 4 of the hierarchy. Compared with GBD 2010, six new risk factors have been added: handwashing practices, occupational exposure to trichloroethylene, childhood wasting, childhood stunting, unsafe sex, and low glomerular filtration rate. For most risks, data for exposure were synthesised with a Bayesian meta-regression method, DisMod-MR 2.0, or spatial-temporal Gaussian process regression. Relative risks were based on meta-regressions of published cohort and intervention studies. Attributable burden for clusters of risks and all risks combined took into account evidence on the mediation of some risks such as high body-mass index (BMI) through other risks such as high systolic blood pressure and high cholesterol. Findings All risks combined account for 57·2% (95% uncertainty interval [UI] 55·8–58·5) of deaths and 41·6% (40·1–43·0) of DALYs. Risks quantified account for 87·9% (86·5–89·3) of cardiovascular disease DALYs, ranging to a low of 0% for neonatal disorders and neglected tropical diseases and malaria. In terms of global DALYs in 2013, six risks or clusters of risks each caused more than 5% of DALYs: dietary risks accounting for 11·3 million deaths and 241·4 million DALYs, high systolic blood pressure for 10·4 million deaths and 208·1 million DALYs, child and maternal malnutrition for 1·7 million deaths and 176·9 million DALYs, tobacco smoke for 6·1 million deaths and 143·5 million DALYs, air pollution for 5·5 million deaths and 141·5 million DALYs, and high BMI for 4·4 million deaths and 134·0 million DALYs. Risk factor patterns vary across regions and countries and with time. In sub-Saharan Africa, the leading risk factors are child and maternal malnutrition, unsafe sex, and unsafe water, sanitation, and handwashing. In women, in nearly all countries in the Americas, north Africa, and the Middle East, and in many other high-income countries, high BMI is the leading risk factor, with high systolic blood pressure as the leading risk in most of Central and Eastern Europe and south and east Asia. For men, high systolic blood pressure or tobacco use are the leading risks in nearly all high-income countries, in north Africa and the Middle East, Europe, and Asia. For men and women, unsafe sex is the leading risk in a corridor from Kenya to South Africa. Interpretation Behavioural, environmental and occupational, and metabolic risks can explain half of global mortality and more than one-third of global DALYs providing many opportunities for prevention. Of the larger risks, the attributable burden of high BMI has increased in the past 23 years. In view of the prominence of behavioural risk factors, behavioural and social science research on interventions for these risks should be strengthened. Many prevention and primary care policy options are available now to act on key risks.

Alloying gold with copper makes for a highly selective visible-light photocatalyst for the reduction of nitroaromatics to anilines

Finely control of product selectivity is an essential issue in organic chemical production. In the synthesis of functionalized anilines via reduction of the corresponding nitroarenes, the challenge is to selectively reduce only the nitro group in the presence of other reducible functional groups in nitroarene molecules at a high reaction rate. Normally, the nitroarene is reduced stepwise through a series of intermediates that remain as byproducts, increasing the aniline synthesis cost. Here we report that alloying small amounts of copper into gold nanoparticles can alter the reaction pathway of the catalytic reduction under visible-light irradiation at ambient temperature, allowing nitroaromatics to be transformed directly to anilines in a highly selective manner. The reasons for the high efficiency of the photocatalytic reduction under these comparatively benign conditions as well as the light-excited reaction mechanisms are discussed. This photocatalytic process avoids byproducts, exhibits a high reaction rate and excellent substituent tolerance, and can be used for the synthesis of many useful functionalized anilines under environmentally benign conditions. Switching of the reaction pathway simply by tailoring the bimetallic alloy NPs of the photocatalysts is effective for engineering of product chemoselectivity.

Metabolomic and proteomic analysis of breast cancer patient samples suggests that glutamate and 12-HETE in combination with CA15-3 may be useful biomarkers reflecting tumour burden

Evaluation of protein and metabolite expression patterns in blood using mass spectrometry and high-throughput antibody-based screening platforms has potential for the discovery of new biomarkers for managing breast cancer patient treatment. Previously identified blood-based breast cancer biomarkers, including cancer antigen 15.3 (CA15-3) are useful in combination with imaging (computed tomography scans, magnetic resonance imaging, X-rays) and physical examination for monitoring tumour burden in advanced breast cancer patients. However, these biomarkers suffer from insufficient levels of accuracy and with new therapies available for the treatment of breast cancer, there is an urgent need for reliable, non-invasive biomarkers that measure tumour burden with high sensitivity and specificity so as to provide early warning of the need to switch to an alternative treatment. The aim of this study was to identify a biomarker signature of tumour burden using cancer and non-cancer (healthy controls/non-malignant breast disease) patient samples. Results demonstrate that combinations of three candidate biomarkers from Glutamate, 12-Hydroxyeicosatetraenoic acid, Beta-hydroxybutyrate, Factor V and Matrix metalloproteinase-1 with CA15-3, an established biomarker for breast cancer, were found to mirror tumour burden, with AUC values ranging from 0.71 to 0.98 when comparing non-malignant breast disease to the different stages of breast cancer. Further validation of these biomarker panels could potentially facilitate the management of breast cancer patients, especially to assess changes in tumour burden in combination with imaging and physical examination.

The mating system of the true fruit fly Bactrocera tryoni and its sister-species, Bactrocera neohumeralis

The frugivorous 'true' fruit fly, Bactrocera tryoni (Queensland fruit fly), is presumed to have a non-resourced-based lek mating system. This is largely untested, and contrary data exists to suggest Bactrocera tryoni may have a resource-based mating system focused on fruiting host plants. We tested the mating system of Bactrocera tryoni, and its close sibling Bactrocera neohumeralis, in large field cages using laboratory reared flies. We used observational experiments that allowed us to determine if: - (i) mating pairs were aggregated or non-aggregated; - (ii) mating system was resource or non-resource based; - (iii) flies utilised possible landmarks (tall trees over short) as mate-rendezvous sites, and; - (iv) males called females from male-dominated leks. We recorded nearly 250 Bactrocera tryoni mating pairs across all experiments, revealing that: - (i) mating pairs were aggregated; - (ii) mating nearly always occurred in tall trees over short; - (iii) mating was non-resource based, and; - (iv) that males and females arrived at the mate-rendezvous site together with no evidence that males preceded females. Bactrocera neohumeralis copulations were much more infrequent (only 30 mating pairs in total), but for those pairs there was a similar preference for tall trees and no evidence of a resource-based mating system. Some aspects of Bactrocera tryoni mating behaviour align with theoretical expectations of a lekking system, but others do not. Until evidence for unequivocal female choice can be provided (as predicted under a true lek), the mating system of Bactrocera tryoni is best described as a non-resource based, aggregation system for which we also have evidence that land-marking may be involved. This article is protected by copyright. All rights reserved.