A central role for heme iron in colon carcinogenesis associated with red meat intake

Epidemiology shows that red and processed meat intake is associated with an increased risk of colorectal cancer. Heme iron, heterocyclic amines and endogenous N-nitroso compounds (NOC) are proposed to explain this effect, but their relative contribution is unknown. Our study aimed at determining, at nutritional doses, which is the main factor involved and proposing a mechanism of cancer promotion by red meat. The relative part of heme iron (1% in diet), heterocyclic amines (PhIP+MeIQx, 50+25 μg/kg in diet) and NOC (induced by NaNO2+NaNO3 0.17+0.23 g/l of drinking water) was determined by a factorial design and preneoplastic endpoints in chemically-induced rats and validated on tumors in Min mice. The molecular mechanisms (genotoxicity, cytotoxicity) were analyzed in vitro in normal and Apc- deficient cell lines and confirmed on colon mucosa. Heme iron increased the number of preneoplastic lesions but dietary heterocyclic amines and NOC had no effect on carcinogenesis in rats. Dietary hemoglobin increased tumor load in Min mice (control diet: 67±39 mm2; 2,5% hemoglobin diet: 114±47 mm2, p=0.004). In vitro, fecal water from rats given hemoglobin was rich in aldehydes and was cytotoxic to normal cells, but not to premalignant cells. The aldehydes 4-hydroxynonenal and 4-hydroxyhexenal were more toxic to normal versus mutated cells and were only genotoxic to normal cells. Genotoxicity was also observed in colon mucosa of mice given hemoglobin. These results highlight the role of heme iron in the promotion of colon cancer by red meat and suggest that heme iron could initiate carcinogenesis through lipid peroxidation.

Real estate and social inequality in Latin America: approaches in Argentina, Brazil, Chile and Colombia

Latin America is known as the most unequal region in the world, where extreme displays of wealth and exposure to scarcity lay bare in the urban landscape. Inequality is not just a social issue; it has considerable impact on economic development. This is because social inequality generates instability and conflict, which can create unsettling conditions for investment. At the macro level, social inequality can also present barriers to economic development, as most government policies and resources tend to be directed in solving social conflict rather than to promote and generate growth. This is one of the reasons usually cited in explaining the development gap between Latin America and other emerging economies, take East Asia for example - they have similar policies to those applied recently in Latin America, but are achieving better growth. The other reason cited is institutional; this includes governance as well as property rights and enforcement of contracts. The latter is the focus of this chapter.

Symmorphosis through dietary regulation: a combinatorial role for proteolysis, autophagy and protein synthesis in normalising muscle metabolism and function of hypertrophic mice after acute starvation

Animals are imbued with adaptive mechanisms spanning from the tissue/organ to the cellular scale which insure that processes of homeostasis are preserved in the landscape of size change. However we and others have postulated that the degree of adaptation is limited and that once outside the normal levels of size fluctuations, cells and tissues function in an aberant manner. In this study we examine the function of muscle in the myostatin null mouse which is an excellent model for hypertrophy beyond levels of normal growth and consequeces of acute starvation to restore mass. We show that muscle growth is sustained through protein synthesis driven by Serum/Glucocorticoid Kinase 1 (SGK1) rather than Akt1. Furthermore our metabonomic profiling of hypertrophic muscle shows that carbon from nutrient sources is being channelled for the production of biomass rather than ATP production. However the muscle displays elevated levels of autophagy and decreased levels of muscle tension. We demonstrate the myostatin null muscle is acutely sensitive to changes in diet and activates both the proteolytic and autophagy programmes and shutting down protein synthesis more extensively than is the case for wild-types. Poignantly we show that acute starvation which is detrimental to wild-type animals is beneficial in terms of metabolism and muscle function in the myostatin null mice by normalising tension production.

Deforestation, leakage and avoided deforestation policies: a spatial analysis

This paper analyses the impact of several avoided deforestation policies within a patchy forested landscape. Central is the idea that deforestation choices in one area influence deforestation decisions in nearby patches. We explore the interplay between forest landscapes comprising heterogeneous patches, localised spatial displacement, and avoided deforestation policies. Avoided deforestation policies at a landscape level are respectively: two Payments for Environmental Services (PES) policies, one focused on deforestation hotspots, the second being equally available to all agents; a conservation area; and, an agglomeration bonus. We demonstrate how the "best" policy, in terms of reduced leakage, depends on landscape heterogeneity. Agglomeration bonuses are shown to be more effective where there is less landscape heterogeneity, whilst conservation areas are most effective where there is more spatial heterogeneity.

A global proteomics approach identifies novel phosphorylated signaling proteins in GPVI-activated platelets: involvement of G6f, a novel platelet Grb2-binding membrane adapter.

Collagen-related peptide (CRP) stimulates powerful activation of platelets through the glycoprotein VI (GPVI)-FcR gamma-chain complex. We have combined proteomics and traditional biochemistry approaches to study the proteome of CRP-activated platelets, focusing in detail on tyrosine phosphorylation. In two separate approaches, phosphotyrosine immunoprecipitations followed by 1-D-PAGE, and 2-DE, were used for protein separation. Proteins were identified by MS. By following these approaches, 96 proteins were found to undergo PTM in response to CRP in human platelets, including 11 novel platelet proteins such as Dok-1, SPIN90, osteoclast stimulating factor 1, and beta-Pix. Interestingly, the type I transmembrane protein G6f was found to be specifically phosphorylated on Tyr-281 in response to platelet activation by CRP, providing a docking site for the adapter Grb2. G6f tyrosine phoshporylation was also found to take place in response to collagen, although not in response to the G protein-coupled receptor agonists, thrombin and ADP. Further, we also demonstrate for the first time that Grb2 and its homolog Gads are tyrosine-phosphorylated in CRP-stimulated platelets. This study provides new insights into the mechanism of platelet activation through the GPVI collagen receptor, helping to build the basis for the development of new drug targets for thrombotic disease.

New use of global warming potentials to compare cumulative and short-lived climate pollutants

Parties to the United Nations Framework Convention on Climate Change (UNFCCC) have requested guidance on common greenhouse gas metrics in accounting for Nationally determined contributions (NDCs) to emission reductions1. Metric choice can affect the relative emphasis placed on reductions of ‘cumulative climate pollutants’ such as carbon dioxide versus ‘short-lived climate pollutants’ (SLCPs), including methane and black carbon2, 3, 4, 5, 6. Here we show that the widely used 100-year global warming potential (GWP100) effectively measures the relative impact of both cumulative pollutants and SLCPs on realized warming 20–40 years after the time of emission. If the overall goal of climate policy is to limit peak warming, GWP100 therefore overstates the importance of current SLCP emissions unless stringent and immediate reductions of all climate pollutants result in temperatures nearing their peak soon after mid-century7, 8, 9, 10, which may be necessary to limit warming to “well below 2 °C” (ref. 1). The GWP100 can be used to approximately equate a one-off pulse emission of a cumulative pollutant and an indefinitely sustained change in the rate of emission of an SLCP11, 12, 13. The climate implications of traditional CO2-equivalent targets are ambiguous unless contributions from cumulative pollutants and SLCPs are specified separately.

Discovering biomarkers for antidepressant response: protocol from the Canadian biomarker integration network in depression (CAN-BIND) and clinical characteristics of the first patient cohort

Background Major Depressive Disorder (MDD) is among the most prevalent and disabling medical conditions worldwide. Identification of clinical and biological markers (“biomarkers”) of treatment response could personalize clinical decisions and lead to better outcomes. This paper describes the aims, design, and methods of a discovery study of biomarkers in antidepressant treatment response, conducted by the Canadian Biomarker Integration Network in Depression (CAN-BIND). The CAN-BIND research program investigates and identifies biomarkers that help to predict outcomes in patients with MDD treated with antidepressant medication. The primary objective of this initial study (known as CAN-BIND-1) is to identify individual and integrated neuroimaging, electrophysiological, molecular, and clinical predictors of response to sequential antidepressant monotherapy and adjunctive therapy in MDD. Methods CAN-BIND-1 is a multisite initiative involving 6 academic health centres working collaboratively with other universities and research centres. In the 16-week protocol, patients with MDD are treated with a first-line antidepressant (escitalopram 10–20 mg/d) that, if clinically warranted after eight weeks, is augmented with an evidence-based, add-on medication (aripiprazole 2–10 mg/d). Comprehensive datasets are obtained using clinical rating scales; behavioural, dimensional, and functioning/quality of life measures; neurocognitive testing; genomic, genetic, and proteomic profiling from blood samples; combined structural and functional magnetic resonance imaging; and electroencephalography. De-identified data from all sites are aggregated within a secure neuroinformatics platform for data integration, management, storage, and analyses. Statistical analyses will include multivariate and machine-learning techniques to identify predictors, moderators, and mediators of treatment response. Discussion From June 2013 to February 2015, a cohort of 134 participants (85 outpatients with MDD and 49 healthy participants) has been evaluated at baseline. The clinical characteristics of this cohort are similar to other studies of MDD. Recruitment at all sites is ongoing to a target sample of 290 participants. CAN-BIND will identify biomarkers of treatment response in MDD through extensive clinical, molecular, and imaging assessments, in order to improve treatment practice and clinical outcomes. It will also create an innovative, robust platform and database for future research.

The extreme physical properties of the CoRoT-7b super-Earth

The search for rocky exoplanets plays an important role in our quest for extra-terrestrial life. Here, we discuss the extreme physical properties possible for the first characterised rocky super-Earth, CoRoT-7b (R(pl) = 1.58 +/- 0.10 R(Earth), M(pl) = 6.9 +/- 1.2 M(Earth)). It is extremely close to its star (a = 0.0171 AU = 4.48 R(st)), with its spin and orbital rotation likely synchronised. The comparison of its location in the (M(pl), R(pl)) plane with the predictions of planetary models for different compositions points to an Earth-like composition, even if the error bars of the measured quantities and the partial degeneracy of the models prevent a definitive conclusion. The proximity to its star provides an additional constraint on the model. It implies a high extreme-UV flux and particle wind, and the corresponding efficient erosion of the planetary atmosphere especially for volatile species including water. Consequently, we make the working hypothesis that the planet is rocky with no volatiles in its atmosphere, and derive the physical properties that result. As a consequence, the atmosphere is made of rocky vapours with a very low pressure (P <= 1.5 Pa), no cloud can be sustained, and no thermalisation of the planet is expected. The dayside is very hot (2474 +/- 71 K at the sub-stellar point) while the nightside is very cold (50-75 K). The sub-stellar point is as hot as the tungsten filament of an incandescent bulb, resulting in the melting and distillation of silicate rocks and the formation of a lava ocean. These possible features of CoRoT-7b could be common to many small and hot planets, including the recently discovered Kepler-10b. They define a new class of objects that we propose to name ""Lava-ocean planets"". (C) 2011 Elsevier Inc. All rights reserved.

Recurrent Deletion of ZNF630 at Xp11.23 Is Not Associated With Mental Retardation

ZNF630 is a member of the primate-specific Xp11 zinc finger gene cluster that consists of six closely related genes, of which ZNF41, ZNF81, and ZNF674 have been shown to be involved in mental retardation. This suggests that mutations of ZNF630 might influence cognitive function. Here, we detected 12 ZNF630 deletions in a total of 1,562 male patients with mental retardation from Brazil, USA, Australia, and Europe. The breakpoints were analyzed in 10 families, and in all cases they were located within two segmental duplications that share more than 99% sequence identity, indicating that the deletions resulted from non-allelic homologous recombination. In 2,121 healthy male controls, 10 ZNF630 deletions were identified. In total, there was a 1.6-fold higher frequency of this deletion in males with mental retardation as compared to controls, but this increase was not statistically significant (P-value = 0.174). Conversely, a 1.9-fold lower frequency of ZNF630 duplications was observed in patients, which was not significant either (P-value = 0.163). These data do not show that ZNF630 deletions or duplications are associated with mental retardation. (C) 2010 Wiley-Liss, Inc.

Use of Experimental Design for the Optimization of the Production of New Secondary Metabolites by Two Penicillium Species

A fractional factorial design approach has been used to enhance secondary metabolite production by two Penicillium strains. The method was initially used to improve the production of bioactive extracts as a whole and subsequently to optimize the production of particular bioactive metabolites. Enhancements of over 500% in secondary metabolite production were observed for both P. oxalicum and P. citrinum. Two new alkaloids, citrinalins A (5) and B (6), were isolated and identified from P. citrinum cultures optimized for production of minor metabolites.

Pyrodysinoic Acid Derivatives from the Marine Sponge Dysidea robusta

Three new nitrogen-containing terpenes related to pyrodysinoic acid (1) have been isolated from the sponge Dysidea robusta collected in Brazil. Isopyrodysinoic acid (2), 13-hydroxyisopyrodysinoic acid (3), and pyrodysinoic acid B (4) were obtained from the crude extract of D. robusta and identified by analysis of spectroscopic data. Pyrodysinoic acid B (4) is the first furodysin or furodysinin sesquiterpene derivative with a trans junction between the two six-membered rings of the 1,2,3,4,4a,7,8,8a-octahydro-1,1,6-trimethylnaphthalene moiety.

One career, two identities : an assessment of gay men`s career trajectory

Most of the research on career development of sexual minorities focuses on lesbians. Gay men, on the other hand, have received little attention in the literature as it is assumed that they face fewer difficulties in career development because they are men. This paper redresses this gap by presenting an analysis of the impact of sexual identity on the career development of gay men, drawing on both a literature review of the literature on sexual identity, gay organizational studies and career development and the results of a recent interview study. In accord with other literature, the study demonstrates that gay men, like other sexual minorities, are confronted with a conflict between personal and career needs, and have to deal with society's expectations and intolerance towards homosexuality. Suggestions are given for research that will lead to a deeper understanding of the career decisions and attitudes of gay men.