Exploring the biophysical evidence that mammalian two pore channels are NAADP-activated calcium-permeable channels

Nicotinic acid adenine dinucleotide phosphate (NAADP) potently releases Ca2+ from acidic intracellular endo-lysosomal Ca2+-stores. It is widely accepted that two types of two pore channels, termed TPC1 and TPC2, are responsible for the NAADP-mediated Ca2+-release but the underlying mechanisms regulating their gating appear to be different. For example, although both TPC1 and TPC2 are activated by NAADP, TPC1 appears to be additionally regulated by cytosolic Ca2+. Ion conduction and permeability also differ markedly. TPC1 and TPC2 are permeable to a range of cations although biophysical experiments suggest that TPC2 is slightly more selective for Ca2+ over K+ than TPC1 and hence capable of releasing greater quantities of Ca2+ from acidic stores. TPC1 is also permeable to H+ and therefore may play a role in regulating lysosomal and cytosolic pH, possibly creating localised acidic domains. The significantly different gating and ion conducting properties of TPC1 and TPC2 suggest that these two ion channels may play complementary physiological roles as Ca2+ release channels of the endo-lysosomal system.PostprintPeer reviewe

Social justice in education in \u27new times\u27

This thesis considers social justice in education in ‘new times’. To facilitate the investigation a number of research questions were pursued. These questions were: • What is meant by the label ‘social justice’? • How is social justice to be understood in contemporary terms? • Are there tensions between traditional and contemporary views of social justice? • How effective are policy developments in delivering social justice via education? • What difference do such policies make at the local level? To answer these questions a critical case analysis of a country community and one of its primary schools was carried out. Data were gathered using a variety of methods. As a researcher who was also a teacher in the school I kept a personal professional journal during 1993 and 1994. During this period I was the teacher in the school with responsibility for curriculum development related to issues of social justice. In 1994 I conducted interviews with twenty students, parents and teachers at the school in relation to social justice issues. I also interviewed the CEO of the town’s Council. A number of relevant Federal and State Government and school policy documents were consulted and an archival search of the local newspaper from 1956 to 1994 was undertaken. Statistical information from the Australian Bureau of Statistics as well as from school records was used. A number of local history books were consulted as well as the minutes of relevant school committee meetings. Contemporary social theory, more specifically the work of Anthony Giddens, provided the major methodological tool. Giddens structuration theory was selected as it provided a way of interpreting society from both macro and micro perspectives, it provided a way of studying the interconnectedness of the individual and society. In addition to this, a metaphor was used as a way of developing an understanding of the data. The river was chosen as the metaphor as it has significance to the case study community and it also provides a way of understanding interconnectedness. At an interpretive level, both social theory and moral philosophy were drawn on, including the work of Geoffrey Sharp, Anthony Giddens and Alisdair MacIntyre. A review of selected literature indicated three main areas of concern in relation to this thesis. We live in a time of constant and ongoing change, understanding how this change impacts on the lives of individuals and society is important. Such an understanding relates directly to issues of ontology. In addition it was necessary to consider schools in these ‘new times’. The literature revealed that the changes occurring in the wider society were related to the changes currently being seen in schools. Specifically this related to the increasing emphasis on economics and on individualism, emphases also reflected in the findings of this thesis. Finally the literature related to social justice was discussed, the focus here was on distributive theories of justice and the way these are reflected in programs such as the DSP. The data, as expressed in the metaphor of the flowing river, revealed dominant and marginal currents in social justice in education in ‘new times’. The dominant social group are the intellectually trained and the dominant issues were related to technology, globalisation and economic and bureaucratic rationalism. In the marginal currents we find the under-employed and the unemployed and marginal issues relating to housing, the black economy, poverty and the survival of rural communities. The data also revealed a marginal tributary running into the river. This tributary shows that social cohesion is still a part of life in ‘new times’, albeit a marginalised part. The dominant and marginal currents in social justice in ‘new times’ reveal changes at a deep cultural level. Social justice in ‘new times’ is set within the limits provided by economic rationalism. Such a position is closely linked to the rise of liberal democracy as a political ideology. A rise which has been on a global scale. This valorizes the individual as compared with the group, and the family as compared to the social whole, within the context of expanded economic groupings and markets. Such an ideological position sees the role of the state as providing the ‘legitimising muscle’ to advance the cause of individuals and their families as compared to larger social groupings. These perceptions were applied in Australia, even under a Labor Government. In this sense social justice policies in ‘new times’ are ideological, they act as a political lever to legitimate economic restructuring. They are policies designed to carry disparate groups forward and together on a common wave of economic reform. They are used to ‘sell’ economic reform as being ‘good’ for all of society. Against the backdrop of economic rationalism and liberal democratic ideals there emerges a language geared to the production of an economically viable self, self image, self identity, self esteem and self confidence. As a result, the sense of identity as ‘social’ is lost from view. This thesis argues that what is needed is a new way of looking at social justice in education. A way that reaches beyond the solutions forwarded by the political Left and the Right. It is about the development of an understanding of the way in which an assimilation of the hyper individual and the social group can result in the emergence of the socially responsible individual. This is a cultural shift that sees the individual/society dualism presented in a new way. The categories enter into a new relationship where the balance shifts away from the individual towards society. A shift to a culture where the individual’s rights and responsibilities are respected within a social whole. Such a cultural shift would result in a curriculum which would build social identity, promoted socially responsible independent thought and make space for creativity and the aesthetic. A ‘curriculum for social responsibility’ would be a socially just curriculum

USE OF PROBIOTICS IN COLORRETAL CANCER INDUCED BY 1,2-DIMETHYLHYDRAZINE IN ANIMAL MODEL: A REVIEW

Colorectal cancer is one of the most frequent in the Brazilian population. The available forms of treatment are associated with a high risk of complications, thus highlighting the need to elaborate new therapeutic strategies. Intake of probiotics may be a viable therapeutical option for the treatment of colorectal cancer. The goal of the present study was to review the use of probiotics in the treatment of colorectal cancer induced by 1,2-dimethylhydrazine in rats. This is a literature review of articles published between 1999 and 2017 in the pubmed database, with the descriptors: "probiotics", "colorectal cancer" and "dimethylhydrazine". Found 23 articles within the search inclusion criteria. The probiotic strains studied showed differences in type, concentration and mode of intervention. The use of probiotics was mostly isolated or associated with prebiotic fibers. The main benefits were: reduction of incidence and size of tumors, modulation of the microbiota in a positive way, better anti-inflammatory response and lower DNA damage. The need for more studies to provide more complete and delineated data, with mixtures of strains and specific amounts, provides more conclusive results on the real benefits of this type of supplementation in colorectal cancer.Keywords - Colorectal Cancer. Probiotics. Dimethylhydrazine. Supplementation

TPC2 is a novel NAADP-sensitive Ca2+ release channel, operating as a dual sensor of luminal pH and Ca2+

Nicotinic acid adenine dinucleotide phosphate (NAADP) is a molecule capable of initiating the release of intracellular Ca2+ required for many essential cellular processes. Recent evidence links two-pore channels (TPCs) with NAADP-induced release of Ca2+ from lysosome-like acidic organelles; however, there has been no direct demonstration that TPCs can act as NAADP-sensitive Ca2+-release channels. Controversial evidence also proposes ryanodine receptors as the primary target of NAADP. We show that TPC2, the major lysosomal targeted isoform, is a cation channel with selectivity for Ca2+ that will enable it to act as a Ca2+ release channel in the cellular environment. NAADP opens TPC2 channels in a concentration-dependent manner, binding to high affinity activation and low affinity inhibition sites. At the core of this process is the luminal environment of the channel. The sensitivity of TPC2 to NAADP is steeply dependent on the luminal [Ca2+] allowing extremely low levels of NAADP to open the channel. In parallel, luminal pH controls NAADP affinity for TPC2 by switching from reversible activation of TPC2 at low pH to irreversible activation at neutral pH. Further evidence earmarking TPCs as the likely pathway for NAADP-induced intracellular Ca2+ release is obtained from the use of Ned-19, the selective blocker of cellular NAADP-induced Ca2+ release. Ned-19 antagonizes NAADP-activation of TPC2 in a non-competitive manner at 1 μM but potentiates NAADP activation at nanomolar concentrations. This single-channel study provides a long awaited molecular basis for the peculiar mechanistic features of NAADP signaling and a framework for understanding how NAADP can mediate key physiological events.Publisher PDFPeer reviewe

A high fat diet induces sex-specific differences in hepatic lipid metabolism and nitrite/nitrate in rats

This work is supported by the grants No.173033 and III41028 from the Ministry of Science, Republic of Serbia.Men and women differ substantially in regard to the severity of insulin resistance (IR) but the underlying mechanism(s) of how this occurs is poorly characterized. We investigated whether a high fat (HF) diet resulted in sex-specific differences in nitrite/nitrate production and lipid metabolism and whether these variances may contribute to altered obesity-induced IR. Male and female Wistar rats were fed a standard laboratory diet or a HF diet for 10 weeks. The level of plasma nitrite/nitrate, as well as free fatty acid (FFA), in both plasma and liver lysates were assessed. The levels of inducible nitric oxide (NO) synthase (iNOS), p65 subunit of NFκB, total and phosphorylated forms of Akt, mTOR and PDK-1 in lysates, and the levels of glucose transporter 2 (Glut-2) and fatty acid translocase/cluster of differentiation 36 (FAT/CD36) in plasma membrane fractions of liver were assessed. HF-fed male rats exhibited a significant increase in plasma nitrite/nitrate, and hepatic FFA and FAT/CD36 levels compared with controls. They also displayed a relative decrease in iNOS and Glut-2 levels in the liver. Phosphorylation of Akt (at Ser473 and Thr308), mTOR and PDK-1 was also reduced. HF-fed female rats exhibited increased levels of NFκB-p65 in liver compared with controls, while levels of Glut-2, FAT/CD36 and Akt phosphorylation at Thr308 and PDK-1 were decreased. Our results reveal that altered lipid and glucose metabolism in obesity, lead to altered iNOS expression and nitrite/nitrate production. It is likely that this mechanism contributes to sex-specific differences in the development of IR.PostprintPeer reviewe

Food for life: A social return on investment analysis of the locally commissioned programme. Full Report

A Social Return on Investment Analysis of two locally commissioned Food for Life programme

Evaluation of Food for Life 2013-15: Summary and synthesis report

This is the final report of the phase two evaluation of Food for Life undertaken by the University of the West of England, Bristol 2013-15. The research encompassed five workstreams: 1.Long term impacts and durability - understanding how and why the Food for Life approach is embedded in schools for the medium to long-term. 2.Review of local commissions - understanding strategic support for Food for Life, and recommending monitoring and evaluation systems.3.Cross sectional study of pupils’ diets in Food for Life local commissions - evaluating Food for Life’s impact on healthy eating behaviours in schools in local commission areas. 4.New settings - exploring innovative approaches to extending the Food for Life whole setting approach beyond schools.5.Social value of Food for Life in local authority commissions – understanding the social, health, economic and environmental value of Food for Life commissions. The report presents summaries of the findings of each workstream, discusses themes emerging across the research, and sets out recommendations for Food for Life and associated evaluation activity

Armillaria mellea na maslini i nove perspektive u zaštiti od truleži korijena

Gljiva Armillari amellea uzročnik je truleži korijena mnogih voćnih vrsta i vinove loze. Tijekom posljednjih nekoliko godina zabilježena je češća pojava gljive A. mellea na maslini u Hrvatskoj. Bolest uzrokuje odumiranje stabala i u pojedinim slučajevima može se smatrati ekonomski značajnom. U članku su ukratko opisani simptomi bolesti te mogućnosti zaštite masline od A. mellea otkopavanjem korijena i primjenom bioloških sredstava na osnovi Trichoderma vrsta.Basidiomycete fungus Armillaria mellea is the causal agent of root rot on many fruit species and on grapevine. Several outbreaks of A. mella on olive have been recorded in Croatia during the last few years. A. mellea causes decline and mortality of olive trees and can be regarded as economically important in particular cases.Armillaria root rot symptoms on olive and the possibility of disease management with root collar excavation or with Trichoderma‐based biological products are briefly described in the article

Aspergillus Genomes and the Aspergillus Cloud

Aspergillus Genomes is a public resource for viewing annotated genes predicted by various Aspergillus sequencing projects. It has arisen from the union of two significant resources: the Aspergillus/Aspergillosis website and the Central Aspergillus Data REpository (CADRE). The former has primarily served the medical community, providing information about Aspergillus and associated diseases to medics, patients and scientists; the latter has focused on the fungal genomic community, providing a central repository for sequences and annotation extracted from Aspergillus Genomes. By merging these databases, genomes benefit from extensive cross-linking with medical information to create a unique resource, spanning genomics and clinical aspects of the genus. Aspergillus Genomes is accessible from http://www.aspergillus-genomes.org.uk