We are entering an important new chapter in the story of hepatitis C virus (HCV) infection. There are clear challenges and opportunities. On the one hand, new HCV infections are still occurring, and ...an estimated 185 million people are or have previously been infected worldwide. Most HCV-infected persons are unaware of their status yet are at risk for life-threatening diseases such as cirrhosis and hepatocellular carcinoma (HCC), whose incidences are predicted to rise in the coming decade. On the other hand, new HCV infections can be prevented, and those that have already occurred can be detected and treated--viral eradication is even possible. How the story ends will largely be determined by the extent to which these rapidly advancing opportunities overcome the growing challenges and by the vigor of the public health response.
•The phagocyte respiratory burst is driven by both membrane-bound and cytosolic subunits of the phagocyte NADPH oxidase.•It involves the transfer of electrons from NAPDH to molecular oxygen as a ...mechanism to control the replication of microbes.•The phagocyte respiratory burst is essential for host defence to common and serious pathogens.•The respiratory burst is also a key regulator of the immune system. Deficiency of the subunits also leads to autoimmunity.•Biochemical studies and analysis of patients deficient in subunits have driven characterisation of the NADPH oxidase.
When exposed to certain stimuli, phagocytes (including neutrophils, macrophages and eosinophils) undergo marked changes in the way they handle oxygen. Firstly, their rate of oxygen uptake increases greatly. This is accompanied by (i) the production of large amounts of superoxide and hydrogen peroxide and (ii) the metabolism of large quantities of glucose through the hexose monophosphate shunt. We now know that the oxygen used is not for respiration but for the production of powerful microbiocidal agents downstream of the initial production of superoxide. Concomitantly, glucose is oxidised through the hexose monophosphate shunt to re-generate the NADPH that has been consumed through the reduction of molecular oxygen to generate superoxide.
This phagocyte respiratory burst is generated by an NADPH oxidase multi-protein complex that has a catalytic core consisting of membrane-bound gp91phox (CYBB) and p22phox (CYBA) sub-units and cytosolic components p47phox (NCF1), p67phox (NCF2) and p40phox (NCF4). Finally, another cytosolic component, the small G-protein Rac (Rac2 in neutrophils and Rac1 in macrophages) is also required for full activation. The importance of the complex in host defence is underlined by chronic granulomatous disease, a severe life-limiting immunodeficiency caused by mutations in the genes encoding the individual subunits.
In this review, I will discuss the experimental evidence that underlies our knowledge of the respiratory burst, outlining how elegant biochemical analysis, coupled with study of patients deficient in the various subunits has helped elucidate the function of this essential part of innate immunity. I will also discuss some exciting recent studies that shed new light on how the abundance of the various components is controlled. Finally, I will explore the emerging role of reactive oxygen species such as superoxide and hydrogen peroxide in the pathogenesis of major human diseases including auto-inflammatory diseases.
It is often assumed that use of so-called "member checks" improves the credibility of qualitative research. Published literature mentioning member checks was reviewed to identify the purposes and ...procedures for seeking feedback from research participants as well as outcomes reported from member checks. Four themes reflecting underlying assumptions about the purposes of research that have implications for member checks were identified: theory generalisation, representation, participation, and change. Member checks are unlikely to be relevant to research focussed on theory development and generalisation. For other types of research, member checks might be justifiable, but there was little evidence that member checks improved research findings. Member checks can be useful for obtaining participant approval for using quotations or case studies and where anonymity cannot be guaranteed. In evaluation, stakeholder reviews of draft reports can be seen as good research practice. In participatory or collaborative research, ongoing contact might include member checks.
Through excerpts from works of four theologians, this book shows how tenth century Muslims employed Christian doctrines to confirm the correctness of their own theology, and how Christianity had ...stopped attracting serious attention from Muslims as a rival to Islam.
•As climate has always been changing, there is nothing new about climate change to indigenous communities: these communities have coping and adaptation knowledge that has been transmitted from one ...generation to the next.•What is new to them however, are the rates and variabilities of change including the magnitudes of the associated impacts.•This paper suggests that the mode for combining different knowledge systems (i.e., traditional or indigenous and scientific knowledge) is potentially one of the surest ways to successful adaptation.
The implementation of climate change response programmes for adaptation and resilience is anchored on western scientific knowledge. However, this has led to a tendency to marginalise indigenous knowledge as it is considered unimportant in this process (Belfer et al., 2017; Lesperance, 2017; Whitfield et al., 2015). Yet, knowledge systems rarely develop in isolation as they normally tend to cross-fertilize and benefit from each other. In this regard, we think that indigenous knowledge is just as important as scientific knowledge and the two must be integrated through multiple evidence base approach for climate change adaptation and mitigation. In this paper, focussing on African traditional society, we combine oral history with the available literature to examine traditional knowledge and awareness of climate change and related environmental risks. Interesting themes emerge from the knowledge holders themselves and our analysis uncovers a wide range of adaptive coping strategies applied with mixed success. From spotting and reading the position and shape of the ‘new moon’ to the interpretative correctness of its symbolism in “applied traditional climatology,” and from rain-making rituals to conservation of wetlands and forests. Generally, findings seem to suggest that traditional African knowledge of environmental change may be as old as the society itself, with local knowledge transmitted from one generation to the next. Based on the perceived vulnerability of indigenous communities, many scholars tend to argue generically for the integration of indigenous knowledge into climate change policies and implementation (Ross, 2009; Maldonado et al., 2016; Etchart, 2017). In this paper however, we attempt to supplement these arguments by providing specific and contextualised evidence of indigenous knowledge linked to climate change adaptation. It is demonstrated that indigenous knowledge is neither singular nor universal, but rather, a voluminous, diverse and highly localised source of wisdom. We conclude that integration of such unique and specific indigenous knowledge systems into other evidence bases of knowledge, could be one of the best ways to the more effective and sustainable implementation of climate change adaptation strategies among target indigenous communities.
Between 1990 and 2020, our understanding of the significance of arsenic biomethylation changed in remarkable ways. At the beginning of this period, the conversion of inorganic arsenic into mono- and ...di-methylated metabolites was viewed primarily as a process that altered the kinetic behavior of arsenic. By increasing the rate of clearance of arsenic, the formation of methylated metabolites reduced exposure to this toxin; that is, methylation was detoxification. By 2020, it was clear that at least some of the toxic effects associated with As exposure depended on formation of methylated metabolites containing trivalent arsenic. Because the trivalent oxidation state of arsenic is associated with increased potency as a cytotoxin and clastogen, these findings were consistent with methylation-related changes in the dynamic behavior of arsenic. That is, methylation was activation. Our current understanding of the role of methylation as a modifier of kinetic and dynamic behaviors of arsenic is the product of research at molecular, cellular, organismic, and population levels. This information provides a basis for refining our estimates of risk associated with long term exposure to inorganic arsenic in environmental media, food, and water. This report summarizes the growth of our knowledge of enzymatically catalyzed methylation of arsenic over this period and considers the prospects for new discoveries.
We describe the nature of recent (50 year) rainfall variability in the summer rainfall zone, South Africa, and how variability is recognised and responded to on the ground by farmers. Using daily ...rainfall data and self-organising mapping (SOM) we identify 12 internally homogeneous rainfall regions displaying differing parameters of precipitation change. Three regions, characterised by changing onset and timing of rains, rainfall frequencies and intensities, in Limpopo, North West and KwaZulu Natal provinces, were selected to investigate farmer perceptions of, and responses to, rainfall parameter changes. Village and household level analyses demonstrate that the trends and variabilities in precipitation parameters differentiated by the SOM analysis were clearly recognised by people living in the areas in which they occurred. A range of specific coping and adaptation strategies are employed by farmers to respond to climate shifts, some generic across regions and some facilitated by specific local factors. The study has begun to understand the complexity of coping and adaptation, and the factors that influence the decisions that are taken.
When honey bee colonies collapse from high infestations of Varroa mites, neighboring colonies often experience surges in their mite populations. Collapsing colonies, often called "mite bombs", seem ...to pass their mites to neighboring colonies. This can happen by mite-infested workers from the collapsing colonies drifting into the neighboring colonies, or by mite-free workers from the neighboring colonies robbing out the collapsing colonies, or both. To study inter-colony mite transmission, we positioned six nearly mite-free colonies of black-colored bees around a cluster of three mite-laden colonies of yellow-colored bees. We then monitored the movement of bees between the black-bee and yellow-bee colonies before, during, and after mite-induced collapse of the yellow-bee colonies. Throughout the experiment, we monitored each colony's mite level. We found that large numbers of mites spread to the black-bee colonies (in both nearby and distant hives) when the yellow-bee colonies collapsed from high mite infestations and became targets of robbing by the black-bee colonies. We conclude that "robber lures" is a better term than "mite bombs" for describing colonies that are succumbing to high mite loads and are exuding mites to neighboring colonies.
The Hippo pathway and human cancer Harvey, Kieran F; Zhang, Xiaomeng; Thomas, David M
Nature reviews. Cancer,
04/2013, Letnik:
13, Številka:
4
Journal Article
Recenzirano
The Hippo pathway controls organ size in diverse species, whereas pathway deregulation can induce tumours in model organisms and occurs in a broad range of human carcinomas, including lung, ...colorectal, ovarian and liver cancer. Despite this, somatic or germline mutations in Hippo pathway genes are uncommon, with only the upstream pathway gene neurofibromin 2 (NF2) recognized as a bona fide tumour suppressor gene. In this Review, we appraise the evidence for the Hippo pathway as a cancer signalling network, and discuss cancer-relevant biological functions, potential mechanisms by which Hippo pathway activity is altered in cancer and emerging therapeutic strategies.
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