The Human Fungal Pathogen Cryptococcus neoformans Escapes Macrophages by a Phagosome Emptying Mechanism That Is Inhibited by Arp2/3 Complex-Mediated Actin Polymerisation

The lysis of infected cells by disease-causing microorganisms is an efficient but risky strategy for disseminated infection, as it exposes the pathogen to the full repertoire of the host's immune system. Cryptococcus neoformans is a widespread fungal pathogen that causes a fatal meningitis in HIV and other immunocompromised patients. Following intracellular growth, cryptococci are able to escape their host cells by a non-lytic expulsive mechanism that may contribute to the invasion of the central nervous system. Non-lytic escape is also exhibited by some bacterial pathogens and is likely to facilitate long-term avoidance of the host immune system during latency. Here we show that phagosomes containing intracellular cryptococci undergo repeated cycles of actin polymerisation. These actin ‘flashes’ occur in both murine and human macrophages and are dependent on classical WASP-Arp2/3 complex mediated actin filament nucleation. Three dimensional confocal imaging time lapse revealed that such flashes are highly dynamic actin cages that form around the phagosome. Using fluorescent dextran as a phagosome membrane integrity probe, we find that the non-lytic expulsion of Cryptococcus occurs through fusion of the phagosome and plasma membranes and that, prior to expulsion, 95% of phagosomes become permeabilised, an event that is immediately followed by an actin flash. By using pharmacological agents to modulate both actin dynamics and upstream signalling events, we show that flash occurrence is inversely related to cryptococcal expulsion, suggesting that flashes may act to temporarily inhibit expulsion from infected phagocytes. In conclusion, our data reveal the existence of a novel actin-dependent process on phagosomes containing cryptococci that acts as a potential block to expulsion of Cryptococcus and may have significant implications for the dissemination of, and CNS invasion by, this organism.\ud \u

Friendship as a Political Concept: A Groundwork for Analysis

What kind of a concept is friendship, and what is its connection to politics? Critics sometimes claim that friendship does not have a role to play in the study of politics. Such objections misconstrue the nature of the concept of friendship and its relation to politics. In response, this article proposes three approaches to understanding the concept of friendship: (1) as a ‘family resemblance’ concept, (2) as an instance of an ‘essentially contested’ concept, and (3) as a concept indicating a problématique. The article thus responds to the dismissal of friendship by undertaking the groundwork for understanding what kind of a concept friendship might be, and how it might serve different purposes. In doing so, it opens the way for understanding friendship’s relation to politics

Neuroimaging in cluster headache and other trigeminal autonomic cephalalgias

The central nervous system mechanisms involved in trigeminal autonomic cephalalgias, a group of primary headaches characterized by strictly unilateral head pain that occurs in association with ipsilateral craniofacial autonomic features, are still not comprehensively understood. However, functional imaging methods have revolutionized our understanding of mechanisms involved in these primary headache syndromes. The present review provides a brief overview of the major modern functional neuroimaging techniques used to examine brain structure, biochemistry, metabolic state, and functional capacity. The available functional neuroimaging data in cluster headache and other TACs will thus be summarized. Although the precise brain structures responsible for these primary headache syndromes still remain to be determined, neuroimaging data suggest a major role for posterior hypothalamus activation in initiating and maintaining attacks. Furthermore, pathophysiological involvement of the pain neuromatrix and of the central descending opiatergic pain control system was observed. Given the rapid advances in functional and structural neuroimaging methodologies, it can be expected that these non-invasive techniques will continue to improve our understanding into the nature of the brain dysfunction in cluster headache and other trigeminal autonomic cephalalgias

Thermodynamic curvature and black holes

I give a relatively broad survey of thermodynamic curvature $R$, one spanning results in fluids and solids, spin systems, and black hole thermodynamics. $R$ results from the thermodynamic information metric giving thermodynamic fluctuations. $R$ has a unique status in thermodynamics as being a geometric invariant, the same for any given thermodynamic state. In fluid and solid systems, the sign of $R$ indicates the character of microscopic interactions, repulsive or attractive. $|R|$ gives the average size of organized mesoscopic fluctuating structures. The broad generality of thermodynamic principles might lead one to believe the same for black hole thermodynamics. This paper explores this issue with a systematic tabulation of results in a number of cases.Comment: 27 pages, 10 figures, 7 tables, 78 references. Talk presented at the conference Breaking of Supersymmetry and Ultraviolet Divergences in extended Supergravity, in Frascati, Italy, March 27, 2013. v2 corrects some small problem

Phylogeography of Japanese encephalitis virus:genotype is associated with climate

The circulation of vector-borne zoonotic viruses is largely determined by the overlap in the geographical distributions of virus-competent vectors and reservoir hosts. What is less clear are the factors influencing the distribution of virus-specific lineages. Japanese encephalitis virus (JEV) is the most important etiologic agent of epidemic encephalitis worldwide, and is primarily maintained between vertebrate reservoir hosts (avian and swine) and culicine mosquitoes. There are five genotypes of JEV: GI-V. In recent years, GI has displaced GIII as the dominant JEV genotype and GV has re-emerged after almost 60 years of undetected virus circulation. JEV is found throughout most of Asia, extending from maritime Siberia in the north to Australia in the south, and as far as Pakistan to the west and Saipan to the east. Transmission of JEV in temperate zones is epidemic with the majority of cases occurring in summer months, while transmission in tropical zones is endemic and occurs year-round at lower rates. To test the hypothesis that viruses circulating in these two geographical zones are genetically distinct, we applied Bayesian phylogeographic, categorical data analysis and phylogeny-trait association test techniques to the largest JEV dataset compiled to date, representing the envelope (E) gene of 487 isolates collected from 12 countries over 75 years. We demonstrated that GIII and the recently emerged GI-b are temperate genotypes likely maintained year-round in northern latitudes, while GI-a and GII are tropical genotypes likely maintained primarily through mosquito-avian and mosquito-swine transmission cycles. This study represents a new paradigm directly linking viral molecular evolution and climate

Responsibility Ascriptions in Technology Development and Engineering: Three Perspectives

In the last decades increasing attention is paid to the topic of responsibility in technology development and engineering. The discussion of this topic is often guided by questions related to liability and blameworthiness. Recent discussions in engineering ethics call for a reconsideration of the traditional quest for responsibility. Rather than on alleged wrongdoing and blaming, the focus should shift to more socially responsible engineering, some authors argue. The present paper aims at exploring the different approaches to responsibility in order to see which one is most appropriate to apply to engineering and technology development. Using the example of the development of a new sewage water treatment technology, the paper shows how different approaches for ascribing responsibilities have different implications for engineering practice in general, and R&D or technological design in particular. It was found that there was a tension between the demands that follow from these different approaches, most notably between efficacy and fairness. Although the consequentialist approach with its efficacy criterion turned out to be most powerful, it was also shown that the fairness of responsibility ascriptions should somehow be taken into account. It is proposed to look for alternative, more procedural ways to approach the fairness of responsibility ascriptions

Community responses to communication campaigns for influenza A (H1N1): a focus group study

<p>Abstract</p> <p>Background</p> <p>This research was a part of a contestable rapid response initiative launched by the Health Research Council of New Zealand and the Ministry of Health in response to the 2009 influenza A pandemic. The aim was to provide health authorities in New Zealand with evidence-based practical information to guide the development and delivery of effective health messages for H1N1 and other health campaigns. This study contributed to the initiative by providing qualitative data about community responses to key health messages in the 2009 and 2010 H1N1 campaigns, the impact of messages on behavioural change and the differential impact on vulnerable groups in New Zealand.</p> <p>Methods</p> <p>Qualitative data were collected on community responses to key health messages in the 2009 and 2010 Ministry of Health H1N1 campaigns, the impact of messages on behaviour and the differential impact on vulnerable groups. Eight focus groups were held in the winter of 2010 with 80 participants from groups identified by the Ministry of Health as vulnerable to the H1N1 virus, such as people with chronic health conditions, pregnant women, children, Pacific Peoples and Māori. Because this study was part of a rapid response initiative, focus groups were selected as the most efficient means of data collection in the time available. For Māori, focus group discussion (hui) is a culturally appropriate methodology.</p> <p>Results</p> <p>Thematic analysis of data identified four major themes: personal and community risk, building community strategies, responsibility and information sources. People wanted messages about specific actions that they could take to protect themselves and their families and to mitigate any consequences. They wanted transparent and factual communication where both good and bad news is conveyed by people who they could trust.</p> <p>Conclusions</p> <p>The responses from all groups endorsed the need for community based risk management including information dissemination. Engaging with communities will be essential to facilitate preparedness and build community resilience to future pandemic events. This research provides an illustration of the complexities of how people understand and respond to health messages related to the H1N1 pandemic. The importance of the differences identified in the analysis is not the differences per se but highlight problems with a "one size fits all" pandemic warning strategy.</p

Scapinin, the Protein Phosphatase 1 Binding Protein, Enhances Cell Spreading and Motility by Interacting with the Actin Cytoskeleton

Copyright (c) 2009 Sagara et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Scapinin, also named phactr3, is an actin and protein phosphatase 1 (PP1) binding protein, which is expressed in the adult brain and some tumor cells. At present, the role(s) of scapinin in the brain and tumors are poorly understood. We show that the RPEL-repeat domain of scapinin, which is responsible for its direct interaction with actin, inhibits actin polymerization in vitro. Next, we established a Hela cell line, where scapinin expression was induced by tetracycline. In these cells, expression of scapinin stimulated cell spreading and motility. Scapinin was colocalized with actin at the edge of spreading cells. To explore the roles of the RPEL-repeat and PP1-binding domains, we expressed wild-type and mutant scapinins as fusion proteins with green fluorescence protein (GFP) in Cos7 cells. Expression of GFP-scapinin (wild type) also stimulated cell spreading, but mutation in the RPEL-repeat domain abolished both the actin binding and the cell spreading activity. PP1-binding deficient mutants strongly induced cell retraction. Long and branched cytoplasmic processes were developed during the cell retraction. These results suggest that scapinin enhances cell spreading and motility through direct interaction with actin and that PP1 plays a regulatory role in scapinin-induced morphological changes.ArticlePLOS ONE. 4(1):e4247 (2009)journal articl

A New Dolphin Species, the Burrunan Dolphin Tursiops australis sp. nov., Endemic to Southern Australian Coastal Waters

Small coastal dolphins endemic to south-eastern Australia have variously been assigned to described species Tursiops truncatus, T. aduncus or T. maugeanus; however the specific affinities of these animals is controversial and have recently been questioned. Historically ‘the southern Australian Tursiops’ was identified as unique and was formally named Tursiops maugeanus but was later synonymised with T. truncatus. Morphologically, these coastal dolphins share some characters with both aforementioned recognised Tursiops species, but they also possess unique characters not found in either. Recent mtDNA and microsatellite genetic evidence indicates deep evolutionary divergence between this dolphin and the two currently recognised Tursiops species. However, in accordance with the recommendations of the Workshop on Cetacean Systematics, and the Unified Species Concept the use of molecular evidence alone is inadequate for describing new species. Here we describe the macro-morphological, colouration and cranial characters of these animals, assess the available and new genetic data, and conclude that multiple lines of evidence clearly indicate a new species of dolphin. We demonstrate that the syntype material of T. maugeanus comprises two different species, one of which is the historical ‘southern form of Tursiops’ most similar to T. truncatus, and the other is representative of the new species and requires formal classification. These dolphins are here described as Tursiops australis sp. nov., with the common name of ‘Burrunan Dolphin’ following Australian aboriginal narrative. The recognition of T. australis sp. nov. is particularly significant given the endemism of this new species to a small geographic region of southern and south-eastern Australia, where only two small resident populations in close proximity to a major urban and agricultural centre are known, giving them a high conservation value and making them susceptible to numerous anthropogenic threats