Workshop to identify critical windows of exposure for children's health: cardiovascular and endocrine work group summary.

The work group on cardiovascular and endocrine effects was asked to review the current state of knowledge about children's windows of vulnerability to developmental toxicants and to recommend how that information may be used to improve risk assessment and public health. We considered differences between structural defects, where periods of vulnerability are rather well defined, and functional defects, where periods of vulnerability are quite elusive

Production of Superoxide Anions by Keratinocytes Initiates P. acnes-Induced Inflammation of the Skin

Acne vulgaris is a chronic inflammatory disorder of the sebaceous follicles. Propionibacterium acnes (P. acnes), a gram-positive anareobic bacterium, plays a critical role in the development of these inflammatory lesions. This study aimed at determining whether reactive oxygen species (ROS) are produced by keratinocytes upon P. acnes infection, dissecting the mechanism of this production, and investigating how this phenomenon integrates in the general inflammatory response induced by P. acnes. In our hands, ROS, and especially superoxide anions (O2•−), were rapidly produced by keratinocytes upon stimulation by P. acnes surface proteins. In P. acnes-stimulated keratinocytes, O2•− was produced by NAD(P)H oxidase through activation of the scavenger receptor CD36. O2•− was dismuted by superoxide dismutase to form hydrogen peroxide which was further detoxified into water by the GSH/GPx system. In addition, P. acnes-induced O2•− abrogated P. acnes growth and was involved in keratinocyte lysis through the combination of O2•− with nitric oxide to form peroxynitrites. Finally, retinoic acid derivates, the most efficient anti-acneic drugs, prevent O2•− production, IL-8 release and keratinocyte apoptosis, suggesting the relevance of this pathway in humans

Comparing individual-based approaches to modelling the self-organization of multicellular tissues.

The coordinated behaviour of populations of cells plays a central role in tissue growth and renewal. Cells react to their microenvironment by modulating processes such as movement, growth and proliferation, and signalling. Alongside experimental studies, computational models offer a useful means by which to investigate these processes. To this end a variety of cell-based modelling approaches have been developed, ranging from lattice-based cellular automata to lattice-free models that treat cells as point-like particles or extended shapes. However, it remains unclear how these approaches compare when applied to the same biological problem, and what differences in behaviour are due to different model assumptions and abstractions. Here, we exploit the availability of an implementation of five popular cell-based modelling approaches within a consistent computational framework, Chaste (http://www.cs.ox.ac.uk/chaste). This framework allows one to easily change constitutive assumptions within these models. In each case we provide full details of all technical aspects of our model implementations. We compare model implementations using four case studies, chosen to reflect the key cellular processes of proliferation, adhesion, and short- and long-range signalling. These case studies demonstrate the applicability of each model and provide a guide for model usage

Evaluation of two sets of immunohistochemical and Western blot confirmatory methods in the detection of typical and atypical BSE cases

<p>Abstract</p> <p>Background</p> <p>Three distinct forms of bovine spongiform encephalopathy (BSE), defined as classical (C-), low (L-) or high (H-) type, have been detected through ongoing active and passive surveillance systems for the disease.</p> <p>The aim of the present study was to compare the ability of two sets of immunohistochemical (IHC) and Western blot (WB) BSE confirmatory protocols to detect C- and atypical (L- and H-type) BSE forms.</p> <p>Obex samples from cases of United States and Italian C-type BSE, a U.S. H-type and an Italian L-type BSE case were tested in parallel using the two IHC sets and WB methods.</p> <p>Results</p> <p>The two IHC techniques proved equivalent in identifying and differentiating between C-type, L-type and H-type BSE. The IHC protocols appeared consistent in the identification of PrP^Scdistribution and deposition patterns in relation to the BSE type examined. Both IHC methods evidenced three distinct PrP^Scphenotypes for each type of BSE: prevailing granular and linear tracts pattern in the C-type; intraglial and intraneuronal deposits in the H-type; plaques in the L-type.</p> <p>Also, the two techniques gave comparable results for PrP^Scstaining intensity on the C- and L-type BSE samples, whereas a higher amount of intraglial and intraneuronal PrP^Scdeposition on the H-type BSE case was revealed by the method based on a stronger demasking step.</p> <p>Both WB methods were consistent in identifying classical and atypical BSE forms and in differentiating the specific PrP^Scmolecular weight and glycoform ratios of each form.</p> <p>Conclusions</p> <p>The study showed that the IHC and WB BSE confirmatory methods were equally able to recognize C-, L- and H-type BSE forms and to discriminate between their different immunohistochemical and molecular phenotypes. Of note is that for the first time one of the two sets of BSE confirmatory protocols proved effective in identifying the L-type BSE form. This finding helps to validate the suitability of the BSE confirmatory tests for BSE surveillance currently in place.</p

The Promoter of Rv0560c Is Induced by Salicylate and Structurally-Related Compounds in Mycobacterium tuberculosis

Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), is a major global health threat. During infection, bacteria are believed to encounter adverse conditions such as iron depletion. Mycobacteria synthesize iron-sequestering mycobactins, which are essential for survival in the host, via the intermediate salicylate. Salicylate is a ubiquitous compound which is known to induce a mild antibiotic resistance phenotype. In M. tuberculosis salicylate highly induces the expression of Rv0560c, a putative methyltransferase. We identified and characterized the promoter and regulatory elements of Rv0560c. PRv0560c activity was highly inducible by salicylate in a dose-dependent manner. The induction kinetics of PRv0560c were slow, taking several days to reach maximal activity, which was sustained over several weeks. Promoter activity could also be induced by compounds structurally related to salicylate, such as aspirin or para-aminosalicylic acid, but not by benzoate, indicating that induction is specific to a structural motif. The −10 and −35 promoter elements were identified and residues involved in regulation of promoter activity were identified in close proximity to an inverted repeat spanning the −35 promoter element. We conclude that Rv0560c expression is controlled by a yet unknown repressor via a highly-inducible promoter

Climate Change Hastens the Conservation Urgency of an Endangered Ungulate

Global climate change appears to be one of the main threats to biodiversity in the near future and is already affecting the distribution of many species. Currently threatened species are a special concern while the extent to which they are sensitive to climate change remains uncertain. Przewalski's gazelle (Procapra przewalskii) is classified as endangered and a conservation focus on the Qinghai-Tibetan Plateau. Using measures of species range shift, we explored how the distribution of Przewalski's gazelle may be impacted by projected climate change based on a maximum entropy approach. We also evaluated the uncertainty in the projections of the risks arising from climate change. Modeling predicted the Przewalski's gazelle would be sensitive to future climate change. As the time horizon increased, the strength of effects from climate change increased. Even assuming unlimited dispersal capacity of gazelles, a moderate decrease to complete loss of range was projected by 2080 under different thresholds for transforming the probability prediction to presence/absence data. Current localities of gazelles will undergo a decrease in their occurrence probability. Projections of the impacts of climate change were significantly affected by thresholds and general circulation models. This study suggests climate change clearly poses a severe threat and increases the extinction risk to Przewalski's gazelle. Our findings 1) confirm that endangered endemic species is highly vulnerable to climate change and 2) highlight the fact that forecasting impacts of climate change needs an assessment of the uncertainty. It is extremely important that conservation strategies consider the predicted geographical shifts and be planned with full knowledge of the reliability of projected impacts of climate change

Consistency of Leadership in Shoals of Mosquitofish (Gambusia holbrooki) in Novel and in Familiar Environments

In social animal groups, an individual's spatial position is a major determinant of both predation risk and foraging rewards. Additionally, the occupation of positions in the front of moving groups is generally assumed to correlate with the initiation of group movements. However, whether some individuals are predisposed to consistently occupy certain positions and, in some instances, to consistently lead groups over time is as yet unresolved in many species. Using the mosquitofish (Gambusia holbrooki), we examined the consistency of individuals' spatial positions within a moving group over successive trials. We found that certain individuals consistently occupied front positions in moving groups and also that it was typically these individuals that initiated group decisions. The number of individuals involved in leading the group varied according to the amount of information held by group members, with a greater number of changes in leadership in a novel compared to a relatively familiar environment. Finally, our results show that the occupation of lead positions in moving groups was not explained by characteristics such as dominance, size or sex, suggesting that certain individuals are predisposed to leadership roles. This suggests that being a leader or a follower may to some extent be an intrinsic property of the individual

‘This In-Between’: How Families Talk about Death in Relation to Severe Brain Injury and Disorders of Consciousness

These comments encapsulate some common themes in how people describe having a severely brain-injured relative in a coma-like condition, medically known as a ‘disorder of consciousness’. In the past it was highly unusual for such individuals to survive very long after the initial trauma that caused their injury. However, the emergence of modern medical technologies, and how they are deployed, has led to the creation of new long-term conditions including the ‘vegetative state’ (in which the patient shows no awareness at all) and the ‘minimally conscious state’ (in which the the patient displays some intermittent and minimal awareness). These conditions are modern phenomena — the vegetative diagnostic category was first created in the early 1970s (Jennett and Plum, 1972) and the ‘minimally conscious state’ [MCS] was only defined in 2002 (Giacino et al., 2002). Patients with disorders of consciousness disrupt previous ways of understanding life. The family may experience their vegetative or minimally conscious relative as ‘present but absent’, ‘living, but dead’, making comments such as ‘this is no life’ and ‘my son is gone’ — and experiencing a sense of loss and grief that may be ‘like a death’, although not a death