The proteomes of neurotransmitter receptor complexes form modular networks with distributed functionality underlying plasticity and behaviour

Neuronal synapses play fundamental roles in information processing, behaviour and disease. Neurotransmitter receptor complexes, such as the mammalian N-methyl-D-aspartate receptor complex (NRC/MASC) comprising 186 proteins, are major components of the synapse proteome. Here we investigate the organisation and function of NRC/MASC using a systems biology approach. Systematic annotation showed that the complex contained proteins implicated in a wide range of cognitive processes, synaptic plasticity and psychiatric diseases. Protein domains were evolutionarily conserved from yeast, but enriched with signalling domains associated with the emergence of multicellularity. Mapping of protein–protein interactions to create a network representation of the complex revealed that simple principles underlie the functional organisation of both proteins and their clusters, with modularity reflecting functional specialisation. The known functional roles of NRC/MASC proteins suggest the complex co-ordinates signalling to diverse effector pathways underlying neuronal plasticity. Importantly, using quantitative data from synaptic plasticity experiments, our model correctly predicts robustness to mutations and drug interference. These studies of synapse proteome organisation suggest that molecular networks with simple design principles underpin synaptic signalling properties with important roles in physiology, behaviour and disease

TLR7-mediated skin inflammation remotely triggers chemokine expression and leukocyte accumulation in the brain

Background: The relationship between the brain and the immune system has become increasingly topical as, although it is immune-specialised, the CNS is not free from the influences of the immune system. Recent data indicate that peripheral immune stimulation can significantly affect the CNS. But the mechanisms underpinning this relationship remain unclear. The standard approach to understanding this relationship has relied on systemic immune activation using bacterial components, finding that immune mediators, such as cytokines, can have a significant effect on brain function and behaviour. More rarely have studies used disease models that are representative of human disorders. Methods: Here we use a well-characterised animal model of psoriasis-like skin inflammation—imiquimod—to investigate the effects of tissue-specific peripheral inflammation on the brain. We used full genome array, flow cytometry analysis of immune cell infiltration, doublecortin staining for neural precursor cells and a behavioural read-out exploiting natural burrowing behaviour. Results: We found that a number of genes are upregulated in the brain following treatment, amongst which is a subset of inflammatory chemokines (CCL3, CCL5, CCL9, CXCL10, CXCL13, CXCL16 and CCR5). Strikingly, this model induced the infiltration of a number of immune cell subsets into the brain parenchyma, including T cells, NK cells and myeloid cells, along with a reduction in neurogenesis and a suppression of burrowing activity. Conclusions: These findings demonstrate that cutaneous, peripheral immune stimulation is associated with significant leukocyte infiltration into the brain and suggest that chemokines may be amongst the key mediators driving this response

Developing cartoons for long-term condition self-management information

Background: Advocating the need to adopt more self-management policies has brought with it an increasing demand for information about living with and making decisions about long-term conditions, with a significant potential for using cartoons. However, the purposeful use of cartoons is notably absent in many areas of health care as is evidence of their acceptability to patients and lay others. This paper outlines the process used to develop and evaluate cartoons and their acceptability for a series of self-management guidebooks for people with inflammatory bowel disease, irritable bowel syndrome, diabetes, chronic obstructive pulmonary disease and chronic kidney disease (CKD). Methods: Principles for a process to develop information and cartoons were developed. Cartoon topics were created using qualitative research methods to obtain lay views and experiences. The CKD guidebook was used to provide a detailed exemplar of the process. Focus group and trial participants were recruited from primary care CKD registers. The book was part of a trial intervention; selected participants evaluated the cartoons during in-depth interviews which incorporated think-aloud methods. Results: In general, the cartoons developed by this process depict patient experiences, common situations, daily management dilemmas, making decisions and choices and the uncertainties associated with conditions. CKD cartoons were developed following two focus groups around the themes of getting a diagnosis; understanding the problem; feeling that facts were being withheld; and setting priorities. Think-aloud interviews with 27 trial participants found the CKD cartoons invoked amusement, recognition and reflection but were sometimes difficult to interpret. Conclusion: Humour is frequently utilised by people with long-term conditions to help adjustment and coping. Cartoons can help provide clarity and understanding and could address concerns related to health literacy. Using cartoons to engage and motivate people is a consideration untapped by conventional theories with the potential to improve information to support self-management

On staying grounded and avoiding Quixotic dead ends

The 15 articles in this special issue on The Representation of Concepts illustrate the rich variety of theoretical positions and supporting research that characterize the area. Although much agreement exists among contributors, much disagreement exists as well, especially about the roles of grounding and abstraction in conceptual processing. I first review theoretical approaches raised in these articles that I believe are Quixotic dead ends, namely, approaches that are principled and inspired but likely to fail. In the process, I review various theories of amodal symbols, their distortions of grounded theories, and fallacies in the evidence used to support them. Incorporating further contributions across articles, I then sketch a theoretical approach that I believe is likely to be successful, which includes grounding, abstraction, flexibility, explaining classic conceptual phenomena, and making contact with real-world situations. This account further proposes that (1) a key element of grounding is neural reuse, (2) abstraction takes the forms of multimodal compression, distilled abstraction, and distributed linguistic representation (but not amodal symbols), and (3) flexible context-dependent representations are a hallmark of conceptual processing

A rocky planet transiting a nearby low-mass star

M-dwarf stars -- hydrogen-burning stars that are smaller than 60 per cent of the size of the Sun -- are the most common class of star in our Galaxy and outnumber Sun-like stars by a ratio of 12:1. Recent results have shown that M dwarfs host Earth-sized planets in great numbers: the average number of M-dwarf planets that are between 0.5 to 1.5 times the size of Earth is at least 1.4 per star. The nearest such planets known to transit their star are 39 parsecs away, too distant for detailed follow-up observations to measure the planetary masses or to study their atmospheres. Here we report observations of GJ 1132b, a planet with a size of 1.2 Earth radii that is transiting a small star 12 parsecs away. Our Doppler mass measurement of GJ 1132b yields a density consistent with an Earth-like bulk composition, similar to the compositions of the six known exoplanets with masses less than six times that of the Earth and precisely measured densities. Receiving 19 times more stellar radiation than the Earth, the planet is too hot to be habitable but is cool enough to support a substantial atmosphere, one that has probably been considerably depleted of hydrogen. Because the host star is nearby and only 21 per cent the radius of the Sun, existing and upcoming telescopes will be able to observe the composition and dynamics of the planetary atmosphere.Comment: Published in Nature on 12 November 2015, available at http://dx.doi.org/10.1038/nature15762. This is the authors' version of the manuscrip

Mitochondrial and nuclear markers reveal a lack of genetic structure in the entocommensal nemertean Malacobdella arrokeana in the Patagonian gulfs

Abstract Malacobdella arrokeana is an entocommensal nemertean exclusively found in the bivalve geoduck Panopea abbreviata, and it is the only representative of the genus in the southern hemisphere. To characterize its genetic diversity, population structure and recent demographic history, we conducted the first genetic survey on this species, using sequence data for the cytochrome oxidase I gene (COI), 16S rRNA (16S) and the internal transcribed spacer (ITS2). Only four different ITS2 genotypes were found in the whole sample, and the two main haplotypes identified in the mitochondrial dataset were present among all localities with a diversity ranging from 0.583 to 0.939. Nucleotide diversity was low (p = 0.001?0.002). No significant genetic structure was detected between populations, and mismatch distribution patterns and neutrality tests results are consistent with a population in expansion or under selection. Analysis of molecular variance (AMOVA) revealed that the largest level of variance observed was due to intrapopulation variation (100, 100 and 94.39 % for 16S, COI and ITS2, respectively). Fst values were also non-significant. The observed lack of population structure is likely due to high levels of genetic connectivity in combination with the lack or permeability of biogeographic barriers and episodes of habitat modification.Fil: Fernandez Alfaya, Jose Elias. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Nacional Patagónico; ArgentinaFil: Bigatti, Gregorio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Nacional Patagónico; ArgentinaFil: Machordom, Annie. Consejo Superior de Investigaciones Cientificas. Museo Nacional de Cs. Naturales; Españ

Matrix models and sensitivity analysis of populations classified by age and stage : a vec-permutation matrix approach

© The Author(s), 2011. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Theoretical Ecology 5 (2012): 403-417, doi:10.1007/s12080-011-0132-2.Matrix population models in which individuals are classified by both age and stage can be constructed using the vec-permutation matrix. The resulting age-stage models can be used to derive the age-specific consequences of a stage-specific life history or to describe populations in which the vital rates respond to both age and stage. I derive a general formula for the sensitivity of any output (scalar, vector, or matrix-valued) of the model, to any vector of parameters, using matrix calculus. The matrices describing age-stage dynamics are almost always reducible; I present results giving conditions under which population growth is ergodic from any initial condition. As an example, I analyze a published stage-specific model of Scotch broom (Cytisus scoparius), an invasive perennial shrub. Sensitivity analysis of the population growth rate finds that the selection gradients on adult survival do not always decrease with age but may increase over a range of ages. This may have implications for the evolution of senescence in stage-classified populations. I also derive and analyze the joint distribution of age and stage at death and present a sensitivity analysis of this distribution and of the marginal distribution of age at death.This research was supported by National Science Foundation Grant DEB-0816514 and by a Research Award from the Alexander von Humboldt Foundation

Vaccines for the Leishmaniases: Proposals for a Research Agenda

The International Symposium on Leishmaniasis Vaccines, held in Olinda, Brazil, on March 9–11, 2009, congregated international experts who conduct research on vaccines against the leishmaniases. The questions that were raised during that meeting and the ensuing discussions are compiled in this report and may assist in guiding a research agenda. A group to further discussion on issues raised in this policy platform has been set up at http://groups.google.com/group/leishvaccines-l