Loss of Dictyostelium HSPC300 causes a scar-like phenotype and loss of SCAR protein

<p>Abstract</p> <p>Background</p> <p>SCAR/WAVE proteins couple signalling to actin polymerization, and are thus fundamental to the formation of pseudopods and lamellipods. They are controlled as part of a five-membered complex that includes the tiny HSPC300 protein. It is not known why SCAR/WAVE is found in such a large assembly, but in <it>Dictyostelium </it>the four larger subunits have different, clearly delineated functions.</p> <p>Results</p> <p>We have generated <it>Dictyostelium </it>mutants in which the HSPC300 gene is disrupted. As has been seen in other regulatory complex mutants, SCAR is lost in these cells, apparently by a post-translational mechanism, though PIR121 levels do not change. HSPC300 knockouts resemble <it>scar </it>mutants in slow migration, roundness, and lack of large pseudopods. However <it>hspc300</it>-colonies on bacteria are larger and more similar to wild type, suggesting that some SCAR function can survive without HSPC300. We find no evidence for functions of HSPC300 outside the SCAR complex.</p> <p>Conclusion</p> <p>HSPC300 is essential for most SCAR complex functions. The phenotype of HSPC300 knockouts is most similar to mutants in <it>scar</it>, not the other members of the SCAR complex, suggesting that HSPC300 acts most directly on SCAR itself.</p

The Lore of Low Methane Livestock:Co-Producing Technology and Animals for Reduced Climate Change Impact

Methane emissions from sheep and cattle production have gained increasing profile in the context of climate change. Policy and scientific research communities have suggested a number of technological approaches to mitigate these emissions. This paper uses the concept of co-production as an analytical framework to understand farmers’ evaluation of a 'good animal’. It examines how technology and sheep and beef cattle are co-produced in the context of concerns about the climate change impact of methane. Drawing on 42 semi-structured interviews, this paper demonstrates that methane emissions are viewed as a natural and integral part of sheep and beef cattle by farmers, rather than as a pollutant. Sheep and beef cattle farmers in the UK are found to be an extremely heterogeneous group that need to be understood in their specific social, environmental and consumer contexts. Some are more amenable to appropriating methane reducing measures than others, but largely because animals are already co-constructed from the natural and the technical for reasons of increased production efficiency

Strategic options development and analysis

Strategic Options Development and Analysis (SODA) enables a group or individual to construct a graphical representation (map) or a problematic situation, and thus explore options and their ramifications with respect to a complex system of goals or objectives. In addition the approach aims to help groups arrive at a negotiated agreement about how to act to resolve the situation. It is based upon the use of causal mapping – a formally constructed means-ends network. Because the map has been constructed using the natural language of the problem owners it becomes a model of the situation that is ‘owned’ by those who define the problem. The use of formalities for the construction of the model makes it amenable to a range of analyses encouraging reflection and a deeper understanding. These analyses can be used in a ‘rough and ready’ manner by visual inspection or through the use of specialist causal mapping software. Each of the analyses helps a group or individual discover important features of the problem situation. And these features facilitate agreeing a good solution. The SODA process is aimed at helping a group learn about the situation they face before they reach agreements. Most significantly the exploration through the causal map leads to a higher probability of more creative solutions and promotes solutions that are more likely to be implemented because the problem construction process is more likely to include richer social dimensions about the blockages to action and organizational change. The basic theories that inform SODA derive from cognitive psychology and social negotiation, where the model acts as a continuously changing representation of the problematic situation (a transitional object) – changing as the views of a person or group shift through learning and exploration. This chapter jointly written by two leading practitioner academics and the original developers of SODA, Colin Eden and Fran Ackermann, describe the SODA approach as it is applied in practice

Suppression of the ATP-binding cassette transporter ABCC4 impairs neuroblastoma tumour growth and sensitises to irinotecan in vivo

The ATP-binding cassette transporter ABCC4 (multidrug resistance protein 4, MRP4) mRNA level is a strong predictor of poor clinical outcome in neuroblastoma which may relate to its export of endogenous signalling molecules and chemotherapeutic agents. We sought to determine whether ABCC4 contributes to development, growth and drug response in neuroblastoma in vivo. In neuroblastoma patients, high ABCC4 protein levels were associated with reduced overall survival. Inducible knockdown of ABCC4 strongly inhibited the growth of human neuroblastoma cells in vitro and impaired the growth of neuroblastoma xenografts. Loss of Abcc4 in the Th-MYCN transgenic neuroblastoma mouse model did not impact tumour formation; however, Abcc4-null neuroblastomas were strongly sensitised to the ABCC4 substrate drug irinotecan. Our findings demonstrate a role for ABCC4 in neuroblastoma cell proliferation and chemoresistance and provide rationale for a strategy where inhibition of ABCC4 should both attenuate the growth of neuroblastoma and sensitise tumours to ABCC4 chemotherapeutic substrates

The two-loop dilatation operator of N=4 super Yang-Mills theory in the SO(6) sector

The dilatation operator of planar N=4 super Yang-Mills in the pure scalar SO(6) sector is derived at the two-loop order. Representation theory allows for eight free coefficients in an ansatz for the corresponding spin-chain hamiltonian acting on three adjacent scalar states. While four out of these follow from the known SU(2|3) sector two-loop dilatation operator, the remaining four coefficients are derived by diagrammatic techniques and a match to the known dimension of a length three primary operator. Finally, comments upon the use of this result for the evaluation of three-point structure functions of scalar operators at the one-loop order are given.Comment: 16 pages, 5 figure

Системный анализ процесса затвердевания литых заготовок разной массы и назначения

Выявлены особенности пространственно-временной эволюции температурных полей в процессе затвердевания разных заготовок (слитков и отливок) для повышения их качества.Виявлено особливості просторово-часової еволюції температурних полів в процесі тверднення різних заготовок (зливків та виливків) для підвищення їх якості.It is revealed the peculiarities of distance-time evolution of the temperature fields in solidification process different billets (ingots and casts) for raise them quality

An approach for the identification of targets specific to bone metastasis using cancer genes interactome and gene ontology analysis

Metastasis is one of the most enigmatic aspects of cancer pathogenesis and is a major cause of cancer-associated mortality. Secondary bone cancer (SBC) is a complex disease caused by metastasis of tumor cells from their primary site and is characterized by intricate interplay of molecular interactions. Identification of targets for multifactorial diseases such as SBC, the most frequent complication of breast and prostate cancers, is a challenge. Towards achieving our aim of identification of targets specific to SBC, we constructed a 'Cancer Genes Network', a representative protein interactome of cancer genes. Using graph theoretical methods, we obtained a set of key genes that are relevant for generic mechanisms of cancers and have a role in biological essentiality. We also compiled a curated dataset of 391 SBC genes from published literature which serves as a basis of ontological correlates of secondary bone cancer. Building on these results, we implement a strategy based on generic cancer genes, SBC genes and gene ontology enrichment method, to obtain a set of targets that are specific to bone metastasis. Through this study, we present an approach for probing one of the major complications in cancers, namely, metastasis. The results on genes that play generic roles in cancer phenotype, obtained by network analysis of 'Cancer Genes Network', have broader implications in understanding the role of molecular regulators in mechanisms of cancers. Specifically, our study provides a set of potential targets that are of ontological and regulatory relevance to secondary bone cancer.Comment: 54 pages (19 pages main text; 11 Figures; 26 pages of supplementary information). Revised after critical reviews. Accepted for Publication in PLoS ON

Spinning strings and integrable spin chains in the AdS/CFT correspondence

In this introductory review we discuss dynamical tests of the AdS_5 x S^5 string/N=4 super Yang-Mills duality. After a brief introduction to AdS/CFT we argue that semiclassical string energies yield information on the quantum spectrum of the string in the limit of large angular momenta on the S^5. The energies of the folded and circular spinning string solutions rotating on a S^3 within the S^5 are derived, which yield all loop predictions for the dual gauge theory scaling dimensions. These follow from the eigenvalues of the dilatation operator of N=4 super Yang-Mills in a minimal SU(2) subsector and we display its reformulation in terms of a Heisenberg s=1/2 spin chain along with the coordinate Bethe ansatz for its explicit diagonalization. In order to make contact to the spinning string energies we then study the thermodynamic limit of the one-loop gauge theory Bethe equations and demonstrate the matching with the folded and closed string result at this loop order. Finally the known gauge theory results at higher-loop orders are reviewed and the associated long-range spin chain Bethe ansatz is introduced, leading to an asymptotic all-loop conjecture for the gauge theory Bethe equations. This uncovers discrepancies at the three-loop order between gauge theory scaling dimensions and string theory energies and the implications of this are discussed. Along the way we comment on further developments and generalizations of the subject and point to the relevant literature.Comment: 40 pages, invited contribution to Living Reviews in Relativity. v2: improvements in the text and references adde

A compendium and functional characterization of mammalian genes involved in adaptation to Arctic or Antarctic environments

Many mammals are well adapted to surviving in extremely cold environments. These species have likely accumulated genetic changes that help them efficiently cope with low temperatures. It is not known whether the same genes related to cold adaptation in one species would be under selection in another species. The aims of this study therefore were: to create a compendium of mammalian genes related to adaptations to a low temperature environment; to identify genes related to cold tolerance that have been subjected to independent positive selection in several species; to determine promising candidate genes/pathways/organs for further empirical research on cold adaptation in mammals

Modulation of T Cell Function by Combination of Epitope Specific and Low Dose Anticytokine Therapy Controls Autoimmune Arthritis

Innate and adaptive immunity contribute to the pathogenesis of autoimmune arthritis by generating and maintaining inflammation, which leads to tissue damage. Current biological therapies target innate immunity, eminently by interfering with single pro-inflammatory cytokine pathways. This approach has shown excellent efficacy in a good proportion of patients with Rheumatoid Arthritis (RA), but is limited by cost and side effects. Adaptive immunity, particularly T cells with a regulatory function, plays a fundamental role in controlling inflammation in physiologic conditions. A growing body of evidence suggests that modulation of T cell function is impaired in autoimmunity. Restoration of such function could be of significant therapeutic value. We have recently demonstrated that epitope-specific therapy can restore modulation of T cell function in RA patients. Here, we tested the hypothesis that a combination of anti-cytokine and epitope-specific immunotherapy may facilitate the control of autoimmune inflammation by generating active T cell regulation. This novel combination of mucosal tolerization to a pathogenic T cell epitope and single low dose anti-TNFα was as therapeutically effective as full dose anti-TNFα treatment. Analysis of the underlying immunological mechanisms showed induction of T cell immune deviation