Realizing the classical XY Hamiltonian in polariton simulators.

The vast majority of real-life optimization problems with a large number of degrees of freedom are intractable by classical computers, since their complexity grows exponentially fast with the number of variables. Many of these problems can be mapped into classical spin models, such as the Ising, the XY or the Heisenberg models, so that optimization problems are reduced to finding the global minimum of spin models. Here, we propose and investigate the potential of polariton graphs as an efficient analogue simulator for finding the global minimum of the XY model. By imprinting polariton condensate lattices of bespoke geometries we show that we can engineer various coupling strengths between the lattice sites and read out the result of the global minimization through the relative phases. Besides solving optimization problems, polariton graphs can simulate a large variety of systems undergoing the U(1) symmetry-breaking transition. We realize various magnetic phases, such as ferromagnetic, anti-ferromagnetic, and frustrated spin configurations on a linear chain, the unit cells of square and triangular lattices, a disordered graph, and demonstrate the potential for size scalability on an extended square lattice of 45 coherently coupled polariton condensates. Our results provide a route to study unconventional superfluids, spin liquids, Berezinskii-Kosterlitz-Thouless phase transition, and classical magnetism, among the many systems that are described by the XY Hamiltonian

Geometric frustration in polygons of polariton condensates creating vortices of varying topological charge.

Vorticity is a key ingredient to a broad variety of fluid phenomena, and its quantised version is considered to be the hallmark of superfluidity. Circulating flows that correspond to vortices of a large topological charge, termed giant vortices, are notoriously difficult to realise and even when externally imprinted, they are unstable, breaking into many vortices of a single charge. In spite of many theoretical proposals on the formation and stabilisation of giant vortices in ultra-cold atomic Bose-Einstein condensates and other superfluid systems, their experimental realisation remains elusive. Polariton condensates stand out from other superfluid systems due to their particularly strong interparticle interactions combined with their non-equilibrium nature, and as such provide an alternative testbed for the study of vortices. Here, we non-resonantly excite an odd number of polariton condensates at the vertices of a regular polygon and we observe the formation of a stable discrete vortex state with a large topological charge as a consequence of antibonding frustration between nearest neighbouring condensates

Activation of the Low Molecular Weight Protein Tyrosine Phosphatase in Keratinocytes Exposed to Hyperosmotic Stress

Herein, we provide new contribution to the mechanisms involved in keratinocytes response to hyperosmotic shock showing, for the first time, the participation of Low Molecular Weight Protein Tyrosine Phosphatase (LMWPTP) activity in this event. We reported that sorbitol-induced osmotic stress mediates alterations in the phosphorylation of pivotal cytoskeletal proteins, particularly Src and cofilin. Furthermore, an increase in the expression of the phosphorylated form of LMWPTP, which was followed by an augment in its catalytic activity, was observed. of particular importance, these responses occurred in an intracellular milieu characterized by elevated levels of reduced glutathione (GSH) and increased expression of the antioxidant enzymes glutathione peroxidase and glutathione reductase. Altogether, our results suggest that hyperosmostic stress provides a favorable cellular environment to the activation of LMWPTP, which is associated with increased expression of antioxidant enzymes, high levels of GSH and inhibition of Src kinase. Finally, the real contribution of LMWPTP in the hyperosmotic stress response of keratinocytes was demonstrated through analysis of the effects of ACP1 gene knockdown in stressed and non-stressed cells. LMWPTP knockdown attenuates the effects of sorbitol induced-stress in HaCaT cells, mainly in the status of Src kinase, Rac and STAT5 phosphorylation and activity. These results describe for the first time the participation of LMWPTP in the dynamics of cytoskeleton rearrangement during exposure of human keratinocytes to hyperosmotic shock, which may contribute to cell death.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Univ Estadual Campinas, Dept Bioquim, Inst Biol, São Paulo, BrazilUniversidade Federal de São Paulo, Dept Bioquim, São Paulo, SP, BrazilUniv Estadual Paulista, Dept Quim & Bioquim, IBB, São Paulo, BrazilUniv São Paulo, Dept Genet & Biol Evolut, São Paulo, SP, BrazilUniv Fed ABC, Ctr Ciencias Nat & Humanas, São Paulo, BrazilUniversidade Federal de São Paulo, Dept Ciencias Biol, São Paulo, SP, BrazilUniversidade Federal de São Paulo, Dept Bioquim, São Paulo, SP, BrazilUniversidade Federal de São Paulo, Dept Ciencias Biol, São Paulo, SP, BrazilFAPESP: 2006/07315-3CNPq: PQ-2Web of Scienc

Immune-Complex Mimics as a Molecular Platform for Adjuvant-Free Vaccine Delivery

Protein-based vaccine development faces the difficult challenge of finding robust yet non-toxic adjuvants suitable for humans. Here, using a molecular engineering approach, we have developed a molecular platform for generating self-adjuvanting immunogens that do not depend on exogenous adjuvants for induction of immune responses. These are based on the concept of Immune Complex Mimics (ICM), structures that are formed between an oligomeric antigen and a monoclonal antibody (mAb) to that antigen. In this way, the roles of antigens and antibodies within the structure of immune complexes are reversed, so that a single monoclonal antibody, rather than polyclonal sera or expensive mAb cocktails can be used. We tested this approach in the context of Mycobacterium tuberculosis (MTB) infection by linking the highly immunogenic and potentially protective Ag85B with the oligomeric Acr (alpha crystallin, HspX) antigen. When combined with an anti-Acr monoclonal antibody, the fusion protein formed ICM which bound to C1q component of the complement system and were readily taken up by antigen-presenting cells in vitro. ICM induced a strong Th1/Th2 mixed type antibody response, which was comparable to cholera toxin adjuvanted antigen, but only moderate levels of T cell proliferation and IFN-γ secretion. Unfortunately, the systemic administration of ICM did not confer statistically significant protection against intranasal MTB challenge, although a small BCG-boosting effect was observed. We conclude that ICM are capable of inducing strong humoral responses to incorporated antigens and may be a suitable vaccination approach for pathogens other than MTB, where antibody-based immunity may play a more protective role

Cathepsin K induces platelet dysfunction and affects cell signaling in breast cancer - molecularly distinct behavior of cathepsin K in breast cancer

Background: Breast cancer comprises clinically and molecularly distinct tumor subgroups that differ in cell histology and biology and show divergent clinical phenotypes that impede phase III trials, such as those utilizing cathepsin K inhibitors. Here we correlate the epithelial-mesenchymal-like transition breast cancer cells and cathepsin K secretion with activation and aggregation of platelets. Cathepsin K is up-regulated in cancer cells that proteolyze extracellular matrix and contributes to invasiveness. Although proteolytically activated receptors (PARs) are activated by proteases, the direct interaction of cysteine cathepsins with PARs is poorly understood. In human platelets, PAR-1 and -4 are highly expressed, but PAR-3 shows low expression and unclear functions. Methods: Platelet aggregation was monitored by measuring changes in turbidity. Platelets were immunoblotted with anti-phospho and total p38, Src-Tyr-416, FAK-Tyr-397, and TGF beta monoclonal antibody. Activation was measured in a flow cytometer and calcium mobilization in a confocal microscope. Mammary epithelial cells were prepared from the primary breast cancer samples of 15 women with Luminal-B subtype to produce primary cells. Results: We demonstrate that platelets are aggregated by cathepsin K in a dose-dependent manner, but not by other cysteine cathepsins. PARs-3 and -4 were confirmed as the cathepsin K target by immunodetection and specific antagonists using a fibroblast cell line derived from PARs deficient mice. Moreover, through co-culture experiments, we show that platelets activated by cathepsin K mediated the up-regulation of SHH, PTHrP, OPN, and TGF beta in epithelial-mesenchymal-like cells from patients with Luminal B breast cancer. Conclusions: Cathepsin K induces platelet dysfunction and affects signaling in breast cancer cells.Associacao Beneficente de Coleta de Sangue (Colsan)Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP)Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES)Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq)Univ Fed Sao Paulo, Dept Gynecol, BR-04024002 Sao Paulo, SP, BrazilCOLSAN, Charitable Assoc Blood Collect, BR-04080006 Sao Paulo, SP, BrazilUniv Fed Sao Paulo, Dept Biophys, BR-04024002 Sao Paulo, SP, BrazilUniv Fed Sao Paulo, Dept Biochem, BR-04024002 Sao Paulo, SP, BrazilAntonio Prudente Fdn, AC Camargo Canc Ctr, AC Camargo Hosp Biobank, Dept Pathol, BR-01509010 Sao Paulo, SP, BrazilUniv Fed Sao Paulo, Cellular Gynecol Lab, Dept Gynecol, Rua Napoleao Barros 608, BR-04024002 Sao Paulo, BrazilUniv Fed Sao Paulo, Dept Gynecol, BR-04024002 Sao Paulo, SP, BrazilUniv Fed Sao Paulo, Dept Biophys, BR-04024002 Sao Paulo, SP, BrazilUniv Fed Sao Paulo, Dept Biochem, BR-04024002 Sao Paulo, SP, BrazilUniv Fed Sao Paulo, Cellular Gynecol Lab, Dept Gynecol, Rua Napoleao Barros 608, BR-04024002 Sao Paulo, BrazilFAPESP: 2012/19780-3FAPESP: 2012/19851-8FAPESP: 2009/53766-5Web of Scienc

The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer.

Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1, BRCA2, PALB2, ATM, and CHEK2 are associated with breast cancer risk. FANCM, which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants FANCM:p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of BRCA1 or BRCA2. These three variants were also studied functionally by measuring survival and chromosome fragility in FANCM -/- patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that FANCM:p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44, P = 0.034 and OR = 3.79; P = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for FANCM:p.Arg658* and found that also FANCM:p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96; P = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with FANCM:p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare FANCM deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat FANCM-associated tumors

Fall prevention intervention technologies: A conceptual framework and survey of the state of the art

In recent years, an ever increasing range of technology-based applications have been developed with the goal of assisting in the delivery of more effective and efficient fall prevention interventions. Whilst there have been a number of studies that have surveyed technologies for a particular sub-domain of fall prevention, there is no existing research which surveys the full spectrum of falls prevention interventions and characterises the range of technologies that have augmented this landscape. This study presents a conceptual framework and survey of the state of the art of technology-based fall prevention systems which is derived from a systematic template analysis of studies presented in contemporary research literature. The framework proposes four broad categories of fall prevention intervention system: Pre-fall prevention; Post-fall prevention; Fall injury prevention; Cross-fall prevention. Other categories include, Application type, Technology deployment platform, Information sources, Deployment environment, User interface type, and Collaborative function. After presenting the conceptual framework, a detailed survey of the state of the art is presented as a function of the proposed framework. A number of research challenges emerge as a result of surveying the research literature, which include a need for: new systems that focus on overcoming extrinsic falls risk factors; systems that support the environmental risk assessment process; systems that enable patients and practitioners to develop more collaborative relationships and engage in shared decision making during falls risk assessment and prevention activities. In response to these challenges, recommendations and future research directions are proposed to overcome each respective challenge.The Royal Society, grant Ref: RG13082

Evidence that breast cancer risk at the 2q35 locus is mediated through IGFBP5 regulation.

GWAS have identified a breast cancer susceptibility locus on 2q35. Here we report the fine mapping of this locus using data from 101,943 subjects from 50 case-control studies. We genotype 276 SNPs using the 'iCOGS' genotyping array and impute genotypes for a further 1,284 using 1000 Genomes Project data. All but two, strongly correlated SNPs (rs4442975 G/T and rs6721996 G/A) are excluded as candidate causal variants at odds against >100:1. The best functional candidate, rs4442975, is associated with oestrogen receptor positive (ER+) disease with an odds ratio (OR) in Europeans of 0.85 (95% confidence interval=0.84-0.87; P=1.7 × 10(-43)) per t-allele. This SNP flanks a transcriptional enhancer that physically interacts with the promoter of IGFBP5 (encoding insulin-like growth factor-binding protein 5) and displays allele-specific gene expression, FOXA1 binding and chromatin looping. Evidence suggests that the g-allele confers increased breast cancer susceptibility through relative downregulation of IGFBP5, a gene with known roles in breast cell biology

Towards the development of agent-based organizations through MDD

Electronic version of an article published as International Journal on Artificial Intelligence Tools, 22, 2, 2013, DOI 10.1142/S0218213013500024 © World Scientific Publishing Company http://www.worldscientific.com/worldscinet/ijaitVirtual Organizations are a mechanism where agents can demonstrate their social skills since they can work in a cooperative and collaborative way. Nonetheless, the development of organizations using Multi-Agent Systems (MAS) requires extensive experience in different methodologies and platforms. Model-Driven Development (MDD) is a technique for generating application code that is developed from basic models and meta-models using a variety of automatic transformations. This paper presents an approach to develop and deploy organization-oriented Multi-Agent Systems using a model-driven approach. Based on this idea, we introduce a relatively generic agent-based meta-model for a Virtual Organization, which was created by a comprehensive analysis of the organization-oriented methodologies used in MAS. Following the MDD approach, the concepts and relationships obtained were mapped into two different platforms available for MAS development, allowing the validation of our proposal. In this way, the resultant approach can generate Virtual Organization deployments from unified meta-models, facilitating the development process of agent-based software from the user point of view.This work was partially supported by TIN2009-13839-C03-01 and PROMETEO/2008/051 projects of the Spanish government and CONSOLIDER-INGENIO 2010 under grant CSD2007-00022.Agüero, J.; Carrascosa Casamayor, C.; Rebollo Pedruelo, M.; Julian Inglada, VJ. (2013). Towards the development of agent-based organizations through MDD. International Journal on Artificial Intelligence Tools. 22(2):1-34. https://doi.org/10.1142/S0218213013500024S134222Argente, E., Julian, V., & Botti, V. (2006). Multi-Agent System Development Based on Organizations. Electronic Notes in Theoretical Computer Science, 150(3), 55-71. doi:10.1016/j.entcs.2006.03.005Bézivin, J. (2005). On the unification power of models. Software & Systems Modeling, 4(2), 171-188. doi:10.1007/s10270-005-0079-0Bresciani, P., Perini, A., Giorgini, P., Giunchiglia, F., & Mylopoulos, J. (2004). Tropos: An Agent-Oriented Software Development Methodology. Autonomous Agents and Multi-Agent Systems, 8(3), 203-236. doi:10.1023/b:agnt.0000018806.20944.efFoster, I., Kesselman, C., & Tuecke, S. (2001). The Anatomy of the Grid: Enabling Scalable Virtual Organizations. The International Journal of High Performance Computing Applications, 15(3), 200-222. doi:10.1177/109434200101500302Hahn, C., Madrigal-Mora, C., & Fischer, K. (2008). A platform-independent metamodel for multiagent systems. Autonomous Agents and Multi-Agent Systems, 18(2), 239-266. doi:10.1007/s10458-008-9042-0HORLING, B., & LESSER, V. (2004). A survey of multi-agent organizational paradigms. The Knowledge Engineering Review, 19(4), 281-316. doi:10.1017/s0269888905000317Huhns, M. N., & Singh, M. P. (2005). Service-oriented computing: key concepts and principles. IEEE Internet Computing, 9(1), 75-81. doi:10.1109/mic.2005.21Huhns, M. N., Singh, M. P., Burstein, M., Decker, K., Durfee, E., Finin, T., … Zavala, L. (2005). Research Directions for Service-Oriented Multiagent Systems. IEEE Internet Computing, 9(6), 65-70. doi:10.1109/mic.2005.132Kolp, M., Giorgini, P., & Mylopoulos, J. (2006). Multi-Agent Architectures as Organizational Structures. Autonomous Agents and Multi-Agent Systems, 13(1), 3-25. doi:10.1007/s10458-006-5717-6OHTANI, T., CASE, S., AZARMI, N., & THINT, M. (2002). AN INTELLIGENT SYSTEM FOR MANAGING AND UTILIZING INFORMATION RESOURCES OVER THE INTERNET. International Journal on Artificial Intelligence Tools, 11(01), 117-138. doi:10.1142/s0218213002000800Omicini, A., Ricci, A., & Viroli, M. (2005). RBAC for Organisation and Security in an Agent Coordination Infrastructure. Electronic Notes in Theoretical Computer Science, 128(5), 65-85. doi:10.1016/j.entcs.2004.11.045Papazoglou, M. P., & Georgakopoulos, D. (2003). Introduction. Communications of the ACM, 46(10), 24. doi:10.1145/944217.944233Papazoglou, M. P., Traverso, P., Dustdar, S., & Leymann, F. (2007). Service-Oriented Computing: State of the Art and Research Challenges. Computer, 40(11), 38-45. doi:10.1109/mc.2007.400Selic, B. (2003). The pragmatics of model-driven development. IEEE Software, 20(5), 19-25. doi:10.1109/ms.2003.1231146SKARMEAS, N. P., & CLARK, K. L. (2002). COMPONENT BASED AGENT CONSTRUCTION. International Journal on Artificial Intelligence Tools, 11(01), 139-163. doi:10.1142/s0218213002000812Zambonelli, F., Jennings, N. R., & Wooldridge, M. (2003). Developing multiagent systems. ACM Transactions on Software Engineering and Methodology, 12(3), 317-370. doi:10.1145/958961.95896