Creative clusters and innovation (C.Chapain, P.Cooke, L.De Propris, S.MacNeill, J.Mateos-Garcia, NESTA)

Copyright @ 2012 Intellec

Is our Sun a Singleton?

Most stars are formed in a cluster or association, where the number density of stars can be high. This means that a large fraction of initially-single stars will undergo close encounters with other stars and/or exchange into binaries. We describe how such close encounters and exchange encounters can affect the properties of a planetary system around a single star. We define a singleton as a single star which has never suffered close encounters with other stars or spent time within a binary system. It may be that planetary systems similar to our own solar system can only survive around singletons. Close encounters or the presence of a stellar companion will perturb the planetary system, often leaving planets on tighter and more eccentric orbits. Thus planetary systems which initially resembled our own solar system may later more closely resemble some of the observed exoplanet systems.Comment: 2 pages, 1 figure. To be published in the proceedings of IAUS246 "Dynamical Evolution of Dense Stellar Systems". Editors: E. Vesperini (Chief Editor), M. Giersz, A. Sill

A Method to Polarize Stored Antiprotons to a High Degree

Polarized antiprotons can be produced in a storage ring by spin--dependent interaction in a purely electron--polarized hydrogen gas target. The polarizing process is based on spin transfer from the polarized electrons of the target atoms to the orbiting antiprotons. After spin filtering for about two beam lifetimes at energies $T\approx 40-170$ MeV using a dedicated large acceptance ring, the antiproton beam polarization would reach $P=0.2-0.4$. Polarized antiprotons would open new and unique research opportunities for spin--physics experiments in $\bar{p}p$ interactions

Plasmodium falciparum Drug Resistance Genes pfmdr1 and pfcrt In Vivo Co-Expression During Artemether-Lumefantrine Therapy

Background: Artemisinin-based combination therapies (ACTs) are the global mainstay treatment of uncomplicated Plasmodium falciparum infections. PfMDR1 and PfCRT are two transmembrane transporters, associated with sensitivity to several antimalarials, found in the parasite food vacuole. Herein, we explore if their relatedness extends to overlapping patterns of gene transcriptional activity before and during ACT administration.Methods: In a clinical trial performed in Tanzania, we explored the pfmdr1 and pfcrt transcription levels from 48 patients with uncomplicated P. falciparum malaria infections who underwent treatment with artemether-lumefantrine (AL). Samples analyzed were collected before treatment initiation and during the first 24 h of treatment. The frequency of PfMDR1 N86Y and PfCRT K76T was determined through PCR-RFLP or direct amplicon sequencing. Gene expression was analyzed by real-time quantitative PCR.Results: A wide range of pre-treatment expression levels was observed for both genes, approximately 10-fold for pfcrt and 50-fold for pfmdr1. In addition, a significant positive correlation demonstrates pfmdr1 and pfcrt co-expression. After AL treatment initiation, pfmdr1 and pfcrt maintained the positive co-expression correlation, with mild downregulation throughout the 24 h post-treatment. Additionally, a trend was observed for PfMDR1 N86 alleles and higher expression before treatment initiation.Conclusion: pfmdr1 and pfcrt showed significant co-expression patterns in vivo, which were generally maintained during ACT treatment. This observation points to relevant related roles in the normal parasite physiology, which seem essential to be maintained when the parasite is exposed to drug stress. In addition, keeping the simultaneous expression of both transporters might be advantageous for responding to the drug action

The causes of epistasis

[EN] Since Bateson's discovery that genes can suppress the phenotypic effects of other genes, gene interactions-called epistasis-have been the topic of a vast research effort. Systems and developmental biologists study epistasis to understand the genotype-phenotype map, whereas evolutionary biologists recognize the fundamental importance of epistasis for evolution. Depending on its form, epistasis may lead to divergence and speciation, provide evolutionary benefits to sex and affect the robustness and evolvability of organisms. That epistasis can itself be shaped by evolution has only recently been realized. Here, we review the empirical pattern of epistasis, and some of the factors that may affect the form and extent of epistasis. Based on their divergent consequences, we distinguish between interactions with or without mean effect, and those affecting the magnitude of fitness effects or their sign. Empirical work has begun to quantify epistasis in multiple dimensions in the context of metabolic and fitness landscape models. We discuss possible proximate causes (such as protein function and metabolic networks) and ultimate factors (including mutation, recombination, and the importance of natural selection and genetic drift). We conclude that, in general, pleiotropy is an important prerequisite for epistasis, and that epistasis may evolve as an adaptive or intrinsic consequence of changes in genetic robustness and evolvability.We thank Fons Debets, Ryszard Korona, Alexey Kondrashov, Joachim Krug, Sijmen Schoustra and an anonymous reviewer for constructive comments, and funds from the European Union Seventh Framework Programme (FP7/2007-2013) under grant agreement 225167 (eFLUX), a visitor grant from Research School Production Ecology and Resource Conservation for S.F.E., and NSF grant DEB-0844355 for T.F.C.De Visser, JAGM.; Cooper, TF.; Elena Fito, SF. (2011). The causes of epistasis. Proceedings of the Royal Society B: Biological Sciences. 278(1725):3617-3624. https://doi.org/10.1098/rspb.2011.1537S361736242781725Costanzo, M., Baryshnikova, A., Bellay, J., Kim, Y., Spear, E. D., Sevier, C. S., … Mostafavi, S. (2010). The Genetic Landscape of a Cell. Science, 327(5964), 425-431. doi:10.1126/science.1180823Moore, J. H., & Williams, S. M. (2005). Traversing the conceptual divide between biological and statistical epistasis: systems biology and a more modern synthesis. BioEssays, 27(6), 637-646. doi:10.1002/bies.20236Phillips, P. C. (2008). Epistasis — the essential role of gene interactions in the structure and evolution of genetic systems. Nature Reviews Genetics, 9(11), 855-867. doi:10.1038/nrg2452Azevedo, R. B. R., Lohaus, R., Srinivasan, S., Dang, K. K., & Burch, C. L. (2006). Sexual reproduction selects for robustness and negative epistasis in artificial gene networks. Nature, 440(7080), 87-90. doi:10.1038/nature04488Desai, M. M., Weissman, D., & Feldman, M. W. (2007). Evolution Can Favor Antagonistic Epistasis. Genetics, 177(2), 1001-1010. doi:10.1534/genetics.107.075812Gros, P.-A., Le Nagard, H., & Tenaillon, O. (2009). The Evolution of Epistasis and Its Links With Genetic Robustness, Complexity and Drift in a Phenotypic Model of Adaptation. Genetics, 182(1), 277-293. doi:10.1534/genetics.108.099127Liberman, U., & Feldman, M. (2008). On the evolution of epistasis III: The haploid case with mutation. Theoretical Population Biology, 73(2), 307-316. doi:10.1016/j.tpb.2007.11.010Liberman, U., & Feldman, M. W. (2005). On the evolution of epistasis I: diploids under selection. Theoretical Population Biology, 67(3), 141-160. doi:10.1016/j.tpb.2004.11.001Liberman, U., Puniyani, A., & Feldman, M. W. (2007). On the evolution of epistasis II: A generalized Wright–Kimura framework. Theoretical Population Biology, 71(2), 230-238. doi:10.1016/j.tpb.2006.10.002Martin, O. C., & Wagner, A. (2009). Effects of Recombination on Complex Regulatory Circuits. Genetics, 183(2), 673-684. doi:10.1534/genetics.109.104174Misevic, D., Ofria, C., & Lenski, R. E. (2005). Sexual reproduction reshapes the genetic architecture of digital organisms. Proceedings of the Royal Society B: Biological Sciences, 273(1585), 457-464. doi:10.1098/rspb.2005.3338Bateson W. Saunders E. R. Punnett R. C.& Hurst C. C.. 1905 Reports to the Evolution Committee of the Royal Society Report II. London UK: Harrison and Sons.Fisher, R. A. (1919). XV.—The Correlation between Relatives on the Supposition of Mendelian Inheritance. Transactions of the Royal Society of Edinburgh, 52(2), 399-433. doi:10.1017/s0080456800012163Kondrashov, F. A., & Kondrashov, A. S. (2001). Multidimensional epistasis and the disadvantage of sex. Proceedings of the National Academy of Sciences, 98(21), 12089-12092. doi:10.1073/pnas.211214298Barton, N. H. (1995). A general model for the evolution of recombination. 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Journal of Evolutionary Biology, 16(5), 976-985. doi:10.1046/j.1420-9101.2003.00582.xJasnos, L., & Korona, R. (2007). Epistatic buffering of fitness loss in yeast double deletion strains. Nature Genetics, 39(4), 550-554. doi:10.1038/ng1986Lenski, R. E., Ofria, C., Collier, T. C., & Adami, C. (1999). Genome complexity, robustness and genetic interactions in digital organisms. Nature, 400(6745), 661-664. doi:10.1038/23245Maisnier-Patin, S., Roth, J. R., Fredriksson, Å., Nyström, T., Berg, O. G., & Andersson, D. I. (2005). Genomic buffering mitigates the effects of deleterious mutations in bacteria. Nature Genetics, 37(12), 1376-1379. doi:10.1038/ng1676Sanjuan, R., Moya, A., & Elena, S. F. (2004). The contribution of epistasis to the architecture of fitness in an RNA virus. Proceedings of the National Academy of Sciences, 101(43), 15376-15379. doi:10.1073/pnas.0404125101Zeyl, C. (2005). The Number of Mutations Selected During Adaptation in a Laboratory Population of Saccharomyces cerevisiae. Genetics, 169(4), 1825-1831. doi:10.1534/genetics.104.027102Peña, M. de la, Elena, S. F., & Moya, A. (2000). EFFECT OF DELETERIOUS MUTATION-ACCUMULATION ON THE FITNESS OF RNA BACTERIOPHAGE MS2. Evolution, 54(2), 686. doi:10.1554/0014-3820(2000)054[0686:eodmao]2.0.co;2De Visser, J. A. G. M., Hoekstra, R. F., & van den Ende, H. (1997). Test of Interaction Between Genetic Markers That Affect Fitness in Aspergillus niger. Evolution, 51(5), 1499. doi:10.2307/2411202Elena, S. F. (1999). Little Evidence for Synergism Among Deleterious Mutations in a Nonsegmented RNA Virus. Journal of Molecular Evolution, 49(5), 703-707. doi:10.1007/pl00000082Elena, S. F., & Lenski, R. E. (1997). Test of synergistic interactions among deleterious mutations in bacteria. Nature, 390(6658), 395-398. doi:10.1038/37108Hall, D. W., Agan, M., & Pope, S. C. (2010). Fitness Epistasis among 6 Biosynthetic Loci in the Budding Yeast Saccharomyces cerevisiae. Journal of Heredity, 101(Supplement 1), S75-S84. doi:10.1093/jhered/esq007Kelly, J. K. (2005). Epistasis in Monkeyflowers. Genetics, 171(4), 1917-1931. doi:10.1534/genetics.105.041525Segrè, D., DeLuna, A., Church, G. M., & Kishony, R. (2004). Modular epistasis in yeast metabolism. Nature Genetics, 37(1), 77-83. doi:10.1038/ng1489He, X., Qian, W., Wang, Z., Li, Y., & Zhang, J. (2010). Prevalent positive epistasis in Escherichia coli and Saccharomyces cerevisiae metabolic networks. Nature Genetics, 42(3), 272-276. doi:10.1038/ng.524Carneiro, M., & Hartl, D. L. (2009). Adaptive landscapes and protein evolution. Proceedings of the National Academy of Sciences, 107(suppl_1), 1747-1751. doi:10.1073/pnas.0906192106Franke, J., Klözer, A., de Visser, J. A. G. M., & Krug, J. (2011). Evolutionary Accessibility of Mutational Pathways. PLoS Computational Biology, 7(8), e1002134. doi:10.1371/journal.pcbi.1002134Weinreich, D. M. (2006). Darwinian Evolution Can Follow Only Very Few Mutational Paths to Fitter Proteins. Science, 312(5770), 111-114. doi:10.1126/science.1123539Lunzer, M. (2005). The Biochemical Architecture of an Ancient Adaptive Landscape. Science, 310(5747), 499-501. doi:10.1126/science.1115649O’Maille, P. E., Malone, A., Dellas, N., Andes Hess, B., Smentek, L., Sheehan, I., … Noel, J. P. (2008). Quantitative exploration of the catalytic landscape separating divergent plant sesquiterpene synthases. Nature Chemical Biology, 4(10), 617-623. doi:10.1038/nchembio.113Lozovsky, E. R., Chookajorn, T., Brown, K. M., Imwong, M., Shaw, P. J., Kamchonwongpaisan, S., … Hartl, D. L. (2009). Stepwise acquisition of pyrimethamine resistance in the malaria parasite. Proceedings of the National Academy of Sciences, 106(29), 12025-12030. doi:10.1073/pnas.0905922106De Visser, J. A. G. M., Park, S., & Krug, J. (2009). Exploring the Effect of Sex on Empirical Fitness Landscapes. The American Naturalist, 174(S1), S15-S30. doi:10.1086/599081Khan, A. I., Dinh, D. M., Schneider, D., Lenski, R. E., & Cooper, T. F. (2011). Negative Epistasis Between Beneficial Mutations in an Evolving Bacterial Population. Science, 332(6034), 1193-1196. doi:10.1126/science.1203801Chou, H.-H., Chiu, H.-C., Delaney, N. F., Segre, D., & Marx, C. J. (2011). Diminishing Returns Epistasis Among Beneficial Mutations Decelerates Adaptation. Science, 332(6034), 1190-1192. doi:10.1126/science.1203799Da Silva, J., Coetzer, M., Nedellec, R., Pastore, C., & Mosier, D. E. (2010). Fitness Epistasis and Constraints on Adaptation in a Human Immunodeficiency Virus Type 1 Protein Region. Genetics, 185(1), 293-303. doi:10.1534/genetics.109.112458Hinkley, T., Martins, J., Chappey, C., Haddad, M., Stawiski, E., Whitcomb, J. M., … Bonhoeffer, S. (2011). A systems analysis of mutational effects in HIV-1 protease and reverse transcriptase. Nature Genetics, 43(5), 487-489. doi:10.1038/ng.795Kvitek, D. J., & Sherlock, G. (2011). Reciprocal Sign Epistasis between Frequently Experimentally Evolved Adaptive Mutations Causes a Rugged Fitness Landscape. PLoS Genetics, 7(4), e1002056. doi:10.1371/journal.pgen.1002056MacLean, R. C., Perron, G. G., & Gardner, A. (2010). Diminishing Returns From Beneficial Mutations and Pervasive Epistasis Shape the Fitness Landscape for Rifampicin Resistance in Pseudomonas aeruginosa. Genetics, 186(4), 1345-1354. doi:10.1534/genetics.110.123083Rokyta, D. R., Joyce, P., Caudle, S. B., Miller, C., Beisel, C. J., & Wichman, H. A. (2011). Epistasis between Beneficial Mutations and the Phenotype-to-Fitness Map for a ssDNA Virus. PLoS Genetics, 7(6), e1002075. doi:10.1371/journal.pgen.1002075Salverda, M. L. M., Dellus, E., Gorter, F. A., Debets, A. J. M., van der Oost, J., Hoekstra, R. F., … de Visser, J. A. G. M. (2011). Initial Mutations Direct Alternative Pathways of Protein Evolution. PLoS Genetics, 7(3), e1001321. doi:10.1371/journal.pgen.1001321Hayashi, Y., Aita, T., Toyota, H., Husimi, Y., Urabe, I., & Yomo, T. (2006). Experimental Rugged Fitness Landscape in Protein Sequence Space. PLoS ONE, 1(1), e96. doi:10.1371/journal.pone.0000096De Visser, J. A. G., & Lenski, R. E. (2002). BMC Evolutionary Biology, 2(1), 19. doi:10.1186/1471-2148-2-19Kryazhimskiy, S., Tkacik, G., & Plotkin, J. B. (2009). The dynamics of adaptation on correlated fitness landscapes. Proceedings of the National Academy of Sciences, 106(44), 18638-18643. doi:10.1073/pnas.0905497106Lehner, B. (2011). Molecular mechanisms of epistasis within and between genes. Trends in Genetics, 27(8), 323-331. doi:10.1016/j.tig.2011.05.007Feist, A. M., Henry, C. S., Reed, J. L., Krummenacker, M., Joyce, A. R., Karp, P. D., … Palsson, B. Ø. (2007). A genome‐scale metabolic reconstruction for Escherichia coli K‐12 MG1655 that accounts for 1260 ORFs and thermodynamic information. Molecular Systems Biology, 3(1), 121. doi:10.1038/msb4100155Szappanos, B., Kovács, K., Szamecz, B., Honti, F., Costanzo, M., Baryshnikova, A., … Papp, B. (2011). An integrated approach to characterize genetic interaction networks in yeast metabolism. Nature Genetics, 43(7), 656-662. doi:10.1038/ng.846Dean, A. M., Dykhuizen, D. E., & Hartl, D. L. (1986). Fitness as a function of β-galactosidase activity in Escherichia coli. Genetical Research, 48(1), 1-8. doi:10.1017/s0016672300024587Trindade, S., Sousa, A., Xavier, K. B., Dionisio, F., Ferreira, M. G., & Gordo, I. (2009). Positive Epistasis Drives the Acquisition of Multidrug Resistance. PLoS Genetics, 5(7), e1000578. doi:10.1371/journal.pgen.1000578Agrawal, A. F., & Whitlock, M. C. (2010). Environmental duress and epistasis: how does stress affect the strength of selection on new mutations? Trends in Ecology & Evolution, 25(8), 450-458. doi:10.1016/j.tree.2010.05.003Bonhoeffer, S. (2004). Evidence for Positive Epistasis in HIV-1. Science, 306(5701), 1547-1550. doi:10.1126/science.1101786Burch, C. L., & Chao, L. (2004). Epistasis and Its Relationship to Canalization in the RNA Virus φ6. Genetics, 167(2), 559-567. doi:10.1534/genetics.103.021196Martin, G., Elena, S. F., & Lenormand, T. (2007). Distributions of epistasis in microbes fit predictions from a fitness landscape model. Nature Genetics, 39(4), 555-560. doi:10.1038/ng1998DePristo, M. A., Weinreich, D. M., & Hartl, D. L. (2005). Missense meanderings in sequence space: a biophysical view of protein evolution. Nature Reviews Genetics, 6(9), 678-687. doi:10.1038/nrg1672Wang, X., Minasov, G., & Shoichet, B. K. (2002). Evolution of an Antibiotic Resistance Enzyme Constrained by Stability and Activity Trade-offs. Journal of Molecular Biology, 320(1), 85-95. doi:10.1016/s0022-2836(02)00400-xBjörkman, J. (2000). Effects of Environment on Compensatory Mutations to Ameliorate Costs of Antibiotic Resistance. 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The Rate of Compensatory Mutation in the DNA Bacteriophage φX174. Genetics, 170(3), 989-999. doi:10.1534/genetics.104.039438Remold, S. K., & Lenski, R. E. (2004). Pervasive joint influence of epistasis and plasticity on mutational effects in Escherichia coli. Nature Genetics, 36(4), 423-426. doi:10.1038/ng1324Crow, J. F., & Kimura, M. (1979). Efficiency of truncation selection. Proceedings of the National Academy of Sciences, 76(1), 396-399. doi:10.1073/pnas.76.1.396Hamilton, W. D., Axelrod, R., & Tanese, R. (1990). Sexual reproduction as an adaptation to resist parasites (a review). Proceedings of the National Academy of Sciences, 87(9), 3566-3573. doi:10.1073/pnas.87.9.3566Jasnos, L., Tomala, K., Paczesniak, D., & Korona, R. (2008). Interactions Between Stressful Environment and Gene Deletions Alleviate the Expected Average Loss of Fitness in Yeast. Genetics, 178(4), 2105-2111. doi:10.1534/genetics.107.084533Kishony, R., & Leibler, S. (2003). 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PLoS ONE, 3(3), e1715. doi:10.1371/journal.pone.0001715Kashtan, N., & Alon, U. (2005). Spontaneous evolution of modularity and network motifs. Proceedings of the National Academy of Sciences, 102(39), 13773-13778. doi:10.1073/pnas.0503610102De Visser, J. A. G. M., Hermisson, J., Wagner, G. P., Meyers, L. A., Bagheri-Chaichian, H., Blanchard, J. L., … Whitlock, M. C. (2003). PERSPECTIVE:EVOLUTION AND DETECTION OF GENETIC ROBUSTNESS. Evolution, 57(9), 1959. doi:10.1554/02-750rWilke, C. O., & Christoph, A. (2001). Interaction between directional epistasis and average mutational effects. Proceedings of the Royal Society of London. Series B: Biological Sciences, 268(1475), 1469-1474. doi:10.1098/rspb.2001.1690Sanjuan, R., & Elena, S. F. (2006). Epistasis correlates to genomic complexity. Proceedings of the National Academy of Sciences, 103(39), 14402-14405. doi:10.1073/pnas.0604543103Sanjuán, R., & Nebot, M. R. (2008). 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J., Ferrada, E., & Wagner, A. (2011). Cryptic genetic variation promotes rapid evolutionary adaptation in an RNA enzyme. Nature, 474(7349), 92-95. doi:10.1038/nature1008

Universal Rights and Wrongs

This paper argues for the important role of customers as a source of competitive advantage and firm growth, an issue which has been largely neglected in the resource-based view of the firm. It conceptualizes Penrose’s (1959) notion of an ‘inside track’ and illustrates how in-depth knowledge about established customers combines with joint problem-solving activities and the rapid assimilation of new and previously unexploited skills and resources. It is suggested that the inside track represents a distinct and perhaps underestimated way of generating rents and securing long-term growth. This also implies that the sources of sustainable competitive advantage in important respects can be sought in idiosyncratic interfirm relationships rather than within the firm itself

Adiponectin, free fatty acids, and cardiovascular outcomes in patients with type 2 diabetes and acute coronary syndrome

OBJECTIVE: In observational cohorts, adiponectin is inversely associated and free fatty acids (FFAs) are directly associated with incident coronary heart disease (CHD). Adiponectin tends to be reduced and FFAs elevated in type 2 diabetes. We investigated relationships of adiponectin and FFA and major adverse cardiovascular events (MACEs) and death in patients with acute coronary syndrome (ACS) and type 2 diabetes using data from the AleCardio trial, which compared the PPAR-α/γ agonist aleglitazar with placebo. RESEARCH DESIGN AND METHODS: Using Cox regression adjusted for demographic, laboratory, and treatment variables, we determined associations of baseline adiponectin and FFAs, or the change in adiponectin and FFAs from baseline, with MACEs (cardiovascular death, myocardial infarction, or stroke) and death. RESULTS: A twofold higher baseline adiponectin (n = 6,998) was directly associated with risk of MACEs (hazard ratio [HR] 1.17 [95% CI 1.08-1.27]) and death (HR 1.53 [95% CI 1.35-1.73]). A doubling of adiponectin from baseline to month 3 (n = 6,325) was also associated with risk of death (HR 1.20 [95% CI 1.03-1.41]). Baseline FFAs (n = 7,038), but not change in FFAs from baseline (n = 6,365), were directly associated with greater risk of MACEs and death. There were no interactions with study treatment. CONCLUSIONS: In contrast to prior observational data for incident CHD, adiponectin is prospectively associated with MACEs and death in patients with type 2 diabetes and ACS, and an increase in adiponectin from baseline is directly related to death. These findings raise the possibility that adiponectin has different effects in patients with type 2 diabetes and ACS than in populations without prevalent cardiovascular disease. Consistent with prior data, FFAs are directly associated with adverse outcomes

Study protocol for a randomized controlled trial of supportive parents – coping kids (SPARCK)—a transdiagnostic and personalized parent training intervention to prevent childhood mental health problems

Background: To meet the scientific and political call for effective prevention of child and youth mental health problems and associated long-term consequences, we have co-created, tested, and optimized a transdiagnostic preventive parent-training intervention, Supportive parents – coping kids (SPARCK), together with and for the municipal preventive frontline services. The target group of SPARCK is parents of children between 4 and 12 years who display symptoms of anxiety, depression, and/or behavioral problems, that is, indicated prevention. The intervention consists of components from various empirically supported interventions representing different theorical models on parent–child interactions and child behavior and psychopathology (i.e., behavioral management interventions, attachment theory, emotion socialization theory, cognitive-behavioral therapy, and family accommodation intervention). The content and target strategies of SPARCK are tailored to the needs of the families and children, and the manual suggests how the target strategies may be personalized and combined throughout the maximum 12 sessions of the intervention. The aim of this project is to investigate the effectiveness of SPARCK on child symptoms, parenting practices, and parent and child stress hormone levels, in addition to later use of specialized services compared with usual care (UC; eg. active comparison group). Methods: We describe a randomized controlled effectiveness trial in the frontline services of child welfare, health, school health and school psychological counselling services in 24 Norwegian municipalities. It is a two-armed parallel group randomized controlled effectiveness and superiority trial with 252 families randomly allocated to SPARCK or UC. Assessment of key variables will be conducted at pre-, post-, and six-month follow-up. Discussion: The current study will contribute with knowledge on potential effects of a preventive transdiagnostic parent-training intervention when compared with UC. Our primary objective is to innovate frontline services with a usable, flexible, and effective intervention for prevention of childhood mental health problems to promote equity in access to care for families and children across a heterogeneous service landscape characterized by variations in available resources, personnel, and end user symptomatology. Trial registration: ClinicalTrials.gov ID: NTCT0580052

Calcitonin gene-related peptide promotes cellular changes in trigeminal neurons and glia implicated in peripheral and central sensitization

<p>Abstract</p> <p>Background</p> <p>Calcitonin gene-related peptide (CGRP), a neuropeptide released from trigeminal nerves, is implicated in the underlying pathology of temporomandibular joint disorder (TMD). Elevated levels of CGRP in the joint capsule correlate with inflammation and pain. CGRP mediates neurogenic inflammation in peripheral tissues by increasing blood flow, recruiting immune cells, and activating sensory neurons. The goal of this study was to investigate the capability of CGRP to promote peripheral and central sensitization in a model of TMD.</p> <p>Results</p> <p>Temporal changes in protein expression in trigeminal ganglia and spinal trigeminal nucleus were determined by immunohistochemistry following injection of CGRP in the temporomandibular joint (TMJ) capsule of male Sprague-Dawley rats. CGRP stimulated expression of the active forms of the MAP kinases p38 and ERK, and PKA in trigeminal ganglia at 2 and 24 hours. CGRP also caused a sustained increase in the expression of c-Fos neurons in the spinal trigeminal nucleus. In contrast, levels of P2X₃in spinal neurons were only significantly elevated at 2 hours in response to CGRP. In addition, CGRP stimulated expression of GFAP in astrocytes and OX-42 in microglia at 2 and 24 hours post injection.</p> <p>Conclusions</p> <p>Our results demonstrate that an elevated level of CGRP in the joint, which is associated with TMD, stimulate neuronal and glial expression of proteins implicated in the development of peripheral and central sensitization. Based on our findings, we propose that inhibition of CGRP-mediated activation of trigeminal neurons and glial cells with selective non-peptide CGRP receptor antagonists would be beneficial in the treatment of TMD.</p