Clades and clans: a comparison study of two evolutionary models

The Yule-Harding-Kingman (YHK) model and the proportional to distinguishable arrangements (PDA) model are two binary tree generating models that are widely used in evolutionary biology. Understanding the distributions of clade sizes under these two models provides valuable insights into macro-evolutionary processes, and is important in hypothesis testing and Bayesian analyses in phylogenetics. Here we show that these distributions are log-convex, which implies that very large clades or very small clades are more likely to occur under these two models. Moreover, we prove that there exists a critical value $\kappa(n)$ for each $n\geqslant 4$ such that for a given clade with size $k$, the probability that this clade is contained in a random tree with $n$ leaves generated under the YHK model is higher than that under the PDA model if $1<k<\kappa(n)$, and lower if $\kappa(n)<k<n$. Finally, we extend our results to binary unrooted trees, and obtain similar results for the distributions of clan sizes.Comment: 21page

Orientia tsutsugamushi in Human Scrub Typhus Eschars Shows Tropism for Dendritic Cells and Monocytes Rather than Endothelium

Scrub typhus is a common and underdiagnosed cause of febrile illness in Southeast Asia, caused by infection with Orientia tsutsugamushi. Inoculation of the organism at a cutaneous mite bite site commonly results in formation of a localized pathological skin reaction termed an eschar. The site of development of the obligate intracellular bacteria within the eschar and the mechanisms of dissemination to cause systemic infection are unclear. Previous postmortem and in vitro reports demonstrated infection of endothelial cells, but recent pathophysiological investigations of typhus patients using surrogate markers of endothelial cell and leucocyte activation indicated a more prevalent host leucocyte than endothelial cell response in vivo. We therefore examined eschar skin biopsies from patients with scrub typhus to determine and characterize the phenotypes of host cells in vivo with intracellular infection by O. tsutsugamushi, using histology, immunohistochemistry, double immunofluorescence confocal laser scanning microscopy and electron microscopy. Immunophenotyping of host leucocytes infected with O. tsutsugamushi showed a tropism for host monocytes and dendritic cells, which were spatially related to different histological zones of the eschar. Infected leucocyte subsets were characterized by expression of HLADR+, with an “inflammatory” monocyte phenotype of CD14/LSP-1/CD68 positive or dendritic cell phenotype of CD1a/DCSIGN/S100/FXIIIa and CD163 positive staining, or occasional CD3 positive T-cells. Endothelial cell infection was rare, and histology did not indicate a widespread inflammatory vasculitis as the cause of the eschar. Infection of dendritic cells and activated inflammatory monocytes offers a potential route for dissemination of O. tsutsugamushi from the initial eschar site. This newly described cellular tropism for O. tsutsugamushi may influence its interaction with local host immune responses

Anxiety and self-esteem as mediators of the relation between family communication and indecisiveness in adolescence

Abstract In this study, we explored the unique and common contributions of anxiety, self-esteem, and family communication on indecisiveness among adolescents. Three hundred and fifty pupils from 13 to 16 years of age completed selfreport measures on indecisiveness, quality of family communication, trait anxiety, and self-esteem. The findings in this study showed that students\u2019 indecisiveness is predicted by family communication mediated by anxiety and self-esteem. These results have important implications for practice as it stresses the importance of anxiety and self-esteem. Nevertheless, the counselors could also focus on enhancing relationship-building skills by introducing the adolescents\u2019 career formation as an adolescent\u2013parent joint project.L\u2019anxie\ub4te\ub4 et l\u2019estime de soi comme me\ub4diateurs de la relation entre communication au sein de la famille et indecision chronique a` l\u2019adolescence. Dans cette e\ub4tude, nous avons explore\ub4 les contributions uniques et communes de l\u2019anxiete\ub4, de l\u2019estime de soi et de la communication au sein de la famille sur l\u2019indecision chronique aupres d\u2019adolescents. Trois cent cinquante e\ub4le`ves a\u2c6ge\ub4s de 13 a` 16 ans ont rempli des mesures d\u2019auto-e\ub4valuation de l\u2019inde\ub4cision chronique, de la qualite\ub4 de la communication familiale, de l\u2019anxie\ub4te\ub4-trait et de l\u2019estime de soi. Les re\ub4sultats de cette e\ub4tude ont montre\ub4 que l\u2019inde\ub4cision des e\ub4tudiants est explique\ub4e par la communication au sein de la famille et que ce lien est me\ub4diatise\ub4 par l\u2019anxie\ub4te\ub4 et l\u2019estime de soi. Ces re\ub4sultats ont des implications importantes pour la pratique car ils soulignent l\u2019importance de l\u2019anxie\ub4te\ub4 et l\u2019estime de soi. Ne\ub4anmoins, les conseillers pourraient e\ub4galement se concentrer sur l\u2019ame\ub4lioration des compe\ub4tences de construction relationnelle en introduisant la formation professionnelle des adolescents comme un projet conjoint adolescent-parent.Resumen. Ansiedad y Autoestima como Mediadores de la Relacio\ub4n entre Comunicacio\ub4n Familiar e Indecisio\ub4n en la Adolescencia. En este estudio, exploramos las contribuciones u\ub4nicas y comunes de la ansiedad, la autoestima y la comunicacio\ub4n de familia en la indecisio\ub4n de los adolescentes. Tres y cientos cincuenta alumnos entre los 13 y 16 an\u2dcos completaron auto-evaluaciones sobre la indecisio\ub4n, la calidad de comunicacio\ub4n familiar, los rasgos de ansiedad y la autoestima. Los resultados en este estudio muestran que la indecisio\ub4n en los estudiantes es prevista por la comunicacio\ub4n familiar mediada por la ansiedad y la autoestima. Estos resultados tiene importantes implicaciones para la practica ya que destacan la importancia de la ansiedad y la autoestima. Sin embargo, los consejeros podr\u131\ub4an tambie\ub4n focalizarse en el aumento de sus habilidades para construir relaciones mediante la introduccio\ub4n de la formacio\ub4n profesional para adolescentes como un proyecto conjunto del adolescente-padre.Angst und Selbstwertgefu\ua8 hl als Mediatoren der Beziehung zwischen Kommunikation in der Familie und Unentschlossenheit in der Adoleszenz. In dieser Studie untersuchten wir die spezifischen und gemeinsamen Beitra\ua8ge von Angst, Selbstwertgefu\ua8hl und Kommunikation in der Familie auf Unentschlossenheit unter Jugendlichen. Dreihundertfu\ua8nfzig Schu\ua8ler, zwischen 13 bis 16 Jahre alt, fu\ua8llten Skalen zur Unentschlossenheit, Qualita\ua8t der Kommunikation in der Familie, A\ua8 ngstlichkeit und Selbstwertgefu\ua8hl aus. Die Ergebnisse dieser Studie zeigten, dass Unentschlossenheit der Schu\ua8ler von Kommunikation in der Familie vorhergesagt wird, vermittelt durch Angst und Selbstwertgefu\ua8 hl. Diese Ergebnisse haben wichtige Implikationen fu\ua8r die Praxis, da sie die Bedeutung von Angst und Selbstwertgefu\ua8hl hervorheben. Dennoch ko\ua8nnten sich die Beratungspersonen durch die Einfu\ua8hrung der beruflichen Bildung der Jugendlichen als ein gemeinsames Projekt von Jugendliche-Elternteil auch auf die Verbesserung der Fa\ua8higkeiten zum Aufbau von Beziehungen konzentrieren

"Open Innovation" and "Triple Helix" Models of Innovation: Can Synergy in Innovation Systems Be Measured?

The model of "Open Innovations" (OI) can be compared with the "Triple Helix of University-Industry-Government Relations" (TH) as attempts to find surplus value in bringing industrial innovation closer to public R&D. Whereas the firm is central in the model of OI, the TH adds multi-centeredness: in addition to firms, universities and (e.g., regional) governments can take leading roles in innovation eco-systems. In addition to the (transversal) technology transfer at each moment of time, one can focus on the dynamics in the feedback loops. Under specifiable conditions, feedback loops can be turned into feedforward ones that drive innovation eco-systems towards self-organization and the auto-catalytic generation of new options. The generation of options can be more important than historical realizations ("best practices") for the longer-term viability of knowledge-based innovation systems. A system without sufficient options, for example, is locked-in. The generation of redundancy -- the Triple Helix indicator -- can be used as a measure of unrealized but technologically feasible options given a historical configuration. Different coordination mechanisms (markets, policies, knowledge) provide different perspectives on the same information and thus generate redundancy. Increased redundancy not only stimulates innovation in an eco-system by reducing the prevailing uncertainty; it also enhances the synergy in and innovativeness of an innovation system.Comment: Journal of Open Innovations: Technology, Market and Complexity, 2(1) (2016) 1-12; doi:10.1186/s40852-016-0039-

Phenotypic and functional analysis of lymphocytes infiltrating osteolytic tumors: use as a possible therapeutic approach of osteosarcoma

BACKGROUND: Osteosarcoma is the most common type of primary bone tumor. The use of aggressive chemotherapy has drastically improved the prognosis of the patients with non-metastatic osteosarcomas, however the prognosis of the patients with metastasis is still very poor. Then, new and more effective treatments for curing osteosarcoma, such as immunotherapy are needed. Tumor-infiltrating lymphocytes (TIL) have been involved in the control of tumor development and already assessed with success for the treatment of several cancers including melanoma. While TIL represent a fascinating therapeutic approach in numerous malignant pathologies, there is few report concerning adult bone-associated tumors including osteosarcoma. METHODS: Human TIL were isolated and characterized (phenotype, lytic activity) from twenty-seven patients with bone-associated tumors (osteosarcoma, Ewing's sarcoma, giant cell tumor, chondrosarcoma, plasmocytoma and bone metastases). Similar experiments were performed using rat osteosarcoma model. RESULTS: While TIL with a main CD4(+ )profile were easily isolated from most of the tumor samples, only TIL extracted from osteosarcoma were cytotoxic against allogeneic tumor cells. In all cases, TIL lytic activity was significantly higher compared to autologous peripheral blood leukocytes. Similar data were observed in rat osteosarcoma model where TIL were characterized by a main CD4(+ )profile and high lytic activity against allogeneic and autologous tumor cells. Moreover, rat TIL expansion was not accompanied by refractoriness to further activation stimulus mainly by tumor antigens. CONCLUSION: These results demonstrated that TIL therapy could be a very efficient strategy for the treatment of adult osteosarcoma

An Initial In Vitro Investigation into the Potential Therapeutic Use of SupT1 Cells to Prevent AIDS in HIV-Seropositive Individuals

HIV infection usually leads to a progressive decline in number and functionality of CD4+ T lymphocytes, resulting in AIDS development. In this study, I investigated the strategy of using inoculated SupT1 cells to move infection from HIV-1 X4 strains toward the inoculated cells, which should theoretically prevent infection and depletion of normal CD4+ T cells, preventing the development of AIDS-related pathologies. Interestingly, the persistent in vitro replication in SupT1 cells renders the virus less cytopathic and more sensitive to antibody-mediated neutralization, suggesting that replication of the virus in the inoculated SupT1 cells may have a vaccination effect in the long run. In order to mimic the scenario of a therapy in which SupT1 cells are inoculated in an HIV-seropositive patient, I used infected SupT1/PBMC cocultures and a series of control experiments. Infections were done with equal amounts of the wild type HIV-1 LAI virus. The SupT1 CD4+CD8+ T cell population was distinguished from the PBMC CD4+CD8− T cell population by FACS analysis. The results of this study show that the virus-mediated killing of primary CD4+ T cells in the SupT1/PBMC cocultures was significantly delayed, suggesting that the preferential infection of SupT1 cells can induce the virus to spare primary CD4+ T cells from infection and depletion. The preferential infection of SupT1 cells can be explained by the higher viral tropism for the SupT1 cell line. In conclusion, this study demonstrates that it's possible in an in vitro system to use SupT1 cells to prevent HIV infection of primary CD4+ T cells, suggesting that further exploration of the SupT1 cell line as a cell-based therapy against HIV-1 may prove worthwhile

Phylogenetic Codivergence Supports Coevolution of Mimetic Heliconius Butterflies

The unpalatable and warning-patterned butterflies _Heliconius erato_ and _Heliconius melpomene_ provide the best studied example of mutualistic M&#xfc;llerian mimicry, thought &#x2013; but rarely demonstrated &#x2013; to promote coevolution. Some of the strongest available evidence for coevolution comes from phylogenetic codivergence, the parallel divergence of ecologically associated lineages. Early evolutionary reconstructions suggested codivergence between mimetic populations of _H. erato_ and _H. melpomene_, and this was initially hailed as the most striking known case of coevolution. However, subsequent molecular phylogenetic analyses found discrepancies in phylogenetic branching patterns and timing (topological and temporal incongruence) that argued against codivergence. We present the first explicit cophylogenetic test of codivergence between mimetic populations of _H. erato_ and _H. melpomene_, and re-examine the timing of these radiations. We find statistically significant topological congruence between multilocus coalescent population phylogenies of _H. erato_ and _H. melpomene_, supporting repeated codivergence of mimetic populations. Divergence time estimates, based on a Bayesian coalescent model, suggest that the evolutionary radiations of _H. erato_ and _H. melpomene_ occurred over the same time period, and are compatible with a series of temporally congruent codivergence events. This evidence supports a history of reciprocal coevolution between M&#xfc;llerian co-mimics characterised by phylogenetic codivergence and parallel phenotypic change

Inference of population splits and mixtures from genome-wide allele frequency data

Many aspects of the historical relationships between populations in a species are reflected in genetic data. Inferring these relationships from genetic data, however, remains a challenging task. In this paper, we present a statistical model for inferring the patterns of population splits and mixtures in multiple populations. In this model, the sampled populations in a species are related to their common ancestor through a graph of ancestral populations. Using genome-wide allele frequency data and a Gaussian approximation to genetic drift, we infer the structure of this graph. We applied this method to a set of 55 human populations and a set of 82 dog breeds and wild canids. In both species, we show that a simple bifurcating tree does not fully describe the data; in contrast, we infer many migration events. While some of the migration events that we find have been detected previously, many have not. For example, in the human data we infer that Cambodians trace approximately 16% of their ancestry to a population ancestral to other extant East Asian populations. In the dog data, we infer that both the boxer and basenji trace a considerable fraction of their ancestry (9% and 25%, respectively) to wolves subsequent to domestication, and that East Asian toy breeds (the Shih Tzu and the Pekingese) result from admixture between modern toy breeds and "ancient" Asian breeds. Software implementing the model described here, called TreeMix, is available at http://treemix.googlecode.comComment: 28 pages, 6 figures in main text. Attached supplement is 22 pages, 15 figures. This is an updated version of the preprint available at http://precedings.nature.com/documents/6956/version/

Regional Genetic Structure in the Aquatic Macrophyte Ruppia cirrhosa Suggests Dispersal by Waterbirds

The evolutionary history of the genus Ruppia has been shaped by hybridization, polyploidisation and vicariance that have resulted in a problematic taxonomy. Recent studies provided insight into species circumscription, organelle takeover by hybridization, and revealed the importance of verifying species identification to avoid distorting effects of mixing different species, when estimating population connectivity. In the present study, we use microsatellite markers to determine population diversity and connectivity patterns in Ruppia cirrhosa including two spatial scales: (1) from the Atlantic Iberian coastline in Portugal to the Siculo-Tunisian Strait in Sicily and (2) within the Iberian Peninsula comprising the Atlantic-Mediterranean transition. The higher diversity in the Mediterranean Sea suggests that populations have had longer persistence there, suggesting a possible origin and/or refugial area for the species. The high genotypic diversities highlight the importance of sexual reproduction for survival and maintenance of populations. Results revealed a regional population structure matching a continent-island model, with strong genetic isolation and low gene flow between populations. This population structure could be maintained by waterbirds, acting as occasional dispersal vectors. This information elucidates ecological strategies of brackish plant species in coastal lagoons, suggesting mechanisms used by this species to colonize new isolated habitats and dominate brackish aquatic macrophyte systems, yet maintaining strong genetic structure suggestive of very low dispersal.Fundacao para a Cincia e Tecnologia (FCT, Portugal) [PTDC/MAR/119363/2010, BIODIVERSA/0004/2015, UID/Multi/04326/2013]Pew FoundationSENECA FoundationMurcia Government, Spain [11881/PI/09]FCT Investigator Programme-Career Development [IF/00998/2014]Spanish Ministry of Education [AP2008-01209]European Community [00399/2012]info:eu-repo/semantics/publishedVersio

Tumor-Targeted Delivery of IL-2 by NKG2D Leads to Accumulation of Antigen-Specific CD8+ T Cells in the Tumor Loci and Enhanced Anti-Tumor Effects

Interleukin-2 (IL-2) has been shown to promote tumor-specific T-cell proliferation and differentiation but systemic administration of IL-2 results in significant toxicity. Therefore, a strategy that can specifically deliver IL-2 to the tumor location may alleviate concerns of toxicity. Because NKG2D ligands have been shown to be highly expressed in many cancer cells but not in healthy cells, we reason that a chimeric protein consisting of NKG2D linked to IL-2 will lead to the specific targeting of IL-2 to the tumor location. Therefore, we created chimeric proteins consisting of NKG2D linked to Gaussia luciferase (GLuc; a marker protein) or IL-2 to form NKG2D-Fc-GLuc and NKG2D-Fc-IL2, respectively. We demonstrated that NKG2D linked to GLuc was able to deliver GLuc to the tumor location in vivo. Furthermore, we showed that TC-1 tumor-bearing mice intramuscularly injected with DNA encoding NKG2D-Fc-IL2, followed by electroporation, exhibited an increased number of luciferase-expressing E7-specific CD8+ T cells at the tumor location. More importantly, treatment with the DNA construct encoding NKG2D-Fc-IL2 significantly enhanced the therapeutic anti-tumor effects generated by intradermal vaccination with therapeutic HPV DNA in tumor-bearing mice. Therefore, by linking NKG2D to IL2, we are able to specifically deliver IL-2 to the tumor location, enhancing antigen-specific T-cell immune response and controlling tumor growth. Our approach represents a platform technology to specifically deliver proteins of interest to tumor loci