Isolation of a novel monkey adenovirus reveals a new phylogenetic clade in the evolutionary history of simian adenoviruses

Adenoviruses of primates include human (HAdV) and simian (SAdV) isolates classified into 8 species (Human Adenovirus A to G, and Simian Adenovirus A). In this study, a novel adenovirus was isolated from a colony of cynomolgus macaques (Macaca fascicularis) and subcultured in VERO cells. Its complete genome was purified and a region encompassing the hexon gene, the protease gene, the DNA binding protein (DBP) and the 100 kDa protein was amplified by PCR and sequenced by primer walking. Sequence analysis of these four genes showed that the new isolate had 80% identity to other primate adenoviruses and lacked recombination events. The study of the evolutionary relationships of this new monkey AdV based on the combined sequences of the four genes supported a close relationship to SAdV-3 and SAdV-6, lineages isolated from Rhesus monkeys. The clade formed by these three types is separated from the remaining clades and establishes a novel branch that is related to species HAdV-A, F and G. However, the genetic distance corresponding to the newly isolated monkey AdV considerably differs from these as to belong to a new, not yet established species. Results presented here widen our knowledge on SAdV and represents an important contribution to the understanding of the evolutionary history of primate adenoviruses.

Bootstrapping pairs in Distance-Based Regression

La regressió basada en distàncies és un mètode de predicció que consisteix en dos passos: a partir de les distàncies entre observacions obtenim les variables latents, les quals passen a ser els regressors en un model lineal de mínims quadrats ordinaris. Les distàncies les calculem a partir dels predictors originals fent us d'una funció de dissimilaritats adequada. Donat que, en general, els regressors estan relacionats de manera no lineal amb la resposta, la seva selecció amb el test F usual no és possible. En aquest treball proposem una solució a aquest problema de selecció de predictors definint tests estadístics generalitzats i adaptant un mètode de bootstrap no paramètric per a l'estimació dels p-valors. Incluim un exemple numèric amb dades de l'assegurança d'automòbils.

Isolation of a novel monkey adenovirus reveals a new phylogenetic clade in the evolutionary history of simian adenoviruses

Adenoviruses of primates include human (HAdV) and simian (SAdV) isolates classified into 8 species (Human Adenovirus A to G, and Simian Adenovirus A). In this study, a novel adenovirus was isolated from a colony of cynomolgus macaques (Macaca fascicularis) and subcultured in VERO cells. Its complete genome was purified and a region encompassing the hexon gene, the protease gene, the DNA binding protein (DBP) and the 100 kDa protein was amplified by PCR and sequenced by primer walking. Sequence analysis of these four genes showed that the new isolate had 80% identity to other primate adenoviruses and lacked recombination events. The study of the evolutionary relationships of this new monkey AdV based on the combined sequences of the four genes supported a close relationship to SAdV-3 and SAdV-6, lineages isolated from Rhesus monkeys. The clade formed by these three types is separated from the remaining clades and establishes a novel branch that is related to species HAdV-A, F and G. However, the genetic distance corresponding to the newly isolated monkey AdV considerably differs from these as to belong to a new, not yet established species. Results presented here widen our knowledge on SAdV and represents an important contribution to the understanding of the evolutionary history of primate adenoviruses.

An evolutionary perspective on self-organized division of labor in social insects

Division of labor is a complex phenomenon observed throughout nature. Theoretical studies have focused either on its emergence through self-organization mechanisms or on its adaptive consequences. We suggest that the interaction of self-organization, which undoubtedly characterizes division of labor in social insects, and evolution should be further explored. We review the factors empirically shown to influence task choice. In light of these factors, we review the most important self-organization and evolutionary models for division of labor and outline their advantages and limitations. We describe ways to unify evolution and self-organization in the theoretical study of division of labor and recent results in this area. Finally, we discuss some benchmarks and primary challenges of this approach.

The evolutionary conserved BER1 gene is involved in microtubule stability in yeast

In yeast, microtubules are dynamic filaments necessary for spindle and nucleus positioning, as well as for proper chromosome segregation. We identify a function for the yeast gene BER1 (Benomyl REsistant 1) in microtubule stability. BER1 belongs to an evolutionary conserved gene family whose founding member Sensitivity to Red light Reduced is involved in red-light perception and circadian rhythms in Arabidopsis. Here, we present data showing that the ber1Delta mutant is affected in microtubule stability, particularly in presence of microtubule-depolymerising drugs. The pattern of synthetic lethal interactions obtained with the ber1Delta mutant suggests that Ber1 may function in N-terminal protein acetylation. Our work thus suggests that microtubule stability might be regulated through this post-translational modification on yet-to-be determined proteins

EADock: docking of small molecules into protein active sites with a multiobjective evolutionary optimization.

In recent years, protein-ligand docking has become a powerful tool for drug development. Although several approaches suitable for high throughput screening are available, there is a need for methods able to identify binding modes with high accuracy. This accuracy is essential to reliably compute the binding free energy of the ligand. Such methods are needed when the binding mode of lead compounds is not determined experimentally but is needed for structure-based lead optimization. We present here a new docking software, called EADock, that aims at this goal. It uses an hybrid evolutionary algorithm with two fitness functions, in combination with a sophisticated management of the diversity. EADock is interfaced with the CHARMM package for energy calculations and coordinate handling. A validation was carried out on 37 crystallized protein-ligand complexes featuring 11 different proteins. The search space was defined as a sphere of 15 A around the center of mass of the ligand position in the crystal structure, and on the contrary to other benchmarks, our algorithm was fed with optimized ligand positions up to 10 A root mean square deviation (RMSD) from the crystal structure, excluding the latter. This validation illustrates the efficiency of our sampling strategy, as correct binding modes, defined by a RMSD to the crystal structure lower than 2 A, were identified and ranked first for 68% of the complexes. The success rate increases to 78% when considering the five best ranked clusters, and 92% when all clusters present in the last generation are taken into account. Most failures could be explained by the presence of crystal contacts in the experimental structure. Finally, the ability of EADock to accurately predict binding modes on a real application was illustrated by the successful docking of the RGD cyclic pentapeptide on the alphaVbeta3 integrin, starting far away from the binding pocket.

Chemical defenses in Sacoglossan Opisthobranchs: Taxonomic trends and evolutionary implications

Sacoglossan sea slugs (Mollusca: Opisthobranchia) are one of the few groups of specialist herbivores in the marine environment. Sacoglossans feed suctorially on the cell sap of macroalgae, from which they 'steal' chloroplasts (kleptoplasty) and deterrent substances (kleptochemistry), retaining intracellularly both host plastids and chemicals. The ingested chloroplasts continue to photosynthesize for periods ranging from a few hours or days up to 3 months in some species. Shelled, more primitive sacoglossans feed only on the siphonalean green algal genus Caulerpa, and they do not have functional kleptoplasty. The diet of sacoglossans has radiated out from this ancestral food. Among the shell-less Plakobranchidae (=Elysiidae), the more primitive species feed on other siphonales (families Derbesiaceae, Caulerpaceae, Bryopsidaceae and Codiaceae) and fix carbon, while the more 'advanced' species within the Plakobranchidae and Limapontioidae have a more broad dietary range. Most of these 'advanced' species are unable to fix carbon because the chloroplasts of their food algae are mechanically disrupted during ingestion. Mesoherbivores are likely to be eaten if they live on palatable seaweeds, their cryptic coloration and form not always keeping them safe from predators. Sacoglossans prefer to live on and eat chemically defended seaweeds, and they use ingested algal chemicals as deterrents of potential predators. The most ancestral shelled sacoglossans (Oxynoidae) and some Plakobranchidae such as Elysia translucens, Thuridilla hopei and Bosellia mimetica have developed a diet-derived chemical defense mechanism. Oxynoids and Thuridilla hopei are able to biomodify the algal metabolites. However, the Plakobranchidae Elysia timida and E. viridis, together with Limapontioidea species, are characterized by their ability to de novo synthesize polypropionate metabolites. A whole analysis of kleptoplasty and chemical defenses in sacoglossans may offer a better understanding of the ecology and evolution of these specialized opisthobranchs. In this paper we summarize some of the latest findings, related mainly to Mediterranean species, and offer a plausible evolutionary scenario based on the biological and chemical trends we can distinguish in them.

Robust accelerated failure time regression

Robust estimators for accelerated failure time models with asymmetric (or symmetric) error distribution and censored observations are proposed. It is assumed that the error model belongs to a log-location-scale family of distributions and that the mean response is the parameter of interest. Since scale is a main component of mean, scale is not treated as a nuisance parameter. A three steps procedure is proposed. In the first step, an initial high breakdown point S estimate is computed. In the second step, observations that are unlikely under the estimated model are rejected or down weighted. Finally, a weighted maximum likelihood estimate is computed. To define the estimates, functions of censored residuals are replaced by their estimated conditional expectation given that the response is larger than the observed censored value. The rejection rule in the second step is based on an adaptive cut-off that, asymptotically, does not reject any observation when the data are generat ed according to the model. Therefore, the final estimate attains full efficiency at the model, with respect to the maximum likelihood estimate, while maintaining the breakdown point of the initial estimator. Asymptotic results are provided. The new procedure is evaluated with the help of Monte Carlo simulations. Two examples with real data are discussed.

New grass phylogeny resolves deep evolutionary relationships and discovers C4 origins.

• Grasses rank among the world's most ecologically and economically important plants. Repeated evolution of the C(4) syndrome has made photosynthesis highly efficient in many grasses, inspiring intensive efforts to engineer the pathway into C(3) crops. However, comparative biology has been of limited use to this endeavor because of uncertainty in the number and phylogenetic placement of C(4) origins. • We built the most comprehensive and robust molecular phylogeny for grasses to date, expanding sampling efforts of a previous working group from 62 to 531 taxa, emphasizing the C(4)-rich PACMAD (Panicoideae, Arundinoideae, Chloridoideae, Micrairoideae, Aristidoideae and Danthonioideae) clade. Our final matrix comprises c. 5700 bp and is > 93% complete. • For the first time, we present strong support for relationships among all the major grass lineages. Several new C(4) lineages are identified, and previously inferred origins confirmed. C(3)/C(4) evolutionary transitions have been highly asymmetrical, with 22-24 inferred origins of the C(4) pathway and only one potential reversal. • Our backbone tree clarifies major outstanding systematic questions and highlights C(3) and C(4) sister taxa for comparative studies. Two lineages have emerged as hotbeds of C(4) evolution. Future work in these lineages will be instrumental in understanding the evolution of this complex trait.

Delphinium L. subgen Delphinium: origin and evolutionary trends

Les caractéristiques avançades de Delphinium L. subgèn. Delphinium (taxons anuals) son comparades amb les del subgèn. Delphinastrum (DC.) Wang i del subgèn. Oligophyllon Dimitrova (taxons perennes). La morfología floral mostra un intercanvi de funcions entre els petals laterals i els petals superiors i restructura de la inflorescencia de molts taxons anuals afavoreix un augment de les taxes de geitonogàmia-autogàmia. L'evolució dels cariotips és basada en una disminució de la longitud total dels cromosomes i en un increment del grau d'asimetria; el nombre cromosómic roman constant per a totes les especies anuals (2n = 16). Leficàcia de la dispersió de les especies anuals és mes gran que no pas la de les especies perennes, per causa d'un increment en la producció de granes i per l'augment de la flotabilitat, tant a l'aire com a l'aigua. D'altres caractéristiques adaptatives avançades son l'adquisició de noves defenses químiques i l'aparició d'un nou tipus embriogènic. Els nínxols ecologies del subgèn. Delphinium corresponen a habitats oberts i alterats, en comparado amb els habitats estables i relativament tancats dels subgéneros Delphinastrum i Oligophyllon. Es presenta una hipótesi global de les tendencies évolutives observades en anuals vs. perennes en connexió amb consideracions biogeogràfiques, així corn un resum taxonomic final.

Blocking hypoxia-induced autophagy in tumors restores cytotoxic T-cell activity and promotes regression.

The relationship between hypoxic stress, autophagy, and specific cell-mediated cytotoxicity remains unknown. This study shows that hypoxia-induced resistance of lung tumor to cytolytic T lymphocyte (CTL)-mediated lysis is associated with autophagy induction in target cells. In turn, this correlates with STAT3 phosphorylation on tyrosine 705 residue (pSTAT3) and HIF-1α accumulation. Inhibition of autophagy by siRNA targeting of either beclin1 or Atg5 resulted in impairment of pSTAT3 and restoration of hypoxic tumor cell susceptibility to CTL-mediated lysis. Furthermore, inhibition of pSTAT3 in hypoxic Atg5 or beclin1-targeted tumor cells was found to be associated with the inhibition Src kinase (pSrc). Autophagy-induced pSTAT3 and pSrc regulation seemed to involve the ubiquitin proteasome system and p62/SQSTM1. In vivo experiments using B16-F10 melanoma tumor cells indicated that depletion of beclin1 resulted in an inhibition of B16-F10 tumor growth and increased tumor apoptosis. Moreover, in vivo inhibition of autophagy by hydroxychloroquine in B16-F10 tumor-bearing mice and mice vaccinated with tyrosinase-related protein-2 peptide dramatically increased tumor growth inhibition. Collectively, this study establishes a novel functional link between hypoxia-induced autophagy and the regulation of antigen-specific T-cell lysis and points to a major role of autophagy in the control of in vivo tumor growth.

Thrombin-sensitive dual fluorescence imaging and therapeutic agent for detection and treatment of synovial inflammation in murine rheumatoid arthritis.

We have developed a thrombin-sensitive polymeric photosensitizer prodrug (T-PS) to selectively image and eradicate inflammatory lesions in rheumatoid arthritis (RA). Thrombin is a serine protease up-regulated in synovial tissues of rheumatoid arthritis (RA) patients. T-PS consists of a polymeric backbone, to which multiple photosensitizer (PS) units are tethered via short thrombin-cleavable peptide linkers. Fluorescence emission and phototoxicity of the prodrug are efficiently quenched due to the interaction of neighboring photosensitizer units. The prodrug is passively delivered to the inflammation site via the enhanced permeability and retention (EPR) effect. Subsequent site-selective proteolytic cleavage of the peptide linkers restores its photoactivity by increasing the mutual distance between PS. Whole animal imaging in murine collagen-induced arthritis, an experimental model of RA revealed a dose-dependent fluorescence increase in arthritic paws after systemic prodrug injection. In addition, administration of T-PS resulted in much higher fluorescence selectivity for arthritic joints as compared to the free PS. Irradiation of the arthritic joints induced light dose dependent phototoxic effects such as apoptosis, vascular damage and local hemorrhage. Long-term observations showed complete regression of the latter. Irradiated non-arthritic tissues or non-irradiated arthritic tissues showed no histological effects after photodynamic therapy with T-PS. This illustrates that T-PS can localize inflammatory lesions with excellent selectivity and induce apoptosis and vascular shut down after irradiation.