THE GEMINI NICI PLANET-FINDING CAMPAIGN: DISCOVERY OF A SUBSTELLAR L DWARF COMPANION TO THE NEARBY YOUNG M DWARF CD-35 2722

We present the discovery of a wide (67 AU) substellar companion to the nearby (21 pc) young solar-metallicity M1 dwarf CD-35 2722, a member of the approximate to 100 Myr AB Doradus association. Two epochs of astrometry from the NICI Planet-Finding Campaign confirm that CD-35 2722 B is physically associated with the primary star. Near-IR spectra indicate a spectral type of L4 +/- 1 with a moderately low surface gravity, making it one of the coolest young companions found to date. The absorption lines and near-IR continuum shape of CD-35 2722 B agree especially well the dusty field L4.5 dwarf 2MASS J22244381-0158521, while the near-IR colors and absolute magnitudes match those of the 5 Myr old L4 planetary-mass companion, 1RXS J160929.1-210524 b. Overall, CD-35 2722 B appears to be an intermediate-age benchmark for L dwarfs, with a less peaked H-band continuum than the youngest objects and near-IR absorption lines comparable to field objects. We fit Ames-Dusty model atmospheres to the near-IR spectra and find T(eff) = 1700-1900 K and log(g) = 4.5 +/- 0.5. The spectra also show that the radial velocities of components A and B agree to within +/- 10 km s(-1), further confirming their physical association. Using the age and bolometric luminosity of CD-35 2722 B, we derive a mass of 31 +/- 8 M(Jup) from the Lyon/Dusty evolutionary models. Altogether, young late-M to mid-L type companions appear to be overluminous for their near-IR spectral type compared with field objects, in contrast to the underluminosity of young late-L and early-T dwarfs.

Barriers to interventions aimed at promoting the health of health care workers in Brazil

Objective. To search the literature for circumstances that impede injury and disease prevention and other activities intended to improve the health of the health care worker. Methods. The SciELO database was searched for articles published in 1967-2008. This was supplemented by a PubMed search for the period 1950-2008. The following key words were used to identify articles in English, Portuguese, and Spanish: work, health personnel, occupational, risks, diseases, ergonomics, work ability, quality of life, organization, accidents, work conditions, intervention, and administration. Articles on injury and disease prevention and occupational health in a health care setting in Latin America were selected, along with articles focused on health promotion in the health sector. Results. The following shortcomings were identified: activities lacked a sound theoretical foundation and were not integrated with the health services management; a failure to evaluate the effectiveness of the activity; health surveillance focused solely on a specific disease or injury; management not committed to the proposed activity; miscommunication; inability of workers to participate, or control the work environment; and, programs or efforts that were limited to changing the workers` behaviors. Conclusions. The literature shows that all the barriers identified by this study affect both the health care workers` health as well as their productivity.

Discovery of two distinct red clumps in NGC 419: a rare snapshot of a cluster at the onset of degeneracy

Colour-magnitude diagrams (CMDs) of the Small Magellanic Cloud (SMC) star cluster NGC 419, derived from Hubble Space Telescope (HST)/Advanced Camera for Surveys (ACS) data, reveal a well-delineated secondary clump located below the classical compact red clump typical of intermediate-age populations. We demonstrate that this feature belongs to the cluster itself, rather than to the underlying SMC field. Then, we use synthetic CMDs to show that it corresponds very well to the secondary clump predicted to appear as a result of He-ignition in stars just massive enough to avoid e(-)-degeneracy settling in their H-exhausted cores. The main red clump instead is made of the slightly less massive stars which passed through e(-) degeneracy and ignited He at the tip of the red giant branch. In other words, NGC 419 is the rare snapshot of a cluster while undergoing the fast transition from classical to degenerate H-exhausted cores. At this particular moment of a cluster`s life, the colour distance between the main-sequence turn-off and the red clump(s) depends sensitively on the amount of convective core overshooting, Lambda(c). By coupling measurements of this colour separation with fits to the red clump morphology, we are able to estimate simultaneously the cluster mean age (1.35(-0.04)(+0.11) Gyr) and overshooting efficiency (Lambda(c) = 0.47(-0.04)(+0.14)). Therefore, clusters like NGC 419 may constitute important marks in the age scale of intermediate-age populations. After eye inspection of other CMDs derived from HST/ACS data, we suggest that the same secondary clump may also be present in the Large Magellanic Cloud clusters NGC 1751, 1783, 1806, 1846, 1852 and 1917.

Natural products biological screening and ligand-based virtual screening for the discovery of new antileishmanial agents

In the course of our research program to discover novel antileishmanial agents, a biological screening of natural products against Leishmania major promastigotes allowed the identification of a furoquinoline alkaloid (1) and a furanocoumarin (2) as new hits. Subsequently, an integrated ligand-based virtual screening approach was employed to search for new antileishmanial compounds using these naturally occurring molecules as templates. Fourteen out of 40 compounds selected from a database of about 800,000 compounds (extracted from ZINC, a free database for virtual screening) were experimentally confirmed to possess significant in vitro antileishmanial properties. The application of ligand-based virtual screening as a complementary approach to experimental natural product screening was a useful strategy to facilitate the identification of new promising lead candidates.

Integration of Ligand- and Target-Based Virtual Screening for the Discovery of Cruzain Inhibitors

A myriad of methods are available for virtual screening of small organic compound databases. In this study we have successfully applied a quantitative model of consensus measurements, using a combination of 3D similarity searches (ROCS and EON), Hologram Quantitative Structure Activity Relationships (HQSAR) and docking (FRED, FlexX, Glide and AutoDock Vina), to retrieve cruzain inhibitors from collected databases. All methods were assessed individually and then combined in a Ligand-Based Virtual Screening (LBVS) and Target-Based Virtual Screening (TBVS) consensus scoring, using Receiving Operating Characteristic (ROC) curves to evaluate their performance. Three consensus strategies were used: scaled-rank-by-number, rank-by-rank and rank-by-vote, with the most thriving the scaled-rank-by-number strategy, considering that the stiff ROC curve appeared to be satisfactory in every way to indicate a higher enrichment power at early retrieval of active compounds from the database. The ligand-based method provided access to a robust and predictive HQSAR model that was developed to show superior discrimination between active and inactive compounds, which was also better than ROCS and EON procedures. Overall, the integration of fast computational techniques based on ligand and target structures resulted in a more efficient retrieval of cruzain inhibitors with desired pharmacological profiles that may be useful to advance the discovery of new trypanocidal agents.

Plasmodium falciparum Accompanied the Human Expansion out of Africa

Plasmodium falciparum is distributed throughout the tropics and is responsible for an estimated 230 million cases of malaria every year, with a further 1.4 billion people at risk of infection [1-3]. Little is known about the genetic makeup of P. falciparum populations, despite variation in genetic diversity being a key factor in morbidity, mortality, and the success of malaria control initiatives. Here we analyze a worldwide sample of 519 P. falciparum isolates sequenced for two housekeeping genes (63 single nucleotide polymorphisms from around 5000 nucleotides per isolate). We observe a strong negative correlation between within-population genetic diversity and geographic distance from sub-Saharan Africa (R(2) = 0.95) over Africa, Asia, and Oceania. In contrast, regional variation in transmission intensity seems to have had a negligible impact on the distribution of genetic diversity. The striking geographic patterns of isolation by distance observed in P. falciparum mirror the ones previously documented in humans [4-7] and point to a joint sub-Saharan African origin between the parasite and its host. Age estimates for the expansion of P. falciparum further support that anatomically modern humans were infected prior to their exit out of Africa and carried the parasite along during their colonization of the world.

Discovery of novel Trypanosoma cruzi glyceraldehyde-3-phosphate dehydrogenase inhibitors

Based on its essential role in the life cycle of Trypanosoma cruzi, the glycolytic enzyme glyceraldehyde 3-phosphate dehydrogenase (GAPDH) has been considered a promising target for the development of novel chemotherapeutic agents for the treatment of Chagas` disease. In the course of our research program to discover novel inhibitors of this trypanosomatid enzyme, we have explored a combination of structure and ligand-based virtual screening techniques as a complementary approach to a biochemical screening of natural products using a standard biochemical assay. Seven natural products, including anacardic acids,. avonoid derivatives, and one glucosylxanthone were identified as novel inhibitors of T. cruzi GAPDH. Promiscuous inhibition induced by nonspecific aggregation has been discarded as specific inhibition was not reversed or affected in all cases in the presence of Triton X-100, demonstrating the ability of the assay to find authentic inhibitors of the enzyme. The structural diversity of this series of promising natural products is of special interest in drug design, and should therefore be useful in future medicinal chemistry efforts aimed at the development of new GAPDH inhibitors having increased potency. (C) 2009 Elsevier Ltd. All rights reserved.

Discovery of New Inhibitors of Schistosoma mansoni PNP by Pharmacophore-Based Virtual Screening

Schistosomiasis is considered the second most important tropical parasitic disease, with severe socioeconomic consequences for millions of people worldwide. Schistosoma monsoni, one of the causative agents of human schistosomiasis, is unable to synthesize purine nucleotides de novo, which makes the enzymes of the purine salvage pathway important targets for antischistosomal drug development. In the present work, we describe the development of a pharmacophore model for ligands of S. mansoni purine nucleoside phosphorylase (SmPNP) as well as a pharmacophore-based virtual screening approach, which resulted in the identification of three thioxothiazolidinones (1-3) with substantial in vitro inhibitory activity against SmPNP. Synthesis, biochemical evaluation, and structure activity relationship investigations led to the successful development of a small set of thioxothiazolidinone derivatives harboring a novel chemical scaffold as new competitive inhibitors of SmPNP at the low-micromolar range. Seven compounds were identified with IC(50) values below 100 mu M. The most potent inhibitors 7, 10, and 17 with 1050 of 2, 18, and 38 mu M, respectively, could represent new potential lead compounds for further development of the therapy of schistosomiasis.

Synthesis and analgesic profile of conformationally constrained N-acylhydrazone analogues: Discovery of novel N-arylideneamino quinazolin-4(3H)-one compounds derived from natural safrole

In this work we reported the synthesis and evaluation of the analgesic, anti-inflammatory, and platelet anti-aggregating properties of new 3-(arylideneamino)-2-methyl-6,7-methylenedioxy-quinazolin-4 (3H)-one derivatives (3a-j), designed as conformationally constrained analogues of analgesic 1,3- benzodioxolyl-N- acylhydrazones (1) previously developed at LASSBio. Target compounds were synthesized in very good yields exploiting abundant Brazilian natural product safrole (2) as starting material. The pharmacological assays lead us to identify compounds LASSBio-1240 (3b) and LASSBio-1272 (3d) as new analgesic prototypes, presenting an antinociceptive pro. le more potent and effective than dipyrone and indomethacin used, respectively, as standards in AcOH-induced abdominal constrictions assay and in the formalin test. These results confirmed the success in the exploitation of conformation restriction strategy for identification of novel cyclic N-acylhydrazone analogues with optimized analgesic profile (C) 2009 Elsevier Ltd. All rights reserved.

Discovery of Phthalimides as Immunomodulatory and Antitumor Drug Prototypes

Brazilian National Council of Research (CNPq)[471834/2006-8]