Synthetic Lethal Targeting of ARID1A-Mutant Ovarian Clear Cell Tumors with Dasatinib

New targeted approaches to ovarian clear cell carcinomas (OCCC) are needed, given the limited treatment options in this disease and the poor response to standard chemotherapy. Using a series of high-throughput cell-based drug screens in OCCC tumor cell models, we have identified a synthetic lethal (SL) interaction between the kinase inhibitor dasatinib and a key driver in OCCC, ARID1A mutation. Imposing ARID1A deficiency upon a variety of human or mouse cells induced dasatinib sensitivity, both in vitro and in vivo, suggesting that this is a robust synthetic lethal interaction. The sensitivity of ARID1A-deficient cells to dasatinib was associated with G₁ -S cell-cycle arrest and was dependent upon both p21 and Rb. Using focused siRNA screens and kinase profiling, we showed that ARID1A-mutant OCCC tumor cells are addicted to the dasatinib target YES1. This suggests that dasatinib merits investigation for the treatment of patients with ARID1Amutant OCCC. Mol Cancer Ther; 15(7); 1472-84. Ó2016 AACR.

Size-selective mortality and environmental factors affecting early marine growth during early marine life stages of sub-yearling Chinook salmon in Puget Sound, Washington

Thesis (Master's)--University of Washington, 2016-08

Estudo dos efeitos de temporada de treinamento físico sobre a Performance de uma equipe de handebol feminino sub-21

Handball is a sport that demands endurance associated with fast and powerful actions such as jumps, blocks, sprints and throws. The aim of this study was to evaluate the effects of a 38-week systematic physical training applied to a women's under 21 handball team on upper and lower limb power, 30m sprints speed and endurance. The periodization applied was an adaptation of the Verkhoshansky theory, and aimed at two performance peaks during the season with six data collections. The median and range values for three kg medicine ball throwing was: 2.98m (2.15-3.50); 2.84m (2.43-3.20); 2.90m (2.60-3.38); 3.10 (2.83-3.81); 2.84 (2.55-3.57) and 3.34 (2.93-3.83). Regarding the three-pass running test: 5.60m (4.93-6.58); 5.37m (5.04-6.38); 5.36m (4.93-6.12); 5.65m (4.80-6.78); 5.63m (5.00-6.40) and 5.83m (5.14-6.05). Regarding the 30-m sprint test: 5.8m/s (5.45-6.44); 6,64 m/s (6,24-7,09); 5.65m/s (5.17-5.95); (there was not IV moment for this test); 6.19 m/s (5.57-6.26) and 5.83 (5.14-6.05).Regarding the 30-m sprint endurance test until 10% decrease: 4 sprints (4-6); 5 sprints (4-9); 4,5 sprints (4-16); (there was not IV moment for this test); 6 sprints (4-12) and 5 sprints (4-5). Significant differences (p<0.05) were observed in three kg medicine ball throwing and three-pass running tests at least in one of the performance peak planned, with no significant differences in 30-m sprint speed or endurance tests. The applied physical training was efficient at improving the specific physical fitness in the performance peaks, as well as giving support for better physical training adjustment for the upcoming season.

Efeitos de uma periodização de treinamento fisico sobre o desempenho anual de uma equipe de handebol feminino sub-21

Universidade Estadual de Campinas . Faculdade de Educação Física

Avaliação isocinetica de joelho em jogadores de futebol categoria sub-20

Universidade Estadual de Campinas . Faculdade de Educação Física

Variação do equilíbrio muscular durante uma temporada em jogadores de futebol categoria sub-20

O objetivo deste estudo foi analisar o equilíbrio muscular dos flexores e extensores (RFE) de joelho ao longo de uma temporada de treinamento em jogadores de futebol categoria sub-20. Fizeram parte da amostra 15 sujeitos pertencentes à equipe sub-20 da Associação Atlética Ponte Preta de Campinas. Os atletas participaram de um macrociclo de preparação (MP) de 29 semanas, composto por período preparatório e competitivo que foram divididos em quatro mesociclos: etapa geral (M1), etapa especial (M2), etapa pré-competitiva (M3) e etapa competitiva (M4). A RFE de ambos os membros foi determinada em dinamômetro isocinético utilizando o pico de torque (PT) obtido em três séries consecutivas de cinco repetições com velocidade de 60º/s. Avaliação isocinética foi realizada em quatro momentos ao longo do MP, sempre ao final de cada mesociclo (M1, M2, M3 e M4). Para análise estatística, foi empregado teste Friedman de medidas repetidas, seguida do teste de Wilcoxon e teste U de Mann-Whitney, com nível de significância de p<0,05. O PT nos músculos flexores de joelho, em ambos os membros, no M2 e M3 foram superiores aos observados em M1 e M4. O PT dos extensores de joelho em M1 foi significantemente inferior aos demais momentos do estudo (M2, M3 e M4), em ambos os membros. A RFE, em ambos os membros, foi inferior em M1 quando comparado a M2 e M3. A comparação da RFE entre os membros não revelou diferenças significantes em nenhum dos momentos do estudo (M1, M2, M3 e M4). Os resultados encontrados na presente investigação indicaram existência de alterações na magnitude da RFE, porém dentro da normalidade, e, manutenção da proporcionalidade entre os membros ao longo do MP. Esses resultados sugerem que não existem períodos sensíveis para a ocorrência de lesões em virtude de desequilíbrios musculares ao longo do MP em jogadores de futebol da categoria sub-20.

Sub-telomere directed gene expression during initiation of invasive aspergillosis

Aspergillus fumigatus is a common mould whose spores are a component of the normal airborne flora. Immune dysfunction permits developmental growth of inhaled spores in the human lung causing aspergillosis, a significant threat to human health in the form of allergic, and life-threatening invasive infections. The success of A. fumigatus as a pathogen is unique among close phylogenetic relatives and is poorly characterised at the molecular level. Recent genome sequencing of several Aspergillus species provides an exceptional opportunity to analyse fungal virulence attributes within a genomic and evolutionary context. To identify genes preferentially expressed during adaptation to the mammalian host niche, we generated multiple gene expression profiles from minute samplings of A. fumigatus germlings during initiation of murine infection. They reveal a highly co-ordinated A. fumigatus gene expression programme, governing metabolic and physiological adaptation, which allows the organism to prosper within the mammalian niche. As functions of phylogenetic conservation and genetic locus, 28% and 30%, respectively, of the A. fumigatus subtelomeric and lineage-specific gene repertoires are induced relative to laboratory culture, and physically clustered genes including loci directing pseurotin, gliotoxin and siderophore biosyntheses are a prominent feature. Locationally biased A. fumigatus gene expression is not prompted by in vitro iron limitation, acid, alkaline, anaerobic or oxidative stress. However, subtelomeric gene expression is favoured following ex vivo neutrophil exposure and in comparative analyses of richly and poorly nourished laboratory cultured germlings. We found remarkable concordance between the A. fumigatus host-adaptation transcriptome and those resulting from in vitro iron depletion, alkaline shift, nitrogen starvation and loss of the methyltransferase LaeA. This first transcriptional snapshot of a fungal genome during initiation of mammalian infection provides the global perspective required to direct much-needed diagnostic and therapeutic strategies and reveals genome organisation and subtelomeric diversity as potential driving forces in the evolution of pathogenicity in the genus Aspergillus.

Transiting exoplanets from the CoRoT space mission XI. CoRoT-8b: a hot and dense sub-Saturn around a K1 dwarf

Aims. We report the discovery of CoRoT-8b, a dense small Saturn-class exoplanet that orbits a K1 dwarf in 6.2 days, and we derive its orbital parameters, mass, and radius. Methods. We analyzed two complementary data sets: the photometric transit curve of CoRoT-8b as measured by CoRoT and the radial velocity curve of CoRoT-8 as measured by the HARPS spectrometer**. Results. We find that CoRoT-8b is on a circular orbit with a semi-major axis of 0.063 +/- 0.001 AU. It has a radius of 0.57 +/- 0.02 R(J), a mass of 0.22 +/- 0.03 M(J), and therefore a mean density of 1.6 +/- 0.1 g cm(-3). Conclusions. With 67% of the size of Saturn and 72% of its mass, CoRoT-8b has a density comparable to that of Neptune (1.76 g cm(-3)). We estimate its content in heavy elements to be 47-63 M(circle plus), and the mass of its hydrogen-helium envelope to be 7-23 M(circle plus). At 0.063 AU, the thermal loss of hydrogen of CoRoT-8b should be no more than similar to 0.1% over an assumed integrated lifetime of 3 Ga.

Syzygium jambolanum treatment improves survival in lethal sepsis induced in mice

Background: The leaves and the fruits from Syzygium jambolanum DC.(Myrtaceae), a plant known in Brazil as sweet olive or 'jambolao', have been used by native people to treat infectious diseases, diabetes, and stomachache. Since the bactericidal activity of S. jambolanum has been confirmed in vitro, the aim of this work was to evaluate the effect of the prophylactic treatment with S. jambolanum on the in vivo polymicrobial infection induced by cecal ligation and puncture (CLP) in mice. Methods: C57BI/6 mice were treated by the subcutaneous route with a hydroalcoholic extract from fresh leaves of S. jambolanum (HCE). After 6 h, a bacterial infection was induced in the peritoneum using the lethal CLP model. The mice were killed 12 h after the CLP induction to evaluate the cellular influx and local and systemic inflammatory mediators' production. Some animals were maintained alive to evaluate the survival rate. Results: The prophylactic HCE treatment increased the mice survival, the neutrophil migration to infectious site, the spreading ability and the hydrogen peroxide release, but decreased the serum TNF and nitrite. Despite the increased migration and activation of peritoneal cells the HCE treatment did not decrease the number of CFU. The HCE treatment induced a significant decrease on the bone marrow cells number but did not alter the cell number of the spleen and lymph node. Conclusion: We conclude that the treatment with S. jambolanum has a potent prophylactic antiseptic effect that is not associated to a direct microbicidal effect but it is associated to a recruitment of activated neutrophils to the infectious site and to a diminished systemic inflammatory response.

Leishmania-Specific Surface Antigens Show Sub-Genus Sequence Variation and Immune Recognition

Background: A family of hydrophilic acylated surface (HASP) proteins, containing extensive and variant amino acid repeats, is expressed at the plasma membrane in infective extracellular (metacyclic) and intracellular (amastigote) stages of Old World Leishmania species. While HASPs are antigenic in the host and can induce protective immune responses, the biological functions of these Leishmania-specific proteins remain unresolved. Previous genome analysis has suggested that parasites of the sub-genus Leishmania (Viannia) have lost HASP genes from their genomes. Methods/Principal Findings: We have used molecular and cellular methods to analyse HASP expression in New World Leishmania mexicana complex species and show that, unlike in L. major, these proteins are expressed predominantly following differentiation into amastigotes within macrophages. Further genome analysis has revealed that the L. (Viannia) species, L. (V.) braziliensis, does express HASP-like proteins of low amino acid similarity but with similar biochemical characteristics, from genes present on a region of chromosome 23 that is syntenic with the HASP/SHERP locus in Old World Leishmania species and the L. (L.) mexicana complex. A related gene is also present in Leptomonas seymouri and this may represent the ancestral copy of these Leishmania-genus specific sequences. The L. braziliensis HASP-like proteins (named the orthologous (o) HASPs) are predominantly expressed on the plasma membrane in amastigotes and are recognised by immune sera taken from 4 out of 6 leishmaniasis patients tested in an endemic region of Brazil. Analysis of the repetitive domains of the oHASPs has shown considerable genetic variation in parasite isolates taken from the same patients, suggesting that antigenic change may play a role in immune recognition of this protein family. Conclusions/Significance: These findings confirm that antigenic hydrophilic acylated proteins are expressed from genes in the same chromosomal region in species across the genus Leishmania. These proteins are surface-exposed on amastigotes (although L. (L.) major parasites also express HASPB on the metacyclic plasma membrane). The central repetitive domains of the HASPs are highly variant in their amino acid sequences, both within and between species, consistent with a role in immune recognition in the host.

Floral development in the tribe Cedreleae (Meliaceae, sub-family Swietenioideae): Cedrela and Toona

Background and Aims Floral development of Cedrela and Toona, the genera comprising the basal tribe Cedreleae of the sub-family Swietenioideae of Meliaceae, is described. The focus was on three endangered, ecologically and economically important species: Cedrela fissilis, Cedrela odorata and Toona ciliata. The aims of the study were to characterize the patterns of floral development in the tribe and to establish apomorphic and plesiomorphic floral characters in relation to other taxa within the family based on the current molecular phylogeny of Meliaceae. Methods A detailed floral structural and developmental study was completed using both scanning electron microscopy and visualization of microtome sections with a light microscope. Key Results Twelve floral developmental stages were identified. The initial development of the pentamerous flowers of both Toona and Cedrela is strikingly similar. The morphological differences observed between them are due to differential patterns of organ elongation and adnation/connation occurring late in development. Additionally, the formation of functionally male and female flowers was found to occur at specific positions within the inflorescence. Conclusions Due to the basal position of the tribe Cedreleae in the phylogeny of Meliaceae, functionally either male or female pentamerous flowers and the presence of (at least partially) free stamens may be considered plesiomorphic traits within the family. In contrast, sympetaly and the absence of nectaries in Cedrela species are synapomorphies.

Predation and reproductive output of the ladybird beetle Stethorus tridens preying on tomato red spider mite Tetranychus evansi

Predatory behaviour and reproductive output of the ladybird beetle Stethorus tridens Gordon as function of the tomato red spider mite (TRSM), Tetranychus evansi Baker & Pritchard, densities was investigated in the laboratory. Adult female of S. tridens were isolated in cylindrical plastic arenas, containing a leaf disc of Solanum americanum Mill. with 5, 20, 40, 60, 80 or 100 T. evansi nymphs. The number of prey consumed and eggs laid were evaluated daily for ten consecutive days, starting at the oviposition. Oviposition of S. tridens was positively correlated with prey consumption and lower threshold prey consumption for S. tridens laying eggs was 16.3 mites per day. The instantaneous rate of attack (ca. discovery area) and the handling time were 0.0062 h(-1) and 0.83 h, and 0.00254 h(-1) and 0.78 h, respectively, for predators at the 1st- and 10th-oviposition day. The predator exhibited a type II functional response at 1st- and 10th-oviposition day with a maximum consumption per predator of 33 T. evansi nymphs per day at the highest prey density. The ladybird beetle S. tridens is often collected associated with red spider mite colonies on solanaceous wild plants and the results suggest the potential of this ladybird beetle to control T. evansi in tomatoes crops.

Predation potential and biology of Protogamasellopsis posnaniensis Wisniewski & Hirschmann (Acari: Rhodacaridae)

Rhodacaridae are cosmopolitan mites mentioned as predators, although nothing is known about their potential as biological control agents. One of the objectives of the work reported in this paper was to evaluate the potential of Protogamasellopsis posnaniensis (Acari: Rhodacaridae) as predator of representative species of insects of the families Sciaridae (Bradysia matogrossensis (Lane)) and Thripidae (Frankliniella occidentalis (Pergande)), of mites of the family Acaridae (Tyrophagus putrescentiae (Schrank) and Rhizoglyphus echinopus (Fumouze & Robin) and of nematodes of the family Rhabditidae (Protorhabditis sp.). Another objective was to determine the biological cycle of P. posnaniensis when fed the prey on which it performed best in the preceding predation test. The study was conducted in a laboratory where the experimental units were maintained at 25 +/- 1 degrees C, 97 +/- 3% RH and in the dark. Although the predator was able to kill all prey species considered in this study, the most favorable prey were T. putrescentiae, F. occidentalis and Protorhabditis sp. Survivorship of the predator in predation tests was always 98% or higher. Life table biological parameters when the predator was fed T. putrescentiae were: R(o) = 109.29; T = 19.06 days; lambda = 1.28 e r(m) = 0.32 female/female/day. Despite preying upon larvae of B. matogrossensis, eggs of the former can also be killed by the latter. The results indicated that A posnaniensis is a promising biological control agent, deserving additional studies on its possible use for the control of soil pests. (C) 2008 Elsevier Inc. All rights reserved.

Phytoseiid mites of the tribe Typhlodromini (Acari: Phytoseiidae) from sub-Saharan Africa

This is the ninth publication in a series on the taxonomy of phytoseiid mites of sub-Saharan Africa. Sixty-five phytoseiid species of the tribe Typhlodromini Wainstein, all of which are in the genus Typhlodromus Scheuten are reported in this paper (62 in the subgenus Anthoseius DeLeon and 3 in the subgenus Typhlodromus Scheuten). They refer to all species of this tribe known to occur in sub-Saharan Africa. Fifteen new species are described and 41 species are redescribed. Most of the reported species were collected in various habitats in southern Africa and in cassava habitats in tropical Africa. A key is included for the separation of these species.

Compatibility of Neoseiulus paspalivorus and Proctolaelaps bickleyi, candidate biocontrol agents of the coconut mite Aceria guerreronis: spatial niche use and intraguild predation

The eriophyid mite Aceria guerreronis occurs in most coconut growing regions of the world and causes enormous damage to coconut fruits. The concealed environment of the fruit perianth under which the mite resides renders its control extremely difficult. Recent studies suggest that biological control could mitigate the problems caused by this pest. Neoseiulus paspalivorus and Proctolaelaps bickleyi are two of the most frequently found predatory mites associated with A. guerreronis on coconut fruits. Regarding biological control, the former has an advantage in invading the tight areas under the coconut fruit perianth while the latter is more voracious on the pest mites and has a higher reproductive capacity. Based on the idea of the combined use/release of both predators on coconut fruits, we studied their compatibility in spatial niche use and intraguild predation (IGP). Spatial niche use on coconut fruits was examined on artificial arenas mimicking the area under the coconut fruit perianth and the open fruit surface. Both N. paspalivorus and P. bickleyi preferentially resided and oviposited inside the tight artificial chamber. Oviposition rate of P. bickleyi and residence time of N. paspalivorus inside the chamber were reduced in the presence of a conspecific female. Residence of N. paspalivorus inside the chamber was also influenced by the presence of P. bickleyi. Both N. paspalivorus and P. bickleyi preyed upon each other with relatively moderate IGP rates of adult females on larvae but neither species yielded nutritional benefits from IGP in terms of adult survival and oviposition. We discuss the relevance of our findings for a hypothetic combined use of both predators in biological control of A. guerreronis.