Virtual screening and computational optimization for the discovery of covalent prolyl oligopeptidase inhibitors with activity in human cells.

Our docking program, Fitted, implemented in our computational platform, Forecaster, has been modified to carry out automated virtual screening of covalent inhibitors. With this modified version of the program, virtual screening and further docking-based optimization of a selected hit led to the identification of potential covalent reversible inhibitors of prolyl oligopeptidase activity. After visual inspection, a virtual hit molecule together with four analogues were selected for synthesis and made in one-five chemical steps. Biological evaluations on recombinant POP and FAPα enzymes, cell extracts, and living cells demonstrated high potency and selectivity for POP over FAPα and DPPIV. Three compounds even exhibited high nanomolar inhibitory activities in intact living human cells and acceptable metabolic stability. This small set of molecules also demonstrated that covalent binding and/or geometrical constraints to the ligand/protein complex may lead to an increase in bioactivity.

Adaptabilidade e estabilidade de cultivares de milho-pipoca na região centro-sul do Brasil

Este trabalho teve como objetivo estudar a adaptabilidade e estabilidade de cultivares de milho-pipoca avaliadas pela Embrapa-Centro Nacional de Pesquisa de Milho e Sorgo, no ano agrícola 1991/92. Foram avaliadas 15 cultivares em 19 locais quanto à produtividade, e em 15 locais quanto ao índice de capacidade de expansão (ICE) na região centro-sul do Brasil. As cultivares GO 100P, MF 1001, Pirapoca-Amarela, Pirapoca-Branca e Colorado Pop 1, foram mais promissoras, pois apresentaram boas médias de produtividade (1.700 a 2.100 kg/ha de grãos) e razoáveis ICE (17 a 21 mL/mL). Quanto à variável produtividade, as cultivares Pirapoca-Amarela e Colorado Pop 1 apresentaram-se adaptadas a ambientes favoráveis, e foram estáveis. As cultivares MF 1001, Pirapoca-Branca e GO 100P, demonstraram capacidade satisfatória no aproveitamento dos estímulos ambientais, e foram estáveis. Todas foram estáveis em relação ao ICE, e as cultivares MF 1001, Colorado Pop 1, Pirapoca-Amarela e Pirapoca-Branca demonstraram capacidade satisfatória no aproveitamento dos estímulos ambientais. A cultivar GO 100P foi melhor adaptada para ambientes favoráveis.

Mortality rates in by-caught loggerhead turtle Caretta caretta in the Mediterranean Sea and implications for the Atlantic populations

Reliable estimates of the post-release mortality probability of marine turtles after incidental by-catch are essential for assessing the impact of longline fishing on these species.Large numbers of loggerhead turtles Caretta caretta from rookeries in the northwestern Atlantic Ocean have been by-caught annually in the southwestern Mediterranean Sea since the 1980s, but nothing is known about their post-release mortality probability under natural conditions. Pop-up archival transmitting tags were attached to 26 loggerhead turtles following incidental capture by Spanish longliners. Hooks were not removed, and 40 cm of line was left in place. The post-release mortality probability during the 90 d following release ranged from 0.308 to 0.365, and was independent of hook location. When the post-release mortality probability was combined with previously reported estimates of the mortality probability before hauling, the aggregated by-catch mortality probability ranged from 0.321 to 0.378. Assuming a total annual by-catch of 10656 loggerhead turtles by the Spanish longline fleet operating in the southwestern Mediterranean, by-catch results in 3421 to 4028 turtle deaths annually. This range is equivalent to 8.5−10.1% of the approximately 40000 turtles inhabiting the fishing grounds used by Spanish longliners, most of them from rookeries in the northwestern Atlantic. As a consequence, the accumulated mortality during the oceanic stage is expected to be larger for those loggerhead turtles of Atlantic origin that spend several years in the Mediterranean Sea than for turtles of the same cohort that remain in the Atlantic. For this reason, the Mediterranean can be considered a dead end for loggerhead turtle populations nesting in the Atlantic, although the actual demographic relevance of by-catch mortality of loggerhead turtles in the Mediterranean remains unknown.

Population pharmacokinetics in chronic myeloid leukaemia patients: observations under field-conditions

Introduction: Therapeutic drug monitoring (TDM) of imatinib has been increasingly proposed for chronic myeloid leukaemia (CML) patients, as several studies have found a correlation between trough concentrations (Cmin) >=1000ng/ml and improved response. The pharmacological monitoring project of EUTOS (European Treatment and Outcome Study) was launched to increase the availability of imatinib TDM, standardize labs, and validate proposed Cmin thresholds. Using the collected data, the objective of this analysis was to characterize imatinib Population pharmacokinetics (Pop-PK) in a large cohort of European patients, to quantify its variability and the influence of demographic factors and comedications, and to derive individual exposure variables suitable for further concentration-effect analyses.¦Methods: 4095 PK samples from 2478 adult patients were analyzed between 2006 and 2010 by LC-MS-MS and considered for Pop-PK analysis by NONMEM®. Model building used data from 973 patients with >=2 samples available (2590 samples). A sensitivity analysis was performed using all data. Available comedications (27%) were classified into inducers or inhibitors of P-glycoprotein, CYP3A4/5 and organic-cation-transporter-1 (hOCT-1).¦Results: A one-compartment model with linear elimination, zero-order absorption fitted the data best. Estimated Pop-PK parameters (interindividual variability, IIV %CV) for a 40-year old male patient were: clearance CL = 17.3 L/h (37.7%), volume V = 429L (51.1%), duration of absorption D1 = 3.2h. Outliers, reflecting potential compliance and time recording errors, were taken into account by estimating an IIV on the residual error (35.4%). Intra-individual residuals were 29.1% (proportional) plus ± 84.6 ng/mL (additive). Female patients had a 15.2% lower CL (14.6 L/h). A piece-wise linear effect of age estimated a CL of 18.7 L/h at 20 years, 17.3 L/h at 40 and 13.8 L/h at 60 years. These covariates explained 2% (CL) and 4.5% (V) of IIV variability. No effect of comedication was found. The sensitivity analysis expectedly estimated increased IIV, but similar fixed effect parameters.¦Conclusion: Imatinib PK was well described in a large cohort of CML patients under field conditions and results were concordant with previous studies. Patient characteristics explain only little IIV, confirming limited utility of prior dosage adjustment. As intra-variability is smaller than inter-patient variability, dose adjustment guided by TDM could however be beneficial in order to bring Cmin into a given therapeutic target.

Under the Stones, the beach. Vínculos generacionales y pulsiones subversivas en el cine a través de los Rolling Stones

Este trabajo busca investigar el fenómeno de lo generacional en el cine a través de su relación con la música. Para ello, utiliza como punto de partida la filmografía de los Rolling Stones y aplica elconcepto de aura de Walter Benjamin. Así, explora las tensiones generacionales entre jóvenes y adultos, que se reflejan en los ámbitos del creador, la audiencia y la industria como tensiones entre invención y comercialización, entre libertad y represión o entre rebeldía y conservadurismo. De ese modo, procura identificar en la puesta en escena la capacidad contracultural del cine que apela a lo juvenil y oponerla a los simulacros oportunistas que utiliza el sistema de la industria cultural.

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This chapter looks at the place of the Gothic in Batman's history and current revival via the Nolan films. It examines the specificity of comic book characters, which exist in a wide variety of texts, forms and media, and focuses on the way that Batman has oscillated between light and dark versions while always returning to the Gothic as a means of commercial reanimation when the franchise seems to wane.

Meta-analyses identify 13 loci associated with age at menopause and highlight DNA repair and immune pathways.

To newly identify loci for age at natural menopause, we carried out a meta-analysis of 22 genome-wide association studies (GWAS) in 38,968 women of European descent, with replication in up to 14,435 women. In addition to four known loci, we identified 13 loci newly associated with age at natural menopause (at P < 5 × 10(-8)). Candidate genes located at these newly associated loci include genes implicated in DNA repair (EXO1, HELQ, UIMC1, FAM175A, FANCI, TLK1, POLG and PRIM1) and immune function (IL11, NLRP11 and PRRC2A (also known as BAT2)). Gene-set enrichment pathway analyses using the full GWAS data set identified exoDNase, NF-κB signaling and mitochondrial dysfunction as biological processes related to timing of menopause.

Mirjam Kinoksen exlibris-kokoelma

Mirjam Kinoksen exlibris-kokoelma sisältää yli 10 000 kotimaista exlibristä, ulkomaisia exlibriksiä sekä suuren määrän aiheeseen liittyvää kirjallisuutta. Oululainen kuvaamataidon lehtori Mirjam Kinos (1915-2002) vaikutti pitkään oululaisessa taide-elämässä, kuten kaupungin kuvataidelautakunnassa vuosina 1959-84. Hän on aktiivisesti tuonut exlibris-aihetta esiin järjestämällä näyttelyitä eri puolilla maata ja opettamalla exlibristen tekemistä kursseilla. Vuonna 1989 Kinos julkaisi ensimmäisen suomenkielisen, eurooppalaisen exlibriksen historiaa esittelevän teoksen Exlibris. Mirjam Kinos on myös itse piirtänyt huomattavan määrän exlibriksiä, kaikkiaan noin 330 kappaletta. Suurin osa niistä syntyi 1980-90-luvuilla sen jälkeen, kun hän siirtyi eläkkeelle Oulun Lyseon kuvaamataidon opettajan työstä.