The tetravalent guanylhydrazone CNI-1493 blocks the toxic effects of interleukin-2 without diminishing antitumor efficacy

The use of interleukin 2 (IL-2) as an antineoplastic agent has been limited by the serious toxicities that accompany the doses necessary for a tumor response. Elevation of nitric oxide (NO) and tumor necrosis factor (TNF) both have been implicated in IL-2 toxicities. CNI-1493, a tetravalent guanylhydrazone, is an inhibitor of macrophage activation including the synthesis of TNF and other cytokines. Doses of CNI-1493 as low as 1 mg/kg/day conferred complete protection against fatal toxicity of IL-2 with IL-2 doses tenfold higher than the safely tolerated level in Sprague–Dawley rats. Moreover, typical pathologic changes in the lungs, kidneys, and the liver caused by IL-2 infusion were blocked by cotreatment with CNI-1493. When animals bearing established hepatomas were given IL-2 and CNI-1493 combination therapy, 10 of 10 hepatomas regressed from 1 cm3 to <1 mm3. Intracytoplasmic TNF levels were increased in normal tissues from IL-2 treated animals, and treatment with CNI-1493 maintained TNF at control levels. The degree of apoptosis measured by terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling staining of tumors following IL-2 therapy was not reduced compared with IL-2 cotreated with CNI-1493. In contrast, apoptosis in the liver and lung parenchyma following IL-2 therapy was blocked completely by cotreatment with CNI-1493. Taken together, these data showed that low and infrequent doses of CNI-1493 markedly protected animals from IL-2 systemic toxicities whereas not affecting tumor response to IL-2 therapy. With the protection afforded by CNI-1493 treatment, IL-2 therapy dose levels could be increased to provide significant antitumor effects in animals with established hepatomas.

Peptide inhibitors of HIV-1 protease and viral infection of peripheral blood lymphocytes based on HIV-1 Vif

We recently reported that HIV-1 Vif (virion infectivity factor) inhibits HIV-1 protease in vitro and in bacteria, suggesting that it may serve as the basis for the design of new protease inhibitors and treatment for HIV-1 infection. To evaluate this possibility, we synthesized peptide derivatives from the region of Vif, which inhibits protease, and tested their activity on protease. In an assay of cleavage of virion-like particles composed of HIV-1 Gag precursor polyprotein, full-length recombinant Vif, and a peptide consisting of residues 21–65 of Vif, but not a control peptide or BSA, inhibited protease activity. Vif21–65 blocked protease at a molar ratio of two to one. We then tested this peptide and a smaller peptide, Vif41–65, for their effects on HIV-1 infection of peripheral blood lymphocytes. Both Vif peptides inhibited virus expression below the limit of detection, but control peptides had no effect. To investigate its site of action, Vif21–65 was tested for its effect on Gag cleavage by protease during HIV-1 infection. We found that commensurate with its reduction of virus expression, Vif21–65 inhibited the cleavage of the polyprotein p55 to mature p24. These results are similar to those obtained by using Ro 31–8959, a protease inhibitor in clinical use. We conclude that Vif-derived peptides inhibit protease during HIV-1 infection and may be useful for the development of new protease inhibitors.

ACTIVITY: a database on DNA/RNA sites activity adapted to apply sequence-activity relationships from one system to another

ACTIVITY is a database on DNA/RNA site sequences with known activity magnitudes, measurement systems, sequence-activity relationships under fixed experimental conditions and procedures to adapt these relationships from one measurement system to another. This database deposits information on DNA/RNA affinities to proteins and cell nuclear extracts, cutting efficiencies, gene transcription activity, mRNA translation efficiencies, mutability and other biological activities of natural sites occurring within promoters, mRNA leaders, and other regulatory regions in pro- and eukaryotic genomes, their mutant forms and synthetic analogues. Since activity magnitudes are heavily system-dependent, the current version of ACTIVITY is supplemented by three novel sub-databases: (i) SYSTEM, measurement systems; (ii) KNOWLEDGE, sequence-activity relationships under fixed experimental conditions; and (iii) CROSS_TEST, procedures adapting a relationship from one measurement system to another. These databases are useful in molecular biology, pharmacogenetics, metabolic engineering, drug design and biotechnology. The databases can be queried using SRS and are available through the Web, http://wwwmgs.bionet.nsc.ru/systems/Activity/.

rSNP_Guide, a database system for analysis of transcription factor binding to target sequences: application to SNPs and site-directed mutations

rSNP_Guide is a novel curated database system for analysis of transcription factor (TF) binding to target sequences in regulatory gene regions altered by mutations. It accumulates experimental data on naturally occurring site variants in regulatory gene regions and site-directed mutations. This database system also contains the web tools for SNP analysis, i.e., active applet applying weight matrices to predict the regulatory site candidates altered by a mutation. The current version of the rSNP_Guide is supplemented by six sub-databases: (i) rSNP_DB, on DNA–protein interaction caused by mutation; (ii) SYSTEM, on experimental systems; (iii) rSNP_BIB, on citations to original publications; (iv) SAMPLES, on experimentally identified sequences of known regulatory sites; (v) MATRIX, on weight matrices of known TF sites; (vi) rSNP_Report, on characteristic examples of successful rSNP_Tools implementation. These databases are useful for the analysis of natural SNPs and site-directed mutations. The databases are available through the Web, http://wwwmgs.bionet.nsc.ru/mgs/systems/rsnp/.

Estimation of divergence times from multiprotein sequences for a few mammalian species and several distantly related organisms

When many protein sequences are available for estimating the time of divergence between two species, it is customary to estimate the time for each protein separately and then use the average for all proteins as the final estimate. However, it can be shown that this estimate generally has an upward bias, and that an unbiased estimate is obtained by using distances based on concatenated sequences. We have shown that two concatenation-based distances, i.e., average gamma distance weighted with sequence length (d2) and multiprotein gamma distance (d3), generally give more satisfactory results than other concatenation-based distances. Using these two distance measures for 104 protein sequences, we estimated the time of divergence between mice and rats to be approximately 33 million years ago. Similarly, the time of divergence between humans and rodents was estimated to be approximately 96 million years ago. We also investigated the dependency of time estimates on statistical methods and various assumptions made by using sequence data from eubacteria, protists, plants, fungi, and animals. Our best estimates of the times of divergence between eubacteria and eukaryotes, between protists and other eukaryotes, and between plants, fungi, and animals were 3, 1.7, and 1.3 billion years ago, respectively. However, estimates of ancient divergence times are subject to a substantial amount of error caused by uncertainty of the molecular clock, horizontal gene transfer, errors in sequence alignments, etc.

A type IB topoisomerase with DNA repair activities

Previously we have characterized type IB DNA topoisomerase V (topo V) in the hyperthermophile Methanopyrus kandleri. The enzyme has a powerful topoisomerase activity and is abundant in M. kandleri. Here we report two characterizations of topo V. First, we found that its N-terminal domain has sequence homology with both eukaryotic type IB topoisomerases and the integrase family of tyrosine recombinases. The C-terminal part of the sequence includes 12 repeats, each repeat consisting of two similar but distinct helix-hairpin-helix motifs; the same arrangement is seen in recombination protein RuvA and mammalian DNA polymerase β. Second, on the basis of sequence homology between topo V and polymerase β, we predict and demonstrate that topo V possesses apurinic/apyrimidinic (AP) site-processing activities that are important in base excision DNA repair: (i) it incises the phosphodiester backbone at the AP site, and (ii) at the AP endonuclease cleaved AP site, it removes the 5′ 2-deoxyribose 5-phosphate moiety so that a single-nucleotide gap with a 3′-hydroxyl and 5′-phosphate can be filled by a DNA polymerase. Topo V is thus the prototype for a new subfamily of type IB topoisomerases and is the first example of a topoisomerase with associated DNA repair activities.

Os efeitos da adoção de práticas de inovação gerencial sobre a flexibilidade organizacional

desenvolvem capacidades dinâmicas. Um tipo de inovação é a inovação gerencial que trata de mudanças na maneira de gerir a empresa. As capacidades dinâmicas são responsáveis pela percepção de oportunidades e ameaças e ajustamento da organização respondendo a elas. Tais capacidades causam o desenvolvimento de flexibilidade. Assim, o objetivo deste trabalho é relacionar a adoção de práticas de inovação gerencial à sua contribuição para o desenvolvimento de capacidades dinâmicas, medidas por meio da flexibilidade. O estudo é importante pela pequena atenção dada aos fatores organizacionais nos estudos de inovação, do pequeno número de pesquisas empíricas sobre capacidades dinâmicas e do desconhecimento dos mecanismos que atuam nessas capacidades. Para atender ao objetivo foi realizada uma pesquisa descritiva com etapas qualitativa e quantitativa. Na etapa qualitativa foram listadas práticas de inovação gerencial encontradas na bibliografia. Um painel de especialistas classificou essas práticas de acordo com os tipos de inovação gerencial. Na etapa quantitativa foi feito um levantamento usando questionário estruturado aplicado online no qual se mediu a adoção das práticas de inovação gerencial e uma escala pré-existente mediu a flexibilidade. A lista de respondentes foi obtida da Brasscom, do prêmio Great Place to Work, do Anuário Informática Hoje e Anuário Telecom. Compuseram a população da pesquisa 343 empresas escolhidas por conveniência. O questionário foi enviado para indivíduos do nível estratégico e foram obtidas respostas de 102 empresas. Os dados foram analisados por meio de estatística descritiva, análise fatorial exploratória e modelagem de equações estruturais. Os resultados mostram que entre as empresas do setor de TIC as práticas de organização do local de trabalho são as mais adotadas, e que as empresas que mais adotam inovação e são mais flexíveis são empresas entre 13 e 21 anos de idade, de capital estrangeiro ou misto, e que atuam também no Exterior. Verificou-se ainda que a flexibilidade estratégica, estrutural e operacional compõem as capacidades dinâmicas que por sua vez são afetadas pela adoção de inovação gerencial, especialmente das práticas de negócio. Para as empresas recomenda-se cuidado na adoção de práticas, para que estas não precisem ser abandonadas causando perda de flexibilidade. Nesse processo a atuação proativa dos gestores contribui para manter o ciclo de inovação gerencial funcionando. Como contribuição para a academia, destaca-se uma maior compreensão de como as capacidades dinâmicas são colocadas em prática e a medida dessa capacidade por meio da flexibilidade. Para pesquisas futuras recomendam-se estudos que identifiquem causas e consequências do abandono de práticas de inovação gerencial e a comprovação do modelo com dados de outros setores. Conclui-se que maior atenção deve ser dada ao estudo da inovação gerencial e seus efeitos sobre as capacidades dinâmicas.

Videos matemáticos

El proyecto de videos de divulgación de Matemática tiene el objetivo de poner en común algunos conceptos y fundamentos de esta ciencia que están presentes en la vida diaria y dar a conocer la importancia de los mismos, desmistificando la aparente dificultad y el prejuicio que se tiene hacia las Matemáticas. De esta forma se intenta democratizar el acceso a estos conocimientos para que más gente pueda sentirlos cerca de su realidad y también para que más niños y jóvenes los hagan suyos con la idea de que muchos de ellos podrían decidir estudiar carreras relacionadas a la Matemática si la vieran como una opción. Los videos cortos protagonizados por niños son ideales para lograr por un lado, la identificación del espectador con los protagonistas y por otro, para desarrollar los conceptos de forma comprensible para un público general. Estos videos pueden ser emitidos en la televisión, puedan usarse como disparadores de charlas en los colegios secundarios, pueden ser exhibidos en eventos y conferencias o ciclos de cine. La idea es que lleguen a la mayor cantidad de personas posible con el objetivo de acortar la brecha que existe entre la generación de conocimiento científico y la efectiva participación de los jóvenes en la cultura científica.

When do adults learn? A cohort analysis of adult education in Europe. CEPS Working Document No. 383, 21 May 2013

Adult learning is seen as a key factor for enhancing employment, innovation and growth, and it should concern all age cohorts. The aim of this paper is to understand the points in the life cycle at which adult learning takes place and whether it leads to reaching a medium or high level of educational attainment. To this end we perform a synthetic panel analysis of adult learning for cohorts aged 25 to 64 in 27 European countries using the European Labour Force Survey. We find, as previous results suggest, that a rise in educational attainment as well as participation in education and training happens mostly at the age range of 25-29. However, investment across the life cycle by cohorts older than 25 still occurs: in most countries in our sample, participation in education and training as well as educational attainment increases observably across all cohorts. We also find that the decline with age slows down or is even reversed for older cohorts, for both participation in education and educational attainment. Finally, we can identify a Nordic model in which adult learning is achieved through participation in education and training, a Central European model in which adult learning occurs in the form of increasing educational attainment and a liberal model in which both approaches to adult learning are observable.

(Table 1) Chemical composition of interstitial waters from the area of gas hydrate generation, Sea of Okhotsk

Distributions of halogens (Cl, Br and I) in interstitial waters from sediments containing methane hydrate and in water of the hydrate itself are presented. High concentrations of halogens do not occur in interstitial waters from sediments that contain gas hydrates. The main reason for their low concentrations is the poverty of organic matter in sediments.

Chemical and isotopic composition of interstitial waters from the Kara Sea and Yenisey estuary

Processes of early sediment diagenesis, including chemical composition of interstitial waters, content of different sulfur compounds, and rates of sulfate reduction were investigated. Along a profile from the Yenisey River to the Kara Sea, sulfate reduction intensities were high (up to 1.5 µg S/kg/day) in the delta region and in its northern part. Intensities were comparable to those found in shallow-water sediments of the North Sea. In estuarine sediments, where different transformations were possible, lower rates of bacterial sulfate reduction were observed (0.03 to 0.06 µg S/kg/day). Annual production of reduced sulfur in sediments was 24 million tons, and only 0.5 million tons (2%) were deposited. Annual consumption of organic carbon during process of sulfate reduction in the Yenisey delta region was 17.6 million tons.

Abundance and biomass of phytoplankton in the water column in the northern subtropical Pacific

Species composition, cell number and biomass of pico-, nanno- and microalgae were estimated for open waters of the northern subtropical zone of the Pacific Ocean and coastal waters off the North America. Total phytoplankton abundance was also evaluated. Productivity of these waters was newly estimated. Distribution of phytoplankton, its size, and taxonomic groups were compared with chlorophyll distribution estimated during the same cruise. Dissimilarities between distribution of small and large forms result from their adaptation to various peculiarities of the environment.