Triazolopyridinyl-acrylonitrile derivatives as antimicrotubule agents: Synthesis, in vitro and in silico characterization of antiproliferative activity, inhibition of tubulin polymerization and binding thermodynamics

In this paper we report the synthesis, in vitro anticancer activity, and the experimental/computational characterization of mechanism of action of a new series of E isomers of triazolo[4,5-b/c]pyridin-acrylonitrile derivatives (6c-g, 7d-e, 8d-e, 9c-f, 10d-e, 11d-e). All new compounds are endowed with moderate to interesting antiproliferative activity against 9 different cancer cell lines derived from solid and hematological human tumors. Fluorescence-based assays prove that these molecules interfere with tubulin polymerization. Furthermore, isothermal titration calorimetry (ITC) provides full tubulin/compound binding thermodynamics, thereby ultimately qualifying and quantifying the interactions of these molecular series with the target protein. Lastly, the analysis based on the tight coupling of in vitro and in silico modelling of the interactions between tubulin and the title compounds allows to propose a molecular rationale for their biological activity

Design, synthesis and antitubercular activity of 4-alkoxy-triazoloquinolones able to inhibit the M.\ua0tuberculosis DNA gyrase

A number of new F-triazolequinolones (FTQs) and alkoxy-triazolequinolones (ATQs) were designed, synthesized and evaluated for their activity against Mycobacterium tuberculosis H37Rv. Five out of 21 compounds exhibited interesting minimum inhibitory concentration (MIC) values (6.6-57.9 microM), ATQs generally being more potent than FTQs. Two ATQs, 21a and 30a, were endowed with the best anti-Mtb potency (MIC = 6.9 and 6.6 microM, respectively), and were not cytotoxic in a Vero cell line. Tested for activity against M. tuberculosis DNA gyrase in a DNA supercoiling activity assay, 21a and 30a showed IC50 values (27-28 microM) comparable to that of ciprofloxacin (10.6 microM). 21a was next selected for screening against several Mtb strains obtained from clinical isolates, including multi-drug-resistant (MDR) variants. Importantly, this compound was effective in all cases, with very promising MIC values (4 microM) in the case of some isoniazid/rifampicin-resistant Mtb strains. Finally, computer-based simulations revealed that the binding mode of 21a in the Mtb gyrase cleavage core complexed with DNA and the relevant network of intermolecular interactions are utterly similar to those described for ciprofloxacin, yielding a molecular rationale for the comparable anti-mycobacterial and DNA gyrase inhibition activity of this quinolone

Synthesis, cytotoxicity and antiviral evaluation of new series of imidazo[4,5-g]quinoline and pyrido[2,3-g]quinoxalinone derivatives

Linear aromatic N-tricyclic compounds with promising antiviral activity and minimal cytotoxicity were prepared and analyzed in the last years. Specifically, the pyrido[2,3-g]quinoxalinone nucleus was found endowed with high potency against several pathogenic RNA viruses as etiological agents of important veterinary and human pathologies. Following our research program on new antiviral agents we have designed, synthesized and assayed new series of imidazo[4,5-g]quinoline and pyrido[2,3-g]quinoxalinone derivatives. Lead compounds 1-4 were further modified to enhance their antiviral activity and reduce their cytotoxicity. Thus, different substituents were introduced on N atom at position 1 or the O atom at position 2 of the leads; contextually, several groups were inserted on the nitrogen atom at position 7 of diaminoquinoline intermediates. Title compounds were tested in cell-based assays for cytotoxicity and antiviral activity against RNA virus families containing single-stranded (either positive-sense (ssRNA+) or negative-sense (ssRNA-)), and double-stranded genomes (dsRNA), and against two representatives of DNA virus families. Some derivatives emerged as potential leads for further development as antiviral agents against some viruses of public health significance, such as RSV, Reo, BVDV and HCV. Particularly, compounds 4, 11b, 11c, 13c, 15a, 18 and 21 resulted active against BVDV at concentrations ranging from 1.3 to 5\ua0\u3bcM. Compound 21 was also evaluated for its activity on the BVDV RdRp. Compound 4 was also tested as potential anti-HCV compound in a subgenomic replication assay. Molecular simulation results provided a molecular rationale for the anti-BVDV activity of these compounds

Intervalo de dobleces

Mathematics today becomes a complex and often difficult subject for the students who study it, it is a fact that many times this difficulty is based on the teaching that is given by the teacher for not being able to transmit their knowledge in a simple way, or also due to lack of interest from the students themselves. One strategy that brings great interest to students is folding sheets of paper. Hence, there are different formulas to find the maximum number of folds in a sheet of a material, however, through this article we find a different formula that helps us calculate the folds. In addition, we arrive at some formulas that give us the interval that a sheet of a material must measure to reach a certain number of folds. Then, we check the formulas with sheets of different materials, reaching the folds indicated by the formulas cited in this article. Finally, we managed to break a world record for folding a sheet (the record was 13), achieving 14 numbers of folds.Las matemáticas hoy en día se hacen una materia compleja y muchas veces difícil por parte de los estudiantes que la cursa, es un hecho, que muchas veces esta dificultad se basa en la enseñanza que se da por parte del profesor por no poder transmitir sus conocimientos de una manera sencilla, o también por falta de interés de los mismos estudiantes. Una estrategia qué aporta gran interés a los estudiantes es doblar hojas de papel. De ahí, que existen diferentes fórmulas para encontrar el número de dobleces máximo de una hoja de un material, sin embargo, a través de este artículo encontramos una fórmula distinta que nos ayudan a calcular los dobleces. Además, llegamos a unas fórmulas que nos dan el intervalo que debe de medir una hoja de un material para alcanzar cierto número de dobleces. Luego, comprobamos las fórmulas con hojas de distintos materiales, alcanzando los dobleces señalados por las fórmulas citadas de este artículo. Por último, logramos vencer un récord mundial de dobleces de una hoja (el récord era de 13), logrando 14 número de dobleces

Dichloro-Phenyl-Benzotriazoles: A New Selective Class of Human Respiratory Syncytial Virus Entry Inhibitors

Human Respiratory Syncytial Virus (RSV) is the primary cause of bronchopneumonia in infants and children worldwide. Clinical studies have shown that early treatments of RSV patients with ribavirin improve prognosis, even if the use of this drug is limited due to myelosuppression and toxicity effects. Furthermore, effective vaccines to prevent RSV infection are currently unavailable. Thus, the development of highly effective and specific antiviral drugs for pre-exposure prophylaxis and/or treatment of RSV infections is a compelling need. In the quest of new RSV inhibitors, in this work we evaluated the antiviral activity of a series of variously substituted 5,6-dichloro-1-phenyl-1(2)H-benzo[d][1,2,3]triazole derivatives in cell-based assays. Several 1- and 2-phenyl-benzotriazoles resulted fairly potent (\ub5M concentrations) inhibitors of RSV infection in plaque reduction assays, accompanied by low cytotoxicity in human highly dividing T lymphoid-derived cells and primary cell lines. Contextually, no inhibitory effects were observed against other RNA or DNA viruses assayed, suggesting specific activity against RSV. Further results revealed that the lead compound 10d was active during the early phase of the RSV infection cycle. To understand whether 10d interfered with virus attachment to target cells or virus-cell fusion events, inhibitory activity tests against the RSV mutant strain B1 cp-52 \u2013 expressing only the F envelope glycoprotein \u2013 and a plasmid-based reporter assay that quantifies the bioactivity of viral entry were also performed. The overall biological results, in conjunction with in silico modeling studies, supported the conclusion that the RSV fusion process could be the target of this new series of compounds

Extreme Evolutionary Disparities Seen in Positive Selection across Seven Complex Diseases

Positive selection is known to occur when the environment that an organism inhabits is suddenly altered, as is the case across recent human history. Genome-wide association studies (GWASs) have successfully illuminated disease-associated variation. However, whether human evolution is heading towards or away from disease susceptibility in general remains an open question. The genetic-basis of common complex disease may partially be caused by positive selection events, which simultaneously increased fitness and susceptibility to disease. We analyze seven diseases studied by the Wellcome Trust Case Control Consortium to compare evidence for selection at every locus associated with disease. We take a large set of the most strongly associated SNPs in each GWA study in order to capture more hidden associations at the cost of introducing false positives into our analysis. We then search for signs of positive selection in this inclusive set of SNPs. There are striking differences between the seven studied diseases. We find alleles increasing susceptibility to Type 1 Diabetes (T1D), Rheumatoid Arthritis (RA), and Crohn's Disease (CD) underwent recent positive selection. There is more selection in alleles increasing, rather than decreasing, susceptibility to T1D. In the 80 SNPs most associated with T1D (p-value <7.01×10−5) showing strong signs of positive selection, 58 alleles associated with disease susceptibility show signs of positive selection, while only 22 associated with disease protection show signs of positive selection. Alleles increasing susceptibility to RA are under selection as well. In contrast, selection in SNPs associated with CD favors protective alleles. These results inform the current understanding of disease etiology, shed light on potential benefits associated with the genetic-basis of disease, and aid in the efforts to identify causal genetic factors underlying complex disease

Expressed sequence tags from Atta laevigata and identification of candidate genes for the control of pest leaf-cutting ants

<p>Abstract</p> <p>Background</p> <p>Leafcutters are the highest evolved within Neotropical ants in the tribe Attini and model systems for studying caste formation, labor division and symbiosis with microorganisms. Some species of leafcutters are agricultural pests controlled by chemicals which affect other animals and accumulate in the environment. Aiming to provide genetic basis for the study of leafcutters and for the development of more specific and environmentally friendly methods for the control of pest leafcutters, we generated expressed sequence tag data from <it>Atta laevigata</it>, one of the pest ants with broad geographic distribution in South America.</p> <p>Results</p> <p>The analysis of the expressed sequence tags allowed us to characterize 2,006 unique sequences in <it>Atta laevigata</it>. Sixteen of these genes had a high number of transcripts and are likely positively selected for high level of gene expression, being responsible for three basic biological functions: energy conservation through redox reactions in mitochondria; cytoskeleton and muscle structuring; regulation of gene expression and metabolism. Based on leafcutters lifestyle and reports of genes involved in key processes of other social insects, we identified 146 sequences potential targets for controlling pest leafcutters. The targets are responsible for antixenobiosis, development and longevity, immunity, resistance to pathogens, pheromone function, cell signaling, behavior, polysaccharide metabolism and arginine kynase activity.</p> <p>Conclusion</p> <p>The generation and analysis of expressed sequence tags from <it>Atta laevigata </it>have provided important genetic basis for future studies on the biology of leaf-cutting ants and may contribute to the development of a more specific and environmentally friendly method for the control of agricultural pest leafcutters.</p

Aboveground biomass density models for NASA's Global Ecosystem Dynamics Investigation (GEDI) lidar mission

NASA's Global Ecosystem Dynamics Investigation (GEDI) is collecting spaceborne full waveform lidar data with a primary science goal of producing accurate estimates of forest aboveground biomass density (AGBD). This paper presents the development of the models used to create GEDI's footprint-level (similar to 25 m) AGBD (GEDI04_A) product, including a description of the datasets used and the procedure for final model selection. The data used to fit our models are from a compilation of globally distributed spatially and temporally coincident field and airborne lidar datasets, whereby we simulated GEDI-like waveforms from airborne lidar to build a calibration database. We used this database to expand the geographic extent of past waveform lidar studies, and divided the globe into four broad strata by Plant Functional Type (PFT) and six geographic regions. GEDI's waveform-to-biomass models take the form of parametric Ordinary Least Squares (OLS) models with simulated Relative Height (RH) metrics as predictor variables. From an exhaustive set of candidate models, we selected the best input predictor variables, and data transformations for each geographic stratum in the GEDI domain to produce a set of comprehensive predictive footprint-level models. We found that model selection frequently favored combinations of RH metrics at the 98th, 90th, 50th, and 10th height above ground-level percentiles (RH98, RH90, RH50, and RH10, respectively), but that inclusion of lower RH metrics (e.g. RH10) did not markedly improve model performance. Second, forced inclusion of RH98 in all models was important and did not degrade model performance, and the best performing models were parsimonious, typically having only 1-3 predictors. Third, stratification by geographic domain (PFT, geographic region) improved model performance in comparison to global models without stratification. Fourth, for the vast majority of strata, the best performing models were fit using square root transformation of field AGBD and/or height metrics. There was considerable variability in model performance across geographic strata, and areas with sparse training data and/or high AGBD values had the poorest performance. These models are used to produce global predictions of AGBD, but will be improved in the future as more and better training data become available