140 research outputs found
Progresses in the pursuit of aldose reductase inhibitors: The structure-based lead optimization step
No full textAldose reductase (ALR2) is a crucial enzyme in the development of the major complications of diabetes
mellitus. Very recently it has been demonstrated that the ARL2 inhibitor, fidarestat, significantly prevents
inflammatory signals (TNF-a, LPS) that cause cancer (colon, breast, prostate and lung), metastasis,
asthma, and other inflammatory diseases. Currently, fidarestat is in phase III clinical trial for diabetic
neuropathy and was found to be safe. Thus the finding of novel, potent ARL2 inhibitors is today more
than in the past in great demand as they can pave the way for a novel therapeutic approach for a number
of diseases besides the diabetes. Herein, starting from the virtual screening-derived ALR2 inhibitor
S12728 (1), a rational receptor-based lead optimization has been undertaken. The design and synthetic
efforts here reported led to the discovery of several new compounds endowed with low micromolar/
submicromolar activities
Progresses in the pursuit of aldose reductase inhibitors: the structure-based lead optimization step
No full textAldose reductase (ALR2) is a crucial enzyme in the development of the major complications of diabetes mellitus. Very recently it has been demonstrated that the ARL2 inhibitor, fidarestat, significantly prevents inflammatory signals (TNF-α, LPS) that cause cancer (colon, breast, prostate and lung), metastasis, asthma, and other inflammatory diseases. Currently, fidarestat is in phase III clinical trial for diabetic neuropathy and was found to be safe. Thus the finding of novel, potent ARL2 inhibitors is today more than in the past in great demand as they can pave the way for a novel therapeutic approach for a number of diseases besides the diabetes. Herein, starting from the virtual screening-derived ALR2 inhibitor S12728 (1), a rational receptor-based lead optimization has been undertaken. The design and synthetic efforts here reported led to the discovery of several new compounds endowed with low micromolar/submicromolar activities
Structure and dynamics of the pan-genome of Streptococcus pneumoniae and closely related species
No full textBACKGROUND:
Streptococcus pneumoniae is one of the most important causes of microbial diseases in humans. The genomes of 44 diverse strains of S. pneumoniae were analyzed and compared with strains of non-pathogenic streptococci of the Mitis group.
RESULTS:
Despite evidence of extensive recombination, the S. pneumoniae phylogenetic tree revealed six major lineages. With the exception of serotype 1, the tree correlated poorly with capsular serotype, geographical site of isolation and disease outcome. The distribution of dispensable genes--genes present in more than one strain but not in all strains--was consistent with phylogeny, although horizontal gene transfer events attenuated this correlation in the case of ancient lineages. Homologous recombination, involving short stretches of DNA, was the dominant evolutionary process of the core genome of S. pneumoniae. Genetic exchange occurred both within and across the borders of the species, and S. mitis was the main reservoir of genetic diversity of S. pneumoniae. The pan-genome size of S. pneumoniae increased logarithmically with the number of strains and linearly with the number of polymorphic sites of the sampled genomes, suggesting that acquired genes accumulate proportionately to the age of clones. Most genes associated with pathogenicity were shared by all S. pneumoniae strains, but were also present in S. mitis, S. oralis and S. infantis, indicating that these genes are not sufficient to determine virulence.
CONCLUSIONS:
Genetic exchange with related species sharing the same ecological niche is the main mechanism of evolution of S. pneumoniae. The open pan-genome guarantees the species a quick and economical response to diverse environments
Protocolo de PCR para la detección de Brucella ovis, Histophilus somni y Actinobacillus seminis
No full textAdaptado de Primers utilizados correspondientes al gen BOV_A0500 de B. ovis, tomados de: Tsolis, R.M., Seshadri, R., Santos, R.L., Sangari, F.J., Lobo, J.M., de Jong, M.F., Ren, Q., Myers, G., Brinkac, L.M., Nelson, W.C., Deboy, R.T., Angiuoli, S., Khouri, H., Dimitrov, G., Robinson, J.R., Mulligan, S., Walker, R.L., Elzer, P.E., Hassan, K.A., Paulsen, I.T., 2009. Genome degradation in Brucella ovis corresponds with narrowing of its host range and tissue tropism. PLoS One. 4, e5519.Estación Experimental Agropecuaria BarilocheFil: Alvarez, Lucía Paula. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria Bariloche. Área de Producción Animal. Grupo de Sanidad Animal; ArgentinaFil: Robles, Carlos Alejandro. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria Bariloche. Area de Produccion Animal. Grupo de Sanidad Animal; Argentin
Cunningham: a BLAST Runtime Estimator
No full textBLAST is arguably the single most important piece of software ever written for the biological sciences. It is the core of most bioinformatics workflows, being a critical component of genome homology searches and annotation. It has influenced the landscape of biology by aiding in everything from functional characterization of genes to pathogen detection to the development of novel vaccines. While BLAST is very popular, it is also often one of the most computationally intensive parts of bioinformatics analysis. In our workflows, BLAST typically takes the majority of cpu time, and we need to parallelize to finish in a reasonable time frame. Waiting for BLAST to finish without having any clue of how long it’s going to take is kind of depressing, and you could waste a day of work trying to run a job that would never finish. If you feel the same way we do, then check out Cunningham, a tool we designed to estimate BLAST runtimes for shotgun sequence datasets using sequence composition statistics. We’ve trained its models on real metagenomic sequence data using the Amazon EC2 cloud, and it will provide a relatively quick estimate for datasets with up to tens of millions of sequences. It’s not perfect, but it’ll give you at least some idea of expected runtime, how large a cluster you’re going to need, how much you’ll need to partition your data, etc. We use it all the time now, so we hope it’ll be useful to someone else out there. Cunningham has been implemented in CloVR for efficient autoscaling in the cloud and is freely available at http://clovr.org
Complete genome sequence of Rhizobium leguminosarum bv. trifolii strain WSM1325, an effective microsymbiont of annual Mediterranean clovers
No full textRhizobium leguminosarum bv trifolii is a soil-inhabiting bacterium that has the capacity to be an effective nitrogen fixing microsymbiont of a diverse range of annual Trifolium (clover) species. Strain WSM1325 is an aerobic, motile, non-spore forming, Gram-negative rod isolated from root nodules collected in 1993 from the Greek Island of Serifos. WSM1325 is produced commercially in Australia as an inoculant for a broad range of annual clovers of Mediterranean origin due to its superior attributes of saprophytic competence, nitrogen fixation and acid-tolerance. Here we describe the basic features of this organism, together with the complete genome sequence, and annotation. This is the first completed genome sequence for a microsymbiont of annual clovers. We reveal that its genome size is 7,418,122 bp encoding 7,232 protein-coding genes and 61 RNA-only encoding genes. This multipartite genome contains 6 distinct replicons; a chromosome of size 4,767,043 bp and 5 plasmids of size 828,924 bp, 660,973 bp, 516,088 bp, 350,312 bp and 294,782 bp
Complete genome sequence of Rhizobium leguminosarum bv trifolii strain WSM2304, an effective microsymbiont of the South American clover Trifolium polymorphum.
No full textRhizobium leguminosarum bv trifolii is the effective nitrogen fixing microsymbiont of a diverse range of annual and perennial Trifolium (clover) species. Strain WSM2304 is an aerobic, motile, non-spore forming, Gram-negative rod, isolated from Trifolium polymorphum in Uruguay in 1998. This microsymbiont predominated in the perennial grasslands of Glencoe Research Station, in Uruguay, to competitively nodulate its host, and fix atmospheric nitrogen. Here we describe the basic features of WSM2304, together with the complete genome sequence, and annotation. This is the first completed genome sequence for a nitrogen fixing microsymbiont of a clover species from the American center of origin. We reveal that its genome size is 6,872,702 bp encoding 6,643 protein-coding genes and 62 RNA only encoding genes. This multipartite genome was found to contain 5 distinct replicons; a chromosome of size 4,537,948 bp and four circular plasmids of size 1,266,105 bp, 501,946 bp, 308,747 bp and 257,956 bp
Draft genome of the filarial nematode parasite Brugia malayi
No full textParasitic nematodes that cause elephantiasis and river blindness threaten hundreds of millions of people in the developing world. We have sequenced the approximately 90 megabase (Mb) genome of the human filarial parasite Brugia malayi and predict approximately 11,500 protein coding genes in 71 Mb of robustly assembled sequence. Comparative analysis with the free-living, model nematode Caenorhabditis elegans revealed that, despite these genes having maintained little conservation of local synteny during approximately 350 million years of evolution, they largely remain in linkage on chromosomal units. More than 100 conserved operons were identified. Analysis of the predicted proteome provides evidence for adaptations of B. malayi to niches in its human and vector hosts and insights into the molecular basis of a mutualistic relationship with its Wolbachia endosymbiont. These findings offer a foundation for rational drug design
Comparative phylogenomics of Streptococcus pneumoniae isolated from invasive disease and nasopharyngeal carriage from West Africans.
No full textBACKGROUND: We applied comparative phylogenomics (whole genome comparisons of microbes using DNA microarrays combined with Bayesian-based phylogenies) to investigate S. pneumoniae isolates from West Africa, with the aim of providing insights into the pathogenicity and other features related to the biology of the organism. The strains investigated comprised a well defined collection of 58 invasive and carriage isolates that were sequenced typed and included eight different S. pneumoniae serotypes (1, 3, 5, 6A, 11, 14, 19 F and 23 F) of varying invasive disease potential. RESULTS: The core genome of the isolates was estimated to be 38% and was mainly represented by gene functional categories associated with housekeeping functions. Comparison of the gene content of invasive and carriage isolates identified at least eleven potential genes that may be important in virulence including surface proteins, transport proteins, transcription factors and hypothetical proteins. Thirteen accessory regions (ARs) were also identified and did not show any loci association with the eleven virulence genes. Intraclonal diversity (isolates of the same serotype and MLST but expressing different patterns of ARs) was observed among some clones including ST 1233 (serotype 5), ST 3404 (serotype 5) and ST 3321 (serotype 14). A constructed phylogenetic tree of the isolates showed a high level of heterogeneity consistent with the frequent S. pneumoniae recombination. Despite this, a homogeneous clustering of all the serotype 1 strains was observed. CONCLUSIONS: Comparative phylogenomics of invasive and carriage S. pneumoniae isolates identified a number of putative virulence determinants that may be important in the progression of S. pneumoniae from the carriage phase to invasive disease. Virulence determinants that contribute to S. pneumoniae pathogenicity are likely to be distributed randomly throughout its genome rather than being clustered in dedicated loci or islands. Compared to other S. pneumoniae serotypes, serotype 1 appears most genetically uniform
Genomic dissection of the 1994 Cronobacter sakazakii outbreak in a French neonatal intensive care unit
No full textBackground: Cronobacter sakazakii is a member of the genus Cronobacter that has frequently been isolated from powdered infant formula (PIF) and linked with rare but fatal neonatal infections such as meningitis and necrotising enterocolitis. The Cronobacter MLST scheme has reported over 400 sequence types and 42 clonal complexes; however C. sakazakii clonal complex 4 (CC4) has been linked strongly with neonatal infections, especially meningitis. There have been a number of reported Cronobacter outbreaks over the last three decades. The largest outbreak of C. sakazakii was in a neonatal intensive care unit (NICU) in France (1994) that lasted over 3 months and claimed the lives of three neonates. The present study used whole genome sequencing data of 26 isolates obtained from this outbreak to reveal their relatedness. This study is first of its kind to use whole genome sequencing data to analyse a Cronobacter outbreak. Methods: Whole genome sequencing data was generated for 26 C. sakazakii isolates on the Illumina MiSeq platform. The whole genome phylogeny was determined using Mugsy and RaxML. SNP calls were determined using SMALT and SAMtools, and filtered using VCFtools. Results: The whole genome phylogeny suggested 3 distant clusters of C. sakazakii isolates were associated with the outbreak. SNP typing and phylogeny indicate the source of the C. sakazakii could have been from extrinsic contamination of reconstituted infant formula from the NICU environment and personnel. This pool of strains would have contributed to the prolonged duration of the outbreak, which was up to 3 months. Furthermore 3 neonates were co-infected with C. sakazakii from two different genotype clusters. Conclusion: The genomic investigation revealed the outbreak consisted of an heterogeneous population of C. sakazakii isolates. The source of the outbreak was not identified, but probably was due to environmental and personnel reservoirs resulting in extrinsic contamination of the neonatal feeds. It also indicated that C. sakazakii isolates from different genotype clusters have the ability to co-infect neonates
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