New compound sets identified from high throughput phenotypic screening against three kinetoplastid parasites:an open resource

Using whole-cell phenotypic assays, the GlaxoSmithKline high-throughput screening (HTS) diversity set of 1.8 million compounds was screened against the three kinetoplastids most relevant to human disease, i.e. Leishmania donovani, Trypanosoma cruzi and Trypanosoma brucei. Secondary confirmatory and orthogonal intracellular anti-parasiticidal assays were conducted, and the potential for non-specific cytotoxicity determined. Hit compounds were chemically clustered and triaged for desirable physicochemical properties. The hypothetical biological target space covered by these diversity sets was investigated through bioinformatics methodologies. Consequently, three anti-kinetoplastid chemical boxes of ~200 compounds each were assembled. Functional analyses of these compounds suggest a wide array of potential modes of action against kinetoplastid kinases, proteases and cytochromes as well as potential host–pathogen targets. This is the first published parallel high throughput screening of a pharma compound collection against kinetoplastids. The compound sets are provided as an open resource for future lead discovery programs, and to address important research questions.The support and funding of Tres Cantos Open Lab Foundation is gratefully acknowledgedPeer reviewe

Teoria asintotica de vigas elasticas lineales anisotropas y no homogeneas

Available from Centro de Informacion y Documentacion Cientifica CINDOC. Joaquin Costa, 22. 28002 Madrid. SPAIN / CINDOC - Centro de Informaciòn y Documentaciòn CientìficaSIGLEESSpai

Development and Validation of Single Nucleotide Polymorphisms (SNPs) Markers from Two Transcriptome 454-Runs of Turbot (Scophthalmus maximus) Using High-Throughput Genotyping

Abstract: The turbot (Scophthalmus maximus) is a commercially valuable flatfish and one of the most promising aquaculture species in Europe. Two transcriptome 454-pyrosequencing runs were used in order to detect Single Nucleotide Polymorphisms (SNPs) in genes related to immune response and gonad differentiation. A total of 866 true SNPs were detected in 140 different contigs representing 262,093 bp as a whole. Only one true SNP was analyzed in each contig. One hundred and thirteen SNPs out of the 140 analyzed were feasible (genotyped), while Ш were polymorphic in a wild population. Transition/transversion ratio (1.354) was similar to that observed in other fish studies. Unbiased gene diversity (He) estimates ranged from 0.060 to 0.510 (mean = 0.351), minimum allele frequency (MAF) from 0.030 to 0.500 (mean = 0.259) and all loci were in Hardy-Weinberg equilibrium after Bonferroni correction. A large number of SNPs (49) were located in the coding region, 33 representing synonymous and 16 non-synonymous changes. Most SNP-containing genes were related to immune response and gona

De novo assembly of Manila clam (<i>Ruditapes philippinarum</i>) and protozoan parasite (<i>Perkinsus olseni</i>) transcriptome from RNA-Seq data

Manila clam (Ruditapes philippinarum) with its high commercial value has become a major contributor to the world´s clam production from both bivalve fishery and aquaculture ventures. But, the production of manila clam is at greater risk from diseases, especially caused by Perkinsus olseni. Considering the limited genomic resources of R. philippinarum and P. olseni as well as the increasing interest in immune-genes response in the host, the present work was conducted to analyze the transcriptome profile of R. philippinarum and of P. olseni using RNA-Seq technology. Data obtained will be used to construct transcriptome databases and to design oligo-microarrays both in the host and the parasite for understanding their transcriptional expressions through host-pathogen interactions. cDNA libraries were synthesized using RNA aliquots of clam haemocytes and perkinsus trophozoites collected from different experimental conditions (in vitro, in vivo and natural environment) for further sequencing carried out on Illumina HiSeq 2000 (Oxford Genomics Center, UK). A total of 131,037,742 pair-end reads for R. philippinarum and 67,840,472 for P. olseni were produced. De novo assembly was evaluated using different parameters of Trinity and Abyss assembler programs. De novo transcriptome of clam was further undergone through filtering steps by expression (> 5 FPKM), and length (500 bp) for improving transcriptome quality. CAP3 software was executed to cluster final de novo transcriptomes. Trinity+CAP3 assembly was the best approach after manual evaluation of 30 annotated contigs randomly sampled from each strategy and was chosen finally to assemble transcriptomes. 33,182 unique transcripts (3,031 contigs and 30,151 singletons) from de novo clam transcriptome, and 47,590 unique transcripts (7,251 contigs and 40,339 singletons) from perkinsus transcriptome were obtained. Among them; 3,031 (9.13%) unigenes of R. philippinarum, and 7,251 (15.24%) of P. olseni were annotated with NCBI nucleotide (nt) databases based on e-value P. olseni, and also the first one from RNA-Seq for R. philippinarum. Using these de novo transcriptome resources, microarrays will be designed for all the unique sequences and their splice variants identified in each database. The comparative analysis will provide new insights into understanding molecular mechanisms of gene expressions through clam-perkinsus interactions

Development and Validation of Single Nucleotide Polymorphisms (SNPs) Markers from Two Transcriptome 454-Runs of Turbot (Scophthalmus maximus) Using High-Throughput Genotyping

The turbot (Scophthalmus maximus) is a commercially valuable flatfish and one of the most promising aquaculture species in Europe. Two transcriptome 454-pyrosequencing runs were used in order to detect Single Nucleotide Polymorphisms (SNPs) in genesrelated to immune response and gonad differentiation. A total of 866 true SNPs were detected in 140 different contigs representing 262,093 bp as a whole. Only one true SNP was analyzed in each contig. One hundred and thirteen SNPs out of the 140 analyzed were feasible (genotyped), while Ш were polymorphic in a wild population. Transition/transversion ratio (1.354) was similar to that observed in other fish studies. Unbiased gene diversity (He) estimates ranged from 0.060 to 0.510 (mean = 0.351), minimum allele frequency (MAF) from 0.030 to 0.500 (mean = 0.259) and all loci were in Hardy-Weinberg equilibrium after Bonferroni correction. A large number of SNPs (49) were located in the coding region, 33 representing synonymous and 16 non-synonymous changes. Most SNP-containing genes were related to immune response and gonad differentiation processes, and could be candidates for functional changes leading to phenotypic changes. These markers will be useful for population screening to look for adaptive variation in wild and domestic turbo

Identification of Bacillus and Yersinia species and hoax agents by protein profiling using microfluidic capillary electrophoresis with peak detection algorithms

Bacillus anthracis and Yersinia pestis are biological agents that pose an increasing concern to national security if deliberately disseminated. Hoax agents, including suspicious white powders and environmental bacterial species, can also cause disruption. In either scenario it is of high importance to rapidly and accurately identify any suspicious powder as hazardous or hoax. Protein profiling, using microfluidic capillary electrophoresis, provides a rapid (less than 40 minutes), reliable and field-based screening method.This work was supported by the Australian Commonwealth Government [Endeavour Fellowship

Packet Optical Transport Network Slicing with Hard and Soft Isolation

Network operators have been dealing with the necessity of a dynamic network resources allocation to provide a new generation of customer-tailored applications. In that sense, Telecom providers have to migrate their BSS/OSS systems and network infrastructure to more modern solutions to introduce end-to-end automation and support the new use cases derived from the 5G adoption and transport network slices. In general, there is a joint agreement on making this transition to an architecture defined by programmable interfaces and standard protocols. Hence, this paper uses the iFusion architecture to control and program the network infrastructure. The work presents an experimental validation of the network slicing instantiation in an IP/Optical environment using a set of standard protocols and interfaces. The work provides results of the creation, modification and deletion of the network slices. Furthermore, it demonstrates the usage of standard communication protocols (Netconf and Restconf) in combination with standard YANG data models

EPI.14-15 Real World Clinical Experience of the Galician Lung Cancer Group: Afatinib in Patients with EGFR Positive Mutation

Background Treatment with tyrosine kinasa inhibitors has been a revolution for the patients with non-small cell lung cancer and EGFR positive mutation, especially in patients with exon 19 deletions. Afatinib seems one of the best options of treatment. Method Retrospective study on patients from different hospitals in Galicia (Spain) diagnosed of metastasic lung adenocarcinoma with EGFR positive mutation who have received first line treatment with afatinib between July 2015 and September 2018 were included. Main objective was to compare our clinical experience concerning response rate, progression free survival and toxicity with published data. Result 45 Caucasians patients were included in our analysis (33 women, 12 men). Median age was 71.2 years (range 39-91 years) and 29 patients had never smoked. Exon 19 deletion was the most common mutation (41 patients, 91.1%). The objective overall response was 68.9% (95% CI: 82.4-55.3), complete responses were observed in 6 patients (13.3%) and partial responses were found in 25 patients (55.6%). Stable disease was observed in 8 patients (17.8%) and disease progression in 1 patient (2.2%), 5 patients have not been reevaluated (11.1%). Median progression free survival (PFS) was 27 months (95% CI: 14.8-39.1) and overall survival was not reached. Common adverse events grade 3/4 were mucositis and skin toxicity in 11 patients (24.4%) and diarrhea in 6 patients (13.3%), respectively. The dose was reduced in 28 patients (62.2%) and treatment was discontinued in 8 patients (17.8%) owing to adverse events. Conclusion Median PFS in our patients is 15 months longer than the information retrieved from differents studies with similar response rates and toxicity. This might be due to a majority of population with exon 19 deletion which, according to published data, seems to benefit more from afatinib than from other EGFR mutations

Evaluation of the lung immune prognostic index in advanced non-small cell lung cancer patients under nivolumab monotherapy

The lung immune prognostic index (LIPI) has been proposed as a new categorical blood-based biomarker to select advanced non-small cell lung cancer (NSCLC) patients for anti-programmed cell death-1 (PD-1) or programmed death ligand 1 (PD-L1) therapy. In this study, we investigate for the first time to the best of our knowledge the prognostic and predictive utility of the LIPI in a multicenter nivolumab monotherapy-based cohort. We retrospectively analyzed the influence of the baseline LIPI on overall survival (OS), progression-free survival (PFS), disease control rate (DCR), and overall response rate (ORR) among 153 patients of a cohort of 188 advanced NSCLC patients treated with nivolumab in the second line of therapy or beyond. Worse LIPI was significantly associated with shorter OS in univariate [hazard ratio (HR) =3.12, 95% confidence interval (CI), 2.12-4.60; P<0.0001] and multivariate (HR =3.67, 95% CI, 1.96-6.86; P<0.0001) analyses. Worse LIPI was associated with shorter PFS (HR =1.45, 95% CI, 1.05-2.03; P=0.03), but this correlation did not reach statistical significance in multivariate analysis (HR =1.49, 95% CI, 0.94-2.38; P=0.09). Worse LIPI was associated with lower DCR in univariate [odds ratio (OR) =0.41, 95% CI, 0.24-0.70; P=0.001] and multivariate (OR =0.44, 95% CI, 0.25-0.78; P=0.005) analyses. This study confirms the utility of the LIPI in prognostication and disease control prediction in advanced NSCLC patients treated with nivolumab in the second line of therapy or beyond