Влияние магнитного поля на седиментацию клеток, содержащих магнитные частицы

Magnetic field influence on the macrophage with the absorbed magnetic particles is investigated. It is demonstrated that the application of magnetic field changes the speed of sedimentation of cells. Changes of the nonsymmetrical indicatrix of the scattered light indicates that shape of the cells have changed under the influence of the magnetic field.Исследовано влияние магнитного поля на макрофаги с поглощенными магнитными частицами. Показано, что наложение магнитного поля изменяет скорость оседания клеток, но в более значительной степени оказывает влияние на изменение параметра асимметричности индикатрисы светорассеяния, что свидетельствует об изменении формы оседающих клеток под воздействием магнитного поля

Перспективы терапевтического воздействия на сигнальный путь FGFR

Fibroblast growth factors (FGFs) and their receptors (FGFRs) are involved in key cellular functions and cancerogenesis. Nowadays FGFR and their ligands are one of the most investigated markers in oncology and targets for specific therapy. There are a lot of clinical trials in on- cology include drugs with anti-FGFR activities. The most of these drugs are tyrosine kinase inhibitors and monoclonal antibodies. When we say about therapeutic effects on the FGFR signaling pathway, we say about opportunity not only block the ligands and FGFRs, but the under- lying molecular and signaling pathways activated by FGFRs. Nowadays the number of tyrosine kinase inhibitors selectively blocking FGFRs is extremely small. Typically, tyrosine kinase inhibitors can block a wide range of targets. Some of these inhibitors have entered in clinical practice in the treatment of metastatic tumors of different localizations, others are in clinical trials. On August 2014, 74 studies investigating inhibitors of FGFRs are registered on clinicaltrials.gov. A number of marketed drugs at high concentrations also has the ability to inhibit FGFR – sorafenib, vandetanib, motesanib, however, increasing the concentration of these drugs is associated with severe toxicity of treat- ment. In the recommended therapeutic concentrations, adequate blocking FGFR tyrosine kinase domain is doubtful. The review paid atten- tion to such drugs as pazopanib, nintedanib, cediranib, brivanib, dovitinib, ponatinib. We showed the results of treatment with inhibitors of FGFR in different cancers such as breast cancer, colon cancer, endometrial cancer, gastric cancer, thyroid cancer, lung cancer, ovarian cancer. Despite the fact that anti-FGFR therapy are at an early stage of clinical investigation, some difficulties in implementing this thera- peutic approach have been seen, such as high toxicity, not validated targets, the need for patient selection, depending on the activity of FGF– FGFR pathway, as well as mutations in genes of downstream molecular signaling pathways. In summary in the article we reviewed relevant literature to identify current status, difficulties and future perspectives in development of anti- FGFR drugs. In this article, we review FGFR signaling and describe the therapeutic intervention in patients with solid tumors. Одними из наиболее исследуемых в онкологии биомаркеров являются рецепторы к фактору роста фибробластов (FGFR), а также лиганды к фактору роста фибробластов (FGF). Молекулярные изменения в генах различных представителей семейства FGF или FGFR – довольно частое событие при злокачественных новообразованиях. Определение значимости комплекса FGF–FGFR в процессах канцерогенеза и в прогрессировании опухолей различной нозологии послужило толчком к появлению работ, посвященных поиску возможностей лекарственного воздействия на данный сигнальный путь. С точки зрения терапевтического воздействия на сигнальный путь FGFR возможно блокировать не только лиганды FGF и FGFR, но и нижележащие молекулы сигнальных путей, активирующихся под действием FGFR. Число ингибиторов тирозинкиназ, селективно блокирующих FGFR, на данный момент крайне невелико. Как правило, тирозинкиназные ингибиторы обладают широким спектром мишеней. Некоторые из таких ингибиторов уже вошли в клиническую практику лечения диссеминированных опухолей различной локализации, другие еще находятся на стадии клинических испытаний. Всего на сайте клинических испытаний clinicaltrials.gov на август 2014 г. зарегистрировано 74 исследования, посвященных изучению ингибиторов FGFR. Способностью ингибировать FGFR обладает также ряд существующих препаратов в высоких концентрациях – сорафениб, вандетаниб, мотесаниб, однако повышение концентрации этих препаратов ассоциировано с выраженной токсичностью лечения. В рекомендованных же терапевтических концентрациях адекватное блокирование тирозин-киназного домена FGFR сомнительно. В статье уделено внимание таким препаратам, как пазопаниб, нинтеданиб, цедираниб, бриваниб, довитиниб, понатиниб. Рассмотрены результаты терапии ингибиторами FGFR при различных нозологиях: рак молочной железы, рак толстой кишки, рак эндометрия, рак желудка, рак щитовидной железы, рак легкого, рак яичников.Несмотря на то, что анти-FGFR-терапия находится на раннем этапе клинического изучения в онкологии, уже сейчас видны определенные трудности в реализации данного лечебного подхода, такие как высокая токсичность, не всегда валидированная мишень воздействия, необходимость отбора пациентов в зависимости от активности FGF–FGFR-пути, а также наличия мутаций в генах молекул нижележащих сигнальных путей. В обзоре рассмотрены молекулярные процессы, возникающие при активации комплекса FGF–FGFR, а также пути терапевтического воздействия на данный комплекс, результаты исследований и перспективы применения ингибиторов сигнального пути FGFR

MicrobesOnline: an integrated portal for comparative and functional genomics

Since 2003, MicrobesOnline (http://www.microbesonline.org) has been providing a community resource for comparative and functional genome analysis. The portal includes over 1000 complete genomes of bacteria, archaea and fungi and thousands of expression microarrays from diverse organisms ranging from model organisms such as Escherichia coli and Saccharomyces cerevisiae to environmental microbes such as Desulfovibrio vulgaris and Shewanella oneidensis. To assist in annotating genes and in reconstructing their evolutionary history, MicrobesOnline includes a comparative genome browser based on phylogenetic trees for every gene family as well as a species tree. To identify co-regulated genes, MicrobesOnline can search for genes based on their expression profile, and provides tools for identifying regulatory motifs and seeing if they are conserved. MicrobesOnline also includes fast phylogenetic profile searches, comparative views of metabolic pathways, operon predictions, a workbench for sequence analysis and integration with RegTransBase and other microbial genome resources. The next update of MicrobesOnline will contain significant new functionality, including comparative analysis of metagenomic sequence data. Programmatic access to the database, along with source code and documentation, is available at http://microbesonline.org/programmers.html.United States. Dept. of Energy (Genomics: GTL program (grant DE-AC02-05CH11231)

Representative Proteomes: A Stable, Scalable and Unbiased Proteome Set for Sequence Analysis and Functional Annotation

The accelerating growth in the number of protein sequences taxes both the computational and manual resources needed to analyze them. One approach to dealing with this problem is to minimize the number of proteins subjected to such analysis in a way that minimizes loss of information. To this end we have developed a set of Representative Proteomes (RPs), each selected from a Representative Proteome Group (RPG) containing similar proteomes calculated based on co-membership in UniRef50 clusters. A Representative Proteome is the proteome that can best represent all the proteomes in its group in terms of the majority of the sequence space and information. RPs at 75%, 55%, 35% and 15% co-membership threshold (CMT) are provided to allow users to decrease or increase the granularity of the sequence space based on their requirements. We find that a CMT of 55% (RP55) most closely follows standard taxonomic classifications. Further analysis of this set reveals that sequence space is reduced by more than 80% relative to UniProtKB, while retaining both sequence diversity (over 95% of InterPro domains) and annotation information (93% of experimentally characterized proteins). All sets can be browsed and are available for sequence similarity searches and download at http://www.proteininformationresource.org/rps, while the set of 637 RPs determined using a 55% CMT are also available for text searches. Potential applications include sequence similarity searches, protein classification and targeted protein annotation and characterization

All-particle primary energy spectrum in the 3-200 PeV energy range

We present all-particle primary cosmic-ray energy spectrum in the 3-200 PeV energy range obtained by a multi-parametric event-by-event evaluation of the primary energy. The results are obtained on the basis of an expanded EAS data set detected at mountain level (700 g/cm^2) by the GAMMA experiment. The energy evaluation method has been developed using the EAS simulation with the SIBYLL interaction model taking into account the response of GAMMA detectors and reconstruction uncertainties of EAS parameters. Nearly unbiased (<5%) energy estimations regardless of a primary nuclear mass with an accuracy of about 15-10% in the 3-200 PeV energy range respectively are attained. An irregularity ('bump') in the spectrum is observed at primary energies of ~74 PeV. This bump exceeds a smooth power-law fit to the data by about 4 standard deviations. Not rejecting stochastic nature of the bump completely, we examined the systematic uncertainties of our methods and conclude that they cannot be responsible for the observed feature.Comment: Accepted by J.Phys.G: Nucl.Part.Phy

Collaborative annotation of genes and proteins between UniProtKB/Swiss-Prot and dictyBase

UniProtKB/Swiss-Prot, a curated protein database, and dictyBase, the Model Organism Database for Dictyostelium discoideum, have established a collaboration to improve data sharing. One of the major steps in this effort was the ‘Dicty annotation marathon’, a week-long exercise with 30 annotators aimed at achieving a major increase in the number of D. discoideum proteins represented in UniProtKB/Swiss-Prot. The marathon led to the annotation of over 1000 D. discoideum proteins in UniProtKB/Swiss-Prot. Concomitantly, there were a large number of updates in dictyBase concerning gene symbols, protein names and gene models. This exercise demonstrates how UniProtKB/Swiss-Prot can work in very close cooperation with model organism databases and how the annotation of proteins can be accelerated through those collaborations

Functional analysis of multiple genomic signatures demonstrates that classification algorithms choose phenotype-related genes

Gene expression signatures of toxicity and clinical response benefit both safety assessment and clinical practice; however, difficulties in connecting signature genes with the predicted end points have limited their application. The Microarray Quality Control Consortium II (MAQCII) project generated 262 signatures for ten clinical and three toxicological end points from six gene expression data sets, an unprecedented collection of diverse signatures that has permitted a wide-ranging analysis on the nature of such predictive models. A comprehensive analysis of the genes of these signatures and their nonredundant unions using ontology enrichment, biological network building and interactome connectivity analyses demonstrated the link between gene signatures and the biological basis of their predictive power. Different signatures for a given end point were more similar at the level of biological properties and transcriptional control than at the gene level. Signatures tended to be enriched in function and pathway in an end point and model-specific manner, and showed a topological bias for incoming interactions. Importantly, the level of biological similarity between different signatures for a given end point correlated positively with the accuracy of the signature predictions. These findings will aid the understanding, and application of predictive genomic signatures, and support their broader application in predictive medicine