1,500 research outputs found
Цифровая трансформация государственного управления: возможности и риски
No full textThe article discusses the priorities and socio – economic risks of the digital transformation of public administration. The main approaches to the problem of the use of advanced digital technologies in the activities of state and municipal government bodies aimed at the formation of a modern system digital environment are investigated. The main directions of the digital transition in public administration are considered, which include the digitalization of communications between public authorities, the active introduction of digital technologies into the practice of providing state and municipal services to business structures and households, stimulating the introduction of effective digital solutions as one of the important conditions for social dynamics.The article identifies the factors and social risks affecting the digital transformation of public administration in the Russian Federation. Among them are the high level of digital inequality, deep social differentiation of regional development, the costly nature of digitalization, risks to the labor market and traditional forms and conditions of employment, problems of adaptation of citizens to the active use of digital technologies in the public administration system, as well as the unconditional provision of citizens' rights and information security in the digital environment. The importance of the course of the Russian state to dynamize the digital transformation of the state and society in the conditions of unprecedented aggravation of international relations in the modern world and tough economic and political sanctions imposed against our country was confirmed.В статье рассматриваются приоритеты и социально – экономические риски цифровой трансформации государственного управления. Исследованы основные подходы к проблеме использования в деятельности органов государственного и муниципального управления передовых цифровых технологий, направленного на формирование современной системной цифровой среды. Рассмотрены основные направления цифрового перехода в государственном управлении, которые включают цифровизацию коммуникаций между институтами публичной власти, активное внедрение цифровых технологий в практики предоставления государственных и муниципальных услуг бизнес – структурам и домохозяйствам, стимулирование внедрения эффективных цифровых решений как одного из важных условий социальной динамики.В статье определены факторы и социальные риски, влияющие на цифровую трансформацию государственного управления в Российской Федерации. Среди них – высокий уровень цифрового неравенства, глубокая социальная дифференциация регионального развития, затратный характер цифровизации, риски для рынка труда и традиционных форм, и условий занятости населения, проблемы адаптации граждан к активному использованию цифровых технологий в системе государственного управления, а также безусловному обеспечению прав граждан и информационной безопасности в цифровой среде. Подтверждена значимость курса российского государства на динамизацию цифровой трансформации государства и общества в условиях беспрецедентного обострения международных отношений в современном мире и жёстких экономических и политических санкций, введённых против нашей страны
MAPK kinase signalling dynamics regulate cell fate decisions and drug resistance
No full textThe RAS/RAF/MEK/MAPK kinase pathway has been extensively studied for more than 25 years, yet we continue to be puzzled by its intricate dynamic control and plasticity. Different spatiotemporal MAPK dynamics bring about distinct cell fate decisions in normal vs cancer cells and developing organisms. Recent modelling and experimental studies provided novel insights in the versatile MAPK dynamics concerted by a plethora of feedforward/feedback regulations and crosstalk on multiple timescales. Multiple cancer types and various developmental disorders arise from persistent alterations of the MAPK dynamics caused by RAS/RAF/MEK mutations. While a key role of the MAPK pathway in multiple diseases made the development of novel RAF/MEK inhibitors a hot topic of drug development, these drugs have unexpected side-effects and resistance inevitably occurs. We review how RAF dimerization conveys drug resistance and recent breakthroughs to overcome this resistance
Sensory indicators of suluguni cheese when using enzyme preparations of different origins in the technology of soft cheeses
No full textCheeses are food products obtained by concentration and biotransformation of the main components of milk under the influence of physicochemical factors of rennet enzyme preparations and microorganisms. Suluguni occupies an important place among cheeses in Ukraine. Suluguni cheese has been known for a long time, it was first mentioned in the book of the Pope's personal chef Bartolomeo Scipri. Industrial production of the product was established at the end of the 18th century. The main operation in the production of rennet cheese is the enzymatic coagulation of milk under the action of chymosin, resulting in the formation of a milk clot with a large part of casein and whey. In the body of animals, chymosin, similar to cheese-making technology, coagulates milk at the beginning of its digestion. Thus, the processing of milk in the process of cheese production corresponds to natural physiological processes. III groups of milk samples (n = 5) were formed to conduct the experiment. In the control group of samples, rennet enzyme of microbial origin was used for curdling milk. In the 1st experimental group of samples, an enzyme preparation from the rennet of dairy calves, extracted according to the method of Yu. Ya. Svyridenko, was used. In the II experimental group, an enzyme preparation was used, which was extracted from the rennet of dairy calves according to the method of S. V. Merzlova. The duration of protein coagulation during the production of “Suluguni” cheese using a microbial enzyme preparation is 23 min., when using enzymes of the first research group – 27 min. and when using rennet enzymes of the II research group – 33 min. In view of the output of ready-made Suluguni cheese with a commercial purpose to obtain more profit, it is advisable to use an enzyme of microbial origin. According to sensory analysis, samples using calf rennet enzyme extracted according to the method of S. V. Merzlova (I research group of samples) were characterized by pronounced cheesy, sour-milk, without extraneous tastes and smells, taste and smell characteristic of soft fresh cheese; the surface is clean without mechanical damage, elastic; the consistency of the smear is gentle, moderately dense; the color is white, uniform throughout the mass. Samples of the II experimental group were characterized by the worst organoleptic indicators
Isolation of Induced Pluripotent Cells from Stromal Liver Cells of Patients with Alcoholic Cirrhosis
No full textUsing large-scale perturbations in gene network reconstruction
No full textBackground: Recent analysis of the yeast gene network shows that most genes have few inputs, indicating that enumerative gene reconstruction methods are both useful and computationally feasible. A simple enumerative reconstruction method based on a discrete dynamical system model is used to study how microarray experiments involving modulated global perturbations can be designed to obtain reasonably accurate reconstructions. The method is tested on artificial gene networks with biologically realistic in/out degree characteristics.Results: It was found that a relatively small number of perturbations significantly improve inference accuracy, particularly for low-order inputs of one or two genes. The perturbations themselves should alter the expression level of approximately 50-60% of the genes in the network.Conclusions: Time-series obtained from perturbations are a common form of expression data. This study illustrates how gene networks can be significantly reconstructed from such time-series while requiring only a relatively small number of calibrated perturbations, even for large networks, thus reducing experimental costs
Función del represor capicua en la Interpretación de señales RTK-Ras-MAPK en "Drosophila"
No full text[spa] Las señales receptor tirosina kinasa (RTK) controlan un amplio abanico de decisiones durante el desarrollo de un animal, como la proliferación celular, diferenciación, morfogénesis y supervivencia. Muchas de estas señales se transducen a través de la cascada de Ras-MAPK que en última instancia fosforilan un factor de transcripción regulando la expresión de distintos genes. Los mecanismos moleculares por los que la señalización por RTKs inducen repuestas tan diversas permanecen aún sin esclarecer. Los efectores de la vía más estudiados en Drosophila son Pointed y Yan donde en ausencia de señalización, los genes diana se mantienen reprimidos por Yan, mientras que la actividad de la vía fosforila Pointed y Yan, resultando en la activación transcripcional a través de la asociación de Pointed al ADN. Estudios más recientes han mostrado que otro de los factores fosforilado por la vía es Capicua (Cic). Cic es un represor materno que es fosforilado por la MAPK y esta fosforilación dirige la desactivación de la proteína.
En este trabajo, hemos mostrado que las secuencias de unión a Cic en sus genes diana representan un mecanismo general de interpretación de la señal por Ras-MAPK. Hemos descrito el mecanismo por el que la vía de Torso regula los genes huckebein (hkb) y tailless (tll) a través de la desactivación de Cic en los polos del embrión en el estadio de blastodermo sincitial. La expresión restringida de tll y hkb a los polos del embrión por la proteína Cic, permite la expresión de genes del tronco para la correcta segmentación del eje A/P del animal. Además, hemos definido una nueva diana de Cic en el eje dorsoventral (D/V) del embrión, intermediate neuroblast defective (ind), que alberga la función de diferenciar la células que dan lugar a los neuroblastos intermedios del sistema nervioso central.
Experimentos adicionales nos han permitido describir el mecanismo por el que Cic regula el gen argos en repuesta a la señalización por EGFR, en el disco imaginal de ala. En este contexto, al contrario que en los casos del embrión, la desactivación de la proteína Cic en respuesta a la vía de EGFR no es el único mecanismo por el que se induce el gen diana. Trabajos posteriores tendrán que explicar esta red de regulaciones más compleja.
Además de la identificación de la secuencia de unión de Cic a los elementos reguladores de sus genes diana, hemos estudiado el papel del correpresor Groucho (Gro) en la regulación de hkb. Trabajos anteriores habían implicado a Gro en la regulación de los genes hkb y tll ya que embriones mutantes para gro muestran un patrón expandido de estos genes terminales. Este patrón, es muy similar al que se observa en embriones mutantes cic por lo que se ha sugerido que Gro podría actuar junto a Cic para la regulación de hkb y tll. Nosotros hemos podido demostrar que los lugares de unión de Cic en el enhancer de hkb son importantes para reclutar Gro al ADN. Este resultado nos indica que Gro está actuando a través de Cic para mediar la represión y no a través de otro factor que también pudiera regular la expresión de hkb.
La señalización por EGFR en las células dorsoanteriores del ovario está implicada en el establecimiento del eje D/V a través de la represión del gen pipe (pip) en esta región. Nosotros hemos podido demostrar que esta regulación ocurre de manera análoga a la del embrión. Cic reprime los represores inducidos por la vía de señalización, Tll y Mirror (Mirr) en el embrión y ovario respectivamente, para posibilitar la expresión de sus genes diana, Kruppel (Kr) y pip, y así determinar las regiones que les corresponden como el tronco en el embrión y la región ventral en el ovario.
Por otro lado hemos descrito un nuevo mecanismo por el que los substratos de la MAPK compiten entre ellos por la fosforilación por debajo de la vía de Torso. Así, hemos explicado la razón por la que aún habiendo más MAPK fosforilada en el polo anterior del embrión, existe una menor desactivación de Cic y cómo este efecto puede afectar la regulación de los genes diana.[eng] "The function of Capicua repressor in the interpretation of RTK-Ras-MAPK signaling in Drosophila". Receptor tyrosine kinase (RTK) signaling pathways control multiple decisions during Drosophila development such as proliferation, differentiation, morphogenesis, and survival. Many RTKs signal through the very well conserved Ras-MAPK cassette that ultimately phosphorylate a nuclear factor altering the transcriptional output in many different contexts. The molecular mechanisms that lead to so many different outputs are still under study.
In this work we have analyzed the molecular mechanism by which Capicua (Cic), a recently described downstream repressor of the pathway, regulates gene expression in different contexts. We found that the Cic binding sites represent a general mechanism of Ras-MAPK signaling interpretation. Cic is downregulated in the cells with active signaling pathway alleviating the repression on its target genes. In the cells with no active signaling, Cic is repressing its targets localizing their expression to restricted patterns. We showed that Cic regulates huckebein (hkb) and tailless (tll) expression at the poles of the blastoderm embryo allowing a correct A/P axis formation. hkb regulation by Cic requires the association to the global co-repressor Gro. We also found that Cic regulates intermediate neuroblast defective (ind) gene in the D/V axis of the embryo for the intermediate neuroblast formation and it regulates argos (aos) gene expression in the wing imaginal disc for a stereotyped wing vein pattern formation.
We also showed that the mechanism by which the EGFR signaling pathway restricts pipe (pip) expression to the ventral follicle cells of the ovary is analogous to that occurring in the embryo: Cic restricts mirr expression to the cells with active EGFR signaling in the dorsoanterior follicle cells to allow the expression of its target, pip, in the ventral region.
Finally, we also showed a novel mechanism by which MAPK substrates compete for the phosphorylation, and this mechanism explains why in the anterior pole of the embryo, containing higher concentration of phosphorylated MAPK, Cic protein concentration is higher
A generic approach to behaviour-driven biochemical model construction
No full textThis thesis was submitted for the degree of Doctor of Philosophy and awarded by Brunel University.Modelling of biochemical systems has received considerable attention over the last decade from bioengineering, biochemistry, computer science, and mathematics. This thesis investigates the applications of computational techniques to computational systems biology, for the construction of biochemical models in terms of topology and kinetic rates. Due to the complexity of biochemical systems, it is natural to construct models representing the biochemical systems incrementally in a piecewise manner. Syntax and semantics of two patterns are defined for the instantiation of components which are extendable, reusable and fundamental building blocks for models composition. We propose and implement a set of genetic operators and composition rules to tackle issues of piecewise composing models from scratch. Quantitative Petri nets are evolved by the genetic operators, and evolutionary process of modelling are guided by the composition rules. Metaheuristic algorithms are widely applied in BioModel Engineering to support intelligent and heuristic analysis of biochemical systems in terms of structure and kinetic rates. We illustrate parameters of biochemical models based on Biochemical Systems Theory, and then the topology and kinetic rates of the models are manipulated by employing evolution strategy and simulated annealing respectively. A new hybrid modelling framework is proposed and implemented for the models construction. Two heuristic algorithms are performed on two embedded layers in the hybrid framework: an outer layer for topology mutation and an inner layer for rates optimization. Moreover, variants of the hybrid piecewise modelling framework are investigated. Regarding flexibility of these variants, various combinations of evolutionary operators, evaluation criteria and design principles can be taken into account. We examine performance of five sets of the variants on specific aspects of modelling. The comparison of variants is not to explicitly show that one variant clearly outperforms the others, but it provides an indication of considering important features for various aspects of the modelling. Because of the very heavy computational demands, the process of modelling is paralleled by employing a grid environment, GridGain. Application of the GridGain and heuristic algorithms to analyze biological processes can support modelling of biochemical systems in a computational manner, which can also benefit mathematical modelling in computer science and bioengineering. We apply our proposed modelling framework to model biochemical systems in a hybrid piecewise manner. Modelling variants of the framework are comparatively studied on specific aims of modelling. Simulation results show that our modelling framework can compose synthetic models exhibiting similar species behaviour, generate models with alternative topologies and obtain general knowledge about key modelling features
LFV and exotics at the NA62 experiment
No full textThe NA62 experiment at the CERN SPS is aimed at measuring the branching fraction of the ultrarare decay K+ → π+v with ∼10% precision by collecting ∼1013 kaon decays in two years of data taking. This amount of data will allow to carry out a wide program of searching for rare and forbidden (within the Standard Model) K+ and π0 decays, including sterile neutrinos, lepton flavor violating modes, exotic particles (e.g. "dark photons"). The expected performances of the NA62 setup will allow to improve existing limits for several decay modes
The NA62 experiment at CERN: Status and perspectives
No full textThe NA62 experiment at CERN will measure the branching ratio of the K+ → π+νν decay with a precision of 10%, collecting about 100 events in two years of run. This paper will review the design of the experiment, the strategy for the measurement and the actual status of the installation. Prospects for the data collection and for the measurement of other rare K+ channels will be presented
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