The central regulatory circuit in the gene network controlling the morphogenesis of Drosophila mechanoreceptors: an in silico analysis.

Identification of the mechanisms underlying the genetic control of spatial structure formation is among the relevant tasks of developmental biology. Both experimental and theoretical approaches and methods are used for this purpose, including gene network methodology, as well as mathematical and computer modeling. Reconstruction and analysis of the gene networks that provide the formation of traits allow us to integrate the existing experimental data and to identify the key links and intra-network connections that ensure the function of networks. Mathematical and computer modeling is used to obtain the dynamic characteristics of the studied systems and to predict their state and behavior. An example of the spatial morphological structure is the Drosophila bristle pattern with a strictly defined arrangement of its components - mechanoreceptors (external sensory organs) - on the head and body. The mechanoreceptor develops from a single sensory organ parental cell (SOPC), which is isolated from the ectoderm cells of the imaginal disk. It is distinguished from its surroundings by the highest content of proneural proteins (ASC), the products of the achaete-scute proneural gene complex (AS-C). The SOPC status is determined by the gene network we previously reconstructed and the AS-C is the key component of this network. AS-C activity is controlled by its subnetwork - the central regulatory circuit (CRC) comprising seven genes: AS-C, hairy, senseless (sens), charlatan (chn), scratch (scrt), phyllopod (phyl), and extramacrochaete (emc), as well as their respective proteins. In addition, the CRC includes the accessory proteins Daughterless (DA), Groucho (GRO), Ubiquitin (UB), and Seven-in-absentia (SINA). The paper describes the results of computer modeling of different CRC operation modes. As is shown, a cell is determined as an SOPC when the ASC content increases approximately 2.5-fold relative to the level in the surrounding cells. The hierarchy of the effects of mutations in the CRC genes on the dynamics of ASC protein accumulation is clarified. AS-C as the main CRC component is the most significant. The mutations that decrease the ASC content by more than 40 % lead to the prohibition of SOPC segregation.

[Gene Network Controlling the Morphogenesis of D. melanogaster Macrochaetes: An Expanded Model of the Central Regulatory Circuit].

The drosophila macrochaetes act as mechanoreceptors, the sensory organs of the peripheral nervous system. Each mechanoreceptor consists of four specialized cells, namely, the shaft, socket, neuron, and sheath. All these cells develop from a single cell referred to as the sensory organ precursor (SOP) cell. The SOP cell segregates from the surrounding cells of imaginal disc, thereby launching multistage sensory organ development. A characteristic feature of the SOP cell is the highest content of the proneural proteins Achaete and Scute (ASC) as compared with the surrounding cells. The pattern of changes in the content of proneural proteins in the SOP cell is determined by a gene network with the achaete-scute (AS-C) gene complex as its key component. The activity of this complex is controlled by the central regulatory circuit (CRC), containing the genes hairy, senseless (sens), charlatan (chn), scratch (scrt), daughterless (da), extramacrochaete (emc), and groucho (gro), encoding the transcription factors involved in the system of feedforwards and feedbacks and implementing the activation­repression of CRC components, as well as the gene phyllopod (phyl), an adaptor protein that controls the degradation of ASC proteins. A mathematical model describing the CRC functioning in the SOP cell as a regulator of the content of ASC proneural proteins is proposed.

[TREATMENT OF ACUTE CALCULOUS CHOLECYSTITIS: "EARLY" OR "PLANNED" LAPAROSCOPIC CHOLECYSTECTMIVY].

The comparative analysis of results of surgical treatment of 82 patients with acute cholecystitis, which made "early" (ELCE) or "planned" (PLCE) laparoscopic cholecystectomy (LCE) in the surgical department for the period from 2012 to 2014. The analysis showed that LCE can be set in any time from the beginning of acute cholecystitis. However, priority should be given ELCE, providing significant reduction in duration of treatment of patients in hospitals and is more cost effective.

[The Mechanisms Determining Bristle Pattern in Drosophila melanogaster].

Macrochaetes (large bristles) are arranged on the drosophila head and notum in a specific bristle pattern. The number and positions of the macrochaetes forming the pattern are important species-specific characteristics, which are determined by a strict positioning of the proneural clusters in the in the imaginal disc ectoderm in the third instar larvae and prepupae. In turn, the positioning of proneural clusters depends on the distribution of the so-called prepattern factors, responsible for the bristle prepatterning. The current concept identifies the prepattern factors with the transcription factors that initiate the local expression of the achaete-scute complex (AS-C) genes. Expression of these genes confined to certain regions of the ectoderm is the particular factor that determines the macrochaete pattern on the adult fly body. The review considers and systematizes the data on establishment of the prepatterning as the final stage in the functioning of hierarchically organized molecular genetic system resulting in the local expression of AS-C genes in the ectoderm of imaginal discs.

Type I interferon signaling genes in recurrent major depression: increased expression detected by whole-blood RNA sequencing.

A study of genome-wide gene expression in major depressive disorder (MDD) was undertaken in a large population-based sample to determine whether altered expression levels of genes and pathways could provide insights into biological mechanisms that are relevant to this disorder. Gene expression studies have the potential to detect changes that may be because of differences in common or rare genomic sequence variation, environmental factors or their interaction. We recruited a European ancestry sample of 463 individuals with recurrent MDD and 459 controls, obtained self-report and semi-structured interview data about psychiatric and medical history and other environmental variables, sequenced RNA from whole blood and genotyped a genome-wide panel of common single-nucleotide polymorphisms. We used analytical methods to identify MDD-related genes and pathways using all of these sources of information. In analyses of association between MDD and expression levels of 13 857 single autosomal genes, accounting for multiple technical, physiological and environmental covariates, a significant excess of low P-values was observed, but there was no significant single-gene association after genome-wide correction. Pathway-based analyses of expression data detected significant association of MDD with increased expression of genes in the interferon α/ß signaling pathway. This finding could not be explained by potentially confounding diseases and medications (including antidepressants) or by computationally estimated proportions of white blood cell types. Although cause-effect relationships cannot be determined from these data, the results support the hypothesis that altered immune signaling has a role in the pathogenesis, manifestation, and/or the persistence and progression of MDD.

[Model investigation of central regulatory contour of gene net of D. melanogaster macrochaete morphogenesis].

Morphogenesis of drosophila macrochaete functioning as mechanoreceptors includes several steps, each of which has their own genetic support described in terms of gene nets. Mechanoreceptor develops from one parental cell (Parental Cell of Sensor Organ-PCSO), the determination of which has a critical role in macrochaete development. The highest content of AS-C proneural proteins with respect to surrounding cells that initiate a neural way of cellular development and by means of it mechanoreceptor morphogenesis is typical for PCSO. The key object of gene net providing PCSO determination consists of gene complex achaete-scute (AS-C). This complex activity is controlled by central regulatory contour (CRC). Besides AS-C, CRC includes the following genes: hairy, senseless (sens), charlatan (chn), scratch (scrt), daughterless (da), extramacrochaete (emc), and groucho (gro). The system of direct relation and feedback and induction and repression relations between CRC components are realized via the coding by these genes proteins. A mathematical model of CRC functioning as a regulator of proneural AS-C protein content in PCSO determining successful passing of the main phase of morphogenesis of D. melanogaster mechanoreceptor is discussed.

Morphogenesis of Drosophila melanogaster macrochaetes: cell fate determination for bristle organ.

Formation of specialized spatial structures comprising various cell types is most important in the ontogenesis of multicellular organisms. An example is the D. melanogaster bristle organs. Bristles (micro- and macrochaetes) are external sensory organs, elements of the peripheral nervous system, playing the role of mechanoreceptors. Their comparatively simple organization comprising only four specialized cells and a common origin of these cells make macrochaetes a convenient model for studying cell differentiation. The four cells forming bristle organ result from two successive divisions of a single cell, sensory organ precursor (SOP) cell. The number of macrochaetes on drosophila body corresponds to the number of SOP cells. The morphogenesis of macrochaetes comprises three stages, the first two determining a neural fate of the cells. The third stage is cell specialization into components of the bristle organ-neuron, thecogen, tormogen, and trichogen. Development of each bristle commences from segregation of proneural clusters, of 20-30 cells, from the massif of undifferentiated cells of the wing imaginal disc. At this stage, each cluster cell can potentially become a SOP cell. At the second stage, the only SOP cell and its position are determined within each cluster. Finally, two asymmetric divisions of the SOP cell with subsequent differentiation of the daughter cells gives the bristle organ. Several dozens genes are involved in the control of macrochaete morphogenesis. The main component of this system is the proneural genes of achaete-scute complex (AS-C). An increased content of proneural proteins fundamentally distinguished the cells that will follow the neural developmental pathway from the disc epidermal cells. A local AS-C expression, initiated at specified disc sites by specific transcription factors, determines the number and topology of proneural clusters. The expression of AS-C genes, continuing in the cells of the cluster, increases the difference in proneural protein content, first, between the cluster cells and then, between the cluster cells and the single SOP cell, where it reaches the maximum level. This process is provided by both the intracellular regulation of AS-C gene activity and intercellular events mediated via the EGFR and Notch signaling pathways. The third stage in macrochaete morphogenesis comprises two successive asymmetric SOP cell divisions, determining the final specialization. The selector genes, in particular, numb, neuralized, tramtrack, and musashi, play the key role in cell type specification. This review systematizes the data on molecular genetic system controlling drosophila bristle morphogenesis and proposes an integral scheme of its functioning.

[Asymmetric cell division in the morphogenesis of Drosophila melanogaster macrochaetae].

Asymmetric cell division (ACD) is the basic process which creates diversity in the cells of multicellular organisms. As a result of asymmetric cell division, daughter cells acquire the ability to differentiate and specialize in a given direction, which is different from that of their parent cells and from each other. This type of division is observed in a wide range of living organisms from bacteria to vertebrates. It has been shown that the molecular-genetic control mechanism of ACD is evolutionally conservative. The proteins involved in the process of ACD in different kinds of animals have a high degree of homology. Sensory organs--setae (macrochaetae)--of Drosophila are widely used as a model system for studying the genetic control mechanisms of asymmetric division. Setae located in an orderly manner on the head and body of the fly play the role of mechanoreceptors. Each of them consists of four specialized cells--offspring of the only sensory organ precursor cell (SOPC), which differentiates from the imaginal wing disc at the larval stage of the late third age. The basic differentiation and further specialization of the daughter cells of SOPC is an asymmetric division process. In this summary, experimental data on genes and their products controlling asymmetric division of SOPC and daughter cells, and also the specialization of the latter, have been systemized. The basic mechanisms which determine the time cells enter into asymmetric mitosis and which provides the structural characteristics of the asymmetric division process--the polar distribution of protein determinants Numb and Neuralized--the orientation of the mitotic spindle in relation to these determinants, and the uneven segregation of the determinants into the daughter cells that determines the direction of their development have been discussed.

[Genetic control of macrochaetae development in Drosophila melanogaster].

The Drosophila head and body have a regular species-specific pattern of strictly defined number of external sensory organs--macrochaetae (large bristles). The pattern constancy and relatively simple organization of each bristle organ composed of only four specialized cells makes macrochaetae a convenient model to study the developmental patterns of spatial structures with a fixed number of elements in specific positions as well as the mechanisms of cell differentiation. The experimental data on the major genes and their products controlling three stages of macrochaetae development--the emergence of proneural clusters in the imaginal disc ectoderm, the precursor cell determination in the proneural clusters, and the specialization of cells of the definitive sensory organ--were reviewed. The role of the achaeta-scute gene complex, EGFR and Notch signaling, and selector genes in these processes was considered. Analysis of published data allowed us to propose an integrated diagram of the system controlling macrochaetae development in D. melanogaster.

How Drosophila melanogaster Forms its Mechanoreceptors.

A strictly determined number of external sensory organs, macrochaetes, acting as mechanoreceptors, are orderly located on drosophila head and body. Totally, they form the bristle pattern, which is a species-specific characteristic of drosophila.Each mechanoreceptor comprises four specialized cells derived from the single sensory organ precursor (SOP) cell. The conserved bristle pattern combined with a comparatively simple structure of each mechanosensory organ makes macrochaetes a convenient model for studying the formation spatial structures with a fixed number of elements at certain positions and the mechanism underlying cell differentiation.The macrochaete morphogenesis consists of three stages. At the first stage, the proneural clusters segregate from the massive of ectodermal cells of the wing imaginal disc. At the second stage, the SOP cell is determined and its position in the cluster is specified. At the third stage, the SOP cell undergoes two asymmetric divisions, and the daughter cells differentiate into the components of mechanoreceptor: shaft, socket, bipolar neuron, and sheath.The critical factor determining the neural pathway of cell development is the content of proneural proteins, products of the achaete-scute (AS-C) gene complex, reaching its maximum in the SOP cell.The experimental data on the main genes and their products involved in the control of bristle pattern formation are systematized. The roles of achaete-scute complex, EGFR and Notch signaling pathways, and selector genes in these processes are considered. An integral scheme describing the functioning of the system controlling macrochaete development in D. melanogaster is proposed based on analysis of literature data.

ACTIVITY: a database on DNA/RNA sites activity adapted to apply sequence-activity relationships from one system to another.

ACTIVITY is a database on DNA/RNA site sequences with known activity magnitudes, measurement systems, sequence-activity relationships under fixed experimental conditions and procedures to adapt these relationships from one measurement system to another. This database deposits information on DNA/RNA affinities to proteins and cell nuclear extracts, cutting efficiencies, gene transcription activity, mRNA translation efficiencies, mutability and other biological activities of natural sites occurring within promoters, mRNA leaders, and other regulatory regions in pro- and eukaryotic genomes, their mutant forms and synthetic analogues. Since activity magnitudes are heavily system-dependent, the current version of ACTIVITY is supplemented by three novel sub-databases: (i) SYSTEM, measurement systems; (ii) KNOWLEDGE, sequence-activity relationships under fixed experimental conditions; and (iii) CROSS_TEST, procedures adapting a relationship from one measurement system to another. These databases are useful in molecular biology, pharmacogenetics, metabolic engineering, drug design and biotechnology. The databases can be queried using SRS and are available through the Web, http://wwwmgs. bionet.nsc.ru/systems/Activity/.

[Phases of the effect of the homeotic Walker mutation in the development of Drosophila melanogaster]. / Fazy deistviia gomeozisnoi mutatsii Walker v ontogeneze Drosophila melanogaster]

In this work, critical ontogenetic stages for wing traits affected by temperature-sensitive mutation Walker (Wk) were determined. The interaction between the Wk gene and some genes responsible for the cell-cycle control was studied. At various ontogenetic stages, the mutants were exposed to 17 degrees C for 12 h, and, at the beginning of oviposition, the fly age was registered. Nine types of wing abnormalities were classified. The temperature treatment during three developmental stages (12-24, 48-60, and 96-108 h) resulted in a decrease in normal wing number and a substantial increase in wing abnormalities. Different morphological types of imaginal disks were revealed: nondifferentiated disks, those lacking the notum region, and those with duplications of wing-forming regions. The allele-specific interaction between Wk and allele v27 of the Klp61F gene was also revealed. We suggest that gene Wk is a high-ranking gene in the system of genetic control of ontogeny, because the Wk mutation is manifested in numerous phenotypic variants both in the control and in the experiment and a complete set of these variants was observed at each developmental stage upon temperature treatment. The pleiotropic effect of the Wk gene on the formation of some Drosophila organs, including eyes and halters which are beyond the scope of this report, is in agreement with this suggestion.

[Identification of polygenes in the system achaete-scute in Drosophila melanogaster using cluster analysis]. / Identifikatsiia poligenov v sisteme achaete-scute u Drosophila melanogaster metodami klasternogo analiza.

Data on location of mobile elements mdg1, Dm412, copia, and B104 in 33 isogenic lines of Drosophila melanogaster has been processed by means of cluster analysis to reveal the relationship between the penetrance for bristle reduction and the distribution of mobile elements. The presence of two groups of sites specific for lines with contrasting penetrance levels have been demonstrated. The specificity suggests that the sites can be associated with the location of corresponding polygenes, affecting the penetrance level in mutant lines.

Analysis of lasing in gas-flow lasers with stable resonators.

A model is developed that describes the power extraction in chemical oxygen-iodine lasers (COIL's) and CO(2) gasdynamic lasers with stable resonators when a large number of transverse Hermite-Gaussian eigenmodes oscillate. The extraction efficiency, mode intensities, and intensity distribution along the flow depend only on two parameters. The first is the ratio gamma(0) of the residence time of the gas in the resonator to the O(2)((1)D) or N(2)(v) energy extraction time and the second is the ratio of the threshold to the small-signal gain. The efficiency is maximum for gamma(0) ? infinity and decreases rapidly as gamma(0) decreases. It is found that for a range of parameters corresponding to the highest efficiencies the intensity distribution along the flow is nonuniform and has two peaks near the upstream and downstream sections of the resonator. In this case only the highest-order modes that totally fill the resonator cross section oscillate (the so-called, experimentally observed sugar scooping bimodal intensity distribution). For the range of parameters corresponding to smaller efficiencies the intensity is uniform. In this case all the modes participate in lasing; however, the intensities of the high-order modes are larger than those of the low order. The current model is compared with the plane-mirror Fabry-Perot resonator model and with the constant intraresonator intensity and rooftop models of COIL's with stable resonators. The extraction efficiency calculated with the last two models is close to that estimated from our model. However, the intensity distribution cannot be calculated correctly using the Fabry-Perot, the constant intraresonator intensity, or the rooftop model.

[An increase in transposition frequency of copia-like elements in isogenic crosses with a balancer line]. / Uvelichenie chastoty transpozitsii copia-podobnykh élementov pri izogeniziruiushchikh skreshchivaniiakh s balansernoi liniei.

Distribution spectra of mdg1, Dm412, copia, and B104 in a descending series of isogenic scute lines of Drosophila melanogaster were analyzed. Transpositions of mobile elements occurring during isogenization were shown to be the main source of insertion site polymorphism detected in daughter lines. Isogenization resulted in a significant increase in transposition frequency (approximately approximately 10(-2) per site per genome per generation).

[Mobile elements of the Drosophila genome as a marker of crossing over in isogenic crosses with a balancer strain]. / Mobil'nye élementy genoma Drozofily kak markery krossingovera v izogeniziruiushchikh skreshchivaniiakh s balansernoi liniei.

The ability of the Cy/Pm; D/Sb balancer strain to inhibit crossing over in isogenic crosses was studied. Regions of interchromosomal exchange were detected within and outside the inverted regions with the help of the MDG1, Dm412, copia, and B104 mobile elements. Certification of mobile element distribution patterns in balancer strains was proposed. Crossing over was suggested as a possible reason for the polymorphism of daughter strains and as useful for estimating frequency of transposition of mobile elements in similar interstrain crosses.

[P-M hybrid dysgenesis in natural population of Drosophila from Altai region]. / P-M gibridnyi disgenez v prirodnoi populiatsii drozofil Altaia.

P-M status of 13 isofemale lines from a natural population of Drosophila melanogaster from Biisk (Altai) was determined by estimation of frequency of female gonadal sterility in diagnostic crosses. Content of P-elements in genomes was estimated by in situ hybridization. The average level of P-sensitivity was 97.3%; the average number of P-element copies per genome was 27.5. This value is significantly higher than estimates of average copy number of the P-element obtained for other populations with similar levels of P-sensitivity. No relationship between P-element copy number in the lines and level of their P-sensitivity was demonstrated. Based on the data obtained, the Altai population may be assigned to populations of M'-type.