РАЗВИТИЕ ОРГАНИЗАЦИОННО-ЭКОНОМИЧЕСКОГО МЕХАНИЗМА УПРАВЛЕНИЯ КОММЕРЧЕСКОЙ ДЕЯТЕЛЬНОСТЬЮ

The research is devoted to the development of measures aimed at improving the organizational and economic mechanism of commercial activities of medium- and large-scale commercial organizations in Ukraine. The author’s approach involves improving the management of complex business processes, optimizing the organizational structure and enhancement of the work motivation efficiency. The testing of the improvement measures took place at the sales network of Lvivkholod LLC (Lvov). It was demonstrated that the above retail organization had increased its competitiveness by improving financial and economic indicators as well as criteria of the organizational structure. Исследование посвящено разработке направлений совершенствования организационно-экономического механизма управления коммерческой деятельностью средних и  крупных торговых организаций Украины. Авторский подход предполагает комплексное улучшение менеджмента бизнес-процессов, оптимизации организационного построения и повышения эффективности мотивации труда. Апробация мероприятий по совершенствованию механизма управления проходила во Львовской торговой сети ООО ТПК «Львовхолод». Продемонстрировано повышение конкурентоспособности этой розничной организации благодаря улучшению финансово-экономических показателей и критериев организационного построения.

From Amplification to Gene in Thyroid Cancer: A High-Resolution Mapped Bacterial-Artificial-Chromosome Resource for Cancer Chromosome Aberrations Guides Gene Discovery after Comparative Genome Hybridization

SummaryChromosome rearrangements associated with neoplasms provide a rich resource for definition of the pathways of tumorigenesis. The power of comparative genome hybridization (CGH) to identify novel genes depends on the existence of suitable markers, which are lacking throughout most of the genome. We now report a general approach that translates CGH data into higher-resolution genomic-clone data that are then used to define the genes located in aneuploid regions. We used CGH to study 33 thyroid-tumor DNAs and two tumor-cell-line DNAs. The results revealed amplifications of chromosome band 2p21, with less-intense amplification on 2p13, 19q13.1, and 1p36 and with least-intense amplification on 1p34, 1q42, 5q31, 5q33-34, 9q32-34, and 14q32. To define the 2p21 region amplified, a dense array of 373 FISH-mapped chromosome 2 bacterial artificial chromosomes (BACs) was constructed, and 87 of these were hybridized to a tumor-cell line. Four BACs carried genomic DNA that was amplified in these cells. The maximum amplified region was narrowed to 3–6 Mb by multicolor FISH with the flanking BACs, and the minimum amplicon size was defined by a contig of 420 kb. Sequence analysis of the amplified BAC 1D9 revealed a fragment of the gene, encoding protein kinase C epsilon (PKCɛ), that was then shown to be amplified and rearranged in tumor cells. In summary, CGH combined with a dense mapped resource of BACs and large-scale sequencing has led directly to the definition of PKCɛ as a previously unmapped candidate gene involved in thyroid tumorigenesis

Zebrafish disease model of human RNASET2-deficient cystic leukoencephalopathy displays abnormalities in early microglia

Human infantile-onset RNASET2-deficient cystic leukoencephalopathy is a Mendelian mimic of in utero cytomegalovirus brain infection with prenatally developing inflammatory brain lesions. We used an RNASET2-deficient zebrafish model to elucidate the underlying disease mechanisms. Mutant and wild-type zebrafish larvae brain development between 2 and 5 days post fertilization (dpf) was examined by confocal live imaging in fluorescent reporter lines of the major types of brain cells. In contrast to wild-type brains, RNASET2-deficient larvae displayed increased numbers of microglia with altered morphology, often containing inclusions of neurons. Furthermore, lysosomes within distinct populations of the myeloid cell lineage including microglia showed increased lysosomal staining. Neurons and oligodendrocyte precursor cells remained unaffected. This study provides a first look into the prenatal onset pathomechanisms of human RNASET2-deficient leukoencephalopathy, linking this inborn lysosomal disease to the innate immune system and other immune-related childhood encephalopathies like Aicardi-Goutières syndrome (AGS)

The competitive nature of STAT complex formation drives phenotype switching of T cells

This is the author accepted manuscript.Signal transducers and activators of transcription (STATs) are key molecular determinants of T cell fate and effector function. A number of inflammatory diseases are characterized by an altered balance of T cell phenotypes and cytokine secretion. STATs, therefore, represent viable therapeutic targets in numerous pathologies. However, the underlying mechanisms of how the same STAT proteins regulate both the development of different T cell phenotypes and their plasticity during changes in extracellular conditions remain unclear. In this study, we investigated the STAT mediated regulation of T cell phenotype formation and plasticity using mathematical modeling and experimental data for intracellular STAT signaling proteins. The close fit of our model predictions to the experimental data for IFN-{\gamma} to IL-10 switching allows us to propose a potential mechanism for T cell switching that regulates human Th1/Tr1 responses. According to this mechanism, T cell phenotype switching is due to the relative redistribution of STAT dimer complexes caused by the extracellular cytokine-dependent STAT competition effects. The proposed model is applicable to a number of STAT signaling circuits

Effect of personal exposure to black carbon on changes in allergic asthma gene methylation measured 5 days later in urban children: importance of allergic sensitization

Background Asthma gene DNA methylation may underlie the effects of air pollution on airway inflammation. However, the temporality and individual susceptibility to environmental epigenetic regulation of asthma has not been fully elucidated. Our objective was to determine the timeline of black carbon (BC) exposure, measured by personal sampling, on DNA methylation of allergic asthma genes 5 days later to capture usual weather variations and differences related to changes in behavior and activities. We also sought to determine how methylation may vary by seroatopy and cockroach sensitization and by elevated fractional exhaled nitric oxide (FeNO). Methods Personal BC levels were measured during two 24-h periods over a 6-day sampling period in 163 New York City children (age 9–14 years), repeated 6 months later. During home visits, buccal cells were collected as noninvasive surrogates for lower airway epithelial cells and FeNO measured as an indicator of airway inflammation. CpG promoter loci of allergic asthma genes (e.g., interleukin 4 (IL4), interferon gamma (IFNγ), inducible nitric oxide synthase (NOS2A)), arginase 2 (ARG2)) were pyrosequenced at the start and end of each sampling period. Results Higher levels of BC were associated with lower methylation of IL4 promoter CpG−48 5 days later. The magnitude of association between BC exposure and demethylation of IL4 CpG−48 and NOS2A CpG+5099 measured 5 days later appeared to be greater among seroatopic children, especially those sensitized to cockroach allergens (RR [95% CI] 0.55 [0.37–0.82] and 0.67 [0.45–0.98] for IL4 CpG−48 and NOS2A CpG+5099, respectively), compared to non-sensitized children (RR [95% CI] 0.87 [0.65–1.17] and 0.95 [0.69–1.33] for IL4 CpG−48 and NOS2A CpG+5099, respectively); however, the difference was not statistically different. In multivariable linear regression models, lower DNA methylation of IL4 CpG−48 and NOS2A CpG+5099 were associated with increased FeNO. Conclusions Our results suggest that exposure to BC may exert asthma proinflammatory gene demethylation 5 days later that in turn may link to airway inflammation. Our results further suggest that seroatopic children, especially those sensitized to cockroach allergens, may be more susceptible to the effect of acute BC exposure on epigenetic changes

Efficacious preparation of Oppolzer's Glycylsultam via the delepine reaction

We developed a process that results in Oppolzer's glycylsultam in three steps. The protocol begins with readily available camphorsultam. The methods used in this research are standard organic chemistry synthesis protocols. Reactions were performed under ambient conditions. Purification of produced compounds was accomplished by crystallization. Monitoring of reaction completion was performed via thin layer chromatography (TLC). The analysis and characterization of resulting compounds was accomplished by nuclear magnetic resonance (NMR) spectroscopy, TLC, melting point, optical rotation, and combustion analysis. Reducing the manufacturing steps and created a scalable, "green procedure" for the synthesis of Oppolzer's glycylsultam will increase access to functionalized pyrrolidines, furthering medicinal drug development