Development of a Mathematical Model of Business Process to Optimize the Budget Department’s Work in Machine-building Enterprises

The article covers the highlights in the development of an optimal mathematical model of business process of the budget department’s work in machine-building enterprises. There has been done the analysis of basic problems in the engineering field, arising in the course of economic instability and deterioration of the businessstrategy. The investigation discussed is aimed to improve the competitiveness in the market and optimize the strategy of the organization’s activities as a whole. Special attention is paid to the methods of mathematical modeling of business process on the basis of queuing theory to develop the authoring mathematical model. The developed model would make it possible to evaluate and optimize the performance of the budgetdepartments of engineering enterprises

Temperature effect on low-k dielectric thin films studied by ERDA

Low-k dielectric materials are becoming increasingly interesting as alternative to SiO2 with device geometries shrinking beyond the 65 nm technology node. At elevated temperatures hydrogen migration becomes an important degradation mechanism for conductivity breakdown in semiconductor devices. The possibility of hydrogen release during the fabrication process is, therefore, of great interest in the understanding of device reliability. In this study, various low-k dielectric films were subjected to thermal annealing at temperatures that are generally used for device fabrication. Elastic recoil detection analysis (ERDA) was used to investigate compositional changes and hydrogen redistribution in thin films of plasma-enhanced tetraethylortho-silicate (PETEOS), phosphorus doped silicon glass (PSG), silicon nitride (SiN) and silicon oxynitride (SiON). Except for an initial hydrogen release from the surface region in films of PETEOS and PSG, the results indicate that the elemental composition of the films was stable for at least 2 hours at 450◦C

SORL1 mutation in a Greek family with Parkinson's disease and dementia

Whole exome sequencing and linkage analysis were performed in a three generational pedigree of Greek origin with a broad phenotypic spectrum spanning from Parkinson’s disease and Parkinson’s disease dementia to dementia of mixed type (Alzheimer disease and vascular dementia). We identified a novel heterozygous c.G1135T (p.G379W) variant in SORL1 which segregated with the disease in the family. Mutation screening in sporadic Greek PD cases identified one additional individual with the mutation, sharing the same 12.8Mb haplotype. Our findings provide support for SORL1 mutations resulting in a broad range of additional phenotypes and warrants further studies in neurodegenerative diseases beyond AD

Контроль бронхиальной астмы в амбулаторных условиях

Outpatient care for bronchial asthma patients, is one of the primary problems of the Russian healthcare.The article shows an analysis of 4-year work for outpatient management of asthma patients based on a pharmacoeconomic modelling method. A gradual implication of GINA principles allowed to improve the asthma detection in 4 times, to reduce a number of admitting to a hospital and of emergency care calls in 5.8 and 4.8 times accordingly. Treatment expenses for one asthma patient in the polyclinic №15 considering hospitalizations and privilege medication cost was 43% less than totally at Samara city.An analysis of quality of life using the SF-36 questionnaire demonstrated the asthma patients observed in the polyclinic №15 to have a higher quality of life compared with other asthma patients at Samara especially on the criteria of their social activity and mental status.Организация амбулаторной помощи больным бронхиальной астмой — одна из приоритетных задач Российского здравоохранения.В работе представлен анализ четырехлетней работы по амбулаторному ведению бронхиальной астмы в условиях пульмонологического кабинета, основанному на методе фармакоэкономического моделирования. Последовательное внедрение принципов формулярной системы по бронхиальной астме позволило улучшить выявляемость заболевания в 4 раза, уменьшить число случаев госпитализации и вызовов неотложной помощи в 5,8 и 4,8 раза соответственно. Расходы на одного больного с бронхиальной астмой в поликлинике №15 с учетом госпитализации и затрат на приобретение льготных медикаментов были на 43% меньше, чем по Самаре.Проведенный анализ качества жизни (КЖ) по опроснику ББ-Зб показал, что больные бронхиальной астмой, находящиеся под наблюдением в поликлинике №15, обладают в целом более высоким уровнем КЖ, чем пациенты других ЛПУ Самары, особенно по критериям, связанным с их социальной активностью и ментальной сферой

The Phylogenetics and Ecology of the Orthopoxviruses Endemic to North America

The data presented herein support the North American orthopoxviruses (NA OPXV) in a sister relationship to all other currently described Orthopoxvirus (OPXV) species. This phylogenetic analysis reaffirms the identification of the NA OPXV as close relatives of “Old World” (Eurasian and African) OPXV and presents high support for deeper nodes within the Chordopoxvirinae family. The natural reservoir host(s) for many of the described OPXV species remains unknown although a clear virus-host association exists between the genus OPXV and several mammalian taxa. The hypothesized host associations and the deep divergence of the OPXV/NA OPXV clades depicted in this study may reflect the divergence patterns of the mammalian faunas of the Old and New World and reflect a more ancient presence of OPXV on what are now the American continents. Genes from the central region of the poxvirus genome are generally more conserved than genes from either end of the linear genome due to functional constraints imposed on viral replication abilities. The relatively slower evolution of these genes may more accurately reflect the deeper history among the poxvirus group, allowing for robust placement of the NA OPXV within Chordopoxvirinae. Sequence data for nine genes were compiled from three NA OPXV strains plus an additional 50 genomes collected from Genbank. The current, gene sequence based phylogenetic analysis reaffirms the identification of the NA OPXV as the nearest relatives of “Old World” OPXV and presents high support for deeper nodes within the Chordopoxvirinae family. Additionally, the substantial genetic distances that separate the currently described NA OPXV species indicate that it is likely that many more undescribed OPXV/NA OPXV species may be circulating among wild animals in North America

PDXK mutations cause polyneuropathy responsive to pyridoxal 5'-phosphate supplementation.

OBJECTIVE: To identify disease-causing variants in autosomal recessive axonal polyneuropathy with optic atrophy and provide targeted replacement therapy. METHODS: We performed genome-wide sequencing, homozygosity mapping, and segregation analysis for novel disease-causing gene discovery. We used circular dichroism to show secondary structure changes and isothermal titration calorimetry to investigate the impact of variants on adenosine triphosphate (ATP) binding. Pathogenicity was further supported by enzymatic assays and mass spectroscopy on recombinant protein, patient-derived fibroblasts, plasma, and erythrocytes. Response to supplementation was measured with clinical validated rating scales, electrophysiology, and biochemical quantification. RESULTS: We identified biallelic mutations in PDXK in 5 individuals from 2 unrelated families with primary axonal polyneuropathy and optic atrophy. The natural history of this disorder suggests that untreated, affected individuals become wheelchair-bound and blind. We identified conformational rearrangement in the mutant enzyme around the ATP-binding pocket. Low PDXK ATP binding resulted in decreased erythrocyte PDXK activity and low pyridoxal 5'-phosphate (PLP) concentrations. We rescued the clinical and biochemical profile with PLP supplementation in 1 family, improvement in power, pain, and fatigue contributing to patients regaining their ability to walk independently during the first year of PLP normalization. INTERPRETATION: We show that mutations in PDXK cause autosomal recessive axonal peripheral polyneuropathy leading to disease via reduced PDXK enzymatic activity and low PLP. We show that the biochemical profile can be rescued with PLP supplementation associated with clinical improvement. As B6 is a cofactor in diverse essential biological pathways, our findings may have direct implications for neuropathies of unknown etiology characterized by reduced PLP levels. ANN NEUROL 2019;86:225-240

Genome-wide association study of REM sleep behavior disorder identifies polygenic risk and brain expression effects

Rapid-eye movement (REM) sleep behavior disorder (RBD), enactment of dreams during REM sleep, is an early clinical symptom of alpha-synucleinopathies and defines a more severe subtype. The genetic background of RBD and its underlying mechanisms are not well understood. Here, we perform a genome-wide association study of RBD, identifying five RBD risk loci near SNCA, GBA, TMEM175, INPP5F, and SCARB2. Expression analyses highlight SNCA-AS1 and potentially SCARB2 differential expression in different brain regions in RBD, with SNCA-AS1 further supported by colocalization analyses. Polygenic risk score, pathway analysis, and genetic correlations provide further insights into RBD genetics, highlighting RBD as a unique alpha-synucleinopathy subpopulation that will allow future early intervention

Innate Immune Response of Human Plasmacytoid Dendritic Cells to Poxvirus Infection Is Subverted by Vaccinia E3 via Its Z-DNA/RNA Binding Domain

Plasmacytoid dendritic cells (pDCs) play important roles in antiviral innate immunity by producing type I interferon (IFN). In this study, we assess the immune responses of primary human pDCs to two poxviruses, vaccinia and myxoma virus. Vaccinia, an orthopoxvirus, was used for immunization against smallpox, a contagious human disease with high mortality. Myxoma virus, a Leporipoxvirus, causes lethal disease in rabbits, but is non-pathogenic in humans. We report that myxoma virus infection of human pDCs induces IFN-α and TNF production, whereas vaccinia infection does not. Co-infection of pDCs with myxoma virus plus vaccinia blocks myxoma induction effects. We find that heat-inactivated vaccinia (Heat-VAC; by incubating the virus at 55°C for 1 h) gains the ability to induce IFN-α and TNF in primary human pDCs. Induction of IFN-α in pDCs by myxoma virus or Heat-VAC is blocked by chloroquine, which inhibits endosomal acidification required for TLR7/9 signaling, and by inhibitors of cellular kinases PI3K and Akt. Using purified pDCs from genetic knockout mice, we demonstrate that Heat-VAC-induced type I IFN production in pDCs requires the endosomal RNA sensor TLR7 and its adaptor MyD88, transcription factor IRF7 and the type I IFN feedback loop mediated by IFNAR1. These results indicate that (i) vaccinia virus, but not myxoma virus, expresses inhibitor(s) of the poxvirus sensing pathway(s) in pDCs; and (ii) Heat-VAC infection fails to produce inhibitor(s) but rather produces novel activator(s), likely viral RNA transcripts that are sensed by the TLR7/MyD88 pathway. Using vaccinia gene deletion mutants, we show that the Z-DNA/RNA binding domain at the N-terminus of the vaccinia immunomodulatory E3 protein is an antagonist of the innate immune response of human pDCs to poxvirus infection and TLR agonists. The myxoma virus ortholog of vaccinia E3 (M029) lacks the N-terminal Z-DNA/RNA binding domain, which might contribute to the immunostimulating properties of myxoma virus