Arithmeticity of ideal hyperbolic right-angled polyhedra and hyperbolic link complements

In this paper we provide a generalized construction of nonarithmetic hyperbolic orbiifolds in the spirit of Gromov and Piatetski-Shapiro. Nonarithmeticity of such orbifolds is based on recently obtained results connecting a behaviour of the so-called fc-subspaces (totally geodesic subspaces fixed by finite order elements of the commensurator) with arithmetic properties of hyperbolic orbifolds and manifolds. As an application, we verify arithmeticity of some particular class of ideal hyperbolic right-angled $3$-polyhedra and hyperbolic link complements.Comment: 7 pages, 3 figure

Influence of nonmetallic inclusions on the resistance of metal weld to brittle fractures

According to statistics, up to 80% of all fixed metal structure accidents are associated with welded joints. However, most of the emergency destructions, usually caused by non-metallic inclusions in the weld metal, are fragile. The probability of brittle fracture decreases with increasing plasticity. And plasticity, that depends on the mobility of dislocations to a great degree, decreases with temperature decrease and increase in the strain rate. The plasticity of the metal is a structurally sensitive property and depends on the type of crystal lattice that determines the number of densely packed directions and slip planes. Low-alloy steels, mainly used in welded steel structures, have a volume-centered cubic lattice with a relatively small number of planes and sliding direction. These steels are ductile at relatively high temperatures and become brittle at negative temperatures. The only way to improve the ductility of the metal without significantly reducing its strength is to grind grain. One of the effective ways to obtain finegrained structure of the weld metal is to introduce modifiers into the weld pool. The modifiers should be in the form of refractory compounds (oxides, carbides, nitrides), which in the crystallization zone of the weld pool are crystallization centers and increase the number of grains per unit volume. Studies of the modification of the crystallizing metal in the conditions of casting and fusion welding have shown that the melt overheating reduces the effect of modification. In electric arc welding with an arc temperature of more than 6000K, the danger of deactivation of the modifier is high. One way to reduce overheating and improve the efficiency of modifiers in welding is the introduction of modifying particles in the weld pool in combination with more massive granules in the form of chopped wire, serving as micro-refrigerators. This method, called welding with a metalchemical additive (MCA), is successfully used in bridge construction. Modification of the weld pool with refractory particles, along with the positive effect of grinding grain in the weld there is also a negative moment: modifying particles that remain in the weld in the form of non-metallic inclusions are stress concentrators and can become centers of crackin

Antiviral Properties of Chemical Inhibitors of Cellular Anti-Apoptotic Bcl-2 Proteins

Viral diseases remain serious threats to public health because of the shortage of effective means of control. To combat the surge of viral diseases, new treatments are urgently needed. Here we show that small-molecules, which inhibit cellular anti-apoptotic Bcl-2 proteins (Bcl-2i), induced the premature death of cells infected with different RNA or DNA viruses, whereas, at the same concentrations, no toxicity was observed in mock-infected cells. Moreover, these compounds limited viral replication and spread. Surprisingly, Bcl-2i also induced the premature apoptosis of cells transfected with viral RNA or plasmid DNA but not of mock-transfected cells. These results suggest that Bcl-2i sensitizes cells containing foreign RNA or DNA to apoptosis. A comparison of the toxicity, antiviral activity, and side effects of six Bcl-2i allowed us to select A-1155463 as an antiviral lead candidate. Thus, our results pave the way for the further development of Bcl-2i for the prevention and treatment of viral diseases.Peer reviewe

Antiviral properties of chemical inhibitors of cellular anti-apoptotic Bcl-2 proteins

Viral diseases remain serious threats to public health because of the shortage of effective means of control. To combat the surge of viral diseases, new treatments are urgently needed. Here we show that small-molecules, which inhibit cellular anti-apoptotic Bcl-2 proteins (Bcl-2i), induced the premature death of cells infected with different RNA or DNA viruses, whereas, at the same concentrations, no toxicity was observed in mock-infected cells. Moreover, these compounds limited viral replication and spread. Surprisingly, Bcl-2i also induced the premature apoptosis of cells transfected with viral RNA or plasmid DNA but not of mock-transfected cells. These results suggest that Bcl-2i sensitizes cells containing foreign RNA or DNA to apoptosis. A comparison of the toxicity, antiviral activity, and side effects of six Bcl-2i allowed us to select A-1155463 as an antiviral lead candidate. Thus, our results pave the way for the further development of Bcl-2i for the prevention and treatment of viral diseases.</p

Editing the genome of chicken primordial germ cells to introduce alleles and study gene function

With continuing advances in genome sequencing technology, the chicken genome assembly is now better annotated with improved accuracy to the level of single nucleotide polymorphisms. Additionally, the genomes of other birds such as the duck, turkey and zebra finch have now been sequenced. A great opportunity exists in avian biology to use genome editing technology to introduce small and defined sequence changes to create specific haplotypes in chicken to investigate gene regulatory function, and also perform rapid and seamless transfer of specific alleles between chicken breeds. The methods for performing such precise genome editing are well established for mammalian species but are not readily applicable in birds due to evolutionary differences in reproductive biology. A significant leap forward to address this challenge in avian biology was the development of long-term culture methods for chicken primordial germ cells (PGCs). PGCs present a cell line in which to perform targeted genetic manipulations that will be heritable. Chicken PGCs have been successfully targeted to generate genetically modified chickens. However, genome editing to introduce small and defined sequence changes has not been demonstrated in any avian species. To address this deficit, the application of CRISPR/Cas9 and short oligonucleotide donors in chicken PGCs for performing small and defined sequence changes was investigated in this thesis. Specifically, homology-directed DNA repair (HDR) using oligonucleotide donors along with wild-type CRISPR/Cas9 (SpCas9-WT) or high fidelity CRISPR/Cas9 (SpCas9-HF1) was investigated in cultured chicken PGCs. The results obtained showed that small sequences changes ranging from a single to a few nucleotides could be precisely edited in many loci in chicken PGCs. In comparison to SpCas9-WT, SpCas9-HF1 increased the frequency of biallelic and single allele editing to generate specific homozygous and heterozygous genotypes. This finding demonstrates the utility of high fidelity CRISPR/Cas9 variants for performing sequence editing with high efficiency in PGCs. Since PGCs can be converted into pluripotent stem cells that can potentially differentiate into many cell types from the three germ layers, genome editing of PGCs can, therefore, be used to generate PGC-derived avian cell types with defined genetic alterations to investigate the host-pathogen interactions of infectious avian diseases. To investigate this possibility, the chicken ANP32A gene was investigated as a target for genetic resistance to avian influenza virus in PGC-derived chicken cell lines. Targeted modification of ANP32A was performed to generate clonal lines of genome-edited PGCs. Avian influenza minigenome replication assays were subsequently performed in the ANP32A-mutant PGC-derived cell lines. The results verified that ANP32A function is crucial for the function of both avian virus polymerase and human-adapted virus polymerase in chicken cells. Importantly, an asparagine to isoleucine mutation at position 129 (N129I) in chicken ANP32A failed to support avian influenza polymerase function. This genetic change can be introduced into chickens and validated in virological studies. Importantly, the results of my investigation demonstrate the potential to use genome editing of PGCs as an approach to generate many types of unique cell models for the study of avian biology. Genome editing of PGCs may also be applied to unravel the genes that control the development of the avian germ cell lineage. In the mouse, gene targeting has been extensively applied to generate loss-of-function mouse models to use the reverse genetics approach to identify key genes that regulate the migration of specified PGCs to the genital ridges. Avian PGCs express similar cytokine receptors as their mammalian counterparts. However, the factors guiding the migration of avian PGCs are largely unknown. To address this, CRISPR/Cas9 was used in this thesis to generate clonal lines of chicken PGCs with loss-of-function deletions in the CXCR4 and c-Kit genes which have been implicated in controlling mouse PGC migration. The results showed that CXCR4-deficient PGCs are absent from the gonads whereas c-Kit-deficient PGCs colonise the developing gonads in reduced numbers and are significantly reduced or absent from older stages. This finding shows a conserved role for CXCR4 and c-Kit signalling in chicken PGC development. Importantly, other genes suspected to be involved in controlling the development of avian germ cells can be investigated using this approach to increase our understanding of avian reproductive biology. Finally, the methods developed in this thesis for editing of the chicken genome may be applied in other avian species once culture methods for the PGCs from these species are develope

New technology for production of granular adding material with nanomodifying additives for steel arc welding

The chemical analysis of metal seam showed that introduction of titanium dioxide with MCA intensifies transition of Al2O3 from slag into metal pool and provides double concentration of titanium in the seam compared to the one which appears in the interaction of bathtub with melted flux AH-47 without TiO2 additives. The presence of oxides of titanium and aluminium of endogenous origin in the melt leads to formation of refractory particles with the center of TiO2 and Al2O3 in it. These particles are the centers of crystallization in the tail part of the molten pool and they remain in seam metal in the form of evenly distributed fine nonmetallic inclusions, which have crystallographic affinity with a matrix (α-iron). That provides the fine-grained seam structure with the raised and stable strength characteristics. This article compares the existing and developed technologies for production of MCA. The granulometric analysis of the powder TiO2 has demonstrated that when MCA is processed in the planetary mill, particles of titanium dioxide are crushed to a nanodimensional order. It is shown that the preparation of MCA in high-energy planetary mill (due to double increase of durability in coupling of the modifier with granulate) provides its stable structure, increases the cold resistance (20–25%) and stability of strength characteristics along the length of welded seam. Metalgraphic researches determined that the fine-grained structure which linear size of grain is twice smaller than the one obtained in the old technology welding is formed in a seam. However the direct introduction of nanomodifiers in a molten pool through the flux or an electrode wire is not efficient because of their deactivation and high temperature in welding zone. Therefore it was offered to use modifiers in the mix with the cooling macroparticles in case of automatic welding of a bridge metalware under flux using metalchemical additive (MCA). The MCA consists of a chopped welding wire (granulate), the powdering modifying chemical additive TiO2 in the mixer with the displaced rotation axis «piyanay bochka» accorfint to the existing technology. However this MCA's technology doesn't provide the stable durability of modifier's coupling with the granulate's surface and it is not able to control its structure under production conditions that, certainly, negatively affects on stability of welded connections' properties. Therefore one of the main task in this research was to improve the existing technology to increase durability of the modifier' coupling with granulate. Welding is one of the main technological methods to connect details and nodes in production process. However 70–80% of metalware destruction occuring in operational process are related to welded connections. These destructions are mainly fragile. The increased firmness of welded connections against the fragile destruction is needed due to development of northern and east regions in Russia. The most perspective method to increase cold resistance of welded connections is the crush of seam metal grain by means of nanomodification