Targeting ATM pathway for therapeutic intervention in cancer

The Ataxia Telangiectasia Mutated gene encodes the ATM protein, a key element in the DNA damage response (DDR) signalling pathway responsible for maintaining genomic integrity within the cell. The ATM protein belongs to a family of large protein kinases containing the phosphatidylinositol-3 catalytic domain, including ATM, ATR and PI3K. ATM provides the crucial link between DNA damage, cell cycle progression and cell death by first sensing double stranded DNA breaks and subsequently phosphorylating and activating other downstream proteins functioning in DNA damage repair, cell cycle arrest and apoptotic pathways,. Mammalian cells are constantly challenged by genotoxic agents from a variety of sources and therefore require a robust sensing and repair mechanism to maintain DNA integrity or activate alternative cell fate pathways. This review covers the role of ATM in DDR signalling and describes the interaction of the ATM kinase with other proteins in order to fulfil its various functions. Special emphasis is given to how the growing knowledge of the DDR can help identify drug targets for cancer therapy, thus providing a rationale for exploiting the ATM pathway in anticancer drug development. Moreover, we discuss how a network modelling approach can be used to identify and characterise ATM inhibitors and predict their therapeutic potential

Dissipation signatures of the normal and superfluid phases in torsion pendulum experiments with 3He in aerogel

We present data for energy dissipation factor (Q^{-1}) over a broad temperature range at various pressures of a torsion pendulum setup used to study 3He confined in a 98% open silica aerogel. Values for Q^{-1} above T_c are temperature independent and have a weak pressure dependence. Below T_c, a deliberate axial compression of the aerogel by 10% widens the range of metastability for a superfluid Equal Spin Pairing (ESP) state; we observe this ESP phase on cooling and the B phase on warming over an extended temperature region. While the dissipation for the B phase tends to zero as T goes to 0, Q^{-1} exhibits a peak value greater than that at T_c at intermediate temperatures. Values for Q^{-1} in the ESP phase are consistently higher than in the B phase and are proportional to \rho_s/\rho until the ESP to B phase transition is attained. We apply a viscoelastic collision-drag model, which couples the motion of the helium and the aerogel through a frictional relaxation time \tau_f. Our dissipation data is not sensitive to the damping due to the presumed small but non-zero value of \tau_f. The result is that an additional mechanism to dissipate energy not captured in the collision-drag model and related to the emergence of the superfluid order must exist. The extra dissipation below T_c is possibly associated with mutual friction between the superfluid phases and the clamped normal fluid. The pressure dependence of the measured dissipation in both superfluid phases is likely related to the pressure dependence of the gap structure of the "dirty" superfluid. The large dissipation in the ESP state is consistent with the phase being the A or the Polar with the order parameter nodes oriented in the plane of the cell and perpendicular to the aerogel anisotropy axis.Comment: 12 pages, 7 figure

Demodex cati and feline immunodeficiency virus co-infection in a cat

A case of co-infection due to Demodex cati and feline immunodeficiency virus in a cat is described. A 5 year-old neutered male cat was presented to the Small Animal Clinic at the Faculty of Veterinary Medicine, Trakia University with lethargy, diarrhoea, pyrexia, anorexia, adipsia, skin lesions, intense itching and alopecia. Parasitological, mycological and serological examinations were carried out. Adult D. cati mites and antibodies against FIV were detected. A proper therapy with an endectocide, antibiotic and antihistamine drug was prescribed. The improvement of the general condition was ob-served after a month of treatment. Later, the disease recurred twice and the animal was humanely euthanased for medical reasons and at the owner’s request

Breather decay into a vortex/anti-vortex pair in a Josephson Ladder

We present experimental evidence for a new behavior which involves discrete breathers and vortices in a Josephson Ladder. Breathers can be visualized as the creation and subsequent annihilation of vortex/anti-vortex pairs. An externally applied magnetic field breaks the vortex/anti-vortex symmetry and causes the breather to split apart. The motion of the vortex or anti-vortex creates multi-site breathers, which are always to one side or the other of the original breather depending on the sign of the applied field. This asymmetry in applied field is experimentally observed.Comment: 10 pages, 5 figure

Impact of Digitalization on the Industrial Enterprises Activities

The relevance of the study is determined by the change of technological structure of the Russian economy: digital technologies are becoming an integral part of the fulfilling life of both individual and legal entities. The use of digital technologies in the activities of manufacturing enterprises allows them to become more competitive. However, the change in almost all processes of an enterprise because of digitalization simplifies some of them and reduces their cost but complicates others and makes them more expensive. In addition, the digitalization leads to the emergence of new processes at enterprises that often means the emergence of new risks and additional costs. The purpose of this research is to study the impact of the digitalization on activities of industrial enterprises. Objectives of the study are: to study the concept of digitalization, areas of activity of industrial enterprises as well as consequences of the introduction of digital technologies into each of the activity area of industrial enterprises and the impact of digitalization on the results of a production enterprise

Physical and chemical processes and the morphofunctional characteristics of human erythrocytes in hyperglycaemia

Background: This study examines the effect of graduated hyperglycaemia on the state and oxygen-binding ability of hemoglobin, the correlation of phospholipid fractions and their metabolites in the membrane, the activity of proteolytic enzymes and the morphofunctional state of erythrocytes. Methods: Conformational changes in the molecule of hemoglobin were determined by Raman spectroscopy. The structure of the erythrocytes was analyzed using laser interference microscopy (LIM). To determine the activity of NADN-methemoglobinreductase, we used the P.G. Board method. The degree of glycosylation of the erythrocyte membranes was determined using a method previously described by Felkoren et al. Lipid extraction was performed using the Bligh and Dyer method. Detection of the phospholipids was performed using V. E. Vaskovsky method. Results: Conditions of hyperglycaemia are characterized by a low affinity of hemoglobin to oxygen, which is manifested as a parallel decrease in the content of hemoglobin oxyform and the growth of deoxyform, methemoglobin and membrane-bound hemoglobin. The degree of glycosylation of membrane proteins and hemoglobin is high. For example, in the case of hyperglycaemia, erythrocytic membranes reduce the content of all phospholipid fractions with a simultaneous increase in lysoforms, free fatty acids and the diacylglycerol (DAG). Step wise hyperglycaemia in incubation medium and human erythrocytes results in an increased content of peptide components and general trypsin-like activity in the cytosol, with a simultaneous decreased activity of µ-calpain and caspase 3. Conclusions: Metabolic disorders and damage of cell membranes during hyperglycaemia cause an increase in the population of echinocytes and spherocytes. The resulting disorders are accompanied with a high probability of intravascular haemolysis.</p

Isolation and primary identification of shiga toxin producing Escherichia coli O157 in dairy cattle

During the last years, the significance of diseases associated etiologically to Shiga-toxin producing Escherichia coli (STEC) is continuously increasing at a global scale, while the O157 serotype is con-sidered as one of the most important pathogens of animal origin. Large ruminants play a key role in the epidemiology of E. coli diseases among men. Bovine faeces are a primary source of contamina-tion of the environment and foods with this agent. The purpose of this study was to test a specific, microbiological algorithm for primary identification of STEC isolates from bovine faeces using sorbi-tol McConkey agar supplemented with cefixime and tellurite. The attempts were focused not only on increasing the sensitivity and specificity of serotype identification, but also on optimisation of labour and analysis costs. From May 2013 to October 2014, a total number of 1104 faecal swab samples from calves 3 to 6 months of age were collected from 19 farms in different administrative and geo-graphical regions of Bulgaria. Thirty six sorbitol-negative E. coli isolates (3.26%) were detected as belonging to the O157 serotype after slide agglutination test

Modification of the 3He Phase Diagram by Anisotropic Disorder

Motivated by the recent prediction that uniaxially compressed aerogel can stabilize the anisotropic A phase over the isotropic B phase, we measure the pressure dependent superfluid fraction of 3He entrained in 10% axially compressed, 98% porous aerogel. We observe that a broad region of the temperature-pressure phase diagram is occupied by the metastable A phase. The reappearance of the A phase on warming from the B phase, before superfluidity is extinguished at Tc, is in contrast to its absence in uncompressed aerogel. The phase diagram is modified from that of pure 3He, with the disappearance of the polycritical point (PCP) and the appearance of a region of A phase extending below the PCP of bulk 3He, even in zero applied magnetic field. The expected alignment of the A phase texture by compression is not observed.Comment: 4 pages, 4 figures. Submitted for review to PR