Minimal deformations of the commutative algebra and the linear group GL(n)

We consider the relations of generalized commutativity in the algebra of formal series $M_q (x^i )$, which conserve a tensor $I_q$-grading and depend on parameters $q(i,k)$ . We choose the $I_q$-preserving version of differential calculus on $M_q$ . A new construction of the symmetrized tensor product for $M_q$-type algebras and the corresponding definition of minimally deformed linear group $QGL(n)$ and Lie algebra $qgl(n)$ are proposed. We study the connection of $QGL(n)$ and $qgl(n)$ with the special matrix algebra \mbox{Mat} (n,Q) containing matrices with noncommutative elements. A definition of the deformed determinant in the algebra \mbox{Mat} (n,Q) is given. The exponential parametrization in the algebra \mbox{Mat} (n,Q) is considered on the basis of Campbell-Hausdorf formula.Comment: 14 page

Optimization of roll calibration for flange shape rolling. Groove space

The most important component of any rolling mill is the calibration of the rolls. The ability to obtain a finished product of high quality at minimal cost depends on the right calibration. According to the previous experience and practice a large number of different calibrations for the flange profiles production are known. The universal 'concept of two-stage optimization', consisting of two successively carried out optimization stages developed in the Department of Metal Forming of the Ural Federal University in relation to optimization of the roll calibration for flange shape rolling is considered in this article. Common features of these shapes classification and their variation levels are identified and justified. This developed classification structure is the basis for the formation of spaces of groove schemes, due to which the groove space is formed. In the software implementation the groove space is represented as a 'groove database'. In the future this database will be used to form the space of calibration schemes that are fundamentally suitable for these shapes rolling. © Published under licence by IOP Publishing Ltd.The reported study was funded by RFBR according to the research project 20-38-90246

BCG-INDUCED PRO-INFLAMMATORY PHENOTYPE OF MESENCHYMAL STEM CELLS: EFFECT OF IMMUNE MODULATORS

In case of mycobacterial infection the granulomatous infiltration foci contain the significant amount of mesenchymal stem cells (MSC), which functional phenotype and respective function in anti-tuberculosis immune defense remain unknown.Goal of the study: to characterize the MSC phenotype, formed by their interaction with BCG of M. bovis and to evaluate the changes in this phenotype caused by the action of inhibitors and stimulants of immune regulatory action.Materials and methods: MSC retrieved from bone marrow of mice were cultured with the presence and absence of BCG of M. bovis and/or poludanum TLR3 agonist; and the effect of two latter on the production of pro- and anti-inflammatory cytokines was evaluated by enzyme multiplied immunoassay. Flow cytometry and radioactive testing were used to evaluate the impact of cultured BCG fluid and poludanum-conditioned MSC on the proliferative and apoptotic activity of splenocytes. The inhibitors of indoleamine 2,3-dioxygenase (IDO), cyclooxygenase-2 (COG-2) or NO synthase were added to certain cultures alone with BCG and poludanum, and the contributions of IDO, COG-2 and NO to BCG and poludanum-induced response were assessed.Results. Pro-inflammatory polarization of MSC under the action of BCG and poludanum was demonstrated. Pro-inflammatory MSC phenotype correlated to their anti-apoptogenic and growth-stimulating actions on the splenocytes. It was demonstrated that IDO and NO restrained BCG-induced polarization and conversely COG-2 promoted BCG-induced pro-inflammatory polarization of MSC.Conclusions. 1. MSC actively participate in the formation of immunologic anti-mycobacterial resistance. 2. Targeted regulation of IDO and NO production can be feasibly applied for formation of anti-tuberculous vaccinal immunity and control mycobacterial infection

THE OPTIMIZATION OF THE SCHEME OF METAL DEFORMATION WHILE ROLLING CHANNELS

The decrease in the magnitude of the unevenness of the deformation was chosen as one of the goals of optimizing the calibration of the rolling rolls. With the use of the universal “Concept of Optimal Calibration”, channels of channel calibers and channel calibrations are formed, and an algorithm for forming the space of channel calibrations schemes and for selecting the optimal calibration scheme.Уменьшение величины неравномерности деформации выбрано в качестве одной из целей оптимизации калибровки прокатных валков. С использованием универсальной «Концепции оптимальной калибровки» сформированы пространства швеллерных калибров и швеллерных калибровок, а также разработан алгоритм формирования пространства схем швеллерных калибровок и выбора оптимальной схемы калибровки

The ansamycin antibiotic, rifamycin SV, inhibits BCL6 transcriptional repression and forms a complex with the BCL6-BTB/POZ domain

BCL6 is a transcriptional repressor that is over-expressed due to chromosomal translocations, or other abnormalities, in ~40% of diffuse large B-cell lymphoma. BCL6 interacts with co-repressor, SMRT, and this is essential for its role in lymphomas. Peptide or small molecule inhibitors, which prevent the association of SMRT with BCL6, inhibit transcriptional repression and cause apoptosis of lymphoma cells in vitro and in vivo. In order to discover compounds, which have the potential to be developed into BCL6 inhibitors, we screened a natural product library. The ansamycin antibiotic, rifamycin SV, inhibited BCL6 transcriptional repression and NMR spectroscopy confirmed a direct interaction between rifamycin SV and BCL6. To further determine the characteristics of compounds binding to BCL6-POZ we analyzed four other members of this family and showed that rifabutin, bound most strongly. An X-ray crystal structure of the rifabutin-BCL6 complex revealed that rifabutin occupies a partly non-polar pocket making interactions with tyrosine58, asparagine21 and arginine24 of the BCL6-POZ domain. Importantly these residues are also important for the interaction of BLC6 with SMRT. This work demonstrates a unique approach to developing a structure activity relationship for a compound that will form the basis of a therapeutically useful BCL6 inhibitor

SELECTING THE OPTIMAL CALIBRATION OF THE ROLLERS FOR THE IMPROVEMENT OF THE STRUCTURE OF THE READY SHEVLER

Улучшение структуры готового изделия выбрано в качестве цели оптимизации калибровки прокатных валков. С использованием теории систем и теории графов сформированы пространства швеллерных калибров и швеллерных калибровок, а так же составлены матрицы смежности швеллерных калибров.The improvement in the structure of the finished product is chosen as the goal of optimizing the calibration of the rolling rolls. Using the theory of systems and the theory of graphs, spaces of channel calibers and channel calibrations are formed, and matrices of adjacent channel calibers are also made up

MAGE-A cancer/testis antigens inhibit MDM2 ubiquitylation function and promote increased levels of MDM4

Melanoma antigen A (MAGE-A) proteins comprise a structurally and biochemically similar sub-family of Cancer/Testis antigens that are expressed in many cancer types and are thought to contribute actively to malignancy. MAGE-A proteins are established regulators of certain cancer-associated transcription factors, including p53, and are activators of several RING finger-dependent ubiquitin E3 ligases. Here, we show that MAGE-A2 associates with MDM2, a ubiquitin E3 ligase that mediates ubiquitylation of more than 20 substrates including mainly p53, MDM2 itself, and MDM4, a potent p53 inhibitor and MDM2 partner that is structurally related to MDM2. We find that MAGE-A2 interacts with MDM2 via the N-terminal p53-binding pocket and the RING finger domain of MDM2 that is required for homo/hetero-dimerization and for E2 ligase interaction. Consistent with these data, we show that MAGE-A2 is a potent inhibitor of the E3 ubiquitin ligase activity of MDM2, yet it does not have any significant effect on p53 turnover mediated by MDM2. Strikingly, however, increased MAGE-A2 expression leads to reduced ubiquitylation and increased levels of MDM4. Similarly, silencing of endogenous MAGE-A expression diminishes MDM4 levels in a manner that can be rescued by the proteasomal inhibitor, bortezomid, and permits increased MDM2/MDM4 association. These data suggest that MAGE-A proteins can: (i) uncouple the ubiquitin ligase and degradation functions of MDM2; (ii) act as potent inhibitors of E3 ligase function; and (iii) regulate the turnover of MDM4. We also find an association between the presence of MAGE-A and increased MDM4 levels in primary breast cancer, suggesting that MAGE-A-dependent control of MDM4 levels has relevance to cancer clinically

БЦЖ-ИНДУЦИРОВАННЫЙ ПРОВОСПАЛИТЕЛЬНЫЙ ФЕНОТИП МЕЗЕНХИМАЛЬНЫХ СТВОЛОВЫХ КЛЕТОК: ВЛИЯНИЕ ИММУНОМОДУЛЯТОРОВ

In case of mycobacterial infection the granulomatous infiltration foci contain the significant amount of mesenchymal stem cells (MSC), which functional phenotype and respective function in anti-tuberculosis immune defense remain unknown.Goal of the study: to characterize the MSC phenotype, formed by their interaction with BCG of M. bovis and to evaluate the changes in this phenotype caused by the action of inhibitors and stimulants of immune regulatory action.Materials and methods: MSC retrieved from bone marrow of mice were cultured with the presence and absence of BCG of M. bovis and/or poludanum TLR3 agonist; and the effect of two latter on the production of pro- and anti-inflammatory cytokines was evaluated by enzyme multiplied immunoassay. Flow cytometry and radioactive testing were used to evaluate the impact of cultured BCG fluid and poludanum-conditioned MSC on the proliferative and apoptotic activity of splenocytes. The inhibitors of indoleamine 2,3-dioxygenase (IDO), cyclooxygenase-2 (COG-2) or NO synthase were added to certain cultures alone with BCG and poludanum, and the contributions of IDO, COG-2 and NO to BCG and poludanum-induced response were assessed.Results. Pro-inflammatory polarization of MSC under the action of BCG and poludanum was demonstrated. Pro-inflammatory MSC phenotype correlated to their anti-apoptogenic and growth-stimulating actions on the splenocytes. It was demonstrated that IDO and NO restrained BCG-induced polarization and conversely COG-2 promoted BCG-induced pro-inflammatory polarization of MSC.Conclusions. 1. MSC actively participate in the formation of immunologic anti-mycobacterial resistance. 2. Targeted regulation of IDO and NO production can be feasibly applied for formation of anti-tuberculous vaccinal immunity and control mycobacterial infection. При микобактериальной инфекции в очагах гранулематозной инфильтрации содержится большое количество мезенхимальных стволовых клеток (МСК), функциональный фенотип которых и, соответственно, функция в противотуберкулезном иммунитете неизвестны.Цель исследования: охарактеризовать фенотип МСК, формирующийся при их взаимодействии с M. bovis БЦЖ, и оценить изменения этого фенотипа под действием ингибиторов и стимуляторов иммунорегуляторной активности.Материалы и методы: МСК, полученные из костного мозга мышей, культивировали в присутствии или отсутствии M. bovis БЦЖ и/или агониста TLR3 полудана и методами иммуноферментного анализа оценивали влияние последних на продукцию про- и антивоспалительных цитокинов. Методами проточной цитометрии и радиоактивного анализа оценивали влияние культуральной жидкости БЦЖ- и полудан-кондиционированных МСК на пролиферативную и апоптотическую активность спленоцитов. В часть культур вместе с БЦЖ или полуданом добавляли ингибиторы индоламин-2,3-диоксигеназы (ИДО), циклооксигеназы-2 (ЦОГ-2) или NO синтазы и оценивали вклад ИДО, ЦОГ-2 и NO в БЦЖ- и полудан-индуцированный ответ.Результаты. Показана провоспалительная поляризация МСК под действием БЦЖ и полудана. Провоспалительный фенотип МСК коррелировал с их антиапоптогенной и ростостимулирующей активностью по отношению к спленоцитам. Продемонстрировано, что ИДО и NO сдерживают БЦЖ-индуцированную поляризацию, а активность ЦОГ-2, наоборот, способствует БЦЖ-индуцированной провоспалительной поляризации МСК.Выводы. 1. МСК являются активными участники формирования иммунологической антимикобактериальной резистентности. 2. Таргетное регулирование продукции ИДО и оксида азота может быть целесообразно для формирования противотуберкулезного вакцинального иммунитета и для борьбы с микобактериальной инфекцией

The relationship between the preoperative systemic inflammatory response and cancer-specific survival in patients undergoing potentially curative resection for renal clear cell cancer

The relationship between tumour stage, grade (Fuhrman), performance status (ECOG), a combined score (UCLA Integrated Staging System, UISS), systemic inflammatory response (elevated C-reactive protein concentration), and cancer-specific survival was examined in patients undergoing potentially curative resection for renal clear cell cancer (n=100). On univariate survival analysis, sex (P=0.050), tumour stage (P=0.001), Fuhrman grade (P<0.001), UISS (P<0.001), C-reactive protein (P=0.002) were significant predictors of survival. On multivariate analysis with sex, UISS and C-reactive protein entered as covariates, only UISS (HR 2.70, 95% CI 1.00–7.30, P=0.050) and C-reactive protein (HR 4.00, 95% CI 1.21–13.31, P=0.024) were significant independent predictors of survival. The presence of a preoperative systemic inflammatory response predicts poor cancer-specific survival in patients who have undergone potentially curative resection for renal clear cell cancer

Varespladib and cardiovascular events in patients with an acute coronary syndrome: the VISTA-16 randomized clinical trial

IMPORTANCE: Secretory phospholipase A2(sPLA2) generates bioactive phospholipid products implicated in atherosclerosis. The sPLA2inhibitor varespladib has favorable effects on lipid and inflammatory markers; however, its effect on cardiovascular outcomes is unknown. OBJECTIVE: To determine the effects of sPLA2inhibition with varespladib on cardiovascular outcomes. DESIGN, SETTING, AND PARTICIPANTS: A double-blind, randomized, multicenter trial at 362 academic and community hospitals in Europe, Australia, New Zealand, India, and North America of 5145 patients randomized within 96 hours of presentation of an acute coronary syndrome (ACS) to either varespladib (n = 2572) or placebo (n = 2573) with enrollment between June 1, 2010, and March 7, 2012 (study termination on March 9, 2012). INTERVENTIONS: Participants were randomized to receive varespladib (500 mg) or placebo daily for 16 weeks, in addition to atorvastatin and other established therapies. MAIN OUTCOMES AND MEASURES: The primary efficacy measurewas a composite of cardiovascular mortality, nonfatal myocardial infarction (MI), nonfatal stroke, or unstable angina with evidence of ischemia requiring hospitalization at 16 weeks. Six-month survival status was also evaluated. RESULTS: At a prespecified interim analysis, including 212 primary end point events, the independent data and safety monitoring board recommended termination of the trial for futility and possible harm. The primary end point occurred in 136 patients (6.1%) treated with varespladib compared with 109 patients (5.1%) treated with placebo (hazard ratio [HR], 1.25; 95%CI, 0.97-1.61; log-rank P = .08). Varespladib was associated with a greater risk of MI (78 [3.4%] vs 47 [2.2%]; HR, 1.66; 95%CI, 1.16-2.39; log-rank P = .005). The composite secondary end point of cardiovascular mortality, MI, and stroke was observed in 107 patients (4.6%) in the varespladib group and 79 patients (3.8%) in the placebo group (HR, 1.36; 95% CI, 1.02-1.82; P = .04). CONCLUSIONS AND RELEVANCE: In patients with recent ACS, varespladib did not reduce the risk of recurrent cardiovascular events and significantly increased the risk of MI. The sPLA2inhibition with varespladib may be harmful and is not a useful strategy to reduce adverse cardiovascular outcomes after ACS. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01130246. Copyright 2014 American Medical Association. All rights reserved