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NK cells regulate CD4+ and CD8+ T cells in acute viral infection, vaccination, and the tumor microenvironment. NK cells also become exhausted in chronic activation settings. The mechanisms causing these ILC responses and their impact on adaptive immunity are unclear. CD8+ T cell exhaustion develops during chronic Toxoplasma gondii (T. gondii) infection resulting in parasite reactivation and death. How chronic T. gondii infection impacts the NK cell compartment is not known. We demonstrate that NK cells do not exhibit hallmarks of exhaustion. Their numbers are stable and they do not express high PD1 or LAG3. NK cell depletion with anti-NK1.1 is therapeutic and rescues chronic T. gondii infected mice from CD8+ T cell exhaustion dependent death, increases survival after lethal secondary challenge and alters cyst burdens in brain. Anti-NK1.1 treatment increased polyfunctional CD8+ T cell responses in spleen and brain and reduced CD8+ T cell apoptosis in spleen. Chronic T. gondii infection promotes the development of a modified NK cell compartment, which does not exhibit normal NK cell characteristics. NK cells are Ly49 and TRAIL negative and are enriched for expression of CD94/NKG2A and KLRG1. These NK cells are found in both spleen and brain. They do not produce IFNγ, are IL-10 negative, do not increase PDL1 expression, but do increase CD107a on their surface. Based on the NK cell receptor phenotype we observed NKp46 and CD94-NKG2A cognate ligands were measured. Activating NKp46 (NCR1-ligand) ligand increased and NKG2A ligand Qa-1b expression was reduced on CD8+ T cells. Blockade of NKp46 rescued the chronically infected mice from death and reduced the number of NKG2A+ cells. Immunization with a single dose non-persistent 100% protective T. gondii vaccination did not induce this cell population in the spleen, suggesting persistent infection is essential for their development. We hypothesize chronic T. gondii infection induces an NKp46 dependent modified NK cell population that reduces functional CD8+ T cells to promote persistent parasite infection in the brain. NK cell targeted therapies could enhance immunity in people with chronic infections, chronic inflammation and cancer.

Статья посвящена важности включения изучения культуры изучаемого иностранного языка, приобретения навыков межкультурного общения и культурной осведомленности в преподавание иностранного языка. Авторы подчеркивают, что обучение культуре в контексте преподавания иностранного языка должно включать культурные знания, культурные ценности, культурные навыки и поведение. Авторы также отмечают, что отношение к преподаванию культуры в процессе обучения иностранному языку подразумевает, с одной стороны, рассмотрение преподавания культуры как преподавания пятого языкового навыка вместе с говорением, аудированием, чтением и письмом, включая понятия культурной чувствительности и культурного сознания и поведения в определенных культурных ситуациях, с другой стороны, рассмотрение языка как социальной практики, определяемой культурой, при этом культура становится ядром преподавания языка, а культурная осведомленность рассматривается как возможность овладения языком в совершенстве. Культурная осведомленность является основой коммуникации, способствующей пониманию культурных ценностей, убеждений и восприятию языка изучаемой культуры. Обучение студентов, в одинаковой степени владеющих двумя языками и двумя культурами в высшем учебном заведении, имеет первостепенное значение. Межкультурная осведомленность предполагает ряд навыков, улучшающих понимание учащимися как родной культуры, так и других культур. Авторы приходят к выводу, что навыки межкультурной осведомленности подразумевают преодоление непонимания иной культуры и принятие различий между различными культурами., The article is devoted to the importance of incorporating of a foreign culture learning, acquiring cross-cultural communication and cultural awareness skills in a foreign language teaching. The authors point out that teaching culture in foreign language teaching context should include cultural knowledge, cultural values, cultural skills and behavior. The author also emphasize that attitudes to teaching culture in the process of foreign language teaching involve, on the one side, considering teaching culture as teaching the fifth language skill along with speaking, listening, reading and writing, implying teaching cultural sensitivity and cultural awareness or the behavior in certain cultural situations, and on the other side, regarding language as social practice being defined by culture in which culture becomes the core of language teaching with cultural awareness viewed as enabling language proficiency. Cultural awareness is the foundation of communication; it helps to understand cultural values, beliefs, and perceptions of the other culture. Training of both bilingual and bicultural students at higher educational institutions is of primary significance. Intercultural awareness presumes a number of skills, improving students’ native culture and other cultures’ awareness and understanding. The authors come to the conclusion that intercultural awareness skills imply overcoming misinterpretations and accepting differences.

Glioblastomas are the most lethal tumors affecting the central nervous system in adults. Simple and inexpensive syngeneicin vivomodels that closely mirror human glioblastoma, including interactions between tumor and immune cells, are urgently needed for deciphering glioma biology and developing more effective treatments. Here, we generated glioblastoma cell lines by repeatedin-vivopassaging of cells isolated from a neural stem cell-specific Pten/p53 double-knockout genetic mouse brain tumor model. Transcriptome and genome analyses of the cell lines revealed molecular heterogeneity comparable to that observed in human glioblastoma. Upon orthotopic transplantation into syngeneic hosts they formed high-grade gliomas that faithfully recapitulated the histopathological features, invasiveness and myeloid cell infiltration characteristic of human glioblastoma. These features make our cell lines unique and useful tools to study multiple aspects of glioblastoma pathomechanism and test novel treatments, especially immunotherapies in syngeneic preclinical models.

By using the Cre-mediated genetic switch technology, we were able to successfully generate a conditional knock-in mouse, bearing the KIF2A p.His321Asp missense point variant, identified in a subject with malformations of cortical development. These mice present with neuroanatomical anomalies and microcephaly associated with behavioral deficiencies and susceptibility to epilepsy, correlating with the described human phenotype. Using the flexibility of this model, we investigated RosaCre-, NestinCre- and NexCre-driven expression of the mutation to dissect the pathophysiological mechanisms underlying neurodevelopmental cortical abnormalities. We show that the expression of the p.His321Asp pathogenic variant increases apoptosis and causes abnormal multipolar to bipolar transition in newborn neurons, providing therefore insights to better understand cortical organization and brain growth defects that characterize KIF2A-related human disorders. We further demonstrate that the observed cellular phenotypes are likely to be linked to deficiency in the microtubule depolymerizing function of KIF2A.

The processes of structuring in cast iron of different chemical composition in the range of cooling rates of 0.5 ... 5.5 deg / s, which take place in the roll casting mould, are investigated. Scientifically based theoretical and experimental results were obtained, the set of which allowed to develop highly effective technologies of casting of rolling rolls from cast iron with vermicular graphite with increased operational characteristics. Optimum content of rare earth metal (REM) in roller cast iron with vermicular graphite at different cooling rates was experimentally established. In the low sulfur (up to 0,03%) cast iron, the rare earth metal residual (REMres) content is -0,065 ... 0,176 (for a cooling rate of 0,5 deg / s) and 0,01 ... 0,156% (for a cooling rate of 5,5 deg / s) . In the cast iron with high sulfur content (up to 0.10%), at the cooling rates studied, the intervals of concentrations of REMres have been experimentally established to provide the vermicular inclusions of graphite: at a cooling rate of 5.5 deg / c - 0.081-0.129%, and at a speed of 0.5 deg / s - 0.161 ... 0.190%. When modifying melts with a complex modifier based on magnesium KMg9, the Mg content at cooling rates of 5.5 and 0.5 deg / s should be within 0.022 ... 0.03 and 0.019 ... 0.03%, respectively, when treated with the complex KMg9 and FS30RZM30 in the cast iron it is necessary to have 0,0071 ... 0,015% Mg and 0,023 ... 0,025% REMres. With such content of modifiers, the best combinations of microstructure and physical and mechanical properties of castings are obtained. The areas of formation of vermicular graphite inclusions in roll cast irons were determined when processed with a complex modifier based on rare-earth metals and ferrotitanium: at a cooling rate of 5.5 degrees / s and a titanium content of 0.40 ... 0.42%, the concentration range of the rare-earth bridge for stable production of graphite inclusions of vermicular form has expanded and was 0.061 ... 0.169%, and at a cooling rate of 0.5 deg / s –0.129 ... 0.230%. The technological process of casting of bleached roller rolls has been improved due to the application of a highly effective complex modifier (ligature) of optimal composition for the modification of the base metal. The technology for the production of pig iron with vermicular graphite is developed and mastered at casting of rollers with the use of mixtures for modification consisting of two ligatures in the ratio of 1: 3.

The Object of the Study. Innovative development of regionsThe Subject of the Study. Social factors of innovative development of regionsThe Purpose of the Study. Analysis of the main social factors affecting the innovative development of the regions.The main Provisions of the Article. The most important condition for the innovative development of the regions is the effective management impact on the entire set of indicators aimed at improving the functioning of the innovative economy. The most significant and important factors affecting the innovative development of the regions include social factors that are closely related to legal, political and economic factors. The article analyzes the main social factors in the dynamics over the past 10 years and identifies the main problems that negatively affect the innovative development of the regions

The article deals with a new trend in foreign language teaching based on the cross-cultural approach. The challenge for teachers today is to develop students common, communicative and language competences which are essential conditions for the realization of such a task of modern language policy as the establishment of mutual understanding between different cultures. The components of communicative competence are established. The development of communicative competence is considered to be an obligatory condition for mutual understanding between nations in modern world.

The reactions of 4-[(1-oxo-3,4-dihydro-2H-naphmalen-2-ylidene)methyl]benzoic acid with 3-(1,3-dioxobutane-1-yl)-2H-chromen-2-one in the presence of nitrogenous bases (piperidine, triethylamine or pyridine) were used to synthesize for the first time hybrid systems containing the pharmacophoric fragments of the reagents. The reaction scheme involves formation of a condensed dihydropyran structure and its subsequent aromatization into a benzodihydrochromenilium salt under the action of HCl. The process may be accompanied by the competing addition of an azanucleophile by the double bond of the chalcone.

Objectives of the TAIGA Astrophysical complex include the study of the flux of charged cosmic rays and diffuse gamma rays with energies above 100 TeV. This complex is located in the Tunka Valley about 50 km from Lake Baikal at the site of the Tunka-133 Cherenkov facility. TAIGA includes the TAIGA-HiSCORE wide-angle Cherenkov array, the network of Imaging Atmospheric Cherenkov Telescopes (TAIGA-IACT), the Tunka-Grande and TAIGA-Muon scintillation arrays. In this work, we present the results of an analysis of the joint events of the Tunka-Grande scintillation array and TAIGA-HiSCORE and Tunka-133 Cherenkov facilities. The results verify sufficient accuracy of the scintillation experiment for the hybrid study of mass composition of cosmic rays and gamma-hadron separation.

The characteristics and growth rates of mash frogs introduced upon the completion of metamorphosis into the cooling ponds of heating stations have been studied. The age composition of frog populations has been determined. It has been shown that an extra year must be added to the visible adhesion lines in the tissue of long bones. It has been found that the population of mash frogs inhabiting the Verkhnii Tagil Reservoir is characterized by not only a longer life span than in the Reftinskoe Reservoir, but also by a sufficiently high frequency of occurrence in the samples of older age groups.

The design for the TAIGA-HiSCORE array, a part of the TAIGA Gamma Ray Observatory, is considered. The observatory is being constructed in the Tunka Valley, 50 km from Lake Baikal. Preliminary results obtained using the first 28 optical stations of the array are presented.

The trial was performed on 10 clinically healthy Ross hybrid chickens, 5 from each gender, weighing 2.75-2.84 kg. The tested quinolone was applied at the same dose for both routes of application - 10 mg/kg of body weight. Ciprofloxacin hydrochloridum 5% solution for i.v. and 1% solution for intraingluvial treatment were prepared. In a crossover study design, ciprofloxacin hydrochloridum was administered as 5 % solution for i.v. bolus injection to broiler chickens and after 14 days as 1 % solution for intraingluvial administration into a crop to the same birds. Serum ciprofloxacin concentrations were assayed by HPLC with UV detection at a wavelength of 279 nm. After intravenous injection the following pharmacokinetic parameters were determined: t1/2β = 9.07 h; t1/2α= 0.36 h; MRT = 10.20 h and MRT = 10.75 h; AUC0→∞ = 19.560 μg.h/mL and AUC0→∞ = 19.843 μg.h/mL. After intraingluvial application parameters determined by the two pharmacokinetic models were as: t1/2α= 0.86 h; t1/2β = 7,20 h and t1/2β = 7.89 h; MRT = 12.67 h and MRT = 12.93 h; AUC0→∞ = 11.340 μg.h/mL and AUC0→24 h = 11.973 μg.h/mL; Cmax = 2.841 μg/mL and Cmax = 2.638 μg/mL; Tmax = 0.48 h and Tmax = 0.39 h; t1/2abs. = 0.146 h; MAT = 2.47 h and MAT = 2.18 h; F = 57.91% and F = 63.89%. These results suggested that a dose of 10 mg/kg of body weight provides maximum plasma concentration ater intraingluvial administration and is effective in the control of many infectious diseases of poultry.

Fibre Channel (FC) is the protocol that is used for high-speed data transfer without loss and corruption of data blocks. It is commonly used in the Storage Area Networks. The Port State Machine is used to synchronization the connected FC-ports. This paper propose Broadcom switch FC-ports states analysis based on the Port Log Dumps. Log analysis allows to restore FC-ports state changing history and detect errors.

The paper examines the features of visual thinking, the authors note the importance of visual examples in modern engineering education. The article describes a methodological approach to presenting the course, based on visual theorem proofs. An example is considered the course “Theory of multivariable function” Visual examples were created at the Department of Computational Mathematics and Mathematical Physics of the Bauman Moscow State Technical University. The proposed methodological approach to the development of the course “Theory of multivariable function” allows you to use the elements of the created course in various variations for disciplines using the concept of functions of many variables, depending on the direction of training (specialty).

In this article, the authors consider the problem of automatic check of tasks on the example of tasks on the topic of lines and planes. The authors raise the question of the influence of arithmetic errors on automatic verification. The paper discusses methods that will reduce the impact of arithmetic error on automated problem checking. The article provides several examples that are given to students to solve at control events held at the Bauman Moscow State Technical University.

NK cells regulate CD4+ and CD8+ T cells in acute viral infection, vaccination and the tumor microenvironment. NK cells also become exhausted in chronic activation settings. The mechanisms causing these ILC responses and their impact on adaptive immunity are unclear. CD8+ T cell exhaustion develops during chronicToxoplasma gondii(T. gondii) infection resulting in parasite reactivation and death. How chronicT. gondiiinfection impacts the NK cell compartment is not known. We demonstrate that NK cells do not exhibit hallmarks of exhaustion. Their numbers are stable and they do not express high PD1 or LAG3. NK cell depletion with anti-NK1.1 is therapeutic and rescues chronicT. gondiiinfected mice from CD8+ T cell exhaustion dependent death, increases survival after lethal secondary challenge and reduces parasite reactivation. Anti-NK1.1 treatment increased polyfunctional CD8+ T cell responses in spleen and brain and reduced CD8+ T cell apoptosis. ChronicT. gondiiinfection promotes the development of a modified NK cell compartment, which does not exhibit normal NK cell behavior. This splenic CD49a-CD49b+NKp46+ NK cell population develops during the early chronic phase of infection and increases through the late chronic phase of infection. They are Ly49 and TRAIL negative and are enriched for expression of CD94/NKG2A and KLRG1. They do not produce IFNγ, are IL-10 negative, do not increase PDL1 expression, but do increase CD107a on their surface. They are also absent from brain. Based on the NK cell receptor phenotype we observed NKp46 and CD94-NKG2A cognate ligands were measured. Activating NKp46 (NCR1-ligand) ligand increased and NKG2A ligand Qa-1b expression was reduced. Blockade of NKp46 also rescued the chronically infected mice from death. Immunization with a single dose non-persistent 100% protectiveT. gondiivaccination did not induce this cell population in the spleen, suggesting persistent infection is essential for their development. We hypothesize chronicT. gondiiinfection induces an NKp46 dependent modified NK cell population that reduces functional CD8+ T cells to promote persistent parasite infection in the brain. NK cell targeted therapies could enhance immunity in people with chronic infections, chronic inflammation and cancer.

NK cells regulate CD4+ and CD8+ T cells in acute viral infection, vaccination, and the tumor microenvironment. NK cells also become exhausted in chronic activation settings. The mechanisms causing these ILC responses and their impact on adaptive immunity are unclear. CD8+ T cell exhaustion develops during chronic Toxoplasma gondii (T. gondii) infection resulting in parasite reactivation and death. How chronic T. gondii infection impacts the NK cell compartment is not known. We demonstrate that NK cells do not exhibit hallmarks of exhaustion. Their numbers are stable and they do not express high PD1 or LAG3. NK cell depletion with anti-NK1.1 is therapeutic and rescues chronic T. gondii infected mice from CD8+ T cell exhaustion dependent death, increases survival after lethal secondary challenge and alters cyst burdens in brain. Anti-NK1.1 treatment increased polyfunctional CD8+ T cell responses in spleen and brain and reduced CD8+ T cell apoptosis in spleen. Chronic T. gondii infection promotes the development of a modified NK cell compartment, which does not exhibit normal NK cell characteristics. NK cells are Ly49 and TRAIL negative and are enriched for expression of CD94/NKG2A and KLRG1. These NK cells are found in both spleen and brain. They do not produce IFNγ, are IL-10 negative, do not increase PDL1 expression, but do increase CD107a on their surface. Based on the NK cell receptor phenotype we observed NKp46 and CD94-NKG2A cognate ligands were measured. Activating NKp46 (NCR1-ligand) ligand increased and NKG2A ligand Qa-1b expression was reduced on CD8+ T cells. Blockade of NKp46 rescued the chronically infected mice from death and reduced the number of NKG2A+ cells. Immunization with a single dose non-persistent 100% protective T. gondii vaccination did not induce this cell population in the spleen, suggesting persistent infection is essential for their development. We hypothesize chronic T. gondii infection induces an NKp46 dependent modified NK cell population that reduces functional CD8+ T cells to promote persistent parasite infection in the brain. NK cell targeted therapies could enhance immunity in people with chronic infections, chronic inflammation and cancer.

De novo heterozygous missense variants in the γ-tubulin gene TUBG1 have been linked to human malformations of cortical development associated with intellectual disability and epilepsy. Here, we investigated through in-utero electroporation and in-vivo studies, how four of these variants affect cortical development. We show that TUBG1 mutants affect neuronal positioning, disrupting the locomotion of new-born neurons but without affecting progenitors’ proliferation. We further demonstrate that pathogenic TUBG1 variants are linked to reduced microtubule dynamics but without major structural nor functional centrosome defects in subject-derived fibroblasts. Additionally, we developed a knock-in Tubg1Y92C/+ mouse model and assessed consequences of the mutation. Although centrosomal positioning in bipolar neurons is correct, they fail to initiate locomotion. Furthermore, Tubg1Y92C/+ animals show neuroanatomical and behavioral defects and increased epileptic cortical activity. We show that Tubg1Y92C/+ mice partially mimic the human phenotype and therefore represent a relevant model for further investigations of the physiopathology of cortical malformations., New mutations and genes associated with malformations of cortical development keep being identified, yet there is little known about the underlying cellular mechanisms controlling these impairments. Here, authors generate and characterize a heterozygous TUBG1 knock-in mouse model bearing one of these known mutations and show that TUBG1 mutation leads to the miss-positioning of neurons in the cortical wall due to migration, because of defective microtubules dynamics, and not proliferation defects during corticogenesis.

In the era of rapid development and the emergence of new methods and ideas for the employees’ training in small and medium sized enterprises in Russia, managers need to think about the role that the methodological organization of the educational process, which refers, not only with respect to vocational training, but also in providing the methodological foundation for teaching certain disciplines in small and medium sized enterprises in Russia. The article describes the integrative-praxicological approach in the professional training of employees, it describes the principles and requirements as a methodological basis for the educational process.

Background:Evidence suggests rheumatoid arthritis (RA) confers an increased risk of psychological morbidity, particularly anxiety and depression, which may affect the subsequent management and treatment adherence.1,2Few studies have studied psychological factors over time in RA patients.3Objectives:To evaluate the prevalence of anxiety and depression in RA patients following rituximab treatment.Methods:92 biologics-naïve RA patients [mean (SD) age 49.5 (9.9) years, 78 women; median (IQR) DAS28 5.67 (3.94–8.45); median (IQR) HAQ 1.87 (1.2–3.5)] were followed up for 27 months after commencing and continuing rituximab therapy (1, 2, 3 standard courses). Anxiety and depression, and health-related quality of life (HRQoL) were assessed at baseline, 3, 15 and 27 months using the Hospital Anxiety and Depression Scale (HADS) and the Short Form (SF-36 v.1) Health Survey questionnaire, respectively.Results:Median anxiety and depression scores decreased significantly between baseline and 3 months and continued depress over the 27-month period – Table. The prevalence of depression cases decreased twice from baseline to 27 months (pAnxiety, depression, and quality of lifeBaseline3 months15 months27 months(n=92)(n=92)(n=53)(n=14)Anxiety cases (HADS-A score ≥8), n (%)72 (78.3)48 (52.2)24 (45.3)*5 (35.7)**Median (IQR) Anxiety score12.6 (10–15)8.2 (5–12)*6.4 (3–10)**5.5 (3–8)***Depression cases (HADS-D score ≥8), n (%)62 (67.4)50 (54.3)19 (35.8)*4 (28.6)**Median (IQR) Depression score9.2 (7.8–9.6)5.6 (3–8)**4.5 (2–7)**3.6 (2–6)***Mean (SD) Mental Health score42.8 (15.2)51.2 (18.3)68.7 (11.2)*72.9 (10.5)**Mean (SD) Physical Function score24.4 (8.3)32.5 (9.8)53.8 (10.5)*54.5 (9.3)*Mean (SD) Social Function score48.2 (15.4)56.8 (25.5)59.8 (18.7)65.9 (9.2)*Mean (SD) General Health score35.8 (11.2)48.7 (10.8)67.8 (8.6)**75.9 (12.6)*** pConclusion:Anxiety and depression levels decrease significantly in RA patients following commencement and continuity of rituximab. B cell-directed therapy for patients with RA helps achieve remission of both anxiety and depression, and improves HRQoL.References:[1]McWilliams LA, Goodvin RD, Cox BJ. Depression and anxiety associated with three pain conditions: results from a nationally representative sample.Pain2004;111:77–83.[2]Garcia-Cebrian A, Gandhi P, Demyttenaere K et al. The association of depression and painful physical symptoms: a review of the European literature.Eur Psychiatry2006;21:379–88.[3]Overman CL, Bossema ER, van Middendorp H et al. The prospective association between psychological distress and disease activity in rheumatoid arthritis: a multilevel regression analysis.Ann Rheum Dis2012;71:192–7.Disclosure of Interests:Ilshat Gaisin Speakers bureau: Boehringer Ingelheim, KRKA, Berlin-Chemie Menarini, Sanofi, Larisa Ivanova Speakers bureau: Bayer, Novartis, KRKA, Nikolay Maximov Speakers bureau: Pfizer, KRKA, Anastasia Vedekhina: None declared, Dilara Yurk: None declared, Nuriya Garaeva: None declared

Background:Similarities in risk factors, initial stages, progression and final stage of both atherosclerotic cardiovascular disease (ACVD) and chronic kidney disease (CKD) allowed formulating a concept of cardiorenal continuum.1ACVD and CKD remain the main causes of mortality in rheumatoid arthritis (RA) patients.2,3Objectives:To evaluate the effects of rituximab (RTM) therapy on cardiorenal continuum of RA patients.Methods:Biologics-naïve RA patients (n=92; age 49.5±9.9) were followed up for 72 months after commencing and continuing RTM therapy (1–10 standard courses) compared with 50 control RA patients (age 49.2±9.8). All control and 63% of RTM patients received methotrexate or leflunomide.Results:There were no baseline differences between two groups – Table. At year 6, RTM patients have fewer incidences of hypertension, anxiety/depression, atherosclerosis and diastolic dysfunction than controls. RTM decreased prevalence of albuminuria and CKD.Table.Cardiorenal continuum of rheumatoid arthritis patients (%)FeaturesRituximab groupControl grouppRTM–C1 year n=923 years n=476 years n=311 yearn=503 years n=266 years n=16Risk factorsHypertension52.238.325.8p6–1=0.02250.038.550.0p6=0.032Dyslipidaemia44.636.238.748.046.250.0>0.05Pre-diabetes41.336.241.944.034.656.3>0.05Metabolic syndrome12.06.43.210.07.712.5>0.05Diabetes mellitus3.2002.000>0.05Anxiety/depression78.341.5p3–1=0.00535.3p6–176.073.168.8p3=0.009p6=0.008Initial stages (asymptomatic organ damage)Atherosclerosis34.821.312.9p6–1=0.04536.034.637.5p6=0.02Left ventricular hypertrophy8.74.308.07.70>0.05Diastolic dysfunction57.638.322.6p6–1=0.01856.050.056.3p6=0.04Albuminuria19.600p6–1=0.03812.006.3>0.05Kidney impairment6.52.106.000>0.05ProgressionAngina6.5004.000>0.05Chronic kidney disease26.18.59.7p6–1=0.04212.000>0.05End stageMyocardial infarction000000>0.05Stroke000000>0.05Heart failure4.400000>0.05Acute/chronic renal failure000000>0.05Death000000>0.05There were no significant differences in frequencies of other risk factors, signs of organ damage and cases of established heart, cerebrovascular and renal diseases/complications.Conclusion:RTM may be effective in delay of the movement of RA patients on cardiorenal continuum. The clinical implications of RTM for cardiorenal correlations in RA patients need to be confirmed in large-scale clinical outcome trials.References:[1]Sarnak MJ, Levey AS. Cardiovascular disease and chronic renal disease: a new paradigm.Am J Kidney Dis2000;35(4, Suppl. 1):117–31.[2]Avina-Zubieta JA, Choi HK, Sadatsafarvi M,et al.Risk of cardiovascular mortality in patients with rheumatoid arthritis: a meta-analysis of observational studies.Arthritis Rheum2008;59:1690–7.[3]Gullick NJ, Scott DL. Co-morbidities in established rheumatoid arthritis.Best Pract Res Clin Rheumatol2011;25:469–83.Disclosure of Interests:Ilshat Gaisin Speakers bureau: Boehringer Ingelheim, KRKA, Berlin-Chemie Menarini, Sanofi, Larisa Ivanova Speakers bureau: Bayer, Novartis, KRKA, Nikolay Maximov Speakers bureau: Pfizer, KRKA, Rosa Valeeva: None declared, Dilara Yurk: None declared, Anastasia Vedekhina: None declared, Nuriya Garaeva: None declared, Irina Sabelnikova: None declared

NK cells can develop cell-intrinsic memory-like characteristics. Whether they develop these characteristics during Toxoplasma gondii infection is unknown. We addressed this question and dissected the mechanisms involved in secondary NK cell responses using a vaccine-challenge mouse model of T. gondii infection. NK cells were required for control of and survival after secondary T. gondii infection. NK cells increased in number at the reinfection site and produced IFN-γ. To test if these T. gondii experienced NK cells were intrinsically different from naive NK cells, we performed NK cell adoptive transfer into RAG2/cγ-chain−/− mice, NK cell fate mapping, and RAG1−/− mice vaccine-challenge experiments. Although NK cells contributed to immunity after reinfection, they did not develop cell-intrinsic memory-like characteristics after T. gondii vaccination. The mechanisms required for generating these secondary NK cell responses were investigated. Secondary NK cell responses were CD4+ or CD8+ T cell independent. Although IL-12 alone is required for NK cell IFN-γ production during primary T. gondii infection, in the absence of IL-12 using IL-12p35−/− mice or anti–IL-12p70, secondary NK cell responses were only partially reduced after reinfection. IL-23 depletion with anti–IL-23p19 in vivo also significantly reduced the secondary NK cell response. IL-12 and IL-23 blockade with anti–IL-12p40 treatment completely eliminated secondary NK cell responses. Importantly, blockade of IL-12, IL-23, or both significantly reduced control of parasite reinfection and increased parasite burden. Our results define a previously unknown protective role for NK cells during secondary T. gondii infection that is dependent on IL-12 and IL-23.

Apicomplexans are a diverse and complex group of protozoan pathogens including Toxoplasma gondii, Plasmodium spp., Cryptosporidium spp., Eimeria spp., and Babesia spp. They infect a wide variety of hosts and are a major health threat to humans and other animals. Innate immunity provides early control and also regulates the development of adaptive immune responses important for controlling these pathogens. Innate immune responses also contribute to immunopathology associated with these infections. Natural killer (NK) cells have been for a long time known to be potent first line effector cells in helping control protozoan infection. They provide control by producing IL-12 dependent IFNγ and killing infected cells and parasites via their cytotoxic response. Results from more recent studies indicate that NK cells could provide additional effector functions such as IL-10 and IL-17 and might have diverse roles in immunity to these pathogens. These early studies based their conclusions on the identification of NK cells to be CD3–, CD49b+, NK1.1+, and/or NKp46+ and the common accepted paradigm at that time that NK cells were one of the only lymphoid derived innate immune cells present. New discoveries have lead to major advances in understanding that NK cells are only one of several populations of innate immune cells of lymphoid origin. Common lymphoid progenitor derived innate immune cells are now known as innate lymphoid cells (ILC) and comprise three different groups, group 1, group 2, and group 3 ILC. They are a functionally heterogeneous and plastic cell population and are important effector cells in disease and tissue homeostasis. Very little is known about each of these different types of ILCs in parasitic infection. Therefore, we will review what is known about NK cells in innate immune responses during different protozoan infections. We will discuss what immune responses attributed to NK cells might be reconsidered as ILC1, 2, or 3 population responses. We will then discuss how different ILCs may impact immunopathology and adaptive immune responses to these parasites.

The importance of enriched asialylated sphingolipid GM1 (ASGM1) in CD8+ T cell dependent protective immunity against T. gondii infection is unknown. Using a vaccine challenge model of T. gondii infection, we observed treatment of animals with anti-ASGM1 resulted in 100% death and greater parasite burden at the site of infection. Upon further dissection of this phenotype, we found that anti-ASGM1 treatment depleted not only NK cells but also T cells in vaccinated mice. While both CD8+ and CD4+ T cells were affected, CD8+ T cells were more susceptible to the anti-ASGM1 treatment. ASGM1 on the surface of the T cells was expressed on a higher percentage of CD8+ T cells than CD4+ T cells. ASGM1 was highly enriched on the surface of memory CD8+ T cells (Tem and Tcm). However, Tem were more susceptible to anti-ASGM1 treatment. Anti-ASGM1 treatment during rechallenge resulted in greater depletion of activated CD8+ IFNγ+, Granzyme B+, Tem and Tef than Tcm cells. In addition, anti-ASGM1 depleted IFNγ+ CD4+ T cells. Recombinant IFNγ supplementation prolonged the survival of anti-ASGM1 treated mice, demonstrating that this antibody eliminated the protective T. gondii specific IFNγ-producing T cells important for control of the parasite. This study demonstrates that ASGM1 is enriched on effector T cells during T. gondii infection and the potential importance of changes in sialylation in lipid rafts for T cell activation during T. gondii infection.

ZMIZ1 is a coactivator of several transcription factors, including p53, the androgen receptor, and NOTCH1. Here, we report 19 subjects with intellectual disability and developmental delay carrying variants in ZMIZ1. The associated features include growth failure, feeding difficulties, microcephaly, facial dysmorphism, and various other congenital malformations. Of these 19, 14 unrelated subjects carried de novo heterozygous single-nucleotide variants (SNVs) or single-base insertions/deletions, 3 siblings harbored a heterozygous single-base insertion, and 2 subjects had a balanced translocation disrupting ZMIZ1 or involving a regulatory region of ZMIZ1. In total, we identified 13 point mutations that affect key protein regions, including a SUMO acceptor site, a central disordered alanine-rich motif, a proline-rich domain, and a transactivation domain. All identified variants were absent from all available exome and genome databases. In vitro, ZMIZ1 showed impaired coactivation of the androgen receptor. In vivo, overexpression of ZMIZ1 mutant alleles in developing mouse brains using in utero electroporation resulted in abnormal pyramidal neuron morphology, polarization, and positioning, underscoring the importance of ZMIZ1 in neural development and supporting mutations in ZMIZ1 as the cause of a rare neurodevelopmental syndrome.

The variety of mineral resources, complex multicomponent composition of many of them, various technological methods for comprehensive processing at different production stages, as well as the instability of competitive market environment, cause the multivariate functioning and development of the system of mineral resources use. The main scientific problems of evaluating the economic feasibility of extracting valuable components in the combined processing of multicomponent ores and the responsibility of subsoil users for the full use of Arctic resources are considered. The special relevance of rational use of mineral resources taking into account specific Arctic conditions, including increased production costs, is noted. Scientifically based principles, tasks and methodological approaches to determining the economic efficiency of integrated multi-productive use of mineral resources are proposed. For successful large-scale realization of the benefits of integrated development and use of mineral resources, the need for further scientific research, as well as the formation of a special State program to solve the problem of integrated use of the Arctic subsoil, is shown.

At present, the university graduates have to acquire not only profound knowledge but unique skills and competencies to be successful in the labour market. One of the main competencies of modern engineers is their proficiency to reason, to debate or to argue reasonably. The Russian tertiary education standards consider argumentation skills as a key competence for university graduates. These skills are critical for making decisions and students can develop their argumentation skills in their English classes at a technical university. The paper reviews and analyzes the issues of teaching reasoning in the ESP course. The authors share their ideas on the ESP design course applying IT tools and indicate the ways to pursue further research. To improve communicative competence in the specialist area, the authors suggest shaping the skills of argumentation through the ESP course acquisition. Teaching strategies, regarding stages of skills development, are identified. Theoretical background and literature review give grounds for designing effective assignments to promote fruitful communication and make our graduates more competitive in the workforce.

Natural Killer (NK) cells can develop cell intrinsic memory-like characteristics. Whether they develop these characteristics during Toxoplasma gondii (T. gondii) infection is unknown. We addressed this question and dissected the mechanisms involved in secondary NK cell responses using a vaccine-challenge mouse model of T. gondii infection. NK cells were required for control of and survival after secondary T. gondii infection. NK cells increased in number at the reinfection site and produced IFNγ. To test if these T. gondii experienced NK cells were intrinsically different from naïve NK cells we performed NK cell adoptive transfer into RAG2/cγ-chain−/− mice, NK-cell fate mapping and RAG1−/− mice vaccine-challenge experiments. Although NK cells contributed to immunity after reinfection, they did not develop cell intrinsic memory-like characteristics after T. gondii vaccination. The mechanisms required for generating these secondary NK cell responses were investigated. Secondary NK cell responses were CD4+ or CD8+ T cell independent. Although IL-12 alone is required for NK cell IFNγ production during primary T. gondii infection, in the absence of IL-12 using IL-12p35−/− mice or anti-IL-12p70 secondary NK cell responses were only partially reduced after reinfection. IL-23 depletion with anti-IL-23p19 in vivo also significantly reduced the secondary NK-cell response. IL-12 and IL-23 blockade with anti-IL-12p40 treatment, completely eliminated secondary NK-cell responses. Importantly, blockade of IL-12, IL-23 or both significantly reduced control of parasite reinfection and increased parasite burden. Our results define a previously unknown protective role for NK cells during secondary T. gondii infection that is dependent on IL-12 and IL-23.

We studied the sensitivity of domestic proprietary human and animal cell lines from the collection of M. P. Chumakov Federal Scientific Center for Research and Development of Immuneand-Biological Products to infection with different enterovirus 71 strains. A cell system based on domestic proprietary permanent cell line 4647 was for the first time used for reproduction of four enterovirus 71 strains (BrCr, 42266, 42934, and 43374). It was shown that strain 4647 is the optimal cell substrate for enterovirus 71 reproduction. The titers of enterovirus 71 for all four strains considerably (by 2 lgTCID50/ml and more) increased during sequential passages in permanent cell line 4647. The prospects of using permanent cell line 4647 for creation of diagnostic and preventive preparations against 71 was demonstrated.

The working time of a single mine surveyor or the working time of a whole “Mine Surveying Ergatic System” (MSES) depends on various factors. These factors are: different qualities of a surveyor as a professional and a person, his emotion and attention, accuracy and comfort of mine surveying instruments, and the mine working environment. These factors make it possible to conclude the MSES working time to be a stochastic quality. In our research, a unimodal alpha-distribution was used. We have studied the working time of 1 type of MSES: “measurements of horizontal angle”. More than 80 mine surveyors and students have taken part in the experiments. The alpha-graphic line shows an accurate interpretation of different points, so it may be used in testing mine surveyors’ professional skills.

International audience; Genetic findings reported by our group and others showed that de novo missense variants in the KIF2A gene underlie malformations of brain development called pachygyria and microcephaly. Though KIF2A is known as member of the Kinesin-13 family involved in the regulation of microtubule end dynamics through its ATP dependent MT-depolymerase activity, how KIF2A variants lead to brain malformations is still largely unknown. Using cellular and in utero electroporation approaches, we show here that KIF2A disease-causing variants disrupts projection neuron positioning and interneuron migration, as well as progenitors proliferation. Interestingly, further dissection of this latter process revealed that ciliogenesis regulation is also altered during progenitors cell cycle. Altogether, our data suggest that deregulation of the coupling between ciliogenesis and cell cycle might contribute to the pathogenesis of KIF2A-related brain malformations. They also raise the issue whether ciliogenesis defects are a hallmark of other brain malformations, such as those related to tubulins and MT-motor proteins variants.

Background Similarities in risk factors, initial stages, progression and final stage of both atherosclerotic cardiovascular disease (CVD) and chronic kidney disease (CKD) allowed formulating a concept of cardiorenal continuum. 1 CVD and CKD remain the main causes of mortality in rheumatoid arthritis (RA) patients. 2,3 Objectives We aimed to evaluate the effects of rituximab biologic therapy on cardiorenal continuum of RA patients. Methods Biologics-naive RA patients (n=50; age 55.1±10.3) were followed up for 72 months after commencing and continuing rituximab therapy (1–10 standard courses) compared with 30 control RA patients (age 53.2±9.8). Results At year 6, rituximab patients have fewer incidences of hypertension, anxiety/depression, atherosclerosis and diastolic dysfunction than control patients (Table). There were no significant differences in frequencies of other risk factors, signs of asymptomatic multiorgan damage and cases of established heart, cerebrovascular and renal diseases/complications. Conclusions Rituximab may be effective in delay of the movement of RA patients on cardiorenal continuum. The clinical implications of rituximab for cardiorenal correlations in RA patients need to be confirmed in large-scale clinical outcome trials. References Sarnak MJ, Levey AS. Cardiovascular disease and chronic renal disease: a new paradigm. Am J Kidney Dis 2000;35(4, Suppl. 1):117–31. Avina-Zubieta JA, Choi HK, Sadatsafarvi M, et al. Risk of cardiovascular mortality in patients with rheumatoid arthritis: a meta-analysis of observational studies. Arthritis Rheum 2008;59:1690–7. Gullick NJ, Scott DL. Co-morbidities in established rheumatoid arthritis. Best Pract Res Clin Rheumatol 2011;25:469–83. Disclosure of Interest None declared

Neurodevelopmental disorders with periventricular nodular heterotopia (PNH) are etiologically heterogeneous, and their genetic causes remain in many cases unknown. Here we show that missense mutations in the HECT domain of the E3 ubiquitin ligase NEDD4L lead to PNH associated with toes syndactyly, cleft palate and neurodevelopmental delay. Cellular and expression data showed a sensitivity of PNH-associated mutants to proteasome degradation. Moreover, in utero electroporation approach showed that PNH-related mutants and excess of wild type (WT) NEDD4L affect neurogenesis, neuronal positioning and terminal translocation. Further investigations, including rapamycin based experiments, revealed differential deregulation of pathways involved. Excess of WT NEDD4L leads to a disruption of Dab1 and mTORC1 pathways, while PNH-related mutations are associated with a deregulation of mTORC1 and AKT activities. Altogether, these data provide insights to better understand the critical role of NEDD4L in the regulation of mTOR pathways and their contributions in cortical development.

Summary The pharmacokinetics of zinc was investigated in broiler chickens after single crop intubation of 50 mg/kg 5% zinc aspartate suspension in 2% carboxymethyl cellulose solution. Blood serum zinc concentrations were assayed on a biochemical analyzer. The pharmacokinetics of zinc was evaluated using two approaches – compartmental method and non-compartmental analysis using pharmacokinetic software (TopFit, v. 2.0). After the intraingluvial application, zinc was rapidly absorbed (t1/2abs. =0.1040.02 h) by the alimentary system of birds attaining Cmax of 63.603.94 mol/ml by hour 0.77 (compartmental method) and Cmax =69.274.35 mol/ml by hour 0.92 h (non-compartmental method). It is characterized with a long biological half-life (t1/2) of 13.821.63 h (compartmental analysis) and 15.961.73 h (non-compartmental analysis) and long mean residence times (MRT) 20.122.35 h and 23.002.50 h, respectively. The distribution in blood and extracellular fluid was good as seen from Vd(area) values 0.770.05 l/kg (compartmental analysis) and 0.650.05 l/kg (non-compartmental analysis).