Репозиторий Университета

© 2018 Elsevier B.V. Background: To examine efficacy of Subetta as an add-on to insulin therapy in patients with type 1 diabetes mellitus (T1DM) a multicenter, double-blind, placebo-controlled, randomized clinical trial was performed. Derived by technological treatment of antibodies to insulin receptor β-subunit and endothelial NO synthase Subetta was previously proved to activate insulin signaling pathway. Methods: A total of 144 randomized patients with poor glycemic control in basal-bolus insulin regime were included in intention-to-treat analysis in Subetta add-on therapy or placebo (n = 72 in both groups). Hemoglobin A1c (HbA1c), fasting plasma glucose (FPG), basal and prandial insulin doses, number of hypoglycemia episodes confirmed by self-monitoring of blood glucose were recorded for 36 weeks. Results: The baseline characteristics of subjects did not differ between the two groups. HbA1c mean (±standard deviation) change was −0.59 ± 0.99% (95% CI −0.84 to −0.37) after 36 weeks in Subetta (vs. −0.20 ± 1.14%; 95% CI −0.44 to 0.11 in placebo; p = 0.028). The rate of overall hypoglycemia events was 7.9 per patient year (95% CI 7.1–8.6) in Subetta group and 7.6 (95% CI 6.9–8.4) in Placebo group (p = 0.63). The basal and total insulin doses did not change at the end of 36 weeks in both groups. Conclusions: Subetta add-on therapy boosting insulin activity and improving glycemic control in patients with T1DM is proved to be beneficial. Clinical trial registration: ClinicalTrials.gov identifier: NCT01868594.

© 2018, Springer Science+Business Media, LLC, part of Springer Nature. The original version of this article unfortunately contained mistake in its Funding inforation. That is, the Grant Number has an error currently read as “This work was supported by the Fondo de Ciencia y Tecnología (FONDECYT) de Chile, Grant #1150149”.

© 2017, Springer Science+Business Media, LLC, part of Springer Nature. The primary objective of the present study was to assess the level of selenium and toxic trace elements in wheat, rice, maize, and mustard from seleniferous areas of Punjab, India. The content of selenium (Se) and toxic trace elements, including aluminum (Al), arsenic (As), cadmium (Cd), mercury (Hg), nickel (Ni), lead (Pb), and tin (Sn), in crop samples was assessed using inductively coupled plasma mass-spectrometry after microwave digestion of the samples. The obtained data demonstrate that cultivation of crops on seleniferous soils significantly increased Se level in wheat, mustard, rice, and maize by a factor of more than 590, 111, 85, and 64, respectively. The study also showed that Se exposure affected toxic metal content in crops. In particular, Se-rich wheat was characterized by a significant decrease in Al, As, Ni, Pb, and Sn levels. The level of As, Cd, Ni, Pb, and Sn was significantly decreased in Se-rich rice, whereas As content was increased. In turn, the decrease in Al, As, Cd, Ni, Pb, and Sn levels in Se-rich maize was associated with a significant elevation of Hg content. Finally, Se-rich mustard was characterized by a significant increase in Al, As, and Hg levels, while the content of Ni, Pb, and Sn was significantly lower than the control levels. These findings should be taken into account while developing the nutritional strategies for correction of Se status. At the same time, the exact mechanisms underlying the observed differences are to be estimated.

© 2017, Springer Science+Business Media, LLC, part of Springer Nature. The objective of the current study is to perform a comparative analysis of hair trace element content in 393 apparently healthy adults living in Taipei, Taiwan, Republic of China (94 women and 46 men) and Yuzhno-Sakhalinsk, Sakhalin, Russia (186 women and 67 men). The obtained data indicate that Yuzhno-Sakhalinsk inhabitants were characterized by significantly higher hair Co, Cr, Mn, and V levels, exceeding the respective Taipei values by a factor of 3, 2, 7, and 5, respectively (all p < 0.001). Hair Cu, Fe, and Si levels were also higher in examinees from Yuzhno-Sakhalinsk than those from Taipei by 10% (p = 0.001), 61% (p < 0.001), and 68% (p < 0.001), respectively. It is notable that the only essential element, being significantly higher (+ 30%; p < 0.001) in Taipei inhabitants, is selenium. Yuzhno-Sakhalinsk inhabitants were characterized by 60% higher levels of hair Sn, and nearly two- and threefold higher scalp hair content of Be and Cd in comparison to Taipei values, respectively (all p < 0.001). Oppositely, the examinees from Taipei had 14% (p = 0.040) and 47% (p = 0.001) higher levels of hair As and Hg as compared to Yuzhno-Sakhalinsk inhabitants. Further analysis demonstrated that men from both Yuzhno-Sakhalinsk and Taipei were characterized by significantly higher hair Mn, As, and Pb levels in comparison to women. The intensive development of heavy industry in Yuzhno-Sakhalinsk may result in increased metal emissions, whereas fish consumption may result in elevation of hair Hg, As, and Se levels in Taiwan inhabitants.

© Kolosova et al. P62/SQSTM1, a multi-domain protein that regulates inflammation, apoptosis, and autophagy, has been linked to age-related pathologies. For example, previously we demonstrated that administration of p62/SQSTM1- encoding plasmid reduced chronic inflammation and alleviated osteoporosis and metabolic syndrome in animal models. Herein, we built upon these findings to investigate effect of the p62-encoding plasmid on an agerelated macular degeneration (AMD), a progressive neurodegenerative ocular disease, using spontaneous retinopathy in senescence-accelerated OXYS rats, as a model. Overall, the p62DNA decreased the incidence and severity of retinopathy. In retinal pigment epithelium (RPE), p62DNA administration slowed down development of the destructive alterations of RPE cells, including loss of regular hexagonal shape, hypertrophy, and multinucleation. In neuroretina, p62DNA prevented gliosis, retinal thinning, and significantly inhibited microglia/macrophages migration to the outer retina, prohibiting their subretinal accumulation. Taken together, our results suggest that the p62DNA has a strong retinoprotective effect in AMD.

© 2018 American Society for Clinical Investigation. All rights reserved. High-risk neuroblastoma is a devastating malignancy with very limited therapeutic options. Here, we identify withaferin A (WA) as a natural ferroptosis-inducing agent in neuroblastoma, which acts through a novel double-edged mechanism. WA dose-dependently either activates the nuclear factor-like 2 pathway through targeting of Kelch-like ECH-associated protein 1 (noncanonical ferroptosis induction) or inactivates glutathione peroxidase 4 (canonical ferroptosis induction). Noncanonical ferroptosis induction is characterized by an increase in intracellular labile Fe(II) upon excessive activation of heme oxygenase-1, which is sufficient to induce ferroptosis. This double-edged mechanism might explain the superior efficacy of WA as compared with etoposide or cisplatin in killing a heterogeneous panel of high-risk neuroblastoma cells, and in suppressing the growth and relapse rate of neuroblastoma xenografts. Nano-targeting of WA allows systemic application and suppressed tumor growth due to an enhanced accumulation at the tumor site. Collectively, our data propose a novel therapeutic strategy to efficiently kill cancer cells by ferroptosis.

Copyright © 2018. All rights reserved. Objective: Evaluate growth in patients with polyarticular-course juvenile idiopathic arthritis (pcJIA) treated with tocilizumab (TCZ) for up to 2 years in a phase III trial. Methods: Patients with pcJIA lasting at least 6 months and inadequate response to methotrexate received open-label TCZ intravenously every 4 weeks (randomly assigned to 8 or 10 mg/kg if they weighed < 30 kg; received 8 mg/kg if they weighed ≥ 30 kg) for 16 weeks. Patients with JIA American College of Rheumatology 30 response at Week 16 were randomly assigned to TCZ or placebo for 24 weeks, with an open-label extension through Week 104. Mean ± SD height velocity (cm/yr) and World Health Organization (WHO) height SD score (SDS) were measured in patients receiving ≥ 1 dose of TCZ who did not receive growth hormone and in patients whose baseline Tanner stage was ≤ 3. Results: The study included 187 of 188 patients (99.5%) with mean WHO height SDS -0.5 ± 1.2, which was unrelated to age or disease duration (Spearman rank correlations r = 0.08 and r = -0.12, respectively). There were 123 patients at Tanner stage ≤ 3 at baseline, among whom 103 completed the study with 2 years of height SDS data. Mean height SDS increased from baseline to year 2 (+0.40, p < 0.0001). In 74 of 103 patients (72%), height SDS was greater than at baseline, and mean height velocity was 6.7 ± 2.0 cm/year. Conclusion. Among patients with pcJIA at Tanner stage ≤ 3 at baseline, 72% (74/103) had increased height SDS at the end of the study.

© 2018 WILEY-VCH Verlag GmbH  &  Co. KGaA, Weinheim Nature has long inspired scientists and engineers. As one ubiquitous example of this, nature has provided all with several clever methods to absorb, repel, and/or allow both sunlight and water to pass through surfaces. Moth's eyes (highly antireflective) and lotus leaves (highly hydrophobic and self-cleaning) represent durable natural surfaces which exhibit nearly ideal physical and optical properties. Man-made transparent surfaces must also be able to cope with water and dust while reaching the maximum possible light transmission for solar collectors, displays, and other optical devices. To explore the link between these – particularly for transparent surfaces – this review puts the physics, progress, and limitations of synthetic materials in context with natural materials. This perspective reveals that there is still much more to learn (and implement) if it is hoped to match the multifunctionality and resilience of natural materials.

© 2018, © 2018 Informa UK Limited, trading as Taylor  &  Francis Group. Paip2 (Poly(A)-binding protein–interacting protein 2) is a conserved metazoan-specific protein that has been implicated in regulating the translation and stability of mRNAs. However, we have found that Paip2 is not restricted to the cytoplasm but is also found in the nucleus in Drosophila embryos, salivary glands, testes, and tissue culture cells. Nuclear Paip2 is associated with chromatin, and in chromatin immunoprecipitation experiments it maps to the promoter regions of active genes. However, this chromatin association is indirect, as it is RNA-dependent. Thus, Paip2 is one more item in the growing list of translation factors that are recruited to mRNAs co-transcriptionally.

© The Author(s) 2018. Published by Oxford University Press on behalf of the Society for Experimental Biology. Potato is the most economically important non-cereal food crop. Tuber formation in potato is regulated by phytohormones, cytokinins (CKs) in particular. The present work studied CK signal perception in potato. The sequenced potato genome of doubled monoploid Phureja was used for bioinformatic analysis and as a tool for identification of putative CK receptors from autotetraploid potato cv. Désirée. All basic elements of multistep phosphorelay required for CK signal transduction were identified in the Phureja genome, including three genes orthologous to three CK receptor genes (AHK 2-4) of Arabidopsis. As distinct from Phureja, autotetraploid potato contains at least two allelic isoforms of each receptor type. Putative receptor genes from Désirée plants were cloned, sequenced and expressed, and the main characteristics of encoded proteins were determined, in particular their consensus motifs, modelled structure, ligand-binding properties, and ability to transmit CK signals. In all studied aspects the predicted sensor histidine kinases met the requirements for genuine CK receptors. Expression of potato CK receptors was found to be organ-specific and sensitive to growth conditions, particularly to sucrose content. Our results provide a solid basis for further in-depth study of CK signaling system and biotechnological improvement of potato.

© 2018 IOP Publishing Ltd. Maintaining the epithelial status of cells in vitro and fabrication of a multilayered epithelial lining is one of the key problems in the therapy using cell technologies. When cultured in a monolayer, epithelial cells change their phenotype from epithelial to epithelial-mesenchymal or mesenchymal that makes it difficult to obtain a sufficient number of cells in a 2D culture and to use them in tissue engineering. Here, using buccal epithelial cells from the oral mucosa, we developed a novel approach to recover and maintain the stable cell phenotype and form a multilayered epithelial lining in vitro via the 2D/3D cell self-assembling. Transitioning the cells from the monolayer to non-adhesive 3D culture conditions led to formation of self-assembling spheroids, with restoration of their epithelial characteristics after epithelial-mesenchymal transition. In 7 days, the cells within spheroids restored the apical-basal polarity, and the formation of both tight (ZO1) and adherent (E-cadherin) intercellular junctions was shown. Thus, culturing buccal epithelial cells in a 3D system allowed us to recover and durably maintain the morphological and functional characteristics of epithelial cells. The multilayered epithelial lining formation was achieved after placing spheroids for 7 days onto a hybrid matrix, which consisted of collagen layers and reinforcing poly (lactide-co-glycolide) fibers and was proven promising for replacement of the urothelium. Thus, we offer an effective technique of forming multilayered epithelial linings on carrier-matrices using cell spheroids that was not previously described elsewhere and can find a wide range of applications in tissue engineering, replacement surgery, and regenerative medicine.

© 2018 Chernokhaeva, Rogova, Kozlovskaya, Romanova, Osolodkin, Vorovitch and Karganova. Tick-borne encephalitis (TBE), caused by the TBE virus (TBEV), is a serious public health threat in northern Eurasia. Three subtypes of TBEV are distinguished. Inactivated vaccines are available for TBE prophylaxis, and their efficacy to prevent the disease has been demonstrated by years of implication. Nevertheless, rare TBE cases among the vaccinated have been registered. The present study aimed to evaluate the protective efficacy of 4 TBEV vaccines against naturally circulating TBEV variants. For the first time, the protection was evaluated against an extended number of phylogenetically distinct TBEV strains isolated in different years in different territories. The protective effect did not strongly depend on the infectious dose of the challenge virus or the scheme of vaccination. All vaccines induced neutralizing antibodies in protective titers against the TBEV strains used, although the vaccines varied in the spectra of induced antibodies and protective efficacy. The protective efficacy of the vaccines depended on the individual properties of the vaccine strain and the challenge virus, rather than on the subtypes. The neutralization efficiency appeared to be dependent not only on the presence of antibodies to particular epitopes and the amino acid composition of the virion surface but also on the intrinsic properties of the challenge virus E protein structure.

© 2018 Wiley Periodicals, Inc. A new approach to making a photopolymeric composition was first elaborated in this work based on the use of poly-N,N′-(m-phenylene)isophtalamide as the heterochain polymer matrix together with 4,4′-diphenyl oxide diacrylamide as the crosslinking agent. Reproducible three-dimensional (3D) objects have been formed using a laser stereolithograph completed with a laser with wavelength of 405 nm. According to the thermogravimetric analysis, the thermal stability of the formed objects could be changed through a control from 260 to 405 °C. Moreover, it was proven that the tensile strength of samples of the crosslinked films reached 90.1 ± 3.2 MPa at the elongation at break of 12.4 ± 2.3%, depending on the forming parameters of such samples. © 2018 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2018, 135, 46463.

© 2018 Elsevier Masson SAS A series of analogues of potent antiviral perylene nucleoside dUY11 with methylthiomethyl (MTM), azidomethyl (AZM) and HO-C1–4-alkyl-1,2,3-triazol-1,4-diyl groups at 3′-O-position as well as the two products of copper-free alkyne-azide cycloaddition of the AZM derivative were prepared and evaluated against tick-borne encephalitis virus (TBEV). Four compounds (4, 6, 8a, 8b) showed EC50 ≤ 10 nM, thus appearing the most potent TBEV inhibitors to date. Moreover, these nucleosides have higher lipophilicity (clogP) and increased solubility in aq. DMSO vs. parent compound dUY11.

© The Author(s) 2018. Published by Oxford University Press for the Infectious Diseases Society of America. Background We report the association of the FAST strategy (find cases actively, separate safely, and treat effectively) with reduction of hospital-based acquisition of multidrug-resistant tuberculosis in the Russian Federation. Methods We used preintervention and postintervention cohorts in 2 Russian hospitals to determine whether the FAST strategy was associated with a reduced odds of converting MDR tuberculosis within 12 months among patients with tuberculosis susceptible to isoniazid and rifampin at baseline. Results Sixty-three of 709 patients (8.9%) with isoniazid and rifampin-susceptible tuberculosis acquired MDR tuberculosis; 55 (12.2%) were in the early cohort, and 8 (3.1%) were in the FAST cohort. The FAST strategy was associated with a reduced odds (adjusted odds ratio, 0.16; 95% confidence interval,.07-.39) and 9.2% absolute reduction in the risk of MDR tuberculosis acquisition. Conclusion Use of the FAST strategy in 2 Russian hospitals was associated with significantly less MDR tuberculosis 12 months after implementation.

© 2018 Elsevier Ltd A nickel oxyhydroxide [NiO(OH)] anode was exploited to develop a new synthetic route for the electrocatalytic N-N homocoupling of N-alkylaminopyrazoles in an alkaline aqueous medium. The advantages of this green electrochemical methodology include low cost, atom economy and high yields.

© 2018 Published by AIP Publishing. The spread of Cooper pairs in a ferromagnet in proximity coupled superconductor-ferromagnet structures is shown to cause a strong inverse electromagnetic phenomenon, namely, the long-range transfer of the magnetic field from the ferromagnet to the superconductor. Contrary to the previously investigated inverse proximity effect resulting from the spin polarization of a superconducting surface layer, the characteristic length of the above inverse electrodynamic effect is of the order of the London penetration depth, which usually is much larger than the superconducting coherence length. The corresponding spontaneous currents appear even in the absence of the stray field of the ferromagnet and are generated by the vector-potential of magnetization near the S/F interface, and they should be taken into account in the design of nanoscale S/F devices. Similarly to the well-known Aharonov-Bohm effect, the discussed phenomenon can be viewed as a manifestation of the role of vector potential in quantum physics.

© 2018 The American Society of Gene and Cell Therapy Treatment of myocardial infarction (MI) with bone marrow cells (BMCs) improves post-MI cardiac function in rodents. However, clinical trials of BMC therapy have been less effective. While most rodent experiments use young healthy donors, patients undergoing autologous cell therapy are older and post-MI. We previously demonstrated that BMCs from aged and post-MI donor mice are therapeutically impaired, and that donor MI induces inflammatory changes in BMC composition including reduced levels of B lymphocytes. Here, we hypothesized that B cell alterations in bone marrow account for the reduced therapeutic potential of post-MI and aged donor BMCs. Injection of BMCs from increasingly aged donor mice resulted in progressively poorer cardiac function and larger infarct size. Flow cytometry revealed fewer B cells in aged donor bone marrow. Therapeutic efficacy of young healthy donor BMCs was reduced by depletion of B cells. Implantation of intact or lysed B cells improved cardiac function, whereas intact or lysed T cells provided only minor benefit. We conclude that B cells play an important paracrine role in effective BMC therapy for MI. Reduction of bone marrow B cells because of age or MI may partially explain why clinical autologous cell therapy has not matched the success of rodent experiments. Implantation of bone marrow cells into mouse hearts after myocardial infarction is therapeutic, but if the cells are from donors that are older or post-MI (mimicking autologous cell therapy), they are less effective. This report presents evidence that a decrease in B lymphocytes is responsible for the reduced therapeutic response.

© 2017 Informa UK Limited, trading as Taylor  &  Francis Group. Sub-constructs of morning–evening preference might be differentially related to polymorphisms in circadian clock genes. We previously reported significant association between a single nucleotide polymorphism in PER3 (rs2640909) and Morning but not Evening Lateness scale of the Sleep–Wake Pattern Assessment Questionnaire. To further explore such a scale-specific relationship, seven single nucleotide polymorphisms in five circadian clock genes were studied using exploratory and confirmatory samples (in total, n = 698). The association of rs2640909 with Morning Lateness scale was not replicated in the confirmatory sample but remained significant in the merged sample. Moreover, we found and confirmed an association of this scale with rs1159814 in RORα. The results provided further evidence for differential relationship of polymorphisms in circadian clock genes with morning and evening components of morning–evening preference. We also suggested possibility to take into account the pattern of geographic variation in allele frequency for prioritization of circadian clock polymorphisms in candidate gene studies.

© 2018 The Author(s). Background: The approaches to the diagnosis and treatment of chronic spontaneous urticaria (CSU) differ in various parts of the world. We sought to determine the adherence to international and national urticaria guidelines as well as the motives to deviate from the guidelines among physicians worldwide. Methods: A web-based questionnaire was created and launched via e-mail by the World Allergy Organization (WAO) to representatives of all WAO Member Societies, the members of the American Academy of Allergy, Asthma & Immunology (AAAAI) and the members of the WAO Junior Members Group (JMG), regardless of the specialty, affiliation, or nationality in March 2017. Results: We received 1140 completed surveys from participating physicians from 99 countries. Virtually all participants (96%) were aware of at least one urticaria guideline and reported that they follow a guideline. However, one in five physicians who follow a guideline (22%) reported to deviate from it. Reliance on own clinical experience is the most frequent reason for deviation from guidelines or not following them (44%). Young (< 40 years) and less experienced physicians more often follow a guideline and less often deviate than older and experienced ones. Physicians who follow a urticaria guideline showed higher rates of routinely ordering a complete blood count, the erythrocyte sedimentation rate, C-reactive protein, anti-thyroid antibodies, and thyroid-stimulating hormone and of performing the autologous serum skin test as compared to those who do not. Physicians who follow a urticaria guideline showed higher rates of using second generation antihistamines as their first-line treatment of CSU (p = 0.001) and more frequently observed higher efficacy of these drugs (or had more confidence that it would work, p < 0.019) as compared to those who do not follow the guidelines. Conclusions: Physicians' characteristics (e.g. age, clinical experience, and specialty) and country specifics and regional features (e.g. availability of drugs for CSU treatment) importantly influence adherence to urticaria guidelines and CSU patient care and should be addressed in more detail in future research.