A model of the ternary complex of interleukin-10 with its soluble receptors

BACKGROUND: Interleukin-10 (IL-10) is a cytokine whose main biological function is to suppress the immune response by induction of a signal(s) leading to inhibition of synthesis of a number of cytokines and their cellular receptors. Signal transduction is initiated upon formation of a ternary complex of IL-10 with two of its receptor chains, IL-10R1 and IL-10R2, expressed on the cell membrane. The affinity of IL-10R1 toward IL-10 is very high, which allowed determination of the crystal structure of IL-10 complexed with the extracellular/soluble domain of IL-10R1, while the affinity of IL-10R2 toward either IL-10 or IL-10/sIL-10R1 complex is quite low. This so far has prevented any attempts to obtain structural information about the ternary complex of IL-10 with its receptor chains. RESULTS: Structures of the second soluble receptor chain of interleukin-10 (sIL-10R2) and the ternary complex of IL-10/sIL-10R1/sIL-10R2 have been generated by homology modeling, which allowed us to identify residues involved in ligand-receptor and receptor-receptor interactions. CONCLUSION: The previously experimentally determined structure of the intermediate/binary complex IL-10/sIL-10R1 is the same in the ternary complex. There are two binding sites for the second receptor chain on the surface of the IL-10/sIL-10R1 complex, involving both IL-10 and sIL-10R1. Most of the interactions are hydrophilic in nature, although each interface includes two internal hydrophobic clusters. The distance between C-termini of the receptor chains is 25 Å, which is common for known structures of ternary complexes of other cytokines. The structure is likely to represent the biologically active signaling complex of IL-10 with its receptor on the surface of the cell membrane

Investigation of longitudinal reinforcement contribution in shear punching of reinforced concrete flat slabs without transverse reinforcement

The shear punching of the reinforced concrete slabs is a complex process occurring when considerable force is concentrated on the relatively small area of a column-slab connection. An incorrect assessment of load capacity of slab under the punching shear may lead to an accident. One of the most significant factors affecting the slab capacity is longitudinal reinforcement. In this article much attention is given to the analysis of the longitudinal rebar impact on the maximum loading capacity of reinforced concrete slabs without transverse reinforcement affected by punching shear force using the finite element method. The results obtained via the finite element simulation are compared with laboratory tests and manual calculations carried-out using various methods represented in different national building Codes of practice

The neurovirulence and neuroinvasiveness of chimeric tick-borne encephalitis/dengue virus can be attenuated by introducing defined mutations into the envelope and NS5 protein genes and the 3′ non-coding region of the genome

AbstractTick-borne encephalitis (TBE) is a severe disease affecting thousands of people throughout Eurasia. Despite the use of formalin-inactivated vaccines in endemic areas, an increasing incidence of TBE emphasizes the need for an alternative vaccine that will induce a more durable immunity against TBE virus (TBEV). The chimeric attenuated virus vaccine candidate containing the structural protein genes of TBEV on a dengue virus genetic background (TBEV/DEN4) retains a high level of neurovirulence in both mice and monkeys. Therefore, attenuating mutations were introduced into the envelope (E315) and NS5 (NS5654,655) proteins, and into the 3′ non-coding region (Δ30) of TBEV/DEN4. The variant that contained all three mutations (vΔ30/E315/NS5654,655) was significantly attenuated for neuroinvasiveness and neurovirulence and displayed a reduced level of replication and virus-induced histopathology in the brains of mice. The high level of safety in the central nervous system indicates that vΔ30/E315/NS5654,655 should be further evaluated as a TBEV vaccine

Chemokine receptor CCR5 promotes leukocyte trafficking to the brain and survival in West Nile virus infection

The molecular immunopathogenesis of West Nile virus (WNV) infection is poorly understood. Here, we characterize a mouse model for WNV using a subcutaneous route of infection and delineate leukocyte subsets and immunoregulatory factors present in the brains of infected mice. Central nervous system (CNS) expression of the chemokine receptor CCR5 and its ligand CCL5 was prominently up-regulated by WNV, and this was associated with CNS infiltration of CD4+ and CD8+ T cells, NK1.1+ cells and macrophages expressing the receptor. The significance of CCR5 in pathogenesis was established by mortality studies in which infection of CCR5−/− mice was rapidly and uniformly fatal. In the brain, WNV-infected CCR5−/− mice had increased viral burden but markedly reduced NK1.1+ cells, macrophages, and CD4+ and CD8+ T cells compared with WNV-infected CCR5+/+ mice. Adoptive transfer of splenocytes from WNV-infected CCR5+/+ mice into infected CCR5−/− mice increased leukocyte accumulation in the CNS compared with transfer of splenocytes from infected CCR5−/− mice into infected CCR5−/− mice, and increased survival to 60%, the same as in infected CCR5+/+ control mice. We conclude that CCR5 is a critical antiviral and survival determinant in WNV infection of mice that acts by regulating trafficking of leukocytes to the infected brain

Proposed Revision to the Taxonomy of the Genus Pestivirus; Family Flaviviridae

We propose the creation of seven new species in the genus Pestivirus (family Flaviviridae) in addition to the four existing species, and naming species in a host-independent manner using the format Pestivirus X. Only the virus species names would change; virus isolates would still be referred to by their original names. The original species would be re-designated as Pestivirus A (original designation Bovine viral diarrhea virus 1), Pestivirus B (Bovine viral diarrhea virus 2), Pestivirus C (Classical swine fever virus) and Pestivirus D (Border disease virus). The seven new species (and example isolates) would be Pestivirus E (pronghorn pestivirus), Pestivirus F (Bungowannah virus), Pestivirus G (giraffe pestivirus), Pestivirus H (Hobi-like pestivirus), Pestivirus I (Aydin-like pestivirus), Pestivirus J (rat pestivirus) and Pestivirus K (atypical porcine pestivirus). A bat-derived virus and pestiviruses identified from sheep and goat (Tunisian sheep pestiviruses), which lack complete coding region sequences, may represent two additional species

Proposed update to the taxonomy of the genera Hepacivirus and Pegivirus within the Flaviviridae family

Proposals are described for the assignment of recently reported viruses, infecting rodents, bats and other mammalian species, to new species within the Hepacivirus and Pegivirus genera (Family Flaviviridae). Assignments into 14 Hepacivirus species (Hepacivirus A to N) and 11 Pegivirus species (Pegivirus A to K) are based on phylogenetic relationships and sequence distances between conserved regions extracted from complete coding sequences of each proposed taxon. We propose that the species hepatitis C virus is renamed Hepacivirus C in order to acknowledge its unique historical position and so as to minimise confusion. Despite the newly documented genetic diversity of hepaciviruses and pegiviruses, members of these genera remain phylogenetically distinct, and differ in hepatotropism and the possession of a basic core protein; pegiviruses in general lack these features. However, other characteristics that were originally used to support their division into separate genera are no longer definitive; there is overlap between the two genera in the type of internal ribosomal entry site (IRES) and the presence of miR-122 sites in the 5'untranslated region (UTR), the predicted number of N-linked glycosylation sites in the envelope E1 and E2 proteins, the presence of poly U tracts in the 3' UTR and the propensity of viruses to establish a persistent infection. While all classified hepaciviruses and pegiviruses have mammalian hosts, the recent description of a hepaci-/pegi-like virus from a shark and the likely existence of further homologues in other non-mammalian species indicates that further species or genera remain to be defined in the future

First-In-Human Study in Cancer Patients Establishing the Feasibility of Oxygen Measurements in Tumors Using Electron Paramagnetic Resonance With the OxyChip

Objective: The overall objective of this clinical study was to validate an implantable oxygen sensor, called the ‘OxyChip’, as a clinically feasible technology that would allow individualized tumor-oxygen assessments in cancer patients prior to and during hypoxia-modification interventions such as hyperoxygen breathing. Methods: Patients with any solid tumor at ≤3-cm depth from the skin-surface scheduled to undergo surgical resection (with or without neoadjuvant therapy) were considered eligible for the study. The OxyChip was implanted in the tumor and subsequently removed during standard-of-care surgery. Partial pressure of oxygen (pO2) at the implant location was assessed using electron paramagnetic resonance (EPR) oximetry. Results: Twenty-three cancer patients underwent OxyChip implantation in their tumors. Six patients received neoadjuvant therapy while the OxyChip was implanted. Median implant duration was 30 days (range 4–128 days). Forty-five successful oxygen measurements were made in 15 patients. Baseline pO2 values were variable with overall median 15.7 mmHg (range 0.6–73.1 mmHg); 33% of the values were below 10 mmHg. After hyperoxygenation, the overall median pO2 was 31.8 mmHg (range 1.5–144.6 mmHg). In 83% of the measurements, there was a statistically significant (p ≤ 0.05) response to hyperoxygenation. Conclusions: Measurement of baseline pO2 and response to hyperoxygenation using EPR oximetry with the OxyChip is clinically feasible in a variety of tumor types. Tumor oxygen at baseline differed significantly among patients. Although most tumors responded to a hyperoxygenation intervention, some were non-responders. These data demonstrated the need for individualized assessment of tumor oxygenation in the context of planned hyperoxygenation interventions to optimize clinical outcomes

ЭВРИСТИЧЕСКИЙ ПОТЕНЦИАЛ ТЕОРИИ АНОМИИ В СОВРЕМЕННОЙ КРИМИНОЛОГИИ

This article deals with modern English theories of anomie. They can be used in Russian criminology.  The main goal of article consists in detection of actual theories of anomie and definition of prospects of their use. As modern theories of anomie are poorly submitted in the Russian sociological and criminological literature, the subject of research is actual. This work contains the analysis of opportunities for adoption of modern conceptions of anomie of individual in Russian practice. During research development of the theory of anomie in the history of sociology was considered. The problem of anomie was admitted actual antique Greece. Anomie which is today concerned with normlessness and related to alienation is associated primarily with the works of Durkheim and Merton. Anomia developed in research by MacIver and Srole as a characteristic of individuals and related to the breakdown of the individual’s sense of attachment to society. Results of theoretical research show that theories of anomie of the personality have the greatest heuristic potential for modern Russian science. Other important conclusion of research is one that the anomie can have some sources of emergence. Further studying of this subject is necessary because English-language theories of anomie contain a set of theoretical and empirical results which can be used in the Russian criminology.В статье рассматриваются современные англоязычные теории аномии, которые могут быть использованы в отечественной криминологии. Главная цель статьи заключается в выявлении актуальных теорий аномии и определении перспектив их использования. Поскольку современные теории аномии слабо представлены в российской социологической и криминологической литературе, тема исследования является актуальной. Представленная работа содержит анализ возможности применения современных концепций аномии личности в российской практике. В ходе исследования было рассмотрено развитие теории аномии в истории социологии. Проблема аномии признавалась актуальной еще в античной Греции. Аномия, которая сегодня понимается как безнормие и связывается с отчуждением, ассоциируется прежде всего с работами Дюркгейма и Мертона. Аномия как характеристика личности развивалась в исследованиях Макайвера и Сроула и понималась как потеря индивидом ощущения принадлежности к обществу. Результаты теоретического исследования показывают, что для современной российской науки наибольшим эвристическим потенциалом обладают теории аномии личности. Другим важным выводом исследования является вывод о том, что аномия может иметь несколько источников возникновения. Необходимо дальнейшее изучение данной темы, поскольку англоязычные теории аномии содержат множество теоретических и эмпирических результатов, которые можно использовать в российской криминологии.

ПРОЛОНГИРОВАННАЯ АННИГИЛЯЦИЯ ЦЕННОСТЕЙ КАК ФАКТОР АНОМИИ НА УКРАИНЕ

The problem of valuable crisis and valuable uncertainty in modern Ukraine is considered in article. The most important conclusion of the article is the statement that the social situation in the Ukrainian society has a number of distinctive features among other Post-Soviet countries. The main reason of it is continuous opposition of two steady groups dividing opposite values. Permission of this situation is disturbed by influence on Ukraine of other states and a state erosion as social institute in Ukraine. The long valuable conflict brings in result to an annigilyatsiya of values – gradual loss by all participants of the conflict of valuable re-ference points. This circumstance causes development of a strong anomy in Ukraine which is great both in quantitative, and in a qualitative sense. The prolonged annigilyatsiya of values in Ukraine interferes with formation of tendencies to an exit from an anomy which are cha-racteristic for other Post-Soviet countries.В статье рассматривается проблема ценностного кризиса и ценностной неопределенности в современной Украине. Наиболее важным выводом статьи является утверждение, что социальная ситуация в украинском обществе обладает рядом отличительных особенностей среди других постсоветских стран. Главной причиной этого является постоянное противостояние двух устойчивых групп, разделяющих противоположные ценности. Разрешению этой ситуации мешает влияние на Украину других государств и эрозия государства как социального института на Украине. Длительный ценностный конфликт приводит в результате к аннигиляции ценностей – постепенной утрате всеми участниками конфликта ценностных ориентиров. Это обстоятельство обуславливает развитие сильной аномии на Украине, которая велика как в количественном, так и в качественном отношении. Пролонгированная аннигиляция ценностей на Украине препятствует формированию тенденций к выходу из аномии, которые характерны для других постсоветских стран