ANALYSIS OF DOMAIN SPECIFICITY OF THE PROTECTIVE CHIMERIC ANTIBODY ch14D5a AGAINST GLYCOPROTEIN E OF TICK-BORNE ENCEPHALITIS VIRUS

A drug for the prevention and therapy of tick-borne encephalitis virus is being developed on the basis of the protective chimeric antibody ch14D5a. At the same time, the epitope recognized by this antibody on the surface of glycoprotein E has not been localized yet. The aim of this work was to identify the domain of glycoprotein E, to which the protective antibody ch14D5a binds. As a result, four recombinant variants of glycoprotein E were generated using the bacterial expression system: (1) the rE protein containing the domains D1, D2, and D3 of glycoprotein E; (2) the rED1+2 protein containing domains D1 and D2; (3) the rED3_301 protein, which is domain D3 of glycoprotein E, and (4) the rED3_294 protein comprising domain D3 and a hinge region connecting domains D1 and D3. The rED3_294 and rED3_301 proteins were obtained in soluble monomeric form. The rE and rED1+2 proteins were extracted from the inclusion bodies of Escherichia coli. Using Western blot analysis and surface plasmon resonance analysis, it was demonstrated that the protective chimeric antibody ch14D5a and its Fab fragment bound specifically to domain D3 of glycoprotein E. Since the antibodies recognizing epitopes on the surface of domain D3 do not tend to cause antibody-dependent enhancement of the infection as compared to antibodies directed to domains D1 and D2, the data obtained confirm the promise of using the antibody ch14D5a in the development of a therapeutic preparation against the tick-borne encephalitis virus

Chimeric Antibody 14D5 Protects Mice against the Far-Eastern, Siberian, and European Tick-borne Encephalitis Virus

Tick-borne encephalitis virus (TBEV), belonging to the Flaviviridae family, is the most significant pathogen transmitted by Ixodes ticks and causing one of the most severe human neuroinfections. In Russia, serum immunoglobulin produced from the donor blood is currently used for post-exposure prophylactic and therapy of tick-borne encephalitis virus. However, it is known that preparations obtained from donated blood have certain disadvantages, and therefore development of novel preparations for post exposure prophylaxis and therapy of tick-borne encephalitis is required. To develop an alternative preparation, which does not include donor blood, a chimeric antibody ch14D5 against glycoprotein E of TBEV was constructed.This study was aimed to investigate protective efficacy of the chimeric antibody ch14D5 against the Far-Eastern, Siberian, and European subtypes of TBEV in in vivo experiments.A peripheral mouse model of tick-borne encephalitis was used in this study: the chimeric antibody ch14D5 was administrated intravenously in mice one day after their intraperitoneal infection with TBEV strains Sofjin, Vasilchenko, and Absettarov. Anti-TBEV serum immunoglobulin was used as a control preparation, which was administered in the same way. Protective efficacy of the chimeric antibodies 14D5 was assessed using the log-rank test. In the study, the presence or absence of antibody-dependent enhancement of infection (ADE) was examined when mice, infected with different subtypes of the TBEV, got the antibody ch14d5.Obtained results demonstrated high efficacy of the ch14D5 antibody in post-exposure prophylaxis of the disease in mice infected with any of the used TBEV strains, as well as the absence of ADE.It was shown that protective efficacy of antibody ch14D5 is higher than that of the anti-TBEV serum immunoglobulin, and antibody ch14D5 could be used for development of a therapeutic preparation for post-exposure prophylaxis

Studying of the character and prevalence of thermal injuries under emergency situations in Sverdlovsk region

The article discusses the main aspects of thermal lesions in emergency situations, provides a quantitative analysis of data for 2017 and 2018 in the Sverdlovsk region, justifies tactics for managing patients with a burn injuryВ статье рассмотрены основные аспекты термических поражений при чрезвычайных ситуациях, приведен количественный анализ данных за 2017 и 2018 год по Свердловской области, обоснована тактика ведения пациентов с ожоговой травмо

НАСЛЕДСТВЕННЫЙ РАК МОЛОЧНОЙ ЖЕЛЕЗЫ И ЯИЧНИКОВ

The annual incidence of breast cancer (BC) in the world is 1,383,000 cases. Genetic predisposition is one of the major risk factors for breast cancer and ovarian cancer (OC). The proportion of hereditary breast cancer ranges from 5 to 10%, which amounts 69 150-138 000 cases. Family history of accumulation of breast cancer and tumors of the female reproductive system have 25% of patients. Thus, patients with hereditary forms and family breast cancer account 345,700 of all diagnosed cases of breast cancer. Hereditary ovarian cancer occurs in 10-17% cases. Hereditary breast and ovarian cancer are characterized by autosomal dominant inheritance with high (incomplete) penetrance, incidence in early age and pronounced phenotypic and genotypic heterogeneity. According to numerous studies, 20-50% of hereditary breast cancer cases and 90-95% of hereditary ovarian cancer cases in women, and from 4 to 40% of breast cancer cases in men are caused by germinal mutations in the BRCA1 and BRCA2 genes. Considering the syndromic pathology of hereditary BC and OC and can also be associated with mutations in genes TP53, CHEK2, MLH1, MSH2, PALB2, PTEN, NBS1, ATM, BRIP1, RAD50, BLM, FGFR2, and others.Ежегодная заболеваемость раком молочной железы (РМЖ) в мире составляет 1 383 000 случаев. Генетическая предрасположенность является одним из основных факторов риска развития РМЖ и рака яичников (РЯ). Доля наследственно-обусловленного РМЖ колеблется от 5 до 10 %, что составляет 69 150-138 000 случаев. Семейную историю накопления РМЖ и опухолей женской репродуктивной системы отмечают 25 % заболевших женщин. Таким образом, пациенты с наследственными и семейными формами РМЖ в целом составляют 345 700 от всех диагностированных случаев РМЖ [1]. Наследственный рак яичников встречается с частотой 10-17 % [2,3]. Наследственные РМЖ и РЯ характеризуются аутосомно-доминантным типом наследования с высокой (неполной) пенетрантностью, ранним возрастом возникновения и выраженной генотипической и фенотипической гетерогенностью [3-6]. По данным многочисленных исследований, 20-50 % наследственного рака молочной железы (НРМЖ) и 90-95 % — наследственного рака яичников (НРЯ) у женщин, а также от 4 до 40 % РМЖ у мужчин обусловлены герминальными мутациями в генах BRCA1 и BRCA2 [2,3,7,8]. С учетом синдромальной патологии НРМЖ и НРЯ могут быть ассоциированы также с мутациями в генах TP53, CHEK2, MLH1, MSH2, PALB2, PTEN, NBS1, ATM, BRIP1, RAD50, BLM, FGFR2 и др. (таблица 1)

Nat Genet

The function of the majority of genes in the mouse and human genomes remains unknown. The mouse embryonic stem cell knockout resource provides a basis for the characterization of relationships between genes and phenotypes. The EUMODIC consortium developed and validated robust methodologies for the broad-based phenotyping of knockouts through a pipeline comprising 20 disease-oriented platforms. We developed new statistical methods for pipeline design and data analysis aimed at detecting reproducible phenotypes with high power. We acquired phenotype data from 449 mutant alleles, representing 320 unique genes, of which half had no previous functional annotation. We captured data from over 27,000 mice, finding that 83% of the mutant lines are phenodeviant, with 65% demonstrating pleiotropy. Surprisingly, we found significant differences in phenotype annotation according to zygosity. New phenotypes were uncovered for many genes with previously unknown function, providing a powerful basis for hypothesis generation and further investigation in diverse systems.Comment in : Genetic differential calculus. [Nat Genet. 2015] Comment in : Scaling up phenotyping studies. [Nat Biotechnol. 2015

Automated measurement of brain dimensions

This paper describes a technique for automating the measurement of brain width and length at the level of the bi-parietal diameter, by processing an axial computed tomography (CT) brain scan image. The development of this algorithm derives from the wish to normalise patient data according to skull size and shape, for the purpose of comparing new patient data with that from past cases. This algorithm uses image processing techniques to find the inner edge of the cavity of the skull. The width and length of the brain are measured as inner dimensions of this bone periphery. The main challenges facing this work are the structural asymmetry of the brain and the angle of rotation commonly encountered when working with axial CT images. Both of these must be taken into account prior to measuring the brain width and length. The algorithm was designed and tested to operate on a database containing CT brain scans from 530 patients. The results indicate that the algorithm has a 90.56% success rate

Quantifying skull shape

This paper describes a technique for automatically quantifying the shape of the skull cavity seen on an axial slice in a CT brain scan. The development of this algorithm derives from the need to normalise CT scan data according to skull size and shape for the purpose of comparing new patient data with that from past cases. This algorithm uses image processing techniques to find the inner edge of the bones of the skull on an axial slice, so that its shape can be represented by a radius function. A simple measure of shape asymmetry is defined. It is also shown that this shape can be quantified more precisely by harmonic analysis using the Fourier Transform of the radius function. This paper describes the design of the algorithm and its performance on axial slices taken from a database of CT brain scans from 528 patients

A Century of Demographic Ageing in Arctic Canada (1950–2050)

The aim of this study is to identify the major characteristics of demographic ageing in the Canadian Arctic - Yukon, Nunavut, and Northwest Territories (NWT) - in the period 1950 to 2050. We measure ageing first conventionally, based on "chronological" age, as a point of comparison for results obtained applying new measures of ageing based on "prospective" age. The latter takes into account upward changes in life expectancy and longevity over recent decades. The findings are discussed for the territories with the oldest and youngest average ages, the regions ageing the fastest and slowest, for both sexes and (to some extent) across ethnic differences. The paper considers whether the territories of Arctic Canada are converging or diverging in their ageing pathways and the links between the northern and nationwide patterns were traced. We find that NWT and Nunavut are the youngest and are diverging from nationwide ageing dynamics while Yukon is no longer different from the rest of Canada. The results of this study can help devise policies for coping with the population ageing in the Arctic part of Canada