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Introduction: Today sensor systems based on integrated photonics devices are the most important branch of embedded information and control systems for various functions. The output characteristics of a sensor system are significantly determined by the efficiency of the interrogator. The intensity interrogator based on a microring resonator can provide a high scanning rate and sensitivity that meets the requirements of a wide range of applications. Purpose: To develop an effective sensor system composed of a refractometric sensor and an interrogator located on the same photonic integrated circuit for marker-free determination of the concentration of substances in liquids. Methods: We use the numerical simulation of electromagnetic field propagation in a waveguide system (integrated silicon waveguides on a silicon dioxide substrate) in the research. The simulation has been carried out using the Ansys Lumerical environment, the FDTD (Finite Difference Time Domain) solver. The parameters of the microring resonators were optimized to obtain the coupling coefficients between the waveguides, providing the operation in the critical coupling mode. Results: We propose the concept of a fully integrated photonic sensor system based on micro-ring add-drop resonators. A sensor based on microring resonators has been developed, which consists of two half-rings with a radius of 18 μm, connected by sections of straight waveguides 3 μm long. An interrogator represented by a microring resonator with a radius of 10 µm has been developed. According to simulation results with a broadband source, the achieved sensor sensitivity was 110 nm per refractive index change, or 1350 dB per refractive index change. We propose a technique for choosing the optimal characteristics of the sensor and interrogator targeted to improve the complete system efficiency. Practical relevance: Sensor systems based on photonic integrated circuits can meet the demand for devices characterized by low power consumption, small size, immunity to electromagnetic interference and low cost.

In the cohort of Russian patients with cystic fibrosis, the p.[Leu467Phe;Phe508del] complex allele (legacy name [L467F;F508del]) of the CFTR gene is understudied. In this research, we present the results of frequency evaluation of the [L467F;F508del] complex allele in the Russian Federation among patients with a F508del/F508del genotype, its effect on the clinical course of cystic fibrosis, the intestinal epithelium ionic channel function, and the effectiveness of target therapy. The frequency of the [L467F;F508del] complex allele among patients with homozygous F508del was determined with multiplex ligase-dependent probe amplification followed by polymerase chain reaction and fragment analysis. The function of ionic channels, including the residual CFTR function, and the effectiveness of CFTR modulators was analyzed using intestinal current measurements on rectal biopsy samples and the forskolin-induced swelling assay on organoids. The results showed that the F508del/[L467F;F508del] genotype is present in 8.2% of all Russian patients with F508del in a homozygous state. The clinical course of the disease in patients with the F508del/[L467F;F508del] genotype is severe and does not vary from the course in the cohort with homozygous F508del, although the CFTR channel function is significantly lower. For patients with the F508del/[L467F;F508del] genotype, we can recommend targeted therapy using a combined ivacaftor + tezacaftor + elexacaftor medication.

The pathogenic variant E92K (c.274G > A) of the CFTR gene is rare in America and Europe, but it is common for people with cystic fibrosis from Russia and Turkey. We studied the effect of the E92K genetic variant on the CFTR function. The function of the CFTR channel was studied using the intestinal current measurements (ICM) method. The effects of CFTR modulators on the restoration of the CFTR function were studied in the model of intestinal organoids. To assess the effect of E92K on pre-mRNA splicing, the RT-PCR products obtained from patients’ intestinal organoid cultures were analyzed. Patients with the genetic variant E92K are characterized by an older age of diagnosis compared to homozygotes F508del and a high frequency of pancreatic sufficiency. The results of the sweat test and the ICM method showed partial preservation of the function of the CFTR channel. Functional analysis of CFTR gene expression revealed a weak effect of the E92K variant on mRNA-CFTR splicing. Lumacaftor (VX-809) has been shown to restore CFTR function in an intestinal organoid model, which allows us to consider the E92K variant as a promising target for therapy with CFTR correctors.

Background: The problem of vitamin D deficiency is particularly relevant for the entire territory of Russia, since most parts of the country are located above the 42nd geographical latitude and the residents are therefore at risk of vitamin D deficiency. Despite the urgency of the problem, a comprehensive study of the molecular and genetic mechanisms and exogenous factors of vitamin D deficiency in children living in various geographical areas of the Russian Federation has not been conducted. Different variants in the loci of the genes responsible for the synthesis, hydroxylation, and transport of vitamin D (such as DHCR7, CYP2R1, CYP24A1, and GC), as well as VDR gene polymorphisms may also be associated with the risk of vitamin D deficiency. The aim of this study was to analyze the influence of exogenous factors on the blood levels of 25-hydroxyvitamin D (25(OH)D) in children of three regions of the Russian Federation, as well as the relationship of blood 25(OH)D levels with polymorphic variants of cytochrome P450 genes and VDR gene.Methods: We conducted blood 25(OH)D level analysis in 333 healthy children and adolescents in three regions located in different geographical zones of the Russian Federation. We studied the polymorphic variants c.1075A>C (I359L, rs1057910, CYP2C9*3) and c.430C>T (R144C, rs1799853, CYP2C9*2) in the CYP2C9 gene, c.1334T>C (M445T, rs4986910, CYP3A4*3), and CYP3A4*1B (c.-392C>T, rs2740574) in the CYP3A4 gene, 1846G>A, (rs3892097, CYP2D6*4) in the CYP2D6gene, TaqI (NM_000376.2: c.1056T>C; rs731236), FokI (NM_000376.2:c.2T>C; (rs2228570), and BsmI (NM_000376.2: c.1024+283G>A; rs1544410) in the VDR gene. We also analyzed the influence of exogenous factors on the level of 25(OH)D in children of the three study regions, as well as the relationship of the level of 25(OH)D with variants CYP2C9*2 (c.430C>T; R144C), CYP2C9*3 (c,1075A>C; I359L), CYP2D6*4 (1846G>A), CYP3A4*3 (c.1334T>C), and CYP3A4*1B (c.-392C>T) and rs731236, rs2228570 and rs1544410 in the VDR gene.Results: We found that the blood level of 25(OH)D depended on the geographical location and the number of sunny days per year. The average blood level of 25(OH)D in adolescent boys was statistically significantly lower than in girls of this age group. The level of 25(OH)D also significantly depended on the prophylactic dose of cholecalciferol administered to the subjects. In the study, it was shown that a dose of cholecalciferol ≥1,000 IU per day can achieve a normal level of 25(OH)D in healthy children. We found no statistically significant association between single-nucleotide polymorphic variants of cytochrome P450 genes (CYP2C9*3, CYP3A4*3, CYP2C9*2, CYP2D6*4, and CYP3A4*1B) and blood level of 25(OH)D in the subjects. We also did not find a relationship between the TaqI, FokI, and BsmI polymorphisms of the VDR gene and serum 25(OH)D concentration.Conclusion: Exogenous factors (time of year, place of residence, and prophylactic administration of cholecalciferol), as well as endogenous factors (age and sex), play a determining role in the development of vitamin D deficiency and insufficiency; in contrast to genetic factors—polymorphic variants of the genes of xenobiotic phase 1 enzymes (CYP2C9, CYP2C19, CYP2D6, and CYP3A4) and the VDR gene—which do not play such role. This study shows the need to create a diagnostic algorithm for Vitamin D deficiency based on the age, season of the year, and prophylactic dose of cholecalciferol.

The goal was to study the phenotypic manifestations of c.3844T>C (p.Trp1282Arg, W1282R) variant, a CF-causing mutation, in patients from the Russian Federation. Clinical manifestations and complications (the age at CF diagnosis, sweat test, pancreatic status, lung function, microbial infection, body mass index (BMI), the presence of meconium ileus (MI), diabetes, and severe liver disease) were compared in four groups: group 1—patients carrying c.3844T>C and severe class I or II variant in trans; group 2—3849+10kbC>T/F508del patients; group 3—F508del/F508del patients; and group 4—patients with W1282R and “mild” variant in trans. Based on the analyses, W1282R with class I or II variant in trans appears to cause at least as severe CF symptoms as F508del homozygotes as reflected in the early age of diagnosis, high sweat chloride concentration, insufficient pancreatic function, and low lung function, in contrast to 3849+10kbC-T/F508del compound heterozygotes having milder clinical phenotypes. The W1282R pathogenic variant is seemed to lead to severe disease phenotype with pancreatic insufficiency similarly to the F508del homozygous genotype.

The distribution and frequency of the CFTR gene mutations vary considerably between countries and ethnic groups. Russians are an East Slavic ethnic groups are native to Eastern Europe. Russians, the most numerous people of the Russian Federation (RF), make about 80% of the population. The aim is to reveal the molecular causes of CF in ethnic Russian patients as comprehensively as possible. The analysis of most common CFTR mutations utilized for CF diagnosis in multiethnic RF population accounts for about 83% of all CF-causing mutations in 1384 ethnic Russian patients. Variants c.1521_1523delCTT (F508del), c.54-5940_273+10250del21kb (CFTRdele2,3), c.2012delT (2143delT), c.2052_2053insA (2184insA), and c.3691delT (3821delT) are most typical for CF patients of Russian origin. DNA of 154 CF patients, Russian by origin, in whom at least one mutant allele was not previously identified (164 CF alleles), was analyzed by Sanger sequencing followed by the multiplex ligase-dependent probe amplification (MLPA) method. In addition to the 29 variants identified during the previous test for common mutations, 91 pathogenic CFTR variants were also revealed: 29 missense, 19 nonsense, 14 frame shift in/del, 17 splicing, 1 in frame ins, and 11 copy number variations (CNV). Each of the 61 variants was revealed once, and 17 twice. Each of the variants c.1209G&gt, C (E403D), c.2128A&gt, T (K710X), c.3883delA (4015delA), and c.3884_3885insT (4016insT) were detected for three, c.1766+1G&gt, A (1898+1G&gt, A) and c.2834C&gt, T (S945L) for four, c.1766+1G&gt, C (1898+1G&gt, C) and c.(743+1_744-1)_(1584+1_1585-1)dup (CFTRdup6b-10) for five, c.2353C&gt, T (R785X) and c.4004T&gt, C (L1335P) for six, c.3929G&gt, A (W1310X) for seven, c.580-1G&gt, T (712-1G&gt, T for eight, and c.1240_1244delCAAAA (1365del5) for 11 unrelated patients. A comprehensive analysis of CFTR mutant alleles with sequencing followed by MLPA, allowed not only the identification of 163 of 164 unknown alleles in our patient sample, but also expansion of the mutation spectrum with novel and additional frequent variants for ethnic Russians.

Significant progress has been made in cystic fibrosis (CF) treatment using new antibiotic (AB) therapy options. However, the spectrum of bacterial pathogens and their susceptibility to AB have changed as well. Study objective: to investigate microflora prevailing in CF subjects’ respiratory tract (RT) change over 15 years. CF subjects’ sputum culture test results collected from 2000 till 2015 were analyzed. There were 9774 samples reviewed, 16703 strains identified. “MYCROB” system of microbiological monitoring was used for entry, statistical processing and analysis of data. Study results: S. aur. identification dropped from 42% (2000-03) to 32% (2012-15). P. aerug. from 24% (2000-03) to 11% (2011-15), P. aerug. muc. from 17% (2000-03) to 9% (2012-15). Incidence of chronic P. aerug. infection in CF children decreased from 57% in 1999 to 26% in 2011 and even 14% in 2014. MRSA identification growth from 6% (2000-03) to 9,5% (2008-11) and further to 12% (2012-15) is worrisome. B. cepacia comp. identification grew from 1% (2000-03) to 11% (2008-11) and 7% (2012-15). S. maltophilia identification dropped from 6% (2000-03) to 3% (2012-15). A. xylosoxidans identification grew from 3% (2000-03) to 5% (2012-15). The data presented demonstrate significant change in the distribution of the species identified. In parallel with P. aerug, and P. aerug. muc. identification frequency drop and reduction of chronic P. aerug. infection cases, there is a tendency to higher incidence of B.cepacia complex, A. xylosoxidans and MRSA identification which is quite challenging for further CF subjects care.

In this paper a mathematical model of the electrochemical machining the flywheel car is built. When we treat a part in stationary mode, at the corner points (point B in Figure 1) the flow velocity increases sharply and as a consequence there are arising cavities, fulfilled by air bubbles. In these areas electrical conductivity of electrolyte is broken and they play the role of insulator. This leads to the formation of irregularities on the surface to be treated.