[Genome-Wide Analysis of DNA Methylation in Cd4+ T Lymphocytes of Patients with Primary Progressive Multiple Sclerosis Indicates Involvement of This Epigenetic Process in the Disease Immunopathogenesis].

The pathogenesis of multiple sclerosis (MS), a chronic disease of the CNS, includes autoimmune and neurodegenerative components. In most cases, patients develop relapsing-remitting MS (RRMS), while 10-15% of patients develop primary progressive MS (PPMS), which differs from RRMS in the mechanisms of the pathological process, some demographic, and some clinical characteristics. These differences may be explained by the epigenetic regulation of gene expression in PPMS including DNA methylation as one of the key epigenetic processes. The features of DNA methylation in various cell populations in PPMS patients remain understudied. The goal of this study is to identify differentially methylated CpG sites (DMSs) of the genome of CD4+ T lymphocytes, which characterize PPMS. The study included eight treatment-naive PPMS patients and eight healthy controls. Genome-wide analysis of DNA methylation of CD4+ T lymphocytes was performed using high-density DNA microarrays. We have identified 108 DMSs, which distinguish PPMS patients from healthy controls. In PPMS patients 81% of the DMSs are hypermethylated. More than a half of the identified DMSs are located in known genes in CpG islands and adjacent regions, which indicates a high functional significance of these DMSs in PPMS development. Analysis of the overrepresentation of DMS-containing genes in the main biological processes demonstrates their involvement in the regulation of cell adhesion to the extracellular matrix and the development of the immune response, i.e., antigen processing and presentation, and development of the immune system. Genome-wide analysis of DNA methylation in CD4+ T lymphocytes of PPMS patients indicates the involvement of this epigenetic process in the immunopathogenesis of the disease. These results may help better understand the pathogenesis of this severe form of MS.

Whole-Genome DNA Methylation Analysis of Peripheral Blood Mononuclear Cells in Multiple Sclerosis Patients with Different Disease Courses.

Multiple sclerosis (MS) is a severe neurodegenerative disease of polygenic etiology affecting the central nervous system. In addition to genetic factors, epigenetic mechanisms, primarily DNA methylation, which regulate gene expression, play an important role in MS development and progression. In this study, we have performed the first whole-genome DNA methylation profiling of peripheral blood mononuclear cells in relapsing-remitting MS (RRMS) and primary-progressive MS (PPMS) patients and compared them to those of healthy individuals in order to identify the differentially methylated CpG-sites (DMSs) associated with these common clinical disease courses. In addition, we have performed a pairwise comparison of DNA methylation profiles in RRMS and PPMS patients. All three pairwise comparisons showed significant differences in methylation profiles. Hierarchical clustering of the identified DMS methylation levels and principal component analysis for data visualization demonstrated a clearly defined aggregation of DNA samples of the compared groups into separate clusters. Compared with the control, more DMSs were identified in PPMS patients than in RRMS patients (67 and 30, respectively). More than half of DMSs are located in genes, exceeding the expected number for random distribution of DMSs between probes. RRMS patients mostly have hypomethylated DMSs, while in PPMS patients DMSs are mostly hypermethylated. CpG-islands and CpG-shores contain 60% of DMSs, identified by pairwise comparison of RRMS and control groups, and 79% of those identified by pairwise comparison of PPMS and control groups. Pairwise comparison of patients with two clinical MS courses revealed 51 DMSs, 82% of which are hypermethylated in PPMS. Overall, it was demonstrated that there are more changes in the DNA methylation profiles in PPMS than in RRMS. The data confirm the role of DNA methylation in MS development. We have shown, for the first time, that DNA methylation as an epigenetic mechanism is involved in the formation of two distinct clinical courses of MS: namely, RRMS and PPMS.

[Computer analysis of regulating metabolism of glycerol-3-phosphate in proteobacteria genome]. / Komp'iuternyi analiz reguliatsii metabolizma glitserol-3-fosfata v genomakh proteobakterii.

Comparative computer-assisted analysis was used to study putative GlpR-regulons responsible for metabolism of glycerol and glycerol-3-phosphate in genomes of alpha-, beta-, and gamma-proteobacteria. New palindromic GlpR-binding signals were identified in gamma-proteobacteria; consensus sequences being TGTTCGATAACGAACA for Enterobacteriaceae, wTTTTCGTATACGAAAAw for Pseudomonadaceae, and AATGCTCGATCGAGCATT for Vibrionaceae. The signals in alpha- and beta-proteobacteria were also identified: they contained 3-4 direct TTTCGTT repeats separated by 3-4 nucleotide pairs.

[Algorithms for isolating regulatory signals in DNA sequences]. / Algoritm vydeleniia reguliatornykh signalov v posledovatel'nostiakh DNK.

An algorithm is proposed for extracting regulatory signals from DNA sequences. The algorithm complexity is nearly quadratic. The results of testing the algorithm on artificial and natural sequences are presented.

[Ultrastructure of the silkworm testis. II. Ductus deferens]. / Ul'trastruktura semennika tutovogo shelkopriada. II. Semiavyodiashchii kanal (inductus derrerens)

Ultrastructure of the silkworm's ducts defferens is described after spermatozoa went out of lobulli testis and after the end of secretion. D. defferens is composed of an external layer of the ring and longitudinal muscles and of an internal layer of glandular cells. Both layers are separated by structurless lamina--tunica propria. Z-discs of irregular form are placed at the borders of sarcomeres. M-lines are absent. Sarcolemma intrudes into the muscle fibers at the level of Z-discs and gives origin to T-system the tubes of which together with sarcoplasmic reticulum form dyades. Structures like intercalate discs are observed in muscle tissue at the level of Z-discs. Glandular cells have unusually developed nucleoli, many ribosomes, lysosome-like and residual bodies. There are comb desmosomes between the glandular cells.

[Achievements in the study of the development and ultrastructure of spermatozoa (on the 300th anniversary of the discovery of spermatozoa)]. / Uspekhi v izuchenii razvitiia i ul'trastruktury spermatozoidov (k 300-letiiu otkrytiia spermatozoida).

A review of principal advances in studying spermiogenesis and fine structure of spermatozoa is given on the occasion of the 3rd centennary of the discovery of spermatozoa by Loevenhuk. The most important achievements are the discovery of acrosome and its role in fertilization, the discovery of centriole and its role in the formation of flagellum, the discovery of axial complex and the role of its components in the flagellum movement. A study of spermatogenesis has revealed the syncytial nature of spermatogenic epithelium, synaptinemal complexes and their role in chromosome conjugation. The role of nuclear membrane in chromosome conjugation was established, the ultrastructural and biochemical transformation of chromatin was investigated, as well as that of microtubules in spermatogenesis. Some other discoveries were made which are of great importance for diagnosis of sterility.

[Ultrastructure of the spermatozoids of the pulmonate molluscs, Trichia hispida and succinea putris]. / Ul'trastruktura spermatozoidov legochnykh molliuskov Trichia hispida i Succinea putris.

The ultrastructural study of spermatozoa of hermaphroditic land molluscs Trichia hispida and Succinea putris has shown that the general pattern of their structure is similar. At the same time differences were found in the fine structure of acrosome, centriolar region (neck) and mitochondrial derivate (accessory nucleus). The mitochondrial derivate of spermatozoa of both the species contains three secondary spirals of varying length (vs. one-two in other species of pulmonate molluscs).

[The activation of the type I interferon signaling pathway in multiple sclerosis patients treated with russian analogue of Β-interferon-1b: transcriptome profiling data]. / Aktivatsiia signal'nogo puti interferonov tipa I u bol'nykh rasseiannym sklerozom pod vozdeistviem rossiiskogo analoga Β-interferona-1b (po dannym transkriptsionnogo profilirovaniia).

Implementation of the analogues of Β-interferon (Β-IFN), produced by recombinant strains of E. coli (Β-IFN-1b), for internal use in the Russian Federation for the treatment of multiple sclerosis (MS), implies a verification of their action at the transcriptome level in order to confirm the activation of the main signaling pathways involved in IFNb mechanism of action. In this work, the analysis is carried out for Infibeta (Generium, Russia). Using genome-wide transcriptional profiling with ILLUMINA HT-12 microarray, the differentially expressed genes in peripheral blood mononuclear cells of MS patients upon administration of Infibeta were studied. Comparison of gene expression levels in treatment-naive MS patients prior to first Β-IFN administration and 10 hours after it, identified 490 genes with significantly changed expression level, where 191 genes were up-regulated and 299 genes were down-regulated. Among the involved genes are those coding the components of the inflammatory system, innate and adaptive immunity, apoptosis, signal transduction, transcription, translation, degradation. Using gene set analysis, we confirmed the involvement of type I interferon signaling pathway genes and interferon-inducible genes in a patient's individual response to drug. Thus, the transcriptome profiling analysis allows concluding that the mechanism of action of Infibeta immunomodulatory drug is equal to that described for the original Β-IFN drugs.