Towards the mechanism(s) of YB-3 synthesis regulation by YB-1.

Y-box binding proteins are members of the family of proteins containing the evolutionarily conserved cold shock domain. Their cellular functions are quite diverse, including transcription and translation regulation, participation in pre-mRNA splicing, mRNA stabilization and packaging into mRNPs, involvement in DNA repair, and some others. To date, we know little about the plausible functional interchangeability of Y-box binding proteins. Our previous finding was that in YB-1-null HEK293T cells the synthesis of YB-3 is enhanced, thus enabling YB-3 to interact with a larger set of mRNAs and compensate for the YB-1 absence. We suggested the existence of a mechanism of YB-3 synthesis regulation by its paralog, YB-1. Here we demonstrate that YB-1 participates in the translational control and stabilization of YB-3 mRNA through untranslated regions of YB-3 mRNA.

YB-3 substitutes YB-1 in global mRNA binding.

Y-box binding proteins are DNA- and RNA-binding proteins with an evolutionarily ancient and conserved cold shock domain. The Y-box binding protein 1 (YB-1) is the most studied due to its abundance in somatic cells. YB-1 is involved in a variety of cellular processes, including proliferation, differentiation and stress response. Here, using Ribo-Seq and RIP-Seq we confirm that YB-1 binds a wide range of mRNAs and globally acts as a translation inhibitor. Surprisingly, YBX1 knockout results in only minor alterations in the expression of other genes, mostly caused by changes in RNA abundance. But YB-3 mRNA is an exception: it is better translated in the absence of YB-1, thereby producing an increased amount of YB-3 and thus suggesting that its synthesis is under YB-1 negative control. We have shown that the set of mRNAs bound to YB-3 is strikingly similar to that of YB-1, and that the mRNA-binding by YB-3 is enhanced in the absence of YB-1, resulting in a similar global reduction of translation of bound mRNAs in YB-1-null cells. Thus, YB-3 acts as a substitute for YB-1 in mRNA binding and, probably, in global translational control.

Transcriptome profile of yeast reveals the essential role of PMA2 and uncharacterized gene YBR056W-A (MNC1) in adaptation to toxic manganese concentration.

Adaptation of S. cerevisiae to toxic concentrations of manganese provides a physiological model of heavy metal homeostasis. Transcriptome analysis of adapted yeast cells reveals upregulation of cell wall and plasma membrane proteins including membrane transporters. The gene expression in adapted cells differs from that of cells under short-term toxic metal stress. Among the most significantly upregulated genes are PMA2, encoding an ortholog of Pma1 H+-ATPase of the plasma membrane, and YBR056W-A, encoding a putative membrane protein Mnc1 that belongs to the CYSTM family and presumably chelates manganese at the cell surface. We demonstrate that these genes are essential for the adaptation to toxic manganese concentration and propose an extended scheme of manganese detoxification in yeast.

The Y-Box Binding Protein 1 Suppresses Alzheimer's Disease Progression in Two Animal Models.

The Y-box binding protein 1 (YB-1) is a member of the family of DNA- and RNA binding proteins. It is involved in a wide variety of DNA/RNA-dependent events including cell proliferation and differentiation, stress response, and malignant cell transformation. Previously, YB-1 was detected in neurons of the neocortex and hippocampus, but its precise role in the brain remains undefined. Here we show that subchronic intranasal injections of recombinant YB-1, as well as its fragment YB-11-219, suppress impairment of spatial memory in olfactory bulbectomized (OBX) mice with Alzheimer's type degeneration and improve learning in transgenic 5XFAD mice used as a model of cerebral amyloidosis. YB-1-treated OBX and 5XFAD mice showed a decreased level of brain ß-amyloid. In OBX animals, an improved morphological state of neurons was revealed in the neocortex and hippocampus; in 5XFAD mice, a delay in amyloid plaque progression was observed. Intranasally administered YB-1 penetrated into the brain and could enter neurons. In vitro co-incubation of YB-1 with monomeric ß-amyloid (1-42) inhibited formation of ß-amyloid fibrils, as confirmed by electron microscopy. This suggests that YB-1 interaction with ß-amyloid prevents formation of filaments that are responsible for neurotoxicity and neuronal death. Our data are the first evidence for a potential therapeutic benefit of YB-1 for treatment of Alzheimer's disease.

Innate immunity: Bacterial cell-wall muramyl peptide targets the conserved transcription factor YB-1.

The bacterial cell wall muramyl dipeptides MDP and glucosaminyl-MDP (GMDP) are powerful immunostimulators but their binding target remains controversial. We previously reported expression cloning of GMDP-binding polypeptides and identification of Y-box protein 1 (YB-1) as their sole target. Here we show specific binding of GMDP to recombinant YB-1 protein and subcellular colocalization of YB-1 and GMDP. GMDP binding to YB-1 upregulated gene expression levels of NF-κB2, a mediator of innate immunity. Furthermore, YB-1 knockdown abolished GMDP-induced Nfkb2 expression. GMDP/YB-1 stimulation led to NF-κB2 cleavage, transport of activated NF-κB2 p52 to the nucleus, and upregulation of NF-κB2-dependent chemokine Cxcr4 gene expression. Therefore, our findings identify YB-1 as new target for muramyl peptide signaling.

Identification of proteins specifically interacting with YB-1 mRNA 3' UTR and the effect of hnRNP Q on YB-1 mRNA translation.

In this study, proteins specifically interacting with the 3' untranslated region (UTR) of mRNA of the multifunctional Y-box-binding protein 1 (YB-1) were identified. One of these, hnRNP Q, was shown to specifically interact with the regulatory element (RE) in YB-1 mRNA 3' UTR and to inhibit translation of this mRNA. Its binding to the RE was accompanied by displacement from this element of the poly(A)-binding protein (PABP), a positive regulator of YB-1 mRNA translation, and by enhanced binding of the negative YB-1 mRNA translation regulator - YB-1 itself.

Poly(A)-binding proteins: structure, domain organization, and activity regulation.

RNA-binding proteins are of vital importance for mRNA functioning. Among these, poly(A)-binding proteins (PABPs) are of special interest due to their participation in virtually all mRNA-dependent events that is caused by their high affinity for A-rich mRNA sequences. Apart from mRNAs, PABPs interact with many proteins, thus promoting their involvement in cellular events. In the nucleus, PABPs play a role in polyadenylation, determine the length of the poly(A) tail, and may be involved in mRNA export. In the cytoplasm, they participate in regulation of translation initiation and either protect mRNAs from decay through binding to their poly(A) tails or stimulate this decay by promoting mRNA interactions with deadenylase complex proteins. This review presents modern notions of the role of PABPs in mRNA-dependent events; peculiarities of regulation of PABP amount in the cell and activities are also discussed.

A deeper look into transcription regulatory code by preferred pair distance templates for transcription factor binding sites.

MOTIVATION: Modern experimental methods provide substantial information on protein-DNA recognition. Studying arrangements of transcription factor binding sites (TFBSs) of interacting transcription factors (TFs) advances understanding of the transcription regulatory code. RESULTS: We constructed binding motifs for TFs forming a complex with HIF-1α at the erythropoietin 3(')-enhancer. Corresponding TFBSs were predicted in the segments around transcription start sites (TSSs) of all human genes. Using the genome-wide set of regulatory regions, we observed several strongly preferred distances between hypoxia-responsive element (HRE) and binding sites of a particular cofactor protein. The set of preferred distances was called as a preferred pair distance template (PPDT). PPDT dramatically depended on the TF and orientation of its binding sites relative to HRE. PPDT evaluated from the genome-wide set of regulatory sequences was used to detect significant PPDT-consistent binding site pairs in regulatory regions of hypoxia-responsive genes. We believe PPDT can help to reveal the layout of eukaryotic regulatory segments. CONTACT: ivan.kulakovskiy@gmail.com SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

[Preferred distances between DNA binding sites for factors regulating transcription initiation].

Transcriptional regulation of gene expression in higher eukaryotes is driven by sophisticated protein complexes of transcription factors. On the DNA level, there are composite elements containing sites of different DNA-binding proteins. We use the hypoxia-response system to identify preferred localization distances for the 'hypoxia-induced factor-1 binding site-co-factor binding site" pairs in promoter DNA regions of the human genome. Such characteristic colocalization distances agree with the supposed scale of regulatory regions, while being significantly longer than the typical binding site length. We speculate that this phenomenon can provide a key to decipher the structure of DNA regulatory regions of higher eukaryotes.

Y-box-binding protein 1 (YB-1) and its functions.

This review describes the structure and functions of Y-box binding protein 1 (YB-1) and its homologs. Interactions of YB-1 with DNA, mRNAs, and proteins are considered. Data on the participation of YB-1 in DNA reparation and transcription, mRNA splicing and translation are systematized. Results on interactions of YB-1 with cytoskeleton components and its possible role in mRNA localization are discussed. Data on intracellular distribution of YB-1, its redistribution between the nucleus and the cytoplasm, and its secretion and extracellular functions are summarized. The effect of YB-1 on cell differentiation, its involvement in extra- and intracellular signaling pathways, and its role in early embryogenesis are described. The mechanisms of regulation of YB-1 expression in the cell are presented. Special attention is paid to the involvement of YB-1 in oncogenic cell transformation, multiple drug resistance, and dissemination of tumors. Both the oncogenic and antioncogenic activities of YB-1 are reviewed. The potential use of YB-1 in diagnostics and therapy as an early cancer marker and a molecular target is discussed.

[Provision of complex cardioprotection with the help of carvedilol in 1-2 degree arterial hypertension combined with metabolic syndrome].

In an open prospective 16-week study we carried out assessment of clinical efficacy, vaso- and cardioprotective properties of nonselective alpha and beta-adrenoblocker carvedilol used as monotherapy and in combination with nifedipine or as combination of these drugs with metformin and simvastatin. We have shown that the use of carvedilol both as monotherapy and in combination with nifedipine normalizes arterial pressure irrespective of the number of risk factors. We also revealed pronounced cardio- and vasoprotective action without negative effect on carbohydrate and lipid metabolism.

[Clinical-functional of somatic condition and delivery in women with mitral valve prolapse]. / Kliniko-funktsional'nye osobennosti somaticheskogo sostoianiia i techeniia rodov u zhenshchin s prolapsom mitral'nogo klapana.

Pregnancy running with concomitant somatic disease, mitral prolapse (MP), in particular, remains a serious clinical problem because of MP high incidence rate and severity of complications. The author studied somatic condition, perinatal and postnatal periods in women in labor (WLs) with MP in comparison with healthy WL. A comprehensive clinical examination of 130 pregnant women, WLs and puerperae has revealed some regularities. Women with MP are more frequently affected with extragenital infectious and non-infectious diseases, have disorders of intracardiac hemodynamics. Because of frequent occurrence of anomalous labour and postnatal period, pregnant women with MP should be referred to a group of obstetric and perinatal pathology risk. The results of current research urge the necessity of a comprehensive examination of pregnant women for MP. They should be placed under early special observation, adequately treated or get advice on whether the pregnancy should be continued.

[Study of immunodepressive and allergic effects of xenon]. / Issledovaniia immunodepressornykh i allergiziruiuscchikh svoistv ksenona.

Experimental studies on mice showed that after four 30-min and 60-min inhalations of Xe:O2 (80:20) during 2 weeks, weight indexes of the lymphoid organs (spleen and thymus) increased, phagocytic activity did not change, and primary immune response was moderately stimulated. This indicates that xenon exerted no immunotoxic effects and can be used in patients with diseases associated with primary immunodeficiency. Study of allergic effects on albino guinea pigs showed that on days 14 and 21 of sensitization xenon in the resolving dose possessed no anaphylactogenic activity, caused no specific lysis of leukocytes, and did not modulate the counts of basophils and eosinophils. Xenon did not induce allergic reactions and is not a potential allergen, which is important in patients with panallergy.

[Microbial cenoses of the nasopharynx]. / Mikrobnye tsenozy nosoglotki.

The review is devoted to nasopharyngeal microflora, its significance for macroorganisms, and to relations between main representatives of nasopharyngeal microbial associations.

[An analysis of chromosome aberrations and SCE in children from radiation-contaminated regions of Ukraine]. / Analiz aberratsii khromosom i SKhO u detei iz radiatsionno-zagriaznennykh raionov Ukrainy.

About a two years later after the reactor accident in Chernobyl we carried out a three-year cytogenetical study of children, dwelling in two regions of Ukraine where the radiation fallout occurred. Chromosome analyses of these individuals have shown a significant increase of the frequency of aberrant cells and chromosomal type aberrations in comparison to the control. We have discovered the increase of the level of chromosomal type aberrations, extension in spectrum of complicate aberrations of chromosome (dicentrics, rings and exchange aberrations) with the years and the increase with the years a share of children with various chromosomal abnormalities. Analyses of sister chromatid exchanges (SCE) and a replication index (RI) show a significant increase of RI meaning with the years in comparison to the control. The SCE frequency didn't altered as compared to the control during different years of investigation.

[The rapid differential diagnosis of bacterial and viral meningitis by using the lysozyme test]. / Differentsial'naia ékspress-diagnotika bakterial'nykh i virusnykh meningitov s pomoshch'iu lizotsimnogo testa.

The authors have modified the technique of the lysozyme test by adding polimixin M sulfate into the gel bacterial medium. Rapid diagnosis with the use of this test is based on different time of the appearance of the lysis areas: in bacterial meningitides the CSF lysozyme activity is detectable within 15-120 min, whereas in viral meningitides it manifests 40-50 min later or does not manifest at all. The results were found to depend on the time of the CSF collection: the earlier the CSF samples were obtained, the higher was the share of positive results.

[The evaluation of the reactogenicity and immunological activity of an inactivated 3-component influenza vaccine with an elevated hemagglutinin concentration in the inoculation dosage]. / Otsenka reaktogennosti i immunologicheskoi aktivnosti inaktivirovannoi trekhkomponentnoi grippoznoi vaktsiny s povyshennoi kontsentratsiei gemaggliutinina v privivochnoi doze.

In this work the reactogenic properties and antigenic potency of inactivated trivalent influenza vaccine, obtained by elution and centrifugation and containing up to 9-11 micrograms of hemagglutinin for influenza viruses A(H1N1) and A(H3N2) and up to 14 micrograms for influenza virus B, were studied. The reactogenicity of the preparation was found to correspond to the regulations. The immunogenic potency characteristics of individual batches of this trivaccine were higher than the immunogenicity of divaccines, but did not meet the requirements of technical specifications.

[Use of the agar diffusion precipitation method for detecting rotavirus antigen]. / Ispol'zovanie metoda diffuzionnoi pretsipitatsii v agare dlia obnaruzheniia rotavirusnogo antigena.

The possibility of rotavirus detection in feces of patients with acute enteric diseases by the agar gel diffusion (AGD) test was studied. The effectiveness of this method was compared with that of the standard method, direct electron microscopy. Both methods showed good correlation of the results, but the AGD test is methodically much simpler which recommends it for diagnosis of rotavirus infection. Rotavirus-specific hyperimmune calf serum may by used as a serological diagnostic preparation for the detection of human rotavirus antigen.