Dynamics of non-specific antibacterial activity of the peritoneal cells of mice induced with Coxiella burnetii antigen.

It was found that primary immunization with Coxiella burnetii antigen increased mouse resistance to Salmonella typhimurium infection as evidenced by acceleration of bacterial elimination from the peritoneal cavity and a decrease in lethality of experimental animals. The existence of two rises of bactericidal activity of mouse peritoneal cells was ascertained: the "early" on days 1 and 2, and the "late" on day 14 after C. burnetii administration. The first rise was accompanied by some increase in the number of peritoneal cells as well as by some change of their qualitative representation. The second increase of antibacterial activity was detected during the pronounced cellular and humoral immune responses to C. burnetii.     

α1-adrenergic receptors in the liver parenchyma in children: Changes associated with cirrhosis

All-Russian Research Center for Molecular Diagnosis and Treatment, Ministry of Health of Russia. Research Institute of Pediatrics, Russian Academy of Medical Sciences, Moscow. (Presented by Academician of the Russian Academy of Medical Sciences M. Ya. Studenikin.) Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 114, No. 8, pp. 134–135, August, 1992     

Search for methods of lowering the consumption of chlorosulfonic acid in the production of sulfanilamide drugs

Pharmaceutical Chemistry Journal -     

Organization of BCG revaccination of young adults

For the purpose of BCG revaccination of the young people (aged 13-30 years) having a negative tuberculin response, 3 methods of vaccination were practised, including working as a team, launching an expedition and functioning within a residential area. The choice of the method required is dictated by the local conditions and the given task. A high level of tuberculosis infection was recorded, especially among the risk groups in relation to this disease. The circumstances to be taken into account when planning the tuberculosis prevention measures, i. e. BCG revaccination, are defined.     

FGF23 contains two distinct high-affinity binding sites enabling bivalent interactions with α-Klotho

The three members of the endocrine-fibroblast growth factor (FGF) family, FGF19, 21, and 23 are circulating hormones that regulate critical metabolic processes. FGF23 stimulates the assembly of a signaling complex composed of α-Klotho (KLA) and FGF receptor (FGFR) resulting in kinase activation, regulation of phosphate homeostasis, and vitamin D levels. Here we report that the C-terminal tail of FGF23, a region responsible for KLA binding, contains two tandem repeats, repeat 1 (R1) and repeat 2 (R2) that function as two distinct ligands for KLA. FGF23 variants with a single KLA binding site, FGF23-R1, FGF23-R2, or FGF23-wild type (WT) with both R1 and R2, bind to KLA with similar binding affinity and stimulate FGFR1 activation and MAPK response. R2 is flanked by two cysteines that form a disulfide bridge in FGF23-WT; disulfide bridge formation in FGF23-WT is dispensable for KLA binding and for cell signaling via FGFRs. We show that FGF23-WT stimulates dimerization and activation of a chimeric receptor molecule composed of the extracellular domain of KLA fused to the cytoplasmic domain of FGFR and employ total internal reflection fluorescence microscopy to visualize individual KLA molecules on the cell surface. These experiments demonstrate that FGF23-WT can act as a bivalent ligand of KLA in the cell membrane. Finally, an engineered Fc-R2 protein acts as an FGF23 antagonist offering new pharmacological intervention for treating diseases caused by excessive FGF23 abundance or activity.

The large family of fibroblast growth factors (FGFs) has been known for its important roles in regulating critical cellular processes during embryonic development and homeostasis of normal tissues (1–3). While most FGFs act as cytokines or hormonelike proteins that mediate their pleiotropic cellular processes by binding to cell surface receptors endowed with intrinsic tyrosine kinase activity (FGFRs), a subfamily of FGFs (FGF 11–14) was shown to be uniquely expressed intracellularly. The mechanism of action and physiological roles of intracellular FGFs are poorly understood (4–6).In contrast to most receptor tyrosine kinases (RTKs) that are activated by a single ligand molecule that binds with high affinity to the extracellular domain of its cognate RTK with a dissociation constant in the subnanomolar range, the binding affinities of FGFs to FGFRs are, at least, 1,000–10,000 fold weaker with dissociation constants in the submicromolar range (7–9). The weak binding affinities toward FGFRs of the largest subfamily of FGF molecules designated canonical FGFs are offset by interactions with cell surface heparan sulfate proteoglycans (HSPGs). Both biochemical and structural studies revealed how multiple interactions between heparin or HSPG with both FGF and FGFR mediate tight association enabling robust receptor dimerization and tyrosine kinase activation (10, 11).The three endocrine FGFs, FGF19, 21, and 23 are part of an additional subfamily of FGF molecules. Endocrine FGFs function as circulating hormones that play essential roles in the control of various metabolic processes (12). In addition to the conserved FGF-domain found in all FGF ligands, endocrine FGFs contain unique C-terminal tails (CTs) composed of 46 (FGF19), 34 (FGF21), or 89 (FGF23) amino acids that serve as specific and high-affinity ligands for the two members of the Klotho family of surface receptors. It was shown that KLA serves as a high-affinity receptor for FGF23 while β-Klotho (KLB) functions as a high-affinity surface receptor for both FGF19 and FGF21 (13–16). Structural analyses of free and ligand-occupied Klotho proteins revealed the molecular basis underlying the specificity and high affinity of KLA and KLB toward endocrine FGFs. It also showed that Klotho proteins function as the primary receptors for endocrine FGFs whereas FGFR functions as a catalytic subunit that mediates cell signaling via its tyrosine kinase domain (8, 17, 18). Accordingly, endocrine FGFs stimulate their cellular responses by forming a ternary complex with Klotho proteins and FGFRs to induce receptor dimerization, tyrosine kinase activation, and cell signaling. Unlike FGFRs that are ubiquitously expressed, the expressions of KLA and KLB are restricted to specific tissues and organs to enable precise targeting of endocrine FGFs to stimulate their physiological responses in specific cells and tissues (19–22). The ability of endocrine FGFs to circulate is attributed to the loss of conserved heparin binding sites that are essential for the function of canonical FGFs (23).FGF23 is a 32-kDa glycoprotein, mainly produced in the bone by osteoblasts and osteocytes, that serve as a key hormone in regulating phosphate homeostasis, vitamin D, and calcium metabolism (24, 25). Circulating levels of physiologically active FGF23 are regulated by proteolytic cleavage to produce a FGF23 molecule lacking its unique CT (26, 27). The cleavage resulting in FGF23 inactivation prevents assembly and stimulation of the FGF23/FGFR/KLA complex. Additionally, the processing of FGF23 includes several posttranslational modifications which affect its stability and susceptibility toward proteolysis. Secreted FGF23 was shown to be O-glycosylated in its C-terminal cleavage site (28, 29) to protect the protein from C-terminal cleavage. In order for the cleavage site to be exposed, FGF23 has to be first phosphorylated in this region (30). Phosphorylation prevents glycosylation and exposes the cleavage site to proteolysis.In this paper, we demonstrate that the CT of FGF23 contains two tandem repeats and that each repeat binds with high affinity to KLA. This contrasts with FGF19 and FGF21, whose CTs contain a single binding site to KLB. Engineered FGF23 variants containing each of the two repeats individually or both repeats bind specifically to KLA and stimulate cell signaling to a similar extent. We also demonstrate that two cysteine residues flanking the second repeat form a disulfide bridge in FGF23 secreted by mammalian cells. However, both oxidized or unbridged forms of FGF23 exhibit similar KLA binding characteristics and similar cellular stimulatory activities. We also show that FGF23-WT induces mitogen-activated protein kinase (MAPK) activation in cells expressing chimeric KLA-FGFR proteins and use TIRFM imaging of individual KLA molecules on the cell surface to demonstrate that FGF23 has the capacity for simultaneous binding to two KLA molecules. These insights reveal the complexity of FGF23 regulation and its role in assembling the FGF23/FGFR/KLA signaling complex.     

Amplification test-systems in the diagnosis of hemorrhagic fever with renal syndrome and in studies of viral pathogens

The "VectoHantivirus-ampli" test system based on rtPCR was shown as fitting the detection of virus RNA in blood samples of patients with hemorrhagic fever with renal syndrome (HFRS) made at early stages and no later than 7 days from the disease onset. A sequence analysis of viral nucleotide sequences of PCR products produced by the test-system ensured the identification of Hantaviruses (pathogens of HFRS). Two genetic variants of Puumula virus were shown to circulate in the territory of the Bashkortostan Republic; they differ by 10.0-13.8%, one of them is absolutely new. The Hantan virus FE genetic variant was detected in the studied samples from the Khabarovsk Territory.     

Labor conditions of workers monitoring the railways status

The conducted sanitary-and-hygienic investigations contributed to working out the up-to-date sanitary-and-hygienic requirements aimed at maintaining the health status of the mentioned workers, they are also expected to enhance the safety in trains' traffic.