Tatiana Soboleva Honors Portfolio

Tatiana Soboleva\u27s honors portfolio captured in December 2015

3-Hydroxyflavones and 3-Hydroxy-4-oxoquinolines as Carbon Monoxide-Releasing Molecules

Carbon monoxide-releasing molecules (CORMs) that enable the delivery of controlled amounts of CO are of strong current interest for applications in biological systems. In this review, we examine the various conditions under which CO is released from 3-hydroxyflavones and 3-hydroxy-4-oxoquinolines to advance the understanding of how these molecules, or derivatives thereof, may be developed as CORMs. Enzymatic pathways from quercetin dioxygenases and 3-hydroxy-4-oxoquinoline dioxygenases leading to CO release are examined, along with model systems for these enzymes. Base-catalyzed and non-redox-metal promoted CO release, as well as UV and visible light-driven CO release from 3-hydroxyflavones and 3-hydroxy-4-oxoquinolines, are summarized. The visible light-induced CO release reactivity of recently developed extended 3-hydroxyflavones and a 3-hydroxybenzo[g]quinolone, and their uses as intracellular CORMs, are discussed. Overall, this review provides insight into the chemical factors that affect the thermal and photochemical dioxygenase-type CO release reactions of these heterocyclic compounds

Mitochondrial-targeted CO-releasing Molecule

Carbon monoxide is an endogenously produced signalling molecule that is known to exert cytoprotective and homeostatic regulatory functions. Due to its high affinity for heme proteins, one of the recognized targets for CO are mitochondria and their electron transport chain. To date, there are four reported CORMs (CORM-2, CORM-3, CORM-A1, and CORM-401) that have been used as CO donors in mitochondrial studies. However, the differences with respect to their cell penetration, localization and solution-driven CO release chemistry could make the comparison of mitochondrial response data for these systems challenging. To investigate the impact of mitochondrial-specific CO delivery, we have designed and characterized the first mitochondrial-targeted, visible light-triggered CO-releasing molecule. This compound is trackable (green emission) and triggarable with visible light to deliver CO intracellularly. This photoCORM was tested in the context of the effect of CO release on mitochondrial bioenergetics (including oxygen consumption rates (OCR) and glycolysis (ECAR)) which are compared to results from a cytosolic analogue. These studies provide insight into the effects of CO delivery in proximity to mitochondria versus cytosolic delivery

Activity of State-owned Enterprises: How to Evaluate their Effectiveness?

We show that economic well-being is determined by various factors. But at the same time objective attributes don’t always affect the subjective measure of personal well-being. However the formation of stable macroeconomic environment is a core condition of a social development. Modern society claims to increase the number of state functions related to human wellbeing, economic growth, national defense capability etc. Such expansion has to be evaluated. In this paper, we define some approaches to the performance evaluation of the state institutions of development. We analyze the activity of State Corporation Deposit Insurance Agency in the context of the human wellbeing in Russia

CO Sense and Release Flavonols: Progress toward the Development of an Analyte Replacement PhotoCORM for Use in Living Cells

Carbon monoxide (CO) is a signaling molecule in humans. Prior research suggests that therapeutic levels of CO can have beneficial effects in treating a variety of physiological and pathological conditions. To facilitate understanding of the role of CO in biology, molecules that enable fluorescence detection of CO in living systems have emerged as an important class of chemical tools. A key unmet challenge in this field is the development of fluorescent analyte replacement probes that replenish the CO that is consumed during detection. Herein, we report the first examples of CO sense and release molecules that involve combining a common CO-sensing motif with a light-triggered CO-releasing flavonol scaffold. A notable advantage of the flavonol-based CO sense and release motif is that it is trackable via fluorescence in both its pre- and postsensing (pre-CO release) forms. In vitro studies revealed that the PdCl2 and Ru(II)-containing CORM-2 used in the CO sensing step can result in metal coordination to the flavonol, which minimizes the subsequent CO release reactivity. However, CO detection followed by CO release is demonstrated in living cells, indicating that a cellular environment mitigates the flavonol/metal interactions

Properties of Flavonol-based PhotoCORM in Aqueous Buffered Solutions: Influence of Metal Ions, Surfactants and Proteins on Visible Light-induced CO Release

The properties of the extended flavonol 3-hydroxy-2-phenyl-benzo[g]chromen-4-one (2a) in DMSO : aqueous buffer solutions at pH = 7.4, including in the presence of metal ions, surfactants and serum albumin proteins, have been examined. Absorption and emission spectral studies of 2a in 1 : 1 DMSO : PBS buffer (pH = 7.4) indicate that a mixture of neutral and anionic forms of the flavonol are present. Notably, in 1 : 1 DMSO : TRIS buffer (pH = 7.4) only the neutral form of the flavonol is present. These results indicate that the nature of the buffer influences the acid/base equilibrium properties of 2a. Introduction of a Zn(II) complex of 2a− to a 1 : 1 DMSO : aqueous buffer (TRIS or PBS, pH = 7.4) solution produces absorption and emission spectral features consistent with the presence of a mixture of neutral 2a along with Zn(II)-coordinated or free 2a−. The nature of the anionic species present depends on the buffer composition. PBS buffered solutions (pH = 7.4) containing the surfactants CTAB or SDS enable 2a to be solubilized at a much lower percentage of DMSO (3.3–4.0%). Solutions containing the cationic surfactant CTAB include a mixture of 2a and 2a− whereas only the neutral flavonol is present in SDS-containing buffered solution. Compound 2a is also solubilized in TRIS buffer solutions at low cocentrations of DMSO (3.3%, pH = 7.4) in the presence of serum albumin proteins. Stern–Volmer analysis of the quenching of the inherent protein fluorescence indicates static binding of 2a to the proteins. The binding constant for this interaction is lower than that found for naturally-occurring flavonols (quercetin or morin) or 3-hydroxyflavone. Compound 2a binds to Site I of bovine and human serum albumin proteins as indicated by competition studies with warfarin and ibuprofen, as well as by docking investigations. The quantum yield for CO release from 2a (λirr = 419 nm) under aqueous conditions ranges from 0.0006(3) when the compound is bound to bovine serum albumin to 0.017(1) when present as a zinc complex in a 1 : 1 DMSO : H2O solution. Overall, the results of these studies demonstrate that 2a is a predictable visible light-induced CO release compound under a variety of aqueous conditions, including in the presence of proteins

Short Histone H2A Variants: Small in Stature but not in Function

The dynamic packaging of DNA into chromatin regulates all aspects of genome function by altering the accessibility of DNA and by providing docking pads to proteins that copy, repair and express the genome. Different epigenetic-based mechanisms have been described that alter the way DNA is organised into chromatin, but one fundamental mechanism alters the biochemical composition of a nucleosome by substituting one or more of the core histones with their variant forms. Of the core histones, the largest number of histone variants belong to the H2A class. The most divergent class is the designated “short H2A variants” (H2A.B, H2A.L, H2A.P and H2A.Q), so termed because they lack a H2A C-terminal tail. These histone variants appeared late in evolution in eutherian mammals and are lineage-specific, being expressed in the testis (and, in the case of H2A.B, also in the brain). To date, most information about the function of these peculiar histone variants has come from studies on the H2A.B and H2A.L family in mice. In this review, we describe their unique protein characteristics, their impact on chromatin structure, and their known functions plus other possible, even non-chromatin, roles in an attempt to understand why these peculiar histone variants evolved in the first placeThis research was funded by the Australian National and Health Medical Research Council, grant application number 11423

Clarification of the role of N-glycans on the common beta-subunit of the human IL-3, IL-5 and GM-CSF receptors and the murine IL-3 beta-receptor in ligand-binding and receptor activation

Granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin (IL)-3 and IL-5 are related cytokines that play key roles in regulating the differentiation, proliferation, survival and activation of myeloid blood cells. The cell surface receptors for these cytokines are composed of cytokine-specific α-subunits and a common β-receptor (βc), a shared subunit that is essential for receptor signaling in response to GM-CSF, IL-3 and IL-5. Previous studies have reached conflicting conclusions as to whether N-glycosylation of the βc-subunit is necessary for functional GM-CSF, IL-3 and IL-5 receptors. We sought to clarify whether βc N-glycosylation plays a role in receptor function, since all structural studies of human βc to date have utilized recombinant protein lacking N-glycosylation at Asn328. Here, by eliminating individual N-glycans in human βc and the related murine homolog, βIL-3, we demonstrate unequivocally that ligand-binding and receptor activation are not critically dependent on individual N-glycosylation sites within the β-subunit although the data do not preclude the possibility that N-glycans may exert some sort of fine control. These studies support the biological relevance of the X-ray crystal structures of the human βc domain 4 and the complete ectodomain, both of which lack N-glycosylation at Asn328

Organization of physical training at plants (origins, modernity, prospects)

The article researches physical training organization Soviet plants and at those of the present time. Organization of physical activity at Russian plants first appeared in the Soviet period. Also economic efficiency and social significance of sport activities in the Soviet period and nowadays are presented. The article also characterizes the process of formation and implementation of industrial gymnastics and other forms of physical culture at Siberian plants. The data about the most popular sports events and the organization of the working process together with industrial gymnastics at the place of residence are given. The article contains examples of organization of physical activities and sports events in the country nowadays. From this point of view of the experience, all-round implementation of physical-cultural activity is of intense interest. Some international corporations apply physical culture and sports activities as factors improving labour productivity of the staff. In that context, all-round revival of traditions of the bygone epoch is of a great significance for our country