Health care expenditure disparities in the European Union and underlying factors: a distribution dynamics approach

This paper examines health care expenditure (HCE) disparities between the European Union countries over the period 1995-2010. By means of using a continuous version of the distribution dynamics approach, the key conclusions are that the reduction in disparities is very weak and, therefore, persistence is the main characteristic of the HCE distribution. In view of these findings, a preliminary attempt is made to add some insights into potentially main factors behind the HCE distribution. The results indicate that whereas per capita income is by far the main determinant, the dependency ratio and female labour participation do not play any role in explaining the HCE distribution; as for the rest of the factors studied (life expectancy, infant mortality, R&D expenditure and public HCE expenditure share), we find that their role falls somewhat in between

HUMANIZATION OF PUBLIC ADMINISTRATION IN THE CONDITIONS OF TRANSFORMATION PROCESSES: EUROPEAN EXPERIENCE FOR UKRAINE

Most European countries, like Ukraine, have gone through the last two decades through a wave of reforms in the public administration system in line with the New Public Management (NPM). First of all, during the reform process, it was about changing the style, method, and nature of the work of state institutions, increasing the efficiency and effectiveness of their work. The conditions for the implementation and the corresponding results of the reforms differ, which allowed one of the leading experts in the analysis of reforming states to speak of "leaders" and "laggards" in this area. Differences in approaches to public administration led to a modified Model of the state. According to its target functions, the humanization of public administration is a condition for the harmonious activity of a specialist and the enrichment of his potential, the growth of essential forces and abilities. Humanization is a process aimed at developing a manager's personality as a subject, in part, of creative activity. Consider in this article the experience of modernizing public administration on the example of European countries

Fragment-based and structure-guided discovery of perforin inhibitors

Perforin is a pore-forming protein whose normal function enables cytotoxic T and natural killer (NK) cells to kill virus-infected and transformed cells. Conversely, unwanted perforin activity can also result in auto-immune attack, graft rejection and aberrant responses to pathogens. Perforin is critical for the function of the granule exocytosis cell death pathway and is therefore a target for drug development. In this study, by screening a fragment library using NMR and surface plasmon resonance, we identified 4,4-diaminodiphenyl sulfone (dapsone) as a perforin ligand. We also found that dapsone has modest (mM) inhibitory activity of perforin lytic activity in a red blood cell lysis assay in vitro. Sequential modification of this lead fragment, guided by structural knowledge of the ligand binding site and binding pose, and supported by SPR and ligand-detected 19F NMR, enabled the design of nanomolar inhibitors of the cytolytic activity of intact NK cells against various tumour cell targets. Interestingly, the ligands we developed were largely inert with respect to direct perforin-mediated red blood cell lysis but were very potent in the context of perforin's action on delivering granzymes in the immune synapse, the context in which it functions physiologically. Our work indicates that a fragment-based, structure-guided drug discovery strategy can be used to identify novel ligands that bind perforin. Moreover, these molecules have superior physicochemical properties and solubility compared to previous generations of perforin ligands

Structure of granzyme C reveals an unusual mechanism of protease autoinhibition

Proteases act in important homeostatic pathways and are tightly regulated. Here, we report an unusual structural mechanism of regulation observed by the 2.5-Å X-ray crystal structure of the serine protease, granzyme C. Although the active-site triad residues adopt canonical conformations, the oxyanion hole is improperly formed, and access to the primary specificity (S1) pocket is blocked through a reversible rearrangement involving Phe-191. Specifically, a register shift in the 190-strand preceding the active-site serine leads to Phe-191 filling the S1 pocket. Mutation of a unique Glu–Glu motif at positions 192–193 unlocks the enzyme, which displays chymase activity, and proteomic analysis confirms that activity of the wild-type protease can be released through interactions with an appropriate substrate. The 2.5-Å structure of the unlocked enzyme reveals unprecedented flexibility in the 190-strand preceding the active-site serine that results in Phe-191 vacating the S1 pocket. Overall, these observations describe a broadly applicable mechanism of protease regulation that cannot be predicted by template-based modeling or bioinformatic approaches alone

Measuring intra-distribution income dynamics: an application to the European regions

O15, O18, C21,