Azacitidine Omega-3 Self-Assemblies: Synthesis, Characterization, and Potent Applications for Myelodysplastic Syndromes

5-Azacitidine, a cytidine analogue used as a hypomethylating agent, is one of the main drugs for the treatment of myelodysplastic syndromes (MDSs) and acute myeloid leukemia (AML) in the elderly. However, after administration, it exhibits several limitations, including restricted diffusion and cellular internalization due to its hydrophilicity, and a rapid enzymatic degradation by adenosine deaminase. The aim of this study was to improve the drug cell diffusion and protect it from metabolic degradation via the synthesis of amphiphilic prodrugs and their potential self-assembly. Azacitidine was conjugated to two different omega-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). The carboxylic acid group of the omega-3 fatty acids was effectively conjugated to the amine group of the azacitidine base, yielding two amphiphilic prodrugs. Nanoprecipitation of the obtained prodrugs was performed and self-assemblies were successfully obtained for both prodrugs, with a mean diameter of 190 nm, a polydispersity index below 0.2 and a positive zeta potential. The formation of self-assemblies was confirmed using pyrene as a fluorescent dye, and the critical aggregation concentrations were determined: 400 µM for AzaEPA and 688 µM for AzaDHA. Additionally, the stability of the obtained self-assemblies was studied and after 5 days their final stable arrangement was reached. Additionally, cryo-TEM revealed that the self-assemblies attain a multilamellar vesicle supramolecular structure. Moreover, the obtained self-assemblies presented promising cytotoxicity on a leukemia human cell line, having a low IC50 value, comparable to that of free azacitidine.

The Politics of Appointment of Top Civil Servants: Career Backgrounds and Civil Service Politicization in the Czech Republic

This contribution seeks to answer the question whether the new civil service legislation that entered into force in 2015 in the Czech Republic led to the depoliticization of the country’s ministerial bureaucracy. To that end, we compare the career backgrounds of top civil servants before and after the entry into force of the new Civil Service Act. The article examines the career backgrounds of the persons appointed as ministerial deputies between 2013 and 2018, focusing on their last “pre-deputy” jobs and considering a broader set of their career attributes. A focus on the previous job reveals that even before the law was introduced, bureaucrats constituted the largest share of appointees, and their share even increased with the new legislation. The incidence of deputies appointed directly from party-related jobs dropped considerably. However, when a broader set of career attributes is considered, the share of partisans among the pre-2015 deputies nearly matches that of the career bureaucrats. Ostensibly political careers among the post-2015 deputies declined but remain significant. Hence, there has been a decline in the open politicization of the ministerial bureaucracy after 2015. Party political effects also matter, as the new ANO party, after entering the executive, has taken a different approach to top bureaucratic appointments than the other major governing Czech parties. Typically, deputies appointed into the positions under the ANO’s control would not have links to the party itself but would be recruited via non-party channels, e.g. from pre-political networks of the ANO ministers and leaders. Consequently, though less politicized by party agents, the current Czech system is more a product of choices made by government ministers of the day than a stable arrangement resulting from firmly established norms and rules.

Public Administration and the Study of Political Order: Towards a Framework for Analysis

The contribution of this study is two-fold: First, it outlines a conceptual framework on political order; and secondly, it offers empirical illustrations on the case of Nordic cooperation. Taken together, the article makes a plea for public administration scholarship in the study of political order. Political order consists of a relatively stable arrangement of institutions that are fairly formalized and institutionalized. A common political order, moreover, entails that relevant institutions: (i) are fairly independent of pre-existing institutions; (ii) are relatively integrated and internally cohesive; and (iii) are reasonably able to influence governance processes within other institutions. The article empirically suggests that Nordic-level institutions are less likely to act relatively integrated and independently of member-state governments as well as being able to wield significant influence on public governance processes within member-state institutions.

Considerations About Bi and Pb in the Crystal Structure of Cu-Bearing Tourmaline

Copper- and Mn-bearing elbaitic tourmaline (“Paraíba tourmaline”) sometimes contains significant amounts of Pb and Bi. Their position in the tourmaline crystal structure was studied with correlation analysis and bond valence calculations. Correlations between the F content and the X-site charge allow predicting the X-site occupancy. Three sets of tourmaline analyses were studied: (1) Pb-rich tourmalines from the Minh Tien pegmatite, Vietnam; (2) Cu-, Pb- and Bi-bearing tourmalines from the Mulungu mine, Brazil; (3) Cu- and Bi-bearing tourmalines from the Alto dos Quintos mine, Brazil. Two correlations were plotted: (1) the charge by considering only Na1+, Ca2+ and K1+; (2) the charge by adding Pb2+ and Bi3+ to the X-site charge. When plotting correlations for the Minh Tien tourmalines, the correlation significantly improves by adding Pb2+ to the X site. For the Alto dos Quintos tourmalines, only a slight increase of the correlation coefficient is observed, while such a correlation for tourmalines from Mulungu interestingly shows a slight decrease of the correlation coefficient. Bond valence calculations revealed that Bi3+ and Pb2+ can indeed occupy the X site via BiLi(NaAl)−1, PbLi(NaCu)−1 and possibly PbCu(NaAl)−1 substitutions as seen in the investigated tourmaline samples. At the Y site, Pb4+ can be substituted via PbLi(AlCu)−1, and PbVO(AlVOH)−1, while Bi5+ does not have any stable arrangement in Cu-bearing fluor-elbaite. The occurrence of Pb4+ at the Y site could be one explanation for the results of the correlations of the Mulungu tourmalines. Another explanation could be that during the tourmaline crystallization some additional Bi and Pb came into the pegmatitic system and hence disturbed the correlation between the average X-site charge and the F content. Further plots of such correlations in “Paraíba tourmaline” samples might also help to distinguish between the worldwide localities of these rare and sought-after tourmalines.

ON THE NA’T GHAZALS OF ABDURAHMAN JAMI AND ALISHER NAVAI

The article deals with a comparative study of na’t ghazals of the great figures of the Persian and Turkic poetry – Abdurahman Jami and Alisher Navois’ Devans. The ghasals play an important role for the evaluation of the XV century’s religious-philosophical and artistic thinking. In Alisher Navoi's ‘Khazoyin ul-maoni’, which consists of four devan and n’at ghazals of A. Jami’s three devans, which deals with the subject-matters about Muhammad (s.a.v)’s lifestyle, khadises, miracles sent to him and his role in the life of a human being have been stated. Author analyzes the na’ts by both poets’ ghazals, in particular the subject of the artistic knowledge of several images and concepts: Mecca, Batho, Ka'ba, Medina, Yasrib, Zamzam, Prophethood, Adam, Khatam al-Anbiya, Hadisand others. According to the placement of na’t ghazals of A. Navai’s devan, the author emphasizes that they have a stable arrangement in the composition of devons, unlike of A. Jami’s ghazals, which is linked with ‘Shawahid un- Nubuwat’, the life-style of the Prophet Muhammad.

When Equity Matters for Marital Stability: Comparing German and American Couples

Comparing West Germany and the United States, we analyze the association between equity - in terms of the relative gender division of paid and unpaid work hours – and the risk of marriage dissolution. Our aim is to identify under what conditions equity influences couple stability. We apply event-history analysis to marriage histories using data from the German Socio-Economic Panel for Western Germany and the Panel Study of Income Dynamics for the United States for the period 1986 to 2009. For the United States, we find that deviation from equity is particularly destabilizing when the wife under-benefits, and when both partners' paid work hours are similar. In West Germany, equity is less salient. Instead we find that the male breadwinner model remains the single most stable arrangement.

Beyond icosahedral symmetry in packings of proteins in spherical shells

The formation of quasi-spherical cages from protein building blocks is a remarkable self-assembly process in many natural systems, where a small number of elementary building blocks are assembled to build a highly symmetric icosahedral cage. In turn, this has inspired synthetic biologists to design de novo protein cages. We use simple models, on multiple scales, to investigate the self-assembly of a spherical cage, focusing on the regularity of the packing of protein-like objects on the surface. Using building blocks, which are able to pack with icosahedral symmetry, we examine how stable these highly symmetric structures are to perturbations that may arise from the interplay between flexibility of the interacting blocks and entropic effects. We find that, in the presence of those perturbations, icosahedral packing is not the most stable arrangement for a wide range of parameters; rather disordered structures are found to be the most stable. Our results suggest that (i) many designed, or even natural, protein cages may not be regular in the presence of those perturbations and (ii) optimizing those flexibilities can be a possible design strategy to obtain regular synthetic cages with full control over their surface properties.

Stability Of Superposed Fluids Through Magnetic Field With Suspended Particles Of Different Permeability Saturated Through Porous Layer

The instability of plane interface between two superposed Rivlin-Ericksen elastico-viscous fluids saturated through a porous medium has been studied to include the suspended (dust) particles effect. Following the linearized stability theory and normal mode analysis the dispersion relation is obtained. For stationary convection, the Rivlin-Ericksen elastico-viscous fluid behaves like Newtonian fluids. It found that for a potentially stable arrangement the Rivlin-Ericksen elastico-viscous fluid of different permeabilities in the presence of suspended particles in a porous medium is stable, whereas in a potentially unstable case instability of the system occurs. In the presence of a magnetic field for a potentially stable arrangement the system is always stable and for the potentially unstable arrangement, the magnetic field succeeds in stabilizing certain wave-number band which was unstable in the absence of the magnetic field.

Hydrodynamic and Hydromagnetic Stability of Two Superposed Elastico – Viscous Fluids of Different Permeability with Dust in Porous Medium

Rayleigh-Taylor instability of two superposed Walters’ B has elastico-viscous fluids in a uniform magnetic field through a porous medium with different permeability been studied to include the suspended (dust) particles effect. Using normal mode technique a dispersion relation has been derived. The stability analysis has been carried out. The magnetic field stabilizes the unstable configuration for the wave number band K > K* in which the system is unstable in the absence of the magnetic field. It is also found that for a potential stable arrangement for Walters B’ elastico-viscous fluids of different permeabilities in the presence of suspended particles through a porous medium the system is stable, whereas in the potentially unstable case instability of the system occurs.

Identifying the impact of G-Quadruplexes on Affymetrix 3′ Arrays using Cloud Computing

SummaryA tetramer quadruplex structure is formed by four parallel strands of DNA/ RNA containing runs of guanine. These quadruplexes are able to form because guanine can Hoogsteen hydrogen bond to other guanines, and a tetrad of guanines can form a stable arrangement. Recently we have discovered that probes on Affymetrix GeneChips that contain runs of guanine do not measure gene expression reliably. We associate this finding with the likelihood that quadruplexes are forming on the surface of GeneChips.In order to cope with the rapidly expanding size of GeneChip array datasets in the public domain, we are exploring the use of cloud computing to replicate our experiments on 3′ arrays to look at the effect of the location of G-spots (runs of guanines). Cloud computing is a recently introduced high-performance solution that takes advantage of the computational infrastructure of large organisations such as Amazon and Google.We expect that cloud computing will become widely adopted because it enables bioinformaticians to avoid capital expenditure on expensive computing resources and to only pay a cloud computing provider for what is used. Moreover, as well as financial efficiency, cloud computing is an ecologically-friendly technology, it enables efficient data-sharing and we expect it to be faster for development purposes. Here we propose the advantageous use of cloud computing to perform a large data-mining analysis of public domain 3′ arrays.