Dynamics and disorder:on the stability of pyrazinamide polymorphs

This article focuses on the structure and relative stability of four pyrazinamide polymorphs. New single crystal X-ray diffraction data collected for all forms at 10 K and 122 K are presented. By combining periodic ab initio DFT calculations with normal-mode refinement against X-ray diffraction data, both enthalpic and entropic contributions to the free energy of all polymorphs are calculated. On the basis of the estimated free energies, the stability order of the polymorphs as a function of temperature and the corresponding solid state phase transition temperatures are anticipated. It can be concluded that the α and γ forms have higher vibrational entropy than that of the β and δ forms and therefore they are significantly more stabilized at higher temperatures. Due to the entropy which arises from the disorder in γ form, it overcomes form α and is the most stable form at temperatures above ∼500 K. Our findings are in qualitative agreement with the experimental calorimetry results

New refinement strategies for pseudoatom databank - towards wider range of application

Pseudoatom databanks, collecting parameters of multipole model of electron densities for various atom types, are used to replace Independent Atom Model by the more accurate Transferable Aspherical Atom Model (TAAM) in crystal structure refinement. They may also be used to reconstruct electron density of a molecule, crystal or biomacromolecular complex in fast yet quite accurate way and compute from it various properties, like energy of electrostatic interactions, for example. Even faster, but similarly accurate in electrostatic energy estimations model exists, the aug-PROmol. Model analogous to aug-PROmol cannot be built from the current pseudoatom databanks, as they perform badly when truncated to the monopole level. Here we searched for new strategies of multipole model refinements, leading to better parametrization already at the monopole level. This would allow to create in a single route of model parametrization a pseudoatom databank, which would be suitable for both crystal structure refinement and rapid electrostatic energy calculations. Such a route does not exist yet, because as we show here, the aug-PROmol model, alternative to the current pseudoatom databanks, is not suitable for crystal X-ray structure refinement. Here we show that cumulative approach to multipole model refinements, as oppose to simultaneous or iterative refinements of all multipole model parameters (Pv, κ, Plm, κ\u27) leads to substantially different models of electron density. Cumulative refinement of Plm first and then κ\u27 parameters is much worse than simultaneous. It results in electron density model giving wrong estimates of electrostatic interaction energies and atomic displacement parameters. Cumulative refinement of two blocks of parameters, Pv and κ first and then Plm and κ\u27, on the other hand, leads to the Pv|Plm’ model having promising properties. It is similarly good as University at Buffalo DataBank (UBDB) of pseudoatoms in X-ray structure TAAM refinement and electrostatic energy estimations, especially for less polar molecules. When truncated to monopole level, the Pv model has a chance to replace the aug-PROmol in fast yet accurate electrostatics energy calculations, although some improvements in κ parametrization for polar functional groups are still needed. The Pv|Plm’ model is also a source of point charges which behave similarly to the RESP charges in electrostatic interaction energy estimations

Decreased Expression of SRSF2 Splicing Factor Inhibits Apoptotic Pathways in Renal Cancer

Serine and arginine rich splicing factor 2(SRSF2) belongs to the serine/arginine (SR)-rich family of proteins that regulate alternative splicing. Previous studies suggested that SRSF2 can contribute to carcinogenic processes. Clear cell renal cell carcinoma (ccRCC) is the most common subtype of kidney cancer, highly aggressive and difficult to treat, mainly due to resistance to apoptosis. In this study we hypothesized that SRSF2 contributes to the regulation of apoptosis in ccRCC. Using tissue samples obtained from ccRCC patients, as well as independent validation on The Cancer Genome Atlas (TCGA) data, we demonstrate for the first time that expression of SRSF2 is decreased in ccRCC tumours when compared to non-tumorous control tissues. Furthermore, by employing a panel of ccRCC-derived cell lines with silenced SRSF2 expression and qPCR arrays we show that SRSF2 contributes not only to splicing patterns but also to expression of multiple apoptotic genes, including new SRSF2 targets: DIABLO, BIRC5/survivin, TRAIL, BIM, MCL1, TNFRSF9, TNFRSF1B, CRADD, BCL2L2, BCL2A1, and TP53. We also identified a new splice variant of CFLAR, an inhibitor of caspase activity. These changes culminate in diminished caspase-9 activity and inhibition of apoptosis. In summary, we show for the first time that decreased expression of SRSF2 in ccRCC contributes to protection of cancer cells viability