Multiscaling analysis of ferroelectric domain wall roughness

Using multiscaling analysis, we compare the characteristic roughening of ferroelectric domain walls in PZT thin films with numerical simulations of weakly pinned one-dimensional interfaces. Although at length scales up to a length scale greater or equal to 5 microns the ferroelectric domain walls behave similarly to the numerical interfaces, showing a simple mono-affine scaling (with a well-defined roughness exponent), we demonstrate more complex scaling at higher length scales, making the walls globally multi-affine (varying roughness exponent at different observation length scales). The dominant contributions to this multi-affine scaling appear to be very localized variations in the disorder potential, possibly related to dislocation defects present in the substrate.Comment: 5 pages, 4 figure

Sputtering of benzene sample by large Ne, Ar and Kr clusters : molecular dynamics computer simulations

Molecular dynamics simulations are employed to probe the role of an impact angle on emission efficiency of organic molecules sputtered from benzene crystal bombarded by 15 keV $Ne_{2953}$, $Ar_{2953}$, and $Kr_{2953}$ clusters. It is found that both the cluster type and the angle of incidence have significant effect on the emission efficiency. The shape of the impact angle dependence does not resemble the dependence characteristic for medium size clusters ($C_{60}, Ar_{366}$), where sputtering yield only moderately increases with the impact angle, has a shallow maximum around 40° and then decreases. On the contrary, for the large projectiles ($Ne_{2953}, Ar_{2953}$, and $Kr_{2953}$) the emission efficiency steeply increases with the impact angle, has a pronounced maximum around 55° followed by rapid signal decay. It has been found that the sputtering yield is the most sensitive to the impact angle change for Kr cluster projectiles, while change of the impact angle of Ne projectile has the smallest effect on the efficiency of material ejection

The CHK1 inhibitor MU380 significantly increases the sensitivity of human docetaxel-resistant prostate cancer cells to gemcitabine through the induction of mitotic catastrophe.

As treatment options for patients with incurable metastatic castration-resistant prostate cancer (mCRPC) are considerably limited, novel effective therapeutic options are needed. Checkpoint kinase 1 (CHK1) is a highly conserved protein kinase implicated in the DNA damage response (DDR) pathway that prevents the accumulation of DNA damage and controls regular genome duplication. CHK1 has been associated with prostate cancer (PCa) induction, progression, and lethality; hence, CHK1 inhibitors SCH900776 (also known as MK-8776) and the more effective SCH900776 analog MU380 may have clinical applications in the therapy of PCa. Synergistic induction of DNA damage with CHK1 inhibition represents a promising therapeutic approach that has been tested in many types of malignancies, but not in chemoresistant mCRPC. Here, we report that such therapeutic approach may be exploited using the synergistic action of the antimetabolite gemcitabine (GEM) and CHK1 inhibitors SCH900776 and MU380 in docetaxel-resistant (DR) mCRPC. Given the results, both CHK1 inhibitors significantly potentiated the sensitivity to GEM in a panel of chemo-naïve and matched DR PCa cell lines under 2D conditions. MU380 exhibited a stronger synergistic effect with GEM than clinical candidate SCH900776. MU380 alone or in combination with GEM significantly reduced spheroid size and increased apoptosis in all patient-derived xenograft 3D cultures, with a higher impact in DR models. Combined treatment induced premature mitosis from G1 phase resulting in the mitotic catastrophe as a prestage of apoptosis. Finally, treatment by MU380 alone, or in combination with GEM, significantly inhibited tumor growth of both PC339-DOC and PC346C-DOC xenograft models in mice. Taken together, our data suggest that metabolically robust and selective CHK1 inhibitor MU380 can bypass docetaxel resistance and improve the effectiveness of GEM in DR mCRPC models. This approach might allow for dose reduction of GEM and thereby minimize undesired toxicity and may represent a therapeutic option for patients with incurable DR mCRPC

The CHK1 inhibitor MU380 significantly increases the sensitivity of human docetaxel-resistant prostate cancer cells to gemcitabine through the induction of mitotic catastrophe

As treatment options for patients with incurable metastatic castration-resistant prostate cancer (mCRPC) are considerably limited, novel effective therapeutic options are needed. Checkpoint kinase 1 (CHK1) is a highly conserved protein kinase implicated in the DNA damage response (DDR) pathway that prevents the accumulation of DNA damage and controls regular genome duplication. CHK1 has been associated with prostate cancer (PCa) induction, progression, and lethality; hence, CHK1 inhibitors SCH900776 (also known as MK-8776) and the more effective SCH900776 analog MU380 may have clinical applications in the therapy of PCa. Synergistic induction of DNA damage with CHK1 inhibition represents a promising therapeutic approach that has been tested in many types of malignancies, but not in chemoresistant mCRPC. Here, we report that such therapeutic approach may be exploited using the synergistic action of the antimetabolite gemcitabine (GEM) and CHK1 inhibitors SCH900776 and MU380 in docetaxel-resistant (DR) mCRPC. Given the results, both CHK1 inhibitors significantly potentiated the sensitivity to GEM in a panel of chemo-naïve and matched DR PCa cell lines under 2D conditions. MU380 exhibited a stronger synergistic effect with GEM than clinical candidate SCH900776. MU380 alone or in combination with GEM significantly reduced spheroid size and increased apoptosis in all patient-derived xenograft 3D cultures, with a higher impact in DR models. Combined treatment induced premature mitosis from G1 phase resulting in the mitotic catastrophe as a prestage of apoptosis. Finally, treatment by MU380 alone, or in combination with GEM, significantly inhibited tumor growth of both PC339-DOC and PC346C-DOC xenograft models in mice. Taken together, our data suggest that metabolically robust and selective CHK1 inhibitor MU380 can bypass docetaxel resistance and improve the effectiveness of GEM in DR mCRPC models. This approach might allow for dose reduction of GEM and thereby minimize undesired toxicity and may represent a therapeutic o

In silico design of novel probes for the atypical opioid receptor MRGPRX2

The primate-exclusive MRGPRX2 G protein-coupled receptor (GPCR) has been suggested to modulate pain and itch. Despite putative peptide and small molecule MRGPRX2 agonists, selective nanomolar potency probes have not yet been reported. To identify a MRGPRX2 probe, we first screened 5,695 small molecules and found many opioid compounds activated MRGPRX2, including (−)- and (+)-morphine, hydrocodone, sinomenine, dextromethorphan and the prodynorphin-derived peptides, dynorphin A, dynorphin B, and α- and β-neoendorphin. We used these to select for mutagenesis-validated homology models and docked almost 4 million small molecules. From this docking, we predicted ZINC-3573, which represents a potent MRGPRX2-selective agonist, showing little activity against 315 other GPCRs and 97 representative kinases, and an essentially inactive enantiomer. ZINC-3573 activates endogenous MRGPRX2 in a human mast cell line inducing degranulation and calcium release. MRGPRX2 is a unique atypical opioid-like receptor important for modulating mast cell degranulation, which can now be specifically modulated with ZINC-3573

Derived marine microfossils in loesses of the last glaciation and their significance in the reconstruction of loess-forming processes in central-eastern Europe

Documented examples of type sections with Pleistocene deposits in southern Poland (Tłumaczów, Branice, Wożuczyn, Tyszowce, Hrubieszów) and southwestern Ukraine (Bojanice, Horokhov, Zhorniv) indicate that loesses of the last glaciation (Vistulian, Valdayan) contain derived marine microfossils of Cretaceous age. The microfossil assemblages studied are richly represented by foraminifers, which are mostly well-preserved, and derived mainly Cretaceous, forms. Suitable Late Cretaceous exposures are nearby, around data shows that these rocks and their debris, and the overlying Pleistocene tills and sands, which are older than the loesses, represent one of the main sources of the loess silt. This fact and the heavy mineral content are evidence of the participation of local material in loess-forming processes in central-eastern Europe. The spatial distribution of the sections studied in relation to the determined sources of loess material indicate that the accumulation of the loesses took place mainly in the presence of western and/or northwestern winds in the lower parts of the atmosphere