Full control of polarization in ferroelectric thin films using growth temperature to modulate defects

P.P. and C.W. acknowledge partial support by Swiss National Science Foundation Division II grant 200021_178782. L.R.D. acknowledges support from the US National Science Foundation under grant DMR‐1708615. L.W.M. acknowledges support from the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences, Materials Sciences and Engineering Division under Contract No. DE‐AC02‐05‐CH11231 (Materials Project program KC23MP) for the growth and study of defect structures in ferroic materials. A.B.N. gratefully acknowledges support from the Engineering and Physics Sciences Research Council (EPSRC) through grants EP/R023751/1 and EP/L017008/1.Deterministic control of the intrinsic polarization state of ferroelectric thin films is essential for device applications. Independently of the well-established role of electrostatic boundary conditions and epitaxial strain, the importance of growth temperature as a tool to stabilize a target polarization state during thin film growth is shown here. Full control of the intrinsic polarization orientation of PbTiO3 thin films is demonstrated-from monodomain up, through polydomain, to monodomain down as imaged by piezoresponse force microscopy-using changes in the film growth temperature. X-ray diffraction and scanning transmission electron microscopy reveal a variation of c-axis related to out-of-plane strain gradients. These measurements, supported by Ginzburg-Landau-Devonshire free energy calculations and Rutherford backscattering spectroscopy, point to a defect mediated polarization gradient initiated by a temperature dependent effective built-in field during growth, allowing polarization control not only under specific growth conditions, but ex-situ, for subsequent processing and device applications.Publisher PDFPeer reviewe

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

Ekspercka analiza przyczynowo-skutkowa awarii zabytkowych obiektów budowlanych z uwzględnieniem czynników trudnomierzalnych

The protection of Polish architectural heritage in the former eastern borderlands, accomplished through the conservation and technical securing of historical structures, constitutes one of the main programmes that are implemented by the Ministry of Culture and National Heritage. Currently, many Polish historical buildings in the former eastern borderlands are in a very bad technical condition. The load-bearing systems of these elements, as well as elements of their finish, require immediate emergency securing work. The basic steps that precede conservation work are emergency structural works, which guarantee the durability and stability of the entire historical substance. The specifics and complexity of the problem of the failure of historical buildings often demands an in-depth analysis of a series of factors that are difficult to measure and which are responsible for the cause and effect relationship during the early stage of the technical evaluation of a structure. The analyses of failures of numerous historical structures, for instance that were carried out by the authors, have become the inspiration for the search for effective methods of analysis that would allow for an in-depth analysis of the causes and effects of the failures in question. The DEMATEL method (Decision Making Trial and Evaluation Laboratory) that has been presented in this work, and its fuzzy extension, has lately become one of the more popular methods used in the cause-and-effect analysis of various phenomena. The authors demonstrated how this method works on the example of the evaluation and securing of the load-bearing system of the XVII Collegiate church of the Holy Trinity in the town of Olykha in the Volhynskiy Oblast, Ukraine.W artykule przedstawione zostało zagadnienie związane z analizą przyczynowo-skutkową awarii obiektów zabytkowych z uwzględnieniem czynników trudnomierzalnych. Przeprowadzone przez autorów artykułu analizy uszkodzeń wielu obiektów zabytkowych stały się przyczynkiem do poszukiwania efektywnych metod analizy, które pozwolą na wstępną, wnikliwą identyfikację przyczyn i skutków związanych z awarią tego typu obiektów. Zaproponowana w pracy metoda DEMATEL (Fuzzy Decision Making Trial and Evaluation Laboratory) jest ostatnio jedną z bardziej popularnych metod używanych do analizy przyczynowo-skutkowej różnych zjawisk. Metoda ta zdaniem autorów niniejszego artykułu jest właściwym narzędziem służącym do analizy zawartego w pracy problemu technicznego. W literaturze można znaleźć wiele przykładów zastosowania metody DEMETEL do analizy zjawisk przyczynowo skutkowych w budownictwie np. [5,6,7]. W powyższych pozycjach nie uwzględnia się jednak niepewności ocen eksperckich, która w przypadku badania zjawisk trudnomierzalnych zachodzących w obiekcie zabytkowym jest istotna. Dlatego w celu uwzględnienia w analizie niepewności eksperckich ocen oraz agregacji rozbieżnych opinii autorzy niniejszego artykułu zaproponowali zastosowanie rozmytego rozszerzenia [3,9] metody DEMATEL poprzez wprowadzenie do jej algorytmu elementów logiki rozmytej [10,17,18,19]. Działanie powyższej metody autorzy zademonstrowali na przykładzie oceny i zabezpieczenia ustroju nośnego XVII wiecznej Kolegiaty p.w. Św. Trójcy w miejscowości Ołyka w Obwodzie Wołyńskim na Ukrainie

Expert Cause and Effect Analysis of the Failure of Historical Structures Taking Into Account Factors That are Difficult to Measure

The protection of Polish architectural heritage in the former eastern borderlands, accomplished through the conservation and technical securing of historical structures, constitutes one of the main programmes that are implemented by the Ministry of Culture and National Heritage. Currently, many Polish historical buildings in the former eastern borderlands are in a very bad technical condition. The load-bearing systems of these elements, as well as elements of their finish, require immediate emergency securing work. The basic steps that precede conservation work are emergency structural works, which guarantee the durability and stability of the entire historical substance. The specifics and complexity of the problem of the failure of historical buildings often demands an in-depth analysis of a series of factors that are difficult to measure and which are responsible for the cause and effect relationship during the early stage of the technical evaluation of a structure. The analyses of failures of numerous historical structures, for instance that were carried out by the authors, have become the inspiration for the search for effective methods of analysis that would allow for an in-depth analysis of the causes and effects of the failures in question. The DEMATEL method (Decision Making Trial and Evaluation Laboratory) that has been presented in this work, and its fuzzy extension, has lately become one of the more popular methods used in the cause-and-effect analysis of various phenomena. The authors demonstrated how this method works on the example of the evaluation and securing of the load-bearing system of the XVII Collegiate church of the Holy Trinity in the town of Olykha in the Volhynskiy Oblast, Ukraine

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

Methods Of Testing And Assessing The Technical Condition Of Chosen Building Structures Located In The Area Of The Auschwitz-Birkenau National Museum In Oświęcim

The results presented in this article consider the means of assessing the technical condition of two selected buildings, i.e. prisoner barracks number 123 and 124, located at the Auschwitz-Birkenau State Museum in Oświęcim. The work was carried out within the framework of a research project involving the development of methods for preserving, securing and strengthening the structure of buildings, along with their substrate and finishes. The aim of the project was to gain a knowledge base reflecting the actual state of the existing facilities and, on that basis, develop preservation methods and ways to protect the existing facilities against further damage, while maintaining the current character.Przedstawione w artykule wyniki badań dotyczą metody oceny stanu technicznego wybranych dwóch obiektów kubaturowych tj. baraków więźniarskich o numerach B-123 i B-124, które znajdują się na terenie Państwowego Muzeum Auschwitz-Birkenau w Oświęcimiu. Prace były prowadzone w ramach projektu badawczego obejmującego opracowanie metod konserwacji, zabezpieczenia i wzmocnienia konstrukcji obiektów oraz ich podłoża i elementów wykończenia. Celem projektu było pozyskanie bazy informacji odzwierciedlających rzeczywisty stan techniczny istniejących obiektów oraz opracowanie na ich podstawie metod konserwacji i sposobów zabezpieczenia przed dalszym degradacją pełnym zachowaniu cech odzwierciedlających charakter i pełnioną funkcję obiektu w obozie koncentracyjnym