Perturbed-angular-correlation study of phase transformations in nanoscaled Al₂O₃-coated and noncoated ZrO₂ particles synthesized in a microwave plasma

The phase transformations of nanoscaled (n-) Al$_{2}$O$_{3}$-coated and noncoated ZrO$_{2}$ particles synthesized in a microwave plasma have been investigated by perturbed-angular-correlation (PAC) measurements of the electric quadrupole interaction (QI) of $^{181}$Ta on Zr sites between 290 and 1600 K. For the phase identification and structural characterization the QI parameters of the nanoscaled particles are compared to those of coarsegrained ZrO$_{2}$ which were measured between 290 and 2160 K. The PAC spectra of the nanoscaled particles in the as-prepared state are characterized by a broad distribution of strong, axially asymmetric QI’s, which reflects a highly disordered oxygen environment of the Zr sites. Upon annealing, the tetragonal phase is the first well-crystallized structure to emerge at about 500 K, both in coated and noncoated n-ZrO2, in contrast to the previously reported annealing reaction of n-ZrO$_{2}$ synthesized by gas-phase condensation in which the tetragonal phase has not been observed. This disorder-order transformation is partially reversible upon cooling. In n-ZrO$_{2}$ /Al$_{2}$O$_{3}$ synthesized in a microwave plasma the monoclinic phase can be completely suppressed up to 1600 K. In the noncoated particles monoclinic ZrO$_{2}$ starts to appear at 600 K. At 1400 K the transformation from the monoclinic to the tetragonal phase of noncoated n-ZrO2 was observed to occur with a transformation rate of $\lambda$=6.9(1.2)x10$^{-5}$ s$^{-1}$. In nanoscaled coated and noncoated tetragonal ZrO$_{2}$ the T$^{3/2}$-temperature dependence of the quadrupole frequency v$_{q}$ is weaker than in the same phase of the coarse-grained compound, suggesting a decrease of the mean-square vibrational amplitudes with decreasing particle size

Severe thunderstorms with large hail across Germany in June 2019

From 10 to 12 June 2019, severe thunderstorms affected large parts of Germany. Hail larger than golf ball size caused considerable damage, especially in the Munich area where losses amount to EUR 1 billion. This event thus ranks among the ten most expensive hail events in Europe in the last 40 years. Atmospheric blocking in combination with a moist, unstably stratified air mass provided an excellent setting for the development of severe, hail‐producing thunderstorms across the country. imageGerman Research Foundation http://dx.doi.org/10.13039/50110000165

Exploiting Parallel R in the Cloud with SPRINT

BACKGROUND: Advances in DNA Microarray devices and next-generation massively parallel DNA sequencing platforms have led to an exponential growth in data availability but the arising opportunities require adequate computing resources. High Performance Computing (HPC) in the Cloud offers an affordable way of meeting this need. OBJECTIVES: Bioconductor, a popular tool for high-throughput genomic data analysis, is distributed as add-on modules for the R statistical programming language but R has no native capabilities for exploiting multi-processor architectures. SPRINT is an R package that enables easy access to HPC for genomics researchers. This paper investigates: setting up and running SPRINT-enabled genomic analyses on Amazon’s Elastic Compute Cloud (EC2), the advantages of submitting applications to EC2 from different parts of the world and, if resource underutilization can improve application performance. METHODS: The SPRINT parallel implementations of correlation, permutation testing, partitioning around medoids and the multi-purpose papply have been benchmarked on data sets of various size on Amazon EC2. Jobs have been submitted from both the UK and Thailand to investigate monetary differences. RESULTS: It is possible to obtain good, scalable performance but the level of improvement is dependent upon the nature of algorithm. Resource underutilization can further improve the time to result. End-user’s location impacts on costs due to factors such as local taxation. Conclusions: Although not designed to satisfy HPC requirements, Amazon EC2 and cloud computing in general provides an interesting alternative and provides new possibilities for smaller organisations with limited funds

Grb7 SH2 domain structure and interactions with a cyclic peptide inhibitor of cancer cell migration and proliferation

<p>Abstract</p> <p>Background</p> <p>Human growth factor receptor bound protein 7 (Grb7) is an adapter protein that mediates the coupling of tyrosine kinases with their downstream signaling pathways. Grb7 is frequently overexpressed in invasive and metastatic human cancers and is implicated in cancer progression via its interaction with the ErbB2 receptor and focal adhesion kinase (FAK) that play critical roles in cell proliferation and migration. It is thus a prime target for the development of novel anti-cancer therapies. Recently, an inhibitory peptide (G7-18NATE) has been developed which binds specifically to the Grb7 SH2 domain and is able to attenuate cancer cell proliferation and migration in various cancer cell lines.</p> <p>Results</p> <p>As a first step towards understanding how Grb7 may be inhibited by G7-18NATE, we solved the crystal structure of the Grb7 SH2 domain to 2.1 Å resolution. We describe the details of the peptide binding site underlying target specificity, as well as the dimer interface of Grb 7 SH2. Dimer formation of Grb7 was determined to be in the μM range using analytical ultracentrifugation for both full-length Grb7 and the SH2 domain alone, suggesting the SH2 domain forms the basis of a physiological dimer. ITC measurements of the interaction of the G7-18NATE peptide with the Grb7 SH2 domain revealed that it binds with a binding affinity of K_d= ~35.7 μM and NMR spectroscopy titration experiments revealed that peptide binding causes perturbations to both the ligand binding surface of the Grb7 SH2 domain as well as to the dimer interface, suggesting that dimerisation of Grb7 is impacted on by peptide binding.</p> <p>Conclusion</p> <p>Together the data allow us to propose a model of the Grb7 SH2 domain/G7-18NATE interaction and to rationalize the basis for the observed binding specificity and affinity. We propose that the current study will assist with the development of second generation Grb7 SH2 domain inhibitors, potentially leading to novel inhibitors of cancer cell migration and invasion.</p

Hf–Zr anomalies in clinopyroxene from mantle xenoliths from France and Poland: implications for Lu–Hf dating of spinel peridotite lithospheric mantle

Clinopyroxenes in some fresh anhydrous spinel peridotite mantle xenoliths from the northern Massif Central (France) and Lower Silesia (Poland), analysed for a range of incompatible trace elements by laser ablation inductively coupled plasma mass spectrometry, show unusually strong negative anomalies in Hf and Zr relative to adjacent elements Sm and Nd, on primitive mantle-normalised diagrams. Similar Zr–Hf anomalies have only rarely been reported from clinopyroxene in spinel peridotite mantle xenoliths worldwide, and most are not as strong as the examples reported here. Low Hf contents give rise to a wide range of Lu/Hf ratios, which over geological time would result in highly radiogenic εHf values, decoupling them from εNd ratios. The high 176Lu/177Hf could in theory produce an isochronous relationship with 176Hf/177Hf over time; an errorchron is shown by clinopyroxene from mantle xenoliths from the northern Massif Central. However, in a review of the literature, we show that most mantle spinel peridotites do not show such high Lu/Hf ratios in their constituent clinopyroxenes, because they lack the distinctive Zr–Hf anomaly, and this limits the usefulness of the application of the Lu–Hf system of dating to garnet-free mantle rocks. Nevertheless, some mantle xenoliths from Poland or the Czech Republic may be amenable to Hf-isotope dating in the future

Federated repositories of X-ray diffraction images

There is a pressing need for the archiving and curation of raw X-ray diffraction data. This information is critical for validation, methods development and improvement of archived structures. However, the relatively large size of these data sets has presented challenges for storage in a single worldwide repository such as the Protein Data Bank archive. This problem can be avoided by using a federated approach, where each institution utilizes its institutional repository for storage, with a discovery service overlaid. Institutional repositories are relatively stable and adequately funded, ensuring persistence. Here, a simple repository solution is described, utilizing Fedora open-source database software and data-annotation and deposition tools that can be deployed at any site cheaply and easily. Data sets and associated metadata from federated repositories are given a unique and persistent handle, providing a simple mechanism for search and retrieval via web interfaces. In addition to ensuring that valuable data is not lost, the provision of raw data has several uses for the crystallographic community. Most importantly, structure determination can only be truly repeated or verified when the raw data are available. Moreover, the availability of raw data is extremely useful for the development of improved methods of image analysis and data processing

In vitro studies on the modification of low-dose hyper-radiosensitivity in prostate cancer cells by incubation with genistein and estradiol

<p>Abstract</p> <p>Background</p> <p>As the majority of prostate cancers (PC) express estrogen receptors, we evaluated the combination of radiation and estrogenic stimulation (estrogen and genistein) on the radiosensitivity of PC cells in vitro.</p> <p>Methods</p> <p>PC cells LNCaP (androgen-sensitive) and PC-3 (androgen-independent) were evaluated. Estrogen receptor (ER) expression was analyzed by means of immunostaining. Cells were incubated in FCS-free media with genistein 10 μM and estradiol 10 μM 24 h before irradiation and up to 24 h after irradiation. Clonogenic survival, cell cycle changes, and expression of p21 were assessed.</p> <p>Results</p> <p>LNCaP expressed both ER-α and ER-β, PC-3 did not. Incubation of LNCaP and PC-3 with genistein resulted in a significant reduction of clonogenic survival. Incubation with estradiol exhibited in low concentrations (0.01 μM) stimulatory effects, while higher concentrations did not influence survival. Both genistein 10 μM and estradiol 10 μM increased low-dose hyper-radiosensitivity [HRS] in LNCaP, while hormonal incubation abolished HRS in PC-3. In LNCaP cells hormonal stimulation inhibited p21 induction after irradiation with 4 Gy. In PC-3 cells, the proportion of cells in G2/M was increased after irradiation with 4 Gy.</p> <p>Conclusion</p> <p>We found an increased HRS to low irradiation doses after incubation with estradiol or genistein in ER-α and ER-β positive LNCaP cells. This is of high clinical interest, as this tumor model reflects a locally advanced, androgen dependent PC. In contrast, in ER-α and ER-β negative PC-3 cells we observed an abolishing of the HRS to low irradiation doses by hormonal stimulation. The effects of both tested compounds on survival were ER and p53 independent. Since genistein and estradiol effects in both cell lines were comparable, neither ER- nor p53-expression seemed to play a role in the linked signalling. Nevertheless both compounds targeted the same molecular switch. To identify the underlying molecular mechanisms, further studies are needed.</p

Anti-cancer effects and mechanism of actions of aspirin analogues in the treatment of glioma cancer

INTRODUCTION: In the past 25 years only modest advancements in glioma treatment have been made, with patient prognosis and median survival time following diagnosis only increasing from 3 to 7 months. A substantial body of clinical and preclinical evidence has suggested a role for aspirin in the treatment of cancer with multiple mechanisms of action proposed including COX 2 inhibition, down regulation of EGFR expression, and NF-κB signaling affecting Bcl-2 expression. However, with serious side effects such as stroke and gastrointestinal bleeding, aspirin analogues with improved potency and side effect profiles are being developed. METHOD: Effects on cell viability following 24 hr incubation of four aspirin derivatives (PN508, 517, 526 and 529) were compared to cisplatin, aspirin and di-aspirin in four glioma cell lines (U87 MG, SVG P12, GOS – 3, and 1321N1), using the PrestoBlue assay, establishing IC50 and examining the time course of drug effects. RESULTS: All compounds were found to decrease cell viability in a concentration and time dependant manner. Significantly, the analogue PN517 (IC50 2mM) showed approximately a twofold increase in potency when compared to aspirin (3.7mM) and cisplatin (4.3mM) in U87 cells, with similar increased potency in SVG P12 cells. Other analogues demonstrated similar potency to aspirin and cisplatin. CONCLUSION: These results support the further development and characterization of novel NSAID derivatives for the treatment of glioma