The pan-inhibitor of Aurora kinases danusertib induces apoptosis and autophagy and suppresses epithelial-to-mesenchymal transition in human breast cancer cells

Danusertib (Danu) is a pan-inhibitor of Aurora kinases and a third-generation breakpoint cluster region-Abelson murine leukemia viral oncogene homolog 1 (Bcr-Abl) tyrosine kinase inhibitor, but its antitumor effect and underlying mechanisms in the treatment of human breast cancer remain elusive. This study aimed to investigate the effects of Danu on the growth, apoptosis, autophagy, and epithelial-to-mesenchymal transition (EMT) and the molecular mechanisms in human breast cancer MCF7 and MDA-MB-231 cells. The results demonstrated that Danu remarkably inhibited cell proliferation, induced apoptosis and autophagy, and suppressed EMT in both breast cancer cell lines. Danu arrested MCF7 and MDA-MB-231 cells in G2/M phase, accompanied by the downregulation of cyclin-dependent kinase 1 and cyclin B1 and upregulation of p21 Waf1/Cip1, p27 Kip1, and p53. Danu significantly decreased the expression of B-cell lymphoma-extra-large (Bcl-xl) and B-cell lymphoma 2 (Bcl-2), but increased the expression of Bcl-2-associated X protein (Bax) and p53-upregulated modulator of apoptosis (PUMA), and promoted the cleavage of caspases 3 and 9. Furthermore, Danu significantly increased the expression levels of the membrane-bound microtubule-associated protein 1A/1B-light chain 3 (LC3-II) and beclin 1 in breast cancer cells, two markers for autophagy. Danu induced the activation of p38 mitogen-activated protein kinase (MAPK) and extracellular signal-regulated kinases 1 and 2 (Erk1/2) and inhibited the activation of protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling pathways in breast cancer cells. Treatment with wortmannin (a phosphatidylinositol 3-kinase inhibitor) markedly inhibited Danu-induced activation of p38 MAPK and conversion of cytosolic LC3-I to membrane-bound LC3-II. Pharmacological inhibition and small interfering RNA-mediated knockdown of p38 MAPK suppressed Akt activation, resulting in LC3-II accumulation and enhanced autophagy. Pharmacological inhibition and small interfering RNA-mediated knockdown of Erk1/2 also remarkably increased the level of LC3-II in MCF7 cells. Moreover, Danu inhibited EMT in both MCF7 and MDA-MB-231 cells with upregulated E-cadherin and zona occludens protein 1 (ZO-1) but downregulated N-cadherin, zinc finger E-box-binding homeobox 1 (TCF8/ZEB1), snail, slug, vimentin, and β-catenin. Notably, Danu showed lower cytotoxicity toward normal breast epithelial MCF10A cells. These findings indicate that Danu promotes cellular apoptosis and autophagy but inhibits EMT in human breast cancer cells via modulation of p38 MAPK/Erk1/2/Akt/mTOR signaling pathways. Danu may represent a promising anticancer agent for breast cancer treatment. More studies are warranted to fully delineate the underlying mechanisms, efficacy, and safety of Danu in breast cancer therapy.

Pan & zoom

PAN & ZOOM take the effects inscribe in the global language of cinema and turn them into performative and participatory image-making apparatuses. Jondi Keane & Kaya Barry’s installation invites visitors to collaborate in the construction of the images in order to re-explore relations between media technologies and embodied experience. The result is an expanded, amplified and dilated experience of the performative power of image-making and image-viewing. .. PAN activates an accumulating collection of moving panoramic images – provided by Kaya Barry and PSi Fluid States participants from around the world – that one may interactively inhabit. The visitor manipulates relationships between an image projector mounted upon a dolly-track and a ‘trackpad’ that scrolls the projected panorama. The live event of constructing-perceiving panoramic tracking shots open up in ways that expand sensory experience beyond usual peripheries. ZOOM co-opts the ‘dolly-zoom’ effect in cinema, wherein the camera zooms in while moving backwards, or zooms out while moving forwards, resulting in the image expanding to amplify an intense moment of realisation. Keane pulls apart the double movement of the camera effect by himself performing the pulling back and forth of a moving wall as backdrop. Moments of realisation are created between visitors who take up camera operation and as an improvising actor’s role, to accompany Keane’s durational wall moving. An updating collection of short videos were made over the exhibition period shown on one of the installation screen

Dynamic prediction models and optimization of polyacrylonitrile (PAN) stabilization processes for production of carbon fiber

Thermal stabilization process of polyacrylonitrile (PAN) is the slowest and the most energy-consuming step in carbon fiber production. As such, in industrial production of carbonfiber, this step is considered as amajor bottleneck in the whole process. Stabilization process parameters are usually many in number and highly constrained, leading to high uncertainty. The goal of this paper is to study and analyze the carbon fiber thermal stabilization process through presenting several effective dynamic models for the prediction of the process. The key point with using dynamic models is that using an evolutionary search technique, the heat of reaction can be optimized. The employed components of the study are Levenberg–Marquardt algorithm (LMA)-neural network (LMA-NN), Gauss–Newton (GN)-curve fitting, Taylor polynomial method, and a genetic algorithm. The results show that the procedure can effectively optimize a given PAN fiber heat of reaction based on determining the proper values of heating rampand temperature

Investigation of progress of reactions and evolution of radial heterogeneity in the initial stage of thermal stabilization of PAN precursor fibres

The relationship between process parameters and structural transformations in the fibres at each stage of the carbon fibre manufacturing process play a crucial role in developing high performance carbon fibres. Here we report a systematic method which uses the combination of Taguchi approach and scientific evaluation techniques to establish these relationships for the initial stage of thermal stabilization. Density, cyclization index and fraction of reacted nitriles of a precursor containing acrylonitrile, methacrylate and itaconic acid (AN/MA/IA) were used to assess the progress of stabilization in the fibres with respect to various combinations of process parameters. The extent of progress of stabilization improved with increase in temperature (from 225 to 235 °C) and time (from 12 to 24 min) whereas an opposite trend was observed with increase in the tension on the fibres from (1600-2550 cN). According to optical microscopy, radial heterogeneity was observed in the fibres treated at 235 °C. Interestingly, we were able to identify the existence of heterogeneous modulus distribution from skin to core of the precursor fibres which was further transferred to treated fibres. The overall radial modulus of treated fibres was higher than the precursor fibres. In contrast to the literature, the fracture morphology of the fibre samples indicated that initiation of crack is caused by surface defects rather than radial heterogeneity.

Pan-serotype diagnostic for foot-and-mouth disease using the consensus antigen of nonstructural protein 3B

An amino acid consensus sequence for the seven serotypes of foot-and-mouth disease virus (FMDV) nonstructural protein 3B, including all three contiguous repeats, and its use in the development of a pan-serotype diagnostic test for all seven FMDV serotypes are described. The amino acid consensus sequence of the 3B protein was determined from a multiple-sequence alignment of 125 sequences of 3B. The consensus 3B (c3B) protein was expressed as a soluble recombinant fusion protein with maltose-binding protein (MBP) using a bacterial expression system and was affinity purified using amylose resin. The MBP-c3B protein was used as the antigen in the development of a competition enzyme-linked immunosorbent assay (cELISA) for detection of anti-3B antibodies in bovine sera. The comparative diagnostic sensitivity and specificity at 47% inhibition were estimated to be 87.22% and 93.15%, respectively. Reactivity of c3B with bovine sera representing the seven FMDV serotypes demonstrated the pan-serotype diagnostic capability of this bioreagent. The consensus antigen and competition ELISA are described here as candidates for a pan-serotype diagnostic test for FMDV infection.

Design and development of pan-serodiagnostics for foot-and-mouth disease

 A novel consensus approach to biological reagent design was developed to establish a test for detection of infection of livestock animals with Foot-and-mouth disease virus in a type-independent manner. This test has potential as a readily available diagnostic suitable for use in the global control of this disease.

Chemical structure based prediction of PAN and oxidized PAN fiber density through a non-linear mathematical model

The production of carbon fiber, particularly the oxidation/stabilization step, is a complex process. In the present study, a non-linear mathematical model has been developed for the prediction of density of polyacrylonitrile (PAN) and oxidized PAN fiber (OPF), as a key physical property for various applications, such as energy and material optimization, modeling, and design of the stabilization process. The model is based on the available functional groups in PAN and OPF. Expected functional groups, including [Formula presented], [Formula presented], –CH2, [Formula presented], and [Formula presented], were identified and quantified through the full deconvolution analysis of Fourier transform infrared attenuated total reflectance (FT-IR ATR) spectra obtained from fibers. These functional groups form the basis of three stabilization rendering parameters, representing the cyclization, dehydrogenation and oxidation reactions that occur during PAN stabilization, and are used as the independent variables of the non-linear predictive model. The k-fold cross validation approach, with k = 10, has been employed to find the coefficients of the model. This model estimates the density of PAN and OPF independent of operational parameters and can be expanded to all operational parameters. Statistical analysis revealed good agreement between the governing model and experiments. The maximum relative error was less than 1% for the present model.

Book review: Glamour in the Pacific. Cultural internationalism and race politics in the women's Pan-Pacific

Since the publication of Leila J. Rupp’s Worlds of Women: The Making of an International Women’s Movement in 1997, historians have begun to investigate the myriad ways in which women, largely excluded from formal, government-based international relations, nonetheless forged significant personal and institutional relationships across national and cultural boundaries. As a result, women’s international activism has become an increasingly popular field of scholarly enquiry.

Weekday sunlight exposure, but not vitamin D intake, influences the association between vitamin D receptor genotype and circulating concentration 25-hydroxyvitamin D in a pan-European population: the Food4Me study

SCOPE: Little is known about diet- and environment-gene interactions on 25-hydroxyvitamin D (25(OH)D concentration. This cross-sectional study aimed to investigate (i) predictors of 25(OH)D concentration and relationships with vitamin D genotypes and (ii) whether dietary vitamin D intake and sunlight exposure modified these relationships.

METHODS AND RESULTS: Participants from the Food4Me study (n = 1312; age 18-79) were genotyped for vitamin D receptor (VDR) and vitamin D binding protein at baseline and a genetic risk score was calculated. Dried blood spot samples were assayed for 25(OH)D concentration and dietary and lifestyle information collected. Circulating 25(OH)D concentration was lower with increasing genetic risk score, lower in females than males, higher in supplement users than non-users and higher in summer than winter. Carriage of the minor VDR allele was associated with lower 25(OH)D concentration in participants with the least sunlight exposure. Vitamin D genotype did not influence the relationship between vitamin D intake and 25(OH)D concentration.

CONCLUSION: Age, sex, dietary vitamin D intake, country, sunlight exposure, season, and vitamin D genetic risk score were associated with circulating 25(OH)D concentration in a pan-European population. The relationship between VDR genotype and 25(OH)D concentration may be influenced by weekday sunlight exposure but not dietary vitamin D intake.