Physical stratigraphy and geotechnical properties controlling the local seismic response in explosive volcanic settings: the Stracciacappa maar (central Italy)

Nowadays, policies addressed to prevention and mitigation of seismic risk need a consolidated methodology finalised to the assessment of local seismic response in explosive volcanic settings. The quantitative reconstruction of the subsoil model provides a key instrument to understand how the geometry and the internal architecture of outcropping and buried geological units have influence on the propagation of seismic waves. On this regard, we present a multidisciplinary approach in the test area of the Stracciacappa maar (Sabatini Volcanic District, central Italy), with the aim to reconstruct its physical stratigraphy and to discuss how subsoil heterogeneities control the 1D and 2D local seismic response in such a volcanic setting. We first introduce a new multidisciplinary dataset, including geological (fieldwork and log from a 45-m-thick continuous coring borehole), geophysical (electrical resistivity tomographies, single station noise measurements, and 2D passive seismic arrays), and geotechnical (simple shear tests performed on undisturbed samples) approaches. Then, we reconstruct the subsoil model for the Stracciacappa maar in terms of vertical setting and distribution of its mechanical lithotypes, which we investigate for 1D and 2D finite element site response analyses through the application of two different seismic scenarios: a volcanic event and a tectonic event. The numerical modelling documents a significant ground motion amplification (in the 1–1.5 Hz range) revealed for both seismic scenarios, with a maximum within the centre of the maar. The ground motion amplification is related to both 1D and 2D phenomena including lithological heterogeneity within the upper part of the maar section and interaction of direct S-waves with Rayleigh waves generated at edges of the most superficial lithotypes. Finally, we use these insights to associate the expected distribution of ground motion amplification with the physical stratigraphy of an explosive volcanic setting, with insights for seismic microzonation studies and local seismic response assessment in populated environments

po 237 the pro oncogenic transcription factor stat3 regulates ca2 release and apoptosis from the endoplasmic reticulum via interaction with the ca2 channel ip3r3

Introduction Signal Transducer and Activator of Transcription (STAT) 3 is an oncogenic transcription factor found constitutively activated in several tumours, where it exerts its functions both as a canonical transcription factor and as a non-canonical regulator of energy metabolism and mitochondrial functions. These two activities rely on different post-translational activating events; the phosphorylation on Y705 is involved in nuclear activities, while that on S727 is relevant for mitochondrial functions. Mitochondrial STAT3 increases aerobic glycolysis and decreases ROS production, partly by interacting with the Electron Transfer Complexes (ETC). Material and methods By means of cell fractionations, we tested STAT3 localization to the Endoplasmic Reticulum (ER) in breast cancer cell lines dependent or not on STAT3 activity. We then measured Ca2+ release and apoptotic response in the same cells. The physical interaction between inositol 1,4,5-trisphosphate receptor type 3 (IP3R3) and STAT3 was demonstrated by co-IP either of the endogenous proteins or of their truncated/mutated forms, while STAT3 role in the degradation of IP3R3 was tested by serum starvation and refeeding experiments, followed by WB. Results and discussions We describe here the previously undetected abundant localization of STAT3 also to the ER. In this cellular compartment IP3R3, a Ca2+ channel that allows Ca2+ release from the ER and the mitochondrial associated membranes (MAMs) in response to IP3, regulates the balance between mitochondrial activation and Ca2+-triggered apoptosis. We observed that STAT3 within the ER physically interacts with IP3R3 and, via its phosphorylation on S727, it down-regulates Ca2+ release and apoptosis. Indeed, STAT3 silencing enhances both ER Ca2+ release and sensitivity to apoptosis following oxidative stress in STAT3-dependent mammary tumour cells, correlating with increased IP3R3 levels. In line with this, basal-like breast tumours, which frequently display constitutively active STAT3, show an inverse correlation between IP3R3 and STAT3 protein levels. Conclusion Our results indicate that S727-phosphorylated STAT3 contribute to mammary tumour aggressiveness, also by localising to the ER and regulating Ca2+ fluxes. STAT3-mediated enhanced IP3R3 degradation leads to decreased Ca2+ release and thus to resistance to apoptosis. This new non-canonical STAT3 role appears to be particularly relevant in basal-like breast cancers, adding a new mechanisms through which STAT3 exerts its well established pro-oncogenic anti-apoptotic role

Real time Raman imaging to understand dissolution performance of amorphous solid dispersions

We have employed for the first time Raman spectroscopic imaging along with multi-variate curve resolution (MCR) analysis to investigate in real time and in-situ the dissolution mechanisms that underpin amorphous solid dispersions, with data being collected directly from the dosage form itself. We have also employed a novel rotating disk dissolution rate (RDDR) methodology to track, through the use of high-performance liquid chromatography (HPLC), the dissolution trends of both drug and polymer simultaneously in multi-component systems. Two formulations of poorly water-soluble felodipine in a polymeric matrix of copovidone VA64 which have different drug loadings of 5% and 50% w/w were used as models with the aim of studying the effects of increasing the amount of active ingredient on the dissolution performance. It was found that felodipine and copovidone in the 5% dispersion dissolve with the same dissolution rate and that no Raman spectral changes accompanied the dissolution, indicating that the two components dissolve as single entity, whose behaviour is dominated by water-soluble copovidone. For the 50% drug-loaded dispersion, partial RDDR values of both felodipine and copovidone were found to be extremely low. MCR Raman maps along with classical Raman/X-ray powder diffraction (XRPD) characterisation revealed that after an initial loss of copovidone from the extrudate the drug re-crystallises, pointing to a release dynamics dependent on the low water solubility and high hydrophobicity of felodipine. Raman imaging revealed different rates of transition from amorphous to crystalline felodipine at different locations within the dosage form

Identification of novel small molecules that inhibit STAT3-dependent transcription and function

Activation of Signal Transducer and Activator of Transcription 3 (STAT3) has been linked to several processes that are critical for oncogenic transformation, cancer progression, cancer cell proliferation, survival, drug resistance and metastasis. Inhibition of STAT3 signaling has shown a striking ability to inhibit cancer cell growth and therefore, STAT3 has become a promising target for anti-cancer drug development. The aim of this study was to identify novel inhibitors of STAT-dependent gene transcription. A cellular reporter-based system for monitoring STAT3 transcriptional activity was developed which was suitable for high-throughput screening (Z’ = 0,8). This system was used to screen a library of 28,000 compounds (the ENAMINE Drug-Like Diversity Set). Following counter-screenings and toxicity studies, we identified four hit compounds that were subjected to detailed biological characterization. Of the four hits, KI16 stood out as the most promising compound, inhibiting STAT3 phosphorylation and transcriptional activity in response to IL6 stimulation. In silico docking studies showed that KI16 had favorable interactions with the STAT3 SH2 domain, however, no inhibitory activity could be observed in the STAT3 fluorescence polarization assay. KI16 inhibited cell viability preferentially in STAT3-dependent cell lines. Taken together, using a targeted, cell-based approach, novel inhibitors of STAT-driven transcriptional activity were discovered which are interesting leads to pursue further for the development of anti-cancer therapeutic agents

Resistindo ao desenvolvimento neocolonial: a luta do povo de Andalgalá contra projetos megamineiros

A América Latina vem experimentando uma nova era de declarada fé dos governos no mito do desenvolvimento, em articulação com a expansão de políticas extrativistas exportadoras em um contexto de renovada dependência. A face mais dramática do extrativismo na região tem sido a crescente presença de corporações mineiras transnacionais apoiadas por governos nacionais e regionais e por instituições internacionais financeiras e de apoio ao desenvolvimento, e intensamente resistidas por movimentos sociais populares. Neste artigo apresentamos o caso de Andalgalá (uma pequena cidade na Província de Catamarca, na Argentina) e as lutas do povo contra corporações mineiras transnacionais e seus aliados. Na tradição da Filosofia da Libertação e do método ana-dialético de Dussel, nos engajamos com o que tem sido denominado "comunidades argentinas do NÃO", expressando sua oposição a formas neocoloniais de desenvolvimento e gestão. Neste artigo estamos especificamente interessados em compreender como dois dispositivos gerencialistas usados pelas corporações mineiras, responsabilidade social corporativa (RSC) e pactos de governança, impactam a luta do povo. Acima de tudo, este artigo oferece instantâneos de batalhas na linha de frente do extrativismo. Esperamos ter dado voz àquelas pessoas que normalmente não são ouvidas, criando um espaço para suas visões sobre um tipo diferente de desenvolvimento.</jats:p