Mitotic cell death induction by targeting the mitotic spindle with tubulin-inhibitory indole derivative molecules

Tubulin-targeting molecules are widely used cancer therapeutic agents. They inhibit microtubule-based structures, including the mitotic spindle, ultimately preventing cell division. The final fates of microtubule-inhibited cells are however often heterogeneous and difficult to predict. While recent work has provided insight into the cell response to inhibitors of microtubule dynamics (taxanes), the cell response to tubulin polymerization inhibitors remains less well characterized. Arylthioindoles (ATIs) are recently developed tubulin inhibitors. We previously identified ATI members that effectively inhibit tubulin polymerization in vitro and cancer cell growth in bulk cell viability assays. Here we characterise in depth the response of cancer cell lines to five selected ATIs. We find that all ATIs arrest mitotic progression, yet subsequently yield distinct cell fate profiles in time-lapse recording assays, indicating that molecules endowed with similar tubulin polymerization inhibitory activity in vitro can in fact display differential efficacy in living cells. Individual ATIs induce cytological phenotypes of increasing severity in terms of damage to the mitotic apparatus. That differentially triggers MCL-1 down-regulation and caspase-3 activation, and underlies the terminal fate of treated cells. Collectively, these results contribute to define the cell response to tubulin inhibitors and pinpoint potentially valuable molecules that can increase the molecular diversity of tubulin-targeting agents

Effects of perceived social support on maternal stress and breastfeeding: A narrative review

Introducción: Los organismos de salud recomiendan la lactancia materna exclusiva hasta los 6 meses de vida y lactancia materna (LM) continuada hasta los 2 años de edad. Objetivo: Realizar una revisión narrativa de los efectos del apoyo social sobre el estrés materno y la LM. Método: Se realizó una revisión narrativa y no sistemática en la cual se seleccionó artículos de la literatura en PubMed, Redalyc y BVS y en páginas web de entidades como la OMS y la UNICEF. Resultados: Los resultados reflejan que el escaso apoyo social se asocia con un incremento del estrés materno e impacta en el inicio y sostenimiento de la LM. El apoyo social actúa atenuando los niveles de estrés.  Conclusión: Se concluye que el apoyo social es un factor que ha de ser considerado como una estrategia para disminuir los niveles de estrés materno y la promoción de la LM. Es necesario enfatizar el importante rol de los equipos de salud en torno a la promoción de la LM, especialmente en madres que ofrecen crianza monoparental, al proveer apoyo social y formación para la lactancia.Background: Health authorities recommend exclusive breastfeeding until six months of age and continued breastfeeding (BF) until two years. Objective: To conduct a narrative review of the effects of social support on maternal distress and BF. Method: A narrative and non-systematic review was conducted, selecting articles from the literature in PubMed, Redalyc, BVS, and from websites of organisations such as WHO and UNICEF. Results: The results show that low social support is associated with increased maternal stress and affects the initiation and maintenance of breastfeeding. Social support acts to reduce stress levels. Conclusion: Social support is a factor to be considered as a strategy to reduce maternal stress and promote BF. It is necessary to emphasise the role of healthcare teams in promoting BF, especially among single-parent mothers, by providing social support and breastfeeding education

Nuove tecnologie per la climatizzazione. Solar heating and cooling e pompe di calore a R744 (CO2). Analisi sperimentale

Scuola di Dottorato "Pitagora" in Scienze Ingegneristiche, XXI Ciclo, a.a. 2015-2016Università della Calabri

Performance analysis of a rooftop, air-to-air heat pump working with CO2

The air-conditioning sector for large buildings and shopping centers is developing a growing interest in rooftop heat pumps due to their easy installation. Instead of the application of HFC refrigerants, carbon dioxide (CO2) could be an interesting perspective in this sector for environmental reasons. This work presents new performance data of an air-to-air heat pump roof-top system working with a trans-critical carbon dioxide cycle during the heating season. In particular, the experimental results showed how the heating power and the coefficient of performance are affected by the air temperature at the inlet of the gas cooler and by part load working conditions. A thermodynamic analysis pointed out the direct and indirect effects of fans speed and air flow temperatures on the performance, defining a performance map and the optimal range of application of such systems

Refractory hypertension and rapidly progressive renal failure due to bilateral renal artery stenosis: case report

We report a case of refractory hypertension and acute renal failure with mild proteinuria due to an unreported bilateral Renal Artery Stenosis, who underwent renal biopsy in the suspicion of rapidly progressive glomerulonephritis

Visualization of human karyopherin beta-1/importin beta-1 interactions with protein partners in mitotic cells by co-immunoprecipitation and proximity ligation assays

Abstract Karyopherin beta-1/Importin beta-1 is a conserved nuclear transport receptor, acting in protein nuclear import in interphase and as a global regulator of mitosis. These pleiotropic functions reflect its ability to interact with, and regulate, different pathways during the cell cycle, operating as a major effector of the GTPase RAN. Importin beta-1 is overexpressed in cancers characterized by high genetic instability, an observation that highlights the importance of identifying its partners in mitosis. Here we present the first comprehensive profile of importin beta-1 interactors from human mitotic cells. By combining co-immunoprecipitation and proteome-wide mass spectrometry analysis of synchronized cell extracts, we identified expected (e.g., RAN and SUMO pathway factors) and novel mitotic interactors of importin beta-1, many with RNA-binding ability, that had not been previously associated with importin beta-1. These data complement interactomic studies of interphase transport pathways. We further developed automated proximity ligation assay (PLA) protocols to validate selected interactors. We succeeded in obtaining spatial and temporal resolution of genuine importin beta-1 interactions, which were visualized and localized in situ in intact mitotic cells. Further developments of PLA protocols will be helpful to dissect importin beta-1-orchestrated pathways during mitosis

Importin-β/karyopherin-β1 modulates mitotic microtubule function and taxane sensitivity in cancer cells via its nucleoporin-binding region

The nuclear transport receptor importin-β/karyopherin-β1 is overexpressed in cancers that display genomic instability. It is regarded as a promising cancer target and inhibitors are being developed. In addition to its role in nucleo-cytoplasmic transport, importin-β regulates mitosis, but the programmes and pathways in which it operates are defined only in part. To unravel importin-β's mitotic functions we have developed cell lines expressing either wild-type or a mutant importin-β form in characterised residues required for nucleoporin binding. Both forms similarly disrupted spindle pole organisation, while only wild-type importin-β affected microtubule plus-end function and microtubule stability. A proteome-wide search for differential interactors identified a set of spindle regulators sensitive to mutations in the nucleoporin-binding region. Among those, HURP (hepatoma up-regulated protein) is an importin-β interactor and a microtubule-stabilising factor. We found that induction of wild type, but not mutant importin-β, under the same conditions that destabilise mitotic microtubules, delocalised HURP, indicating that the spatial distribution of HURP along the spindle requires importin-β's nucleoporin-binding residues. Concomitantly, importin-β overexpression sensitises cells to taxanes and synergistically increases mitotic cell death. Thus, the nucleoporin-binding domain is dispensable for importin-β function in spindle pole organisation, but regulates microtubule stability, at least in part via HURP, and renders cells vulnerable to certain microtubule-targeting drugs

Black crusts on Venetian built heritage, investigation on the impact of pollution sources on their composition

This paper deals with the characterization of black crusts collected from several historical buildings in the city of Venice. This city suffers from pollution from the industrial area of Marghera, as well as from the maritime traffic. Black crust can be considered as a passive sampler of pollutants, with particular reference to heavy metals. For this reason, in order to fully characterize those samples, several techniques were used, including scanning electron microscopy, thermogravimetric analysis, laser ablation inductively coupled plasma mass spectrometry, infrared spectroscopy and ion chromatography. This integrated approach allowed us to gain information about the mineralogical phases and the elements within the crusts giving the possibility to identify the pollution sources causing the stone decay within the buildings, as well as the variability in composition depending on the exposure of the analyzed surfaces