1,219 research outputs found
Landscape of BRAF transcript variants in human cancer
No full textThe BRAFV600E mutant kinase is widely studied as a cancer driver and therapeutic target. However, the regulation of BRAF gene expression remains largely unexplored. Here in this thesis, I
investigate how the annotation of the biologically relevant protein-coding BRAF-ref and BRAF-X1 isoforms has evolved in public databases, and I faced the challenges posed by the discrimination and quantification of these BRAF isoforms, providing a detailed discussion and comparison of cutting-edge in silico methods such as short-read sequencing, long-read sequencing, and single-cell sequencing, which represent the state-of-the-art approaches for isoform identification and quantification. Furthermore, I investigate the clinical implications of the BRAF-X1/BRAF-ref transcript ratio, examining how this ratio could influence clinical outcomes. Currently, BRAF-ref corresponds to NM_004333.6 (NCBI), ENST00000646891.2/BRAF-220 (Ensembl), MANE select (MANE), PRINCIPAL:4 (APPRIS), and TCONS_00952581 (FLIBase). BRAF-X1 corresponds to NM_001354609.2 (NCBI), ENST00000496384.7/BRAF-204 (Ensembl), ALTERNATIVE BRAF isoform (APPRIS) and TCONS_00952571 (FLIBase). I built IsoWorm, a bioinformatic pipeline specifically tailored to discriminate and quantify BRAF isoforms and I employed it to analyze more than 500 cancer cell lines and 700 cancer tissue samples. Thanks to the FLIBase database, I also re-analyzed TCGA data on more than 9000 cancer tissue samples and 600 adjacent to tumoral tissue samples, and additionally, I examined more than 2,600 normal tissue samples from the GTEx database.
I integrated also additional modules into IsoWorm, enabling me to analyze differents types of short RNA-seq data, such as Quant 3’ sequencing and single-cell sequencing data. This permits me a more detailed investigation into the differences between BRAF isoforms.
I consistently found that BRAF-X1 (now BRAF-204) is the most abundant BRAF isoform in human cancer and in normal tissues samples, it is 1.5 to 75 (in cancer) and 4 to 64 times (in normal samples) more expressed than BRAF-ref (now BRAF-220).
Crucially, I identified how in papillary renal cell carcinoma (KIRP) an extreme BRAF-204/BRAF-220 ratio, together with the tumor stages and metastasis, higher the risk of the patient’s overall survival.
Finally, thanks to the application of in silico structural biology techniques such as modeling with AlphaFold and molecular dynamics simulations, I investigated the structural differences between the C-termini of BRAF-220 and BRAF-204. Preliminary data suggest that the C-terminus of BRAF-220 is more stable compared to that of BRAF-204. This structural stability could differentiate the two isoforms in terms of their biological roles, stability, and functionality.
Together with the experimental characterization undertaken over the years, our in silico analyses ultimately establish BRAF as a mix of isoforms, with BRAF-204 being much more expressed than BRAF-220. These findings prompt a systematic benchmarking of the isoforms regarding molecular mechanisms, biological activities, and clinical relevance
Rowing against decline: Regional Innovation Systems and marginality in the era of digital transition
No full textDigitalization is crucial for local development, and post-Covid European policies are driving this transformation to boost the continent’s development. Despite significant national investment plans, not all regional areas are ready for digital transition, risking further developmental gaps. This article analyses the Regional Innovation System (RIS) in Sicily, Italy, as a case study. The aim is to assess regional readiness and adaptability during this transition, adopting the perspective of a marginal and increasingly depressed economic area. Using a mixed-method approach, combining different data sources, the study emphasises the importance of collaborative networks and trust relationships for successful digital transition.
Weak public coordination and institutional shortcomings hinder Sicily’s RIS,
despite the limited success of private initiatives attempting to bridge the gap by
acting as binding agents
Maturità della materia organica e storia termica in alcune successioni del Triassico superiore (Friuli Venezia Giulia, Italia)
No full textPlatform-basin relationships in the norian of Carnia region (NE italy)
No full textGIOLOGIE MIDITIRRANIENN
Depositi norici di ambiente anossico nelle Prealpi Friulane (Italia nord-orientale)
No full textnon disponibil
Foglio Geologico 049 Gemona del Friuli
No full textCarta geologica alla scala 1:50.000 dell'area del gemonese, Prealpi Carniche e Giulie, completa di sezioni geologiche, schema dei rapporti stratigrafici e schema strutturale
La Dolomia di Forni: evoluzione di un bacino euxinico tardo-triassico nelle Prealpi Carniche
No full textUptake of Cd in hydrozincite, Zn-5(CO3)(2)(OH)(6): evidence from X-ray absorption spectroscopy and anomalous X-ray diffraction
No full textThe activity of a biological photosynthetic community promotes the seasonal precipitation of hydrozincite, Zn(5)(CO(3))(2)(OH)(6), from heavy-metal contaminated waters of the Rio Naracauli stream, Sardinia. The precipitation removes from waters not only zinc, but also other heavy metals, such as Cd, Cu, Pb. The phenomenon has remarkable environmental implications, and may have remediation applications. In this study, we investigate the nature of Cd binding to hydrozincite by release tests in deionized water, backed by X-ray absorption spectroscopy (XAS) spectra collected at the Cd K-edge, and by synchrotron-based anomalous X-ray diffraction (AXRD) spectra. Release tests indicate that Cd is weakly bound to hydrozincite, being released to a significantly higher rate than Zn. The absence of a residual corresponding to a crystalline phase in the anomalous diffraction pattern indicates that, up to bulk concentration of 2 wt%, Cd occurs in hydrozincite in an essentially disordered environment. The analysis of the weak signal of the second shell in the extended X-ray absorption fine structure (EXAFS) spectra suggests a local environment similar to cadmium carbonate, but distinct from otavite. We conclude that Cd is bound to hydrozincite as a disordered amorphous surface precipitate. The loose nature of the binding suggests a limited potential of hydrozincite both as a control on the mobility of cadmium in natural waters, and as a remediation tool for contaminated effluents
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