The Historic Centre of Urbino, UNESCO World Heritage (Marche Region, Italy): an Urban‑Geological Itinerary Across the Building and Ornamental Stones.

The local and extra-regional (national and transnational) stones mainly used as building and ornamental materials in the historic centre of Urbino (UNESCO World Heritage List) were unravelled through a detailed geological and petrographic study. The types of building stones used in the past for the development of an urban centre were mostly affected by the availability of suitable geomaterials in the surrounding areas. For this reason, the stones found in the historical buildings of Urbino generally come from the local sedimentary formations (mostly limestones) belonging to the Umbria–Marche–Romagna Succession Auct., which crops out in the Northern Marche Apennines. Only some ornamental highly prized stones used for monuments and decorations come from both extra-regional Italian areas (Alps, other sectors of the Northern Apennines) and foreign countries (France, Egypt). A brief description of the Northern Marche geology was also reported to exactly match the local provenance of the stones, so highlighting the relationship between the territory and the architecture of Urbino. Because of obvious conservation reasons, no samples were collected from buildings or monuments and only autoptic observations, together with a detailed historical and bibliographic research, were carried out to identify the different materials and the provenance areas. Besides the availability of the local sedimentary rocks, we emphasised how the choice of the building and ornamental stones could have been also influenced by the historic period and artistic style, aesthetic features, economic and social importance of the building and/or monument and the relationship to some distinguished personality (e.g., Pope Clemente XI). An open-air stone itinerary across significant places (10 stops and additional sites and monuments in the urban area) is finally proposed for the best fruition of the geological and cultural heritage of Urbino, also aimed at geotourism development

Cellular Prion Protein and Caveolin-1 Interaction in a Neuronal Cell Line Precedes Fyn/Erk 1/2 Signal Transduction

It has been reported that cellular prion protein (PrPc) is enriched in caveolae or caveolae-like domains with caveolin-1 (Cav-1) participating to signal transduction events by Fyn kinase recruitment. By using the Glutathione-S-transferase (GST)-fusion proteins assay, we observed that PrPc strongly interacts in vitro with Cav-1. Thus, we ascertained the PrPc caveolar localization in a hypothalamic neuronal cell line (GN11), by confocal microscopy analysis, flotation on density gradient, and coimmunoprecipitation experiments. Following the anti-PrPc antibody-mediated stimulation of live GN11 cells, we observed that PrPc clustered on plasma membrane domains rich in Cav-1 in which Fyn kinase converged to be activated. After these events, a signaling cascade through p42/44 MAP kinase (Erk 1/2) was triggered, suggesting that following translocations from rafts to caveolae or caveolaelike domains PrPc could interact with Cav-1 and induce signal transduction events

Stellar populations in the dwarf spheroidal galaxy Leo I

We present a detailed study of the color magnitude diagram (CMD) of the dwarf spheroidal galaxy Leo I, based on archival Hubble Space Telescope data. Our photometric analysis, confirming previous results on the brighter portion of the CMD, allow us to obtain an accurate sampling of the stellar populations also at the faint magnitudes corresponding to the Main Sequence. By adopting a homogeneous and consistent theoretical scenario for both hydrogen and central helium-burning evolutionary phases, the various features observed in the CMD are interpreted and reliable estimations for both the distance modulus and the age(s) for the main stellar components of Leo I are derived. More in details, from the upper luminosity of the Red Giant Branch and the lower luminosity of the Subgiant Branch we simultaneously constrain the galaxy distance and the age of the oldest stellar population in Leo I. In this way we obtain a distance modulus (m-M)_V=22.00$\pm$0.15 mag and an age of 10--15 Gyr or 9--13 Gyr, adopting a metallicity Z=0.0001 and 0.0004, respectively. The reliability of this distance modulus has been tested by comparing the observed distribution of the Leo I anomalous Cepheids in the period-magnitude diagram with the predicted boundaries of the instability strip, as given by convective pulsating models.Comment: 19 pages, 3 tables, 14 figures To be published in A

Pro-apoptotic and size-reducing effects of protein corona-modulating nano-architectures enclosing platinum prodrug in in vivo oral carcinoma

: The selective and localized delivery of active agents to neoplasms is crucial to enhance the chemotherapeutic efficacy while reducing the associated side effects. The encapsulation of chemotherapeutics in nanoparticles decorated with targeting agents is a strategy of special interest to improve drug delivery. However, serum protein adsorption often compromises the in vivo efficiency of targeting agents, leading to protein corona formation that interferes with the targeting process. Here, the enhanced efficacy of hybrid nano-architectures enclosing a platinum prodrug and decorated with a customized peptide (NAs-cisPt-Tf2) is demonstrated by employing alternative in vivo models of oral carcinoma. The peptide binds to transferrin and modulates the protein corona formation on NAs-cisPt-Tf2, supporting the identification of its receptor. Optimized chorioallantoic membrane cancer models (CAMs) enabled a thorough assessment of the tumor-suppressing effect of NAs-cisPt-Tf2 as well as the quantitative evaluation of angiogenesis and cell cycle associated mechanisms. The treatment strategy resulted in a significant tumor volume reduction coupled with anti-angiogenic and pro-apoptotic effects inferred from the downregulation of the vascular endothelial growth factor gene and increased expression of cleaved caspase-3. Overall, this study provides a potentially effective tumor-targeted approach for a non-invasive management of oral carcinoma

Plasma and Skin Concentration of 5-Methoxypsoralen in Psoriatic Patients After Oral Administration

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Effects of bariatric and metabolic surgical procedures on dyslipidemia: a retrospective, observational analysis.

Aim: Obesity and co-existing metabolic comorbidities are associated with increased cardiovascular (CV) morbidity and mortality risks, generally clustered to risk factors such as dyslipidemia. The aim of this study was to evaluate the lipid profile changes in subjects with severe obesity undergoing different procedures of bariatric and metabolic surgery (BMS), sleeve gastrectomy (SG), and Roux-en-Y gastric bypass (RYGB) in a real-world, clinical setting. Methods: A single-center, retrospective, observational clinical study was performed enrolling patients undergoing BMS. The primary outcome was the change in total cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL) cholesterol, and triglycerides. Results: In total, 123 patients were enrolled (males 25.2% and females 74.8%) with a mean age of 48.2 ± 7.9 years and a mean BMI of 47.0 ± 9.1 kg/m2. All patients were evaluated until 16.9 ± 8.1 months after surgery. Total and HDL cholesterol did not change after surgery, while a significant reduction in triglyceride levels was recorded. Moreover, a rapid decline of both LDL and non-HDL cholesterol among follow-up visits was observed. In particular, significant inverse correlations were found between total cholesterol, LDL cholesterol, non-HDL cholesterol, and triglycerides and the number of months elapsed after bariatric surgery. Similarly, a direct correlation was found considering HDL cholesterol. Moreover, total cholesterol, LDL cholesterol, non-HDL cholesterol, and triglycerides significantly changed among visits after RYGB, while no changes were observed in the SG group. Finally, considering lipid-lowering therapies, the improvement in lipid asset was detected only in non-treated patients. Conclusion: This study corroborates the knowledge of the improvement in lipid profile with BMS in clinical practice. Together with sustained weight loss, the BMS approach efficiently corrects dyslipidemia, contributing to decreasing the CV risk

Collagen VI–NG2 axis in human tendon fibroblasts under conditions mimicking injury response

In response to injury, tendon fibroblasts are activated, migrate to the wound, and contribute to tissue repair by producing and organizing the extracellular matrix. Collagen VI is a microfibrillar collagen enriched in the pericellular matrix of tendon fibroblasts with a potential regulatory role in tendon repair mechanism. We investigated the molecular basis of the interaction between collagen VI and the cell membrane both in tissue sections and fibroblast cultures of human tendon, and analyzed the deposition of collagen VI during migration and myofibroblast trans-differentiation, two crucial events for tendon repair. Tendon fibroblast displayed a collagen VI microfibrillar network closely associated with the cell surface. Binding of collagen VI with the cell membrane was mediated by NG2 proteoglycan, as demonstrated by in vitro perturbation of collagen VI–NG2 interaction with a NG2-blocking antibody. Cultures subjected to wound healing scratch assay displayed collagen VI–NG2 complexes at the trailing edge of migrating cells, suggesting a potential role in cell migration. In fact, the addition of a NG2-blocking antibody led to an impairment of cell polarization and delay of wound closure. Similar results were obtained after in vitro perturbation of collagen VI extracellular assembly with the 3C4 anti-collagen VI antibody and in collagen VI-deficient tendon cultures of a Ullrich congenital muscular dystrophy patient carrying mutations in COL6A2 gene. Moreover, in vitro treatment with transforming growth factor β1 (TGFβ1) induced a dramatic reduction of NG2 expression, both at protein and mRNA transcript level, and the impairment of collagen VI association with the cell membrane. Instead, collagen VI was still detectable in the extracellular matrix in association with ED-A fibronectin and collagen I, which were strongly induced by TGFβ1 treatment. Our findings reveal a critical role of the NG2 proteoglycan for the binding of collagen VI to the surface of tendon fibroblasts. By interacting with NG2 proteoglycan and other extracellular matrix proteins, collagen VI regulates fibroblasts behavior and the assembly of tendon matrix, thereby playing a crucial role in tendon repair

Phospholipase c beta 1 (PLCb1) in acute myeloid leukemia (AML): a novel potential therapeutic target

Acute myeloid leukemia (AML) is the most common type of leukemia in adults in which leukemic myeloid derived cells replace normal blood cells leading to a loss in systemic function. Once initiated the disease develops rapidly and is typically fatal within weeks or months if left untreated. AML is a complex disease and although, the exact causes of the development of AML are unknown, risk factors include age, pre-leukemic diseases such as myelodysplastic syndrome, exposure to chemicals and radiation and genetics. The mainstay treatment is still chemotherapy together with stem cell replacement therapy and while life expectancy has increased slowly, the 5 year survival rates range between 12 and 70% with relapse rates as high as 70% depending on the subtype (canceruk). These statistics illustrate the urgent requirement for the development of novel targeted therapeutics. Phospholipases C (PLC) are critical intracellular signaling enzymes that control a wide range of cellular functions including proliferation and apoptosis that have been implicated in myelodysplastic diseases and in leukemia (Faenza et al., 2013; Shah et al.). Importantly they constitute a highly druggable family of enzymes distinct from other well established drug development targets such as protein kinases. Using the human leukemic cell line THP1, we carried out a small targeted RNAi screen to establish a role of all known PLCs in cell growth, differentiation and maintenance of the transformed phenotype. We discovered that silencing of PLCb1 or PLCH2 resulted in a strong growth arrest. PLCb1 knockdown also initiated apoptosis and attenuated growth of THP1 cells in semisolid culture, which is known to reflect the ability of cells to induce leukemia in vivo. Accordingly, we found that knockdown of PLCb1 strongly attenuated THP1-mediated development of leukemia in mice. These growth inhibitory effects of PLCb1 knockdown were extended to a mouse model of human leukaemia induced by the MLL-AF9 translocation and to human primary leukemia cells. Of direct importance to the consideration for drug development we observed that PLCb1 knockdown selectively attenuated the growth of primary human AML cells, without effecting cell growth and differentiation of normal CD34+ hematopoietic stem and progenitor cells from healthy donors. We therefore propose PLCb1 as a novel candidate for a therapeutic target in AML