1,425 research outputs found

    Morphometric analysis in the offshore of the southern Taranto Gulf: unveiling the structures controlling the Late Pleistocene-Holocene bathymetric evolution

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    The present study is focused on a morphometric analysis of high resolution multibeam data (10m, 5m and, locally, 2m resolution), that were acquired during the oceanographic TEATIOCA 2011 campaign along a sector of the Ionian margin of northern Calabria. The integration of morphometric analysis with sparker and chirp data allowed to unveil basic but robust information about: 1. hierarchy of the fault systems controlling the bathymetric evolution; 2. the interplay between tectonic and erosional processes in sea-floor modeling; 3. uplift rates; 4. tilting processes

    Cationic porphyrins are reversible proteasome inhibitors

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    The aim of this study is to verify if watersoluble porphyrins can be used as proteasome inhibitors. We have found that cationic porphyrins inhibit proteasome peptidase activities much more effectively than the corresponding anionic derivatives. The relevance of electrostatics in driving porphyin−proteasome interactions has been confirmed by the observation that the inhibitory efficiency of the cationic macrocycles decreases with the number of positive substituents. We have also investigated various metalloporphyrins, which differ due to the different propension of the central metal ion toward axial coordination. Our experimental results indicate that the naked cationic porphyrins are the most active in reversibly inhibiting the three main protease activities of the proteasome in the micromolar range. A spectroscopic characterization of porphyrin−proteasome interactions by UV−vis spectra parallels the results of inhibition assays: the higher the inhibitory effect the stronger the spectroscopic variations are. To interpret the action of porphyrins at a molecular level, we have performed calculations evidencing that cationic porphyrins may hinder the access to the canonical proteolytic site on the proteasome β5 subunit. In particular, an inspection of the top-scoring docking modes shows that the tetracationic porphyrin blocks the catalytic pocket, close to the N termini of the β5 proteasome subunit, more efficiently than its anionic counterpart. Proteasome inhibition activity of porphyrins unites their known anticancer properties making them suitable as a scaffold for the design of novel multitargeted molecules

    A cost-efficient DC active load laboratory solution

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    The increased use of DC renewable energy resources and DC storage systems, combined with the necessary reduction of energy waste, is boosting the development of DC smart grids. In this scenario, DC load emulation is of great importance. From the hardware point of view, DC buses stability of smart grids and the different DC/DC converter topologies must be tested. From the software point of view, smart grid strategies and job schedulers must be tested with different power absorption profiles. Moreover, DC load emulation can be useful for many other purposes, such as battery characterization, power supply testing, photovoltaic I-V curve measurements, etc. In this work, a cost-efficient DC Active Load (AL) solution is proposed. The principle of the circuit topology is a buck-boost-derived converter. This solution can be designed and tested considering the required voltage, current, and maximum input power. Both simulation and experimental results are shown on a 400 W size prototype. Thermal and electrical results validate the simulation model and the AL feasibility

    Geometry and modeling of an active offshore thrust-related fold system: the Amendolara Ridge, Ionian Sea, southern Italy

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    On the Ionian Sea coast of southern Italy, spanning the transition from the Calabrian Arc to the Apennines, NE-directed motion of the thin-skinned frontal thrust belt of the Apennines toward the Apulian foreland reportedly ceased during the Early-Middle Pleistocene. The submarine extension of the frontal thrust belt is represented by the Amendolara ridge, which stretches for over 80 km to the SE beneath the Taranto Gulf. High-resolution marine geophysical data collected on the Amendolara ridge during the TEATIOCA_2011 cruise provided unequivocal constraints to assert active fault-related fold growth. Single-channel seismic (sparker) and acoustic CHIRP profiles, corroborated by multibeam mapping and shallow coring, form the novel dataset to constrain the near-bottom evolution. The new data were benchmarked to the crustal geometry by means of interpretation of existing multichannel seismic profiles

    Silybins inhibit human IAPP amyloid growth and toxicity through stereospecific interactions

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    Type 2 Diabetes is a major public health threat, and its prevalence is increasing worldwide. The abnormal accumulation of islet amyloid polypeptide (IAPP) in pancreatic β-cells is associated with the onset of the disease. Therefore, the design of small molecules able to inhibit IAPP aggregation represents a promising strategy in the development of new therapies. Here we employ in vitro, biophysical, and computational methods to inspect the ability of Silybin A and Silybin B, two natural diastereoisomers extracted from milk thistle, to interfere with the toxic self-assembly of human IAPP (hIAPP). We show that Silybin B inhibits amyloid aggregation and protects INS-1 cells from hIAPP toxicity more than Silybin A. Molecular dynamics simulations revealed that the higher efficiency of Silybin B is ascribable to its interactions with precise hIAPP regions that are notoriously involved in hIAPP self-assembly i.e., the S20-S29 amyloidogenic core, H18, the N-terminal domain, and N35. These results highlight the importance of stereospecific ligand-peptide interactions in regulating amyloid aggregation and provide a blueprint for future studies aimed at designing Silybin derivatives with enhanced drug-like properties. Keywords: Aggregation; Diabetes; Inhibitors; Molecular dynamics; Peptid

    Analysis and validation of probabilistic models for predicting malignancy in solitary pulmonary nodules in a population in Brazil

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    OBJECTIVE: To analyze clinical and radiographic findings that influence the pathological diagnosis of solitary pulmonary nodule (SPN) and to compare/validate two probabilistic models for predicting SPN malignancy in patients with SPN in Brazil. METHODS: This was a retrospective study involving 110 patients diagnosed with SPN and submitted to resection of SPN at a tertiary hospital between 2000 and 2009. The clinical characteristics studied were gender, age, presence of systemic comorbidities, history of malignancy prior to the diagnosis of SPN, histopathological diagnosis of SPN, smoking status, smoking history, and time since smoking cessation. The radiological characteristics studied, in relation to the SPN, were presence of spiculated margins, maximum transverse diameter, and anatomical location. Two mathematical models, created in 1997 and 2007, respectively, were used in order to determine the probability of SPN malignancy. RESULTS: We found that SPN malignancy was significantly associated with age (p = 0.006; OR = 5.70 for age > 70 years), spiculated margins (p = 0.001), and maximum diameter of SPN (p = 0.001; OR = 2.62 for diameters > 20 mm). The probabilistic model created in 1997 proved to be superior to that created in 2007-area under the ROC curve (AUC), 0.79 ± 0.44 (95% CI: 0.70-0.88) vs. 0.69 ± 0.50 (95% CI: 0.59-0.79). CONCLUSIONS: Advanced age, greater maximum SPN diameter, and spiculated margins were significantly associated with the diagnosis of SPN malignancy. Our analysis shows that, although both mathematical models were effective in determining SPN malignancy in our population, the 1997 model was superior.OBJETIVO: Analisar características clínicas e radiográficas que influenciaram o diagnóstico anatomopatológico de nódulo pulmonar solitário (NPS) e comparar/validar dois modelos probabilísticos de malignidade do NPS em pacientes com NPS no Brasil. MÉTODOS: Análise retrospectiva de 110 pacientes com diagnóstico de NPS submetidos à ressecção em um hospital terciário no período entre 2000 e 2009. As características clínicas estudadas foram gênero, idade, presença de comorbidades sistêmicas, história de neoplasia maligna ao diagnóstico de NPS, diagnóstico histopatológico do NPS, tabagismo, carga tabágica e tempo de cessação do tabagismo. As características radiográficas avaliadas em relação ao NPS foram presença de margens espiculadas, tamanho do maior diâmetro transversal e localização anatômica do NPS. Foram utilizados dois modelos matemáticos, criados em 1997 e 2007, respectivamente, para determinar a probabilidade de malignidade do NPS. RESULTADOS: Houve associações significantes entre malignidade do NPS e idade (p = 0,006; OR = 5,70 para idade >70 anos), presença de margens espiculadas (p = 0,001) e diâmetro maior do NPS (p = 0,001; OR = 2,62 para diâmetro >20 mm). O modelo probabilístico de 1997 mostrou-se superior ao de 2007 - área sob a curva [ASC] ROC = 0,79 ± 0,44 (IC95%: 0,70-0,88) vs. ASC = 0,69 ± 0,50 (IC95%: 0,59-0,79). CONCLUSÕES: Idade elevada, maior diâmetro do NPS e presença de margens espiculadas tiveram associações significantes ao diagnóstico de malignidade do NPS. Nossa análise mostrou que, embora os dois modelos matemáticos sejam eficazes na determinação de malignidade do NPS nessa população, o modelo de 1997 mostrou-se superior.Universidade Federal de São Paulo (UNIFESP) Escola Paulista de Medicina Hospital São PauloUniversidade Federal de São Paulo (UNIFESP) Escola Paulista de MedicinaUNIFESP, EPM, Hospital São PauloUNIFESP, EPMSciEL

    Social Perception of Reconstruction following Orbital Exenteration

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    Background: Orbital exenteration, the removal of the entire globe, eyelids, and orbital content, is indicated in extensive neoplastic disease involving the orbital region. Although a functional reconstruction of orbital exenteration defects is mandatory, aesthetic concerns need to be considered. Facial disfigurement following reconstructive surgery often leads to great discomfort and social retirement, which can limit social interaction. The aim of this study was to explore how the society perceives the aspect of patients who underwent orbital exenteration and subsequent reconstruction, comparing two different types of reconstruction: standard anterolateral thigh (ALT) or "sandwich" fascial ALT (SALT) free flap. Methods: An online survey was created based on four questions regarding the perception of reconstruction (discomfort at looking at that patient, perception of unhealthiness, hypothesis of social life impairment, etc); five possible answers were provided, ranging from "completely" to "not at all." The survey was administered to the general population and to medical students. Results: In total, 255 people participated to the survey (130 medical students and 125 people of the general population); a total of 245 surveys were considered eligible (10 were incomplete and then discharged). Statistical significance was found (P < 0.001) regarding the better overall appearance of the SALT group over the ALT one. Conclusions: After analysis, the surgical outcome after SALT reconstruction has been found to be less disruptive in both groups, due to a reduced scar burden and a more pleasant orbital pocket. Our results encourage more research in the field of postexenteration reconstruction to achieve more aesthetic and social acceptability

    Cooperative Binding of the Cationic Porphyrin Tris-T4 Enhances Catalytic Activity of 20S Proteasome Unveiling a Complex Distribution of Functional States

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    The present study provides new evidence that cationic porphyrins may be considered as tunable platforms to interfere with the structural "key code" present on the 20S proteasome α-rings and, by consequence, with its catalytic activity. Here, we describe the functional and conformational effects on the 20S proteasome induced by the cooperative binding of the tri-cationic 5-(phenyl)-10,15,20-(tri N-methyl-4-pyridyl) porphyrin (Tris-T4). Our integrated kinetic, NMR, and in silico analysis allowed us to disclose a complex effect on the 20S catalytic activity depending on substrate/porphyrin concentration. The analysis of the kinetic data shows that Tris-T4 shifts the relative populations of the multiple interconverting 20S proteasome conformations leading to an increase in substrate hydrolysis by an allosteric pathway. Based on our Tris-T4/h20S interaction model, Tris-T4 is able to affect gating dynamics and substrate hydrolysis by binding to an array of negatively charged and hydrophobic residues present on the protein surface involved in the 20S molecular activation by the regulatory proteins (RPs). Accordingly, despite the fact that Tris-T4 also binds to the α3ΔN mutant, allosteric modulation is not observed since the molecular mechanism connecting gate dynamics with substrate hydrolysis is impaired. We envisage that the dynamic view of the 20S conformational equilibria, activated through cooperative Tris-T4 binding, may work as a simplified model for a better understanding of the intricate network of 20S conformational/functional states that may be mobilized by exogenous ligands, paving the way for the development of a new generation of proteasome allosteric modulators
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