Interaction of silver atomic quantum clusters with living organisms: bactericidal effect of Ag3 clusters mediated by disruption of topoisomerase–DNA complexes

Essential processes for living cells such as transcription and replication depend on the formation of specific protein–DNA recognition complexes. Proper formation of such complexes requires suitable fitting between the protein surface and the DNA surface. By adopting doxorubicin (DOX) as a model probe, we report here that Ag3 atomic quantum clusters (Ag-AQCs) inhibit the intercalation of DOX into DNA and have considerable influence on the interaction of DNA-binding proteins such as topoisomerase IV, Escherichia coli DNA gyrase and the restriction enzyme HindIII. Ag-AQCs at nanomolar concentrations inhibit enzyme activity. The inhibitory effect of Ag-AQCs is dose-dependent and occurs by intercalation into DNA. All these effects, not observed in the presence of Ag+ ions, can explain the powerful bactericidal activity of Ag-AQCs, extending the knowledge of silver bactericidal properties. Lastly, we highlight the interest of the interaction of Ag clusters with living organisms, an area that should be further explored due to the potential consequences that it might have, both beneficial and harmful.This work was supported by Obra Social“la Caixa” (OSLC-2012-007), European Commission through FEDER program (0681 InveNNta 1 E); Ministerio de Ciencia e Innovación, Spain (MAT2010-20442, MAT2011-28673-C02-01); MINECO, Spain (MAT2012-36754-C02-01 and CTQ2014-58812-C2-2-R), Xunta de Galicia, Spain (GRC2013-044, FEDER Funds). C. P.-A. is grateful for the FPU grant from Ministry of Education, Culture and Sports, Madrid, Spain (FPU13/00180)S

Frequency and Characteristics of familial melanoma in Spain: the FAM-GEM-1 Study.

Familial history of melanoma is a well-known risk factor for the disease, and 7% melanoma patients were reported to have a family history of melanoma. Data relating to the frequency and clinical and pathological characteristics of both familial and non-familial melanoma in Spain have been published, but these only include patients from specific areas of Spain and do not represent the data for the whole of Spain. PATIENTS AND METHODS: An observational study conducted by the Spanish Group of Melanoma (GEM) analyzed the family history of patients diagnosed with melanoma between 2011 and 2013 in the dermatology and oncology departments. RESULTS: In all, 1047 patients were analyzed, and 69 (6.6%) fulfilled criteria for classical familial melanoma (two or more first-degree relatives diagnosed with melanoma). Taking into account other risk factors for familial melanoma, such as multiple melanoma, pancreatic cancer in the family or second-degree relatives with melanoma, the number of patients fulfilling the criteria increased to 165 (15.8%). Using a univariate analysis, we determined that a Breslow index of less than 1 mm, negative mitosis, multiple melanoma, and a history of sunburns in childhood were more frequent in familial melanoma patients, but a multivariate analysis revealed no differences in any pathological or clinical factor between the two groups. CONCLUSIONS: Similar to that observed in other countries, familial melanoma accounts for 6.6% of melanoma diagnoses in Spain. Although no differences in the multivariate analysis were found, some better prognosis factors, such as Breslow index, seem more frequent in familial melanoma, which reflect a better early detection marker and/or a different biological behavior

Docencia en Derecho y Proceso: hacia un aprendizaje de calidad en la Universidad

Presentación / Esther Pillado González (pp. 11-13). -- La adaptación de la asignatura derecho procesal penal al grado en la Universidad Carlos III de Madrid: un proceso aún inconcluso / Juan Manuel Alcoceba Gil (pp. 17-26). -- Role playing, cooperación competitiva y method case en la docencia-aprendizaje del Derecho Procesal / Cristina Alonso Salgado (pp. 27-35). -- Esquemas y materiales básicos para explicar en el grado en derecho el sistema de impugnación de actos jurídicos de las administraciones públicas en España / Roberto O. Bustillo Bolado (pp. 37-40). -- Nuevas herramientas y técnicas para la docencia del derecho / Juan Cámara Ruiz (pp. 41-51). -- Novas técnicas na docência em direito / Marco Carvalho Gonçalves (pp. 53-60). -- Experiência de lecionação em Direito em cursos não jurídicos – a lecionação da UC de Direito das Crianças e Jovens ao Mestrado em Intervenção Psicossocial com Crianças, Jovens e Famílias do Instituto de Educação / Cristina M. A. Dias (pp. 61-67). -- Los programas universitarios para mayores: la docencia en Derecho en la Universidad de Vigo / Teresa Estévez Abeleira (pp. 69-79). -- El aprendizaje activo del Derecho Procesal / María Dolores Fernández Fustes (81-92). -- El aprendizaje como método de adquirir los conocimientos / Raquel López Jiménez (pp. 93-101). -- Alumnado con necesidades especiales en el grado en derecho: el reto de la normalización e inclusión / Ángel M. Mariño de Andrés y M. Teresa Martínez Táboas (pp. 103-110). -- Docencia y proceso penal: intentando experimentar el proceso / Sabela Oubiña Barbolla (pp. 111-127). -- La integración de las redes sociales en la enseñanza del Derecho Penal / Natalia Pérez Rivas (pp. 129-135). -- Análisis y prospectiva de una plataforma e-learning en ciencias jurídicas / Amparo Rodríguez Damián, Margarita Pino Juste, Arturo Casar Sarasola y Manuel Pérez Cota (pp. 137-149). -- La evaluación de competencias en las materias “prácticas externas” del Máster Universitario en Abogacía: problemas y retos / Mónica Siota Álvarez (pp. 151-164). -- La enseñanza del derecho procesal a través del método del caso / Helena Soleto Muñoz (pp. 165-178). -- A aprendizagem activa do Direito Processual – reflexão sobre velhos hábitos e novas práticas / Lurdes Varregoso Mesquita (pp. 179-189). -- Acão executiva e metodologia aplicada – demonstração de caso / Lurdes Varregoso Mesquita, Diana Leiras (pp. 191-201). -- Derecho Constitucional y género / Almudena Bergareche Gros (pp. 205-216). -- Aproximación al fenómeno de la violencia de género a través de las novelas como recurso didáctico / María Castro Corredoira (pp. 217-227). -- La formación en género en derecho penal: el cine como recurso didáctico / Natalia Pérez Rivas, Fernando Vázquez-Portomeñe Seijas (pp. 229-240). -- Cuestiones controvertidas de la docencia en el ámbito del derecho constitucional: la perspectiva de género y el principio de transversalidad / Pablo Riquelme Vázquez (pp. 241-253). -- Storytelling y cine extranjero en la explicación del sistema de justicia penal español / Cristina Alonso Salgado (pp. 257-263). -- Direito e Cinema. Breve reflexão a partir da experiência da docência ao 1.º ano do curso de Direito / Maria Clara Calheiros (pp. 265-273). -- El cine como opción pedagógica en la enseñanza del derecho penal / Fernando Vázquez-Portomeñe Seijas y María Castro Corredoira (pp. 275-286). -- El jurista del siglo XXI y la Universidad del siglo pasado: ¿realidades irreconciliables? / Amaya Arnáiz Serrano (pp. 289-307). -- La formación del abogado del siglo XXI / Emiliano Carretero Morales (pp. 309-321). -- El cambio del perfil del alumno y su influencia a la enseñanza superior / Anna Fiodorova (pp. 323-335). -- La enseñanza del derecho en el marco Bolonia: reflexiones en base a las distintas tradiciones jurídicas / Mercedes Llorente Sánchez-Arjona (pp. 337-355)

Treatment with tocilizumab or corticosteroids for COVID-19 patients with hyperinflammatory state: a multicentre cohort study (SAM-COVID-19)

Objectives: The objective of this study was to estimate the association between tocilizumab or corticosteroids and the risk of intubation or death in patients with coronavirus disease 19 (COVID-19) with a hyperinflammatory state according to clinical and laboratory parameters. Methods: A cohort study was performed in 60 Spanish hospitals including 778 patients with COVID-19 and clinical and laboratory data indicative of a hyperinflammatory state. Treatment was mainly with tocilizumab, an intermediate-high dose of corticosteroids (IHDC), a pulse dose of corticosteroids (PDC), combination therapy, or no treatment. Primary outcome was intubation or death; follow-up was 21 days. Propensity score-adjusted estimations using Cox regression (logistic regression if needed) were calculated. Propensity scores were used as confounders, matching variables and for the inverse probability of treatment weights (IPTWs). Results: In all, 88, 117, 78 and 151 patients treated with tocilizumab, IHDC, PDC, and combination therapy, respectively, were compared with 344 untreated patients. The primary endpoint occurred in 10 (11.4%), 27 (23.1%), 12 (15.4%), 40 (25.6%) and 69 (21.1%), respectively. The IPTW-based hazard ratios (odds ratio for combination therapy) for the primary endpoint were 0.32 (95%CI 0.22-0.47; p < 0.001) for tocilizumab, 0.82 (0.71-1.30; p 0.82) for IHDC, 0.61 (0.43-0.86; p 0.006) for PDC, and 1.17 (0.86-1.58; p 0.30) for combination therapy. Other applications of the propensity score provided similar results, but were not significant for PDC. Tocilizumab was also associated with lower hazard of death alone in IPTW analysis (0.07; 0.02-0.17; p < 0.001). Conclusions: Tocilizumab might be useful in COVID-19 patients with a hyperinflammatory state and should be prioritized for randomized trials in this situatio

Clonal chromosomal mosaicism and loss of chromosome Y in elderly men increase vulnerability for SARS-CoV-2

The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, COVID-19) had an estimated overall case fatality ratio of 1.38% (pre-vaccination), being 53% higher in males and increasing exponentially with age. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, we found 133 cases (1.42%) with detectable clonal mosaicism for chromosome alterations (mCA) and 226 males (5.08%) with acquired loss of chromosome Y (LOY). Individuals with clonal mosaic events (mCA and/or LOY) showed a 54% increase in the risk of COVID-19 lethality. LOY is associated with transcriptomic biomarkers of immune dysfunction, pro-coagulation activity and cardiovascular risk. Interferon-induced genes involved in the initial immune response to SARS-CoV-2 are also down-regulated in LOY. Thus, mCA and LOY underlie at least part of the sex-biased severity and mortality of COVID-19 in aging patients. Given its potential therapeutic and prognostic relevance, evaluation of clonal mosaicism should be implemented as biomarker of COVID-19 severity in elderly people. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, individuals with clonal mosaic events (clonal mosaicism for chromosome alterations and/or loss of chromosome Y) showed an increased risk of COVID-19 lethality

Role of age and comorbidities in mortality of patients with infective endocarditis

[Purpose]: The aim of this study was to analyse the characteristics of patients with IE in three groups of age and to assess the ability of age and the Charlson Comorbidity Index (CCI) to predict mortality. [Methods]: Prospective cohort study of all patients with IE included in the GAMES Spanish database between 2008 and 2015.Patients were stratified into three age groups:<65 years,65 to 80 years,and ≥ 80 years.The area under the receiver-operating characteristic (AUROC) curve was calculated to quantify the diagnostic accuracy of the CCI to predict mortality risk. [Results]: A total of 3120 patients with IE (1327 < 65 years;1291 65-80 years;502 ≥ 80 years) were enrolled.Fever and heart failure were the most common presentations of IE, with no differences among age groups.Patients ≥80 years who underwent surgery were significantly lower compared with other age groups (14.3%,65 years; 20.5%,65-79 years; 31.3%,≥80 years). In-hospital mortality was lower in the <65-year group (20.3%,<65 years;30.1%,65-79 years;34.7%,≥80 years;p < 0.001) as well as 1-year mortality (3.2%, <65 years; 5.5%, 65-80 years;7.6%,≥80 years; p = 0.003).Independent predictors of mortality were age ≥ 80 years (hazard ratio [HR]:2.78;95% confidence interval [CI]:2.32–3.34), CCI ≥ 3 (HR:1.62; 95% CI:1.39–1.88),and non-performed surgery (HR:1.64;95% CI:11.16–1.58).When the three age groups were compared,the AUROC curve for CCI was significantly larger for patients aged <65 years(p < 0.001) for both in-hospital and 1-year mortality. [Conclusion]: There were no differences in the clinical presentation of IE between the groups. Age ≥ 80 years, high comorbidity (measured by CCI),and non-performance of surgery were independent predictors of mortality in patients with IE.CCI could help to identify those patients with IE and surgical indication who present a lower risk of in-hospital and 1-year mortality after surgery, especially in the <65-year group

Generación procedimental de coberturas de edificaciones para modelos 3D

Lurtis Rules es una empresa dedicada al desarrollo de herramientas que contribuyan a mejorar la productividad de la industria de creaci´on de contenidos digitales. Su primera herramienta, House Builder, es un asistente que permite a un usuario, sin necesidad de tener conocimientos t´ecnicos de modelado, crear una edificaci´on en 3D que pueda ser importada en sus proyectos directamente. House Builder genera, en pocos minutos, el trabajo equivalente a dos semanas de un modelador profesional. El usuario introduce unas breves descripciones sobre el dise˜no que desea, como el contorno o el n´umero de plantas del edificio, y House Builder crea autom´aticamente una edificaci´on completa con gran cantidad de elementos y detalles. Entre los elementos que House Builder genera procedimentalmente se encuentran las cubiertas o tejados de las edificaciones. Estas cubiertas pueden ser simples o compuestas. Estas ´ultimas son aquellas que, por su contorno irregular, est´an constituidas por la intersecci ´on de varias cubiertas simples (rectangulares). Para la generaci´on de una cubierta compuesta, el algoritmo parte de las dimensiones del ´area que ´esta ocupa sobre el plano horizontal y, a continuaci´on, la divide en sub´areas rectangulares que representen, cada una, las dimensiones de las distintas cubiertas simples en que se descompone la cubierta compuesta. Una vez obtenidas las dimensiones de cada cubierta simple se construye del modelo 3D de cada una de ellas, con el fin de obtener el modelo 3D de la cubierta compuesta. Este algoritmo permite construir distintos tipos o geometr´ıas de cubiertas simples (a dos aguas, a cuatro aguas, etc), lo que da lugar a distintos tipos de cubiertas compuestas que House Builder puede utilizar para enriquecer sus modelos y hacerlos m´as atractivos y realistas.---ABSTRACT---Lurtis Rules is a company dedicated to the development of tools that help the industry of digital content creation to improve their productivity. Lurtis Rules’ first tool, House Builder, is a software that allows a user, without any technical knowledge of 3D modeling, to create a building that can be directly imported into their projects. House Builder generates, in a few minutes, just as much work as a professional modeler would do in two weeks. The user enters brief descriptions of the desired design, as could be its contour or the number of floors, and House Builder automatically creates a complete building with lots of elements and details. Among the elements that House Builder generates procedurally we can find the building covers or roofs, which may be simple or composite. The composite ones are those that, because of their irregular shapes, are formed by the intersection of several simple (rectangular) roofs. In order to generate a composite roof, the algorithm receives the size of the area that it occupies on the horizontal plane, and divides it into rectangular subareas that represent the dimensions of the various simple roofs that shape the composite roof. Once obtained the dimensions of each simple roof, they are individually raised into 3D dimensions, and so the model of the composite roof gets completely built. This algorithm enables the construction of different geometries or types of simple roofs (gable, hipped, mansard, gambrel, etc). This diversity of forms results in different types of composite roofs, which can be used by House Builder to enrich its models and make them more attractive and realistic

Investigation on the Alcian Blue-tetrakis(methylpyridinium) chloride reactivity in presence of DNA, RNA, G-quadruplex structures and BSA

Phtalocyanines have the potential to act as anticancer drugs, thanks to their interactions with proteins and polynucleotides [1]. Their strong and specific interaction with G-quadruplex structures may be responsible for inhibiting cancer cells proliferation [2]. Phtalocyanines are excellent macrocyclic ligands for transition metals and metal coordination deeply modulates their chemical and photophysical properties. We focused our attention on Alcian Blue-tetrakis(methylpyridinium) chloride (ABTP), a commercially-available Cu(II)-phtalocyanine complex with promising features. The binding properties in presence of several polynucleotides and a protein were investigated at physiological conditions through spectrophotometric and spectrofluorometric techniques, thermal denaturation tests and calorimetric measurements. The measurements were repeated at different temperatures and ionic strengths in order to obtain information on the binding modes. The thermodynamic parameters were evaluated as well. The UV-vis absorption titrations suggested that an interaction does occur with calf thymus DNA, telomeric DNA G-quadruplex (Tel23), double stranded RNA (polyA·polyU) and triple stranded RNA (polyA·2polyU). The results were confirmed by the appearance of induced signals in the circular dichroism spectra. The isothermal titration calorimetry also corroborated the interactions and provided the thermodynamic parameters for the bindings. On the other hand, ABTP does not seem to interact with bovine serum albumin at all. The Foster Resonance Energy Transfer (FRET) was exploited in Real Time Quantitative PCR measurements in order to evaluate the binding’s effect on double helix DNA and G-quadruplex structures. Although the previous measurements indicate that ABTP has a strong affinity for the biosubstrates, it does not affect the stability of the polynucleotides. The overall results suggest an external binding mode, with partial intercalation of the substituents. This hypothesis does agree with the dimension and geometry of the system. The obtained results are encouraging and further investigations will be performed in order deepen the mechanistic details of the processes. Furthermore, quantum chemistry studies are still in progress and will be refined. References: [1] N. Rasouli, N. Sohrabi, Physical Chemistry Research, 2016, 4 (1), 83-94 [2] H. Yaku, T. Murashima, D. Miyoshi, N. Sugimoto, Molecules, 2012, 17, 10586-1061

Global optimality in k-means clustering

We study the problem of finding an optimum clustering, a problem known to be NP-hard. Existing literature contains algorithms running in time proportional to the number of points raised to a power that depends on the dimensionality and on the number of clusters. Published validations of some of these algorithms are unfortunately incomplete; besides, the constant factors (with respect to the number of points) in their running time bounds have seen several published important improvements but are still huge, exponential on the dimension and on the number of clusters, making the corresponding algorithms fully impractical. We provide a new algorithm, with its corresponding complexity-theoretic analysis. It reduces both the exponent and the constant factor, to the extent that it becomes feasible for relevant particular cases. Additionally, it parallelizes extremely well, so that its implementation on current high-performance hardware is quite straightforward. Our proposal opens the door to potential improvements along a research line that had no practical significance so far; besides, a long but single-shot run of our algorithm allows one to identify absolutely optimum solutions for benchmark problems, whereby alternative heuristic proposals can evaluate the goodness of their solutions and the precise price paid for their faster running times.Peer Reviewe