Background Recent advances from studies of graphene and graphene-based derivatives have highlighted the great potential of these nanomaterials as migrastatic agents with the ability to modulate tumor microenvironments. Nevertheless, the administration of graphene nanomaterials in suspensions in vivo is controversial. As an alternative approach, herein, we report the immobilization of high concentrations of graphene nanoplatelets in polyacrylonitrile film substrates (named PAN/G10) and evaluate their potential use as migrastatic agents on cancer cells. Results Breast cancer MCF7 cells cultured on PAN/G10 substrates presented features resembling mesenchymal-to-epithelial transition, e.g., (i) inhibition of migratory activity; (ii) activation of the expression of E-cadherin, cytokeratin 18, ZO-1 and EpCAM, four key molecular markers of epithelial differentiation; (iii) formation of adherens junctions with clustering and adhesion of cancer cells in aggregates or islets, and (iv) reorganization of the actin cytoskeleton resulting in a polygonal cell shape. Remarkably, assessment with Raman spectroscopy revealed that the above-mentioned events were produced when MCF7 cells were preferentially located on top of graphene-rich regions of the PAN/G10 substrates. Conclusions The present data demonstrate the capacity of these composite substrates to induce an epithelial-like differentiation in MCF7 breast cancer cells, resulting in a migrastatic effect without any chemical agent-mediated signaling. Future works will aim to thoroughly evaluate the mechanisms of how PAN/G10 substrates trigger these responses in cancer cells and their potential use as antimetastatics for the treatment of solid cancers. Graphical Abstract
Cyber-physical systems (CPSs) are smart systems that include engineered interacting networks of physical and computational components. CPSs have an increasingly presence on critical infrastructures and an impact in almost every aspect of our daily life, including transportation, healthcare, electric power, and advanced manufacturing. However, CPSs face a growing and serious security issue due to the widespread connectivity between the cyber world and the physical world. Although risk assessment methods for traditional IT systems are now very mature, these are not adequate for risk assessment of CPSs due to the different characteristics of the later. As such, there is an urgent need to define approaches that will adequately support risk assessment for CPSs. To contribute to this important challenge, we propose a novel risk analysis technique for CPSs based on MARISMA, a security management methodology, and eMARISMA, a technological environment in the cloud. Our work contributes to the state of the art through the definition of the MARISMA-CPS pattern that incorporates a set of reusable and adaptable elements that allows risks in CPSs to be managed and controlled, which is aligned with the main CPSs frameworks, such as those defined by NIST and ENISA. A case study for a smart hospital is presented, showing how the reusability and adaptability of the proposal allows the proposed MARISMA-CPS pattern to be easily adapted to any CPS environment. Such adaptability is important to ensure wide application in the domain of CPSs.
Polymer-metal gears become increasingly interesting to manufacturers and researchers for their advantages to combine the two material's efficiencies. Despite the variety of studies in the literature, there is a significant drop in the number of studies concerning the Gear Mesh Stiffness (GMS). The variation of the GMS by time has a major influence on the dynamic response of transmission. Therefore, this study proposes to take into consideration the viscoelastic behavior of polymer in order to model effectively the GMS of a gear system. The suggested rheological model is the Generalized Maxwell Model (GMM). It is first used to model the viscoelastic behavior of the plastic material of the pinion. Then, Pole Zero Formulation (PZF) is employed to identify parameters of the proposed model. A numerical simulation is then carried out to illustrate the results of this new approach adopted on a pure Nylon 6,6-steel pinions. The evolution of the GMS is illustrated to highlight the viscoelastic behavior's model presented in this paper. Finally, the influence of the change in the temperature is investigated.
There is a growing need for coastal and marine restoration, but it is not clear how to pay for it given that environmental funding is low, and national budgets are stretched in response to natural hazards. We use risk-industry methods and find that coral reef and mangrove restoration could yield strong Return on Investment (ROI) for flood risk reduction on shorelines across more than 20 Caribbean countries. These results are robust to changes in discount rates and the timing of restoration benefits. Data on restoration costs are sparse, but the Present Value (PV) of restored natural infrastructure shows that ROI would be positive in many locations even if restoration costs are in the hundreds of thousand per hectare for mangroves and millions per km for reefs. Based on these benefits, we identify significant sources of funding for restoring these natural defenses.
Background Cardiometabolic disorders are largely responsible for excess mortality in schizophrenia. Non-alcoholic fatty liver disease (NAFLD) is increasingly relevant in the development of metabolic risk factors that have been associated with antipsychotic treatment. We aimed to assess the incidence of NAFLD and metabolic disturbances during the first 3 years of antipsychotic treatment in patients with first episode of psychosis (FEP), and compare it with the incidence in a control group. Methods Data were obtained from patients with psychosis (n = 160) and healthy controls (n = 66) included in the Cantabria's clinical and research program on FEP (PAFIP) from 2012 to 2018. Fatty Liver Index (FLI) was used to estimate the amount of fat in the liver. FLI has been validated for the diagnosis of NAFLD against different standards such as liver ultrasound and biopsy. FLI and metabolic parameters were registered at baseline, 3 months and then yearly for 3 years. Results At the end of the follow-up (3-years), 21.9 % of patients with psychosis developed a FLI ≥ 60, suggestive of liver steatosis, compared to only a 3 % of subjects within the control group (X² = 12.120; p < 0.001). In the FEP patients group, developing a FLI ≥ 60 was statistically associated with significant increments in metabolic parameters, and with Metabolic Syndrome (MetS) (X² = 16.151; p < 0.001) and high blood pressure (X² = 10.654; p = 0.001). Conclusions Having a first episode of non-affective psychosis was significantly associated with developing liver steatosis (FLI ≥ 60) in the first three years after initiating antipsychotic treatment. The results highlight the importance of early screening the emergence of NAFLD in schizophrenia patients.
In this work we prove the existence of singularities in finite time for the Serre-Green-Naghdi equation when the interface reaches the impervious bottom tangentially. As a consequence , our result complements the paper Camassa, R., Falqui, G., Ortenzi, G., Pedroni, M., & Thomson, C. Hydrodynamic models and confinement effects by horizontal boundaries. Journal of Nonlinear Science, 29(4), 1445-1498, 2019. Furthermore, we also prove that the solution to the abcd−Boussinesq system can change sign in finite time. Finally, we provide with a proof of a scenario of finite time singularity for the abcd−Boussinesq system. These latter mathematical results are related to the numerics in Bona, & Chen, Singular solutions of a Boussinesq system for water waves.
The impacts of severe storms on the coastal zone, combined with rapid population growth in this area, have made coastal risk management an urgent need. However, integrated risk assessment can be a challenging task for many locations worldwide, as it normally requires the use of a large amount of data. The Coastal Risk Assessment Framework phase one (CRAF1) is a recently proposed analytical scheme based on empirical models and spatial analysis that combines different indicators to identify storm-induced hotspots. With a high degree of flexibility, the methodology was originally designed to be of broad use. Still, there is little information about the tool applicability in data scarcity conditions. In this study, we show that this approach can be applied, with some simplifications, on data-poor areas, allowing the identification of hotspots considering one or multiple hazards. Here, the coastal risk was assessed for erosion and coastal flooding events with return periods of 10 and 50 years on the Santa Catarina Central Coast. The study area is characterized by the occurrence of storm-induced impacts that historically cause disruption and damage to local communities. Although the components of risk have been assessed using various methods along this sector, to date, no integrated risk analysis has been presented in probabilistic terms. Predicted scenarios for the Santa Catarina Central Coast suggest that extreme episodes may cause several impacts, exposing urban settlements as well local road systems, especially in the municipalities of Tijucas and Florianópolis. The results show that the CRAF1 is an appropriate approach for a first-level risk analysis, even when implemented with poor data resolution, as it effectively points to some of the most vulnerable stretches detected in the study area.
Background and Aims To assess whether corticosteroids improve prognosis in patients with AS‐AIH, and to identify factors at therapy initiation and during therapy predictive of the response to corticosteroids. Methods This was a retrospective cohort study including all patients with AS‐AIH admitted to 13 tertiary centres from January 2002 to January 2019. The composite primary outcome was death or liver transplantation within 90 days of admission. Kaplan–Meier and Cox regression methods were used for data analysis. Results Of 242 consecutive patients enrolled (mean age [SD] 49.7 [16.8] years), 203 received corticosteroids. Overall 90‐day transplant‐free survival was 61.6% (95% confidence interval [CI] 55.4–67.7). Corticosteroids reduced the risk of a poor outcome (adjusted hazard ratio [HR] 0.25; 95% CI 0.2–0.4), but this treatment failed in 30.5%. An internally validated nomogram composed of older age, MELD, encephalopathy and ascites at the initiation of corticosteroids accurately predicted the response (C‐index 0.82; [95% CI 0.8–0.9]). In responders, MELD significantly improved from days 3 to 14 but remained unchanged in non‐responders. MELD on day 7 with a cut‐off of 25 (sensitivity 62.5%[95% CI: 47.0–75.8]; specificity 95.2% [95% CI: 89.9–97.8]) was the best univariate predictor of the response. Prolonging corticosteroids did not increase the overall infection risk (adjusted HR 0.75; 95% CI 0.3–2.1). Conclusion Older patients with high MELD, encephalopathy or ascites at steroid therapy initiation and during treatment are unlikely to show a favourable response and so prolonged therapy in these patients, especially if they are transplantation candidates, should be avoided.
Atmospheric conditions in any place can affect people's health. In this regard, this study aimed to investigate the climatic conditions of Tabriz (in northwestern Iran) and their relationship with the admission rate of cardiovascular patients in this city. We sought to predict thermal stresses on the hospital admissions rate of cardiovascular patients for the 2030s to 2059. The results of two climate models of CanESM2 and GFDL and three scenarios of RCP2.6, RCP4.5, and RCP8.5 were used to predict climate changes in the coming decades. In the present study, the physiological equivalent temperature (PET) index was applied to monitor and predict thermal stresses. The findings revealed that the colder the PET class, the higher the average of admissions. Based on all climate models and scenarios, it was found that the increase in hospital admissions for the middle classes of the PET index will be more than that of the extreme classes. On the other hand, the effect of global warming will cause an increase in the number of cardiovascular patients at an average rate of 147 people per year.
Increased urbanisation is boosting the intensity and frequency of the Urban Heat Island (UHI) effect in highly developed cities. The advances in satellite measurement are facilitating the analysis of this phenomenon using Land Surface Temperature (LST) as an indicator of the Surface UHI (SUHI). Due to the spatial implications of using remote sensing data, this research developed ArcUHI, a Geographic Information System (GIS) add-in for modelling SUHI. The tool was designed in ArcGIS, which was bound with R to run machine learning algorithms in the background. ArcUHI was tested using the metropolitan area of Madrid (Spain) in 2006, 2012 and 2018 as a case study. The add-in was found to predict observed LST with high accuracy, especially when using Random Forest Regression (RFR). Building height and albedo were identified as the main drivers of SUHI, whose magnitude and extension increased with time. In view of these results, strategic roof and wall greening was suggested as a measure to mitigate the street canyon effect entailed by buildings and offset the heat retention capacity of built-up surfaces.
Between 2018 and 2019, Salmonella enterica serotype Reading caused a large, multistate outbreak linked to contact with raw turkey products in the United States. Here, we provide five Salmonella Reading reference genomes collected from US patients between 2016 and 2018.
Introduction: Melphalan flufenamide (melflufen) is a first-in-class peptide-drug conjugate that takes advantage of increased aminopeptidase activity inside tumor cells to rapidly release alkylating agents therein. Melflufen in combination with dexamethasone has been evaluated in multiple clinical trials in patients with relapsed/refractory multiple myeloma (MM). Areas covered: This profile covers the unique mechanism of action of melflufen, the preclinical results supporting its activity in cellular models of resistance to chemotherapy, its activity in animal models of MM, and the clinical pharmacokinetics of melflufen. Findings from clinical trials evaluating melflufen, including the pivotal phase II HORIZON study and the phase III OCEAN study, are discussed. Expert opinion: Although MM treatment has improved, patients with disease refractory to multiple standard-of-care drug classes face a dismal prognosis. Melflufen demonstrated efficacy and tolerability in select populations, with an initial approval in the United States in patients with ≥ four previous lines of therapy and triple-class-refractory MM. Results from the phase III OCEAN study - currently under discussion with regulatory agencies in the United States and Europe - are more complex and have been put into context herein. Lastly, melflufen provides a proof-of-concept for the utility of the peptide-drug conjugate platform in relapsed/refractory MM.
Background Delayed discharge for non-clinical reasons also affects patients in need of palliative care. Moreover, the number of people dying in hospitals has been increasing in recent years. Our aim was to describe characteristics of patients who died during prolonged stay, in comparison with the rest of patients with delayed discharge, in terms of length of hospital stay, patient characteristics and the context of care. Methods A descriptive cross-sectional study at a high complexity public hospital in Northern Spain (2007–2015) was conducted. To compare the differential characteristics of the groups of patients died during delayed discharge with the rest, Student’s T test and Pearson’s chi-square test ( χ ² ) were used. Results A total of 198 patients died (6.57% of the total), with a mean total stay of 27.45 days and a prolonged stay of 10.69 days. Mean age 77.27 years. These were highly complex cases, 77.79% resided in the urban area, were admitted urgently (95.45%), to internal medicine or oncology wards, and the most common diagnosis was pneumonia. In people with terminal illness, clinicians can better identify when therapeutic possibilities are exhausted and acute hospitalization is not an adequate resource for their needs. Living in an urban area with the availability of palliative care hospital beds is related to the decision to die in hospital.
The complexity in the power system topology, together with the new paradigm in generation and demand, make achieving an adequate level of supply quality a complicated goal for distribution companies. The electrical system power quality is subject to different regulations. On one hand, EN-50160 establishes the characteristics of the voltage supplied by public electricity networks, therefore affecting distribution companies. On the other hand, the EN-61000 series of standards regulates the electromagnetic compatibility of devices connected to the network, therefore affecting the loads. Power companies and device manufacturers are both responsible and affected in the issue of quality of supply. Despite the regulations, there are certain aspects of the supply quality that are not solved. One of the most important is the location of the disturbance’s origin. This paper presents a review of the main techniques to locate the disturbance’s origin in the electric network through two approaches: identification of the disturbance’s cause and the location of the origin.
Autism spectrum disorder (ASD) is associated with high structural heterogeneity in magnetic resonance imaging (MRI). This work uncovers three neuroanatomical dimensions of ASD ( N = 307) using machine learning methods and constructs their characteristic MRI signatures. The presence of these signatures, along with their clinical profiles and genetic architectures, are investigated in the general population. High expression of the first dimension (A1, “aging-related”) is associated with globally reduced brain volume, cognitive dysfunction, and aging-related genetic variants. The second dimension (A2, “schizophrenia-like”) is characterized by enlarged subcortical volume, antipsychotic medication use, and partially overlapping genetic underpinnings to schizophrenia. The third dimension (A3, “classical ASD”) is distinguished by enlarged cortical volume, high non-verbal cognitive performance, and genes and biological pathways implicating brain development and abnormal apoptosis. Thus, we propose a three-dimensional endophenotypic representation to construe the heterogeneity in ASD, which can support precision medicine and the discovery of the biological mechanisms of ASD.
Wave climate is a primary driver of coastal risk, yet how climate change is altering wave climate is not fully understood. Here we identify transitional wave climate regions, coastlines with a future change in the occurrence frequency of a wave climate, with most of the regions located in south-western and eastern ocean basins. Analysis of the spatio-temporal changes in the atmosphere-driven major wave climates (the easterlies, southerlies and westerlies) under 2 emission scenarios for 2075–2099 and 2081–2099 shows increases in frequency from 5 to 20% for the easterly and southerly wave climates. The projected changes in these regions, in addition to sea-level rise and changes in storminess, can modify the general patterns of the prevailing wave climates and severely alter their coastal risks. Consequently, transitional wave climate regions should be recognized as areas of high coastal climate risk that require focus for adaptation in the near term.
Magnetic nanoparticles exhibit two different local symmetry environments, one ascribed to the core and one corresponding to the nanoparticle surface. This implies the existence of a dual spin dynamics, leading to the presence of two different magnetic arrangements governed by different correlation lengths. In this work, two ensembles of NdCu2 nanoparticles with mean sizes of 18 nm and 13 nm have been produced to unravel the magnetic couplings established among the magnetic moments located within the core and at the nanoparticle surface. To this end, we have combined neutron diffraction measurements, appropriate to investigate magnetically-ordered spin arrangements, with time-dependent macroscopic AC susceptibility measurements to reveal memory and aging effects. The observation of the latter phenomena are indicative of magnetically-frustrated states. The obtained results indicate that, while the Nd3+ magnetic moments located within the nanoparticle core keep the bulk antiferromagnetic commensurate structure in the whole magnetic state, the correlations among the surface spins give rise to a collective frustrated spin-glass phase. The interpretation of the magnetic structure of the nanoparticles is complemented by specific-heat measurements, which further support the lack of incommensurability in the nanoparticle state.
In this paper, we offer three examples from our research projects on both technological and pedagogical innovations to illustrate the impact of rapid technology changes on research. Members of our research team both developed and used technology applications in their research projects, utilizing design-based research (DBR). During the experiments, we encountered new challenges by the end of the research cycle due to updates in technologies. Although we had an idea of how to redesign the project for the next cycle based on the analyses of data, we noticed that we needed to not only redesign our approaches based on the research results but the changes in technologies were so rapid that materials and pedagogies needed to be altered as well. In our article, we propose an additional aspect to be considered in DBR while researching technology integration or innovative technologies. Moreover, the rapid change in technology raises further challenges to teachers’ professional development and the integration of those innovative technologies in classrooms. We anticipate our work to contribute to the development of technology resources and related pedagogies as well as the refinement of research methodologies in technology environments. Our contributions for the development of technology resources and refinement of research methods in technology-supported learning environments should, among other things, contribute to a less complex and at the same time more sustainable integration of pedagogical innovations into scientific and school practices.
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Universidad de Cantabria, Avda. de Los Castros, s/n, E-39005, Santander, Cantabria, Spain
Head of institution
Rec. Mag. Ángel Pazos Carro
+34 942 201500