Role of the central cations in the mechanical unfolding of DNA and RNA G-quadruplexes.

Cations are known to mediate diverse interactions in nucleic acids duplexes but they are critical in the arrangement of four-stranded structures. Here, we use all-atom molecular dynamics simulations with explicit solvent to analyse the mechanical unfolding of representative intramolecular G-quadruplex structures: a parallel, a hybrid and an antiparallel DNA and a parallel RNA, in the presence of stabilising cations. We confirm the stability of these conformations in the presence of [Formula: see text] central ions and observe distortions from the tetrad topology in their absence. Force-induced unfolding dynamics is then investigated. We show that the unfolding events in the force-extension curves are concomitant to the loss of coordination between the central ions and the guanines of the G-quadruplex. We found lower ruptures forces for the parallel configuration with respect to the antiparallel one, while the behaviour of the force pattern of the parallel RNA appears similar to the parallel DNA. We anticipate that our results will be essential to interpret the fine structure rupture profiles in stretching assays at high resolution and will shed light on the mechanochemical activity of G-quadruplex-binding machinery.

Macro and nano scale modelling of water-water interactions at ambient and low temperature: relaxation and residence times.

The decay dynamics of ambient and low temperature liquid water has been investigated through all-atom molecular dynamics simulations, residence times calculations and time correlation functions from 300 K down to 243 K. Those simulations replicate the experimental value of the self-diffusion constant as a function of temperature by tuning the damping factor of the Langevin equation of motion. A stretched exponential function exp[-(t/τ)(ß)] has been found to properly describe the relaxation of residence times calculated at different temperatures for solvent molecules in a nanodrop of free water modelled as a sphere of nanometric dimensions. As the temperature goes down the decay time τ increases showing a divergence at Ts = 227 ± 3 K. The temperature independence of the dimensionless stretched exponent ß = 0.59 ± 0.01 suggests the presence of, not a characteristic relaxation time (since ß≠ 1), but a distribution of decay times that also holds at low temperature. An explanation for such heterogeneity can be found at the nanoscopic level. Moreover it can be concluded that the distribution of times already reported for the dynamics of water surrounding proteins (ß≤ 0.5) can not be exclusively due to the presence of the biomolecule itself since isolated water also exhibits such behaviour. The above reported Ts and ß values quantitatively reproduce experimental data.

Highly Fluorescent Green Fluorescent Protein Chromophore Analogues Made by Decorating the Imidazolone Ring.

The synthesis and photophysical behavior of an unexplored family of green fluorescent protein (GFP)-like chromophore analogues is reported. The compound (Z)-4-(4-hydroxybenzylidene)-1-propyl-2-(propylamino)-1H-imidazol-5(4 H)-one (p-HBDNI, 2 a) exhibits significantly enhanced fluorescence properties relative to the parent compound (Z)-5-(4-hydroxybenzylidene)-2,3-dimethyl-3,5-dihydro-4H-imidazol-4-one (p-HBDI, 1). p-HBDNI was considered as a model system and the photophysical properties of other novel 2-amino-3,5-dihydro-4H-imidazol-4-one derivatives were evaluated. Time-dependent DFT calculations were carried out to rationalize the results. The analogue AIDNI (2 c), in which the 4-hydroxybenzyl group of p-HBDNI was replaced by an azaindole group, showed improved photophysical properties and potential for cell staining. The uptake and intracellular distribution of 2 c in living cells was investigated by confocal microscopy imaging.

Analysis of Android Device-Based Solutions for Fall Detection.

Falls are a major cause of health and psychological problems as well as hospitalization costs among older adults. Thus, the investigation on automatic Fall Detection Systems (FDSs) has received special attention from the research community during the last decade. In this area, the widespread popularity, decreasing price, computing capabilities, built-in sensors and multiplicity of wireless interfaces of Android-based devices (especially smartphones) have fostered the adoption of this technology to deploy wearable and inexpensive architectures for fall detection. This paper presents a critical and thorough analysis of those existing fall detection systems that are based on Android devices. The review systematically classifies and compares the proposals of the literature taking into account different criteria such as the system architecture, the employed sensors, the detection algorithm or the response in case of a fall alarms. The study emphasizes the analysis of the evaluation methods that are employed to assess the effectiveness of the detection process. The review reveals the complete lack of a reference framework to validate and compare the proposals. In addition, the study also shows that most research works do not evaluate the actual applicability of the Android devices (with limited battery and computing resources) to fall detection solutions.

On the capability of smartphones to perform as communication gateways in medical wireless personal area networks.

This paper evaluates and characterizes the technical performance of medical wireless personal area networks (WPANs) that are based on smartphones. For this purpose,a prototype of a health telemonitoring system is presented. The prototype incorporates a commercial Android smartphone, which acts as a relay point, or "gateway", between a set of wireless medical sensors and a data server. Additionally, the paper investigates if the conventional capabilities of current commercial smartphones can be affected by their use as gateways or "Holters" in health monitoring applications. Specifically, the profiling has focused on the CPU and power consumption of the mobile devices. These metrics have been measured under several test conditions modifying the smartphone model, the type of sensors connected to the WPAN, the employed Bluetooth profile (SPP (serial port profile) orHDP (health device profile)), the use of other peripherals, such as a GPS receiver, the impact of the use of the Wi-Fi interface or the employed method to encode and forward the data that are collected from the sensors.

Comparison and characterization of Android-based fall detection systems.

Falls are a foremost source of injuries and hospitalization for seniors. The adoption of automatic fall detection mechanisms can noticeably reduce the response time of the medical staff or caregivers when a fall takes place. Smartphones are being increasingly proposed as wearable, cost-effective and not-intrusive systems for fall detection. The exploitation of smartphones' potential (and in particular, the Android Operating System) can benefit from the wide implantation, the growing computational capabilities and the diversity of communication interfaces and embedded sensors of these personal devices. After revising the state-of-the-art on this matter, this study develops an experimental testbed to assess the performance of different fall detection algorithms that ground their decisions on the analysis of the inertial data registered by the accelerometer of the smartphone. Results obtained in a real testbed with diverse individuals indicate that the accuracy of the accelerometry-based techniques to identify the falls depends strongly on the fall pattern. The performed tests also show the difficulty to set detection acceleration thresholds that allow achieving a good trade-off between false negatives (falls that remain unnoticed) and false positives (conventional movements that are erroneously classified as falls). In any case, the study of the evolution of the battery drain reveals that the extra power consumption introduced by the Android monitoring applications cannot be neglected when evaluating the autonomy and even the viability of fall detection systems.

[Access and use of new information and telecommunication technologies among teenagers at high school, health implications. JOITIC Study]. / Acceso y uso de nuevas tecnologías entre los jóvenes de educación secundaria, implicaciones en salud. Estudio JOITIC.

OBJECTIVE: To determine ICT accessibility and use among the adolescents attending High School and to analyse related factors. DESIGN: Cross-sectional multicentric study. SETTING: High Schools participating in the Community Health «Salut i Escola¼ Programme. PARTICIPANTS: 5,538 students from first to fourth degree at 28 centres in the area of Barcelona. MAIN MEASUREMENTS: Self administered questionnaire including sociodemographic information, ICT use and accessibility. RESULTS: Missing answers were below 1% in all items except in school performance (3,13%); 48,6% were female, mean age 14years (range 11-20); 15,5% foreigners; 23% reported low school performance; 75,2% took extracurricular activities; 88,9% refers a good relationship with their parents. ICT access is homogeneously massive: 98% had a computer at home, 44,8% used it for two or more hours daily. 98,6% could access Internet, 47,2% without parental control. 90% owned a mobile phone (83% in first grade, 95% in fourth); 45,6% owned one before 12years old. Girls use it for social relationships and boys for playing. 68,4% played videogames, 36,5% for three or more hours a week and 66,8% without parental control. Their use decreases with age. The ICT parental control is associated with better school performance. CONCLUSIONS: Our high scholars gain access to the ICT at younger ages and they use them in almost every aspect of their lives. There have been detected some gender differences in their use, as well as in the age of the users and between the type of school.

Zurbarán attribution hypothesis supported by pigment analysis and multiband images observation of four paintings by his workshop.

Francisco de Zurbarán was one of the greatest painters of the Spanish Golden Age, with artworks scattered all over the world. Unfortunately, there are hardly any exhaustive studies on the pigments that he used. In this work, four canvas paintings attributed to the Zurbarán Workshop were studied. Each of them presents the figure of a different saint in a particular isolation scene: Saint Bruno, Saint Francis of Assisi, Saint Dominic of Guzman, and Saint Peter Martyr. Nevertheless, the painting of Saint Peter Martyr shows superior quality in both technique and colours, so it is not clear whether this canvas was also made by the Workshop or by Zurbarán himself, as some art historians claim. Coinciding with conservation and restoration works, the paintings were initially analysed with non-invasive techniques such as ultraviolet photography (UV), infrared reflectography (IRR) and X-ray fluorescence (XRF) to determine the characterization of the pigments. Those studies were complemented by stratigraphic analysis of some extracted samples with optical microscopy (OM) and scanning electron microscopy with energy dispersive X-ray spectroscopy (SEM-EDX). Among a number of results obtained, we found significant differences between the pigment palette used in Saint Peter Martyr and the other paintings, supporting the hypothesis that this painting was done by Zurbarán himself instead of his workshop. These results could also help to distinguish other authentic paintings by the master's hand from very similar paintings by his workshop or by other artists.

Water dynamics on the surface of the protein barstar.

Water plays a fundamental function in life and technology. To gain a deeper knowledge to the problem of the hydration of biomolecules, the dynamics of water around an 89-residue protein of interest in molecular recognition, cancer cell research and amyloid fibrils investigations is analyzed. The biomolecule is the ribonuclease inhibitor barstar wild-type. The dynamics of the protein and the 7430 water molecules of the bath in which it is immersed is monitored during a period of 7 ns by using all-atom molecular dynamics simulations. The results confirm the existence of multiple time scales in the dynamics of water (10(-1) to 10(3) ps) at the atomic level. That heterogeneity of residence times is not lost if the system of reference is just one atom of the inhibitor. The dehydration process of barstar is considered through the analysis of time correlation functions, obtaining an averaged decay time of τ = 84.0 ± 0.3 ps. A power law distribution, with scaling exponent α = 0.57 ± 0.04, suggests that this hydration water exhibits a scale free dynamics (with respect to the residence time of solvent molecules). Most of the water molecules located on the surface of the protein spend times smaller than the picosecond while only about 1% of them stay for periods of time on the nanosecond scale.

Chest computed tomography findings associated with severity and mortality in patients with COVID-19. / Hallazgos tomográficos pulmonares asociados a severidad y mortalidad en pacientes con la COVID-19.

OBJECTIVES: To determine chest CT findings associated with severity and mortality in patients with COVID-19 from the Hospital Nacional Edgardo Rebagliati Martins (HNERM) and propose cut-off values for a tomographic severity score (TSS). MATERIALS AND METHODS: A retrospective cohort study was conducted in 254 patients with COVID-19 who underwent chest CT as part of their initial evaluation at the emergency room; they were classified according to clinical severity. Main tomographic findings were described. A multivariate analysis with logistic regression was carried out to determine association with clinical severity, the Cox model was used to evaluate mortality, and ROC curves were elaborated to assess cutoff values for the TSS. RESULTS: CT findings associated with clinical severity were the following: diffuse pattern (OR: 3.23, 95% CI: 1.46-7.14), crazy-paving pattern (OR: 2.48; 95% CI: 1.08-5.68), and high TSS value (OR: 1.73; 95% CI: 1.49-2.02). The crazy-paving pattern (HR: 1.78; 95% CI: 1.03-3.06) and a high TSS value (HR: 1.33; 95% CI: 1.20-1.48) were found to be associated with mortality. A value of 7 in the TSS showed a sensibility of 94.4% and a specificity of 100% for moderate disease, and a value of 13 showed a sensibility of 84.9% and a specificity of 70.6% for severe disease. CONCLUSIONS: The diffuse pattern is associated with higher clinical severity. The crazy-paving pattern and a high TSS value are associated with higher clinical severity and mortality. We propose TSS cutoff values of 7 and 13 for moderate and severe disease, respectively.

OBJETIVOS: Determinar los hallazgos tomográficos pulmonares asociados a severidad y mortalidad en pacientes con la COVID-19 del Hospital Nacional Edgardo Rebagliati Martins (HNERM), y proponer puntos de corte para una puntuación tomográfica de severidad (PTS). MATERIALES Y MÉTODOS: Estudio de cohorte retrospectivo en 254 pacientes con la COVID-19 que contaban con tomografía de tórax clasificada según severidad clínica. Se realizó un análisis multivariado mediante regresión logística para determinar asociación con la severidad clínica, un análisis de regresión de Cox para evaluar mortalidad, y curvas ROC para evaluar la PTS. RESULTADOS: Los hallazgos tomográficos asociados a severidad clínica fueron el patrón difuso de las lesiones (OR: 3,23, IC 95%: 1,46-7,14), patrón en «empedrado¼ (OR: 2,48; IC 95%: 1,08-5,68) y mayor valor en la PTS (OR: 1,73; IC 95%: 1,49-2,02). Los hallazgos asociados a mortalidad fueron el patrón en «empedrado¼ (HR: 1,78; IC 95%: 1,03-3,06) y mayor valor en la PTS (HR: 1,33; IC 95%: 1,20-1,48). Un valor de 7 en la PTS tuvo una sensibilidad de 94,4% y especificidad de 100% para identificar casos moderados y un valor de 13 tuvo una sensibilidad de 84,9% y una especificidad de 70,6% para casos severos. CONCLUSIONES: El patrón difuso de las lesiones se asoció a una mayor severidad clínica. El patrón en «empedrado¼ y un mayor valor en la PTS se asociaron a mayor severidad clínica y a mortalidad. Se proponen los valores de 7 y 13 como puntos de corte de la PTS para identificar casos moderados y severos.

Monitoring the Restoration of a Seventeenth-Century Wooden Artwork Using Laser-Induced Fluorescence and Digital Image Analysis.

The present paper is aimed at demonstrating the capabilities of digital image analysis (DIA) to support conservation of painted artwork. Laser-induced fluorescence (LIF) imaging has been usually used in the diagnosis of wall paintings. In this case, LIF is applied to the case study of a painted wooden canopy, and most successful data processing techniques are presented in the discussion of results. The Jesús del Gran Poder canopy, completed by Francisco Ruiz Gijón in 1692, is an oil panel painting on wood. Eight panels of the canopy have been study by LIF. This technique is capable of remotely acquiring hyperspectral images operating in fluorescence mode following ultraviolet laser excitation. LIF spectra combined with principal component analysis, spectral angle mapper, and DIA provide a chemical mapping of the treated wooden surface of the panels. Besides, LIF spectrum is as a fingerprint of the panels that allows stablishing differences between them. LIF imaging analysis has proven to be a very useful tool for mapping retouching work, tracking previous restorations, and detecting chemicals on the wood in order to monitor restorations.

Bicyclic Diazepinones as Dual Ligands of the α2δ-1 Subunit of Voltage-Gated Calcium Channels and the Norepinephrine Transporter.

The synthesis and pharmacological activity of a new series of bicyclic diazepinones with dual activity toward the α2δ-1 subunit of voltage-gated calcium channels (Cavα2δ-1) and the norepinephrine transporter (NET) are reported. Exploration of the positions amenable for substitution on a nonaminoacidic Cavα2δ-1 scaffold allowed the identification of favorable positions for the attachment of NET pharmacophores. Among the patterns explored, attachment of the 2-ethylamino-9-methyl-6-phenyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-e][1,4]diazepin-5-one framework to the meta-position of the phenyl ring of the 3-methylamino-1-phenylpropoxy and 3-methylamino-1-thiophenylpropoxy moieties provided dual compounds with excellent NET functionality. Alternative bicyclic frameworks were also explored, and some lead molecules were identified, which showed a balanced dual profile and exhibited good ADMET properties.

Role of Isolated Limb Perfusion in the Era of Targeted Therapies and Immunotherapy in Melanoma. A Systematic Review of The Literature.

BACKGROUND: Isolated limb perfusion (ILP) is a locoregional procedure indicated by the unresectable melanoma of the limbs. Its complexity and highly demanding multidisciplinary approach means that it is a technique only implemented in a few referral centers around the globe. This report aims to examine its potential role in the era of targeted therapies and immunotherapy by conducting a systematic review of the literature on ILP. METHODS: PubMed, Embase and Cochrane Library were searched. The eligibility criteria included publications from 2000-2020 providing valid data o effectiveness, survival or toxicity. Studies in which the perfusion methodology was not clearly described, letters to the editor, non-systematic reviews and studies that applied outdated clinical guidelines were excluded. To rule out studies of a low methodological quality and assess the risk of bias, the following aspects were also required: a detailed description of the applied ILP regimen, the clinical context, follow-up periods, analyzed clinical endpoints, and the number of analyzed ILPs. The disagreements were resolved by consensus. The results are presented in tables and figures. RESULTS: Twenty-seven studies including 2637 ILPs were selected. The median overall response rate was 85%, with a median complete response rate of 58.5%. The median overall survival was 38 months, with a 5-year overall survival of 35%. The toxicity was generally mild according to Wieberdink toxicity criteria. DISCUSSION: ILP still offer a high efficacy in selected patients. The main limitation of our review is the heterogeneity and age of most of the articles, as well as the absence of clinical trials comparing ILP with other procedures, making it difficult to transfer its results to the current era. CONCLUSIONS: ILP is still an effective and safe procedure for selected patients with unresectable melanoma of the limbs. In the era of targeted therapies and immunotherapy, ILP remains an acceptable and reasonable palliative treatment alternative, especially to avoid limb amputations. The ongoing clinical trials combining systemic therapies and ILP will provide more valuable information in the future to clarify the potential synergism of both strategies.

Thyroid Metastasis From Cutaneous Melanoma on an 18F-FDG PET/CT Study.

The thyroid gland is an uncommon location for metastasis. We report a 59-year-old woman with a history of cutaneous malignant melanoma. A unique hypermetabolic mass on the left thyroid lobe was identified by control F-FDG PET/CT scan, leading to dysphagia and stridor clinic. Total thyroidectomy and lymphadenectomy were performed with histopathological results concordant with metastasis from melanoma. Despite its rarity, finding focal thyroid lesions in patients with an oncological history should alert us, recommending that its metastatic etiology be ruled out.

Pneumonitis Related to Melanoma Immunotherapy.

Several regimens of immunotherapy have recently proven successful for multiple cancers, due to increased survival and quality of life. Rarely, immunotherapy with anti-programmed cell death protein 1 and programmed death-ligand 1 antibodies across cancer may cause immune-related pulmonary toxicity, with a low overall incidence, being particularly low among patients with melanoma and highest among individuals with lung cancer. In this vein, pulmonary toxicity is staged at 4 degrees according to the severity of the clinic and radiological findings, and its management is based on suppression of immunotherapy and administration of glucocorticoids. We report a case of pulmonary toxicity related to melanoma immunotherapy observed by F-FDG PET/CT.

The perception of emotion-free faces in schizophrenia: a magneto-encephalography study.

OBJECTIVE: To analyze how patients suffering from schizophrenia perceive faces of unknown individuals that show no actual emotions in order to investigate the attribution of meanings to a relatively non-significant but complex sensory experience. DESIGN: Analysis of baseline and poststimulation magneto-encephalographic recordings. The stimuli consisted of four pictures with neutral emotional expression of male and female faces of Spanish individuals unknown to research subjects. PARTICIPANTS: Twelve right-handed patients suffering from schizophrenia (DSM IV-TR criteria), age 18-65, with active delusional activity (SAPS score in delusions above 39) and 15 right-handed sex- and age-matched control subjects. RESULTS: Compared to controls patients have a significant higher activity of both hemispheres (0-700 ms) being the activity in the right hemisphere (RH) higher than in the left hemisphere (LH). Patients also have a higher activity on the middle fusiform gyrus (BA 37) in the LH (200-300 ms), on the superior temporal areas (BA 22, 41 and 42) in both hemispheres (100-700 ms) and on the temporal pole (BA 38) in the RH (300-400 ms) and a lower activity in the LH of the latter. CONCLUSIONS: The areas that are more activated in our study are those involved in the process of thinking, in attributing meanings to perceptions and in activities such as theory of mind, which are essential for social interaction. The anterior temporal areas less activated indicate a reduced semantic memory for faces that could explain the social withdrawal of schizophrenia. These alterations are suggestive of a dysfunction of left hemisphere neuronal networks.

Discovery of potent calpain inhibitors based on the azolo-imidazolidenone scaffold.

A series of new azolopyrimidine-peptide hybrids and indolomethylideneimidazolones were obtained and evaluated as calpain inhibitors. The hybrid compounds were inactive, whereas some members of the initial azolomethylideneimidazolone series showed interesting calpain inhibitory activity. By using 4b as a hit compound, a new series of analogs were synthesized by an efficient synthetic procedure based on a multicomponent reaction followed by an unprecedented reaction at the methylene position of the molecule. The best inhibitor found for calpain I (IC50 = 20 nM) was about 20 times more potent than the hit compound. Studies on 4b showed that its inhibition is consistent with an uncompetitive inhibition mode. This compound did not exhibit cellular toxicity at any of the doses tested (0.1-10 µM) and further studies indicated that it was capable of blockading chemical ischemia induction of apoptosis by preventing sodium azide-dependent calpain activation in intact human kidney tubular epithelial cells. The results of molecular modeling studies rationalized the inhibitory activity found for this series and account, from a structural point of view, for the most active compound identified (4j).

Virchow Node From Prostate Carcinoma by 18F-Choline PET/CT.

F-choline PET/CT is increasingly being used during the follow-up of prostate cancer and is bringing us valuable information for the delineation of local and distant nodal recurrence in patients with hormone-resistant poorly differentiated cell types. Lymphatic spreading usually involves pelvic and retroperitoneal levels, being unusual at supraclavicular levels. We report a 75-year-old man with unsuspected involvement of Virchow node from prostate cancer observed using F-choline PET/CT.