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The inwardly rectifying potassium current of the cardiomyocyte (IK1) is the main determinant of the resting potential. Ion channels Kir2.1, Kir2.2, and Kir2.3 form tetramers and are the molecular correlate of macroscopic IK1 current. Verapamil is an antiarrhythmic drug used to suppress atrial and ventricular arrhythmias. Its primary mechanism of action is via blocking calcium channels. In addition, it has been demonstrated to block IK1 current and the Kir2.1 subunit. Its effect on other subunits that contribute to IK1 current has not been studied to date. We therefore analyzed the effect of verapamil on the Kir channels 2.1, 2.2, and 2.3 in the Xenopus oocyte expression system. Kir2.1, Kir2.2, and Kir2.3 channels were heterologously expressed in Xenopus oocytes. Respective currents were measured with the voltage clamp technique and the effect of verapamil on the current was measured. At a concentration of 300 µM, verapamil inhibited Kir2.1 channels by 41.36% ± 2.7 of the initial current, Kir2.2 channels by 16.51 ± 3.6%, and Kir2.3 by 69.98 ± 4.2%. As a verapamil effect on kir2.3 was a previously unknown finding, we analyzed this effect further. At wash in with 300 µM verapamil, the maximal effect was seen within 20 min of the infusion. After washing out with control solution, there was only a partial current recovery. The current reduction from verapamil was the same at − 120 mV (73.2 ± 3.7%), − 40 mV (85.5 ± 6.5%), and 0 mV (61.5 ± 10.6%) implying no voltage dependency of the block. Using site directed mutations in putative binding sites, we demonstrated a decrease of effect with pore mutant E291A and absence of verapamil effect for D251A. With mutant I214L, which shows a stronger affinity for PIP2 binding, we observed a normalized current reduction to 61.9 ± 0.06% of the control current, which was significantly less pronounced compared to wild type channels. Verapamil blocks Kir2.1, Kir2.2, and Kir2.3 subunits. In Kir2.3, blockade is dependent on sites E291 and D251 and interferes with activation of the channel via PIP2. Interference with these sites and with PIP2 binding has also been described for other Kir channels blocking drugs. As Kir2.3 is preferentially expressed in atrium, a selective Kir2.3 blocking agent would constitute an interesting antiarrhythmic concept.

The global reach-scale “ICESat-2 River Surface Slope” (IRIS, https://doi.org/10.5281/zenodo.7098113) dataset comprises average and extreme water surface slopes (WSS) derived from ICESat-2 observations between October 2018 and August 2022 as a supplement to 121,583 reaches from the “SWOT Mission River Database” (SWORD, Altenau et al., 2021). WSS is required to calculate river discharge, which is among the Essential Climate Variables as defined by the Global Climate Observing System. To gain full advantage of ICESat-2’s unique measurement geometry with six parallel lidar beams, the WSS is determined across pairs of beams or along individual beams, depending on the intersection angle of spacecraft orbit and river centerline. The combined results of both approaches are validated against in-situ data in a regional study at 815 reaches in Europe and North America with a median absolute error of 23 mm/km, almost complying with the SWOT science requirements of 17 mm/km (Scherer et al., 2022). IRIS can be used to research river dynamics, estimate river discharge, and correct water level time series from satellite altimetry for shifting ground tracks. Additionally, by referencing SWORD as a common database, IRIS may be used in combination with observations from the recently launched SWOT mission and could be easily compared against WSS measurements from SWOT’s new wide-swath sensor.

Water surface slope (WSS) of rivers is a key parameter in hydrological modelling, which allows for estimation of the transport and erosion capacity of a river, its flow velocity and discharge. On a local scale, WSS can be measured with a GNSS receiver installed on a boat, using remote sensing techniques (e.g. airborne lidar) or from a Digital Elevation Model (DEM). The most accurate method to measure WSS avoiding high-cost field campaigns is based on Water Surface Elevations (WSE) measured at in-situ stations. However, in poorly gauged rivers the neighboring gauges can be up to hundreds of kilometers apart, which inhibits a proper river profile observation. The gap in decreasing number of gauge readings is partially filled with satellite altimetry over rivers. Altimetry based WSE can be used to estimate WSS between neighboring measurements. Here, we present an innovative approach for estimating high-resolution WSS derived from multi-mission satellite altimetry for the largest Polish rivers.In this study, we used measurements from 9 altimetry missions: CryoSat-2, Envisat, ICESat-2, Jason-2/-3, SARAL, Sentinel-3A/-B, and Sentinel-6A. These observations cover the years from 2002 to 2022. We extracted the river centerlines from the global “SWOT Mission River Database” (SWORD). In order to validate the obtained results, we used WSE from 81 gauges, which are maintained by the Institute of Meteorology and Water Management – National Research Institute (Instytut Meteorologii i Gospodarki Wodnej – Państwowy Instytut Badawczy, IMGW-PIB). These measurements are referenced to the Kronsztadt’86 vertical datum and they range from 01.2016 to 05.2022. Additionally, we used the reach-scale “ICESat-2 River Surface Slope” (IRIS) and the DEM-derived WSS values from SWORD.To obtain WSS, we first determined WSE at each satellite pass crossing the studied river. Next, we split rivers into sections without dams and reservoirs. The Support Vector Regression (SVR) has been applied to reject outliers. Then, water levels were assigned to a given river kilometer (bin). For each of them a median WSE has been calculated. Finally, WSS were calculated at river sections between bins, excluding those disrupted by hydraulic structures. Finally, we weighted the section-wise WSS inversely proportional to the length of each section and applied a Least Square Adjustment with an additional Laplace condition to obtain bin-wise WSS for each river kilometer.To assess the accuracy of the proposed approach, we compared the obtained WSS with the slopes between IMGW-PIB gauges. For large rivers (Vistula, Odra, Warta), the multi-mission approach revealed high accuracy with preliminary Root Mean Squared Error (RMSE) below 30 mm/km. For smaller, mountain rivers (San, Dunajec) the preliminary errors were slightly larger (RMSE ~100 mm/km). We also compared our accuracies with those of the slopes based on DEM models, lidar data, ICESat-2 altimetry, and SWORD database. In general, the multi-mission approach revealed the highest accuracy. The research is supported by the National Science Centre, Poland, through the project no. 2020/38/E/ST10/00295.

For nearly three decades, satellite radar altimetry has provided measurements of the water surface elevation (WSE) of rivers. These observations can be used to calculate the water surface slope (WSS), which is an essential parameter for estimating flow velocity and river discharge. In this study, we calculate a high-resolution WSS of 11 Polish rivers based on multi-mission altimetry observations from 11 satellites in the period from 1994 to 2022. The proposed approach is based on a weighted such gauge stations adjustment with an additional Laplace condition and an a priori gradient condition. The processing is divided into river sections not interrupted by dams and reservoirs. After proper determination of the WSE for each river kilometer (bin), the WSS between adjacent bins is calculated. To assess the accuracy of the estimated WSS, it is compared with slopes between gauge stations, which are referenced to a common vertical datum. Such gauge stations are available for 8 investigated rivers. The root mean squared error (RMSE) ranges from 3 mm/km to 80 mm/km, with an average of 26 mm/km. However, the mean RMSE decreases to 10 mm/km when the 2 mountain rivers are excluded. The WSS accuracies are also compared with those of slope datasets based on digital elevation models, ICESat-2 altimetry, and lidar. For 6 rivers the estimated WSS showed the highest accuracy. The improvement was particularly significant for mountain rivers. The proposed approach allows an accurate, high-resolution WSS even for small and medium-sized rivers and can be applied to almost any river worldwide.

The inwardly rectifying potassium current of the cardiomyocyte (I

Geometry is a branch of mathematics that helps us to work with distances, volumes, and areas of the real world. But spatial geometry presents an unusual obstacle: how to understand the elements of a three-dimensional object when they are normally presented in a two-dimensional form. The study was conducted with two classes in the 2nd year of high school in a public school. Class 1 used traditional resources: textbook, blackboard, and chalk. Class 2 used augmented reality (FLARAS) and 3D visualization (Sketchup) and textbook. It was expected that, with the help of augmented reality, the students of Class 2 would perform better than Class 1. A better understanding of the content was achieved, as they would have better visualization of spatial objects. Consequently, better performance was achieved in the exercises and problem questions presented.

Background Postcardiac injury syndrome (PCIS) is an inflammatory complication that derives from injury to the epicardium, myocardium, or endocardium. It occurs after trauma, myocardial infarction, percutaneous coronary intervention, cardiac surgery, intracardiac ablation, and implantation of cardiac implantable electronic device (CIED). In this study we assessed the incidence of PCIS after CIED implantation and its possible risk factors. Material and methods All patients who received CIED implantation at Heidelberg University Hospital between 2000 and 2014 were evaluated (n = 4989 patients). Clinical data including age, sex, underlying cardiac disease, type of implanted CIED, location of electrode implantation, clinical symptoms, time of symptom onset of PCIS, therapy, and outcome were extracted and analyzed. Results We identified 19 cases of PCIS in 4989 patients, yielding an incidence of 0.38%. The age of patients with PCIS ranged from 39 to 86 years. Dilated cardiomyopathy (DCM) as underlying cardiac disease and right atrial (RA) lead implantation had a significant association with occurrence of PCIS (p = 0.045 in DCM and p Conclusion To the best of our knowledge, this is the largest cohort evaluating the incidence of PCIS after CIED implantation. The data show that PCIS is a rare complication after CIED implantation and occurs more frequently in patients with DCM and those with RA lead implantation. Although rare and mostly benign, PCIS can lead to potentially lethal complications and physicians must be aware of its symptoms.

Compared to mechanical extraction methods, pulsed electric field (PEF) treatment provides an energy-efficient and gentle alternative. However, the biological processes involved are poorly understood. The unicellular green microalga Chlorella vulgaris was used as model organism to investigate the effect of PEF treatment on biological cells. A viability assay using fluorescein diacetate measured by flow cytometry was established. The influence of developmental stage on viability could be shown in synchronised cultures when applying PEF treatment with very low specific energies where one part of cells undergoes cell death, and the other part stays viable after treatment. Reactive oxygen species generation after similar low-energy PEF treatment could be shown, indicating that PEFs could act as abiotic stress signal. Most importantly, a cell-death inducing factor could be extracted. A water-soluble extract derived from microalgae suspensions incubated for 24 h after PEF treatment caused the recipient microalgae to die, even though the recipient cells had not been subjected to PEF treatment directly. The working model assumes that low-energy PEF treatment induces programmed cell death in C. vulgaris while specifically releasing a cell-death inducing factor. Low-energy PEF treatment with subsequent incubation period could be a novel biotechnological strategy to extract soluble proteins and lipids in cascade process.

A 23-year-old male patient presented with very mild visual disturbances, but a distinct prominence of the optic discs, more pronounced in the right than in the left eye. The ophthalmic symptoms initially seemed trivial, but a large-scale interdisciplinary workup later identified them as the presenting symptoms of sarcoidosis affecting lung and eyes. A standard steroid monotherapy successfully caused regression of the ophthalmic findings.

Geometry is a branch of Mathematics that helps us to work with distances, volumes, and areas in the real world. However, learning content related to Spatial Geometry, whose visual appeal should be an invitation to study, presents an unusual obstacle for the student: how to understand the elements of a three-dimensional object if they are normally presented in a two-dimensional way (e.g., drawn on the whiteboard or book)? There is several software that can be used in the teaching of Space Geometry. However, in most times, the teacher has no contact with these tools, either due to unavailability of hardware to interact; or due to difficulty in acquiring the software, which in turn may be due to the cost or lack of knowledge of the means to make the acquisition. The focus of this paper is to present the experience report on the use of Augmented Reality using tutorials developed by NIEP group, aiming to generate personalized material for use in the classroom by high school students in Mathematics, in the teaching/learning of Space Geometry. The results found demonstrate improved learning, better understanding of the content and reduced learning time.

Pregnancy is an important phase in women's lives, prenatal care is important to prevent diseases and ensure that women and babies can have a better quality of life. However, in Brazil, many pregnant women still do not perform due prenatal care, there are several factors that contribute to the failure to perform prenatal care among them: geographical factors. Pregnant women who live far from health units are unable to start pregnancy care in time. This work proposes a viable and low-cost alternative for the government or private sector companies. A Microservices architecture is presented, capable of meeting requests from pregnant women via mobile application and allowing health professionals to monitor the pregnancy evolution of a health unit. The architecture was designed to offer satisfactory performance, scalability and simplicity.

Educational Robotics refers to an application of technology in the pedagogical area that offers participants the opportunity to propose and solve difficult problems. So, what is learned by the child’s own effort has much more meaning for him and adapts better to they mental structures. Educational Robotics can be separated according to the apparatus used, which may be the use of commercial kits (e.g., LEGO EV3 or FISCHER TECHNIC) or low-cost kits (e.g., based on Arduino). Commercial kits typically have graphical programming interfaces tightly coupled to their components. Low-cost kits, on the other hand, do not have a defined interface and, therefore, depend on the search for software that allows their programming, but which have no obligation to work perfectly with all the components of the kit. This article shows an analysis of some Visual Programming Platforms (VPP) for educational robotics. This work also presents the design of a robotics VPP based on Arduino, designed for the inclusion of educational robotics to Brazilian children aged 8 to 14 years old.

Mobile devices have become quite popular over the past few years and as a result, the number of applications for the most diverse functions are available for download, many of them free of charge. However, this range of applications does not follow minimum usability parameters, which results in a high level of rejection by users. Within this mobile world, the insertion of devices that aid the health processes, called m-health, has shown an exponential growth in recent years and with this, the warning signal about the efficiency and security of information has been triggered. To remedy this weakness, the introduction of usability techniques during the application development process appears as crucial for minimizing the problem. Numerous studies cite the need for usability in m-health applications, but none of them points out how to obtain it. In this way, this work aims to verify if the design guidelines provided by the Google / Android platform, which is presented as a contribution to mobile software developers, presents guidelines that make it possible to obtain the maximum usability of these applications, considering the proposed user profile and the context of use involved. To this end, the proposal will be based on the comparison between the guidelines contained in the ISO standard (9241) and in consultation with the style guide of the platform called material design.

Esta pesquisa é uma reflexão sobre minha prática artística que se constrói com base em questões relacionadas ao universo do hiperconsumo na sociedade contemporânea. Tomando como eixo o processo de criação de duas mostras individuais que abordam o próprio contexto mercadológico onde se inscrevem — uma galeria de arte na cidade de Porto Alegre —, a dissertação constrói um cenário que amplia as discussões promovidas por ambas as mostras. Aproximando-as de outras ações artísticas com ocorrência em diferentes pontos do globo, o texto analisa um conjunto diversificado de perspectivas e estratégias que problematizam as instâncias de legitimação e valoração da arte contemporânea. Refletindo sobre o cinismo como uma estratégia renovada de crítica, busco analisar a metodologia da crítica institucional à luz do mercado global contemporâneo. This research is a reflection about my artistic practice, built based on issues related to the universe of hyperconsumerism in contemporary society. Taking as its axis the creative process of two solo exhibitions that approach the market context in which themselves are inscribed — an art gallery in the city of Porto Alegre —, the dissertation creates a setting that enhances the discussions promoted by both shows. By placing them together with other artistic operations occurring in different places around the world, the text analyzes a diversified collection of perspectives and strategies that problematize the instances of legitimization and valuation of contemporary art. Reflecting about cynicism as a renewed critical strategy, my aim is to analyze the methodology of institutional critique in the light of the contemporary global market.

Background: Pregnancy is an important phase in a woman's life, the gestational period however is accompanied by fears and apprehension, especially for women who are experiencing this phase for the first time. Prenatal care is essential to prevent diseases and reduce risk for pregnant women, thus enabling healthy development for the baby. Nowadays many women find it difficult to make an adequate prenatal care, for the most varied reasons. Taking into account that the world is increasingly connected to the internet, it is important to understand, analyzing a set of health applications, which are the best decisions from the design point of view, usability to become a useful application for pregnant women, another relevant point is to understand how the architecture of these solutions were designed to be scalable. Thus, a well-defined systematic review is needed to identify the impacts of architectural, design and performance decisions on health applications, reducing risks and minimizing human errors.Methods/Design: This study will follow a well-defined methodological structure. The methodology is separated into the following sections: Research question identification; Extraction of relevant studies; Selection criteria; Charting the data; Collating, summarizing, and reporting the results. The research question aims to analyze the approaches used to build health applications aiming at design decisions, architecture and the impacts that are generated for the end user. The researchers will use the following electronic databases for data extraction: PubMed (Medline); IEEE Xplore Digital Library; ACM Digital Library; Web of Science; and Scopus Document Search. The search for research will consist of a set of terms and keywords.Discussion: This work has the interest of presenting a model, a standard, a guide for creating a health software interface, always aiming at the quality of the interface, the user experience and the possible gain with the performance of the application, considering that users will have more security to make decisions.Systematic review registration: Submitted on October 11, 2020 Open Science Framework.

Remote sensing data are essential for monitoring the Earth’s surface waters, especially since the amount of publicly available in-situ data is declining. Satellite altimetry provides valuable information on the water levels and variations of lakes, reservoirs and rivers. In combination with satellite imagery, the derived time series allow the monitoring of lake storage changes and river discharge. However, satellite altimetry is limited in terms of its spatial resolution due to its measurement geometry, only providing information in the nadir direction beneath the satellite’s orbit. In a case study in the Mississippi River Basin (MRB), this study investigates the potential and limitations of past and current satellite missions for the monitoring of basin-wide storage changes. For that purpose, an automated target detection is developed and the extracted lake surfaces are merged with the satellites’ tracks. This reveals that the current altimeter configuration misses about 80% of all lakes larger than 0.1 km2 in the MRB and 20% of lakes larger than 10 km2, corresponding to 30% and 7% of the total water area, respectively. Past altimetry configurations perform even more poorly. From the larger water bodies represented by a global hydrology model, at least 91% of targets and 98% of storage changes are captured by the current altimeter configuration. This will improve significantly with the launch of the planned Surface Water and Ocean Topography (SWOT) mission.

Despite increasing interest in monitoring the global water cycle, the availability of in situ gauging and discharge time series is decreasing. However, this lack of ground data can partly be compensated for by using remote sensing techniques to observe river stages and discharge. In this paper, a new approach for estimating discharge by combining water levels from multi-mission satellite altimetry and surface area extents from optical imagery with physical flow equations at a single cross-section is presented and tested at the Lower Mississippi River. The datasets are combined by fitting a hypsometric curve, which is then used to derive the water level for each acquisition epoch of the long-term multi-spectral remote sensing missions. In this way, the chance of detecting water level extremes is increased and a bathymetry can be estimated from water surface extent observations. Below the minimum hypsometric water level, the river bed elevation is estimated using an empirical width-to-depth relationship in order to determine the final cross-sectional geometry. The required flow gradient is derived from the differences between virtual station elevations, which are computed in a least square adjustment from the height differences of all multi-mission satellite altimetry data that are close in time. Using the virtual station elevations, satellite altimetry data from multiple virtual stations and missions are combined to one long-term water level time series. All required parameters are estimated purely based on remote sensing data, without using any ground data or calibration. The validation at three gauging stations of the Lower Mississippi River shows large deviations primarily caused by the below average width of the predefined cross-sections. At 13 additional cross-sections situated in wide, uniform, and straight river sections nearby the gauges the Normalized Root Mean Square Error (NRMSE) varies between 10.95% and 28.43%. The Nash-Sutcliffe Efficiency (NSE) for these targets is in a range from 0.658 to 0.946.

O desenvolvimento de software, em particular, de jogos sempre atraiu a atenção como uma porta de entrada para novos desenvolvedores entrarem no mundo da computação. Inicialmente, era necessário o conhecimento de linguagens de programação altamente complexas (por exemplo, Assembly); depois disso, foi necessário ter conhecimento em uma linguagem de alto nível como C ++ e, finalmente, recentemente o espaço parece ter sido dominado por motores, como Unity e Unreal. É interessante notar que houve uma migração na forma de desenvolvimento, deixando demandas por conhecimentos específicos de programação atingindo situações nas quais o desenvolvimento se baseia quase que exclusivamente no design do jogo desejado. Dessa forma, este trabalho busca analisar os mecanismos de desenvolvimento de jogos, buscando expor suas vantagens e desvantagens, quais recursos, comunidade, suporte e documentação, além de quais requisitos de conhecimento para que o novo desenvolvedor atual possa entrar neste mundo.

A robótica possui quase um atrativo próprio para aglomerar pessoas. Com a possibilidade de movimentar um equipamento, seja via programação ou mesmo via controle (remoto ou via smartphone), a robótica atrai olhares e direciona a vontade de interagir. No caso de alunos, não importando a idade, não é diferente. Infelizmente, no Brasil, o custo para acesso a materiais robóticos, sejam de cunho puramente recreativo ou de potencial educacional, habitualmente, não é convidativo. Neste sentido, tem-se a opção dos materiais de baixo custo e muitas vezes open-source, a exemplo da plataforma Arduino. Entretanto, seu uso, por vezes, demanda conhecimentos para usar e montar as peças e componentes, ter habilidades de eletrônica (para efetivamente construir um robô) até chegar ao ponto da programação do robô criado. Este trabalho apresenta uma visão de uso de robótica de baixo custo baseado na plataforma Arduino, e uma discussão dos motivos que levaram a evolução do robô criado em meados de 2012, custando na época R$228,00, para uma nova versão custando R$145,00.

Despite increasing interest in monitoring the global water cycle, the availability of in-situ discharge time series is decreasing. However, this lack of ground data can be compensated by using remote sensing techniques to observe river discharge.In this contribution, a new approach for estimating the discharge of large rivers by combining various long-term remote sensing data with physical flow equations is presented. For this purpose, water levels derived from multi-mission satellite altimetry and water surface extents extracted from optical satellite images are used, both provided by DGFI-TUM’s “Database of Hydrological Time series of Inland Waters” (DAHITI, https://dahiti.dgfi.tum.de). The datasets are combined by fitting a hypsometric curve in order to describe the stage-width relation, which is then used to derive the water level for each acquisition epoch of the long-term multi-spectral remote sensing missions. In this way, the chance of detecting water level extremes is increased and a bathymetry can be estimated from water surface extent observations. Below the minimum hypsometric water level, the river bed elevation is estimated using an empirical width-to-depth relationship in order to determine the final cross-sectional geometry. The required flow gradient is computed based on a linear adjustment of river surface slope using all altimetry-observed water level differences between synchronous measurements at various virtual stations along the river. The roughness coefficient is set based on geomorphological features quantified by adjustment factors. These are chosen using remote sensing data and a literature decision guide.Within this study, all parameters are estimated purely based on remote sensing data, without using any ground data. In-situ data is only used for the validation of the method at the Lower Mississippi River. It shows that the presented approach yields best results for uniform and straight river sections. The resulting normalized root mean square error for those targets varies between 10% to 35% and is comparable with other studies.

The caged xanthone gambogic acid (GA) is a novel anti-cancer agent which exhibits anti-proliferative, anti-inflammatory and cytotoxic effects in many types of cancer tissues. In a recent phase IIa study, GA exhibits a favourable safety profile. However, limited data are available concerning its interaction with cardiac ion channels. Heteromeric assembly of Kir2.x channels underlies the cardiac inwardly rectifying IK1 current which is responsible for the stabilization of the diastolic resting membrane potential. Inhibition of the cardiac IK1 current may lead to ventricular arrhythmia due to delayed afterdepolarizations. Compared to Kv2.1, hERG and Kir1.1, a slow, delayed inhibition of Kir2.1 channels by GA in a mammalian cell line was reported before but no data exist in literature concerning action of GA on homomeric Kir2.2 and Kir2.3 and heteromeric Kir2.x channels. Therefore, the aim of this study was to provide comparative data on the effect of GA on homomeric and heteromeric Kir2.x channels. Homomeric and heteromeric Kir2.x channels were heterologously expressed in Xenopus oocytes, and the two-microelectrode voltage-clamp technique was used to record Kir2.x currents. To investigate the mechanism of the channel inhibition by GA, alanine-mutated Kir2.x channels with modifications in the channels pore region or at phosphatidylinositol 4,5-bisphosphate (PIP2)-binding sites were employed. GA caused a slow inhibition of homomeric and heteromeric Kir2.x channels at low micromolar concentrations (with IC50 Kir2.1/2.2

The cardiac IK1 current stabilizes the resting membrane potential of cardiomyocytes. Protein kinase A (PKA) induces an inhibition of IK1 current which strongly promotes focal arrhythmogenesis. The molecular mechanisms underlying this regulation have only partially been elucidated yet. Furthermore, the role of A-kinase anchoring proteins (AKAPs) in this regulation has not been examined to date. The objective of this project was to elucidate the molecular mechanisms underlying the inhibition of IK1 by PKA and to identify novel molecular targets for antiarrhythmic therapy downstream β-adrenoreceptors. Patch clamp and voltage clamp experiments were used to record currents and co-immunoprecipitation, and co-localization experiments were performed to show spatial and functional coupling. Activation of PKA inhibited IK1 current in rat cardiomyocytes. This regulation was markedly attenuated by disrupting PKA-binding to AKAPs with the peptide inhibitor AKAP-IS. We observed functional and spatial coupling of the plasma membrane-associated AKAP15 and AKAP79 to Kir2.1 and Kir2.2 channel subunits, but not to Kir2.3 channels. In contrast, AKAPyotiao had no functional effect on the PKA regulation of Kir channels. AKAP15 and AKAP79 co-immunoprecipitated with and co-localized to Kir2.1 and Kir2.2 channel subunits in ventricular cardiomyocytes. In this study, we provide evidence for coupling of cardiac Kir2.1 and Kir2.2 subunits with the plasma membrane-bound AKAPs 15 and 79. Cardiac membrane-associated AKAPs are a functionally essential part of the regulatory cascade determining IK1 current function and may be novel molecular targets for antiarrhythmic therapy downstream from β-adrenoreceptors.

Class IA antiarrhythmic drug quinidine was one of the first clinically used compounds to terminate atrial fibrillation and acts as multichannel inhibitor with well-documented inhibitory effects on several cardiac potassium channels. In the mammalian heart, heteromeric assembly of Kir2.1–2.3 channels underlies IK1 current. Although a low-affinity block of quinidine on Kir2.1 has already been described, a comparative analysis of effects on other Kir2.x channels has not been performed to date. Therefore, we analyzed the effects of quinidine on wild-type and mutant Kir2.x channels in the Xenopus oocyte expression system. Quinidine exerted differential inhibitory effects on Kir2.x channels with the highest affinity toward Kir2.3 subunits. Onset of block was slow and solely reversible in Kir2.2 subunits. Quinidine inhibited Kir2.x currents in a voltage-independent manner. By means of comparative Ala-scanning mutagenesis, we further found that residues E224, F254, D259, and E299 are essential for quinidine block in Kir2.1 subunits. Analogously, quinidine mediated Kir2.3 inhibition by binding corresponding residues E216, D247, D251, and E291. In contrast, Kir2.2 current block merely involved corresponding residue D260. Using channel mutants with altered (phosphatidylinositol 4,5-bisphosphate PIP2) affinities, we were able to demonstrate that high PIP2 affinities (i.e., Kir2.3 I214L) correlate with low quinidine sensitivity. Inversely, mutant channels interacting only weakly with PIP2 (i.e., Kir2.1 K182Q, and L221I) are prone to a higher inhibitory effect. Thus, we conclude that inhibition of Kir2.x channels by quinidine is mediated by joint modes of action involving direct cytoplasmic pore block and an impaired channel stabilization via interference with PIP2.

Pregnancy is an important stage in a woman's life, yet many women still do not get proper prenatal care. Failure to follow prenatal care can cause problems for the woman and the child. An important step in prenatal follow-up is the educational training for the woman, which allows her to overcome fears and get to know herself better. This work proposes a mobile application to support the woman who performs prenatal care in a public health unit and with this receive a better educational training on gestation. In addition, the application should allow a better mapping of pregnancy as well as concentrate data to better analyze the use of public funds and identify needs of public agencies acting based on identified demands.

Educational robotics is one of the ways that educational institutions use to expose that they have curriculum with technological approaches and innovation. Most of the studies that deal with the use of robotics in the classroom approach the student's point of view or even the associated didactics, but without exposing how or even what materials were used. In this work is exposed the report of experience of a teacher in the use of the LEGO EV3 kit, its difficulties in understanding the materials available, assembly and programming of the robot.

In this study, a new approach for the automated extraction of high-resolution time-variable water surfaces is presented. For that purpose, optical images from Landsat and Sentinel-2 are used between January 1984 and June 2018. The first part of this new approach is the extraction of land-water masks by combining five water indexes and using an automated threshold computation. In the second part of this approach, all data gaps caused by voids, clouds, cloud shadows, or snow are filled by using a long-term water probability mask. This mask is finally used in an iterative approach for filling remaining data gaps in all monthly masks which leads to a gap-less surface area time series for lakes and reservoirs. The results of this new approach are validated by comparing the surface area changes with water level time series from gauging stations. For inland waters in remote areas without in situ data water level time series from satellite altimetry are used. Overall, 32 globally distributed lakes and reservoirs of different extents up to 2482.27 km 2 are investigated. The average correlation coefficients between surface area time series and water levels from in situ and satellite altimetry have increased from 0.611 to 0.862 after filling the data gaps which is an improvement of about 41%. This new approach clearly demonstrates the quality improvement for the estimated land-water masks but also the strong impact of a reliable data gap-filling approach. All presented surface area time series are freely available on the Database of Hydrological Time Series of Inland (DAHITI).

In this study, a new approach for the automated extraction of high-resolution time-variable water surfaces is presented. For that purpose, optical images from Landsat and Sentinel-2 are used between January 1984 and June 2018. The first part of this new approach is the extraction of land-water masks by combining five water indexes and using an automated threshold computation. In the second part of this approach, all data gaps caused by voids, clouds, cloud shadows, or snow are filled by using a long-term water probability mask. This mask is finally used in an iterative approach for filling remaining data gaps in all monthly masks which leads to a gap-less surface area time series for lakes and reservoirs. The results of this new approach are validated by comparing the surface area changes with water level time series from gauging stations. For inland waters in remote areas without in situ data water level time series from satellite altimetry are used. Overall, 32 globally distributed lakes and reservoirs of different extents up to 2482.27 km 2 are investigated. The average correlation coefficients between surface area time series and water levels from in situ and satellite altimetry have increased from 0.611 to 0.862 after filling the data gaps which is an improvement of about 41%. This new approach clearly demonstrates the quality improvement for the estimated land-water masks but also the strong impact of a reliable data gap-filling approach. All presented surface area time series are freely available on the Database of Hydrological Time Series of Inland (DAHITI).

IEC ISO 60601-1-6:2015 is the regulatory standard for Medical Device (MD) and directs to ISO IEC 62366:2015 as a technical standard. However, due to the general nature of this standard, it does not provide details about criteria to guide usability testing of MD. In this way, the manufacturer deals with the unpredictability of the user according to the subjective convenience that he deems necessary to the type and class of the device. Objectives: To present a Catalog indicating technologies that can be used to detect the ergonomic or biomechanical behavior of the user. So that the test team has support for the follow-up of the experiment and for assistance in interpreting the test results. Method: A bibliographical review on technologies used to detect human behavior, and a technical survey of the market for products capable of capturing such behavior, were carried out in 2017 to establish and create the Catalog. Results: Findings allowed to list technologies that can be used to analyze the behavior of the user, assisting the execution of usability tests (UT) of the MD, being effective to detect the behavior and generate data to support the analysis and generation of reports. Conclusion: The Catalog classified technologies that can generate information about the usability of the MD, considering the analysis of the user’s behavior. The Catalog contains the association between the technology and behavioral possibilities that can be identified, serving as support to choose the technology most appropriate to the UT.

Left bundle branch block (LBBB) has a predictive value for response to cardiac resynchronization therapy as reported by Zareba et al. (Circulation 123(10):1061–1072, 2011). However, based on ECG criteria, the discrimination between complete LBBB and nonspecific intraventricular conduction delay is challenging. We tested the hypothesis that discrimination can be performed using standard electrophysiological catheters and a simple stimulation protocol. Fifty-nine patients were analyzed retrospectively. Patients were divided into groups of narrow QRS (n = 20), wide QRS of right bundle branch block (RBBB) morphology (n = 14), and wide QRS of LBBB morphology (n = 25). Using a diagnostic catheter placed in the coronary sinus, left ventricular activation was assessed during intrinsic conduction as well as during right ventricular (RV) stimulation. In patients with narrow QRS and RBBB, the Q-LV/QRS ratio was 0.43 ± 0.013 (n = 20) and 0.41 ± 0.026 (n = 14), respectively. In patients with LBBB morphology, the Q-LV/QRS split up into a group of patients with normal (0.43 ± 0.022, n = 7) and a group with delayed left ventricular activation (0.75 ± 0.016, n = 18). By direct comparison of the Q-LV/QRS ratio during intrinsic conduction with the Q-LV/QRS ratio during RV pacing leading to a functional LBBB, a clear distinction between a group of “true LBBB” and another group of “apparent LBBB”/nonspecific intraventricular conduction delay (NICD) could be generated. We present a novel and practical method that might facilitate discrimination between patients with apparent LBBB and true LBBB by comparing Q-LV/QRS ratios during intrinsic activation and during RV stimulation. Although this method can already be directly applied, validation by 3D electrical mapping and prospective correlation to cardiac resynchronization therapy (CRT) response will be required for further translation into clinical practice.

Efficient extraction of valuable products from microalgae and utilization of the residual biomass for biofuel production appear to bring economic benefits for the microalgae biorefineries. The pulsed electric field (PEF) method has been proposed as a promising pre-treatment for microalgae wet extraction. For conversion of microalgae biomass and residues, hydrothermal liquefaction (HTL) is considered a suitable method. Here, a combination of PEF-assisted valuables extraction of microalgae and HTL of the residual biomass is studied for the first time. The microalgae Auxenochlorella protothecoides, Chlorella vulgaris, and Scenedesmus almeriensis were cultivated, harvested, treated by PEF, and then subjected to lipid extraction, protein extraction, or extraction of amino acids after enzymatic protein hydrolysis. The residual biomass obtained from PEF-assisted valuables extraction was subjected to HTL in micro autoclaves at a temperature of 350 °C and pressure of 25 MPa for 15 min holding time. Product yields and analytical results obtained by elemental content measurement, 1H-nuclear magnetic resonance spectroscopy, Fourier-transform infrared spectroscopy, and gel permeation chromatography show that PEF alone has no significant direct influence on microalgae HTL. The harsh HTL conditions decisively determine the product yields and biocrude quality. However, PEF enhances the lipid extraction yield from 4 wt% to 33 wt%. Consequently, the biocrude yield decreases from 58 wt% to 43.2 wt%. Moreover, PEF boosts the protein extraction yield from almost zero to 41.6 wt% of the total protein, resulting in an increased biocrude yield by about 2 wt%. Finally, PEF accelerates the formation of amino acids by enzymatic hydrolysis, improving the extraction efficiency up to 150% in the first 60 min of the extraction. The extracted residue promises to produce a biocrude yield higher by 6 wt% and a better biocrude quality with lower nitrogen content. An overall mass balance of PEF-assisted valuables extraction and HTL is presented.

Pulsed electric field (PEF) treatment has so far been considered as ineffective for protein extraction, but the parameters that influence protein extraction efficiency have not been identified fully. Using Chlorella vulgaris in this study, we show that up to half of the proteins present in the cell can be extracted via PEF treatment and an incubation step for up to 24 h. The extraction efficiency is highly influenced by biomass concentration during the incubation step and the incubation temperature: in our experiments we were able to extract half of the proteins present in the cells at dilute concentrations (5 mg·ml−1), but this efficiency decreases with increasing biomass concentration, indicating that diffusion gradients play a role in the protein release. However, we also show that not only diffusion plays a role, but also a biological process that requires suitable conditions. We observed that PEF treated cells undergo programmed cell death, indicated by DNA laddering. Furthermore cold and hot temperatures as well as protease inhibition impair the release of proteins. In Western blots we can observe that some proteins are not released when the activity of proteases is blocked. We therefore conclude that protein release is facilitated by an enzyme-driven process that occurs after PEF-triggered cell death, and that this process is prone to extreme conditions.

Este artigo descreve a criação de um protótipo de um robô móvel, com finalidade educacional utilizando a plataforma Arduino, tendo como principal finalidade simplificar o uso desta plataforma, eliminando a necessidade de conhecimentos complexos em determinados níveis de ensino como bem como de oferecer uma alternativa a os kits disponíveis no mercado com custos relativamente acessíveis.

Objectives This study sought to test the hypothesis that inducing an autoimmune response against the cardiac sodium channel (NaV1.5) induces arrhythmias. Background Sporadic evidence supports the concept that autoantibodies may cause cardiac arrhythmias but substantial experimental investigations using in vivo models have been lacking to date. The NaV1.5 is essential for cardiac impulse propagation and its dysfunction has been linked to conduction disease. Methods Rats were immunized with a peptide sequence derived from the third extracellular loop of the first domain of NaV1.5. After 28 days, we evaluated in vivo both the electrical and mechanical parameters of cardiac function. Histopathology, myocardial gene and protein expression were assessed. Whole-cell patch-clamp was used to measure sodium current (INa) density in isolated cardiomyocytes. Results NaV1.5-immunized rats had high titers of autoantibodies against NaV1.5. On ECG recording, NaV1.5-immunized animals showed significantly prolonged PR-intervals. During Holter ECG-monitoring we observed repeated prolonged episodes of third-degree atrioventricular and sinoatrial block in every NaV1.5-immunized animal, but not in controls. Immunization had no effect on cardiac function. In comparison to controls, myocardial NaV1.5 mRNA and protein levels were decreased in immunized rats. INa density was reduced in cardiomyocytes incubated with sera from NaV1.5-immunized rats and from patients with idiopathic atrioventricular block (AVB) in comparison to sera from respective controls. In patients with idiopathic AVB, we observed autoantibodies against NaV1.5 that were absent in sera from healthy controls. Conclusions Provocation of an autoimmune response against NaV1.5 induces conductance defects probably caused by a reduced expression level and an inhibition of NaV1.5 by autoantibodies, resulting in decreased INa.

The caged xanthone gambogic acid (GA) is a novel anti-cancer agent which exhibits anti-proliferative, anti-inflammatory and cytotoxic effects in many types of cancer tissues. In a recent phase IIa study, GA exhibits a favourable safety profile. However, limited data are available concerning its interaction with cardiac ion channels. Heteromeric assembly of Kir2.x channels underlies the cardiac inwardly rectifying I

Class IA antiarrhythmic drug quinidine was one of the first clinically used compounds to terminate atrial fibrillation and acts as multichannel inhibitor with well-documented inhibitory effects on several cardiac potassium channels. In the mammalian heart, heteromeric assembly of Kir2.1-2.3 channels underlies I

The cardiac I

Kir2.x channels form the molecular basis of cardiac I(K1) current and play a major role in cardiac electrophysiology. However, there is a substantial lack of selective Kir2 antagonists. We found the β(3)-adrenoceptor antagonist SR59230A to be an inhibitor of Kir2.x channels. Therefore, we characterized the effects of SR59230A on Kir2.x and other relevant cardiac potassium channels. Cloned channels were expressed in the Xenopus oocyte expression system and measured with the double-microelectrode voltage clamp technique. SR59230A inhibited homomeric Kir2.1 channels with an IC(50) of 33μM. Homomeric Kir2.2 and Kir2.3 channels and Kir2.x heteromers were also inhibited by SR59230A with similar potency. In contrast, no relevant inhibitory effects of SR59230A were found in cardiac Kv1.5, Kv4.3 and KvLQT1/minK channels. In hERG channels, SR59230A only induced a weak inhibition at a high concentration. These findings establish SR59230A as a novel inhibitor of Kir2.1-2.3 channels with a favorable profile with respect to additional effects on other cardiac repolarizing potassium channels.

There is genetic and epidemiological evidence demonstrating the association between Lp(a) levels and cardiovascular disease. While evolocumab reduces Lp(a) by 25-30%, the impact of PCSK9 inhibition on plaque at different Lp(a) levels is unknown. GLAGOV compared the effects of the PCSK9 inhibitor

Background and purpose: Atomoxetine is a selective noradrenaline reuptake inhibitor, recently approved for the treatment of attention-deficit/hyperactivity disorder. So far, atomoxetine has been shown to be well tolerated, and cardiovascular effects were found to be negligible. However, two independent cases of QT interval prolongation, associated with atomoxetine overdose, have been reported recently. We therefore analysed acute and subacute effects of atomoxetine on cloned human Ether-a-Go-Go-Related Gene (hERG) channels. Experimental approach: hERG channels were heterologously expressed in Xenopus oocytes and in a human embryonic kidney cell line and hERG currents were measured using voltage clamp and patch clamp techniques. Action potential recordings were made in isolated guinea-pig cardiomyocytes. Gene expression and channel surface expression were analysed using quantitative reverse transcriptase polymerase chain reaction, Western blot and the patch clamp techniques. Key results: In human embryonic kidney cells, atomoxetine inhibited hERG current with an IC50 of 6.3 µmol·L−1. Development of block and washout were fast. Channel activation and inactivation were not affected. Inhibition was state-dependent, suggesting an open channel block. No use-dependence was observed. Inhibitory effects of atomoxetine were attenuated in the pore mutants Y652A and F656A. In guinea-pig cardiomyocytes, atomoxetine lengthened action potential duration without inducing action potential triangulation. Overnight incubation with high atomoxetine concentrations resulted in a decrease of channel surface expression. Conclusions and implications: Whereas subacute effects of atomoxetine seem negligible under therapeutically relevant concentrations, hERG channel block should be considered in cases of atomoxetine overdose and when administering atomoxetine to patients at increased risk for the development of acquired long-QT syndrome.

Background Cardiac inwardly rectifying Kir current (IK1) mediates terminal repolarisation and is critical for the stabilization of the diastolic membrane potential. Its predominant molecular basis in mammalian ventricle is heterotetrameric assembly of Kir2.1 and Kir2.2 channel subunits. It has been shown that PKC inhibition of IK1 promotes focal ventricular ectopy. However, the underlying molecular mechanism has not been fully elucidated to date. Methods and Results In the Xenopus oocyte expression system, we observed a pronounced PKC-induced inhibition of Kir2.2 but not Kir2.1 currents. The PKC regulation of Kir2.2 could be reproduced by an activator of conventional PKC isoforms and antagonized by pharmacological inhibition of PKCβ. In isolated ventricular cardiomyocytes (rat, mouse), pharmacological activation of conventional PKC isoforms induced a pronounced inhibition of IK1. The PKC effect in rat ventricular cardiomyocytes was markedly attenuated following co-application of a small molecule inhibitor of PKCβ. Underlining the critical role of PKCβ, the PKC-induced inhibition of IK1 was absent in homozygous PKCβ knockout-mice. After heterologous expression of Kir2.1-Kir2.2 concatemers in Xenopus oocytes, heteromeric Kir2.1/Kir2.2 currents were also inhibited following activation of PKC. Conclusion We conclude that inhibition of cardiac IK1 by PKC critically depends on the PKCβ isoform and Kir2.2 subunits. This regulation represents a potential novel target for the antiarrhythmic therapy of focal ventricular arrhythmias.

Dronedarone is a novel class III antiarrhythmic drug that is widely used in atrial fibrillation. It has been shown in native cardiomyocytes that dronedarone inhibits cardiac inwardly rectifying current IK1 at high concentrations, which may contribute both its antifibrillatory efficacy and its potential proarrhythmic side effects. However, the underlying mechanism has not been studied in further detail to date. In the mammalian heart, heterotetrameric assembly of Kir2.x channels is the molecular basis of IK1 current. Therefore, we studied the effects of dronedarone on wild-type and mutant Kir2.x channels in the Xenopus oocyte expression system. Dronedarone inhibited Kir2.1 currents but had no effect on Kir2.2 or Kir2.3 currents. Onset of block was slow but completely reversible upon washout. Blockade of Kir2.1 channels did not exhibit strong voltage dependence or frequency dependence. In a screening with different Kir2.1 mutants lacking specific binding sites within the cytoplasmic pore region, we found that residue E224 is essential for binding of dronedarone to Kir2.1 channels. In conclusion, direct block of Kir2.1 channel subunits by dronedarone through binding at E224 may underlie its inhibitory effects on cardiac IK1 current.

Ajmaline is a class Ia anti-arrhythmic compound that is widely used for the diagnosis of Brugada syndrome and the acute treatment of atrial or ventricular tachycardia. For ajmaline, inhibitory effects on a variety of cardiac K+ channels have been observed, including cardiac Kv1 and Kv4 channels. However, the exact pharmacological properties of channel blockade have not yet been addressed adequately. Using two different expression systems, we analysed pharmacological effects of ajmaline on the potassium channels Kv1.5 and Kv4.3 underlying cardiac I Kur and I to current, respectively. When expressed in a mammalian cell line, we find that ajmaline inhibits Kv1.5 and Kv4.3 with an IC50 of 1.70 and 2.66 μM, respectively. Pharmacological properties were further analysed using the Xenopus expression system. We find that ajmaline is an open channel inhibitor of cardiac Kv1.5 and Kv4.3 channels. Whereas ajmaline results in a mild leftward shift of Kv1.5 activation curve, no significant effect on Kv4.3 channel activation could be observed. Ajmaline did not significantly affect channel inactivation kinetics. Onset of block was fast. For Kv4.3 channels, no significant effect on recovery from inactivation or channel deactivation could be observed. Furthermore, there was no use-dependence of block. Taken together, we show that ajmaline inhibits cardiac Kv1.5 and Kv4.3 channels at therapeutic concentrations. These data add to the current understanding of the electrophysiological basis of anti-arrhythmic action of ajmaline.

Este artigo apresenta a proposta de desenvolvimento de duas aplicações, uma usando Realidade Aumentada e outra QR code, para apoiarem a visitação de um museu de artes. Os aplicativos permitirão aos visitantes do museu, acessarem informações adicionais das obras de artes, no primeiro aplicativo, a partir de uma webcam e um monitor de computador que serão disponibilizados no local e no segundo com um celular ou tablet.

In order to prevent human error, it is essential to understand the nature of the user’s behaviour. This chapter proposes a combined approach to increase knowledge of user behaviour by instantiating a programmable user model with data gathered from a user profile. Together, the user profile and user model represent, respectively, the static and dynamic characteristics of user behaviour. Typically, user models have been employed by system designers to explore the user decision-making process and its implications, since user profiles do not account for the dynamic aspects of a user interaction. In this chapter, the user profile and model are employed to study human errors—supporting an investigation of the relationship between user errors and user characteristics. The chapter reviews the literature on user profiles and models and presents the proposed user profile and model. It concludes by discussing the application of the proposed approach in the context of electrical systems’ operation.

article i nfo The transient outward current Ito is an important determinant of the early repolarization phase. Ito and its molecular basis Kv4.3 are regulated by adrenergic pathways including protein kinase C. However, the exact regulatory mechanisms have not been analyzed yet. We here analyzed isoenzyme specific regulation of Kv4.3 and Ito by PKC. Kv4.3 channels were expressed in Xenopus oocytes and currents were measured with double electrode voltage clamp technique. Patch clamp experiments were performed in isolated rat cardiomyocytes. Unspecific PKC stimulation with PMA resulted in a reduction of Kv4.3 current. Similar effects could be observed after activation of conventional PKC isoforms by TMX. Both effects were reversible by pharmacological inhibition of the conventional PKC isoenzymes (Go6976). In contrast, activation of the novel PKC isoforms (ingenol) did not significantly affect Kv4.3 current. Whereas TMX-induced PKC activation was not attenuated inhibition of PKCβ, inhibition of PKCα with HBDDE prevented inhibitory effects of both PMA and TMX. Accordingly, stimulatory effects of PMA and TMX could be mimicked by the α-isoenzyme selective PKC activator iripallidal. Further evidence for the central role of PKCα was provided with the use of siRNAs. We found that PKCα siRNA but not PKCβ siRNA abolished the TMX induced effect. In isolated rat cardiomyocytes, PMA dependent Ito reduction could be completely abolished by pharmacologic inhibition of PKCα. In summary we show that PKCα plays a central role in protein kinase C dependent regulation of Kv4.3 current and native Ito. These results add to the current understanding of isoenzyme selective ion channel regulation by protein kinases.

Documenting accidents and incidents in a clear, precise and unambiguous way is essential to ground the error study and to propose preventive measures. Research in the field of Human Error has yielded many taxonomies and categorizations of errors which are used by companies when analyzing and reporting on accidents and incidents. However, there are difficulties regarding the appropriateness of the terms as applied to a company's specific context, since taxonomies tend to be specific. Moreover, the lack of a clear organization and the adoption of concepts which are not universal among users with different background render their taxonomy's use rather difficult. This paper proposes a taxonomy and an associated supporting tool for describing accidents and incidents in the operation of electrical systems. The proposed taxonomy addresses the concepts and the terms related to the causes of error as well as concepts related to the user cognitive processes that led to the error.