Search

Movimentos sísmicos são eventos de grande perigo para estruturas civis. Estes fenômenos ocorrem com maior intensidade em regiões próximas ao encontro de placas tectônicas. Para mitigar o efeito das vibrações, induzidas pela excitação de base criadas pelas ondas sísmicas, um dos dispositivos utilizados é um absorvedor de vibração denominado TMD (Tuned Mass Damper). Esses sistemas têm chamado a atenção de pesquisadores na última década, desenvolvendo estudos para melhorar seu desempenho. Nesse sentido, este trabalho apresenta o processo de otimização do comprimento, massa e taxa de amortecimento dum TMD alocado no topo da estrutura, as quais conduzem ao objetivo deste trabalho, que é minimizar a vibração da estrutura principal submetida a movimentos sísmicos. A pesquisa iniciou com a modelagem em elementos finitos de 3 estruturas esbeltas de grande altura, com períodos naturais de vibração diferentes. Em cada estrutura foi aplicada uma força estática, para obter a rigidez equivalente, correspondente a um sistema de 1 grau de liberdade (GDL). Em seguida, foi modelado um sistema massa-mola-amortecedor equivalente à estrutura original, à qual foi acoplado uma massa tipo pêndulo (TMD) com caraterísticas de comprimento, massa e taxa de amortecimento não otimizadas. Transformou-se, assim, a estrutura de muitos graus de liberdade em um sistema de 2 GDL (1 GDL da estrutura e1 GDL do pêndulo). Os 2 sistemas de 1 e 2 GDL foram submetidos a forças sísmicas mediante 9 registros de acelerações, para obter os deslocamentos máximos e o histórico do deslocamento durante a ação sísmica, e assim, comparar a variação desses parâmetros. Mediante métodos de teorias de otimização matemática foram obtidos os parâmetros ótimos do TMD, que em um 37% dos 27 casos em estudo, minimizaram as vibrações em um 50%, em mais de 70% dos casos minimizaram as vibrações pelo menos em 30% e somente um caso teve uma redução na vibração de 10%, concluindo que a alocação de um TMD com caraterísticas ótimas é uma boa opção para o controle de vibrações em estruturas altas e esbeltas submetidas a movimentos sísmicos. Earthquakes are some of the most dangerous events for civil structures. These phenomena occur with greater intensity in regions close to the encounter of tectonic plates. To mitigate the effect of vibrations, induced by the base excitation created by the seismic waves, one of the devices used is a vibration absorber called TMD (Tuned Mass Damper). Research into these systems has increased in the last decade, with a growing number of researchers developing studies for their best performance. This fact is reflected in the volume of publications and recent studies, compared to the past decades. In this sense, this work presents the process of optimization of the length, mass and damping rate of a TMD placed on top of the structure, which lead to the objective of this work, which is to minimize the vibration of the main structure subjected to seismic movements. The present work begins with the finite element modeling of a 3 slender high rise structure, with different natural periods of vibration, in each structure a static force was applied, to obtain the equivalent stiffness, corresponding to a 1 degree of freedom (DOF) system. Then, a mass-spring-damper system is modeled equivalent to the original structure, to which a pendulum-type mass TMD was attached, with characteristics of non-optimized longitude, mass and damping rate. The structure of many degrees of freedom is thus transformed into a system of 2 DOFs (1 DOF of the structure and 1DOF of the pendulum). The two systems of 1 and 2 DOF were subjected to seismic forces through 9 accelerations records, to obtain the maximum displacement and displacement history during the seismic action, and thus, compare the variation of these parameters. Through of methods of the mathematical optimization theories, the optimal parameters of TMD were obtained, which in 37% of the 27 cases, vibrations were minimized between 50% and 78%, in more than 70% of the cases, the minimization was of a minimum of 30% and only one case had a reduction in vibration of less than 10%, concluding that the placement of a TMD with optimal characteristics is a good option for vibration control in a tall and slender structures subjected to seismic movements.

Tissular blood perfusion is helpful to assess the health condition of a subject and even monitor superficial lesions. Current state of the art is focused on developing non-invasive, quantitative and accessible methods for blood flow monitoring in large areas. This paper presents an approach based on multispectral images on the VIS-NIR range to quantify blood perfusion. Our goal is to estimate the changes in deoxygenated hemoglobin. To do so, we employ principal component analysis followed by a linear regression model. The proposal was evaluated using in-vivo data from a vascular occlusion protocol, and the results were validated against photoplethysmography measurements. Although the number of subjects in the protocol was limited, our model made a prediction with an average similarity of 91.53% with a mean R-squared adjusted of 0.8104.

The Madeira River rises in the Andes, draining the southwestern Amazon basin and contributing up to 50% of the Amazon River sediment load. The Porto Velho station monitors the Upper Madeira basin and is located just downstream of the Jirau and Santo Antonio hydropower dams. At this station, decreasing trend (p < 0.10) of the surface suspended sediment concentration (SSSC) has been documented during the sediment peak season (December to February) for the 2003–2017 period. This study aims to evaluate the role of the rainfall variability on this documented decreasing trend. For this purpose, we applied correlation and trend analysis in water discharge, SSSC and rainfall time series over the main tributaries of the Upper Madeira basin. The decline of SSSC in December is attributed to the reduction of rainfall in the Madre de Dios sub-basin from the start of the rainy season in October. However, the SSSC negative trend (p < 0.10) in January and February is associated with a shift in the magnitude of rainfall during these months in the Andean region after 2008, and the dilution associated with base flow. These results reveal that the decline of SSSC in the Madeira River should not be evaluated just on the basis of the data downstream from the dams, but also of the processes upstream in the Andean part of the basin. In a context of drastic anthropogenic climate and environmental changes, understanding the combined influence of regional hydroclimate variability and human actions on erosion and sediment transport remains a critical issue for the conservation of the Amazon-Andes system.

The relationship between multiple hydroclimatic variables and vegetation conditions in the upper Madeira Basin (southwestern Amazon) has been analyzed. Vegetative dynamics are characterized using N...

The relationship between multiple hydroclimatic variables and vegetation conditions in the upper Madeira Basin (southwestern Amazon) has been analyzed. Vegetative dynamics are characterized using NDVI dataset as an indicator of the photosynthetic capacities of vegetation. Hydroclimatic variability is analyzed using satellite-based precipitation datasets, observed river discharge, and satellite measurements of terrestrial water storage (TWS). Our results show that the vegetation in the Basin varies from energy- to water-limited. During the peak of the wet season (January-February), rainfall, discharge, and TWS are negatively correlated with NDVI (r=-0.48 to -0.65), suggesting that during this period the vegetation is mainly energy-dependent. Outside this period, these correlations are positive (r=0.55 to 0.9), suggesting that vegetation depends mainly on water availability. This higher water dependence is more noticeable during the vegetation dry season (VDS; June-October). Considering the predominant land cover types, differences in the hydroclimate-NDVI relationship are observed. Evergreen forests remain energy-limited during the beginning of the VDS, but they become water-dependent almost at the end. Savannas show a different behavior, where water dependence occurs months before the onset of the VDS. On the other hand, unlike the other variables, the TWS better explains the NDVI in evergreen forests during the VDS (r=0.7 to 0.85). This is probably because evergreen forests are more dependent on deep soil water. A spatial analysis between hydroclimatic variables and the NDVI shows the predominance of positive correlations in most of the basin. However, specific areas do not show significant correlations. The weak relationship in these areas is explained by two factors i) very wet conditions during most of the year in the "rainfall hotspot" regions, where the vegetation is not water-limited, and ii) recent land-use changes (deforestation) that break the natural response in the hydroclimate-vegetation system. These findings provide new evidence on the impacts of the land cover changes on the natural relationship between vegetation and hydroclimatic variability, which is particularly relevant given the increasing rates of deforestation in this region during recent years.

IntroductionTelemedicine is an important element of healthcare. However, until the COVID-19 pandemic, training in telemedicine was not a substantial element of most residency programs. Social distancing measures changed this. The Cleveland Clinic Internal Medicine Residency Program (IMRP) is one of the largest programs in the United States, which made the task of developing and adopting an effective, expedited telemedicine curriculum challenging. Our goal was to implement a system for teaching telemedicine care skills and supervising the care provided by residents during virtual visits.MethodsThis study was started in April 2020. We developed and implemented a resident-led curriculum and training program for providing telemedicine care in less than five weeks. This entailed creating a formal training program for residents, creating a resource guide for the different video communication tools, and training preceptors to safely supervise care in this new paradigm. We also created an assessment instrument in our education evaluation system that allows residents to receive feedback on their performance during virtual appointments.ResultsOver 2000 virtual visits were performed by residents in a span of 10 weeks. Of 148 residents, 38% responded to the pre-participation survey. A majority had no prior telemedicine experience and expressed only slight comfort with the modality.DiscussionThrough collaboration with experienced residents and faculty, we expeditiously developed an enhancement to our ambulatory care curriculum to teach residents how to provide virtual care and help faculty with supervision. We share our insights on this experience for other residency programs to utilize.

The current information systems for the registration and control of electronic medical records (EMR) present a series of problems in terms of the fragmentation, security, and privacy of medical information, since each health institution, laboratory, doctor, etc. has its own database and manages its own information, without the intervention of patients. This situation does not favor effective treatment and prevention of diseases for the population, due to potential information loss, misinformation, or data leaks related to a patient, which in turn may imply a direct risk for the individual and high public health costs for governments. One of the proposed solutions to this problem has been the creation of electronic medical record (EMR) systems using blockchain networks, however, most of them do not take into account the occurrence of connectivity failures, such as those found in various developing countries, which can lead to failures in the integrity of the system data. To address these problems, HealthyBlock is presented in this paper as an architecture based on blockchain networks, which proposes a unified electronic medical record system that considers different clinical providers, with resilience in data integrity during connectivity failure and with usability, security, and privacy characteristics. On the basis of the HealthyBlock architecture, a prototype was implemented for the care of patients in a network of hospitals. The results of the evaluation showed high efficiency in keeping the EMRs of patients unified, updated, and secure, regardless of the network clinical provider they consult.

Background The vertebrate clade diverged into Chondrichthyes (sharks, rays, and chimeras) and Osteichthyes fishes (bony fishes) approximately 420 mya, with each group accumulating vast anatomical and physiological differences, including skin properties. The skin of Chondrichthyes fishes is covered in dermal denticles, whereas Osteichthyes fishes are covered in scales and are mucous rich. The divergence time among these two fish groups is hypothesized to result in predictable variation among symbionts. Here, using shotgun metagenomics, we test if patterns of diversity in the skin surface microbiome across the two fish clades match predictions made by phylosymbiosis theory. We hypothesize (1) the skin microbiome will be host and clade-specific, (2) evolutionary difference in elasmobranch and teleost will correspond with a concomitant increase in host-microbiome dissimilarity, and (3) the skin structure of the two groups will affect the taxonomic and functional composition of the microbiomes. Results We show that the taxonomic and functional composition of the microbiomes is host-specific. Teleost fish had lower average microbiome within clade similarity compared to among clade comparison, but their composition is not different among clade in a null based model. Elasmobranch’s average similarity within clade was not different than across clade and not different in a null based model of comparison. In the comparison of host distance with microbiome distance, we found that the taxonomic composition of the microbiome was related to host distance for the elasmobranchs, but not the teleost fishes. In comparison, the gene function composition was not related to the host-organism distance for elasmobranchs but was negatively correlated with host distance for teleost fishes. Conclusion Our results show the patterns of phylosymbiosis are not consistent across both fish clades, with the elasmobranchs showing phylosymbiosis, while the teleost fish are not. The discrepancy may be linked to alternative processes underpinning microbiome assemblage, including possible historical host-microbiome evolution of the elasmobranchs and convergent evolution in the teleost which filter specific microbial groups. Our comparison of the microbiomes among fishes represents an investigation into the microbial relationships of the oldest divergence of extant vertebrate hosts and reveals that microbial relationships are not consistent across evolutionary timescales.

Conselho Nacional de Pesquisa e Desenvolvimento Científico e Tecnológico - CNPq The study aimed to evaluate and compare the cardiorespiratory and analgesic parameters of continuous infusion of fentanyl, dexmedetomidine or maropitant in dogs submitted to ovariohysterectomy. Thirty healthy mixed breed bitches with an average body weight of 11±1.78 kg were evaluated. All animals received acepromazine (0.05 mg kg-1) intramuscularly as pre-anesthetic medication, anesthetic induction was performed with intravenous administration of propofol (5.51±0.67 mg kg-1), and anesthesia was maintained with isoflurane. Ten minutes after stabilization, continuous infusion was instituted, preceded by a bolus dose of the drugs evaluated, divided into the following groups: GF (fentanyl 2.0 g kg-1, 3.0 g kg-1 h- 1, n = 10), GD (dexmedetomidine 0.5 g kg-1, 1.0 g kg-1 h-1, n = 10) and GM (maropitant 1 mg kg-1, 150 g kg-1 h-1, n = 10). In the trans-operative period, cardiorespiratory parameters (HR, f, SBP, DBP, MBP, ETCO2, SpO2 and T° C) and analysis of arterial blood gases (pH, PaO2, PaCO2 and HCO3¯) were evaluated. Likewise, analgesic effects were assessed during surgery (trans-operatively) and after (post-operatively), recording cardiorespiratory parameters (HR, f, SBP, DBP, MBP) and using pain scales from the University of Melbourne (EDUM) and the Glasgow scale (EDG), respectively. In the evaluation of cardiorespiratory parameters, at some times, it was observed: lower HR in the GF and in the GD in relation to the baseline and the GM. However, the GF was larger compared to the GD. Blood pressure, compared to baseline, increased in the GF and the GD. Regarding the groups, the GF had lower blood pressure than the GD and higher blood pressure compared to the GM, while the GD was higher compared to the GM in blood pressure. The T° C, in relation to baseline, decreased in GD, GF and GM. in relation to f, ETCO2 and SpO2, there were no significant differences. In the measurements of arterial blood gas variables, there was a decrease in PO2 in the GF in relation to blood samples, while in the other variables pH, PCO2 and HCO3¯ there were no significant differences. The cardiorespiratory variables recorded for analgesic evaluation showed differences in time and between groups with greater pharmacological effect of each drug than with surgical nociceptive effects. In the postoperative analgesic evaluation, there were lower scores on the EDG in the GF, in the GD and in the GM compared to the first evaluation. In relation to the groups, there were lower scores in the GD and in the GM on the EDUM compared to the GF. From the results presented, it is suggested that the continuous infusion of maropitant has trans and postoperative antinociceptive effects, with few changes in cardiopulmonary parameters compared to the continuous infusion of dexmedetomidine or fentanyl O estudo teve por objetivo avaliar e comparar os parâmetros cardiorrespiratórios e analgésicos da infusão contínua de fentanil, dexmedetomidina ou maropitant em cadelas submetidas à ovariohisterectomia. Foram avaliadas 30 cadelas adultas saudáveis, sem raça definida, com peso corporal médio de 11±1,78 kg. Todos os animais receberam acepromazina (0,05 mg kg-1) por via intramuscular como medicação pré-anestésica, a indução anestésica foi realizada com a administração intravenosa de propofol (5,51±0,67 mg kg-1) e a anestesia foi mantida com isoflurano. Após a indução anestésica, os parâmetros cardiorrespiratórios e o plano anestésico foram estabilizados. Dez minutos após a estabilização, a infusão contínua foi instituída, precedida de uma dose em bolus dos fármacos avaliados, divididos nos seguintes grupos: GF (fentanil 2 g kg-1, 3 g kg-1 h-1, n = 10), GD (dexmedetomidina 0,5 g kg-1, 1 g kg-1 h-1, n = 10) e GM (maropitant 1 mg kg-1, 150 g kg-1 h-1, n = 10). No período trans-operatório, foram avaliados parâmetros cardiorrespiratórios (FC, f, PAS, PAD, PAM, ETCO2, SpO2 e T° C) e análise dos gases sanguíneos arteriais (pH, PaO2, PaCO2 e HCO3¯). Da mesma forma, os efeitos analgésicos foram avaliados durante a cirurgia (trans-operatório) e após (pós-operatório), registrando parâmetros cardiorrespiratórios (FC, f, PAS, PAD, PAM) e utilizando escalas de dor da Universidade de Melbourne (EDUM) e a escala de Glasgow (EDG), respectivamente. Na avaliação dos parâmetros cardiorrespiratórios, em alguns tempos, observou-se: menor FC no GF e no GD em relação ao basal e ao GM. No entanto, o GF foi maior em comparação com o GD. Na pressão arterial, comparada ao basal, aumentou no GF e no GD. Em relação aos grupos, o GF apresentou pressão arterial menor do que o GD e pressão arterial maior em relação ao GM, enquanto o GD foi maior em comparação ao GM em pressão arterial. A T° C, em relação ao basal, diminuiu no GD, GF e GM. Em relação à f, ETCO2 e SpO2 não houve diferenças significativas. Nas mensurações das variáveis dos gases sanguíneos arteriais, houve diminuição da PO2 no GF em relação às amostras de sangue, enquanto nas demais variáveis pH, PCO2 e HCO3¯ não houve diferenças significativas. As variáveis cardiorrespiratórias registradas para a avaliação analgésica apresentaram diferenças no tempo e entre os grupos com maior efeito farmacológico de cada fármaco do que com os efeitos nociceptivos cirúrgicos. Na avaliação analgésica pós-operatória, houve escores mais baixos na EDG no GF, GD e GM em comparação à primeira avaliação. Já em relação aos grupos, houve escores mais baixos no GD e no GM na EDUM em comparação ao GF. A partir dos resultados apresentados, sugere-se que a infusão contínua de maropitant têm efeitos analgésicos trans e pós-operatórios, com poucas alterações nos parâmetros cardiorrespiratórios em comparação à infusão contínua de dexmedetomidina ou fentanil.

Globally, soils store two to three times as much carbon as currently resides in the atmosphere, and it is critical to understand how soil greenhouse gas (GHG) emissions and uptake will respond to ongoing climate change. In particular, the soil-to-atmosphere CO(2)flux, commonly though imprecisely termed soil respiration (R-S), is one of the largest carbon fluxes in the Earth system. An increasing number of high-frequencyR(S)measurements (typically, from an automated system with hourly sampling) have been made over the last two decades; an increasing number of methane measurements are being made with such systems as well. Such high frequency data are an invaluable resource for understanding GHG fluxes, but lack a central database or repository. Here we describe the lightweight, open-source COSORE (COntinuous SOil REspiration) database and software, that focuses on automated, continuous and long-term GHG flux datasets, and is intended to serve as a community resource for earth sciences, climate change syntheses and model evaluation. Contributed datasets are mapped to a single, consistent standard, with metadata on contributors, geographic location, measurement conditions and ancillary data. The design emphasizes the importance of reproducibility, scientific transparency and open access to data. While being oriented towards continuously measuredR(S), the database design accommodates other soil-atmosphere measurements (e.g. ecosystem respiration, chamber-measured net ecosystem exchange, methane fluxes) as well as experimental treatments (heterotrophic only, etc.). We give brief examples of the types of analyses possible using this new community resource and describe its accompanying R software package.

Fluvial sediment dynamics plays a key role in the Amazonian environment, with most of the sediments originating in the Andes. The Madeira River, the second largest tributary of the Amazon River, contributes up to 50% of its sediment discharge to the Atlantic Ocean, most of it provided by the Andean part of the Madeira basin, in particular the Beni River. In this study, we assessed the rainfall (R)-surface suspended sediment concentration (SSSC) and discharge (Q)-SSSC relationship at the Rurrenabaque station (200 m a.s.l.) in the Beni Andean piedmont (Bolivia). We started by showing how the R and Q relationship varies throughout the hydrological year (September to August), describing a counter-clockwise hysteresis, and went on to evaluate the R&ndash, SSSC and Q&ndash, SSSC relationships. Although no marked hysteresis is observed in the first case, a clockwise hysteresis is described in the second. In spite of this, the rating curve normally used ( SSSC = aQ b ) shows a satisfactory R2 = 0.73 (p &lt, 0.05). With regard to water discharge components, a linear function relates the direct surface flow Qs&ndash, SSSC, and a hysteresis is observed in the relationship between the base flow Qb and SSSC. A higher base flow index (Qb/Q) is related to lower SSSC and vice versa. This article highlights the role of base flow on sediment dynamics and provides a method to analyze it through a seasonal empirical model combining the influence of both Qb and Qs, which could be employed in other watersheds. A probabilistic method to examine the SSSC relationship with R and Q is also proposed.

Key Points Question Does colchicine prevent intubation and mortality in hospitalized patients with COVID-19 pneumonia? Findings In this randomized clinical trial of 1279 patients hospitalized with COVID-19, patients allocated to receive colchicine plus usual care or to usual care alone demonstrated no significant difference in the coprimary outcome of mechanical ventilation or 28-day mortality. Meaning This randomized clinical trial found that colchicine did not significantly reduce the need for mechanical ventilation or 28-day mortality in patients hospitalized with COVID-19 pneumonia., This randomized clinical trial assesses the efficacy of colchicine in preventing mechanical ventilation and mortality in hospitalized patients with COVID-19 pneumonia., Importance Hospitalized patients with COVID-19 pneumonia have high rates of morbidity and mortality. Objective To assess the efficacy of colchicine in hospitalized patients with COVID-19 pneumonia. Design, Setting, and Participants The Estudios Clínicos Latino América (ECLA) Population Health Research Institute (PHRI) COLCOVID trial was a multicenter, open-label, randomized clinical trial performed from April 17, 2020, to March 28, 2021, in adults with confirmed or suspected SARS-CoV-2 infection followed for up to 28 days. Participants received colchicine vs usual care if they were hospitalized with COVID-19 symptoms and had severe acute respiratory syndrome or oxygen desaturation. The main exclusion criteria were clear indications or contraindications for colchicine, chronic kidney disease, and negative results on a reverse transcription–polymerase chain reaction test for SARS-CoV-2 before randomization. Data were analyzed from June 20 to July 25, 2021. Interventions Patients were assigned in a 1:1 ratio to usual care or usual care plus colchicine. Colchicine was administered orally in a loading dose of 1.5 mg immediately after randomization, followed by 0.5 mg orally within 2 hours of the initial dose and 0.5 mg orally twice a day for 14 days or discharge, whichever occurred first. Main Outcomes and Measures The first coprimary outcome was the composite of a new requirement for mechanical ventilation or death evaluated at 28 days. The second coprimary outcome was death at 28 days. Results A total of 1279 hospitalized patients (mean [SD] age, 61.8 [14.6] years; 449 [35.1%] women and 830 [64.9%] men) were randomized, including 639 patients in the usual care group and 640 patients in the colchicine group. Corticosteroids were used in 1171 patients (91.5%). The coprimary outcome of mechanical ventilation or 28-day death occurred in 160 patients (25.0%) in the colchicine group and 184 patients (28.8%) in the usual care group (hazard ratio [HR], 0.83; 95% CI, 0.67-1.02; P = .08). The second coprimary outcome, 28-day death, occurred in 131 patients (20.5%) in the colchicine group and 142 patients (22.2%) in the usual care group (HR, 0.88; 95% CI, 0.70-1.12). Diarrhea was the most frequent adverse effect of colchicine, reported in 68 patients (11.3%). Conclusions and Relevance This randomized clinical trial found that compared with usual care, colchicine did not significantly reduce mechanical ventilation or 28-day mortality in patients hospitalized with COVID-19 pneumonia. Trial Registration ClinicalTrials.gov Identifier: NCT04328480

Introducción: La rinitis alérgica es una condición común en gran parte de la población en general. Afecta aproximadamente al 32% de la población en general.Materiales y métodos: Estudio prospectivo en cohorte con un diagnóstico clínicode rinitis alérgica en el Hospital Universitario de La Samaritana; se evaluó el cuestionario ESPRINT-15 validado en español previo y 3 post-tratamiento con Beclometasona, Furoato de Mometasona y FluticasonaResultados: Se incluyeron 160 pacientes en el estudio. Previo al tratamiento, los pacientes tratados con Beclometasona y Mometasona no presentaban diferencia entre la puntuación global del cuestionario. Posterior al tratamiento, se evidenció que el grupo tratado con Furoato de Mometasona presentaba una reducción estadísticamente significativa en la severidad de síntomas (2.0 vs. 3.0, p

With 40 million amputees living in poor countries with limited access to health care, there is a significant need for novel prosthetic solutions. This paper presents our preliminary results to develop sustainable prostheses for five upper-extremity amputee patients in Colombia, South America. We utilized a patient-centric methodology, engaging patients at every stage in an effort to increase their satisfaction with their prosthetic and to assess clinical usefulness. We identified patient-specific criteria and compared existing open source hardware systems using the Design Thinking methodology. Finally, we present these data to further the development of myoelectric prosthetics as part of cyber-physical systems.

Introduction: The use of mobile applications has increased in the last years. Most of them require the knowledge of the user location, either for their core service or for marketing purposes. Location-based services (LBS) offer context-based assistance to users based on their location. Although these applications ask the user for permission to use their location and even explain in detail how this information will be used in its terms and conditions, most users are not aware or even interested in the fact that their location information is stored in databases and monetized by selling it to third-party companies. Regarding this situation, we developed a study with the aim to assess perception, concerns and awareness from users about their location information. Methods: This work is based on an exploratory survey applied to the university community, mainly from the North Coast of Colombia, to measure the perception of location privacy of users with mobile devices. The questionnaire was applied using Google Forms. The survey has nineteen questions organized in three sections: personal information, identification of privacy and privacy management. These questions were designed to know the users’ perceptions of privacy concerns in LBS and any actions they take to preserve it. Results: The results show that, in general, the respondents do not have a real concern regarding the privacy of their geolocation data, and the majority is not willing to pay to protect their privacy. Conclusions: This type of surveys can generate awareness among participants about the use of their private information. The results expose in this paper can be used to create government policies and regulations by technology companies about the privacy management. Introducción: El uso de aplicaciones móviles se ha incrementado en los últimos años. La mayoría de ellas requiere conocer la ubicación del usuario, ya sea para su servicio principal o para fines de marketing. Los servicios basados en localización (SBL) ofrecen asistencia contextual para los usuarios según su ubicación. Aunque estas aplicaciones le piden permiso al usuario para usar su ubicación e incluso explican en detalle cómo se usará esta información en sus términos y condiciones, la mayoría de los usuarios no están conscientes ni incluso interesados en el hecho de que la información de su ubicación se almacene en bases de datos y se monetice, vendiéndolo a terceros. Con respecto a esta situación, desarrollamos un estudio con el objetivo de evaluar la percepción, las preocupaciones y el conocimiento de los usuarios sobre la información de su ubicación. Métodos: este trabajo se basa en una encuesta exploratoria aplicada a la comunidad universitaria, principalmente de la costa norte de Colombia, para medir la percepción de la privacidad de ubicación de los usuarios con dispositivos móviles. El cuestionario se aplicó utilizando los formularios de Google. La encuesta tiene diecinueve preguntas organizadas en tres secciones: información personal, identificación de privacidad y gestión de la privacidad. Estas preguntas fueron diseñadas para conocer las percepciones de los usuarios sobre las preocupaciones de privacidad en SBL y cualquier acción que tomen para preservarla. Resultados: los resultados muestran que, en general, los encuestados no tienen una preocupación real con respecto a la privacidad de sus datos de geolocalización, y la mayoría no está dispuesta a pagar para proteger su privacidad. Conclusiones: este tipo de encuestas puede generar conciencia entre los participantes sobre el uso de su información privada. Los resultados expuestos en este documento se pueden utilizar para crear políticas y regulaciones gubernamentales por parte de las compañías de tecnología sobre la administración de la privacidad.

Background Electrical cardioversion is an effective and safe procedure in most patients. While left atrial thrombus is an absolute contraindication for elective cardioversion, there is very limited data on cardioversion in patients with left ventricular thrombus. We sought to better study the safety of cardioversion in this population. Methods We retrospectively reviewed all patients with the diagnosis of left ventricular thrombus on transthoracic echocardiogram (TTE) at our institution from 2010-2019. Patient were included in the study if they had undergone cardioversion and had had a TTE 4 weeks prior or 2 days after cardioversion showing left ventricular thrombus. Medical charts were reviewed for embolic events within three months after cardioversion. Results Out of 790 patients, 39 were included in the study. Mean age was 59.6 +/-14 years. The reason for cardioversion was atrial fibrillation/flutter (n = 14), ventricular arrhythmia (n = 14) and defibrillation threshold testing during defibrillator placement (n = 11). Mean time interval between the TTE and the cardioversion was 6 +/-6.3 days. Mean left ventricular ejection fraction was 24%+/-10%. Left ventricular thrombus was mobile (n = 3), fixed (n = 32) or calcified (n = 4). During a clinical follow-up period of 87+/-35 days, 28 patients (72%) were treated with warfarin, 2 patients (5%) with a direct oral anticoagulants, and 9 patients (23%) with anti-platelet therapy alone. No patient had an embolic complication during the follow-up. Conclusion Within the limitations of this study, cardioversion in patients with left ventricular thrombus appeared to be safe. Further larger studies are needed.

Electronic Medical Records - EMR has been an increasingly major area of research in order to improve quality of health services, by reducing attention time, probability of errors and helping all the actors in the ecosystem for accountability and traceability. However, patients are probably one of the actors that, despite being the main actor to be protected by regulations, have the least access to its information and control over what, who, when, how and why other actors in the healthcare system are doing with their information, especially in cases where just the existence of some tests may reveal an illness or a condition that should remain private. There is existing work and regulations on defining user-centered access control to the data, but the options are usually focused on defining policies on who has access to the information. This work introduces an incremental data access options in order to increase privacy over the data by considering the possibility of offering slightly altered or obfuscated data as an option to protect the original information, revealing just enough to enable the desired services. A differential privacy classification of access is presented, tested on lab data and evaluated, showing that different levels of privacy protection can be used in certain cases and for a limited number of services, while preserving privacy of the data. In addition, this technique can be integrated with other access-control techniques in literature.

Contar con una historia clinica completa de un paciente, en cualquier momento, constituye una herramienta valiosa que permite a los actores del sistema de salud, tales como medicos, enfermeras, farmaceutas, laboratoristas e incluso al mismo paciente, tomar mejores decisiones sobre los tratamientos medicos a seguir al contar con todos los antecedentes clinicos bien documentados. Sin embargo, en la actualidad solo se cuenta con un sistema fragmentado, no estandarizado, no interconectado, que Iimita el acceso a esta informacion de manera integral. En los ultimos tiempos se ha venido trabajando mecanismos para Iograr que esta centralizacion sea una realidad. Un ejemplo de ello es la Blockchain, que surge una tecnologia que permitiria la construccion de un sistema con informacion centralizada, pero no dependiente de una unica instancia, por su caracter participativo. Esta caracteristica serviria para implementar sistemas EMR (Electronic Medical Records) flexible, robusto y seguro para almacenar la informacion medica de los pacientes. Este trabajo presenta el diseno de la plataforma BD-MED para el uso de redes blockchain para el acceso, registro y almacenamiento del historial clinico de los pacientes, incluso en escenarios con fallas de conectividad.

Tailgut cysts, also known as retrorectal hamartomas, are very rare neoplasms located in the presacral/retrorectal space that originate from the embryonic hindgut. Although a majority of lesions in this location are benign, 30% of the reported cases in the literature were found to be malignant. This report describes a case of a presacral mass found on CT of a 37-year-old woman who initially presented with worsening abdominal pain and a history of ovarian cyst rupture. This patient's clinical picture was complicated by an enlarging ovarian cyst. The risk of progression to malignancy warranted excision. She recovered well with resolution of her presenting symptoms. We report this case along with a brief review of the literature with a focus on the surgical considerations.

The more stringent environmental regulations enacted throughout the world have increased the need of more active hydrotreating (HDT) catalysts, in the petroleum refining industry. Usually, the catalysts used for diesel oil hydrotreatment are ?-Al2O3 supported molybdenum or tungsten sulfides promoted with cobalt or nickel. Current strategies for the design of novel HDS catalysts often include variations in the support formulation, catalyst preparation method and active phase formulation. In this sense, the new generations of catalysts, such as NEBULA®, are based on a totally different concept of bulk-like. In this chapter, we present recent research related to the synthesis, characterization and performance of trimetallic sulfide nanocatalysts for hydrodesulfurization. The present chapter analyses the state of art of the ternary sulfide hydrotreating catalysts.

International audience; This paper documents the spatiotemporal evolution of wet-day and dry-day frequency (WDF and DDF) in the western Amazon, its relationships with oceanic and atmospheric variability and possible impact on vegetation. WDF and DDF changed significantly during the 1980–2009 period (p < 0.05). An increase in WDF is observed after 1995 over the northern part of the western Amazon (Marañón basin). The average annual value of WDF changed from 22 days/yr before 1995 to 34 days after that date (+55% after 1995). In contrast, DDF increased significantly over the central and southern part of this region (Ucayali basin) after 1986. Average annual DDF was 16.2 days before 1986 and 23.8 days afterward (+47% after 1986). Interannual variability in WDF appears to be modulated by changes in Pacific SST and the Walker cell during the November–March season. This mechanism enhances convective activity over the northern part of the western Amazon. The increase in DDF is related to warming of the North Tropical Atlantic SST, which produces changes in the Hadley cell and subsidence over the central and the southern western Amazon. More intense seasonal hydrological extremes in the western Amazon therefore appear to be related to changes in WDF and DDF that occurred in 1995 and 1986, respectively. During the 2001–2009 period, an index of vegetation condition (NDVI) appears negatively correlated with DDF (r = -0.95; p < 0.0001). This suggests that vegetation in the western Amazon is mainly water limited, rather than light limited and indicates that the vegetation is highly sensitive to concentration of rainfall.

A 67-year-old woman had recently emigrated from the Dominican Republic where, many years prior, she had been evaluated for ‘tachycardias’ and had unrevealing monitors. She was well until 6 months prior to admission when she started to experience unpredictable, generally exertional palpitations, dyspnoea and left arm discomfort. There was no history of antecedent anxiety. Examination was notable for a 3/6 systolic murmur heard from apex to base and radiating to the neck that ultimately decreased with Valsalva manoeuvre, consistent with aortic sclerosis that was also seen on her echocardiogram. ECG showed …

Transient changes in striatal dopamine (DA) concentration are considered to encode a reward prediction error (RPE) in reinforcement learning tasks. Often, a phasic DA change occurs concomitantly with a dip in striatal acetylcholine (ACh), whereas other neuromodulators, such as adenosine (Adn), change slowly. There are abundant adenylyl cyclase (AC) coupled GPCRs for these neuromodulators in striatal medium spiny neurons (MSNs), which play important roles in plasticity. However, little is known about the interaction between these neuromodulators via GPCRs. The interaction between these transient neuromodulator changes and the effect on cAMP/PKA signaling via Golf- and Gi/o-coupled GPCR are studied here using quantitative kinetic modeling. The simulations suggest that, under basal conditions, cAMP/PKA signaling could be significantly inhibited in D1R+ MSNs via ACh/M4R/Gi/oand an ACh dip is required to gate a subset of D1R/Golf-dependent PKA activation. Furthermore, the interaction between ACh dip and DA peak, via D1R and M4R, is synergistic. In a similar fashion, PKA signaling in D2+ MSNs is under basal inhibition via D2R/Gi/oand a DA dip leads to a PKA increase by disinhibiting A2aR/Golf, but D2+ MSNs could also respond to the DA peak via other intracellular pathways. This study highlights the similarity between the two types of MSNs in terms of high basal AC inhibition by Gi/oand the importance of interactions between Gi/oand Golfsignaling, but at the same time predicts differences between them with regard to the sign of RPE responsible for PKA activation.SIGNIFICANCE STATEMENTDopamine transients are considered to carry reward-related signal in reinforcement learning. An increase in dopamine concentration is associated with an unexpected reward or salient stimuli, whereas a decrease is produced by omission of an expected reward. Often dopamine transients are accompanied by other neuromodulatory signals, such as acetylcholine and adenosine. We highlight the importance of interaction between acetylcholine, dopamine, and adenosine signals via adenylyl-cyclase coupled GPCRs in shaping the dopamine-dependent cAMP/PKA signaling in striatal neurons. Specifically, a dopamine peak and an acetylcholine dip must interact, via D1 and M4 receptor, and a dopamine dip must interact with adenosine tone, via D2 and A2a receptor, in direct and indirect pathway neurons, respectively, to have any significant downstream PKA activation.

The bacteriophage population is large, dynamic, ancient, and genetically diverse. Limited genomic information shows that phage genomes are mosaic, and the genetic architecture of phage populations remains ill-defined. To understand the population structure of phages infecting a single host strain, we isolated, sequenced, and compared 627 phages of Mycobacterium smegmatis. Their genetic diversity is considerable, and there are 28 distinct genomic types (clusters) with related nucleotide sequences. However, amino acid sequence comparisons show pervasive genomic mosaicism, and quantification of inter-cluster and intra-cluster relatedness reveals a continuum of genetic diversity, albeit with uneven representation of different phages. Furthermore, rarefaction analysis shows that the mycobacteriophage population is not closed, and there is a constant influx of genes from other sources. Phage isolation and analysis was performed by a large consortium of academic institutions, illustrating the substantial benefits of a disseminated, structured program involving large numbers of freshman undergraduates in scientific discovery. DOI: http://dx.doi.org/10.7554/eLife.06416.001, eLife digest Viruses are unable to replicate independently. To generate copies of itself, a virus must instead invade a target cell and commandeer that cell's replication machinery. Different viruses are able to invade different types of cell, and a group of viruses known as bacteriophages (or phages for short) replicate within bacteria. The enormous number and diversity of phages in the world means that they play an important role in virtually every ecosystem. Despite their importance, relatively little is known about how different phage populations are related to each other and how they evolved. Many phages contain their genetic information in the form of strands of DNA. Using genetic sequencing to find out where and how different genes are encoded in the DNA can reveal information about how different viruses are related to each other. These relationships are particularly complicated in phages, as they can exchange genes with other viruses and microbes. Previous studies comparing the genomes—the complete DNA sequence—of reasonably small numbers of phages that infect the Mycobacterium group of bacteria have found that the phages can be sorted into ‘clusters’ based on similarities in their genes and where these are encoded in their DNA. However, the number of phages investigated so far has been too small to conclude how different clusters are related. Are the clusters separate, or do they form a ‘continuum’ with different genes and DNA sequences shared between different clusters? Here, Pope, Bowman, Russell et al. compare the individual genomes of 627 bacteriophages that infect the bacterial species Mycobacterium smegmatis. This is by far the largest number of phage genomes analyzed from a single host species. The large number of genomes analyzed allowed a much clearer understanding of the complexity and diversity of these phages to be obtained. The isolation, sequencing and analysis of the hundreds of M. smegmatis bacteriophage genomes was performed by an integrated research and education program, called the Science Education Alliance Phage Hunters Advancing Genomics and Evolutionary Science (SEA-PHAGES) program. This enabled thousands of undergraduate students from different institutions to contribute to the phage discovery and sequencing project, and co-author the report. SEA-PHAGES therefore shows that it is possible to successfully incorporate genuine scientific research into an undergraduate course, and that doing so can benefit both the students and researchers involved. The results show that while the genomes could be categorized into 28 clusters, the genomes are not completely unrelated. Instead, a spread of diversity is seen, as genes and groups of genes are shared between different clusters. Pope, Bowman, Russell et al. further reveal that the phage population is in a constant state of change, and continuously acquires genes from other microorganisms and viruses. DOI: http://dx.doi.org/10.7554/eLife.06416.002

Volume electron microscopy (EM) is an aggregate of techniques (e.g. FIB-SEM, SBF-SEM) which are evolving toward easing the trade-off between resolution and field of view size so that increasingly l ...

Striatum, which is the input nucleus of the basal ganglia, integrates cortical and thalamic glutamatergic inputs with dopaminergic afferents from the substantia nigra pars compacta. The combination of dopamine and glutamate strongly modulates molecular and cellular properties of striatal neurons and the strength of corticostriatal synapses. These actions are performed via intracellular signaling networks, containing several intertwined feedback loops. Understanding the role of dopamine and other neuromodulators requires the development of quantitative dynamical models for describing the intracellular signaling, in order to provide precise unambiguous descriptions and quantitative predictions. Building such models requires integration of data from multiple data sources containing information regarding the molecular interactions, the strength of these interactions, and the subcellular localization of the molecules. Due to the uncertainty, variability, and sparseness of these data, parameter estimation techniques are critical for inferring or constraining the unknown parameters, and sensitivity analysis evaluates which parameters are most critical for a given observed macroscopic behavior. Here, we briefly review the modeling approaches and tools that have been used to investigate biochemical signaling in the striatum, along with some of the models built around striatum. We also suggest a future direction for the development of such models from the, now becoming abundant, high-throughput data.

Kinases and phosphatases that regulate neurite number versus branching versus extension are weakly correlated. The kinase family that most strongly enhances neurite growth is a family of non-protein kinases; sugar kinases related to NADK. Pathway analysis revealed that genes in several cancer pathways were highly active in enhancing neurite growth., In neural development, neuronal precursors differentiate, migrate, extend long axons and dendrites, and finally establish connections with their targets. Clinical conditions such as spinal cord injury, traumatic brain injury, stroke, multiple sclerosis, Parkinson's disease, Huntington's disease, and Alzheimer's disease are often associated with a loss of axon and/or dendrite connectivity and treatment strategies would be enhanced by new therapies targeting cell intrinsic mechanisms of axon elongation and regeneration. Phosphorylation controls most cellular processes, including the cell cycle, proliferation, metabolism, and apoptosis. Neuronal differentiation, including axon formation and elongation, is also regulated by a wide range of kinases and phosphatases. For example, the non-receptor tyrosine kinase Src is required for cell adhesion molecule-dependent neurite outgrowth. In addition to individual kinases and phosphatases, signaling pathways like the MAPK, growth factor signaling, PIP3, cytoskeletal, and calcium-dependent pathways have been shown to impinge on or control neuronal process development. Recent results have implicated GSK3 and PTEN as therapeutically relevant targets in axonal regeneration after injury. However, these and other experiments have studied only a small fraction of the total kinases and phosphatases in the genome. Because of recent advances in genomic knowledge, large-scale cDNA production, and high-throughput phenotypic analysis, it is now possible to take a more comprehensive approach to understanding the functions of kinases and phosphatases in neurons. We performed a large, unbiased set of experiments to answer the question ‘what effect does the overexpression of genes encoding kinases, phosphatases, and related proteins have on neuronal morphology?' We used ‘high-content analysis' to obtain detailed results about the specific phenotypes of neurons. We studied embryonic rat hippocampal neurons because of their stereotypical development in vitro (Dotti et al, 1988) and their widespread use in studies of neuronal differentiation and signaling. We transfected over 700 clones encoding kinases and phosphatases into hippocampal neurons and analyzed the resulting changes in neuronal morphology. Many known genes, including PP1a, ERK1, ErbB2, atypical PKC, Calcineurin, CaMK2, IGF1R, FGFR, GSK3, and PIK3 were observed to have significant effects on neurite outgrowth in our system, consistent with earlier findings in the literature. We obtained quantitative data for many cellular and neuronal morphological parameters from each neuron imaged. These included nuclear morphology (nuclear area and Hoechst dye intensity), soma morphology (tubulin intensity, area, and shape), and numerous parameters of neurite morphology (e.g. tubulin intensity along the neurites, number of primary neurites, neurite length, number of branches, distance from the cell body to the branches, number of crossing points, width and area of the neurites, and longest neurite; Supplementary Figure 1). Other parameters were reported on a ‘per well' basis, including the percentage of transfected neurons in a condition, as well as the percentage of neurons initiating neurite growth. Data for each treatment were normalized to a control (pSport CAT) within the same experiment, then aggregated across replicate experiments. Correlations among the 19 normalized parameters were analyzed for neurons transfected with all kinase and phosphatase clones (Figure 2). On the basis of this analysis, the primary variables that define the neurite morphology are primary neurite count, neurite average length, and average branches. Interestingly, primary neurite count was not well correlated with neurite length or branching. The Pearson correlation coefficient (r2) between the number of primary neurites and the average length of the neurites was 0.3, and between the number of primary neurites and average branching was 0.2. In contrast, the correlation coefficient of average branching with neurite average length was 0.7. The most likely explanation is that signaling mechanisms underlying the neurite number determination are different than those controlling length/branching of the neurites. Related proteins are often involved in similar neuronal functions. For example, families of receptor protein tyrosine phosphatases are involved in motor axon extension and guidance in both Drosophila and in vertebrates, and a large family of Eph receptor tyrosine kinases regulates guidance of retinotectal projections, motor axons, and axons in the corpus callosum. We therefore asked whether families of related genes produced similar phenotypes when overexpressed in hippocampal neurons. Our set of genes covered 40% of the known protein kinases, and many of the non-protein kinases and phosphatases. Gene families commonly exhibit redundant function. Redundant gene function has often been identified when two or more knockouts are required to produce a phenotype. Our technique allowed us to measure whether different members of gene families had similar (potentially redundant) or distinct effects on neuronal phenotype. To determine whether groups of related genes affect neuronal morphology in similar ways, we used sequence alignment information to construct gene clusters (Figure 6). Genes were clustered at nine different thresholds of similarity (called ‘tiers'). The functional effect for a particular parameter was then averaged within each cluster of a given tier, and statistics were performed to determine the significance of the effect. We analyzed the results for three key neurite parameters (average neurite length, primary neurite count, and average branching). Genes that perturbed each of these phenotypes are grouped in Figure 6. Eight families, most with only a few genes, produced significant changes for one or two parameters. A diverse family of non-protein kinases had a positive effect on neurite outgrowth in three of the four parameters analyzed. This family of kinases consisted of a variety of enzymes, mostly sugar and lipid kinases. A similar analysis was performed using pathway cluster analysis with pathways from the KEGG database, rather than sequence homology. Interestingly, pathways involved in cancer cell proliferation potentiated neurite extension and branching. Our studies have identified a large number of kinases and phosphatases, as well as structurally and functionally defined families of these proteins, that affect neuronal process formation in specific ways. We have provided an analytical methodology and new tools to analyze functional data, and have implicated genes with novel functions in neuronal development. Our studies are an important step towards the goal of a molecular description of the intrinsic control of axodendritic growth., Development and regeneration of the nervous system requires the precise formation of axons and dendrites. Kinases and phosphatases are pervasive regulators of cellular function and have been implicated in controlling axodendritic development and regeneration. We undertook a gain-of-function analysis to determine the functions of kinases and phosphatases in the regulation of neuron morphology. Over 300 kinases and 124 esterases and phosphatases were studied by high-content analysis of rat hippocampal neurons. Proteins previously implicated in neurite growth, such as ERK1, GSK3, EphA8, FGFR, PI3K, PKC, p38, and PP1a, were confirmed to have effects in our functional assays. We also identified novel positive and negative neurite growth regulators. These include neuronal-developmentally regulated kinases such as the activin receptor, interferon regulatory factor 6 (IRF6) and neural leucine-rich repeat 1 (LRRN1). The protein kinase N2 (PKN2) and choline kinase α (CHKA) kinases, and the phosphatases PPEF2 and SMPD1, have little or no established functions in neuronal function, but were sufficient to promote neurite growth. In addition, pathway analysis revealed that members of signaling pathways involved in cancer progression and axis formation enhanced neurite outgrowth, whereas cytokine-related pathways significantly inhibited neurite formation.

The convergence of corticostriatal glutamate and dopamine from the midbrain in the striatal medium spiny neurons (MSN) triggers synaptic plasticity that underlies reinforcement learning and pathological conditions such as psychostimulant addiction. The increase in striatal dopamine produced by the acute administration of psychostimulants has been found to activate not only effectors of the AC5/cAMP/PKA signaling cascade such as GluR1, but also effectors of the NMDAR/Ca2+/RAS cascade such as ERK. The dopamine-triggered effects on both these cascades are mediated by D1R coupled to Golf but while the phosphorylation of GluR1 is affected by reductions in the available amount of Golf but not of D1R, the activation of ERK follows the opposite pattern. This segregation is puzzling considering that D1R-induced Golf activation monotonically increases with DA and that there is crosstalk from the AC5/cAMP/PKA cascade to the NMDAR/Ca2+/RAS cascade via a STEP (a tyrosine phosphatase). In this work, we developed a signaling model which accounts for this segregation based on the assumption that a common pool of D1R and Golf is distributed in two D1R/Golf signaling compartments. This model integrates a relatively large amount of experimental data for neurons in vivo and in vitro. We used it to explore the crosstalk topologies under which the sensitivities of the AC5/cAMP/PKA signaling cascade to reductions in D1R or Golf are transferred or not to the activation of ERK. We found that the sequestration of STEP by its substrate ERK together with the insensitivity of STEP activity on targets upstream of ERK (i.e. Fyn and NR2B) to PKA phosphorylation are able to explain the experimentally observed segregation. This model provides a quantitative framework for simulation based experiments to study signaling required for long term potentiation in MSNs., Author Summary The molecular mechanisms by which a dog learns to associate a bell ring with incoming food and by which addiction to cocaine is developed have many things in common. In both cases, glutamate-mediated inputs from the cortex converge on striatal neurons with the neuromodulator dopamine whose level increases upon food delivery or cocaine administration. This convergence triggers intracellular reaction cascades that end up modifying the basal state of these neurons into what is currently considered the cellular correlate of learning and its overblown variant: addiction. Understanding these signaling cascades is required to design interventions for the enhancement of cognitive capacities and the prevention/cure of addiction. With this in mind, we developed a model of the dynamics of these reaction cascades upon the administration of cocaine. We did this by gathering the cascades' molecular components and interactions discovered by experimentalist so far and then setting the reaction parameters so that the model reproduces the timing of the molecular changes that lead to the discovery of those components and interactions. With this integrationist endeavor we disclosed some inconsistencies and provided a rationale for experimental observations that were unexplained. Our predictions are readily challengeable with future experiments.