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Summary: Background: Human Bocaviruses (HBoV) can cause acute respiratory tract infections. High coinfection rates cloud its pathogenicity. This study sought to describe the clinical features of HBoV1 disease in children and adults with Influenza-like illness (ILI), exploring associations between viral load, clinical features, and seasonality. Methods: Patients who tested positive for HBoV1 by polymerase chain reaction, enrolled from April 2010 to March 2014 in the ILI002 prospective observational cohort study were included in this cross-sectional nested study. Participants were included in ILI002 if they presented with signs and/or symptoms suggestive of influenza-like illness. Samples were tested for viral load, and NP1 and VP1/VP2 phylogenetic analyses, except for the samples lacking suitable and viable clinical material for genotyping. Findings: We identified HBoV1 in 157 (2.8%) of participants. Prevalence was 4.5% in children and 1.8% in adults. Single HBoV1 detection occurred in 41.1% and 46.3% of children and adults, respectively. Children commonly experienced fever (83.3%), cough with sputum (74.4%), and shortness of breath (72.2%). In the multivariate analysis of children, significant positive associations were detected between viral loads and age (0.20 [95% CI: 0.07, 0.33]), and the presence of fever (2.64 [95% CI: 1.35, 3.94]), nasal congestion (1.03 [95% CI: 0.07, 1.99]), dry cough (1.32 [95% CI: 0.42, 2.22]), chest congestion (1.57 [95% CI: 0.33, 2.80]), red eyes (1.25 [95% CI: 0.35, 2.14]), cough with sputum (1.79 [95% CI: 0.80, 2.78]), and other signs and symptoms such as chills, dizziness, and diaphoresis (1.73 [95% CI: 0.19, 3.27]). In contrast, significant negative associations were found between viral loads and percent neutrophils on the blood count (−0.04 [95% CI: −0.06, −0.02]), fatigue (−1.60 [95% CI: −2.46, −0.74]) and the presence of other symptoms or signs, including adenopathy and rash (−1.26 [95% CI: −2.31, −0.21]). Adults commonly experienced sore throat (73.1%), fatigue (77.4%), and headache (73.1%). In the multivariate analysis of adults, significant positive associations were detected between viral load and body mass index (0.13 [95% CI: 0.04, 0.21]), and the presence of confusion (1.54 [95% CI: 0.55, 2.53]), and sore throat (1.03 [95% CI: 0.20, 1.85]), and significant negative associations were detected between viral load and chest congestion (−1.16 [95% CI: −2.07, −0.24]). HBoV1 was detected throughout the year irrespective of season, temperature, and humidity. Interpretation: This study demonstrated the importance of detecting HBoV1 in patients with influenza-like illness either as single infection or co-infection, in both adults and children, and improves the characterization of HBoV1 seasonality, clinical features, and viral load. Phylogenetic analyses show a high conservation. Funding: The Mexican Emerging Infectious Diseases Clinical Research Network (LaRed), CONACYT (Fondo Sectorial SSA/IMSS/ISSSTE, Projects No. 71260 and No. 127088), Fondos federales no. HIM/2015/006, NIAID, NIH through a contract with Westat, Inc. (HHSN2722009000031, HHSN27200002), NCI, NIH (75N91019D00024, 75N91019F00130). Additional information at the end of the manuscript.

Fireflies (Coleoptera, Lampyridae) are a globally threatened group of insects due to habitat loss and fragmentation, light pollution, climate change and pesticides. However, against all odds, some firefly populations persist in urbanized environments where all four of these factors are present simultaneously. In this work, we compiled several data sources to document the diversity of fireflies in the urbanized area of Morelia, characterize their current habitats, and determine the main stressors affecting these bioluminescent insects. We found seven genera and 26 species of fireflies (19 nocturnal, seven diurnal) associated with 32 urban, peri-urban and extra-urban areas; at least, 14 are new records for Michoacán, and the list for the state now includes nine genera and 41 species. Five additional sites were documented as extinction sites. We compared the characteristics of these five sites with those of the sites with extant populations. We found that in Morelia, fireflies are mainly associated with areas that have high to moderate proportions of vegetation cover, are near water bodies, have very gentle to moderate slopes, and are exposed to low levels of light pollution. In contrast, the extinction sites showed high proportions of artificial surfaces and high levels of light pollution. Because some fireflies are considered bioindicators of ecosystem integrity as they are associated to specific habitats, are highly diverse and due to their sensitivity to environmental changes, we consider that sites from Morelia’s urban core and extinction sites show the highest levels of environmental degradation, threatening most fireflies and other insects living in the urban core with local extinction. At the same time, our results also suggest that implementing conservation strategies and sustainable planning for the urban development of Morelia in the short term could allow fireflies and other vital elements of the city’s insect communities to persist for future generations. Restoration and conservation of green areas and nighttime environments are essential for biodiversity and human health, especially in intra-urban zones.

Fishes of the family Pomacentridae present a wide diversity of mating systems, ranging from polygyny to promiscuity and from individual territorial defense to the establishment of reproductive colonies of males. The damselfish species Abudefduf troschelii has a reproductive colony mating system, in which males temporarily aggregate in reproductive areas to court and attract females. Males defend an individual territory where they receive eggs and perform paternal care behaviors for their offspring. The present study evaluated the advantages of the colonial mating system in A. troschelii. During an entire reproductive period, in a breeding colony within a rocky reef, we located, marked, geo-referenced, and measured the distances between the territories of all males. We quantified the variance among males in their patterns of paternal care investment, eggs acquired, hatching success, reproductive success, body size, and changes in body coloration. We found that males spatially distributed their nests in groups or independently (i.e., solitary nests). Nesting groups are formed by larger males that show intense nuptial coloration during the entire receptivity period. They are located centrally to the colony and consist of three to six males whose territories overlap. In contrast, small solitary males that fail to acquire or maintain nuptial coloration during the receptivity period establish their nests peripherally to the colony, away from the territories of other males. Our results highlight that the reproductive benefits of colonial nesting are unequal for males, as the spatial distribution of nests within the colony determines the reproductive success of males. Group nesting confers the highest reproductive benefits to males regarding eggs obtained, hatching success, and relative fitness and also enables males to reduce their parental investment in brood care behaviors. The preference of females for oviposition could be associated with greater intrasexual competitiveness, defense ability, body condition, or experience of group-nesting males located at the center of the colony or because their progeny will have a lower probability of predation than they would in solitary nests males.

Abstract Background Biomedical translational science is increasingly using computational reasoning on repositories of structured knowledge (such as UMLS, SemMedDB, ChEMBL, Reactome, DrugBank, and SMPDB in order to facilitate discovery of new therapeutic targets and modalities. The NCATS Biomedical Data Translator project is working to federate autonomous reasoning agents and knowledge providers within a distributed system for answering translational questions. Within that project and the broader field, there is a need for a framework that can efficiently and reproducibly build an integrated, standards-compliant, and comprehensive biomedical knowledge graph that can be downloaded in standard serialized form or queried via a public application programming interface (API). Results To create a knowledge provider system within the Translator project, we have developed RTX-KG2, an open-source software system for building—and hosting a web API for querying—a biomedical knowledge graph that uses an Extract-Transform-Load approach to integrate 70 knowledge sources (including the aforementioned core six sources) into a knowledge graph with provenance information including (where available) citations. The semantic layer and schema for RTX-KG2 follow the standard Biolink model to maximize interoperability. RTX-KG2 is currently being used by multiple Translator reasoning agents, both in its downloadable form and via its SmartAPI-registered interface. Serializations of RTX-KG2 are available for download in both the pre-canonicalized form and in canonicalized form (in which synonyms are merged). The current canonicalized version (KG2.7.3) of RTX-KG2 contains 6.4M nodes and 39.3M edges with a hierarchy of 77 relationship types from Biolink. Conclusion RTX-KG2 is the first knowledge graph that integrates UMLS, SemMedDB, ChEMBL, DrugBank, Reactome, SMPDB, and 64 additional knowledge sources within a knowledge graph that conforms to the Biolink standard for its semantic layer and schema. RTX-KG2 is publicly available for querying via its API at arax.rtx.ai/api/rtxkg2/v1.2/openapi.json . The code to build RTX-KG2 is publicly available at github:RTXteam/RTX-KG2 .

Abstract Incomplete premating barriers in closely related species may result in reproductive interference. This process has different fitness consequences and can lead to three scenarios: niche segregation, sexual exclusion, or reproductive character displacement. In morphologically cryptic species, isolation barriers can be difficult to recognize. Here, we analyzed the morphological, behavioral, and genetic differences between two sympatric cryptic species of the genus Hetaerina to determine the characters that contribute the most to reproductive isolation and the effect of the high rates of behavior interference between the species. We found complete genetic isolation and significant differences in the morphometry of caudal appendages and wing shape, as well as body size variation between species. In contrast, we did not find clear differences in the coloration of the wing spot and observed high rates of interspecific aggression. Our results suggest that divergence in the shape of the caudal appendages is the principal pre-mating barrier that prevents interspecific mating. Moreover, a scenario of character displacement on body size was found. Nevertheless, size could play an important role in both inter- and intrasexual interactions and, therefore, we cannot differentiate if it has resulted from reproductive or aggressive interference.

Predicting whether patients will experience intradialytic hypotension (IDH) during hemodialysis (HD) is not an easy task. IDH is associated with multiple risk factors, meaning that traditional statistical models are unable to find the relationships that affect it. In this context, the use of models based on machine learning (ML) can allow the discovery of complex relationships, since they can solve problems without being explicitly programmed. In this work we developed, evaluated and identified an ML-based model that is capable of predicting at the beginning of the HD session whether a patient will suffer from IDH during its prolonged development. To develop the ML models, we used the hold-out and cross-validation methods; while, to evaluate the performance of the models we used the metrics F1-score, Matthews Correlation Coefficient, areas under the receiver operating characteristic (AUROC) and precision-recall curve (AUPRC). In this sense, we selected and used a reduced combination of variables from clinical records and blood analytics, which have proven to be decisive for the occurrence of IDH. The predictive results obtained through our work confirmed that the best ML model was based on the XGBoost model, achieving values of 0.969 and 0.945 for AUROC and AUPRC respectively. Therefore, our study suggests that the XGBoost model has a very high predictive capacity for the appearance of an IDH in HD patients and presents great versatility and flexibility in terms of supporting informed decision-making by medical staff.

Currently, smart buildings generate large amounts of data due to the many devices and equipment available. Hence, buildings implement building management systems (BMSs), which monitor, control, manage and analyze each of these components. However, current BMSs are incapable of managing a massive amount of data (big data) and therefore cannot extract knowledge or make intelligent decisions in quasi real time. In addition, there are serious limitations to integrating BMSs with other services since they generally use proprietary software. In this sense, service-oriented architecture (SOA) is an architectural style that allows one to build distributed systems and provide functionalities such as services to end users or other types of services. Therefore, an SOA has the great advantage of allowing the expansion of the functionalities of BMSs. In fact, there are several studies that address SOAs for building management. However, we have not found any description or systematic analysis in the literature that allows the development of a versatile and interoperable SOA focused on the energy efficiency of buildings and that can integrate massive data analysis features. For these reasons, this study seeks to fill this knowledge gap and, more specifically, to identify and analyze the various software requirements proposed in the literature and the characteristics of big data that allow for improving the energy efficiency of buildings. To this end, we performed an in-depth review of the literature according to the methodology proposed by Kitchenham. As a result of this review, we provide researchers with a specific vision of the requirements and characteristics to consider for software development aimed at the energy efficiency of unique or historic buildings.

The role and the degree to which environment and geographic isolation contribute to phenotypic diversity has been widely debated. Here, we studied phenotypic variation (morphology and plumage reflectance) in the Sinaloa Wren, an endemic bird distributed throughout the tropical dry forest (TDF) on the Mexican pacific slope where a pronounced variability in environmental conditions has been reported. In particular, we aimed: 1) to characterize phenotypic variation between subspecies; 2) to analyze the relationship between phenotypic and environmental variation in the context of classic ecogeographic rules, such as Bergmann's, Allen's, Gloger's, and Bogert's, and to quantify the relative roles of environment and geographic isolation and their interaction in shaping phenotypic variation; and 3) to test for niche conservatism between subspecies. Our data revealed significant differences among subspecies morphology and plumage reflectance. The environment explained a higher proportion of the morphological variation, while geography explained a smaller proportion. However, variation in plumage reflectance was mainly explained by the joint effect of geography and environment. Our data did not support for Bergmann´s and Allen´s rule. However, longer tails and wings were positively associated with higher elevations, larger tarsus and culmens were positively related to higher latitudes and to greater tree cover, respectively. Our data partially supported Gloger´s rule, where darker plumages were associated with more humid environments. The effects of temperature on plumage coloration were more consistent with Bogert´s rule. In addition, we found darker plumages related to higher levels of UV-B radiation. Finally, niche divergence was detected between T. s. cinereus and T. s. sinaloa vs. T. s. russeus. In a continuously distributed ecosystem such as the TDF on the pacific slope of Mexico, the environmental conditions and geographic isolation have played an important role in promoting phenotypic differentiation in the Sinaloa Wren.

This article describes the design, development and implementation of a set of microservices based on an architecture that enables detection and assisted clinical diagnosis within the field of infectious diseases of elderly patients, via a telemonitoring system. The proposed system is designed to continuously update a medical database fed with vital signs from biosensor kits applied by nurses to elderly people on a daily basis. The database is hosted in the cloud and is managed by a flexible microservices software architecture. The computational paradigms of the edge and the cloud were used in the implementation of a hybrid cloud architecture in order to support versatile high-performance applications under the microservices pattern for the pre-diagnosis of infectious diseases in elderly patients. The results of an analysis of the usability of the equipment, the performance of the architecture and the service concept show that the proposed e-health system is feasible and innovative. The system components are also selected to give a cost-effective implementation for people living in disadvantaged areas. The proposed e-health system is also suitable for distributed computing, big data and NoSQL structures, thus allowing the immediate application of machine learning and AI algorithms to discover knowledge patterns from the overall population.

T CD4+ cells are central to the adaptive immune response against pathogens. Their activation is induced by the engagement of the T-cell receptor by antigens, and of co-stimulatory receptors by molecules also expressed on antigen presenting cells. Then, a complex network of intracellular events reinforce, diversify and regulate the initial signals, including dynamic metabolic processes that strongly influence both the activation state and the differentiation to effector cell phenotypes. The regulation of cell metabolism is controlled by the nutrient sensor adenosine monophosphate-activated protein kinase (AMPK), which drives the balance between oxidative phosphorylation (OXPHOS) and glycolysis. Herein, we put forward a 51-node continuous mathematical model that describes the temporal evolution of the early events of activation, integrating a circuit of metabolic regulation into the main routes of signaling. The model simulates the induction of anergy due to defective co-stimulation, the CTLA-4 checkpoint blockade, and the differentiation to effector phenotypes induced by external cytokines. It also describes the adjustment of the OXPHOS-glycolysis equilibrium by the action of AMPK as the effector function of the T cell develops. The development of a transient phase of increased OXPHOS before induction of a sustained glycolytic phase during differentiation to the Th1, Th2 and Th17 phenotypes is shown. In contrast, during Treg differentiation, glycolysis is subsequently reduced as cell metabolism is predominantly polarized towards OXPHOS. These observations are in agreement with experimental data suggesting that OXPHOS produces an ATP reservoir before glycolysis boosts the production of metabolites needed for protein synthesis, cell function, and growth.

The damselflies Hetaerininae, a subfamily of Calopterygidae, comprise four genera distributed from North to South America: Hetaerina, Mnesarete, Ormenophlebia and Bryoplathanon. While several studies have focused on the intriguing behavioral and morphological modifications within Hetaerina, little of the evolutionary history of the group is well understood. Understanding the biogeographical history of Hetaerininae is further complicated by uncertainty in important geological events, such as the closure of the Central American Seaway (CAS). We generated a phylogenetic hypothesis to test the relationships and divergence times within Hetaerininae using IQtree and BEAST2 and found that Mnesarete and Ormenophlebia render Hetaerina paraphyletic. Reclassification of the genera within Hetaerininae is necessary based on our results. We also tested the fit to our dataset of two different hypotheses for the closure of CAS. Our results supported a gradual closure, starting in the Oligocene and ending in the Pliocene. Using Ancestral Character State Reconstruction, we found that the rubyspot, which is associated with higher fecundity in several species, was ancestral for Hetaerininae and subsequently lost four times. Estimates of diversification in association with the rubyspot are needed to understand the plasticity of this important character. Forest habitat was the ancestral state for Hetaerininae, with transitions to generalist species of Hetaerina found primarily in the Mesoamerican region. These results add to our understanding of the relationship between morphology, biogeography and habitat in a charismatic group of damselflies.

Esta investigación analiza el efecto del ambiente de incertidumbre originado por cambios en la política comercial estadounidense sobre el desempeño de las micro, pequeñas y medianas empresas (mipymes) exportadoras de mezcal de la región de los Valles Centrales de Oaxaca, en México. Particularmente, se enfoca en conocer las estrategias que los directivos de esas empresas implementaron para hacer frente a dicha situación. Para tal fin, se recabó información de 48 mipymes productoras de mezcal mediante un cuestionario estructurado, misma que es procesada a través del Paquete Estadístico para Ciencias Sociales. Según los resultados, el impacto del ambiente de incertidumbre en el desempeño de las mipymes es directo y negativo, aunque poco significativo. No obstante, la implementación de estrategias para disminuir la incertidumbre y adaptarse al ambiente intensifica ese efecto; particularmente las estrategias de estabilidad, en cuya presencia se manifiesta una asociación negativa entre la incertidumbre política-regulatoria y el desempeño empresarial.

Transcriptomes are known to organize themselves into gene co-expression clusters or modules where groups of genes display distinct patterns of coordinated or synchronous expression across independent biological samples. The functional significance of these co-expression clusters is suggested by the fact that highly coexpressed groups of genes tend to be enriched in genes involved in common functions and biological processes. While gene co-expression is widely assumed to reflect close regulatory proximity, the validity of this assumption remains unclear. Here we use a simple synthetic gene regulatory network (GRN) model and contrast the resulting co-expression structure produced by these networks with their known regulatory architecture and with the co-expression structure measured in available human expression data. Using randomization tests, we found that the levels of co-expression observed in simulated expression data were, just as with empirical data, significantly higher than expected by chance. When examining the source of correlated expression, we found that individual regulators, both in simulated and experimental data, fail, on average, to display correlated expression with their immediate targets. However, highly correlated gene pairs tend to share at least one common regulator, while most gene pairs sharing common regulators do not necessarily display correlated expression. Our results demonstrate that widespread co-expression naturally emerges in regulatory networks, and that it is a reliable and direct indicator of active co-regulation in a given cellular context.

Knowledge of drug composition consumed on the streets and the identification and quantification of their adulterants is essential for understanding unexpected side effects, tracking routes, and drug profiling. Therefore, this work aimed to determine the purity and to identify and quantify the main adulterants found in personal doses of cocaine (perico) and coca paste (bazuco) in Cartagena de Indias (Colombia). The data collected in this study describe a first attempt to introduce the qualitative and quantitative analyses of adulterants present in street drugs in Cartagena de Indias to improve surveillance. Through gas chromatography coupled to mass spectrometry (GC-MS), the purity and adulterants were quantified in 45 personal doses of cocaine powder and coca paste. 100% of the personal doses in the city were adulterated; caffeine, phenacetin, and levamisole were the main adulterants identified in cocaine. Besides the above, lidocaine was also found in coca paste. The purity of cocaine varied from 8% to almost 70%, with caffeine ranging from 6% to 42%. In the case of coca paste, the maximum content of cocaine found was 60%, while some samples contained as little as 14%. The results are consistent with other research in terms of the widespread use of caffeine as an adulterant, but they also follow the growing trend of the use of levamisole and phenacetin. The wide range of cocaine content in samples sold in the illicit market could cause undesirable effects on cocaine users who do not know the exact intended dose for consumption; so, this study intends to make these results available not only to academic, public health, and national security agencies but also to tourists entering Cartagena de Indias, so that they are aware of what they are consuming and the risks to which they are exposed.

A formação profissional para jovens é um dos principais temas da política de emprego, principalmente devido às altas taxas de desemprego sofridas por essa faixa etária em nossas sociedades. Geralmente, a baixa qualificação no trabalho é identificada como a principal causa do desemprego. No entanto, aspectos fundamentais do mercado de trabalho são deixados de lado, como estrutura produtiva do país, nível educacional ou legislação trabalhista. Para aliviar essa situação, os Estados buscam corrigi-la por meio de políticas trabalhistas que combinam treinamento profissional e prática profissional, ou seja, promover que os jovens adquiram suas habilidades profissionais por meio de suas próprias atividades em uma empresa ou entidade pública, para que, ao se formarem nesse período de educação trabalhista, possuam as qualificações e a experiência que facilitam sua contratação. Este estudo se concentra na análise das políticas de treinamento para trabalho juvenil implementadas pelo Brasil e pelo Peru, comparando os aspectos legais no desenho normativo de ambas as regulamentações trabalhistas, identificando os pontos fortes e fracos de sua abordagem, bem como medindo, no caso peruano, seu impacto no emprego jovem e concluindo com uma série de propostas que melhoram a política trabalhista nessa área.

Chronic respiratory diseases have been on the rise, especially due to COVID-19, extreme air pollution, and other external circumstances. Millions of people around the world suffer from progressive lung diseases and require supplemental oxygen therapy to maintain blood oxygen (SpO2) levels above 90% to prevent hypoxic episodes that can lead to further organ damage. Today, these chronic episodes are more prevalent in aging populations suffering from Chronic Obstructive Pulmonary Disorder (COPD). Existing SpO2 measurement equipment, designed to assist with treating COPD at home, are suboptimal as they cannot measure SpO2 levels continuously, meaning supplemental oxygen devices are unable to adjust oxygen flow rates to the patient’s needs. These discrepancies can result in hypoxic episodes of blood oxygen levels below 90%. Following this need, our team demonstrates preliminary results of the novel placement of a SpO2 sensor in the nasal septum to allow for comfortable and sustained SpO2 measurement. This will improve the experience of home-respiratory care with continuously obtained data from a novel location.

Background The blockage at the early B lymphoid cell development pathway within the bone marrow is tightly associated with hematopoietic and immune diseases, where the disruption of basal regulatory networks prevents the continuous replenishment of functional B cells. Dynamic computational models may be instrumental for the comprehensive understanding of mechanisms underlying complex differentiation processes and provide novel prediction/intervention platforms to reinvigorate the system. Methods By reconstructing a three-module regulatory network including genetic transcription, intracellular transduction, and microenvironment communication, we have investigated the early B lineage cell fate decisions in normal and pathological settings. The early B cell differentiation network was simulated as a Boolean model and then transformed, using fuzzy logic, to a continuous model. We tested null and overexpression mutants to analyze the emergent behavior of the network. Due to its importance in inflammation, we investigated the effect of NFkB induction at different early B cell differentiation stages. Results While the exhaustive synchronous and asynchronous simulation of the early B cell regulatory network (eBCRN) reproduced the configurations of the hematopoietic progenitors and early B lymphoid precursors of the pathway, its simulation as a continuous model with fuzzy logics suggested a transient IL-7R+ ProB-to-Pre-B subset expressing pre-BCR and a series of dominant B-cell transcriptional factors. This conspicuous differentiating cell population up-regulated CXCR7 and reduced CXCR4 and FoxO1 expression levels. Strikingly, constant but intermediate NFkB signaling at specific B cell differentiation stages allowed stabilization of an aberrant CXCR7+ pre-B like phenotype with apparent affinity to proliferative signals, while under constitutive overactivation of NFkB, such cell phenotype was aberrantly exacerbated from the earliest stage of common lymphoid progenitors. Our mutant models revealed an abnormal delay in the BCR assembly upon NFkB activation, concomitant to sustained Flt3 signaling, down-regulation of Ebf1, Irf4 and Pax5 genes transcription, and reduced Ig recombination, pointing to a potential lineage commitment blockage. Discussion For the first time, an inducible CXCR7hi B cell precursor endowed with the potential capability of shifting central lymphoid niches, is inferred by computational modeling. Its phenotype is compatible with that of leukemia-initiating cells and might be the foundation that bridges inflammation with blockage-related malignancies and a wide range of immunological diseases. Besides the predicted differentiation impairment, inflammation-inducible phenotypes open the possibility of newly formed niches colonized by the reported precursor. Thus, emergent bone marrow ecosystems are predicted following a pro-inflammatory induction, that may lead to hematopoietic instability associated to blockage pathologies.

The adaptive immune response is initiated by the interaction of the T cell antigen receptor/CD3 complex (TCR) with a cognate peptide bound to a MHC molecule. This interaction, along with the activity of co-stimulatory molecules and cytokines in the microenvironment, enables cells to proliferate and produce soluble factors that stimulate other branches of the immune response for inactivation of infectious agents. The intracellular activation signals are reinforced, amplified and diversified by a complex network of biochemical interactions, and includes the activity of molecules that modulate the activation process and stimulate the metabolic changes necessary for fulfilling the cell energy demands. We present an approach to the analysis of the main early signaling events of T cell activation by proposing a concise 46-node hybrid Boolean model of the main steps of TCR and CD28 downstream signaling, encompassing the activity of the anergy factor Ndrg1, modulation of activation by CTLA-4, and the activity of the nutrient sensor AMPK as intrinsic players of the activation process. The model generates stable states that reflect the overcoming of activation signals and induction of anergy by the expression of Ndrg1 in the absence of co-stimulation. The model also includes the induction of CTLA-4 upon activation and its competition with CD28 for binding to the co-stimulatory CD80/86 molecules, leading to stable states that reflect the activation arrest. Furthermore, the model integrates the activity of AMPK to the general pathways driving differentiation to functional cell subsets (Th1, Th2, Th17, and Treg). Thus, the network topology incorporates basic mechanism associated to activation, regulation and induction of effector cell phenotypes. The model puts forth a conceptual framework for the integration of functionally relevant processes in the analysis of the T CD4 cell function.

Endothelial cells (ECs) form the lining of lymph and blood vessels. Changes in tissue requirements or wounds may cause ECs to behave as tip or stalk cells. Alternatively, they may differentiate into mesenchymal cells (MCs). These processes are known as EC activation and endothelial-to-mesenchymal transition (EndMT), respectively. EndMT, Tip, and Stalk EC behaviors all require SNAI1, SNAI2, and Matrix metallopeptidase (MMP) function. However, only EndMT inhibits the expression of VE-cadherin, PECAM1, and VEGFR2, and also leads to EC detachment. Physiologically, EndMT is involved in heart valve development, while a defective EndMT regulation is involved in the physiopathology of cardiovascular malformations, congenital heart disease, systemic and organ fibrosis, pulmonary arterial hypertension, and atherosclerosis. Therefore, the control of EndMT has many promising potential applications in regenerative medicine. Despite the fact that many molecular components involved in EC activation and EndMT have been characterized, the system-level molecular mechanisms involved in this process have not been elucidated. Toward this end, hereby we present Boolean network model of the molecular involved in the regulation of EC activation and EndMT. The simulated dynamic behavior of our model reaches fixed and cyclic patterns of activation that correspond to the expected EC and MC cell types and behaviors, recovering most of the specific effects of simple gain and loss-of-function mutations as well as the conditions associated with the progression of several diseases. Therefore, our model constitutes a theoretical framework that can be used to generate hypotheses and guide experimental inquiry to comprehend the regulatory mechanisms behind EndMT. Our main findings include that both the extracellular microevironment and the pattern of molecular activity within the cell regulate EndMT. EndMT requires a lack of VEGFA and sufficient oxygen in the extracellular microenvironment as well as no FLI1 and GATA2 activity within the cell. Additionally Tip cells cannot undergo EndMT directly. Furthermore, the specific conditions that are sufficient to trigger EndMT depend on the specific pattern of molecular activation within the cell.

Este artículo presenta el diseño y desarrollo de un prototipo portátil para la adquisición, procesamiento y clasificación de señales EEG con el objetivo de caracterizar estímulos visuales y auditivos, se trabajó con dos pacientes diferentes para la validación de los resultados, se realizó el registro de las señales durante 4 segundos a una frecuencia de 500Hz. Los pacientes fueron expuestos a estímulos visuales y auditivos en diferentes casos, cuya frecuencia de aparición permanecía constante. Para el registro de las señales se diseñó un sistema de adquisición de 4 canales configurables entre sí para trabajar con derivación unipolar o bipolar según requiera el experimento. La selección de la mejor base en el análisis multi-resolución de wavelet se tuvieron en cuenta dos parámetros importantes, la medida de la entropía y los porcentajes de clasificación de dichos niveles, debido a que los potenciales evocados son generalmente constantes en su morfología, se hizo promediación coherente dando como resultado la ubicación espacio-tiempo donde aparece dicho potencial evocado, una vez se obtuvo las características de la señal tratada se procedió a clasificarlas mediante dos métodos diferentes de inteligencia artificial, redes neuronales y máquinas de soporte vectorial, en esta etapa se tomó en cuenta la medida de la desviación estándar de los datos, para garantizar que la máquina de aprendizaje se entrene de manera correcta. Los resultados obtenidos demuestran de manera fidedigna el comportamiento general de los potenciales evocados como resultado a los estímulos presentados, además de que se pudo comprobar la variación de las ondas alfa del paciente según su estado de relajación o alerta en cada caso, es recomendable realizar un sistema de filtrado mucho más robusto para aumentar la relación señal a ruido de la señal EEG, facilitar su análisis y mejorar los resultados.

Flight morphological variations and its consequences on animal performance are common in winged insects. In the butterfly Heliconius charithonia, sex-related differences in the wing morphological design have been described resulting in differences in foraging behavior, daily flight distances and flight aerodynamics. It has been suggested that these differences should be reflected in the metabolic capacities and energetic budgets associated with flight in both sexes. In this study, we analyzed the relationship between wing morphological variation and metabolic performance, flight aerodynamics and energetic reserves in females and males of Heliconius charithonia over two years. The results confirm the presence of wing shape sexual dimorphism, but also show an unexpected sex-related annual variation in wing shape, mirrored in the metabolic condition (resting metabolic rate) of individuals. However, contrary to expectation, intersexual variations in wing shape are not related to differences between the sexes in terms of flight aerodynamics, flight metabolic rates, or energetic reserves (carbohydrates, lipids and proteins). Our results indicate a considerable plasticity in H. charithonia wing shape, which we suggest is determined by a trade-off between environmental pressures and reproductive restriction of each sex, maintaining an optimum flight design. Finally, similarities in metabolic rates between young and older males and females in both years may be a consequence of the ability of Heliconius species to feed on pollen.

This article provides a description of an agricultural household survey data of rice growers collected in Ecuador between October 2014 and March 2015. The household survey was implemented using a structured questionnaire administered among 1028 households in the main rice production areas of Ecuador (i.e. Guayas, Los Rios, Manabi, and El Oro provinces). Information collected was provided by household heads (male or female) and included household and plot level data. The survey information includes household socio-demographic characteristics (e.g. age, education, gender, main economic activity, etc.), farm characteristics (e.g. farm land size, assets ownership, other crops planted, etc.), rice management practices (e.g. variety and input use, production costs, etc.), and rice production and utilization (e.g. yields, prices, sales, etc.). Additional socio-economic context variables were also recorded such as government subsidies to rice production, participation in rural organizations, and food security related questions. The dataset contains a total of 6288 variables among numeric, categorical and string variables. The dataset is shared publicly on the Harvard dataverse site and provide access to questionnaires, the complete data and a brief report.

Forecasting the energy consumption of heating, ventilating, and air conditioning systems is important for the energy efficiency and sustainability of buildings. In fact, conventional models present limitations in these systems due to their complexity and unpredictability. To overcome this, the long short-term memory-based model is employed in this work. Our objective is to develop and evaluate a model to forecast the daily energy consumption of heating, ventilating, and air conditioning systems in buildings. For this purpose, we apply a comprehensive methodology that allows us to obtain a robust, generalizable, and reliable model by tuning different parameters. The results show that the proposed model achieves a significant improvement in the coefficient of variation of root mean square error of 9.5% compared to that proposed by international agencies. We conclude that these results provide an encouraging outlook for its implementation as an intelligent service for decision making, capable of overcoming the problems of other noise-sensitive models affected by data variations and disturbances without the need for expert knowledge in the domain.

This article proposes a new framework for a Cloud-based eHealth platform concept focused on Cloud computing environments, since current and emerging approaches using digital clinical history increasingly demonstrate their potential in maintaining the quality of the benefits in medical care services, especially in computer-assisted clinical diagnosis within the field of infectious diseases and due to the worsening of chronic pathologies. Our objective is to evaluate and contrast the performance of the architectural patterns most commonly used for developing eHealth applications (i.e., service-oriented architecture (SOA) and microservices architecture (MSA)), using as reference the quantitative values obtained from the various performance tests and their ability to adapt to the required software attribute (i.e., versatile high-performance). Therefore, it was necessary to modify our platform to fit two architectural variants. As a follow-up to this activity, corresponding tests were performed that showed that the MSA variant functions better in terms of performance and response time compared to the SOA variant; however, it consumed significantly more bandwidth than SOA, and scalability in SOA is generally not possible or requires significant effort to be achieved. We conclude that the implementation of SOA and MSA depends on the nature and needs of organizations (e.g., performance or interoperability).

Breast cancer is one of the most important causes of cancerrelated morbidity and mortality in the world. Probiotics, as functional food, have the potential to act against breast cancer, as evidenced by cell-based and animal model experiments. Probiotic may be useful in prevention or treatment of breast cancer by modulating the gastrointestinal bacteria and the systemic immune system. However, large-scale clinical trials and intensive research are mandatory to confirm the in vitro and in vivo results and exploring the probiotics-related metabolic, immune, and molecular mechanisms in breast cancer. This current review summarizes the available data related to probiotics and their potential role in the treatment of breast cancer.

Urbanization is one of the most significant land cover transformations, and while climate alteration is one of its most cited ecological consequences we have very limited knowledge on its effect on species’ thermal responses. We investigated whether changes in environmental thermal variability caused by urbanization influence thermal tolerance in honey bees (Apis mellifera) in a semi-arid city in central Mexico. Ambient environmental temperature and honey bee thermal tolerance were compared in urban and rural sites. Ambient temperature variability decreased with urbanization due to significantly higher nighttime temperatures in urban compared to rural sites and not from differences in maximum daily temperatures. Honey bee thermal tolerance breadth [critical thermal maxima (CTmax)—critical thermal minima (CTmin)] was narrower for urban bees as a result of differences in cold tolerance, with urban individuals having significantly higher CTmin than rural individuals, and CTmax not differing among urban and rural individuals. Honey bee body size was not correlated to thermal tolerance, and body size did not differ between urban and rural individuals. We found that honey bees’ cold tolerance is modified through acclimation. Our results show that differences in thermal variability along small spatial scales such as urban-rural gradients can influence species’ thermal tolerance breadths.

DNA damage adaptation (DDA) allows the division of cells with unrepaired DNA damage. DNA repair deficient cells might take advantage of DDA to survive. The Fanconi anemia (FA) pathway repairs DNA interstrand crosslinks (ICLs), and deficiencies in this pathway cause a fraction of breast and ovarian cancers as well as FA, a chromosome instability syndrome characterized by bone marrow failure and cancer predisposition. FA cells are hypersensitive to ICLs; however, DDA might promote their survival. We present the FA-CHKREC Boolean Network Model, which explores how FA cells might use DDA. The model integrates the FA pathway with the G2 checkpoint and the checkpoint recovery (CHKREC) processes. The G2 checkpoint mediates cell-cycle arrest (CCA) and the CHKREC activates cell-cycle progression (CCP) after resolution of DNA damage. Analysis of the FA-CHKREC network indicates that CHKREC drives DDA in FA cells, ignoring the presence of unrepaired DNA damage and allowing their division. Experimental inhibition of WIP1, a CHKREC component, in FA lymphoblast and cancer cell lines prevented division of FA cells, in agreement with the prediction of the model.

El efecto contingente de la orientación emprendedora sobre el desempeño de pequeñas empresas en ambientes hostiles Abstract The aim of this study is to analyze the effect of entrepreneurial orientation (EO), perceived as the innovative, proactive and aggressive practices of the business entrepreneur, on the performance of small businesses operating in a hostile environment of economic decline, social turbulence and natural events. A contingency view is adopted in order to determine which EO variables best explain business performance. Data collected from 101 small craft business and analyzed with factor analysis, Pearson’s bivariate correlation and hierarchical regression, indicate that small business performance depends on product innovation and proactive behavior focused on protecting market share, along with a reduced emphasis on price-based competition due to the negative impact of competitive aggressiveness on performance.

Many disease fighting strategies have focused on the generation of NK cells, since they constitute the main immune barrier against cancer and intracellular pathogens such as viruses. Therefore, a predictive model for the development of NK cells would constitute a useful tool to test several hypotheses regarding the production of these cells during both physiological and pathological conditions. Here, we present a boolean network model that reproduces experimental results reported on the literature regarding the progressive stages of the development of NK cells in wild-type and mutant backgrounds. The model allows for the simulation of different conditions, including extracellular micro-environment as well as the simulation of genetic alterations. It also describes how NK cell differentiation depends on a molecular regulatory network that controls the specification of lymphoid lineages, such as T and B cells, which share a common progenitor with NKs. Furthermore, the study shows that the structure of the regulatory network strongly determines the stability of the expression patterns against perturbations.

Precision oncology is now the evidence-based standard of care for the management of many advanced non-small cell lung cancers (NSCLC). Notably, new molecular profiling technologies have permitted dynamic growth in the identification of actionable driver oncogenes including RET rearrangements. RET oncogenes cannot be adequately detected by immunohistochemistry, although fluorescence in situ hybridization, reverse transcriptase polymerase chain reaction and next-generation sequencing are complementary diagnostic tools. In the clinical setting, the benefit of the most developed RET inhibitors, i.e., cabozantinb, vandetanib and lenvatinb, in terms of response and median progression-free survival has been demonstrated. The absence of striking clinical results of RET inhibitors underscores the clear need for development of more selective and potent RET inhibitors. This paper reviews the clinical data available on RET inhibitors in RET-associated NSCLC.

Angiogenesis is an important adaptation mechanism of the blood vessels to the changing requirements of the body during development, aging, and wound healing. Angiogenesis allows existing blood vessels to form new connections or to reabsorb existing ones. Blood vessels are composed of a layer of endothelial cells (ECs) covered by one or more layers of mural cells (smooth muscle cells or pericytes). We constructed a computational Boolean model of the molecular regulatory network involved in the control of angiogenesis. Our model includes the ANG/TIE, HIF, AMPK/mTOR, VEGF, IGF, FGF, PLCγ/Calcium, PI3K/AKT, NO, NOTCH, and WNT signaling pathways, as well as the mechanosensory components of the cytoskeleton. The dynamical behavior of our model recovers the patterns of molecular activation observed in Phalanx, Tip, and Stalk ECs. Furthermore, our model is able to describe the modulation of EC behavior due to extracellular micro-environments, as well as the effect due to loss- and gain-of-function mutations. These properties make our model a suitable platform for the understanding of the molecular mechanisms underlying some pathologies. For example, it is possible to follow the changes in the activation patterns caused by mutations that promote Tip EC behavior and inhibit Phalanx EC behavior, that lead to the conditions associated with retinal vascular disorders and tumor vascularization. Moreover, the model describes how mutations that promote Phalanx EC behavior are associated with the development of arteriovenous and venous malformations. These results suggest that the network model that we propose has the potential to be used in the study of how the modulation of the EC extracellular micro-environment may improve the outcome of vascular disease treatments.

En aves el cuidado parental durante la anidación involucra una gran inversión de energía para mantener la estabilidad térmica (homeotermia) de la progenie. Conservar la homotermia y mantener alta la temperatura en el nido se favorece por selección, al estar relacionado positivamente con el éxito de eclosión de los huevos, la sobrevivencia de los polluelos y con ello en el éxito reproductivo de los padres. En los colibríes, caracterizados por sus altos requerimientos metabólicos y un cuidado exclusivamente materno de la progenie, es factible pensar que las hembras optimizan el tiempo y energía dedicados a diferentes conductas relacionadas con el cuidado parental durante la anidación, y en particular aquellos que mantienen la homotermia del nido. En este estudio evaluamos el efecto de algunas conductas de cuidado materno en el ambiente térmico de la progenie de un nido del colibrí ermitaño cola larga (Phaethornis longirostris). Para ello utilizamos un termopar ultradelgado conectado a un termómetro electrónico con el que registramos la temperatura dentro de un nido de esta especie. Observamos que la hembra realiza salidas de forrajeo muy prolongadas, pero esto no modificó la estabilidad térmica dentro del nido, el cual mantuvo su variación en menos de 1ºC. Esto nos permite sugerir que la hembra que atendía el nido efectivamente optimizó sus conductas de cuidado parental (i.e. incubación y forrajeo), a fin de minimizar la oscilación térmica de la progenie. Sin embargo, aún es necesario evaluar la contribución de otras decisiones de la hembra relacionadas con la conducta de anidación: la forma, materiales de construcción y elección del sitio de anidación, en la homeotermia del nido.

Pregnant mares and post-weaning foals are often fed concentrates rich in soluble carbohydrates, together with forage. Recent studies suggest that the use of concentrates is linked to alterations of metabolism and the development of osteochondrosis in foals. The aim of this study was to determine if broodmare diet during gestation affects metabolism, osteoarticular status and growth of yearlings overfed from 20 to 24 months of age and/or sexual maturity in prepubertal colts.Twenty-four saddlebred mares were fed forage only (n = 12, group F) or cracked barley and forage (n = 12, group B) from mid-gestation until foaling. Colts were gelded at 12 months of age. Between 20 and 24 months of age, all yearlings were overfed (+140% of requirements) using an automatic concentrate feeder. Offspring were monitored for growth between 6 and 24 months of age, glucose homeostasis was evaluated via modified frequently sampled intra veinous glucose tolerance test (FSIGT) at 19 and 24 months of age and osteoarticular status was investigated using radiographic examinations at 24 months of age. The structure and function of testicles from prepubertal colts were analyzed using stereology and RT-qPCR.Post-weaning weight growth was not different between groups. Testicular maturation was delayed in F colts compared to B colts at 12 months of age. From 19 months of age, the cannon bone was wider in B vs F yearlings. F yearlings were more insulin resistant at 19 months compared to B yearlings but B yearlings were affected more severely by overnutrition with reduced insulin sensitivity. The osteoarticular status at 24 months of age was not different between groups.In conclusion, nutritional management of the pregnant broodmare and the growing foal may affect sexual maturity of colts and the metabolism of foals until 24 months of age. These effects may be deleterious for reproductive and sportive performances in older horses.

La literatura sobre emprendedurismo y gestión estratégica sugiere el efecto positivo de la orientación estratégica (OE) sobre el desempeño de las empresas en ambientes hostiles; no obstante, los resultados son de empresas grandes de países desarrollados; en circunstancias de estabilidad económica y social, donde el ambiente hostil se debe a factores tecnológicos, industriales o de mercado. El objetivo de este estudio es analizar el desempeño de negocios artesanales como resultado de la OE de los dueños, en un marco de crisis de deterioro económico, inestabilidad social y cambio climático en Oaxaca, México. Con base en los datos de 101 negocios artesanales, analiza dos con correlación bivariada de Pearson y regresión lineal múltiple, los resultados del estudio indican un efecto positivo de innovación y proactividad sobre el desempeño. En contra de lo esperado, se encuentra un efecto negativo de agresividad competitiva sobre el desempeño. Se concluye que, aunque los dueños de negocios artesanales se comprometen en tres dimensiones de OE para mejorar el desempeño, no todas ellas tienen efecto, ni logran modificarlo de la misma manera, debido a las condiciones contextuales.

Lineage fate decisions of hematopoietic cells depend on intrinsic factors and extrinsic signals provided by the bone marrow microenvironment, where they reside. Abnormalities in composition and function of hematopoietic niches have been proposed as key contributors of acute lymphoblastic leukemia (ALL) progression. Our previous experimental findings strongly suggest that pro-inflammatory cues contribute to mesenchymal niche abnormalities that result in maintenance of ALL precursor cells at the expense of normal hematopoiesis. Here, we propose a molecular regulatory network interconnecting the major communication pathways between hematopoietic stem and progenitor cells (HSPCs) and mesenchymal stromal cells (MSCs) within the bone marrow. Dynamical analysis of the network as a Boolean model reveals two stationary states that can be interpreted as the intercellular contact status. Furthermore, simulations describe the molecular patterns observed during experimental proliferation and activation. Importantly, our model predicts instability in the CXCR4/CXCL12 and VLA4/VCAM1 interactions following microenvironmental perturbation due by temporal signaling from Toll like receptors (TLRs) ligation. Therefore, aberrant expression of NF-κB induced by intrinsic or extrinsic factors may contribute to create a tumor microenvironment where a negative feedback loop inhibiting CXCR4/CXCL12 and VLA4/VCAM1 cellular communication axes allows for the maintenance of malignant cells.

[This corrects the article DOI: 10.1371/journal.pone.0122596.].

Terminal differentiation of B cells is an essential process for the humoral immune response in vertebrates and is achieved by the concerted action of several transcription factors in response to antigen recognition and extracellular signals provided by T-helper cells. While there is a wealth of experimental data regarding the molecular and cellular signals involved in this process, there is no general consensus regarding the structure and dynamical properties of the underlying regulatory network controlling this process. We developed a dynamical model of the regulatory network controlling terminal differentiation of B cells. The structure of the network was inferred from experimental data available in the literature, and its dynamical behavior was analyzed by modeling the network both as a discrete and a continuous dynamical systems. The steady states of these models are consistent with the patterns of activation reported for the Naive, GC, Mem, and PC cell types. Moreover, the models are able to describe the patterns of differentiation from the precursor Naive to any of the GC, Mem, or PC cell types in response to a specific set of extracellular signals. We simulated all possible single loss- and gain-of-function mutants, corroborating the importance of Pax5, Bcl6, Bach2, Irf4, and Blimp1 as key regulators of B cell differentiation process. The model is able to represent the directional nature of terminal B cell differentiation and qualitatively describes key differentiation events from a precursor cell to terminally differentiated B cells.

The objective of the current study was to formulate ketorolac tromethamine-loaded elastic liposomes and evaluate their in vitro drug release and their ex vivo and in vivo transdermal delivery. Ketorolac tromethamine (KT), which is a potent analgesic, was formulated in elastic liposomes using Tween 80 as an edge activator. The elastic vesicles were prepared by film hydration after optimizing the sonication time and number of extrusions. The vesicles exhibited an entrapment efficiency of 73 ± 11%, vesicle size of 127.8 ± 3.4 nm and a zeta potential of −12 mV. In vitro drug release was analyzed from liposomes and an aqueous solution, using Franz diffusion cells and a cellophane dialysis membrane with molecular weight cut-off of 8000 Da. Ex vivo permeation of KT across pig ear skin was studied using a Franz diffusion cell, with phosphate buffer (pH 7.4) at 32 °C as receptor solution. An in vivo drug permeation study was conducted on healthy human volunteers using a tape-stripping technique. The in vitro results showed (i) a delayed release when KT was included in elastic liposomes, compared to an aqueous solution of the drug; (ii) a flux of 0.278 mg/cm2h and a lag time of about 10 h for ex vivo permeation studies, which may indicate that KT remains in the skin (with the possibility of exerting a local effect) before reaching the receptor medium; (iii) a good correlation between the total amount permeated, the penetration distance (both determined by tape stripping) and transepidermal water loss (TEWL) measured during the in vivo permeation studies. Elastic liposomes have the potential to transport the drug through the skin, keep their size and drug charge, and release the drug into deep skin layers. Therefore, elastic liposomes hold promise for the effective topical delivery of KT.

Este trabajo tiene como objetivo analizar la relación entre ambiente hostil y desempeño en 74 negocios de artesanía. Se pone a prueba un modelo en el que se supone que las estrategias de supervivencia que utilizaron los artesanos para enfrentar un ambiente social, económica y políticamente hostil, generado por el enfrentamiento entre el gobernador Ulises Ruiz y la Asamblea Popular de los Pueblos de Oaxaca (appo), modifican la relación entre el ambiente hostil y el desempeño de los negocios de artesanía. De acuerdo a los resultados obtenidos, la crisis del sistema económico, las presiones regulatorias y la corrupción se correlacionan significativa y negativamente con el desempeño de los negocios de artesanía.

Uno de los principales objetivos de la Ingeniería del Software es producir software de calidad, en este trabajo se aplica un Modelo de Calidad en uno de los campos más delicados para el desarrollo de Sistemas como lo son las herramientas CASE, partiendo del hecho de que las herramientas CASE son un producto de software utilizado para soportar todas o casi todas las actividades involucradas en el análisis, diseño y construcción de software. Aquí se describe la concepción del Modelo de Calidad que permite evaluar y seleccionar las herramientas CASE; este modelo utilizó como recursos principales los Indicadores Tecnológicos propuestos por Rojas y Pérez y el Estándar ISO/IEC 14102. Además se detallan los resultados que arrojó la aplicación del mismo a un caso de estudio.

CD4+ T cells orchestrate the adaptive immune response in vertebrates. While both experimental and modeling work has been conducted to understand the molecular genetic mechanisms involved in CD4+ T cell responses and fate attainment, the dynamic role of intrinsic (produced by CD4+ T lymphocytes) versus extrinsic (produced by other cells) components remains unclear, and the mechanistic and dynamic understanding of the plastic responses of these cells remains incomplete. In this work, we studied a regulatory network for the core transcription factors involved in CD4+ T cell-fate attainment. We first show that this core is not sufficient to recover common CD4+ T phenotypes. We thus postulate a minimal Boolean regulatory network model derived from a larger and more comprehensive network that is based on experimental data. The minimal network integrates transcriptional regulation, signaling pathways and the micro-environment. This network model recovers reported configurations of most of the characterized cell types (Th0, Th1, Th2, Th17, Tfh, Th9, iTreg, and Foxp3-independent T regulatory cells). This transcriptional-signaling regulatory network is robust and recovers mutant configurations that have been reported experimentally. Additionally, this model recovers many of the plasticity patterns documented for different T CD4+ cell types, as summarized in a cell-fate map. We tested the effects of various micro-environments and transient perturbations on such transitions among CD4+ T cell types. Interestingly, most cell-fate transitions were induced by transient activations, with the opposite behavior associated with transient inhibitions. Finally, we used a novel methodology was used to establish that T-bet, TGF-β and suppressors of cytokine signaling proteins are keys to recovering observed CD4+ T cell plastic responses. In conclusion, the observed CD4+ T cell-types and transition patterns emerge from the feedback between the intrinsic or intracellular regulatory core and the micro-environment. We discuss the broader use of this approach for other plastic systems and possible therapeutic interventions.

In stud management, broodmares are commonly fed concentrates in late pregnancy. This practice, however, was shown to correlate with an increased incidence of osteochondrosis in foals, which may be related to insulin sensitivity. We hypothesized that supplementation of the mare with barley in the last trimester of pregnancy alters the pre-weaning foal growth, glucose metabolism and osteoarticular status. Here, pregnant multiparous saddlebred mares were fed forage only (group F, n=13) or both forage and cracked barley (group B, n=12) from the 7th month of pregnancy until term, as calculated to cover nutritional needs of broodmares. Diets were given in two daily meals. All mares and foals returned to pasture after parturition. Post-natal growth, glucose metabolism and osteoarticular status were investigated in pre-weaning foals. B mares maintained an optimal body condition score (>3.5), whereas that of F mares decreased and remained low (

HIV-1 is taken up by immature monocyte derived dendritic cells (iMDDCs) into tetraspanin rich caves from which the virus can either be transferred to T lymphocytes or enter into endosomes resulting in degradation. HIV-1 binding and fusion with the DC membrane results in low level de novo infection that can also be transferred to T lymphocytes at a later stage. We have previously reported that HIV-1 can induce partial maturation of iMDDCs at both stages of trafficking. Here we show that CD45⁺ microvesicles (MV) which contaminate purified HIV-1 inocula due to similar size and density, affect DC maturation, de novo HIV-1 infection and transfer to T lymphocytes. Comparing iMDDCs infected with CD45-depleted HIV-1BaL or matched non-depleted preparations, the presence of CD45⁺ MVs was shown to enhance DC maturation and ICAM-1 (CD54) expression, which is involved in DC∶T lymphocyte interactions, while restricting HIV-1 infection of MDDCs. Furthermore, in the DC culture HIV-1 infected (p24⁺) MDDCs were more mature than bystander cells. Depletion of MVs from the HIV-1 inoculum markedly inhibited DC∶T lymphocyte clustering and the induction of alloproliferation as well as limiting HIV-1 transfer from DCs to T lymphocytes. The effects of MV depletion on these functions were reversed by the re-addition of purified MVs from activated but not non-activated SUPT1.CCR5-CL.30 or primary T cells. Analysis of the protein complement of these MVs and of these HIV-1 inocula before and after MV depletion showed that Heat Shock Proteins (HSPs) and nef were the likely DC maturation candidates. Recombinant HSP90α and β and nef all induced DC maturation and ICAM-1 expression, greater when combined. These results suggest that MVs contaminating HIV-1 released from infected T lymphocytes may be biologically important, especially in enhancing T cell activation, during uptake by DCs in vitro and in vivo, particularly as MVs have been detected in the circulation of HIV-1 infected subjects.

En la actualidad, los Procesos de Negocio (PN) complejos son implementados por Sistemas de Información Empresariales (SIE). Sin embargo, el desarrollo de los SIE se ve dificultado sino se garantiza la confiabilidad del Modelo de Tareas (MT) de los PN. Este artículo describe el Enfoque Formal de Verificación Composicional (EFVC); una infraestructura para la especificación formal y verificación de PN, soportado por técnicas de Verificación Automática (VA). Basado en una propuesta de semántica formal temporal para la Business Process Model and Notation (BPMN) que permite obtener el MT de un proceso de negocio, el EFVC soporta la verificación del comportamiento del MT a partir de la verificación individual de sus participantes. La interpretación de los elementos notacionales de BPMN en el lenguaje formal Communicating Sequential Processes + Time (CSP+T) nos permite incorporar herramientas de VA ampliamente utilizadas para verificar el comportamiento de un MT. Se presenta un ejemplo de aplicación real en el área del Manejo de las Relaciones con el Cliente (conocido como CRM) para demostrar el uso práctico de EFVC.

Se estudió el porcentaje de metal expuesto para catalizadores de 0.24 y 0.62% en peso de Pt sobre eta-Alúmina preparados por impregnación con solución amoniacal de Nitrito Diaminplatino. Se caracterizó la superficie por quimisorción de Hidrógeno (HC), título de Oxígeno (OT) y título de Hidrógeno (HT) utilizando una técnica de pulsos desarrollada en un sistema en flujo con Ar (Linde UHP) como gas portador. Expresando el porcentaje de metal expuesto a partir de HT, se observó que éste es intensamente afectado por la temperatura de reducción y en una menor medida por el tiempo de reducción. Haciendo uso de técnicas de Desorción a Temperatura Programada (TPD) para Hidrógeno y estudiando la reacción de hidrogenación de etileno sobre catalizador saturado en Hidrógeno a temperatura ambiente, se pudo identificar la presencia de dos tipos de centros activos (tipo ï§ y ï¤), siendo el tipo ï§ el que participa principalmente en dicha reacción. Se encontró asimismo que la actividad catalítica de hidrogenación es sensible al porcentaje de metal expuesto.

Learning Management System (LMS) development has become a high priority project for educational institutions and organizations, as it provides the virtual environment for online education. Acquiring and deploying a LMS is a difficult task that involves risks related with costs and time. The goal of this research in progress is to introduce an extension in the Rational Unified Process (RUP) in order to integrate the activities of selection and evaluation of LMS into this process framework. The additions of these activities in the RUP, improve the quality of the selection process, obtaining a feasible candidate solution that ensure the exposing mismatches and negotiating tradeoffs among the critical use cases and non-functional requirements, architectural and design constraints, project management constraints and risks. These activities are inserted in the Analysis and Design Discipline during the initial stages of the project. A case study is presented, implementing and deploying a LMS in an organization.

Se estudian los cariotipos de 54 parejas con historia de aborto de repetición, hallándose una translocación y 15 casos con polimorfismos cromosómicos principalmente de los pares 1 y 9 y asociación de los pares 1 y 16. En cuatro casos, no se halló otra causa que justificase el polimorfismo ni la pareja tuvo en momento alguno gestación a término. Se discute el posible papel que los polimorfismos pueden jugar en la etiología de algunos casos de aborto habitual o iterativo.

La emocionalidad condiciona la dinámica educativa en cualquier nivel y modalidad. En tal sentido, el objetivo de estudio fue explicar la emocionalidad en los procesos formativos e-learning de los estudiantes de los programas de Maestría en Educación con mención en Lingüística y Literatura y con mención en Educación Básica de la ULEAM, Extensión El Carmen. Metodológicamente se adscribió al enfoque cualitativo y se aplicó el método fenomenológico. La información se recopiló a través de entrevistas en profundidad y grupos focales. La interpretación de la información se realizó mediante la categorización con el software Atlas.ti. Se concluyó que los sentimientos fueron configurativos de la vivencia educativa favoreciendo la transición del miedo hacia la esperanza. Además, los informantes concibieron el proceso formativo bajo la modalidad e-learning como un medio para desarrollar habilidades prácticas con más autonomía y el cual, amerita la toma de conciencia de la presencia del otro en la virtualidad.