Exploring COX-2 inhibitors in tuberculosis: A whole-blood model approach for immune response and adjunt therapy evaluation.

Pulmonary tuberculosis (TB) inflammation is an underestimated disease complication which anti-inflammatory drugs may alleviate. This study explored the potential use of the COX-2 inhibitors acetylsalicylic acid (ASA) and celecoxib in 12 TB patients and 12 healthy controls using a whole-blood ex vivo model where TNFα, PGE2, and LTB4 plasma levels were quantitated by ELISA; we also measured COX-2, 5-LOX, 12-LOX, and 15-LOX gene expression. We observed a significant TNFα production in response to stimulation with LPS or M. tuberculosis (Mtb). Celecoxib, but not ASA, reduced TNFα and PGE2 production, while increasing LTB4 in patients after infection with Mtb. Gene expression of COX-2 and 5-LOX was higher in controls, while 12-LOX was significantly higher in patients. 15-LOX expression was similar in both groups. We concluded that COX-2 inhibitors downregulate inflammation after Mtb infection, and our methodology offers a straightforward time-efficient approach for evaluating different drugs in this context. Further research is warranted to elucidate the underlying mechanisms and assess the potential clinical benefit.

Serum pro-inflammatory biomarkers associated with improvement in quality of life in pulmonary tuberculosis.

Introduction: Pulmonary dysfunction is an underestimated complication in tuberculosis (TB) infection, affecting quality of life (QoL). Although respiratory function tests objectively reflect lung disturbances in a specific moment, predictors of illness severity at the time of diagnosis are still lacking. Methods: We measured serum pro-inflammatory cytokines (TNF-α and IL-8), eicosanoids (PGE2, LTB4, RvD1, Mar1, and LXA4), a marker of tissue damage (cell-free nucleosomes), and indicators of redox status (malonaldehyde, 8-isoprostane, total oxidants, and antioxidants), as well as a score of radiological abnormalities (SRA) and a QoL questionnaire, in 25 patients with pulmonary TB at the time of diagnosis (t0) and two months after the initiation of treatment (t2). Results: We found higher antioxidant levels in the patients with the worst QoL at t0, and all the indicators of the prooxidant state were significantly reduced at t2, while the total antioxidant levels increased. LTB4, a pro-inflammatory eicosanoid, was diminished at t2, while all the pro-resolutory lipids decreased substantially. Significant correlations between the SRA and the QoL scores were observed, the latter showing a substantial reduction at t2, ranking it as a reliable tool for monitoring disease evolution during TB treatment. Discussion: These results suggest that evaluating a combination of these markers might be a valuable predictor of QoL improvement and a treatment response indicator; in particular, the oxidation metabolites and eicosanoid ratios could also be proposed as a future target for adjuvant therapies to reduce inflammation-associated lung injury in TB disease.

A Boolean network model of the double-strand break repair pathway choice.

Double strand break (DSB) repair is critical to maintaining the integrity of the genome. DSB repair deficiency underlies multiple pathologies, including cancer, chromosome instability syndromes, and, potentially, neurodevelopmental defects. DSB repair is mainly handled by two pathways: highly accurate homologous recombination (HR), which requires a sister chromatid for template-based repair, limited to S/G2 phases of the cell cycle, and canonical non-homologous end joining (c-NHEJ), available throughout the cell cycle in which minimum homology is sufficient for highly efficient yet error-prone repair. Some circumstances, such as cancer, require alternative highly mutagenic DSB repair pathways like microhomology-mediated end-joining (MMEJ) and single-strand annealing (SSA), which are triggered to attend to DNA damage. These non-canonical repair alternatives are emerging as prominent drivers of resistance in drug-based tumor therapies. Multiple DSB repair options require tight inter-pathway regulation to prevent unscheduled activities. In addition to this complexity, epigenetic modifications of the histones surrounding the DSB region are emerging as critical regulators of the DSB repair pathway choice. Modeling approaches to understanding DSBs repair pathway choice are advantageous to perform simulations and generate predictions on previously uncharacterized aspects of DSBs response. In this work, we present a Boolean network model of the DSB repair pathway choice that incorporates the knowledge, into a dynamic system, of the inter-pathways regulation involved in DSB repair, i.e., HR, c-NHEJ, SSA, and MMEJ. Our model recapitulates the well-characterized HR activity observed in wild-type cells in response to DSBs. It also recovers clinically relevant behaviors of BRCA1/FANCS mutants, and their corresponding drug resistance mechanisms ascribed to DNA repair gain-of-function pathogenic variants. Since epigenetic modifiers are dynamic and possible druggable targets, we incorporated them into our model to better characterize their involvement in DSB repair. Our model predicted that loss of the TIP60 complex and its corresponding histone acetylation activity leads to activation of SSA in response to DSBs. Our experimental validation showed that TIP60 effectively prevents activation of RAD52, a key SSA executor, and confirms the suitable use of Boolean network modeling for understanding DNA DSB repair.

In silico analysis of the interaction of de novo peptides derived from Salvia hispanica with anticancer targets.

Cancer is one of the leading causes of death worldwide. Conventional cancer therapies are not selective to cancer cells resulting in serious side effects on patients. Thus, the need for complementary treatments that improve the patient's response to cancer therapy is highly important. To predict and evaluate the physicochemical characteristics and potential anticancer activity of the peptides identified from S. hispanica protein fraction <1 kDa through the use of in silico tools. Peptides derived from Salvia hispanica's protein fraction <1 kDa were identified and analyzed for the prediction of their physicochemical properties. The characterized peptide sequences were then submitted to a multi-criteria decision analysis to identify the peptides that possess the characteristics to potentially exert anticancer activity. Through molecular docking analysis, the potential anticancer activity of the Potentially Anticancer Peptide (PAP)-1, PAP-2, PAP-3, PAP-4, and PAP-5 was estimated by their binding interactions with cancer and apoptosis-related molecules. All five evaluated PAPs exhibited strong binding interactions (< -100 kcal/mol). However, PAP-3 showed the lowest binding free energies with several of the targets. Thus, PAP-3 shows potential to be used as a nutraceutical or ingredient for functional foods that adjuvate in cancer treatment. Conclusions: Through the molecular docking studies, the binding of the PAPs to target molecules of interest for cancer treatment was successfully simulated, from which PAP-3 exhibited the lowest binding free energies. Further in vitro and in vivo studies are required to validate the predictions obtained by the in silico analysis.Communicated by Ramaswamy H. Sarma.

Identifying Barriers and Facilitators for Home Reconstruction for Prevention of Chagas Disease: An Interview Study in Rural Loja Province, Ecuador.

BACKGROUND: Chagas disease (CD) is a tropical parasitic disease spread by triatomine bugs, which are bugs that tend to infest precarious housing in rural and impoverished areas. Reducing exposure to the bugs, and thus the parasite they can carry, is essential to preventing CD in these areas. One promising long-term sustainable solution is to reconstruct precarious houses. Implementing home reconstruction requires an understanding of how householders construct barriers and facilitators they might encounter when considering whether to rebuild their homes. METHODS: To understand barriers and facilitators to home reconstruction, we performed in-depth qualitative interviews with 33 residents of Canton Calvas, Loja, Ecuador, a high-risk endemic region. Thematic analysis was used to identify these barriers and facilitators. RESULTS: The thematic analysis identified three facilitators (project facilitators, social facilitators, and economic facilitators) and two major barriers (low personal economy and extensive deterioration of existing homes). CONCLUSIONS: The study findings provide important loci for assisting community members and for agents of change in home reconstruction projects to prevent CD. Specifically, the project and social facilitators suggest that collective community efforts (minga) are more likely to support home reconstruction intentions than individualist efforts, while the barriers suggest that addressing structural issues of economy and affordability are necessary.

Hemofilia adquirida A en embarazo. Caso clínico de medicina crítica en obstetricia por morbilidad extrema y su abordaje transdisciplinario perioperatorio / Acquired hemophilia A in pregnancy. Clinical case of critical medicine in obstetrics due to extreme morbidity and its perioperative transdisciplinary approach

Resumen: La identificación de múltiples factores de riesgo que predisponen a la hemorragia durante el evento obstétrico, como la hemofilia adquirida que es un trastorno que se desarrolla por la generación de autoanticuerpos inhibidores de factores de la coagulación, la interpretación objetiva de las pruebas de laboratorio rutinarias, el desarrollo de un pensamiento sistematizado en la integración diagnóstico-terapéutica por parte del personal de salud, y la disposición de los recursos farmacológicos hospitalarios, es lo que determina frecuentemente el pronóstico en pacientes obstétricas con morbilidad extrema que requieren atención multidisciplinaria en las diferentes unidades hospitalarias del sector salud de nuestro país. El objetivo es presentar un caso clínico de morbilidad extrema por hemofilia adquirida, su presentación clínica, evolución y desenlace fatal. Se presenta un caso referido de otra unidad del Sector Salud ISEM (Instituto de Salud del Estado de México), atendido en la Unidad de Cuidados Intensivos Obstétricos del Hospital «Mónica Pretelini Sáenz¼, resaltando la importancia en la integración diagnóstico-terapéutica y la interacción multifactorial de variables relacionadas con su desenlace fatal. Conclusiones: Desconocimiento de la patología, retraso en el diagnóstico, múltiples procedimientos condicionantes de hemorragia iatrógena y la limitación en recursos terapéuticos son factores que contribuyen a un desenlace fatal.

Abstract: The identification of multiple risk factors that predispose to bleeding during the obstetric event, such as acquired hemophilia, which is a disorder that develops due to the generation of autoantibodies that inhibit coagulation factors, the objective interpretation of routine laboratory tests , the development of systematized thinking in diagnostic-therapeutic integration by health personnel, and the provision of hospital pharmacological resources, is what frequently determines the prognosis in obstetric patients with extreme morbidity who require multidisciplinary care in the different hospital units of the health sector of our country. The objective is to present a clinical case of extreme morbidity due to acquired hemophilia, its clinical presentation, evolution and fatal outcome. A case referred from another unit of the ISEM (Instituto de Salud del Estado de México) Health Sector, treated at the Obstetric Intensive Care Unit of the «Mónica Pretelini Sáenz¼ Hospital, is presented, highlighting the importance of diagnostic-therapeutic integration, and the multifactorial interaction of variables related to its fatal outcome. Conclusions: Ignorance of the pathology, delay in diagnosis, multiple conditioning procedures of iatrogenic hemorrhage and the limitation in therapeutic resources are factors that contribute to a fatal outcome.

Acute lymphoblastic leukemia-secreted miRNAs induce a proinflammatory microenvironment and promote the activation of hematopoietic progenitors.

Leukemogenesis is proposed to result from the continuous interplay between inducive bone marrow (BM) microenvironments and malignant precursor cells. Recent findings point toward an abnormal production of proinflammatory mediators within the BM from acute lymphoblastic leukemia (ALL) patients, although the mechanism underlying this phenomenon is uncertain. Here, we have identified 3 miRNAs, miR-146a-5p, miR-181b-5p, and miR-199b-3p, as potential candidates for TLR8 ligation, which are overexpressed in ALL and show agonist functional binding. When purified from ALL exosomes, they demonstrated their capacity of inducing cytokine production by both, hematopoietic and stromal BM cells. Of note, the exposure of BM cells from ALL patients to the proinflammatory milieu resulting from these miRNAs agonist activity revealed the proliferation of normal progenitors, while poor effects were recorded in the leukemic counterpart. The unconventional roles of the tumor-secreted miRNAs as TLR8 agonist ligands may provide a novel mechanism contributing a tumor-microenvironment feedback loop by switching on proinflammatory pathways that further activate normal hematopoietic precursors and support ALL progression. Secreted B-ALL TLR8-agonist miRNAs are involved in the promotion of proinflammatory microenvironments that target normal hematopoietic cells. B-lineage ALL cells secrete exosomes containing miRNAs endowed with the ability of functionally binding TLR8 in hematopoietic and BM mesenchymal stromal cells. Upon TLR8 signaling, the activation of the NF-kB pathway induces secretion of proinflammatory cytokines that, in turn, promotes cell proliferation in early hematopoietic cell populations, driving a tumor-microenvironment-hematopoietic activation feedback loop that may reduce the normal hematopoietic stem and progenitor cell compartment and facilitate cancer progression.

In Silico Drug Repositioning to Target the SARS-CoV-2 Main Protease as Covalent Inhibitors Employing a Combined Structure-Based Virtual Screening Strategy of Pharmacophore Models and Covalent Docking.

The epidemic caused by the SARS-CoV-2 coronavirus, which has spread rapidly throughout the world, requires urgent and effective treatments considering that the appearance of viral variants limits the efficacy of vaccines. The main protease of SARS-CoV-2 (Mpro) is a highly conserved cysteine proteinase, fundamental for the replication of the coronavirus and with a specific cleavage mechanism that positions it as an attractive therapeutic target for the proposal of irreversible inhibitors. A structure-based strategy combining 3D pharmacophoric modeling, virtual screening, and covalent docking was employed to identify the interactions required for molecular recognition, as well as the spatial orientation of the electrophilic warhead, of various drugs, to achieve a covalent interaction with Cys145 of Mpro. The virtual screening on the structure-based pharmacophoric map of the SARS-CoV-2 Mpro in complex with an inhibitor N3 (reference compound) provided high efficiency by identifying 53 drugs (FDA and DrugBank databases) with probabilities of covalent binding, including N3 (Michael acceptor) and others with a variety of electrophilic warheads. Adding the energy contributions of affinity for non-covalent and covalent docking, 16 promising drugs were obtained. Our findings suggest that the FDA-approved drugs Vaborbactam, Cimetidine, Ixazomib, Scopolamine, and Bicalutamide, as well as the other investigational peptide-like drugs (DB04234, DB03456, DB07224, DB7252, and CMX-2043) are potential covalent inhibitors of SARS-CoV-2 Mpro.

mHealth Apps for Self-Management of Cardiovascular Diseases: A Scoping Review.

The use of mHealth apps for the self-management of cardiovascular diseases (CVDs) is an increasing trend in patient-centered care. In this research, we conduct a scoping review of mHealth apps for CVD self-management within the period 2014 to 2021. Our review revolves around six main aspects of the current status of mHealth apps for CVD self-management: main CVDs managed, main app functionalities, disease stages managed, common approaches used for data extraction, analysis, management, common wearables used for CVD detection, monitoring and/or identification, and major challenges to overcome and future work remarks. Our review is based on Arksey and O'Malley's methodological framework for conducting studies. Similarly, we adopted the PRISMA model for reporting systematic reviews and meta-analyses. Of the 442 works initially retrieved, the review comprised 38 primary studies. According to our results, the most common CVDs include arrhythmia (34%), heart failure (32%), and coronary heart disease (18%). Additionally, we found that the majority mHealth apps for CVD self-management can provide medical recommendations, medical appointments, reminders, and notifications for CVD monitoring. Main challenges in the use of mHealth apps for CVD self-management include overcoming patient reluctance to use the technology and achieving the interoperability of mHealth applications with other systems.

Three-Dimensional Additive Manufacturing of Artificial Oil Reservoir Rock Core Plugs for Core Flooding Experimental Tests.

Laboratory tests in which a fluid or combination of fluids that are injected into a core rock are designed to determine oil reservoir rock petrophysical properties, understand the mobility of fluid flow in the porous samples, and calibrate porous media fluid flow models. The core material is extracted from the oil reservoir. However, the manufacture of core plugs is challenging because of the complexity of extracting natural rocks from the reservoir and their morphological and atypical heterogeneity. In addition, core flooding tests are essentially destructive, making it impossible to achieve experimental repeatability by using identical cores. The use of 3D printing in digital rock physics has permitted the production and replication of synthetic rock samples with the morphological characteristics of natural rocks for core analysis and core flooding tests. This study proposes the 3D manufacture of artificial core plugs from microcomputed tomography of Berea sandstone. The digital samples were constructed using a digital particle packing approach by systematically manipulating rock textural parameters, such as the grain size and shape, cementation pattern, and sorting grain, making it possible to obtain a core plug that fulfills experimental requirements. Before the 3D printing of the sample, the flow distribution through the porous media structure was numerically simulated using the Lattice Boltzmann method to obtain the core plug samples' permeability and porosity. The core plug was digitally embedded within a core holder to generate a stereolithography file for 3D printing of the core flooding setup, which can be used directly in conventional experiments. The permeabilities of the 3D printed plugs were experimentally determined to permit a direct comparison to the numerical results and evaluate the utility of printed plugs for displacement experiments.

Sweet Syndrome in an Adolescent Patient With Differentiation Syndrome Secondary to Promyelocytic Leukemia Treatment With All-Trans Retinoic Acid.

Sweet syndrome (SS) is an acute febrile neutrophilic dermatosis that is histologically characterized by an infiltration of the dermis by neutrophils. A 12-year-old adolescent female patient recently diagnosed with acute promyelocytic leukemia presented with fever and was hospitalized for antibiotic management after 22 days of being treated with a treatment protocol based on daunorubicin, all-trans retinoic acid (ATRA), and prophylaxis with dexamethasone, the patient developed erythematous skin lesions located mostly on the extremities. Lesions evolved into painful subcutaneous nodules, and one lesion evolved into a 2.5-cm blister with a purple and necrotic base. A skin biopsy was performed and showed neutrophilic dermatosis which confirmed the diagnosis of SS. The patient's clinical features complied with criteria for differentiation syndrome complicated by shock. Two days after ATRA was suspended, the patient presented resolution of the fever and skin lesions. SS is a rare neutrophilic dermatosis secondary to an innate immune disorder classified into four categories: classical (idiopathic), para-inflammatory, paraneoplastic or pregnancy-related. SS has been described in patients with acute myeloid leukemia in adults secondary to the use of drugs such as ATRA or as a part of a paraneoplastic syndrome. SS can occur exceptionally in children with myeloid leukemia secondary to the use of drugs such as ATRA.

Continuous Modeling of T CD4 Lymphocyte Activation and Function.

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.

Roles del docente en la evaluación formativa / Teacher´s roles in formative assessment

RESUMEN Introducción: desde hace algunos años existe un creciente interés por la evaluación formativa, el empoderamiento de sus conceptos y las diferentes estrategias para su aplicación; no obstante, los roles que debe cumplir el docente en su aplicación son fundamentales para lograr efectividad, y siguen siendo objeto de diversas opiniones. Objetivo: identificar algunos roles del docente en la implementación de la evaluación formativa para mejorar los aprendizajes. Métodos: se ejecutó la revisión sistemática de la bibliografía para desarrollar un análisis crítico-reflexivo del contenido de documentos, se tomaron en cuenta tesis de doctorado, maestrías, artículos originales, de revisión y editoriales publicados desde 2010 a 2019 en castellano. La búsqueda fue realizada en las bases de datos SciELO y Google Académico de septiembre a diciembre de 2019; las palabras clave utilizadas fueron: "evaluación educacional", "procesos evaluativos" y "rol docente". Tras la identificación de los estudios preseleccionados, se llevó a cabo la lectura de los títulos, resúmenes y palabras clave para comprobar la pertinencia con el estudio. Resultados: la revisión de los diferentes documentos señalados permitió identificar cinco roles del docente en la implementación de la evaluación formativa: planificar los procesos evaluativos, socializar la evaluación, analizar las evidencias, retroalimentar y reajustar la praxis, los que fueron argumentados metodológicamente. Conclusiones: aunque el éxito de la evaluación formativa depende de los componentes personales del proceso docente educativo, sí corresponde al docente cumplir determinados roles para asegurar su eficacia.

ABSTRACT Introduction: for some years there has been a growing interest in formative evaluation, the empowerment of its concepts and the different strategies for its application; however, the roles that the teacher must fulfill in its application are fundamental to achieve effectiveness, and they continue to be the subject of different opinions. Objective: to identify some roles of the teacher in the implementation of formative assessment to improve learning. Methods: a systematic review of the bibliography was carried out to develop a critical-reflective analysis of the content of documents; doctoral theses, master's degrees, original, review and editorial articles published from 2010 to 2019 in Spanish were taken into account. The search was carried out in the SciELO and Google Academic databases from September to December 2019; the keywords used were: "educational evaluation", "evaluation processes" and "teaching role". After the identification of the preselected studies, the titles, abstracts and keywords were read to check their relevance to the study. Results: the review of the different documents indicated allowed identifying five roles of the teacher in the implementation of the formative evaluation: planning the evaluation processes, socializing the evaluation, analyzing the evidence, providing feedback and readjusting the praxis, which were methodologically argued. Conclusions: although the success of the formative assessment depends on the personal components of the educational teaching process, it does correspond to the teacher to fulfill certain roles to ensure its effectiveness.

Influence of adjuvants on the amount, specificity and functional activity of antibody response to human influenza vaccine in mice.

It's been almost a century since immunologists started using adjuvants as tools to develop more effective vaccines. Despite the rising number of adjuvanted vaccines in the last decades, we still lack knowledge of the adjuvants' effects on antibody response. This study was aimed to test the effect of immunizing mice with the human Inactivated Influenza vaccine (IIV), either alone or combined with different widely used adjuvants on the specific antibody response induced. Differential levels of IgM and IgG subclasses were found with the different adjuvants tested. Higher levels of antibodies did not always correspond with a higher efficacy to interfere with the virus infectivity. Differences in neutralization properties are possibly mediated by the specificity of the repertoire of antibodies induced. The repertoire was studied using a phage display 7-mer peptide library to screen for epitopes/mimotopes recognized by serum pools from vaccinated mice. The selected phage clones included peptides that corresponded to conformational mimotopes since they have no homology with lineal sequences of the Influenza strains' proteins. Five peptides were identified as recognized by sera from mice immunized with the IIV vaccine alone, including peptides from the hemagglutinin stalk domain, and by sera from mice immunized with the vaccine plus the different adjuvants employed. Adjuvants elicited a more diverse repertoire of epitope-recognizing antibodies that recognized epitopes of the HA recombinant globular head. Mimotopes were theoretically located at the neutralizing antigenic sites of the globular head of Influenza A H1N1pdm09, Influenza A H3N2, and Influenza B hemagglutinin. This study illustrates how different adjuvants can modify the extent and quality of humoral immunity against the IIV vaccine and the effectiveness of vaccination.

Statistical Assessment of Discrimination Capabilities of a Fractional Calculus Based Image Watermarking System for Gaussian Watermarks.

In this paper, we explore the advantages of a fractional calculus based watermarking system for detecting Gaussian watermarks. To reach this goal, we selected a typical watermarking scheme and replaced the detection equation set by another set of equations derived from fractional calculus principles; then, we carried out a statistical assessment of the performance of both schemes by analyzing the Receiver Operating Characteristic (ROC) curve and the False Positive Percentage (FPP) when they are used to detect Gaussian watermarks. The results show that the ROC of a fractional equation based scheme has 48.3% more Area Under the Curve (AUC) and a False Positives Percentage median of 0.2% whilst the selected typical watermarking scheme has 3%. In addition, the experimental results suggest that the target applications of fractional schemes for detecting Gaussian watermarks are as a semi-fragile image watermarking systems robust to Gaussian noise.

Notas sobre los factores naturales y culturales en el desarrollo sociopolítico prehispánico en el extremo noroeste de Guanacaste, Costa Rica / Notes on natural and cultural factors in the pre-Hispanic sociopolitical development of the northwest of Guanacaste, Costa Rica

Introducción: El estudio interdisciplinario de los patrones de ocupación y desarrollo de la sociedad humana en tiempos prehispánicos es tenue en la zona del volcán Orosí. El contexto ambiental es usualmente descrito para ilustrar patrones de subsistencia, sin mayor propósito de establecer formas de relación con los cambios que se vislumbran en la composición sociopolítica de los pobladores. Objetivo: En este trabajo, se explora la posibilidad de ilustrar instancias de relación entre los cambios que detecta el registro arqueológico, con potenciales factores naturales y culturales, según se destacan en los aportes de otras disciplinas científicas. Métodos: Una muestra de 111 componentes culturales identificados en sitios arqueológicos fue examinada en cuanto a su localización geográfica en diversos ecosistemas y su posición cronológica, respecto de los períodos culturales definidos en la región de Guanacaste. Resultados: Los componentes arqueológicos se confrontan con diversos factores naturales y culturales que habría incidido como agentes de cambio. Se analizaron las instancias de relación y se valoraron sus efectos por períodos, cubriendo tiempos precerámicos y cerámicos. Conclusiones: Se identifica como agentes naturales de cambio a la calidad de suelos, el tipo de clima, pero, ante todo, destacan los procesos culturales como el intercambio de productos, desarrollo de la agricultura y los movimientos migratorios de la población.

Introduction: Interdisciplinary studies on ancient occupation patterns and the development of human society in the Orosí Volcano region are few. Environmental data are included in archaeological studies of specific sites, mainly to illustrate the likely availability of local subsistence resources, with little regard for biodiversity linked to altitude and an array of different geomorphic areas. Effects surging from volcanic activity and tectonics are largely dispensed. Incidence of all these natural phenomena is rarely considered as agents of sociopolitical changes. Objective: Herein a search is performed in order to detect and illustrate instances of the relationship between sociopolitical change detected by archaeology and diverse natural and cultural factors as described by other scientific disciplines. Methods: A sample of 111 cultural components in archaeological sites were examined in terms of their geographical location, ecological context and chronological position along the periods of the cultural sequence in the Guanacaste region. Results: As settlement models, the archaeological data are confronted with diverse natural and cultural factors looking for their potential incidence as agents for sociopolitical change. Instances of relationship are examined and their apparent effects are evaluated for each period, both in preceramic and ceramic times. Conclusions: Both soil quality and climate are identified as important factors for change and development. Yet, largely salient are distinct cultural factors, namely the exchange of products, agriculture and migration processes.

Dynamical modeling predicts an inflammation-inducible CXCR7+ B cell precursor with potential implications in lymphoid blockage pathologies.

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.

Recent Advances in Micro-Electro-Mechanical Devices for Controlled Drug Release Applications.

In recent years, controlled release of drugs has posed numerous challenges with the aim of optimizing parameters such as the release of the suitable quantity of drugs in the right site at the right time with the least invasiveness and the greatest possible automation. Some of the factors that challenge conventional drug release include long-term treatments, narrow therapeutic windows, complex dosing schedules, combined therapies, individual dosing regimens, and labile active substance administration. In this sense, the emergence of micro-devices that combine mechanical and electrical components, so called micro-electro-mechanical systems (MEMS) can offer solutions to these drawbacks. These devices can be fabricated using biocompatible materials, with great uniformity and reproducibility, similar to integrated circuits. They can be aseptically manufactured and hermetically sealed, while having mobile components that enable physical or analytical functions together with electrical components. In this review we present recent advances in the generation of MEMS drug delivery devices, in which various micro and nanometric structures such as contacts, connections, channels, reservoirs, pumps, valves, needles, and/or membranes can be included in their design and manufacture. Implantable single and multiple reservoir-based and transdermal-based MEMS devices are discussed in terms of fundamental mechanisms, fabrication, performance, and drug release applications.

Decision support system for NPK fertilization: a solution method for minimizing the impact on human health, climate change, ecosystem quality and resources.

Sugarcane cultivation requires correct fertilizer rates. However, when nutrients are not available, or there is over-fertilization, the yields are significantly reduced and the environmental burden increase. In this study, it is proposed a decision support system (DSS) for the correct NPK (nitrogen, phosphorus and potassium) fertilization. The DSS consists of two fuzzy models; the edaphic condition model (EDC-M) and the NPK fertilization model (NPK-M). The DSS using parameters from soil analysis and is based on the experience of two groups of experts to avoid the bias to the reality of a single group of professionals. The results of the DSS are compared with the results of soil analysis and those of the group of experts. One hundred and sixty tests were developed in the NPK-M. The N rate shows R 2=0.981 for the DSS and R 2=0.963 for soil analyzes. The P rate shows R 2=0.9702 for the DSS and R 2=0.9183 for the soil analyzes. The K rate shows R 2=0.9691 for the DSS and R 2=0.9663 for the soil analyzes. Environmental results indicate that the estimated rates with the DSS do reduce the environmental impact on the tests performed.

An Integrative Network Modeling Approach to T CD4 Cell Activation.

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.