Reverse-engineering biological networks from large data sets

Much of contemporary systems biology owes its success to the abstraction of a network, the idea that diverse kinds of molecular, cellular, and organismal species and interactions can be modeled as relational nodes and edges in a graph of dependencies. Since the advent of high-throughput data-acquisition technologies in fields such as genomics, metabolomics, and neuroscience, the automated inference and reconstruction of such interaction networks directly from large sets of activation data, commonly known as reverse-engineering, has become a routine procedure. Whereas early attempts at network reverse-engineering focused predominantly on producing maps of system architectures with minimal predictive modeling, reconstructions now play instrumental roles in answering questions about the statistics and dynamics of the underlying systems they represent. Many of these predictions have clinical relevance, suggesting novel paradigms for drug discovery and disease treatment. While other reviews focus predominantly on the details and effectiveness of individual network inference algorithms, here we examine the emerging field as a whole. We first summarize several key application areas in which inferred networks have made successful predictions. We then outline the two major classes of reverse-engineering methodologies, emphasizing that the type of prediction that one aims to make dictates the algorithms one should employ. We conclude by discussing whether recent breakthroughs justify the computational costs of large-scale reverse-engineering sufficiently to admit it as a mainstay in the quantitative analysis of living systems.Fil: Natale, Joseph J.. University of Emory; Estados UnidosFil: Hofmann, David. University of Emory; Estados UnidosFil: Hernández Lahme, Damián Gabriel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Patagonia Norte; Argentina. Comisión Nacional de Energía Atómica. Gerencia del Area de Investigación y Aplicaciones No Nucleares. Gerencia de Física (Centro Atómico Bariloche); Argentina. University of Emory; Estados UnidosFil: Nemenman, Ilya. University of Emory; Estados Unido

Importaciones de granos básicos y precio interno en México: un enfoque de sistema de demanda inverso

In this article, the reducing effect of imports on prices of five basic products is estimated: rice (Oryza sativa), bean (Phaseolus vulgaris), maize (Zea mays), sorghum (Sorghum spp.), and wheat (Triticum aestivum). After applying an inverse-demand system, the results show that this effect is lower than one, in proportional terms, and therefore a policy of price regulations based on imports turns out to be costly in expenditure.En este artículo se estima el efecto reductor de importaciones en los precios de cinco productos básicos: arroz (Oryza sativa), frijol (Phaseolus vulgaris), maíz (Zea mays), sorgo (Sorghum spp.) y trigo (Triticum aestivum). Después de aplicar un sistema de demanda inverso, los resultados muestran que, en términos proporcionales, dicho efecto es menor que uno, por tanto una política de regulación de precios basada en importaciones resulta costosa en gasto

A framework for studying behavioral evolution by reconstructing ancestral repertoires

Although extensive behavioral changes often exist between closely related animal species, our understanding of the genetic basis underlying the evolution of behavior has remained limited. Here, we propose a new framework to study behavioral evolution by computational estimation of ancestral behavioral repertoires. We measured the behaviors of individuals from six species of fruit flies using unsupervised techniques and identified suites of stereotyped movements exhibited by each species. We then fit a Generalized Linear Mixed Model to estimate the suites of behaviors exhibited by ancestral species, as well as the intra- and inter-species behavioral covariances. We found that much of intraspecific behavioral variation is explained by differences between individuals in the status of their behavioral hidden states, what might be called their "mood." Lastly, we propose a method to identify groups of behaviors that appear to have evolved together, illustrating how sets of behaviors, rather than individual behaviors, likely evolved. Our approach provides a new framework for identifying co-evolving behaviors and may provide new opportunities to study the genetic basis of behavioral evolution

A framework for studying behavioral evolution by reconstructing ancestral repertoires

Although different animal species often exhibit extensive variation in many behaviors, typically scientists examine one or a small number of behaviors in any single study. Here, we propose a new framework to simultaneously study the evolution of many behaviors. We measured the behavioral repertoire of individuals from six species of fruit flies using unsupervised techniques and identified all stereotyped movements exhibited by each species. We then fit a Generalized Linear Mixed Model to estimate the intra-and inter-species behavioral covariances, and, by using the known phylogenetic relationships among species, we estimated the (unobserved) behaviors exhibited by ancestral species. We found that much of intra-specific behavioral variation has a similar covariance structure to previously described long-time scale variation in an individual’s behavior, suggesting that much of the measured variation between individuals of a single species in our assay reflects differences in the status of neural networks, rather than genetic or developmental differences between individuals. We then propose a method to identify groups of behaviors that appear to have evolved in a correlated manner, illustrating how sets of behaviors, rather than individual behaviors, likely evolved. Our approach provides a new framework for identifying co-evolving behaviors and may provide new opportunities to study the mechanistic basis of behavioral evolution.Fil: Hernández Lahme, Damián Gabriel. University of Emory; Estados Unidos. Comisión Nacional de Energía Atómica. Gerencia del Área de Energía Nuclear. Instituto Balseiro; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Patagonia Norte; ArgentinaFil: Rivera, Catalina. University of Emory; Estados UnidosFil: Cande, Jessica. Howard Hughes Medical Institute; Estados UnidosFil: Zhou, Baohua. University of Yale; Estados Unidos. University of Emory; Estados UnidosFil: Stern, David L.. Howard Hughes Medical Institute; Estados UnidosFil: Berman, Gordon J.. University of Emory; Estados Unido

Áreas potenciales para plantaciones de Agave angustifolia Haw en Guerrero, México

Objective: To determine optimum and suboptimal areas for the establishment of plantations of Agave angustifolia Haw. in the state of Guerrero. Design/methodology/approach: A collection of 139 specimens of A. angustifolia was carried out, obtaining for each specimen phenotypic, agroclimatic and agroecological data. The information of 30 specimens of herbarium was consulted. Interviews were conducted with the representatives of the state council of mezcal in Guerrero, the company Sanzekan Tinemi and Mezcalli del Sur, to complement the information of the areas. A database was created where the information of each copy was included, as well as the information obtained from the interviews. Criteria for selecting potential areas of A. angustifoliawere defined, after which a Geographic Information Systems (GIS) was constructed, generating mapping areas with agroclimatic and agro potential, wherein the optimal suboptimal and marginal areas for the establishment of A. angustifolia were delineated. For the validation of the information, field visits were made to specific sites to verify the agroecological conditions of the potential areas obtained in this research. Results: There are approximately 1,020,998.27 ha with optimum aptitude and 618,015.87 ha with suboptimal aptitude. Limitations on study/implications: We suggest to incorporate information referring to the physiology, productivity and genetic diversity of the native populations of A. angustifolia. Findings/conclusions: The regions with the highest and suboptimal potential for the plantations of A. angustifolia are Norte, Tierra Caliente and Centro, where the largest production of mezcal in the state occurs.  Objetivo: Determinar áreas optimas y subóptimas para establecer plantaciones de Agave angustifolia Haw. en el estado de Guerrero, México. Diseño/metodología/aproximación: Se recolectaron 139 ejemplares de A. angustifolia, para cada ejemplar se registraron datos fenotípicos, agroclimáticos y agroecológicos. Se consultó la información de 30 ejemplares de herbario; además se entrevistaron a los representantes del Consejo Estatal del Mezcal en Guerrero, la empresa Sanzekan Tinemi y la empresa Mezcalli del Sur, para complementar la información de las áreas. Se generó una base de datos donde se incluyó la información de cada ejemplar, así como la obtenida de entrevistas. Se definieron criterios para la selección de áreas potenciales de A. angustifolia, después de lo cual se construyó un Sistema de Información Geográfica (SIG),generando la cartografía de las áreas con potencial agroclimático y agroecológico, donde se delimitaron las áreas optimas, subóptimas y marginales, para el establecimiento de A. angustifolia. Para la validación de la información, se realizaron visitas de campo a sitios específicos para verificar las condiciones agroecológicas de las áreas potenciales obtenidas en el presente trabajo. Resultados: Los resultados indican que existen aproximadamente 1,020,998.27 ha con aptitud óptima y 618,015.87 ha con aptitud subóptima. Limitaciones del estudio/implicaciones: se sugiere incorporar información referente a la fisiología, productividad y diversidad genética de las poblaciones nativas de A. angustifolia. Hallazgos/conclusiones: Las regiones con mayor potencial optimo y subóptimo para las plantaciones de A. angustifolia son Norte, Tierra Caliente y Centro, donde además se presenta la mayor producción de mezcal en el estado

Optimization of Mesenchymal Stromal Cell (MSC) Manufacturing Processes for a Better Therapeutic Outcome

MSCs products as well as their derived extracellular vesicles, are currently being explored as advanced biologics in cell-based therapies with high expectations for their clinical use in the next few years. In recent years, various strategies designed for improving the therapeutic potential of mesenchymal stromal cells (MSCs), including pre-conditioning for enhanced cytokine production, improved cell homing and strengthening of immunomodulatory properties, have been developed but the manufacture and handling of these cells for their use as advanced therapy medicinal products (ATMPs) remains insufficiently studied, and available data are mainly related to non-industrial processes. In the present article, we will review this topic, analyzing current information on the specific regulations, the selection of living donors as well as MSCs from different sources (bone marrow, adipose tissue, umbilical cord, etc.), in-process quality controls for ensuring cell efficiency and safety during all stages of the manual and automatic (bioreactors) manufacturing process, including cryopreservation, the use of cell banks, handling medicines, transport systems of ATMPs, among other related aspects, according to European and US legislation. Our aim is to provide a guide for a better, homogeneous manufacturing of therapeutic cellular products with special reference to MSCsThis manuscript has been supported by the Instituto de Salud Carlos III (ISCIII) through the project “RD16/0011: Red de Terapia Celular” (Groups: 0001, 0002, 0004, 0005, 0013, 0015, and 0029), fromthe sub-programme RETICS, integrated in the “Plan Estatal de I+D+I 2013-2016” and co-financed by the European Regional Development Fund (ERDF) “A way to make Europe”, and also by the ISCIII through the project RICORS “RD21/0017;TERAV” (Groups: 001, 002, 003, 006, 009 and 010) that is supported by the Next Generation EU program (Plan de Recuperación, Transformación y Resiliencia); and the Regional Government of Madrid (S2017/BMD-3962, Avancell-CM

Human fibroblast and stem cell resource from the Dominantly Inherited Alzheimer Network

BACKGROUND: Mutations in amyloid precursor protein (APP), presenilin 1 (PSEN1) and presenilin 2 (PSEN2) cause autosomal dominant forms of Alzheimer disease (ADAD). More than 280 pathogenic mutations have been reported in APP, PSEN1, and PSEN2. However, understanding of the basic biological mechanisms that drive the disease are limited. The Dominantly Inherited Alzheimer Network (DIAN) is an international observational study of APP, PSEN1, and PSEN2 mutation carriers with the goal of determining the sequence of changes in presymptomatic mutation carriers who are destined to develop Alzheimer disease. RESULTS: We generated a library of 98 dermal fibroblast lines from 42 ADAD families enrolled in DIAN. We have reprogrammed a subset of the DIAN fibroblast lines into patient-specific induced pluripotent stem cell (iPSC) lines. These cells were thoroughly characterized for pluripotency markers. CONCLUSIONS: This library represents a comprehensive resource that can be used for disease modeling and the development of novel therapeutics

Adipose-derived mesenchymal stromal cells for the treatment of patients with severe SARS-CoV-2 pneumonia requiring mechanical ventilation. A proof of concept study

Background: Identification of effective treatments in severe cases of COVID-19 requiring mechanical ventilation represents an unmet medical need. Our aim was to determine whether the administration of adipose-tissue derived mesenchymal stromal cells (AT-MSC) is safe and potentially useful in these patients. Methods: Thirteen COVID-19 adult patients under invasive mechanical ventilation who had received previous antiviral and/or anti-inflammatory treatments (including steroids, lopinavir/ritonavir, hydroxychloroquine and/or tocilizumab, among others) were treated with allogeneic AT-MSC. Ten patients received two doses, with the second dose administered a median of 3 days (interquartile range-IQR- 1 day) after the first one. Two patients received a single dose and another patient received 3 doses. Median number of cells per dose was 0.98 × 106 (IQR 0.50 × 106) AT-MSC/kg of recipient's body weight. Potential adverse effects related to cell infusion and clinical outcome were assessed. Additional parameters analyzed included changes in imaging, analytical and inflammatory parameters. Findings: First dose of AT-MSC was administered at a median of 7 days (IQR 12 days) after mechanical ventilation. No adverse events were related to cell therapy. With a median follow-up of 16 days (IQR 9 days) after the first dose, clinical improvement was observed in nine patients (70%). Seven patients were extubated and discharged from ICU while four patients remained intubated (two with an improvement in their ventilatory and radiological parameters and two in stable condition). Two patients died (one due to massive gastrointestinal bleeding unrelated to MSC therapy). Treatment with AT-MSC was followed by a decrease in inflammatory parameters (reduction in C-reactive protein, IL-6, ferritin, LDH and d-dimer) as well as an increase in lymphocytes, particularly in those patients with clinical improvement. Interpretation: Treatment with intravenous administration of AT-MSC in 13 severe COVID-19 pneumonia under mechanical ventilation in a small case series did not induce significant adverse events and was followed by clinical and biological improvement in most subjects. Funding: None.We would like to acknowledge the Instituto de Salud Carlos III (ISCIII) through the project “RD16/0011: Red de Terapia Celular”, from the sub-program RETICS, integrated in the “Plan Estatal de I+D+I 2013-2016” and co-financed by the European Regional Development Fund “A way to make Europe”, groups RD16/0011/0001, -/0002, -/005, -/0013, -/0015, -/0029), the Centro en Red de Medicina Regenerativa y Terapia Celular de Castilla y León, Spain and AvanCell-CM (Red de Investigación de Terapia Celular de la Comunidad de Madrid, Spain), for supporting some personnel and networking activities

Desert dust outbreak in the Canary Islands (February 2020): assessment and impacts

World Weather Research Programme (WWRP 2021–1