Desarrollo de una plataforma computacional para el modelado metabólico de microorganismos

La Biología Sintética (BS) se centra en el diseño y la construcción de sistemas genéticos artificiales, capaces de desarrollar una función específica después de haber sido introducidos en un sistema vivo. Con el desarrollo de la BS, se observa una nueva generación de bioingenieros que desarrollan complejos circuitos biológicos genéticos con un alto nivel de integración. La mejora de esta disciplina científica tiene por objeto establecer un marco computacional y conceptual que dé asistencia al desarrollo de sistemas biológicos artificiales modulares basándose en una metodología ingenieril y sistemática, para lo que se necesita proveer a la próxima generación de diseñadores en Biología Sintética y a los futuros biotecnólogos e ingenieros biológicos de nuevas herramientas computacionales integradas en un entorno común para el análisis de fenotipos metabólicos, el diseño de nuevos circuitos genéticos complejos y la visualización de mapas metabólicos. Como resultado de esta investigación se obtiene la plataforma Hydra (Hybrid Draw and Routes Analysis), que integra diversas herramientas para el diseño, análisis y visualización de las redes metabólicas.Synthetic biology focuses on the design and construction of artificial genetic systems that are capable of carrying out a specific function after being inserted into a living system. With the development of synthetic biology a new generation of bioengineers has appeared who develop complex, highly integrated genetic biological pathways. The improvement of this scientific discipline aims to establish a computational and conceptual framework that will support the development of modular artificial biological systems based on an engineering and systematic methodology. To achieve this, it will be necessary to provide new integrated computational tools in a common environment for the analysis of metabolic phenotypes, the design of new complex genetic pathways and the visualisation of metabolic maps to the next generation of designers in synthetic biology and future biotechnologists and biological engineers. A result of this research is the Hydra platform (Hybrid Draw and Routes Analysis) that integrates various tools for the design, analysis, and visualisation of metabolic networks.Ciencias Experimentale

Distribution and outcomes of a phenotype-based approach to guide COPD management: Results from the CHAIN cohort

Rationale: The Spanish guideline for COPD (GesEPOC) recommends COPD treatment according to four clinical phenotypes: non-exacerbator phenotype with either chronic bronchitis or emphysema (NE), asthma-COPD overlap syndrome (ACOS), frequent exacerbator phenotype with emphysema (FEE) or frequent exacerbator phenotype with chronic bronchitis (FECB). However, little is known on the distribution and outcomes of the four suggested phenotypes. Objective: We aimed to determine the distribution of these COPD phenotypes, and their relation with one-year clinical outcomes. Methods: We followed a cohort of well-characterized patients with COPD up to one-year. Baseline characteristics, health status (CAT), BODE index, rate of exacerbations and mortality up to one year of follow-up were compared between the four phenotypes. Results: Overall, 831 stable COPD patients were evaluated. They were distributed as NE, 550 (66.2%); ACOS, 125 (15.0%); FEE, 38 (4.6%); and FECB, 99 (11.9%); additionally 19 (2.3%) COPD patients with frequent exacerbations did not fulfill the criteria for neither FEE nor FECB. At baseline, there were significant differences in symptoms, FEV1 and BODE index (all p<0.05). The FECB phenotype had the highest CAT score (17.1±8.2, p<0.05 compared to the other phenotypes). Frequent exacerbator groups (FEE and FECB) were receiving more pharmacological treatment at baseline, and also experienced more exacerbations the year after (all p<0.05) with no differences in one-year mortality. Most of NE (93%) and half of exacerbators were stable after one year. Conclusions: There is an uneven distribution of COPD phenotypes in stable COPD patients, with significant differences in demographics, patient-centered outcomes and health care resources use

Determinants of penetrance and variable expressivity in monogenic metabolic conditions across 77,184 exomes

Hundreds of thousands of genetic variants have been reported to cause severe monogenic diseases, but the probability that a variant carrier develops the disease (termed penetrance) is unknown for virtually all of them. Additionally, the clinical utility of common polygenetic variation remains uncertain. Using exome sequencing from 77,184 adult individuals (38,618 multi-ancestral individuals from a type 2 diabetes case-control study and 38,566 participants from the UK Biobank, for whom genotype array data were also available), we apply clinical standard-of-care gene variant curation for eight monogenic metabolic conditions. Rare variants causing monogenic diabetes and dyslipidemias display effect sizes significantly larger than the top 1% of the corresponding polygenic scores. Nevertheless, penetrance estimates for monogenic variant carriers average 60% or lower for most conditions. We assess epidemiologic and genetic factors contributing to risk prediction in monogenic variant carriers, demonstrating that inclusion of polygenic variation significantly improves biomarker estimation for two monogenic dyslipidemias

Volumetric power input as a reliable parameter for scale-up from shake flask to stirred-tank bioreactor: Production of a recombinant glycoprotein by Streptomyces lividans

The filamentous morphology of Streptomyces lividans depends on the culture conditions, affecting the production, secretion and post-translational modifications of recombinant glycoproteins. In this work, the previously reported volumetric power input (P/V) in conventional (NF) and coiled (CF) shake flasks were scaled-up to a stirred bioreactor. The effects on the growth and morphology of S. lividans were analyzed, as well as, the production and O-mannosylation of the recombinant APA glycoprotein from Mycobacterium tuberculosis. Specific growth rates of 5. lividans and similar recombinant glycoprotein (rAPA) yields were observed between NF and bioreactor cultures. In addition, we have found up to seven mannose residues attached to the C-terminal of the rAPA in bioreactor cultures, one more than in NF and CF. However, at similar P/V values, morphological and kinetic differences were found. Our data indicate that P/V as scale-up criteria in the production of recombinant glycoproteins in S. lividans can be successful in some, but not all the kinetic and stoichiometric parameters, suggesting that the metabolic cell responses can be affected by aeration/hydrodynamics between bioreactor and shake flasks. © 2019, Universidad Autonoma Metropolitana Iztapalapa. All rights reserved

Volumetric power input as a reliable parameter for scale-up from shake flask to stirred-tank bioreactor: Production of a recombinant glycoprotein by Streptomyces lividans

The filamentous morphology of Streptomyces lividans depends on the culture conditions, affecting the production, secretion and post-translational modifications of recombinant glycoproteins. In this work, the previously reported volumetric power input (P/V) in conventional (NF) and coiled (CF) shake flasks were scaled-up to a stirred bioreactor. The effects on the growth and morphology of S. lividans were analyzed, as well as, the production and O-mannosylation of the recombinant APA glycoprotein from Mycobacterium tuberculosis. Specific growth rates of 5. lividans and similar recombinant glycoprotein (rAPA) yields were observed between NF and bioreactor cultures. In addition, we have found up to seven mannose residues attached to the C-terminal of the rAPA in bioreactor cultures, one more than in NF and CF. However, at similar P/V values, morphological and kinetic differences were found. Our data indicate that P/V as scale-up criteria in the production of recombinant glycoproteins in S. lividans can be successful in some, but not all the kinetic and stoichiometric parameters, suggesting that the metabolic cell responses can be affected by aeration/hydrodynamics between bioreactor and shake flasks. © 2019, Universidad Autonoma Metropolitana Iztapalapa. All rights reserved

Fauna epigeica em sistemas de produção de Nicotiana tabacum L.

O Rio Grande do Sul detém grande relevância na produção de tabaco. Adotam-se três sistemas de manejo: convencional, mínimo e plantio direto. Para analisar o impacto desses sistemas sobre a população da fauna do solo, efetuou-se uma amostragem da fauna epigeica. Foram avaliados preparo convencional (PC), cultivo mínimo (CM) e plantio direto (PD), além de área de reconversão da fumicultura para a vitivinicultura (RV) e de mata nativa (MN). Na amostragem, foram utilizadas dez armadilhas Provid em cada área. Os atributos avaliados foram: abundância de organismos, riqueza, índice de diversidade (H') e equitabilidade de Shannon (J). Collembola (Arthropoda: Hexapoda) foi identificada até o nível de família, devido à sua sensibilidade às modificações do ambiente. Efetuaram-se a análise multivariada de Agrupamento Hierárquico e a Análise de Componentes Principais, e os índices H' e J foram comparados pelo teste t, de Student. O PD apresentou maior número total de organismos, isolando-se das demais áreas pela análise de agrupamento hierárquico. Os valores de riqueza foram muito semelhantes entre as áreas, destacando-se a aproximação entre RV e MN. Os tratamentos PC, PD e RV não diferiram estatisticamente quanto ao H', apresentando valores de 1,58; 1,60; e 1,52, respectivamente. CM apresentou menor valor de H' (1,18) e MN, o valor intermediário (1,33). O comportamento estatístico de J foi muito semelhante ao encontrado em H'. Em relação à Classe Collembola, foram identificadas as famílias Entomobrydae, Sminthuridae, Poduridae e Hipogasturidae. PD apresentou exemplares das quatro famílias identificadas, enquanto nas demais áreas foram identificadas apenas Entomobrydae e Sminthuridae. Pela Análise de Componentes Principais (PCA), as diferenças entre as áreas explicaram 32 % da variabilidade encontrada; desse percentual, 59,3 % foram explicados pelos eixos 1 e 2. A presença ou ausência de revolvimento do solo e a rotação com culturas de cobertura foram os fatores que mais influenciaram as populações de fauna epigeica

Sequence variants in SLC16A11 are a common risk factor for type 2 diabetes in Mexico

10.1038/nature12828Nature506748697-101NATU