Desarrollo de una plataforma computacional para el modelado metabólico de microorganismos

[EN] 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. Te 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.[ES] 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.Los autores desean agradecer el soporte financiero recibido por el Ministerio de Ciencia e Innovación a través de la concesión TIN2009- 12359; la Conselleria de Inmigración y Ciudadanía de la Generalitat Valenciana (concesión 3012/2009) y la Comisión Europea (Proyecto TARPOL FP7 EU KBBE 212894).Reyes, R.; Garrido, J.; Jaime, RA.; Córdova, V.; Triana, J.; Villar, L.; Castro, JC.... (2011). Desarrollo de una plataforma computacional para el modelado metabólico de microorganismos. Nereis. Revista Iberoamericana Interdisciplinar de Métodos, Modelización y Simulación. (3):25-31. http://hdl.handle.net/10251/91952S2531

Type 2 Diabetes Variants Disrupt Function of SLC16A11 through Two Distinct Mechanisms

Type 2 diabetes (T2D) affects Latinos at twice the rate seen in populations of European descent. We recently identified a risk haplotype spanning SLC16A11 that explains ∼20% of the increased T2D prevalence in Mexico. Here, through genetic fine-mapping, we define a set of tightly linked variants likely to contain the causal allele(s). We show that variants on the T2D-associated haplotype have two distinct effects: (1) decreasing SLC16A11 expression in liver and (2) disrupting a key interaction with basigin, thereby reducing cell-surface localization. Both independent mechanisms reduce SLC16A11 function and suggest SLC16A11 is the causal gene at this locus. To gain insight into how SLC16A11 disruption impacts T2D risk, we demonstrate that SLC16A11 is a proton-coupled monocarboxylate transporter and that genetic perturbation of SLC16A11 induces changes in fatty acid and lipid metabolism that are associated with increased T2D risk. Our findings suggest that increasing SLC16A11 function could be therapeutically beneficial for T2D. Video Abstract [Figure presented] Keywords: type 2 diabetes (T2D); genetics; disease mechanism; SLC16A11; MCT11; solute carrier (SLC); monocarboxylates; fatty acid metabolism; lipid metabolism; precision medicin

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

Penetrance of variants in monogenic disease and clinical utility of common polygenic variation has not been well explored on a large-scale. Here, the authors use exome sequencing data from 77,184 individuals to generate penetrance estimates and assess the utility of polygenic variation in risk prediction of monogenic variants

Mortality from gastrointestinal congenital anomalies at 264 hospitals in 74 low-income, middle-income, and high-income countries: a multicentre, international, prospective cohort study

Summary Background Congenital anomalies are the fifth leading cause of mortality in children younger than 5 years globally. Many gastrointestinal congenital anomalies are fatal without timely access to neonatal surgical care, but few studies have been done on these conditions in low-income and middle-income countries (LMICs). We compared outcomes of the seven most common gastrointestinal congenital anomalies in low-income, middle-income, and high-income countries globally, and identified factors associated with mortality. Methods We did a multicentre, international prospective cohort study of patients younger than 16 years, presenting to hospital for the first time with oesophageal atresia, congenital diaphragmatic hernia, intestinal atresia, gastroschisis, exomphalos, anorectal malformation, and Hirschsprung’s disease. Recruitment was of consecutive patients for a minimum of 1 month between October, 2018, and April, 2019. We collected data on patient demographics, clinical status, interventions, and outcomes using the REDCap platform. Patients were followed up for 30 days after primary intervention, or 30 days after admission if they did not receive an intervention. The primary outcome was all-cause, in-hospital mortality for all conditions combined and each condition individually, stratified by country income status. We did a complete case analysis. Findings We included 3849 patients with 3975 study conditions (560 with oesophageal atresia, 448 with congenital diaphragmatic hernia, 681 with intestinal atresia, 453 with gastroschisis, 325 with exomphalos, 991 with anorectal malformation, and 517 with Hirschsprung’s disease) from 264 hospitals (89 in high-income countries, 166 in middleincome countries, and nine in low-income countries) in 74 countries. Of the 3849 patients, 2231 (58·0%) were male. Median gestational age at birth was 38 weeks (IQR 36–39) and median bodyweight at presentation was 2·8 kg (2·3–3·3). Mortality among all patients was 37 (39·8%) of 93 in low-income countries, 583 (20·4%) of 2860 in middle-income countries, and 50 (5·6%) of 896 in high-income countries (p<0·0001 between all country income groups). Gastroschisis had the greatest difference in mortality between country income strata (nine [90·0%] of ten in lowincome countries, 97 [31·9%] of 304 in middle-income countries, and two [1·4%] of 139 in high-income countries; p≤0·0001 between all country income groups). Factors significantly associated with higher mortality for all patients combined included country income status (low-income vs high-income countries, risk ratio 2·78 [95% CI 1·88–4·11], p<0·0001; middle-income vs high-income countries, 2·11 [1·59–2·79], p<0·0001), sepsis at presentation (1·20 [1·04–1·40], p=0·016), higher American Society of Anesthesiologists (ASA) score at primary intervention (ASA 4–5 vs ASA 1–2, 1·82 [1·40–2·35], p<0·0001; ASA 3 vs ASA 1–2, 1·58, [1·30–1·92], p<0·0001]), surgical safety checklist not used (1·39 [1·02–1·90], p=0·035), and ventilation or parenteral nutrition unavailable when needed (ventilation 1·96, [1·41–2·71], p=0·0001; parenteral nutrition 1·35, [1·05–1·74], p=0·018). Administration of parenteral nutrition (0·61, [0·47–0·79], p=0·0002) and use of a peripherally inserted central catheter (0·65 [0·50–0·86], p=0·0024) or percutaneous central line (0·69 [0·48–1·00], p=0·049) were associated with lower mortality. Interpretation Unacceptable differences in mortality exist for gastrointestinal congenital anomalies between lowincome, middle-income, and high-income countries. Improving access to quality neonatal surgical care in LMICs will be vital to achieve Sustainable Development Goal 3.2 of ending preventable deaths in neonates and children younger than 5 years by 2030

Plasma MicroRNAs related to metabolic syndrome in Mexican women

Introduction: The metabolic syndrome (MetS) is a cluster of abnormalities related to cardiovascular disease (CVD). Circulating miRNAs (c-miRNAs) are non-coding RNAs associated with different phenotypes, some of them integrating the MetS. The aim of the study is to compare the c-miRNAs profile in plasma between women with MetS and controls, and explore their possible association with dysregulation of metabolic pathways. Methods: The study was conducted in two phases. At the screening phase, miRNA composition in fasting plasma was compared between 8 participants with MetS and 10 healthy controls, using microarray technology. The validation phase included the analysis by qRT-PCR of 10 selected c-miRNAs in an independent sample (n=29). Results: We found 21 c-miRNAs differentially expressed between cases and controls. The concentration in plasma of the c-miRNAs hsa-miR-1260a, hsa-miR-4514 and hsa-miR-4687-5p were also correlated with risk factors for CVD. Differences of hsa-miR-1260a between cases and controls were validated using qRT-PCR. (Fold-change= 7.0; P= 0.00289). Conclusion: The signature of plasma c-miRNA differed between women with MetS and controls. The identified miRNAs regulate pathways related to the MetS such as insulin resistance and adipokine activity. The role of c-miR-1260a in the MetS remains to be elucidated

Unexpected Roles of Guest Polarizability and Maximum Hardness, and of Host Solvation in Supramolecular Inclusion Complexes: A Dual Theoretical and Experimental Study

The origin of differential binding affinity and structural recognition between the inclusion complexes of cyclobis(paraquat-p-phenylene), 1 4+, and 1,4-substituted phenyl or 4,4‘-substituted biphenyl derivatives has been jointly determined by spectrometric techniques and ab initio and semiempirical molecular orbital methods. The unusual boxed geometry and tetracationic charge distribution in 1 4+ are key molecular features which produce strong intermolecular interactions with guest and solvent molecules. Solvation was addressed by including up to 12 acetonitrile molecules in the theoretical model, which realigned the predicted gas-phase supramolecular structures and energies into excellent agreement with experiment. The computed complexation enthalpies, ΔH bind, from the semiempirical molecular orbital PM3 method are on average within 1 kcal/mol of the experimental free energy binding data collected from absorption spectroscopy in acetonitrile. In addition, the computed geometric penetration and positioning of 1 4+/benzidine and 1 4+/4,4‘-biphenol complexes are consistent with that reported from NMR NOE data. The partitioning of self-consistent field complexation energies from both classical and quantum forces has been determined by using Morokuma's variational energy decomposition technique. It was determined that the primary basis for the molecular recognition between 1,4-substituted phenyl guests and 1 4+ is short-range stabilizing electrostatic forces complemented by small amounts of polarizability and charge-transfer. In contrast, the recognition force between 4,4‘-substituted biphenyl guests and 1 4+ is dominated by polarizability with a small contribution from electrostatics. Therefore, the balance between molecular polarizability and electrostatics controls the differential binding affinity and structural recognition with 1 4+. For the first time, we report that individual molecular properties of substituted guests correlate with the binding energies of corresponding 1 4+ inclusion complexes. Direct correlations between the 1 4+ binding energies and the computed molecular polarizability, maximum hardness, softness, and electronegativity of the guest have been identified. It is now plausible to consider the design and construction of new supramolecular assemblies based upon a few select molecular properties of the constituent molecules