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How to make a synthetic multicellular computer

  • Macía, Javier
  • Solé Vicente, Ricard, 1962-
Biological systems perform computations at multiple scales and they do so in a robust way. Engineering metaphors have often been used in order to provide a rationale for modeling cellular and molecular computing networks and as the basis for their synthetic design. However, a major constraint in this mapping between electronic and wet computational circuits is the wiring problem. Although wires are identical within electronic devices, they must be different when using synthetic biology designs. Moreover, in most cases the designed molecular systems cannot be reused for other functions. A new approximation allows us to simplify the problem by using synthetic cellular consortia where the output of the computation is distributed over multiple engineered cells. By evolving circuits in silico, we can obtain the minimal sets of Boolean units required to solve the given problem at the lowest cost using cellular consortia. Our analysis reveals that the basic set of logic units is typically non-standard. Among the most common units, the so called inverted IMPLIES (N-Implies) appears to be one of the most important elements along with the NOT and AND functions. Although NOR and NAND gates are widely used in electronics, evolved circuits based on combinations of these gates are rare, thus suggesting that the strategy of combining the same basic logic gates might be inappropriate in order to easily implement synthetic computational constructs. The implications for future synthetic designs, the general view of synthetic biology as a standard engineering domain, as well as potencial drawbacks are outlined., This work has been supported by and EU ERC Advanced Grant, the James S. McDonnell Foundation, the Fundaci’on Botin and the Santa Fe Institute

Lifetime occupational exposure to dusts, gases and fumes is associated with bronchitis symptoms and higher diffusion capacity in COPD patients

  • Rodríguez, Esther
  • Zock, Jan-Paul
  • Serra Pons, Ignasi
  • Antó i Boqué, Josep Maria
  • Batlle Garcia, Jordi de, 1981-
  • Donaire González, David
  • Benet, Marta
  • Balcells Vilarnau, Eva, 1967-
  • Monsó, Eduard
  • Gayete, Angel
  • García Aymerich, Judith
  • PAC-COPD Study Group
Background: Occupational exposure to dusts, gases and fumes has been associated with reduced FEV1 and sputum production in COPD patients. The effect of occupational exposure on other characteristics of COPD, especially those reflecting emphysema, has not been studied in these patients. Methods: We studied 338 patients hospitalized for a first exacerbation of COPD in 9 Spanish hospitals, obtaining full occupational history in a face-to-face interview; job codes were linked to a job exposure matrix for semi-quantitative estimation of exposure to mineral/biological dust, and gases/fumes for each job held. Patients underwent spirometry, diffusing capacity testing and analysis of gases in stable conditions. Quality of life, dyspnea and chronic bronchitis symptoms were determined with a questionnaire interview. A high- resolution CT scan was available in 133 patients. Results: 94% of the patients included were men, with a mean age of 68(8.5) years and a mean FEV1% predicted 52 (16). High exposure to gases or fumes was associated with chronic bronchitis, and exposure to mineral dust and gases/fumes was associated with higher scores for symptom perception in the St. George’s questionnaire. No occupational agent was associated with a lower FEV1. High exposure to all occupational agents was associated with better lung diffusion capacity, in long-term quitters. In the subgroup with CT data, patients with emphysema had 18% lower DLCO compared to those without emphysema. Conclusions: In our cohort of COPD patients, high exposure to gases or fumes was associated with chronic bronchitis, and high exposure to all occupational agents was consistently associated with better diffusion capacity in long-term quitters., The PAC-COPD Study is funded by grants from the Fondo de Investigación Sanitaria (FIS PI020541), Ministry of Health, Spain; Agència d’Avaluació de Tecnologia i Recerca Mèdiques (AATRM 035/20/02), Catalan Government; Spanish Society of Pulmonology and Thoracic Surgery (SEPAR 2002/137); Catalan Pulmonology Foundation (FUCAP 2003 Beca Maria Ravà); Red RESPIRA (RTIC C03/11); Red RCESP (RTIC C03/09); Fondo de Investigación Sanitaria (PI052486); Fondo de Investigación Sanitaria (PI052302); Fondo de Investigación Sanitaria (PI060684); Fundació La Marató de TV3 (num. 041110); and Novartis Farmacèutica, Spain. CIBERESP and CIBERES are funded by Instituto de Salud Carlos III, Ministry of Health, Spain. Judith Garcia-Aymerich has a researcher contract from Instituto de Salud Carlos III (CP05/00118), Ministry of Health, Spain

Analysis of the robustness of network-based disease-gene prioritization methods reveals redundancy in the human interactome and functional diversity of disease-genes

  • Güney, Emre, 1983-
  • Oliva Miguel, Baldomero
Complex biological systems usually pose a trade-off between robustness and fragility where a small number of perturbations can substantially disrupt the system. Although biological systems are robust against changes in many external and internal conditions, even a single mutation can perturb the system substantially, giving rise to a pathophenotype. Recent advances in identifying and analyzing the sequential variations beneath human disorders help to comprehend a systemic view of the mechanisms underlying various disease phenotypes. Network-based disease-gene prioritization methods rank the relevance of genes in a disease under the hypothesis that genes whose proteins interact with each other tend to exhibit similar phenotypes. In this study, we have tested the robustness of several network-based disease-gene prioritization methods with respect to the perturbations of the system using various disease phenotypes from the Online Mendelian Inheritance in Man database. These perturbations have been introduced either in the protein-protein interaction network or in the set of known disease-gene associations. As the network-based disease-gene prioritization methods are based on the connectivity between known disease-gene associations, we have further used these methods to categorize the pathophenotypes with respect to the recoverability of hidden disease-genes. Our results have suggested that, in general, disease-genes are connected through multiple paths in the human interactome. Moreover, even when these paths are disturbed, network-based prioritization can reveal hidden disease-gene associations in some pathophenotypes such as breast cancer, cardiomyopathy, diabetes, leukemia, parkinson disease and obesity to a greater extend compared to the rest of the pathophenotypes tested in this study. Gene Ontology (GO) analysis highlighted the role of functional diversity for such diseases., Spanish Ministry of Science and Innovation (MICINN) FEDER BIO2011-22568 (http://www.mineco.gob.es/portal/site/mineco/); and by EU grantEraSysbio+(SHIPREC http://www.erasysbio.net/index.php?index=279) Euroinvestigación (EUI2009-04018)

Polymorphisms in ABC transporter genes and concentrations of mercury in newborns - Evidence from two Mediterranean birth cohorts

  • Llop, Sabrina
  • Engström, Karin
  • Ballester Díez, Ferran
  • Franforte, Elisa
  • Alhamdow, Ayman
  • Pisa, Federica
  • Tratnik, Janja Snoj
  • Mazej, Datja
  • Murcia, Mario
  • Rebagliato, Marisa
  • Bustamante Pineda, Mariona
  • Sunyer Deu, Jordi
  • Sofianou-Katsoulis, Aikaterini
  • Prasouli, Alexia
  • Antonopoulou, Eleni
  • Antoniadou, Ioanna
  • Nakou, Sheena
  • Barbone, Fabio
  • Horvat, Milena
  • Broberg, Karin
Background: The genetic background may influence methylmercury (MeHg) metabolism and neurotoxicity. ATP binding cassette (ABC) transporters actively transport various xenobiotics across biological membranes. Objective: To investigate the role of ABC polymorphisms as modifiers of prenatal exposure to MeHg. Methods: The study population consisted of participants (n = 1651) in two birth cohorts, one in Italy and Greece (PHIME) and the other in Spain (INMA). Women were recruited during pregnancy in Italy and Spain, and during the perinatal period in Greece. Total mercury concentrations were measured in cord blood samples by atomic absorption spectrometry. Maternal fish intake during pregnancy was determined from questionnaires. Polymorphisms (n = 5) in the ABC genes ABCA1, ABCB1, ABCC1 and ABCC2 were analysed in both cohorts. Results: ABCB1 rs2032582, ABCC1 rs11075290, and ABCC2 rs2273697 modified the associations between maternal fish intake and cord blood mercury concentrations. The overall interaction coefficient between rs2032582 and log2-transformed fish intake was negative for carriers of GT (β = −0.29, 95%CI −0.47, −0.12) and TT (β = −0.49, 95%CI −0.71, −0.26) versus GG, meaning that for a doubling in fish intake of the mothers, children with the rs2032582 GG genotype accumulated 35% more mercury than children with TT. For rs11075290, the interaction coefficient was negative for carriers of TC (β = −0.12, 95%CI −0.33, 0.09), and TT (β = −0.28, 95%CI −0.51, −0.06) versus CC. For rs2273697, the interaction coefficient was positive when combining GA+AA (β = 0.16, 95%CI 0.01, 0.32) versus GG. Conclusion: The ABC transporters appear to play a role in accumulation of MeHg during early development., This study was funded by The European Union 6th and 7th framework projects PHIME NEWGENERIS, the Swedish Research Council for Health, Working Life and Welfare, the Swedish Research Council FORMAS. The INMA study was funded by grants from the Instituto de Salud Carlos III (Red INMA G03/176 and CB06/02/0031), UE (FP7-ENV-2011 DENAMIC cod 282957 and HEALTH.2010.2.4.5-1), Spanish Ministry of Health (FIS-FEDER 03/1615, 04/1509, 04/1112, 04/1931, 05/1079, 05/1052, 06/1213, 07/0314, 09/02647, 11/02591, 04/1436, 04/2018, 09/02311, 06/0867, 08/1151, 11/02038, CP11/00178), Conselleria de Sanitat Generalitat Valenciana, Generalitat de Catalunya (CIRIT 1999SGR 00241), Fundació La marató de TV3 (090430) and European Union Sixth Framework Project (NEWGENERIS FP6-2003-Food-3-A-016320). National funding for the PHIME project in Slovenia was provided by the programme ARRS P1-0143.

No evidence that MDMA-induced enhancement of emotional empathy is related to peripheral oxytocin levels or 5-HT1a receptor activation

  • Kuypers, Kim PC
  • Torre Fornell, Rafael de la
  • Farré Albaladejo, Magí
  • Yubero Lahoz, Samanta, 1985-
  • Dziobek, Isabel
  • Van Den Bos, Wouter
  • Ramaekers, Johannes G.
The present study aimed at investigating the effect of MDMA on measures of empathy and social interaction, and the roles of oxytocin and the 5-HT1A receptor in these effects. The design was placebo-controlled within-subject with 4 treatment conditions: MDMA (75 mg), with or without pindolol (20 mg), oxytocin nasal spray (40 IU+16 IU) or placebo. Participants were 20 healthy poly-drug MDMA users, aged between 18–26 years. Cognitive and emotional empathy were assessed by means of the Reading the Mind in the Eyes Test and the Multifaceted Empathy Test. Social interaction, defined as trust and reciprocity, was assessed by means of a Trust Game and a Social Ball Tossing Game. Results showed that MDMA selectively affected emotional empathy and left cognitive empathy, trust and reciprocity unaffected. When combined with pindolol, these effects remained unchanged. Oxytocin did not affect measures of empathy and social interaction. Changes in emotional empathy were not related to oxytocin plasma levels. It was concluded that MDMA (75 mg) selectively enhances emotional empathy in humans. While the underlying neurobiological mechanism is still unknown, it is suggested that peripheral oxytocin does not seem to be the main actor in this; potential candidates are the serotonin 2A and the vasopressin 1A receptors., This work was supported by the Netherlands Organization for Scientific Research (NWO), Grant number: 400-07-2013, awarded to JR and KK.

Human genome variation and the concept of genotype networks

  • Dall'Olio, Giovanni Marco, 1983-
  • Bertranpetit, Jaume, 1952-
  • Wagner, Andreas
  • Laayouni, Hafid, 1968-
Genotype networks are a concept used in systems biology to study sets of genotypes having the same phenotype, and the ability of these to bring forth novel phenotypes. In the past they have been applied to determine the genetic heterogeneity, and stability to mutations, of systems such as metabolic networks and RNA folds. Recently, they have been the base for reconciling the neutralist and selectionist views on evolution. Here, we adapted this concept to the study of population genetics data. Specifically, we applied genotype networks to the human 1000 genomes dataset, and analyzed networks composed of short haplotypes of Single Nucleotide Variants (SNV). The result is a scan of how properties related to genetic heterogeneity and stability to mutations are distributed along the human genome. We found that genes involved in acquired immunity, such as some HLA and MHC genes, tend to have the most heterogeneous and connected networks, and that coding regions tend to be more heterogeneous and stable to mutations than non-coding regions. We also found, using coalescent simulations, that regions under selection have more extended and connected networks. The application of the concept of genotype networks can provide a new opportunity to understand the evolutionary processes that shaped our genome. Learning how the genotype space of each region of our genome has been explored during the evolutionary history of the human species can lead to a better understanding on how selective pressures and neutral factors have shaped genetic diversity within populations and among individuals. Combined with the availability of larger datasets of sequencing data, genotype networks represent a new approach to the study of human genetic diversity that looks to the whole genome, and goes beyond the classical division between selection and neutrality methods., This work was supported by grants BFU2010-19443 (subprogram BMC) awarded to JB by Ministerio de Ciencia y Tecnología (Spain) and by the Direcció General de Recerca, Generalitat de Catalunya (Grup de Recerca Consolidat 2009 SGR 1101). GMD is supported by a FPI fellowship BES-2009-017731. AW would like to acknowledge support by the Swiss National Science Foundation and by the URPP Evolutionary Biology at the University of Zurich

Transient exposure to ethanol during zebrafish embryogenesis results in defects in neuronal differentiation: An alternative model system to study FASD

  • Joya, Xavier
  • García Algar, Oscar
  • Vall, Oriol
  • Pujades Corbi, Cristina
Background: The exposure of the human embryo to ethanol results in a spectrum of disorders involving multiple organ systems, including the impairment of the development of the central nervous system (CNS). In spite of the importance for human health, the molecular basis of prenatal ethanol exposure remains poorly understood, mainly to the difficulty of sample collection. Zebrafish is now emerging as a powerful organism for the modeling and the study of human diseases. In this work, we have assessed the sensitivity of specific subsets of neurons to ethanol exposure during embryogenesis and we have visualized the sensitive embryonic developmental periods for specific neuronal groups by the use of different transgenic zebrafish lines. Methodology/Principal Findings: In order to evaluate the teratogenic effects of acute ethanol exposure, we exposed zebrafish embryos to ethanol in a given time window and analyzed the effects in neurogenesis, neuronal differentiation and brain patterning. Zebrafish larvae exposed to ethanol displayed small eyes and/or a reduction of the body length, phenotypical features similar to the observed in children with prenatal exposure to ethanol. When neuronal populations were analyzed, we observed a clear reduction in the number of differentiated neurons in the spinal cord upon ethanol exposure. There was a decrease in the population of sensory neurons mainly due to a decrease in cell proliferation and subsequent apoptosis during neuronal differentiation, with no effect in motoneuron specification. Conclusion: Our investigation highlights that transient exposure to ethanol during early embryonic development affects neuronal differentiation although does not result in defects in early neurogenesis. These results establish the use of zebrafish embryos as an alternative research model to elucidate the molecular mechanism(s) of ethanol-induced developmental toxicity at very early stages of embryonic development., This study was supported by grants from Fondo de Investigaciones Sanitarias (FIS) (PI10/02593; PI13/01135) and Red de Salud Materno-Infantil y del Desarrollo (SAMID) (RD12/0026/0003) from the Instituto Carlos III (Spain), a grant from Mutua Madrileña (AP150572014), intramural funding of the Neuroscience Program at IMIM (Institut Hospital del Mar ' Investigacions Mèdiques), partially supported by Generalitat de Catalunya (Spain) (2009SGR1388; 2014SGR584) and from Spanish Ministry of Economy and Competitiveness (BFU2012-31994).

Cultural diffusion was the main driving mechanism of the neolithic transition in southern Africa

  • Jerardino, Antonieta
  • Fort, Joaquim
  • Isern, Neus
  • Rondelli, Bernardo
It is well known that the Neolithic transition spread across Europe at a speed of about 1 km/yr. This result has been previously interpreted as a range expansion of the Neolithic driven mainly by demic diffusion (whereas cultural diffusion played a secondary role). However, a long-standing problem is whether this value (1 km/yr) and its interpretation (mainly demic diffusion) are characteristic only of Europe or universal (i.e. intrinsic features of Neolithic transitions all over the world). So far Neolithic spread rates outside Europe have been barely measured, and Neolithic spread rates substantially faster than 1 km/yr have not been previously reported. Here we show that the transition from hunting and gathering into herding in southern Africa spread at a rate of about 2.4 km/yr, i.e. about twice faster than the European Neolithic transition. Thus the value 1 km/yr is not a universal feature of Neolithic transitions in the world. Resorting to a recent demic-cultural wave-of-advance model, we also find that the main mechanism at work in the southern African Neolithic spread was cultural diffusion (whereas demic diffusion played a secondary role). This is in sharp contrast to the European Neolithic. Our results further suggest that Neolithic spread rates could be mainly driven by cultural diffusion in cases where the final state of this transition is herding/pastoralism (such as in southern Africa) rather than farming and stockbreeding (as in Europe)., This work was partially funded by the MINECO projects (http://www.mineco.gob.es/) SimulPast-CSD2010-00034 (all authors), FIS-2009-13050 (JF and NI) and FIS-2012-31307 (JF)

Increased N-glycosylation efficiency by generation of an aromatic sequon on N135 of antithrombin

  • Águila, Sonia
  • Martínez-Martínez, Irene
  • Dichiara, Gilda
  • Gutiérrez Gallego, Ricardo, 1968-
  • Navarro-Fernández, José
  • Vicente, Vicente
  • Corral, Javier
The inefficient glycosylation of consensus sequence on N135 in antithrombin explains the two glycoforms of this key anticoagulant serpin found in plasma: α and β, with four and three N-glycans, respectively. The lack of this N-glycan increases the heparin affinity of the β-glycoform. Recent studies have demonstrated that an aromatic sequon (Phe-Y-Asn-X-Thr) in reverse β-turns enhances N-glycosylation efficiency and stability of different proteins. We evaluated the effect of the aromatic sequon in this defective glycosylation site of antithrombin, despite of being located in a loop between the helix D and the strand 2A. We analyzed the biochemical and functional features of variants generated in a recombinant cell system (HEK-EBNA). Cells transfected with wild-type plasmid (K133-Y-N135-X-S137) generated 50% of α and β-antithrombin. The S137T, as previously reported, K133F, and the double mutant (K133F/S137T) had improved glycosylation efficiency, leading to the secretion of α-antithrombin, as shown by electrophoretic and mass analysis. The presence of the aromatic sequon did not significantly affect the stability of this conformationally sensitive serpin, as revealed by thermal denaturation assay. Moreover, the aromatic sequon hindered the activation induced by heparin, in which is involved the helix D. Accordingly, K133F and particularly K133F/S137T mutants had a reduced anticoagulant activity. Our data support that aromatic sequons in a different structural context from reverse turns might also improve the efficiency of N-glycosylation., This work has been supported by PI12/00657 (ISCIII,(www.isciii.es) & FEDER), and Redes RIC (RD12/0042/0050 & RD12/0042/0009) (ISCIII & FEDER), S.A is holder of a FPI grant from Ministerio de Ciencia e Innovación (www.idi.mineco.gob.es), I.M.M. is a Miguel Servet researcher from ISCIII and J.N.F. holders a post-doctoral contract Sara Borrell from ISCIII.

Evolutionary analysis of genes of two pathways involved in placental malaria infection

  • Sikora, Martin, 1976-
  • Ferrer Admetlla, Anna
  • Mayor, Alfredo
  • Bertranpetit, Jaume, 1952-
  • Casals López, Ferran
Placental malaria is a special form of malaria that causes up to 200,000 maternal and infant deaths every year. Previous studies show that two receptor molecules, hyaluronic acid and chondroitin sulphate A, are mediating the adhesion of parasite-infected erythrocytes in the placenta of patients, which is believed to be a key step in the pathogenesis of the disease. In this study, we aimed at identifying sites of malaria-induced adaptation by scanning for signatures of natural selection in 24 genes in the complete biosynthesis pathway of these two receptor molecules. We analyzed a total of 24 Mb of publicly available polymorphism data from the International HapMap project for three human populations with European, Asian and African ancestry, with the African population from a region of presently and historically high malaria prevalence. Using the methods based on allele frequency distributions, genetic differentiation between populations, and on long-range haplotype structure, we found only limited evidence for malaria-induced genetic adaptation in this set of genes in the African population; however, we identified one candidate gene with clear evidence of selection in the Asian population. Although historical exposure to malaria in this population cannot be ruled out, we speculate that it might be caused by other pathogens, as there is growing evidence that these molecules are important receptors in a variety of host-pathogen interactions. We propose to use the present methods in a systematic way to help identify candidate regions under positive selection as a consequence of malaria.

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