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Program for Theoretical and Computational Biology

This project is coordinated by the Institute for Integrative Systems Biology I2SysBio) and the Universidad San Francisco de Quito. The project explores the presence of microorganisms with electricity generating potential of microbial communities present in the sediments of salt lagoons and salt flats of San Cristóbal Island in the Galapagos archipelago. Galapagos explores the production of electricity from environmental samples, characterizes the metagenomic content of microbial communities and the correlation of the presence of power species with environmental parameters such as pH, salinity, temperature and dissolved oxygen.
This project is coordinated by the Institute for Integrative Systems Biology I2SysBio) and the ICTS The Canfranc Underground Laboratory. The project studies the content and the spatial variability of the microbial communities present in limestone rocks samples from the Pyrenees at hundreds meters deep thanks to access thought the Somport tunnel, located in the Central Pyrenees and linking the Aragon (Spain) and Aspe (France) valleys. Gollum explores a little known extreme environment, characterized by few nutrients, various physicochemical substrates, low levels of any type of radiation and small temperature fluctuations. The presence of native DNA and the identification of a high archaea contents and its correlation with present metals are some of the most relevant results and open the possibility of multiple questions, starting by resolving whether genomic material identified corresponds to relic DNA or, on the contrary, to living microorganisms isolated from the outside since tens of millions of years.

Program for Systems Biology of Molecular Interactions and Regulation

Secondary metabolites influence quality traits in foods such as color, flavor, texture and aroma and represent the building blocks for the development of novel pharmaceuticals. We aim to decipher gene regulatory networks of secondary metabolites based in the use of multi-omics approaches to determine how transcription factors control these pathways.
Genetic material can be programmed to express systems that sense, process (following logic calculations) and respond to (in the form of gene expression) different molecular signals. Synthetic biology aims at approaching this by following fundamental systems engineering principles, that is, through the combination of mathematical modeling to capture gene expression dynamics, experiments to monitor in a quantitative way the features of the system to feedback the design process, and genetic part standardization for modular composability. Certainly, initial circuit design relies on incomplete or simplistic models of regulation established by previous molecular and systems biology developments. Once designed and characterized for its main functionality, a synthetic circuit still presents multiple queries, usually overlooked. For example, are the models used to guide the design predictive enough?, is the behavior consistent at the population and single cell levels?, or what is the evolutionary stability of a synthetic construct in a living organism? We believe that the proper resolution of these questions will lead to a resynthesis in the understanding of circuit function.
New advances in the biological sciences allow the active engineering of proteins and cells for new therapeutic, analytical or synthetic biology approaches. With an expected market worth of billions of dollars by 2020, formal education and research in these fields is not yet well established in continental Europe and requires interdisciplinary skills, combining biology, chemistry and computational sciences with engineering principles. RNAct creates a comprehensive, cross-disciplinary platform to train ESRs, guiding them towards the versatile computational and experimental skills required in this intrinsically multidisciplinary field. RNAct enables ESRs to experience both academic and industrial locations, with support for developing the soft skills they will need to employ and communicate their knowledge. RNAct employs a mix of computational, structural and molecular biology to design and characterize the conformation and function of dynamic proteins, with validation and innovation opportunities in in-cell analytics, therapeutics and synthetic biology, which will help research and companies establish an edge in these competitive fields. We concretely focus on RNA Recognition Motifs (RRMs), which are highly dynamic protein domains with versatile RNA binding functionality. These RRMs play crucial roles in the regulation of in-cell RNA, with very versatile RNA-binding behavior. They could play a key role in synthetic biology.
Duplication events, from gene to whole genome, generate large amount to genetic material and potentially novel functions. The ubiquity of gene duplicating in all levels of life, including unicellular and multicellular organisms, support the universal nature of this phenomenon. Indeed, the modularity of living systems, from the molecular-biochemical to the morphological level, has been driven by events of gene/genome duplication. Although, almost all researchers agree on the existence of a link between gene duplication and innovation, the underlying mechanisms are still not well characterized. In particular, it remains debatable the factors that are mostly determinant of the functional fate of the gene copies after duplication. The adaptive value of increasing gene dosage, maintenance of stoichiometric balance, and mutational robustness has been previously presented as main players in the persistence of duplicated genes in the genome.
As consequence of the exposition to stress-inductors plants trigger a complex regulatory response that results in adaptation to adverse conditions. In general, these environmental conditions are the major limiting factors for development and productivity in agricultural species. Consequently, the molecular basis of the mechanisms that regulate the response to stress has been extensively studied. Current and predicted environmental conditions altered as consequence of climate change, pose a serious challenge for extensive agricultural production in the near future. Conditioned by this new scenario has been a need to implement innovative strategies to attempts understand the mechanisms that are triggered in the plant exposed to multiple stresses. However, commonly, these approaches are not focused in the changes produced at the level of non-coding RNAs, although increasingly evidence suggests to them a major role in biological plant-processes. Recently we have identified and characterized small ncRNAs (sncRNAs) that exhibit differential expression associated to diverse (biotic and/or abiotic) stress conditions. Based in these evidences was computationally inferred a sncRNAs-mediated network that predicted to regulates the stress-response in melon plants. According our functional model this regulatory-network is constituted by specific sncRNAs (stress-receptors) that by means of intermediate sncRNAs spread stress-induced signal to the sncRNAs-core responsible to regulate the global response to stress. Based in these evidences we enunciate as general objective of our proposal characterize and functionally validate the regulatory pathways mediated by sncRNAs involved in stress-response in cucurbits. We expect use this knowledge as enhancer to develop biotechnological tools that will enhance the tolerance of crops to stress multiple.

Program for Pathogen Systems Biology

Mycobacterium tuberculosis is the leading pathogen causing adult death worldwide due to tuberculosis disease. M. tuberculosis affects humans but also a wide range of other mammals including humans, cattle, goats, mice, mercats, suricates, mongoses, seals, chimpanzees, dassies and antilopes. It is well known that the immune system plays a critical role to develop tuberculosis but to our knowledge how specific interactions between bacteria and its host impact disease is still unknown. We therefore will combine in silico and ex-vivo experiments to unmask host-pathogen interactions as a mean to reveal mechanisms of tuberculosis virulence. Deeper knowledge of host specificity will provide vital insights into molecular pathogenesis, the evolution of M. tuberculosis virulence, and the risks of pathogens crossing the species barrier.
Genomic defenses against viruses in plants are actually part of a broader and conserved interconnected system used for a plethora of mechanisms in eukaryotes, including the regulation of gene expression by endogenous siRNAs and other types of small RNAs (sRNAs), defense against genomic invaders like transposons and establishment of the heterochromatin.
A fundamental consequence of Darwin's theory of evolution by natural selection is the explanation of adaptation as the result of a natural process. However, the underlying genetic mechanisms are not yet resolved and constitute a fundamental issue in Evolutionary Biology. New Generation Sequencing (NGS) techniques allow evolutionary issues to be addressed on a scale previously unthinkable. Nevertheless, the rapid evolution of these technologies makes their application very difficult, especially in their analytical and bioinformatics aspects, since many unforeseen problems of management, storage, transmission, analysis or interpretation have to be solved, which represents a very important challenge in this field.
We use directed evolution for creating modified viruses that selectively infect and destroy tumors (oncolytic viruses). Cancer cells typically show innate immunity defects, which makes them highly susceptible to viral infections. By adapting a virus to tumors in the laboratory, it is possible to enhance the ability of this particular virus to kill cancer cells and to stimulate an immune response against the tumor. This may open new avenues for cancer therapy. We are currently focusing our efforts on vesicular stomatitis virus, a simple RNA virus with a natural tropism towards cancer cells.
Antibiotic resistance represents one of the greatest threats to global public health. Our research group has been working for years on the application of methods and concepts of evolution and genetics of molecular populations to the study of pathogenic microorganisms, in what is known as molecular epidemiology. In addition to working on issues of scientific interest, we take problems and return relevant results to the health authorities, achieving an interesting application of a basic biological discipline. In this context, in this project we plan to study a wide prospective collection of isolates of a bacterium of great interest for public health, Klebsiella pneumoniae, to analyse the evolutionary processes that affect its dynamics in the population of the Valencian Community, with special interest in strains resistant to antibiotics. Due to its clinical and public health relevance, we will focus on beta-lactamase producing strains with extended spectrum and/or carbapenemasas.
The main goal of this project is to define the effect of all possible mutations in a viral capsid, and to understand how different cellular and environmental pressures can alter the viability of such mutations in the capsid.
We investigate the ability of viruses to spread as groups (collective infectious units) and how this promotes the evolution of social interactions among viruses. For this, we use model viruses (vesicular stomatitis) as well as human (enteroviruses) and insect (baculoviruses) pathogens. Infecting hosts as groups may allow viruses to better counteract antiviral responses and may promote cooperation among different viral genetic variants, but may also favor the evolution of cheater viruses.
Cellular molecular chaperones are a group of conserved and abundant proteins that oversee protein folding and help maintain protein homeostasis. The goal of this project is to define all the chaperones and co-chaperones involved in the replication of respiratory syncytial virus, the single most important respiratory pathogen in children.
Resistance to antibiotics and antivirals represents one of the greatest threats to health and an issue of great economic importance, as recognised by international organisations such as the WHO and the OECD. Being the result of natural processes but accelerated by human intervention, there are multiple factors that influence their appearance and expansion. Therefore, the strategies adopted and under study to control resistance must include interventions at various levels. From the "Evolution and Health" research group at the Universitat de València, we propose a project that integrates two of our main lines of work, experimental evolution and molecular epidemiology, into a single objective: to analyse how to optimise drug administration strategies in order to delay or avoid the expansion of resistance. To do this, we will apply different designs of experimental evolution under controlled laboratory conditions using two different microorganisms: a bacterium (Pseudomonas aeruginosa) and an RNA virus (human rhinovirus). The experimental system also contemplates two basic environments, one in vitro (cultures) and another in vivo (using the murine model for both pathogens). Resistance development will be functionally evaluated and the appearance and dynamics of genetic variants responsible for resistance will be analysed at regular intervals. For this we will use ultra-sequencing techniques that will allow us to evaluate the genetic variability and its distribution throughout the genome of each population, as well as the effects derived from resistance mutations.
It is generally assumed that genetic variability in host species for susceptibility to infection will necessarily condition the evolution of pathogens populations, either by driving them to the diversification of the pathogen into strains that track the different host defence alleles (e.g., antigenic diversity), or by canalization of the pathogen to infect only the most susceptible genotypes. Associated to these processes of diversification or specialization, virulence may or may not increase concomitantly. In any case, pathogen's fitness must be optimized.

Program for Evolutionary Systems Biology of Symbionts

We are interested in the study of mutualistic symbiosis, a widespread phenomenon in nature. This is the case of endosymbiosis, which normally involves a one-to-one relationship between an intracellular bacterium and the host; but there is also ectosimbiosis, one-to-many associations where a large number of bacterial species are housed in different host organs, constituting its microbiota.
The project proposes the development of two types of tools to study gene functions in aphids. On one side, the project proposes an alternative RNAi methodology which consists in providing aphids with a continuous supply of the dsRNA required to trigger the RNAi by including it in a plant virus that infects the plant the aphid naturally feeds on. This technique, called VIGS (Virus Induced Gene Silencing), is a tool successfully used in the silencing of plant genes. Secondly, we intend to develop the CRISPR / Cas methodology in aphids. In addition to investigating the extension of these techniques to aphids, we will investigate the role of candidate genes that we have identified so far as good candidates to regulate several polyphenisms in aphids (including the reproductive polyphenism).
An explosive growth of research on the gut microbiota, often using rodent models, has amply demonstrated the huge importance of the previously neglected microorganisms for our health. However, the complexity of the system poses a formidable challenge.
The STOP project aims at expanding and consolidating the multi-disciplinary evidence base upon which effective and sustainable policies can be built to prevent and manage childhood obesity. STOP also aims at creating the conditions for evidence to translate into policy and for policy to translate into impacts.
The project aims at identifying and characterizing the key elements governing the mode of reproduction in aphids. We are particularly interested in elucidating the molecular basis responsible for the switch from parthenogenesis to sexual reproduction and analyzing what role (if any) play in this process the circadian clock genes.
The objective of the project is, through a multidisciplinary and inter-institutional approach, to deal with the problems represented by diseases transmitted by two ambrosial complexes (X. glabratus - R. lauricola and Euwallacea sp. - F. euwallaceae). These plagues are composed of a scolytin beetle that acts as a vector and transmits one or several pathogenic fungi that infect the host plant, rapidly causing progressive wilt and finally death.
The InGEMICS­CM (Microbial Engineering, Health and Quality of Life­CM) Program aims to place the Community of Madrid as a technological and scientific reference in Quantitative Microbiology and Precision Medicine using the most innovative –omics and images technologies together with novel and powerful tools for data analysis and mathematical modelling and simulation. This innovative technological development will enable us to address some of the most important current challenges in Biomedicine: (1) the problem of controlling antibiotic resistance; (2) the understanding of the relevance of the Microbiome in Human Health and Pathophysiology; (3) the search for new biological activities and functions for pharmaceutical and biotechnological development and (4) the development of precision medicine with clinical, social and economic impact.
The main objective is to learn the role science communication plays on the origin of beliefs, perceptions and knowledge concerning scientific issues. To achieve this aim, we will carry out five citizen consultations in Lisbon (Portugal), Valencia (Spain), Vicenza (Italy), Trnava (Slovakia) and Lodz (Poland), with the participation of a total of 500 citizensabout four science “hot” topics: vaccines, use of complementary and alternative medicines, climate change, food safety. The researchers aim at gaining a deeper insight into the public understanding of science and identify current science communication models.
Lynch syndrome (LS) is an inherited condition involving a high risk of colorectal cancer (CRC), endometrial cancer and other tumors. It presents an autosomal dominant inheritance and is caused by germline mutations in genes involved in the repair mechanism of errors occurring during DNA replication [mismatch repair genes (MMR)]. LS has an incomplete penetrance and variable expressivity. Significant differences have been described in the clinical phenotype of patients with LS depending on the mutated MMR gene. There is great heterogeneity in the risk of cancer in mutation carriers. The causes of such heterogeneity are unknown, but may be due to modifier genes of the penetrance, epigenetic changes and/or environmental factors. Recently, evidence of a beneficial effect in model mice MMR deficient and genetically predisposed to CCR has been observed after reducing their gut microbiota by antibiotic treatment and/or by a low-carbohydrate diet. Derivatives of carbohydrate metabolism such as the butyrate -generated by species of the phylum Firmicutes - are ultimately responsible for CRC in mice with mutations at MSH2. Apparently, particular alterations in the colorectal microbial community from the above mentioned treatments result in insufficient production of metabolites involved in pathways contributing to protection against CRC progression. In this proposal we will evaluate the functional impact of the microbiota in the development of colorectal oncogenesis in a cohort of healthy individuals at high genetic risk of CRC.
Mutualistic symbiosis between bacteria and eukaryotic hosts is a widespread phenomenon in nature. Two different symbiotic system exist in insects, endosymbiosis, in which intracellular mutualistic bacteria play an essential nutritional role, and ectosymbiosis, formed mainly by bacteria in the gut, which function is still not well understood. Cockroaches are special because the two symbiotic system coexist in a single individual.
The concept of stable microbiota involves the idea that, after a disturbance, the microbial community returns to its initial position in terms of composition (resilience) or function (functional redundancy) when the disturbing factor disappears. Through the application of a new method developed in the group, the Complex Cruncher software, and through the determination of the composition (metagenome) and function (metatranscriptome and metabolome) of the intestinal microbiota we can evaluate its stability in a longitudinal study. For that, volunteers from Valencian Community were involved in this study, 10 infants, 10 adults an 10 elderly unrelated and on the other hand cohort of 12 toddlers, 13 adolescents and 35 adults related. For each volunteer between eight and ten fecal samples were collected and all procedures were reviewed and approved by FISABIO.

Program for Applied Systems Biology and Synthetic Biology

The central intent of SETH is the generation of a knowledge base, a suite of useful strains and a portfolio of matching genetic technologies for enabling a new type of large-scale industrial and environmental processes mediated by whole bacterial cells but executed under (very) low-water conditions. This endeavor builds on the success of the precedent HELIOS project but goes much beyond by capitalizing on the wealth of biological activities found in desiccation-tolerant bacteria and their repurposing for the design of live catalysts able to work under an unprecedented variety of physicochemical settings.
The main objective is to exchange information and knowledge between countries affected by diseases caused by Xylella fastidiosa in order to gather all available data on the bacterium, its vectors, the situation of affected crops in Ibero-American countries and the prevention and control activities that are being carried out. The aim is to generate knowledge to contribute to the development of a technological alert and surveillance system that allows local or national governments to take the necessary measures to follow, contain and eradicate the disease.
The main objective is to learn the role science communication plays on the origin of beliefs, perceptions and knowledge concerning scientific issues. To achieve this aim, we will carry out five citizen consultations in Lisbon (Portugal), Valencia (Spain), Vicenza (Italy), Trnava (Slovakia) and Lodz (Poland), with the participation of a total of 500 citizensabout four science “hot” topics: vaccines, use of complementary and alternative medicines, climate change, food safety. The researchers aim at gaining a deeper insight into the public understanding of science and identify current science communication models.
We propose to gather the most relevant stakeholders of all the aspects of standardisation in biology in Europe in a co-creation scenario; to empirically test cultural (lab-centric) standardisation practices and promote a consensus conceptual and technical redefinitionof biological standards; and, finally, to foster a realistic and flexible toolbox of standard biological parts, including a reduced set of specialised chassis for specific applications as well as a renewed conceptual framework to inform policy makers, scientific and other societal actors.
The project is part of the group's ongoing research line, aimed to provide knowledge bases and derived technological strategies to improve the efficiency of wine yeasts in all the industrial processes where they participate: dry active biomass production and wine fermentation. The specific objectives of this project are oriented to study the integration of the different nutrient signaling pathways and mechanisms of adaptation to oxidative stress in industrial conditions, and to characterize and improve the technological performance of non-conventional yeasts of oenological interest.
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