Temporal and Causal Inference with Longitudinal Multi-omics Microbiome Data

Microbiomes are communities of microbes inhabiting an environmental niche. Thanks to next generation sequencing technologies, it is now possible to study microbial communities, their impact on the host environment, and their role in specific diseases and health. Technology has also triggered the increased generation of multi-omics microbiome data, including metatranscriptomics (quantitative survey of the complete metatranscriptome of the microbial community), metabolomics (quantitative profile of the entire set of metabolites present in the microbiome\u27s environmental niche), and host transcriptomics (gene expression profile of the host). Consequently, another major challenge in microbiome data analysis is the integration of multi-omics data sets and the construction of unified models. Finally, since microbiomes are inherently dynamic, to fully understand the complex interactions that take place within these communities, longitudinal studies are critical. Although the analysis of longitudinal microbiome data has been attempted, these approaches do not attempt to probe interactions between taxa, do not offer holistic analyses, and do not investigate causal relationships. In this work we propose approaches to address all of the above challenges. We propose novel analysis pipelines to analyze multi-omic longitudinal microbiome data, and to infer temporal and causal relationships between the different entities involved. As a first step, we showed how to deal with longitudinal metagenomic data sets by building a pipeline, PRIMAL, which takes microbial abundance data as input and outputs a dynamic Bayesian network model that is highly predictive, suggests significant interactions between the different microbes, and proposes important connections from clinical variables. A significant innovation of our work is its ability to deal with differential rates of the internal biological processes in different individuals. Second, we showed how to analyze longitudinal multi-omic microbiome datasets. Our pipeline, PALM, significantly extends the previous state of the art by allowing for the integration of longitudinal metatranscriptomics, host transcriptomics, and metabolomics data in additional to longitudinal metagenomics data. PALM achieves prediction powers comparable to the PRIMAL pipeline while discovering a web of interactions between the entities of far greater complexity. An important innovation of PALM is the use of a multi-omic Skeleton framework that incorporates prior knowledge in the learning of the models. Another major innovation of this work is devising a suite of validation methods, both in silico and in vitro, enhancing the utility and validity of PALM. Finally, we propose a suite of novel methods (unrolling and de-confounding), called METALICA, consisting of tools and techniques that make it possible to uncover significant details about the nature of microbial interactions. We also show methods to validate such interactions using ground truth databases. The proposed methods were tested using an IBD multi-omics dataset

Inferring directional relationships in microbial communities using signed Bayesian networks

Background: Microbe-microbe and host-microbe interactions in a microbiome play a vital role in both health and disease. However, the structure of the microbial community and the colonization patterns are highly complex to infer even under controlled wet laboratory conditions. In this study, we investigate what information, if any, can be provided by a Bayesian Network (BN) about a microbial community. Unlike the previously proposed Co-occurrence Networks (CoNs), BNs are based on conditional dependencies and can help in revealing complex associations. Results: In this paper, we propose a way of combining a BN and a CoN to construct a signed Bayesian Network (sBN). We report a surprising association between directed edges in signed BNs and known colonization orders. Conclusions: BNs are powerful tools for community analysis and extracting influences and colonization patterns, even though the analysis only uses an abundance matrix with no temporal information. We conclude that directed edges in sBNs when combined with negative correlations are consistent with and strongly suggestive of colonization order

Dark matter candidates in the NMSSM with RH neutrino superfields

R-parity conserving supersymmetric models with right-handed (RH) neutrinos are very appealing since they could naturally explain neutrino physics and also provide a good dark matter (DM) candidate such as the lightest supersymmetric particle (LSP). In this work we consider the next-to-minimal supersymmetric standard model (NMSSM) plus RH neutrino superfields, with effective Majorana masses dynamically generated at the electroweak scale (EW). We perform a scan of the relevant parameter space and study both possible DM candidates: RH sneutrino and neutralino. Especially for the case of RH sneutrino DM we analyse the intimate relation between both candidates to obtain the correct amount of relic density. Besides the well-known resonances, annihilations through scalar quartic couplings and coannihilation mechanisms with all kind of neutralinos, are crucial. Finally, we present the impact of current and future direct and indirect detection experiments on both DM candidates.Comment: Version published in JCAP, 40 pages, 8 figures, 6 table

Managing with (fluorescent)-biomimetic dendrimers

Dendrimers that are modified through their peripheral groups have been employed for many biomedical purposes. Diagnosis via specific interactions with target proteins is one of the objectives that has been given more attention. In this way, we have been developing different methodologies for the detection of immunoglobulins, as an in vitro method for the diagnosis of allergic reactions to drugs [1], [2]. Specific cell interactions of surfaces grafted dendrimers have been applied to the study of cell adhesion. We have studied also the application of dendrimer-based uneven nanopatterns to evaluate the local RGD surface density effects on cell adhesion, as bioactive substrates to evaluate the impact of the RGD local surface density on the chondrogenic induction of adult human mesenchymal stem cells [3], [4], [5]. Although the use of PAMAM dendrimer has allowed us to develop useful methods for this purpose, for certain objectives we have required the development of new dendrimeric models. We have developed a new approach for the production of allaliphatic polyamide dendrimers (BAPAD) by iterative 3,3′-diaminopivalic acid connections as building blocks for dendrimer construction. These dendrimers were studied in explicit solvent by atomistic forcefield-based molecular dynamics to characterize structural properties such as shape, radius and monomer distribution [6]. Fluorescent labeling of these biomimetic dendrimers has been used as a tool to study their interaction with cells.Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech

Estudio sobre la competencia digital de los docentes en las aulas de educación infantil

Existen algunas opiniones encontradas en cuanto al papel y la intensidad de uso de tecnologías en las aulas de infantil, generando controversia y posturas diferentes que influyen en la implementación de metodologías activas basadas en el uso de las TIC Sin embargo, nadie parece discutir la necesidad de la formación digital de todos los docentes en esta etapa, por lo que, cabe preguntarse acerca de las competencias digitales que se requieren en la sociedad del conocimiento realizando la siguiente pregunta a los propios docentes: ¿Cuáles son las competencias digitales necesarias para desarrollar con éxito las tareas diarias de tu aula de infantil? Para ello, primero se preguntó a un grupo innovador de docentes de infantil sobre el tipo de tareas y el tiempo dedicado en el uso de TIC a la semana. Después de una validación mediante Método Delphi por ocho expertos en tecnología educativa y formación del profesorado en Educación Infantil, se elaboró un cuestionario definitivo que se pasó en 91 aulas de infantil. Del análisis de resultados surgieron nueve factores y cuatro dimensiones mediante el estudio del índice KMO (índice de Kaiser-Meyer-Olkin) y la realización del análisis factorial (valor del índice, 0,754). El análisis realizado nos ofreció un coeficiente “alfa de Cronbach” de 0.939, lo que demuestra un alto grado de consistencia interna y nos lleva a asumir que los ítems miden un mismo constructo y están altamente correlacionados entre sí. Los resultados permitieron definir cuáles son las prácticas y las TIC más utilizadas, junto con un listado de competencias digitales más relevantes para la formación inicial y permanente de los docentes de educación infantil. También los resultados del estudio permitieron obtener seis factores relacionados con la creación de contenidos, las explicaciones asociadas a las tareas, evaluación y actas, metodología, comunicación y momento de acogida en el aula.Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech

Beam formulation and FE framework for architected structures under finite deformations

The breakthrough in additive manufacturing (AM) techniques is opening new routes into the conceptualisation of novel architected materials. However, there are still important roadblocks impeding the full implementation of these technologies in different application fields such as soft robotics or bioengineering. One of the main bottlenecks is the difficulty to perform topological optimisation of the structures and their functional design. To help this endeavour, computational models are essential. Although 3D formulations provide the most reliable tools, these usually present very high computational costs. Beam models based on 1D formulations may overcome this limitation but they need to incorporate all the relevant mechanical features of the 3D problem. Here, we propose a mixed formulation for Timoshenko-type beams to consistently account for axial, shear and bending contributions under finite deformation theory. The framework is formulated on general bases and is suitable for most types of materials, allowing for the straightforward particularisation of the constitutive description. To prove validity of the model, we provide original experimental data on a 3D printed elastomeric material. We first validate the computational framework using a benchmark problem and compare the beam formulation predictions with numerical results from an equivalent 3D model. Then, we further validate the framework and illustrate its flexibility to predict the mechanical response of beam-based structures. To this end, we perform original experiments and numerical simulations on two types of relevant structures: a rhomboid lattice and a bi-stable beam structure. In both cases, the numerical results provide a very good agreement with the experiments by means of both quantitative and qualitative results. Overall, the proposed formulation provides a useful tool to help at designing new architected materials and metamaterial structures based on beam components. The framework presented may open new opportunities to guide AM techniques by feeding machine learning optimisation algorithms.The authors acknowledge support from Ministerio de Ciencia e Innovacion MCIN/AEI/10.13039/501100011033 under Grant number PID2020-117894GA-I00, and the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme (grant agreement No. 947723, project: 4D-BIOMAP). DGG acknowledges support from the Talent Attraction grant (CM 2018 - 2018-T2/IND-9992) from the Comunidad de Madrid. JAR acknowledges support from the Programa de Apoyo a la Realización de Proyectos Interdiscisplinares de I + D para Jóvenes Investigadores de la Universidad Carlos III de Madrid and Comunidad de Madrid, Spain (project: OPTIMUM)

Flapless implant surgery: a review of the literature and 3 case reports

Since the 1970s, modern Implantology is based on a concept of surgery with flap elevation. Gradually, several clinical trials demonstrated that a mid-crestal incision gives similar success rates compared to those obtained using the classical protocol. However, over the past decade in medicine it has been established the concept of minimally invasive surgery, consisting in taking advantage of advancements experienced in diagnostic techniques and specific surgical instruments, to perform surgical procedures infringing as less damage as possible to the patient The present work aims to produce a thorough review of the literature published on the field of Implantology with flapless surgery, to determine the current scientific evidence of the technique, along with illustrating the results with different clinical cases. After presenting the clinical cases, and the review of literature, we can say that flapless surgeries should be restricted to well-selected cases in which a proper clinical and radiological planning has been made. Patients treated with anticoagulant drugs or medically compromised equally can get benefitted by this minimal invasion technique

Direct characterization of functional materials by haptenized fluorescent dendrimers for in vitro allergic drug diagnose

β-lactams are the most widely drug prescribed against infections, but they are the most commonly reported medication allergy too. A correct diagnosis of these allergic reactions is crucial to avoid rejecting them by other more expensive broad-spectrum antibiotics, with potential risk factors for the development of multiple drug-resistant bacteria. [1] Skin testing is the most consensual approach to diagnose β-lactam allergy, but this in vivo test is not risky free and should be performed under strict hospital surveillance.[2] In vitro testing is not still widely used on account of their low sensitivity. We report the use of already haptenized fluorescent dendrimers [3] to control the preparation of materials for in vitro test, and their verification by testing on patient sera samples. This fluorescent dendrimer is obtained from a dye with two orthogonal functional groups suitable for click chemistry. [4] Acknowledgments: This work was supported by: MINECO CTQ2016-75870P, Andalusian Regional Ministry Health (PI-0250-2016); European Regional Development Fund and “Plan Propio Universidad de Málaga” (UMA-Andalucía-TECH).Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech

New Approaches in the Manufacture of Biomaterials for Betalactam Allergic Diagnose

Betalactams are the most widely utilized drugs against infections but are the primary cause of allergic reactions to antibiotic drugs. REF1 An accurate diagnosis of these allergic reactions to betalactams is crucial to avoid the use of unnecessary alternative antibiotics that may reduce efficacy, lead to prolonged treatments, have a higher toxicity or induce bacterial resistance. The most consensual approach to diagnose betalactam allergy are in vivo tests. However, they are not risky free, require experienced personnel and are both time-consuming and expensive for health-care systems, being so in vitro test more appropriate or complementary to the in vivo tests. In vitro tests are not still widely used on account of their low sensitivity. Current efforts are in progress to improve these assays, thus allowing for better diagnosis of allergic responses within patients. REF 2 We report progress in the preparation of new functional materials for in vitro allergic diagnosis testing. In particular, the application of new approaches employing orthogonally functionalised fluorescent dyes based upon 4-amino-1,8 naphthalimide joined with the multivalence of polyamide dendrimers. REF 3 The in vitro diagnosis capabilities of these functional materials was verified by testing on patient sera samples, with results demonstrating their potential for application within the healthcare industry. Acknowledgments: The present study has been supported by MINECO CTQ2016-75870P; by Andalusian Regional Ministry Health (grants: PI-0250-2016); by the European Regional Development Fund (ERDF) and “Plan Propio Universidad de Málaga” (UMA-Andalucía-TECH).Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech