Dynamics of the formation of rings of protein filaments

Tesis doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Ciencias, Departamento de Física Teórica de la Materia Condensada. Fecha de lectura: 21-11-201

FtsZ protein on bilayer membranes: Effects of specific lateral bonds

We use a simple lattice model to explore the self-assembled structures of protein filaments. Monte Carlo simulations show polymorphic structures, formed by the competition between the bundling of filaments, their branching and the spontaneous curvature. In the top-down approach, typical of statistical physics, we compare the simulation results with experimental atomic force microscopy images of the bacterial protein FtsZ anchored on bilayer membranes. We identify the relevant aspects of the interactions between protein monomers, which are amplified as a collective effect of the whole system. From the perspective of soft-matter physics, the experimental system and its model representation provide an interesting example of living polymers with tunable interactions. © 2013 The Royal Society of Chemistry.We acknowledge financial support from the Comunidad de Madrid, through projects NOBIMAT-M S2OO9/MAT-1507 and MOD-ELICO-S2009/ESP-1691, and from the Ministerio de Ciencia e Innovación of Spain, through projects Plan Nacional BIO2008-04478-C03-00, FIS2010-22047-C05-01 and CONSOLIDER INGENIO 2010 CSD2007-00010 and DIVINOCELL FP7 HEALTH-F3-2009-223431 (European Commission to MVe).Peer Reviewe

Modeling the interplay between protein and lipid aggregation in supported membranes

© 2014 Elsevier Ireland Ltd. All rights reserved. We present a theoretical model that deals with the complex interplay between lipid segregation and the self-aggregation of lipid-attached proteins. The model, in contrast to previous ones that consider proteins only as passive elements affecting the lipid distribution, describes the system including three terms: the dynamic interactions between protein monomers, the interactions between lipid components, and a mixed term considering protein-lipid interactions. It is used to explain experimental results performed on a well-defined system in which a self-aggregating soluble bacterial cytoskeletal protein polymerizes on a lipid bilayer containing two lipid components. All the elements considered in a previously described protein model, including torsion of the monomers within the filament, are needed to account for the observed filament shapes. The model also points out that lipid segregation can affect the length and curvature of the filaments and that the dynamic behavior of the lipids and proteins can have different time scales, giving rise to memory effects. This simple model that considers a dynamic protein assembly on a fluid and active lipid surface can be easily extended to other biologically relevant situations in which the interplay between protein and lipid aggregation is needed to fully describe the system.We acknowledge financial support by the Spanish Ministry of Science and Innovation (Grant no. FIS2010-22047-C05) and the Comunidad Autónoma de Madrid under program MODELICO (Grant no. S2009/ESP-1691).Peer Reviewe

Torsion and curvature of FtsZ filaments

FtsZ filaments participate in bacterial cell division, but it is still not clear how their dynamic polymerization and shape exert force on the underlying membrane. We present a theoretical description of individual filaments that incorporates information from molecular dynamic simulations. The structure of the crystallized Methanococcus jannaschii FtsZ dimer was used to model a FtsZ pentamer that showed a curvature and a twist. The estimated bending and torsion angles between monomers and their fluctuations were included in the theoretical description. The MD data also permitted positioning the curvature with respect to the protein coordinates and allowed us to explore the effect of the relative orientation of the preferred curvature with respect to the surface plane. We find that maximum tension is attained when filaments are firmly attached and oriented with their curvature perpendicular to the surface and that the twist serves as a valve to release or to tighten the tension exerted by the curved filaments on the membrane. The theoretical model also shows that the presence of torsion can explain the shape distribution of short filaments observed by Atomic Force Microscopy in previously published experiments. New experiments with FtsZ covalently attached to lipid membranes show that the filament on-plane curvature depends on lipid head charge, confirming the predicted monomer orientation effects. This new model underlines the fact that the combination of the three elements, filament curvature, twist and the strength and orientation of its surface attachment, can modulate the force exerted on the membrane during cell division. © 2014 The Royal Society of Chemistry.Comunidad de Madrid; to MVe), DIVINOCELL FP7 HEALTHF3-2009-223431 (European Commision to MVe and P.G-P.), Plan Nacional BIO2008-04478-C03-00 (Ministerio de Ciencia e Innovación; to MVe), CONSOLIDER INGENIO 2010 CSD2007-00010 (Ministerio de Ciencia e Innovación; to MVe) FIS2010-22047-C05-01 (Ministerio de Ciencia e Innovación,to P.T.)Peer Reviewe

BERTIN: Preentrenamiento eficiente de un modelo de lenguaje en español usando muestreo de perplejidad

The pre-training of large language models usually requires massive amounts of resources, both in terms of computation and data. Frequently used web sources such as Common Crawl might contain enough noise to make this pretraining sub-optimal. In this work, we experiment with different sampling methods from the Spanish version of mC4, and present a novel data-centric technique which we name perplexity sampling that enables the pre-training of language models in roughly half the amount of steps and using one fifth of the data. The resulting models are comparable to the current state-of-the-art, and even achieve better results for certain tasks. Our work is proof of the versatility of Transformers, and paves the way for small teams to train their models on a limited budget.El preentrenamiento de grandes modelos de lenguaje generalmente requiere cantidades masivas de recursos, tanto en términos de computación como de datos. Las fuentes web comúnmente usadas, como Common Crawl, pueden contener el suficiente ruido para que el preentrenamiento no sea óptimo. En este trabajo experimentamos con diferentes métodos de muestreo de la versión en español de mC4 y presentamos una técnica novedosa centrada en datos que llamamos muestreo de perplejidad y que permite el preentrenamiento de modelos de lenguaje en aproximadamente la mitad de pasos, y con una quinta parte de los datos normalmente necesarios. Los modelos obtenidos logran resultados comparables e incluso superan el estado del arte para ciertas tareas. Nuestro trabajo es una muestra de la versatilidad de los modelos Transformers en cuanto a aprendizaje práctico y allana el camino para que otros equipos pequeños entrenen sus modelos con un presupuesto limitado.This project was made possible thanks to the Flax/Jax Community Week organized by HuggingFace, and sponsored by Google Cloud, which provided free credits for the use of their TPUs

Impact of diabetes in patients waiting for invasive cardiac procedures during COVID-19 pandemic

Background: During COVID-19 pandemic, elective invasive cardiac procedures (ICP) have been frequently cancelled or postponed. Consequences may be more evident in patients with diabetes. Objectives: The objective was to identify the peculiarities of patients with DM among those in whom ICP were cancelled or postponed due to the COVID-19 pandemic, as well as to identify subgroups in which the influence of DM has higher impact on the clinical outcome. Methods: We included 2,158 patients in whom an elective ICP was cancelled or postponed during COVID-19 pandemic in 37 hospitals in Spain. Among them, 700 (32.4%) were diabetics. Patients with and without diabetes were compared. Results: Patients with diabetes were older and had a higher prevalence of other cardiovascular risk factors, previous cardiovascular history and co-morbidities. Diabetics had a higher mortality (3.0% vs. 1.0%; p = 0.001) and cardiovascular mortality (1.9% vs. 0.4%; p = 0.001). Differences were especially important in patients with valvular heart disease (mortality 6.9% vs 1.7% [p < 0.001] and cardiovascular mortality 4.9% vs 0.9% [p = 0.002] in patients with and without diabetes, respectively). In the multivariable analysis, diabetes remained as an independent risk factor both for overall and cardiovascular mortality. No significant interaction was found with other clinical variables. Conclusion: Among patients in whom an elective invasive cardiac procedure is cancelled or postponed during COVID-19 pandemic, mortality and cardiovascular mortality is higher in patients with diabetes, irrespectively on other clinical conditions. These procedures should not be cancelled in patients with diabetes

Geoeconomic variations in epidemiology, ventilation management, and outcomes in invasively ventilated intensive care unit patients without acute respiratory distress syndrome: a pooled analysis of four observational studies

Background: Geoeconomic variations in epidemiology, the practice of ventilation, and outcome in invasively ventilated intensive care unit (ICU) patients without acute respiratory distress syndrome (ARDS) remain unexplored. In this analysis we aim to address these gaps using individual patient data of four large observational studies. Methods: In this pooled analysis we harmonised individual patient data from the ERICC, LUNG SAFE, PRoVENT, and PRoVENT-iMiC prospective observational studies, which were conducted from June, 2011, to December, 2018, in 534 ICUs in 54 countries. We used the 2016 World Bank classification to define two geoeconomic regions: middle-income countries (MICs) and high-income countries (HICs). ARDS was defined according to the Berlin criteria. Descriptive statistics were used to compare patients in MICs versus HICs. The primary outcome was the use of low tidal volume ventilation (LTVV) for the first 3 days of mechanical ventilation. Secondary outcomes were key ventilation parameters (tidal volume size, positive end-expiratory pressure, fraction of inspired oxygen, peak pressure, plateau pressure, driving pressure, and respiratory rate), patient characteristics, the risk for and actual development of acute respiratory distress syndrome after the first day of ventilation, duration of ventilation, ICU length of stay, and ICU mortality. Findings: Of the 7608 patients included in the original studies, this analysis included 3852 patients without ARDS, of whom 2345 were from MICs and 1507 were from HICs. Patients in MICs were younger, shorter and with a slightly lower body-mass index, more often had diabetes and active cancer, but less often chronic obstructive pulmonary disease and heart failure than patients from HICs. Sequential organ failure assessment scores were similar in MICs and HICs. Use of LTVV in MICs and HICs was comparable (42·4% vs 44·2%; absolute difference -1·69 [-9·58 to 6·11] p=0·67; data available in 3174 [82%] of 3852 patients). The median applied positive end expiratory pressure was lower in MICs than in HICs (5 [IQR 5-8] vs 6 [5-8] cm H2O; p=0·0011). ICU mortality was higher in MICs than in HICs (30·5% vs 19·9%; p=0·0004; adjusted effect 16·41% [95% CI 9·52-23·52]; p&lt;0·0001) and was inversely associated with gross domestic product (adjusted odds ratio for a US$10 000 increase per capita 0·80 [95% CI 0·75-0·86]; p&lt;0·0001). Interpretation: Despite similar disease severity and ventilation management, ICU mortality in patients without ARDS is higher in MICs than in HICs, with a strong association with country-level economic status