Publications by authors named "Nicolas Rodriguez"

54 Publications

Safety and Performance of Titanium Suture Anchors Used in Knee Ligament Repair Procedures.

Medicina (Kaunas) 2021 Mar 19;57(3). Epub 2021 Mar 19.

Real Sporting Gijon SAD, Camino Mareo-Granda, 645, 33390 Gijon, Spain.

Injuries to the knee ligaments can be particularly disabling in young patients, given the risk of long-term disability if adequate fixation is not achieved during initial repair. The TWINFIX™ titanium (Ti) suture anchor with ULTRABRAID™ Suture (Smith and Nephew, London, UK) was designed to secure tendon and ligament reconstructions with increased boney ingrowth at the anchor site with minimal invasive technique. This retrospective analysis looked at 33 patients (41 implants) operated with this device between 2015 and 2019 at a single institution. The average age of patients was 33.18 years (standard deviation [SD], 15.26), with an average body mass index of 24.88 (SD, 3.49). The indications were lateral extra-articular tenodesis during anterior cruciate ligament reconstruction, medial patellofemoral ligament reconstruction, quadriceps or patellar tendon repair and medial collateral ligament repair. After an average follow up of 24.3 + 6.53 months, there was no reports of clinical failure or radiographic evidence of implant failure or loosening. One patient experienced a complication unrelated to the study device, requiring manipulation under anesthesia with resolution of symptoms. This case series supports the safety and performance of this implants for the knee procedures in which its use is indicated. Additional follow-up will be required to determine whether these effects are sustained at medium- and long-term durations.
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http://dx.doi.org/10.3390/medicina57030287DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8003405PMC
March 2021

COVID-19-Associated Mold Infection in Critically Ill Patients, Chile.

Emerg Infect Dis 2021 Mar 24;27(5). Epub 2021 Mar 24.

Patients with severe coronavirus disease (COVID-19) may have COVID-19-associated invasive mold infection (CAIMI) develop. We report 16 cases of CAIMI among 146 nonimmunocompromised patients with severe COVID-19 at an academic hospital in Santiago, Chile. These rates correspond to a CAIMI incidence of 11%; the mortality rate for these patients was 31.2%.
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http://dx.doi.org/10.3201/eid2705.204412DOI Listing
March 2021

Study design and rationale for a randomized controlled trial to assess effectiveness of stochastic vibrotactile mattress stimulation versus standard non-oscillating crib mattress for treating hospitalized opioid-exposed newborns.

Contemp Clin Trials Commun 2021 Mar 11;21:100737. Epub 2021 Feb 11.

Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15213, USA.

The incidence of Neonatal Abstinence Syndrome (NAS) continues to rise and there remains a critical need to develop non-pharmacological interventions for managing opioid withdrawal in newborns. Objective physiologic markers of opioid withdrawal in the newborn remain elusive. Optimal treatment strategies for improving short-term clinical outcomes and promoting healthy neurobehavioral development have yet to be defined. This dual-site randomized controlled trial (NCT02801331) is designed to evaluate the therapeutic efficacy of stochastic vibrotactile stimulation (SVS) for reducing withdrawal symptoms, pharmacological treatment, and length of hospitalization, and for improving developmental outcomes in opioid-exposed neonates. Hospitalized newborns (n = 230) receiving standard clinical care for prenatal opioid exposure will be randomly assigned within 48-hours of birth to a crib with either: 1) Intervention (SVS) mattress: specially-constructed SVS crib mattress that delivers gentle vibrations (30-60 Hz, ~12 μm RMS surface displacement) at 3-hr intervals; or 2) Control mattress (treatment as usual; TAU): non-oscillating hospital-crib mattress. Infants will be studied throughout their hospitalization and post discharge to 14-months of age. The study will compare clinical measures (i.e., withdrawal scores, cumulative dose and duration of medications, velocity of weight gain) and characteristic progression of physiologic activity (i.e., limb movement, cardio-respiratory, temperature, blood-oxygenation) throughout hospitalization between opioid-exposed infants who receive SVS and those who receive TAU. Developmental outcomes (i.e., physical, social, emotional and cognitive) within the first year of life will be evaluated between the two study groups. Findings from this randomized controlled trial will determine whether SVS reduces in-hospital severity of NAS, improves physiologic function, and promotes healthy development.
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http://dx.doi.org/10.1016/j.conctc.2021.100737DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7960539PMC
March 2021

Development of neutralizing antibody responses against SARS-CoV-2 in COVID-19 patients.

J Med Virol 2021 Mar 13. Epub 2021 Mar 13.

Sección Virus Oncogénicos y SubDepto. Genética Molecular, Instituto de Salud Pública de Chile, Ñuñoa, Chile.

The novel coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and coronavirus disease 2019 (COVID-19) are new global problems. The understanding of the host immune response in COVID-19 and its implications in the development of therapeutic agents are new challenges. Here, we evaluated the development of immunoglobulin G (IgG) and neutralizing (Nt) antibodies in symptomatic hospitalized COVID-19 patients. We followed up 117 COVID-19 confirmed patients from a reference health center for COVID-19 during the epidemic in Santiago de Chile. One and two sequential blood samples from 117 to 68 cases were, respectively, obtained to evaluate the immune response. Immunofluorescence and neutralization assays in Vero E6 cells with a Chilean SARS-CoV-2 strain were performed. Out of the 68 patients, 44% were women and 56% men, and the most frequent comorbidities were hypertension (47.7%) and diabetes (27.4%). The most frequent symptoms or signs related to COVID-19 were dyspnea, cough, fever, myalgia, and headache. In all the study population, 76.1% and 60.7% of patients were positive for IgG and Nt antibodies in the first blood sample. All patients except one were positive for IgG and Nt antibodies in the second sample. IgG and Nt antibodies positivity increased significantly according to the disease evolution periods. Higher Nt antibody titers were observed in the first sample in patients under 60 years of age. Obese and diabetic patients had no increase in Nt antibodies, unlike normal weight and diabetes-free patients. Both hypertensive and normotensive patients showed a significant increase in Nt antibodies. These results show an early and robust immune response against SARS-CoV-2 infection during severe COVID-19.
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http://dx.doi.org/10.1002/jmv.26939DOI Listing
March 2021

Corrigendum to "Binding and crossing: Methods for the characterization of membrane-active peptides interactions with membranes at the molecular level" [Arch. Biochem. Biophys. 699 (2021) 108751].

Arch Biochem Biophys 2021 Mar 9:108827. Epub 2021 Mar 9.

Sorbonne Université, École Normale Supérieure, PSL University, CNRS, Laboratoire des Biomolécules, LBM, 75005, Paris, France.

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http://dx.doi.org/10.1016/j.abb.2021.108827DOI Listing
March 2021

Binding and crossing: Methods for the characterization of membrane-active peptides interactions with membranes at the molecular level.

Arch Biochem Biophys 2021 03 7;699:108751. Epub 2021 Jan 7.

Sorbonne Université, École Normale Supérieure, PSL University, CNRS, Laboratoire des Biomolécules, LBM, 75005, Paris, France.

Antimicrobial and cell-penetrating peptides have been the object of extensive studies for more than 60 years. Initially these two families were studied separately, and more recently parallels have been drawn. These studies have given rise to numerous methodological developments both in terms of observation techniques and membrane models. This review presents some of the most recent original and innovative developments in this field, namely droplet interface bilayers (DIBs), new fluorescence approaches, force measurements, and photolabelling.
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http://dx.doi.org/10.1016/j.abb.2021.108751DOI Listing
March 2021

SBML Level 3: an extensible format for the exchange and reuse of biological models.

Mol Syst Biol 2020 08;16(8):e9110

Computing and Mathematical Sciences, California Institute of Technology, Pasadena, CA, USA.

Systems biology has experienced dramatic growth in the number, size, and complexity of computational models. To reproduce simulation results and reuse models, researchers must exchange unambiguous model descriptions. We review the latest edition of the Systems Biology Markup Language (SBML), a format designed for this purpose. A community of modelers and software authors developed SBML Level 3 over the past decade. Its modular form consists of a core suited to representing reaction-based models and packages that extend the core with features suited to other model types including constraint-based models, reaction-diffusion models, logical network models, and rule-based models. The format leverages two decades of SBML and a rich software ecosystem that transformed how systems biologists build and interact with models. More recently, the rise of multiscale models of whole cells and organs, and new data sources such as single-cell measurements and live imaging, has precipitated new ways of integrating data with models. We provide our perspectives on the challenges presented by these developments and how SBML Level 3 provides the foundation needed to support this evolution.
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http://dx.doi.org/10.15252/msb.20199110DOI Listing
August 2020

Triacylglycerols sequester monotopic membrane proteins to lipid droplets.

Nat Commun 2020 08 7;11(1):3944. Epub 2020 Aug 7.

Laboratoire de Physique de l'École Normale Supérieure, ENS, Université PSL, CNRS, Sorbonne Université, Université de Paris, F-75005, Paris, France.

Triacylglycerols (TG) are synthesized at the endoplasmic reticulum (ER) bilayer and packaged into organelles called lipid droplets (LDs). LDs are covered by a single phospholipid monolayer contiguous with the ER bilayer. This connection is used by several monotopic integral membrane proteins, with hydrophobic membrane association domains (HDs), to diffuse between the organelles. However, how proteins partition between ER and LDs is not understood. Here, we employed synthetic model systems and found that HD-containing proteins strongly prefer monolayers and returning to the bilayer is unfavorable. This preference for monolayers is due to a higher affinity of HDs for TG over membrane phospholipids. Protein distribution is regulated by PC/PE ratio via alterations in monolayer packing and HD-TG interaction. Thus, HD-containing proteins appear to non-specifically accumulate to the LD surface. In cells, protein editing mechanisms at the ER membrane would be necessary to prevent unspecific relocation of HD-containing proteins to LDs.
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http://dx.doi.org/10.1038/s41467-020-17585-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7414839PMC
August 2020

Systems biology markup language (SBML) level 3 package: multistate, multicomponent and multicompartment species, version 1, release 2.

J Integr Bioinform 2020 Jul 6;17(2-3). Epub 2020 Jul 6.

NIAID/NIH, Bethesda, USA.

Rule-based modeling is an approach that permits constructing reaction networks based on the specification of rules for molecular interactions and transformations. These rules can encompass details such as the interacting sub-molecular domains and the states and binding status of the involved components. Conceptually, fine-grained spatial information such as locations can also be provided. Through "wildcards" representing component states, entire families of molecule complexes sharing certain properties can be specified as patterns. This can significantly simplify the definition of models involving species with multiple components, multiple states, and multiple compartments. The systems biology markup language (SBML) Level 3 Multi Package Version 1 extends the SBML Level 3 Version 1 core with the "type" concept in the Species and Compartment classes. Therefore, reaction rules may contain species that can be patterns and exist in multiple locations. Multiple software tools such as Simmune and BioNetGen support this standard that thus also becomes a medium for exchanging rule-based models. This document provides the specification for Release 2 of Version 1 of the SBML Level 3 Multi package. No design changes have been made to the description of models between Release 1 and Release 2; changes are restricted to the correction of errata and the addition of clarifications.
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http://dx.doi.org/10.1515/jib-2020-0015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7756619PMC
July 2020

BioModels-15 years of sharing computational models in life science.

Nucleic Acids Res 2020 01;48(D1):D407-D415

European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK.

Computational modelling has become increasingly common in life science research. To provide a platform to support universal sharing, easy accessibility and model reproducibility, BioModels (https://www.ebi.ac.uk/biomodels/), a repository for mathematical models, was established in 2005. The current BioModels platform allows submission of models encoded in diverse modelling formats, including SBML, CellML, PharmML, COMBINE archive, MATLAB, Mathematica, R, Python or C++. The models submitted to BioModels are curated to verify the computational representation of the biological process and the reproducibility of the simulation results in the reference publication. The curation also involves encoding models in standard formats and annotation with controlled vocabularies following MIRIAM (minimal information required in the annotation of biochemical models) guidelines. BioModels now accepts large-scale submission of auto-generated computational models. With gradual growth in content over 15 years, BioModels currently hosts about 2000 models from the published literature. With about 800 curated models, BioModels has become the world's largest repository of curated models and emerged as the third most used data resource after PubMed and Google Scholar among the scientists who use modelling in their research. Thus, BioModels benefits modellers by providing access to reliable and semantically enriched curated models in standard formats that are easy to share, reproduce and reuse.
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http://dx.doi.org/10.1093/nar/gkz1055DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7145643PMC
January 2020

Sex differences in nonmedical prescription tranquilizer and stimulant use trends among secondary school students in Argentina, Chile, and Uruguay.

Drug Alcohol Depend 2019 12 4;205:107607. Epub 2019 Oct 4.

Columbia University Mailman School of Public Health, 722 W 168th St, New York, NY, 10032, USA.

Background: Little is known about recent nonmedical prescription tranquilizer and stimulant use trends in Latin America. We tested whether recent trends among students in three South American countries differed by sex over time.

Methods: Three countries independently collected National School Students Survey on Drugs. Students in 8th, 10th, and 12th grades were sampled in Argentina (2007-2014, N = 328,202), Chile (2007-2015, N = 136,379), and Uruguay (2007-2016, N = 32,371). Weighted linear regression models predicted the prevalences and trends over time of past-year nonmedical tranquilizer and stimulant use by country, and tested whether trends differed by sex, adjusting for school type and grade.

Results: In Argentina from 2007 to 2014, past-year nonmedical prescription tranquilizer (girls: 2.8 to 2.6%, boys: 2.5 to 2.3%) and stimulant (girls: 1.7 to 1.3%, boys: 1.9 to 1.5%) use trends did not differ by sex. In Chile from 2007 to 2015, nonmedical prescription tranquilizer use trends significantly differed comparing girls (3.9 to 10%) with boys (3.2 to 6.9%); stimulant use trends did not differ comparing girls (1.6 to 2.0%) with boys (2.0 to 1.3%). In Uruguay from 2007 to 2014 and 2014-2016, past-year nonmedical prescription tranquilizer (girls: 5.1 to 6.6%; boys: 2.8 to 4.2%) and stimulant (girls: 1.8 to 0.7%; boys: 1.8 to 0.7%) use trends did not differ by sex.

Conclusions: Trends of nonmedical prescription tranquilizer use recently increased in Chile and Uruguay, widening by sex over time in Chile only. The drivers of increasing tranquilizer use among girls in Chile and Uruguay merit further investigation.
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http://dx.doi.org/10.1016/j.drugalcdep.2019.107607DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6943976PMC
December 2019

Salivary cortisol levels as a biomarker for severity of withdrawal in opioid-exposed newborns.

Pediatr Res 2020 05 2;87(6):1033-1038. Epub 2019 Oct 2.

Department of Pediatrics, University of Massachusetts Medical School, Worcester, MA, 01655, USA.

Background: Scoring tools used to quantify withdrawal in infants with neonatal abstinence syndrome (NAS) are often confounded by subjective measurements. This study assessed salivary cortisol as an objective biomarker of withdrawal severity in opioid-exposed newborns.

Methods: A prospective study was conducted in 25 full-term opioid-exposed newborns monitored for NAS. Morning and evening salivary cortisol levels were collected starting within 48 h post birth until initiation of pharmacologic treatment for withdrawal (Pre-Treatment) or when the infant was discharged without pharmacotherapy (No Treatment).

Results: Cortisol levels in the Pre-Treatment group (n = 11) were significantly higher within the first week of life (median 1.74 µg/dl) than in the No Treatment group (n = 11; median 0.72 µg/dl; P = 0.003); three infants had inadequate saliva volume for cortisol assay. Cortisol significantly decreased after 72 h post birth among infants discharged without pharmacotherapy (≤72 h median 1.25 µg/dl; ≥72 h median 0.58 µg/dl; P = 0.022), whereas cortisol remained elevated for infants subsequently treated for severity of withdrawal. No cortisol circadian rhythm was observed for either group.

Conclusions: Salivary cortisol in opioid-exposed newborns may provide an index of stress and help identify infants who will have more severe clinical presentation of NAS. Such a biomarker would allow risk stratification for early treatment and discharge decisions.
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http://dx.doi.org/10.1038/s41390-019-0601-7DOI Listing
May 2020

Multi-Omics and Genome-Scale Modeling Reveal a Metabolic Shift During Aging.

Front Mol Biosci 2019 6;6. Epub 2019 Feb 6.

Department of Epigenetics, Babraham Institute, Cambridge, United Kingdom.

In this contribution, we describe a multi-omics systems biology study of the metabolic changes that occur during aging in . Sampling several time points from young adulthood until early old age, our study covers the full duration of aging and include transcriptomics, and targeted MS-based metabolomics. In order to focus on the metabolic changes due to age we used two strains that are metabolically close to wild-type, yet are conditionally non-reproductive. Using these data in combination with a whole-genome model of the metabolism of and mathematical modeling, we predicted metabolic fluxes during early aging. We find that standard Flux Balance Analysis does not accurately predict measured fluxes nor age-related changes associated with the Citric Acid cycle. We present a novel Flux Balance Analysis method where we combined biomass production and targeted metabolomics information to generate an objective function that is more suitable for aging studies. We validated this approach with a detailed case study of the age-associated changes in the Citric Acid cycle. Our approach provides a comprehensive time-resolved multi-omics and modeling resource for studying the metabolic changes during normal aging in .
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http://dx.doi.org/10.3389/fmolb.2019.00002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6372924PMC
February 2019

Effect of a Resuscitation Strategy Targeting Peripheral Perfusion Status vs Serum Lactate Levels on 28-Day Mortality Among Patients With Septic Shock: The ANDROMEDA-SHOCK Randomized Clinical Trial.

Authors:
Glenn Hernández Gustavo A Ospina-Tascón Lucas Petri Damiani Elisa Estenssoro Arnaldo Dubin Javier Hurtado Gilberto Friedman Ricardo Castro Leyla Alegría Jean-Louis Teboul Maurizio Cecconi Giorgio Ferri Manuel Jibaja Ronald Pairumani Paula Fernández Diego Barahona Vladimir Granda-Luna Alexandre Biasi Cavalcanti Jan Bakker Glenn Hernández Gustavo Ospina-Tascón Lucas Petri Damiani Elisa Estenssoro Arnaldo Dubin Javier Hurtado Gilberto Friedman Ricardo Castro Leyla Alegría Jean-Louis Teboul Maurizio Cecconi Maurizio Cecconi Giorgio Ferri Manuel Jibaja Ronald Pairumani Paula Fernández Diego Barahona Alexandre Biasi Cavalcanti Jan Bakker Glenn Hernández Leyla Alegría Giorgio Ferri Nicolás Rodriguez Patricia Holger Natalia Soto Mario Pozo Jan Bakker Deborah Cook Jean-Louis Vincent Andrew Rhodes Bryan P Kavanagh Phil Dellinger Wim Rietdijk David Carpio Nicolás Pavéz Elizabeth Henriquez Sebastian Bravo Emilio Daniel Valenzuela Magdalena Vera Jorge Dreyse Vanessa Oviedo Maria Alicia Cid Macarena Larroulet Edward Petruska Claudio Sarabia David Gallardo Juan Eduardo Sanchez Hugo González José Miguel Arancibia Alex Muñoz Germán Ramirez Florencia Aravena Andrés Aquevedo Fabián Zambrano Milan Bozinovic Felipe Valle Manuel Ramirez Victor Rossel Pilar Muñoz Carolina Ceballos Christian Esveile Cristian Carmona Eva Candia Daniela Mendoza Aída Sanchez Daniela Ponce Daniela Ponce Jaime Lastra Bárbara Nahuelpán Fabrizio Fasce Cecilia Luengo Nicolas Medel Cesar Cortés Luz Campassi Paolo Rubatto Nahime Horna Mariano Furche Juan Carlos Pendino Lisandro Bettini Carlos Lovesio María Cecilia González Jésica Rodruguez Héctor Canales Francisco Caminos Cayetano Galletti Estefanía Minoldo Maria Jose Aramburu Daniela Olmos Nicolás Nin Jordán Tenzi Carlos Quiroga Pablo Lacuesta Agustín Gaudín Richard Pais Ana Silvestre Germán Olivera Gloria Rieppi Dolores Berrutti Marcelo Ochoa Paul Cobos Fernando Vintimilla Vanessa Ramirez Milton Tobar Fernanda García Fabricio Picoita Nelson Remache Vladimir Granda Fernando Paredes Eduardo Barzallo Paul Garcés Fausto Guerrero Santiago Salazar German Torres Cristian Tana José Calahorrano Freddy Solis Pedro Torres Luís Herrera Antonio Ornes Verónica Peréz Glenda Delgado Alexei López Eliana Espinosa José Moreira Blanca Salcedo Ivonne Villacres Jhonny Suing Marco Lopez Luis Gomez Guillermo Toctaquiza Mario Cadena Zapata Milton Alonso Orazabal Ruben Pardo Espejo Jorge Jimenez Alexander Calderón Gustavo Paredes José Luis Barberán Tatiana Moya Horacio Atehortua Rodolfo Sabogal Guillermo Ortiz Antonio Lara Fabio Sanchez Alvaro Hernán Portilla Humberto Dávila Jorge Antonio Mora Luis Eduardo Calderón Ingrid Alvarez Elena Escobar Alejandro Bejarano Luis Alfonso Bustamante José Luis Aldana

JAMA 2019 02;321(7):654-664

Departmento de Medicina Intensiva, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago.

Importance: Abnormal peripheral perfusion after septic shock resuscitation has been associated with organ dysfunction and mortality. The potential role of the clinical assessment of peripheral perfusion as a target during resuscitation in early septic shock has not been established.

Objective: To determine if a peripheral perfusion-targeted resuscitation during early septic shock in adults is more effective than a lactate level-targeted resuscitation for reducing mortality.

Design, Setting, And Participants: Multicenter, randomized trial conducted at 28 intensive care units in 5 countries. Four-hundred twenty-four patients with septic shock were included between March 2017 and March 2018. The last date of follow-up was June 12, 2018.

Interventions: Patients were randomized to a step-by-step resuscitation protocol aimed at either normalizing capillary refill time (n = 212) or normalizing or decreasing lactate levels at rates greater than 20% per 2 hours (n = 212), during an 8-hour intervention period.

Main Outcomes And Measures: The primary outcome was all-cause mortality at 28 days. Secondary outcomes were organ dysfunction at 72 hours after randomization, as assessed by Sequential Organ Failure Assessment (SOFA) score (range, 0 [best] to 24 [worst]); death within 90 days; mechanical ventilation-, renal replacement therapy-, and vasopressor-free days within 28 days; intensive care unit and hospital length of stay.

Results: Among 424 patients randomized (mean age, 63 years; 226 [53%] women), 416 (98%) completed the trial. By day 28, 74 patients (34.9%) in the peripheral perfusion group and 92 patients (43.4%) in the lactate group had died (hazard ratio, 0.75 [95% CI, 0.55 to 1.02]; P = .06; risk difference, -8.5% [95% CI, -18.2% to 1.2%]). Peripheral perfusion-targeted resuscitation was associated with less organ dysfunction at 72 hours (mean SOFA score, 5.6 [SD, 4.3] vs 6.6 [SD, 4.7]; mean difference, -1.00 [95% CI, -1.97 to -0.02]; P = .045). There were no significant differences in the other 6 secondary outcomes. No protocol-related serious adverse reactions were confirmed.

Conclusions And Relevance: Among patients with septic shock, a resuscitation strategy targeting normalization of capillary refill time, compared with a strategy targeting serum lactate levels, did not reduce all-cause 28-day mortality.

Trial Registration: ClinicalTrials.gov Identifier: NCT03078712.
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http://dx.doi.org/10.1001/jama.2019.0071DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6439620PMC
February 2019

Modeling Meets Metabolomics-The WormJam Consensus Model as Basis for Metabolic Studies in the Model Organism .

Front Mol Biosci 2018 14;5:96. Epub 2018 Nov 14.

Epigenetics Department, Babraham Institute, Cambridge, United Kingdom.

Metabolism is one of the attributes of life and supplies energy and building blocks to organisms. Therefore, understanding metabolism is crucial for the understanding of complex biological phenomena. Despite having been in the focus of research for centuries, our picture of metabolism is still incomplete. Metabolomics, the systematic analysis of all small molecules in a biological system, aims to close this gap. In order to facilitate such investigations a blueprint of the metabolic network is required. Recently, several metabolic network reconstructions for the model organism have been published, each having unique features. We have established the WormJam Community to merge and reconcile these (and other unpublished models) into a single consensus metabolic reconstruction. In a series of workshops and annotation seminars this model was refined with manual correction of incorrect assignments, metabolite structure and identifier curation as well as addition of new pathways. The WormJam consensus metabolic reconstruction represents a rich data source not only for network-based approaches like flux balance analysis, but also for metabolomics, as it includes a database of metabolites present in , which can be used for annotation. Here we present the process of model merging, correction and curation and give a detailed overview of the model. In the future it is intended to expand the model toward different tissues and put special emphasizes on lipid metabolism and secondary metabolism including ascaroside metabolism in accordance to their central role in physiology.
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http://dx.doi.org/10.3389/fmolb.2018.00096DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6246695PMC
November 2018

BioModels: expanding horizons to include more modelling approaches and formats.

Nucleic Acids Res 2018 01;46(D1):D1248-D1253

European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Genome Campus, Hinxton, Cambridge CB10 1SD, UK.

BioModels serves as a central repository of mathematical models representing biological processes. It offers a platform to make mathematical models easily shareable across the systems modelling community, thereby supporting model reuse. To facilitate hosting a broader range of model formats derived from diverse modelling approaches and tools, a new infrastructure for BioModels has been developed that is available at http://www.ebi.ac.uk/biomodels. This new system allows submitting and sharing of a wide range of models with improved support for formats other than SBML. It also offers a version-control backed environment in which authors and curators can work collaboratively to curate models. This article summarises the features available in the current system and discusses the potential benefit they offer to the users over the previous system. In summary, the new portal broadens the scope of models accepted in BioModels and supports collaborative model curation which is crucial for model reproducibility and sharing.
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http://dx.doi.org/10.1093/nar/gkx1023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5753244PMC
January 2018

The effects of using answer sheets on reported drug use and data quality in a classroom survey: A cluster-randomized study.

Drug Alcohol Depend 2017 09 20;178:194-200. Epub 2017 Jun 20.

Violence Prevention Research Program, Department of Emergency Medicine, UC Davis School of Medicine, Sacramento, CA 95817, United States.

Background: We compare self-reported prevalence of drug use and indicators of data quality from two different response modes (with and without an independent answer sheet for recording responses) in a survey conducted in 2015 among secondary school students.

Methods: Stratified cluster-randomized study conducted among students in grades 8-12 from public, private and subsidized schools in Chile (N=2317 students in 122 classes). Measurements included were: percentage reporting substance use (tobacco, alcohol, marijuana, cocaine, ecstasy); number of inconsistent responses; number of item nonresponses; percentage of extreme reports of drug use; percentage reporting using the nonexistent drug, relevón; and completion times.

Results: Compared with those who responded directly in the questionnaire booklet, students who used a separate answer sheet took 17.6 more minutes (95% confidence interval [CI]: 14.4-20.8) to complete the survey and had on average 1.5 more inconsistent responses (95%CI: 0.91-2.14). The prevalence and variance of drug use was higher among those who used an answer sheet for all substances except tobacco; the prevalence ratio (PR) of reported substance use for low-prevalence substances during the past year were: cocaine PR=2.5 (95%CI: 1.6-4.1); ecstasy PR=5.0 (95%CI: 2.4-10.5); relevón PR=4.8 (95%CI: 2.5-9.3).

Conclusions: Using an answer sheet for a self-administered paper-and-pencil survey of drug use among students result in lower quality data and higher reports of drug use. International comparison of adolescent drug use from school-based surveys should be done with caution. The relative ranking of a country could be misleading if different mode of recording answers are used.
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http://dx.doi.org/10.1016/j.drugalcdep.2017.05.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5548613PMC
September 2017

Facile Synthesis of Potassium Poly(heptazine imide) (PHIK)/Ti-Based Metal-Organic Framework (MIL-125-NH) Composites for Photocatalytic Applications.

ACS Appl Mater Interfaces 2017 Jul 27;9(27):22941-22949. Epub 2017 Jun 27.

Department of Colloid Chemistry, Max Planck Institute of Colloids and Interfaces , 14476 Potsdam, Germany.

Photocatalytically active composites comprising potassium poly(heptazine imide) (PHIK) and a Ti-based metal-organic framework (MOF, MIL-125-NH) are prepared in situ by simply dispersing both materials in water. The driving forces of composite formation are the electrostatic interactions between the solids and the diffusion of potassium ions from PHIK to MIL-125-NH. This mechanism implies that other composites of poly(heptazine imide) salts and different MOFs bearing positive surface charge can potentially be obtained in a similar fashion. The suggested strategy thus opens a new avenue for the facile synthesis of such materials. The composites are shown to have a superior photocatalytic activity in Rhodamine B degradation under blue light irradiation. The reaction rate is doubled compared to that of pure MOF compound and is 7 times higher than the activity of the pristine PHIK. The results of the electron paramagnetic resonance (EPR) investigations and the analysis of the electronic structures of the solids suggest the electron transfer from MIL-125-NH to PHIK in the composite. The possible pathways for the dye degradation and the rationalization of the increased activity of the composites are elaborated.
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http://dx.doi.org/10.1021/acsami.7b04745DOI Listing
July 2017

Quantitative fluorescence spectroscopy and flow cytometry analyses of cell-penetrating peptides internalization pathways: optimization, pitfalls, comparison with mass spectrometry quantification.

Sci Rep 2016 11 14;6:36938. Epub 2016 Nov 14.

Sorbonne Universités, UPMC Univ Paris 06, Ecole Normale Supérieure, CNRS, Laboratoire des Biomolécules (LBM), 4 place Jussieu, 75005 Paris, France.

The mechanism of cell-penetrating peptides entry into cells is unclear, preventing the development of more efficient vectors for biotechnological or therapeutic purposes. Here, we developed a protocol relying on fluorometry to distinguish endocytosis from direct membrane translocation, using Penetratin, TAT and R9. The quantities of internalized CPPs measured by fluorometry in cell lysates converge with those obtained by our previously reported mass spectrometry quantification method. By contrast, flow cytometry quantification faces several limitations due to fluorescence quenching processes that depend on the cell line and occur at peptide/cell ratio >6.10 for CF-Penetratin. The analysis of cellular internalization of a doubly labeled fluorescent and biotinylated Penetratin analogue by the two independent techniques, fluorometry and mass spectrometry, gave consistent results at the quantitative and qualitative levels. Both techniques revealed the use of two alternative translocation and endocytosis pathways, whose relative efficacy depends on cell-surface sugars and peptide concentration. We confirmed that Penetratin translocates at low concentration and uses endocytosis at high μM concentrations. We further demonstrate that the hydrophobic/hydrophilic nature of the N-terminal extremity impacts on the internalization efficiency of CPPs. We expect these results and the associated protocols to help unraveling the translocation pathway to the cytosol of cells.
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http://dx.doi.org/10.1038/srep36938DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5107916PMC
November 2016

The systems biology format converter.

BMC Bioinformatics 2016 Apr 5;17:154. Epub 2016 Apr 5.

EMBL European Bioinformatics Institute, Wellcome Trust Genome Campus, CB10 1SD, Cambridge, Hinxton, UK.

Background: Interoperability between formats is a recurring problem in systems biology research. Many tools have been developed to convert computational models from one format to another. However, they have been developed independently, resulting in redundancy of efforts and lack of synergy.

Results: Here we present the System Biology Format Converter (SBFC), which provide a generic framework to potentially convert any format into another. The framework currently includes several converters translating between the following formats: SBML, BioPAX, SBGN-ML, Matlab, Octave, XPP, GPML, Dot, MDL and APM. This software is written in Java and can be used as a standalone executable or web service.

Conclusions: The SBFC framework is an evolving software project. Existing converters can be used and improved, and new converters can be easily added, making SBFC useful to both modellers and developers. The source code and documentation of the framework are freely available from the project web site.
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http://dx.doi.org/10.1186/s12859-016-1000-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4820913PMC
April 2016

Snapshot of sequential SNARE assembling states between membranes shows that N-terminal transient assembly initializes fusion.

Proc Natl Acad Sci U S A 2016 Mar 15;113(13):3533-8. Epub 2016 Mar 15.

Laboratoire de Physique Statistique, École Normale Superieure, L'université de recherche Paris Sciences et Lettres, CNRS UMR 8550, Sorbonne Universités, Université Pierre-et-Marie-Curie (UPMC) University of Paris 06, Université Paris Diderot, 75005 Paris, France;

Many prominent biological processes are driven by protein assembling between membranes. Understanding the mechanisms then entails determining the assembling pathway of the involved proteins. Because the intermediates are by nature transient and located in the intermembrane space, this determination is generally a very difficult, not to say intractable, problem. Here, by designing a setup with sphere/plane geometry, we have been able to freeze one transient state in which the N-terminal domains of SNARE proteins are assembled. A single camera frame is sufficient to obtain the complete probability of this state with the transmembrane distance. We show that it forms when membranes are 20 nm apart and stabilizes by further assembling of the SNAREs at 8 nm. This setup that fixes the intermembrane distance, and thereby the transient states, while optically probing the level of molecular assembly by Förster resonance energy transfer (FRET) can be used to characterize any other transient transmembrane complexes.
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http://dx.doi.org/10.1073/pnas.1518935113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4822643PMC
March 2016

[Historical trauma. Systematic review of a different approach to armed conflict].

Rev Colomb Psiquiatr 2015 Jan-Mar;44(1):41-9. Epub 2014 Dec 11.

Departamento de Salud Mental, Pontificia Universidad Javeriana, Bogotá, Colombia.

Introduction: Historical trauma (HT) is a collective trauma inflicted on a group of people who share an identity or affiliation, and is often characterized by the transgenerational legacy of traumatic experiences, and expressed through various psychological and social responses. This construct is proposed in contrast to post-traumatic stress disorder (PTSD) due to limitations identified with the latter diagnostic category when addressing collective trauma, especially in situations of political and social violence. The purpose of this article is to review the literature published so far on HT.

Methods: A search was performed using the terms "historical trauma" and "mental health" or "trauma histórico" and "salud mental" in the scientific databases, EMBASE, Ebscohost, JSTOR, ProQuest, LILACS, SciELO, PsycARTICLES, ISI Web of Science and PubMed.

Results: The authors reviewed HT definition, paramount characteristics of its traumatic experience, and several theories of on the transgenerational succession if these experiences occur, as well as possible consequences of traumatic events at individual, family and social level. Common characteristics of different therapeutic models are highlighted, in addition to some recommendations for their application.

Conclusions: PTSD has clear limitations in addressing community and cumulative traumatic experiences related to specific social and historical contexts. The authors discuss the potential utility of HT in this task. Finally, several gaps in current knowledge regarding this construct are mentioned, and some recommendations for future research are indicated.
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http://dx.doi.org/10.1016/j.rcp.2014.09.005DOI Listing
September 2016

COMBINE Archive Specification Version 1.

J Integr Bioinform 2015 Sep 4;12(2):261. Epub 2015 Sep 4.

Several standard formats have been proposed that can be used to describe models, simulations, data or other essential information in a consistent fashion. These constitute various separate components required to reproduce a given published scientific result. The Open Modeling EXchange format (OMEX) supports the exchange of all the information necessary for a modeling and simulation experiment in biology. An OMEX file is a ZIP container that includes a manifest file, an optional metadata file, and the files describing the model. The manifest is an XML file listing all files included in the archive and their type. The metadata file provides additional information about the archive and its content. Although any format can be used, we recommend an XML serialization of the Resource Description Framework. Together with the other standard formats from the Computational Modeling in Biology Network (COMBINE), OMEX is the basis of the COMBINE Archive. The content of a COMBINE Archive consists of files encoded in COMBINE standards whenever possible, but may include additional files defined by an Internet Media Type. The COMBINE Archive facilitates the reproduction of modeling and simulation experiments in biology by embedding all the relevant information in one file. Having all the information stored and exchanged at once also helps in building activity logs and audit trails.
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http://dx.doi.org/10.2390/biecoll-jib-2015-261DOI Listing
September 2015

JSBML 1.0: providing a smorgasbord of options to encode systems biology models.

Bioinformatics 2015 Oct 16;31(20):3383-6. Epub 2015 Jun 16.

University of California, San Diego, La Jolla, CA, USA, Center for Bioinformatics Tuebingen (ZBIT), University of Tuebingen, Tübingen, Germany.

Unlabelled: JSBML, the official pure Java programming library for the Systems Biology Markup Language (SBML) format, has evolved with the advent of different modeling formalisms in systems biology and their ability to be exchanged and represented via extensions of SBML. JSBML has matured into a major, active open-source project with contributions from a growing, international team of developers who not only maintain compatibility with SBML, but also drive steady improvements to the Java interface and promote ease-of-use with end users.

Availability And Implementation: Source code, binaries and documentation for JSBML can be freely obtained under the terms of the LGPL 2.1 from the website http://sbml.org/Software/JSBML. More information about JSBML can be found in the user guide at http://sbml.org/Software/JSBML/docs/.

Contact: jsbml-development@googlegroups.com or andraeger@eng.ucsd.edu

Supplementary Information: Supplementary data are available at Bioinformatics online.
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http://dx.doi.org/10.1093/bioinformatics/btv341DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4595895PMC
October 2015

COMBINE archive and OMEX format: one file to share all information to reproduce a modeling project.

BMC Bioinformatics 2014 Dec 14;15:369. Epub 2014 Dec 14.

European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SD, UK.

Background: With the ever increasing use of computational models in the biosciences, the need to share models and reproduce the results of published studies efficiently and easily is becoming more important. To this end, various standards have been proposed that can be used to describe models, simulations, data or other essential information in a consistent fashion. These constitute various separate components required to reproduce a given published scientific result.

Results: We describe the Open Modeling EXchange format (OMEX). Together with the use of other standard formats from the Computational Modeling in Biology Network (COMBINE), OMEX is the basis of the COMBINE Archive, a single file that supports the exchange of all the information necessary for a modeling and simulation experiment in biology. An OMEX file is a ZIP container that includes a manifest file, listing the content of the archive, an optional metadata file adding information about the archive and its content, and the files describing the model. The content of a COMBINE Archive consists of files encoded in COMBINE standards whenever possible, but may include additional files defined by an Internet Media Type. Several tools that support the COMBINE Archive are available, either as independent libraries or embedded in modeling software.

Conclusions: The COMBINE Archive facilitates the reproduction of modeling and simulation experiments in biology by embedding all the relevant information in one file. Having all the information stored and exchanged at once also helps in building activity logs and audit trails. We anticipate that the COMBINE Archive will become a significant help for modellers, as the domain moves to larger, more complex experiments such as multi-scale models of organs, digital organisms, and bioengineering.
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http://dx.doi.org/10.1186/s12859-014-0369-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4272562PMC
December 2014

BioModels: ten-year anniversary.

Nucleic Acids Res 2015 Jan 20;43(Database issue):D542-8. Epub 2014 Nov 20.

European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK.

BioModels (http://www.ebi.ac.uk/biomodels/) is a repository of mathematical models of biological processes. A large set of models is curated to verify both correspondence to the biological process that the model seeks to represent, and reproducibility of the simulation results as described in the corresponding peer-reviewed publication. Many models submitted to the database are annotated, cross-referencing its components to external resources such as database records, and terms from controlled vocabularies and ontologies. BioModels comprises two main branches: one is composed of models derived from literature, while the second is generated through automated processes. BioModels currently hosts over 1200 models derived directly from the literature, as well as in excess of 140,000 models automatically generated from pathway resources. This represents an approximate 60-fold growth for literature-based model numbers alone, since BioModels' first release a decade ago. This article describes updates to the resource over this period, which include changes to the user interface, the annotation profiles of models in the curation pipeline, major infrastructure changes, ability to perform online simulations and the availability of model content in Linked Data form. We also outline planned improvements to cope with a diverse array of new challenges.
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http://dx.doi.org/10.1093/nar/gku1181DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4383975PMC
January 2015

Binding of sperm protein Izumo1 and its egg receptor Juno drives Cd9 accumulation in the intercellular contact area prior to fusion during mammalian fertilization.

Development 2014 Oct 10;141(19):3732-9. Epub 2014 Sep 10.

Laboratoire de Physique Statistique, Ecole Normale Supérieure, Université Pierre et Marie Curie, Université Paris Diderot, Centre National de la Recherche Scientifique UMR8550, 24 rue Lhomond, Paris 75005, France

Little is known about the molecular mechanisms that induce gamete fusion during mammalian fertilization. After initial contact, adhesion between gametes only leads to fusion in the presence of three membrane proteins that are necessary, but insufficient, for fusion: Izumo1 on sperm, its receptor Juno on egg and Cd9 on egg. What happens during this adhesion phase is a crucial issue. Here, we demonstrate that the intercellular adhesion that Izumo1 creates with Juno is conserved in mouse and human eggs. We show that, along with Izumo1, egg Cd9 concomitantly accumulates in the adhesion area. Without egg Cd9, the recruitment kinetics of Izumo1 are accelerated. Our results suggest that this process is conserved across species, as the adhesion partners, Izumo1 and its receptor, are interchangeable between mouse and human. Our findings suggest that Cd9 is a partner of Juno, and these discoveries allow us to propose a new model of the molecular mechanisms leading to gamete fusion, in which the adhesion-induced membrane organization assembles all key players of the fusion machinery.
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http://dx.doi.org/10.1242/dev.111534DOI Listing
October 2014

SBML qualitative models: a model representation format and infrastructure to foster interactions between qualitative modelling formalisms and tools.

BMC Syst Biol 2013 Dec 10;7:135. Epub 2013 Dec 10.

Instituto Gulbenkian de Ciência, Rua da Quinta Grande 6, 2780-156 Oeiras, Portugal.

Background: Qualitative frameworks, especially those based on the logical discrete formalism, are increasingly used to model regulatory and signalling networks. A major advantage of these frameworks is that they do not require precise quantitative data, and that they are well-suited for studies of large networks. While numerous groups have developed specific computational tools that provide original methods to analyse qualitative models, a standard format to exchange qualitative models has been missing.

Results: We present the Systems Biology Markup Language (SBML) Qualitative Models Package ("qual"), an extension of the SBML Level 3 standard designed for computer representation of qualitative models of biological networks. We demonstrate the interoperability of models via SBML qual through the analysis of a specific signalling network by three independent software tools. Furthermore, the collective effort to define the SBML qual format paved the way for the development of LogicalModel, an open-source model library, which will facilitate the adoption of the format as well as the collaborative development of algorithms to analyse qualitative models.

Conclusions: SBML qual allows the exchange of qualitative models among a number of complementary software tools. SBML qual has the potential to promote collaborative work on the development of novel computational approaches, as well as on the specification and the analysis of comprehensive qualitative models of regulatory and signalling networks.
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http://dx.doi.org/10.1186/1752-0509-7-135DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3892043PMC
December 2013

Path2Models: large-scale generation of computational models from biochemical pathway maps.

BMC Syst Biol 2013 Nov 1;7:116. Epub 2013 Nov 1.

European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Trust Genome Campus, Hinxton, Cambridge, UK.

Background: Systems biology projects and omics technologies have led to a growing number of biochemical pathway models and reconstructions. However, the majority of these models are still created de novo, based on literature mining and the manual processing of pathway data.

Results: To increase the efficiency of model creation, the Path2Models project has automatically generated mathematical models from pathway representations using a suite of freely available software. Data sources include KEGG, BioCarta, MetaCyc and SABIO-RK. Depending on the source data, three types of models are provided: kinetic, logical and constraint-based. Models from over 2 600 organisms are encoded consistently in SBML, and are made freely available through BioModels Database at http://www.ebi.ac.uk/biomodels-main/path2models. Each model contains the list of participants, their interactions, the relevant mathematical constructs, and initial parameter values. Most models are also available as easy-to-understand graphical SBGN maps.

Conclusions: To date, the project has resulted in more than 140 000 freely available models. Such a resource can tremendously accelerate the development of mathematical models by providing initial starting models for simulation and analysis, which can be subsequently curated and further parameterized.
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http://dx.doi.org/10.1186/1752-0509-7-116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4228421PMC
November 2013