Structure, Dynamics and Functional Implications of the Eukaryotic Vault Complex.

Vault ribonucleoprotein particles are naturally designed nanocages, widely found in the eukaryotic kingdom. Vaults consist of 78 copies of the major vault protein (MVP) that are organized in 2 symmetrical cup-shaped halves, of an approximate size of 70x40x40 nm, leaving a huge internal cavity which accommodates the vault poly(ADP-ribose) polymerase (vPARP), the telomerase-associated protein-1 (TEP1) and some small untranslated RNAs. Diverse hypotheses have been developed on possible functions of vaults, based on their unique capsular structure, their rapid movements and the distinct subcellular localization of the particles, implicating transport of cargo, but they are all pending confirmation. Vault particles also possess many attributes that can be exploited in nanobiotechnology, particularly in the creation of vehicles for the delivery of multiple molecular cargoes. Here we review what is known about the structure and dynamics of the vault complex and discuss a possible mechanism for the vault opening process. The recent findings in the characterization of the vaults in cells and in its natural microenvironment will be also discussed.

Spontaneous pneumomediastinum: An extra muscular manifestation of anti-MDA5 dermatomyositis. Report of 2 cases.

The use of specific antibodies in inflammatory myopathies has improved the characterization of this disease, identifying different clinical phenotypes. Patients with dermatomyositis (DM) and anti-MDA5 antibodies display typical skin symptoms, lesser muscular involvement, and a prevalence of interstitial lung disease (ILD) of up to 91%. Beyond ILD, spontaneous pneumomediastinum (SN) has been identified as a rare but potentially fatal pulmonary manifestation. Two cases of this complication in patients with anti-MDA5 DM are reported.

Transition of human γ-tubulin ring complex into a closed conformation during microtubule nucleation.

Microtubules are essential for intracellular organization and chromosome segregation. They are nucleated by the γ-tubulin ring complex (γTuRC). However, isolated vertebrate γTuRC adopts an open conformation that deviates from the microtubule structure, raising the question of the nucleation mechanism. In this study, we determined cryo-electron microscopy structures of human γTuRC bound to a nascent microtubule. Structural changes of the complex into a closed conformation ensure that γTuRC templates the 13-protofilament microtubules that exist in human cells. Closure is mediated by a latch that interacts with incorporating tubulin, making it part of the closing mechanism. Further rearrangements involve all γTuRC subunits and the removal of the actin-containing luminal bridge. Our proposed mechanism of microtubule nucleation by human γTuRC relies on large-scale structural changes that are likely the target of regulation in cells.

Ortner's Syndrome (Cardiovocal Syndrome): A Case Report.

Ortner's syndrome, also known as cardiovocal syndrome, refers to vocal cord paralysis caused by an underlying cardiovascular condition. It is often due to the constriction of the left recurrent laryngeal nerve by the pulmonary artery or left atrium. Recurrent aspiration pneumonia is a frequent complication, which can result in substantial morbidity and mortality. Early recognition and treatment, as well as the resolution of the underlying cause, when feasible, can enhance the otherwise unfavorable prognosis of this condition. In this particular case, a 65-year-old man with idiopathic dilated cardiomyopathy was diagnosed with hoarseness and evidence of left vocal cord palsy.

High-Flow Oxygen and Other Noninvasive Respiratory Support Therapies in Bronchiolitis: Systematic Review and Network Meta-Analyses.

OBJECTIVES: We present a systematic review on the effectiveness of noninvasive respiratory support techniques in bronchiolitis. DATA SOURCES: Systematic review with pairwise meta-analyses of all studies and network meta-analyses of the clinical trials. STUDY SELECTION: Patients below 24 months old with bronchiolitis who require noninvasive respiratory support were included in randomized controlled trials (RCTs), non-RCT, and cohort studies in which high-flow nasal cannula (HFNC) was compared with conventional low-flow oxygen therapy (LFOT) and/or noninvasive ventilation (NIV). DATA EXTRACTION: Emergency wards and hospitalized patients with bronchiolitis. DATA SYNTHESIS: A total of 3,367 patients were analyzed in 14 RCTs and 8,385 patients in 14 non-RCTs studies. Only in nonexperimental studies, HFNC is associated with a lower risk of invasive mechanical ventilation (MV) than NIV (odds ratio, 0.49; 95% CI, 0.42-0.58), with no differences in experimental studies. There were no differences between HFNC and NIV in other outcomes. HFNC is more effective than LFOT in reducing oxygen days and treatment failure. In the network meta-analyses of clinical trials, NIV was the most effective intervention to avoid invasive MV (surface under the cumulative ranking curve [SUCRA], 57.03%) and to reduce days under oxygen therapy (SUCRA, 79.42%), although crossover effect estimates between interventions showed no significant differences. The included studies show methodological heterogeneity, but it is only statistically significant for the reduction of days of oxygen therapy and length of hospital stay. CONCLUSIONS: Experimental evidence does not suggest that high-flow oxygen therapy has advantages over LFOT as initial treatment nor over NIV as a rescue treatment.

Síndrome del dedo azul: de la piel a lo multisistémico / Blue digit syndrome: from skin to a multisystemic etiology

El signo del dedo azul (SDA) es una condición poco frecuente causada principalmente por la oclusión de la vasculatura periférica. Clínicamente puede manifestarse como una coloración azulada o eritrocianótica en uno o varios dedos en ausencia de traumatismo y condiciones propias de congelación. Las etiologías son múltiples e incluyen obstrucción del flujo arterial, disminución del flujo venoso y alteración en la viscosidad sanguínea. La importancia de reconocer el signo como motivo de consulta radica en encaminar un diagnóstico temprano e instaurar un tratamiento que evite la evolución natural de la enfermedad hacia la necrosis, amputación o muerte del paciente. Proponemos un algoritmo diagnóstico para reconocer los elementos de la historia clínica que guíen la etiología y los paraclínicos disponibles desde el Servicio de Urgencias.

Blue finger sign (BFS) is a rare condition caused mainly by occlusion of peripheral vasculature. Clinically it may manifest as a bluish, or erythrocyanotic discoloration of one or more fingers in the absence of trauma and freezing conditions. The etiologies are multiple and include arterial flow obstruction, decreased venous flow, and altered blood viscosity. The importance of recognizing the sign as a reason for consultation lies in the early diagnosis and the establishment of a treatment that finally avoids the natural evolution of the disease towards necrosis and finally amputation or death of the patient. We propose a diagnostic algorithm based on recognizing elements of the clinical history that guide the etiology and paraclinical available from the Emergency Department.

Pulsatile parallel flow of air and a viscoelastic fluid with multiple characteristic times. An application to mucus in the trachea and the frequency of cough.

We study the dynamics of a binary fluid, where the two fluids are flowing parallel to each other in a cylindrical geometry, and driven by a pulsatile pressure gradient. One of the fluids is a low viscosity Newtonian fluid, the other one is viscoelastic. In order to be able to apply the model to different biofluids, we consider that the viscoelastic fluid has several characteristic times. We characterize the dynamics of the fluids as generalized Darcy's laws, with linear response functions to pulsatile pressure gradients, whose parameters are coupled for both fluids through the fluid-fluid boundary conditions. We apply our results to the dynamics of mucus and air in the trachea and find that the frequency that allows for a larger movement of the mucus, coincides with the experimental frequency of cough. This allows us to propose a plausible explanation for the frequency of cough in healthy individuals, a mechanical process to expel noxious substances from the respiratory system.

Symmetry disruption commits vault particles to disassembly.

Vaults are ubiquitous ribonucleoprotein particles involved in a diversity of cellular processes, with promising applications as nanodevices for delivery of multiple cargos. The vault shell is assembled by the symmetrical association of multiple copies of the major vault protein that, initially, generates half vaults. The pairwise, anti-parallel association of two half vaults produces whole vaults. Here, using a combination of vault recombinant reconstitution and structural techniques, we characterized the molecular determinants for the vault opening process. This process commences with a relaxation of the vault waist, causing the expansion of the inner cavity. Then, local disengagement of amino-terminal domains at the vault midsection seeds a conformational change that leads to the aperture, facilitating access to the inner cavity where cargo is hosted. These results inform a hitherto uncharacterized step of the vault cycle and will aid current engineering efforts leveraging vault for tailored cargo delivery.

Outbreak of Enterovirus Infection with Neurological Presentations in a Pediatric Population in Northern Spain: A Clinical Observational Study.

OBJECTIVE: The study aimed to describe the cases of neurological disease related to the outbreak of enterovirus (EV) in three regions in Northern Spain during 2016. MATERIALS AND METHODS: Multicenter retrospective observational study. Clinical, radiological, and microbiological data were analyzed from patients younger than 15 years with confirmed EV-associated neurological disease admitted to 10 hospitals of Asturias, Cantabria, and Castile and Leon between January 1 and December 31, 2016. RESULTS: Fifty-five patients were included. Median age was 24 months (interquartile range = 18.5 months). Fifteen patients were classified as aseptic meningitis (27.3%). In total, 37 cases presented brainstem encephalitis (67.3%), 25 of them due to EV-A71 with excellent prognosis (84.6% asymptomatic 2 months following the onset). Three cases of acute flaccid myelitis (5.5%) by EV-D68 were reported and presented persistent paresis 2 months following the onset. Microbiological diagnosis by reverse transcriptase polymerase chain reaction was performed in all cases, finding EV in cerebrospinal fluid in meningitis, but not in brainstem encephalitis and acute flaccid myelitis, where EV was found in respiratory or rectal samples. Step therapy was administrated with intravenous immunoglobulin (IVIG; 32.7%), methylprednisolone (10%), and plasmapheresis (3.6%). Four patients received fluoxetine (7.3%). Twenty patients needed to be admitted to pediatric intensive care unit (36.4%). CONCLUSION: Clinical, microbiological, and radiological diagnosis is essential in outbreaks of EV neurological disease, taking into account that it can be difficult to identify EV-A71 and EV-D68 in CSF, requiring throat or rectal samples. There is not specific treatment to these conditions and the efficacy and understanding of the mechanism of action of immune-modulatory treatment (IVIG, corticosteroids, and plasmapheresis) is limited.

Sistema de actividades para desarrollar habilidades comunicativas en idioma Inglés en los residentes de Estomatología / System of activities for developing communication skills in the English language in dental residents

RESUMEN Fundamento: la preparación idiomática, según lo establecido por el Marco Común Europeo de Referencia (MCER), constituye una necesidad de primer orden en el proceso de formación y superación de los futuros profesionales de las ciencias médicas. Objetivo: diseñar un sistema de actividades para desarrollar habilidades comunicativas en idioma Inglés en los residentes de Estomatología. Métodos: se realizó un estudio descriptivo de corte transversal en la Facultad de Estomatología entre enero 2018-diciembre 2019. Se emplearon métodos teóricos: histórico-lógico, analítico-sintético, inductivo-deductivo y sistémico-estructural; empíricos: análisis documental, encuesta en forma de cuestionario a estudiantes y entrevista a informantes clave. Resultados: el diagnóstico realizado demostró la necesidad de diseñar un sistema de actividades que incluye tres folletos: el primero, con actividades para la impartición de clases dirigido a profesores y estudiantes; el segundo, con respuestas a interrogantes y orientaciones metodológicas generales y un set de audiciones auténticas con sus transcripciones; y el tercero, ofrece ayuda a los estudiantes en su estudio individual. Conclusiones: el sistema de actividades diseñado se caracteriza por su flexibilidad y enfoque interdisciplinar, tiene en cuenta el desarrollo de las cuatro habilidades del idioma, las subhabilidades y sus funciones. Fue valorado de forma satisfactoria por los especialistas quienes reconocieron sus adecuadas pertinencia social y pedagógica, estructura lógica, factibilidad, originalidad y valor científico-pedagógico.

ABSTRACT Background: language preparation, as established by the Common European Framework of Reference (CEFR), constitutes a first order need in the process of training and updating future professionals in the medical sciences. Objective: to design a system of activities to develop communication skills in the English language in Dentistry residents. Methods: a descriptive cross-sectional study was carried out at the Dentistry Faculty from January 2018 to December 2019. Theoretical methods were used: historical-logical, analytical-synthetic, inductive-deductive and systemic-structural; empirical ones: documentary analysis, survey in the form of a questionnaire to students and interview with key informants. Results: the diagnosis showed the need to design a system of activities that includes three booklets: the first, with activities for teaching classes aimed at teachers and students; the second, with answers to questions and general methodological guidelines and a set of authentic auditions with their transcripts; and the third, offers help to students in their individual study. Conclusions: the designed activity system is characterized by its flexibility and interdisciplinary approach; it takes into account the development of the four language skills, sub skills and their functions. It was satisfactorily evaluated by specialists who recognized its adequate social and pedagogical relevance, logical structure, feasibility, originality and pedagogical-scientific value.

Structure and dsRNA-binding activity of the Birnavirus Drosophila X Virus VP3 protein.

The Birnavirus multifunctional protein VP3 plays an essential role coordinating the virus life cycle, interacting with the capsid protein VP2, with the RNA-dependent RNA polymerase VP1 and with the dsRNA genome. Furthermore, the role of this protein in controlling host cell responses triggered by dsRNA and preventing gene silencing has been recently demonstrated. Here we report the X-ray structure and dsRNA-binding activity of the N-terminal domain of Drosophila X virus (DXV) VP3. The domain folds in a bundle of three α-helices and arranges as a dimer, exposing to the surface a well-defined cluster of basic residues. Site directed mutagenesis combined with Electrophoretic Mobility Shift Assays (EMSA) and Surface Plasmon Resonance (SPR) revealed that this cluster, as well as a flexible and positively charged region linking the first and second globular domains of DXV VP3, are essential for dsRNA-binding. Also, RNA silencing studies performed in insect cell cultures confirmed the crucial role of this VP3 domain for the silencing suppression activity of the protein.IMPORTANCE The Birnavirus moonlighting protein VP3 plays crucial roles interacting with the dsRNA genome segments to form stable ribonucleoprotein complexes and controlling host cell immune responses, presumably by binding to and shielding the dsRNA from recognition by the host silencing machinery. The structural, biophysical and functional data presented in this work has identified the N-terminal domain of VP3 as responsible for the dsRNA-binding and silencing suppression activities of the protein in Drosophila X virus.

Rasgo falciforme e infarto esplénico: una entidad no ajena en población antioqueña / Sickle trait and splenic infarction, a non-foreign entity in Antioquia population

Resumen Generalmente, los pacientes con rasgo falciforme sufren pocas manifestaciones del espectro de la anemia de células falciformes. El infarto esplénico es raro, pero es una complicación documentada del rasgo falciforme y, usualmente, se presenta en condiciones de disminución de la presión parcial de oxígeno, como ocurre en grandes alturas. Se presenta el caso de un joven sin antecedentes, quien presentó dolor súbito en hipocondrio izquierdo luego de viaje a zona de gran altura y en quien se documentó infarto esplénico y posteriormente se confirmó como etiología del cuadro, rasgo falciforme mediante electroforesis de hemoglobina. La mayoría de los pacientes desconocen su rasgo falciforme, lo que hace desafiante su enfoque, retrasa el diagnóstico y resulta en manejos inadecuados que pueden aumentar la extensión del infarto esplénico y requerir finalmente esplenectomía.

Abstract Generally, patients with sickle cell trait have few manifestations of the sickle cell spectrum. Splenic infarction is rare, but is a documented complication of sickle cell trait and usually occurs under conditions of decreased partial pressure of oxygen, such as at high altitudes. We present the case of a young man with no previous history who presented sudden pain in the left hypochondrium after traveling to a high-altitude area. Splenic infarction was documented and sickle cell trait was later confirmed with hemoglobin electrophoresis as the etiology of the condition. Most patients remain ignorant of their sickle cell trait, which makes their approach challenging, delays diagnosis, and results in inappropriate management that may increase the extent of splenic infarction and eventually require splenectomy.

[CPAP vs oxygen therapy in infants being transported due to acute respiratory failure]. / CPAP vs oxigenoterapia convencional en lactantes trasladados por insuficiencia respiratoria.

OBJECTIVE: The aims of our study are to evaluate the effectiveness and security of CPAP (continuous positive airway pressure) in infants transferred with acute respiratory failure (ARF) and to compare their evolution in PICU between CPAP vs oxygen therapy. MATERIALS AND METHODS: We conducted a retrospective observational and analytical study by reviewing the health records of infants with ARF aged 0 to 12months that required interhospital transfer to the PICU. RESULTS: We included 110 patients: 71 transported with CPAP and 39 with oxygen therapy. The main cause of ARF was acute bronchiolitis (81.8%). The median level of CPAP was 7cmH2O (interquartile range, 6-7). Controlling by the previous values in specific multivariable models, CPAP produced a significant decrease in the Wood-Downes score (beta = -1.08; 95% CI = -1.76 to -0.40; P = .002) and the heart rate (beta = -19.64, 95% CI = -28.46 to -10.81; P < .001). No patients required endotracheal intubation during transport. During the PICU stay, the intubation rate was similar in the CPAP group (7%) and the oxygen therapy group (5.1%) (P=.689). The proportion of patients that required bilevel positive airway pressure within 6hours of admission to the PICU was higher in the oxygen therapy group: 100% (11/11) vs 69.2% (18/26), P=.04. CONCLUSIONS: Early administration of CPAP to infants with ARF was a safe respiratory support intervention during interhospital transport. During patient transport, the use of CPAP achieved greater decreases in the Wood-Downes score and heart rate compared to oxygen therapy.