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Since the beginning of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)/coronavirus disease 2019 (COVID-19) pandemic, global sequencing efforts have led in the field of inborn errors of immunity, and inspired particularly by previous research on life-threatening influenza, they have revealed that known and novel inborn errors affecting type I interferon immunity underlie critical COVID-19 in up to 5% of cases. In addition, neutralizing autoantibodies against type I interferons have been identified in up to 20% of patients with critical COVID-19 who are older than 80 years and 20% of fatal cases, with a higher prevalence in men and individuals older than 70 years. Also, inborn errors impairing regulation of type I interferon responses and RNA degradation have been found as causes of multisystem inflammatory syndrome in children, a life-threatening hyperinflammatory condition complicating otherwise mild initial SARS-CoV-2 infection in children and young adults. Better understanding of these immunologic mechanisms can aid in designing treatments for severe COVID-19, multisystem inflammatory syndrome in children, long COVID, and neuro-COVID.

El objetivo del presente artículo es esclarecer el valor de la noción de historia en la obra de Gilles Deleuze a partir de su relación con la historia de la filosofía. Esta propuesta es realizada a partir del análisis de los diferentes estilos que para la escritura filosófica ensayó y tematizó el filósofo francés como modo de reinterpretar el canon de la filosofía. Dicha estrategia, en Deleuze, supone perseguir el sentido interno del estilo en la filosofía y su vinculación con la noción de historia a través de un régimen de signos diferente al del ámbito de la representación. Desde esta perspectiva, nuestra investigación recorre la comprensión de la historia a partir de la categoría de producción en tanto que historia de lo contingente y nos obliga a repensar el tiempo y la naturaleza de los acontecimientos históricos, con especial atención a la revolución.

The International Union of Immunological Societies (IUIS) expert committee (EC) on Inborn Errors of Immunity (IEI) reports here the 2022 updated phenotypic classification, which accompanies and complements the most-recent genotypic classification. This phenotypic classification is aimed for clinicians at the bedside and focuses on clinical features and laboratory phenotypes of specific IEI. In this classification, 485 IEI underlying phenotypes as diverse as infection, malignancy, allergy, auto-immunity and auto-inflammation are described, including 55 novel monogenic defects and 1 autoimmune phenocopy. Therefore, all 485 diseases of the genetic classification are presented in this paper in the form of colored tables with essential clinical or immunological phenotype entries.

Presentamos un modelo epidemiológico compartimental para la transmisión del virus Covid-19 que denominamos SEIART, que contempla testeo para individuos infectados sintomáticos y asintomáticos. El modelo es una generalización de los modelos clásicos SIR, SEIR y SEIAR, e incluye las clases de individuos infectados sintomáticos testeados y no testeados, así como individuos asintomáticos testeados y no testeados. Mostramos el número reproductivo básico asociado al sistema y exhibimos que decrece con el aumento en las tasas de testeo y de aplicación tanto en las clases de infectados sintomáticos como asintomáticos. Presentamos simulaciones para mostrar que un aumento en las pruebas y una mayor efectividad en las pruebas de aplicación / detección provocan una reducción en la población infectada y en la mortalidad.

High-silica explosive eruptions are one of the most dangerous natural phenomena, yet it is unclear which processes are involved in this infrequent kind of event. We present the first systematic characterization of near-field seismicity associated with a large high-silica eruption analyzing data recorded before, during and after the 4 June 2011 rhyolitic eruption of Puyehue–Cordón Caulle Volcanic Complex (PCCVC). Results of a first-level data processing, developed by the Southern Andean Volcano Observatory (OVDAS) to monitor unrest and the evolution of the eruption, are complemented here with the relocation of hypocenters into a local 1D velocity model, the time series of the b value and the computation of the focal mechanism. This information allows us to define several phases before and after the onset of the eruption, describing details of the space–time evolution of seismicity, defining and characterizing the seismic sources, and identifying the structural control of the magmatic intrusion and stress variations during the eruption. Our results illuminate several underlying processes, with emphasis on the possible role that basement structures had on the storage, transport and evacuation of magma. Integrating our results with previous findings based on satellite geodesy and petrology of erupted materials, we discuss general conceptual models regarding destabilization of structurally controlled acidic magmatic systems, the pass from unrest to eruption, and changes in eruptive style and waning phases of eruptions, with broader implications for monitoring and forecast of violent silicic eruptions.

The term moonlighting proteins refers to those proteins that present alternative functions performed by a single polypeptide chain acquired throughout evolution (called canonical and moonlighting, respectively). Over 78% of moonlighting proteins are involved in human diseases, 48% are targeted by current drugs, and over 25% of them are involved in the virulence of pathogenic microorganisms. These facts encouraged us to study the link between the functions of moonlighting proteins and disease. We found a large number of moonlighting functions activated by pathological conditions that are highly involved in disease development and progression. The factors that activate some moonlighting functions take place only in pathological conditions, such as specific cellular translocations or changes in protein structure. Some moonlighting functions are involved in disease promotion while others are involved in curbing it. The disease-impairing moonlighting functions attempt to restore the homeostasis, or to reduce the damage linked to the imbalance caused by the disease. The disease-promoting moonlighting functions primarily involve the immune system, mesenchyme cross-talk, or excessive tissue proliferation. We often find moonlighting functions linked to the canonical function in a pathological context. Moonlighting functions are especially coordinated in inflammation and cancer. Wound healing and epithelial to mesenchymal transition are very representative. They involve multiple moonlighting proteins with a different role in each phase of the process, contributing to the current-phase phenotype or promoting a phase switch, mitigating the damage or intensifying the remodeling. All of this implies a new level of complexity in the study of pathology genesis, progression, and treatment. The specific protein function involved in a patient’s progress or that is affected by a drug must be elucidated for the correct treatment of diseases.

SUMMARY Volcano seismology is an essential tool for monitoring volcanic processes in the advent and during eruptions. A variety of seismic signals can be recorded at volcanoes, of which some are thought to be related to the migration of fluids which is of primary importance for the anticipation of imminent eruptions. We investigate the volcanic crises at Villarrica volcano in 2015 and report on a newly discovered very-long-period (VLP) signal that accompanies phases of periodic long period (LP) signal burst. Despite their low amplitude emergent character, we can locate the source region of the 1 Hz LP signals to the close vicinity of the volcano using a network-based correlation method. The source of the VLP signal with a period of about 30–100 s appears to locate in the vicinity of two stations a few kilometres from the summit. Both stations record very similar VLP waveforms that are correlated with the envelope of the LP bursts. A shallow magma reservoir was inferred by Contreras from surface deformation as the source of inflation following the eruption in 2015. Cyclic volume changes of 6 m3 in this reservoir at 3 km depth can explain the observed amplitudes of the vertical VLP signal. We propose that the LP signal is generated by the migration of gas or gas-rich magma that is periodically released from the inflating reservoir through a non-linear valve structure which modulates the flux, and thereby causes bursts of flow-related LP signals and pressure changes observed as VLP deformation. Our model predicts that the correlated occurrence of LP bursts and VLP surface motion depends on the intensity of the fluid flux. A weaker flux of fluids may not exceed the opening pressure of valve structure, and higher rates might maintain pressure above the closing pressure. In both cases, the VLP signal vanishes. Our observation provides constrains for models of fluid transport inside volcanoes. At Villarrica the VLP signal, and its relation to the LP activity, reveal additional information about fluxes in the magmatic reservoir that might aide forecasting of volcanic activity.

BackgroundWe previously reported inborn errors of TLR3- and TLR7-dependent type I interferon (IFN) immunity in 1-5% of unvaccinated patients with life-threatening COVID-19, and auto-antibodies against type I IFN in another 15-20% of cases.MethodsWe report here a genome-wide rare variant burden association analysis in 3,269 unvaccinated patients with life-threatening COVID-19 (1,301 previously reported and 1,968 new patients), and 1,373 unvaccinated SARS-CoV-2-infected individuals without pneumonia. A quarter of the patients tested had antibodies against type I IFN (234 of 928) and were excluded from the analysis.ResultsNo gene reached genome-wide significance. Under a recessive model, the most significant gene with at-risk variants wasTLR7, with an OR of 27.68 (95%CI:1.5-528.7,P=1.1×10−4), in analyses restricted to biochemically loss-of-function (bLOF) variants. We replicated the enrichment in rare predicted LOF (pLOF) variants at 13 influenza susceptibility loci involved in TLR3-dependent type I IFN immunity (OR=3.70 [95%CI:1.3-8.2],P=2.1×10−4). Adding the recently reportedTYK2COVID-19 locus strengthened this enrichment, particularly under a recessive model (OR=19.65 [95%CI:2.1-2635.4];P=3.4×10−3). When these 14 loci andTLR7were considered, all individuals hemizygous (n=20) or homozygous (n=5) for pLOF or bLOF variants were patients (OR=39.19 [95%CI:5.2-5037.0],P=4.7×10−7), who also showed an enrichment in heterozygous variants (OR=2.36 [95%CI:1.0-5.9],P=0.02). Finally, the patients with pLOF or bLOF variants at these 15 loci were significantly younger (mean age [SD]=43.3 [20.3] years) than the other patients (56.0 [17.3] years;P=1.68×10−5).ConclusionsRare variants of TLR3- and TLR7-dependent type I IFN immunity genes can underlie life-threatening COVID-19, particularly with recessive inheritance, in patients under 60 years old.

We report the updated classification of inborn errors of immunity, compiled by the International Union of Immunological Societies Expert Committee. This report documents the key clinical and laboratory features of 55 novel monogenic gene defects, and 1 phenocopy due to autoantibodies, that have either been discovered since the previous update (published January 2020) or were characterized earlier but have since been confirmed or expanded in subsequent studies. While variants in additional genes associated with immune diseases have been reported in the literature, this update includes only those that the committee assessed that reached the necessary threshold to represent novel inborn errors of immunity. There are now a total of 485 inborn errors of immunity. These advances in discovering the genetic causes of human immune diseases continue to significantly further our understanding of molecular, cellular, and immunological mechanisms of disease pathogenesis, thereby simultaneously enhancing immunological knowledge and improving patient diagnosis and management. This report is designed to serve as a resource for immunologists and geneticists pursuing the molecular diagnosis of individuals with heritable immunological disorders and for the scientific dissection of cellular and molecular mechanisms underlying monogenic and related human immune diseases. ispartof: JOURNAL OF CLINICAL IMMUNOLOGY vol:42 issue:7 pages:1473-1507 ispartof: location:Netherlands status: published

The regular practice of physical exercise is extraordinarily effective in the management of a growing number of chronic diseases, some of them with a prevalence of pandemic magnitude, for which the society must assume the incorporation of physical activity as a health strategy to prevent and to serve as a complementary treatment of the disease. Not only medicine and physiotherapy play a fundamental role in the management of exercise for health but also, outside of health, Sports science and physical education degree is crucial in this field of work. From a health point of view, medicine and physiotherapy have a primary role in the management of exercise for health and also, outside of health, sports science and physical education degree occupy a very prominent role in the promotion and implementation of strategies for the promotion of health. These professions have been occupying a position in addressing this problem that, on some occasions, has led to points of friction with respect to their role, responsibilities and function. On the other hand, there is a need to resolve the question of the professions’ areas of competence while maintaining the will to simultaneously recognize the growing areas of competence shared interprofessionally and the highly relevant areas specific to each profession. This document is based on the need to address the incorporation of exercise in the prevention and management of disease in a solid and consistent way, considering the contribution of the professions involved from the perspective of multidisciplinary work and with a non-conflictual but cooperative, transparent and respectful collaboration. In addition, this collaboration should always aim at serving society in the most effective way possible, clearly defining the professional attributions of medicine, physiotherapy and physical activity and sport sciences in everything related to the use of exercise as a tool for health.

Since the arrival of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in December 2019, its characterization as a novel human pathogen, and the resulting coronavirus disease 2019 (COVID-19) pandemic, over 6.5 million people have died worldwide—a stark and sobering reminder of the fundamental and nonredundant roles of the innate and adaptive immune systems in host defense against emerging pathogens. Inborn errors of immunity (IEI) are caused by germline variants, typically in single genes. IEI are characterized by defects in development and/or function of cells involved in immunity and host defense, rendering individuals highly susceptible to severe, recurrent, and sometimes fatal infections, as well as immune dysregulatory conditions such as autoinflammation, autoimmunity, and allergy. The study of IEI has revealed key insights into the molecular and cellular requirements for immune-mediated protection against infectious diseases. Indeed, this has been exemplified by assessing the impact of SARS-CoV-2 infection in individuals with previously diagnosed IEI, as well as analyzing rare cases of severe COVID-19 in otherwise healthy individuals. This approach has defined fundamental aspects of mechanisms of disease pathogenesis, immunopathology in the context of infection with a novel pathogen, and therapeutic options to mitigate severe disease. This review summarizes these findings and illustrates how the study of these rare experiments of nature can inform key features of human immunology, which can then be leveraged to improve therapies for treating emerging and established infectious diseases.

Abstract Background Cryptococcosis is a potentially life-threatening fungal disease caused by encapsulated yeasts of the genus Cryptococcus, mostly C. neoformans or C. gattii. Cryptococcal meningitis is the most frequent clinical manifestation in humans. Neutralizing autoantibodies (auto-Abs) against granulocyte–macrophage colony-stimulating factor (GM-CSF) have recently been discovered in otherwise healthy adult patients with cryptococcal meningitis, mostly caused by C. gattii. We hypothesized that three Colombian patients with cryptococcal meningitis caused by C. neoformans in two of them would carry high plasma levels of neutralizing auto-Abs against GM-CSF. Methods We reviewed medical and laboratory records, performed immunological evaluations, and tested for anti-cytokine auto-Abs three previously healthy HIV-negative adults with disseminated cryptococcosis. Results Peripheral blood leukocyte subset levels and serum immunoglobulin concentrations were within the normal ranges. We detected high levels of neutralizing auto-Abs against GM-CSF in the plasma of all three patients. Conclusions We report three Colombian patients with disseminated cryptococcosis associated with neutralizing auto-Abs against GM-CSF. Further studies should evaluate the genetic contribution to anti-GM-CSF autoantibody production and the role of the GM-CSF signaling pathway in the immune response to Cryptococcus spp.

Tinnitus is the phantom perception of sound that has no external source. A neurological signature of tinnitus, and the frequently associated hyperacusis, is an imbalance between excitatory and inhibitory activity in the central auditory system (CAS), leading to dysregulated network excitability. The large conductance, calcium-activated potassium (BK) channel is a key player in pre- and post-synaptic excitability through its mediation of K+ currents. Changes in BK channel activity are associated with aberrant network activity in sensory regions of the CNS, raising the possibility that BK channel modulation could regulate activity associated with tinnitus and hyperacusis. To test whether BK channel openers are able to suppress biomarkers of drug-induced tinnitus and hyperacusis, the 1,3,4 oxadiazole BMS-191011 was given to young adult CBA mice that had been administered 250 mg/kg sodium salicylate (SS). Systemic treatment with BMS-191011 reduced behavioral manifestations of SS-induced tinnitus, but not hyperacusis, probed via the gap-in-noise startle response method. Systemic BMS-191011 treatment did not influence SS-induced increases in auditory brainstem response functions, but local application at the inferior colliculus did reverse SS-suppressed spontaneous activity, particularly in the frequency region of the tinnitus percept. Thus, action of BMS-191011 in the inferior colliculus may contribute to the reduction in behaviorally measured tinnitus. Together, these findings support the utility of BK channel openers in reducing central auditory processing changes associated with the formation of the tinnitus percept.

Background: COVID-19, caused by SARS-CoV-2, is a potentially lethal, rapidly-expanding pandemic and many efforts are being carried out worldwide to understand and control the disease. COVID-19 patients may display a cytokine release syndrome, which causes severe lung inflammation, leading, in many instances, to death. Objective: This paper is intended to explore the possibilities of controlling the COVID-19-associated hyperinflammation by using licensed drugs with anti-inflammatory effects. Hypothesis: We have previously described that pentoxifylline alone, or in combination with oxypurinol, reduces the systemic inflammation caused by experimentally-induced pancreatitis in rats. Pentoxifylline is an inhibitor of TNF-α production and oxypurinol inhibits xanthine oxidase. TNF-α, in turn, activates other inflammatory genes such as Nos2, Icam or IL-6, which regulate migration and infiltration of neutrophils into the pulmonary interstitial tissue, causing injury to the lung parenchyma. In acute pancreatitis, the anti-inflammatory action of pentoxifylline seems to be mediated by the prevention of the rapid and presumably transient loss of PP2A activity. This may also occur in the hyperinflammatory -cytokine releasing phase- of SARS-CoV-2 infection. Therefore, it may be hypothesized that early treatment of COVID-19 patients with pentoxifylline, alone or in combination with oxypurinol, would prevent the potentially lethal acute respiratory distress syndrome. Conclusion: Pentoxifylline and oxypurinol are licensed drugs used for diseases other than COVID-19 and, therefore, phase I clinical trials would not be necessary for the administration to SARS-CoV-2- infected people. It would be worth investigating their potential effects against the hyperinflammatory response to SARS-CoV-2 infection.

To characterize the pediatric population with inborn errors of immunity (IEI) that was treated with hematopoietic stem cell transplantation (HSCT) in three reference centers in Colombia. What have been the characteristics and outcomes of hematopoietic stem cell transplantation in pediatric patients with inborn errors of immunity in three reference care centers in Colombia between 2007 and 2018? We conducted an observational, retrospective cohort study in children with a diagnosis of IEI who underwent HSCT between 2007 and 2018. Forty-seven patients were identified, and 5 were re-transplanted. Sixty-eight percent were male. The median age at diagnosis was 0.6 years, and for HSCT was 1.4 years. The most common diseases were chronic granulomatous disease (38%) followed by severe combined immune deficiencies (19%) and hemophagocytic lymphohistiocytosis (15%). Cord blood donors were the most used source of HSCT (44%). T cell–replete grafts from haploidentical donors using post-transplantation cyclophosphamide represent 37% of the cohort. All patients received conditioning, 62% with a non-myeloablative regimen. Calcineurin inhibitors were the main graft-versus-host disease prophylaxis (63.8%). Acute graft-versus-host disease developed in 35% of the total patients. The most frequent post-transplant infections were viral and fungal infections. The 1-year overall survival rates for the patients who received HSCT from identical, haploidentical, and cord sources were 80%, 72%, and 63%, respectively. The 5-year overall survival was 63%. HSCT is a curative treatment option for some IEI and can be performed with any donor type. Early and timely treatment in referral centers can improve survival.

Mancozeb (MZ), a manganese/zinc containing ethylene-bis-dithiocarbamate, is a broad-spectrum fungicide. Chronic exposure to MZ has been related to several organisms' neurological, hormonal, and developmental disorders. However, little is known about the post-natal effects of developmental exposure to MZ. In this study

Fungal pollution of indoor environments contributes to several allergic symptoms and represents a public health problem. It is well-established that 1-octen-3-ol, also known as mushroom alcohol, is a fungal volatile organic compound (VOC) commonly found in damp indoor spaces and responsible for the typical musty odor. Previously it was reported that exposure to 1-octen-3-ol induced inflammations and disrupted mitochondrial morphology and bioenergetic rate in

Identifying the source mechanisms of low-frequency earthquakes at ice-covered volcanoes can be challenging due to overlapping characteristics of glacially and magmatically derived seismicity. Here we present an analysis of two months of seismic data from Llaima volcano, Chile, recorded by the permanent monitoring network in 2019. We find over 2,000 repeating low-frequency events split across 82 families, the largest of which contains over 200 events. Estimated locations for the largest families indicate shallow sources directly beneath or near the edge of glaciers around the summit vent. These low-frequency earthquakes are part of an annual cycle in activity at the volcano that is strongly correlated with variations in atmospheric temperature, leading us to conclude that meltwater from ice and snow strongly affects the seismic source mechanisms which is likely dominated by basal slip beneath the glaciers. The results presented here should inform future assessments of eruptive potential at Llaima volcano, as well as other ice-covered volcanoes in Chile and worldwide.

Staphylococcus aureus remains a pathogen of high concern in public health programs worldwide due to antibiotic resistance and emergence of highly virulent strains. Many phytochemicals have demonstrated activity against S. aureus and other Gram-positive bacteria, but the minimum inhibitory concentration (MIC) values comparable to commonly used antibiotics are needed. In the present study, bio-guided fractionation of the ethanol extract of seeds of Mammea americana L. (Calophyllaceae) throughout the antibacterial activity, against S. aureus strains that are sensitive and resistant to methicillin, led to the isolation of four coumarins identified as mammea B/BA, mammea B/BC, mammea A/AA cyclo D and mammea A/AA cyclo F, and a mixture of mammea B/BA cyclo F plus mammea B/BD cyclo F. The extract inhibited the growth of S. aureus with MIC values of 2–4 μg/ml and Mammea B/BA (MaBBA) presented MIC values in a range between 0.5 and 1.0 μg/ml in six methicillin-sensitive strains and eight methicillin-resistant strains evaluated. We consider MaBBA the most potent of all mammea coumarins reported to date, according to the literature review carried out at the time of writing of this article. Toxicity assessment in vivo against the nematode Caenorhabditis elegans and in vitro against human fibroblasts of the extract and the compound MaBBA indicated that both had low toxicity.

BackgroundSince many of the risk factors for cognitive decline can be modified by diet, the study of nutrition and its relationships with cognitive status in aging has increased considerably in recent years. However, there are hardly any studies that have assessed cognitive status using a comprehensive set of neuropsychological tests along with measures of functional capacity and mood and that have related it to nutritional status measured from several nutritional parameters that have shown its relationships with cognitive function.ObjectiveTo test the differences in depressive symptomatology and in several measures of nutritional status between three groups classified according to their cognitive status (CS hereafter).MethodOne hundred thirteen participants from nursing homes in Galicia, Spain, underwent a comprehensive neuropsychological examination, including a general screening test (MMSE) and tests for different cognitive domains along with measures of activities of daily living (ADL) and assessment of depressive symptomatology (GDS-SF). According to established clinical criteria, participants were divided into three CS groups, Cognitively Intact (CI), Mild Cognitive Impairment (MCI), and All-Cause Dementia (ACD). Nutritional status was also examined using blood-derived measures, body mass index (BMI) and a nutritional screening test (MNA-SF). Differences between CS groups in all nutritional variables were studied by one-way ANOVAs with post-hoc Bonferroni correction or Kruskal-Wallis with Games-Howell post-hoc correction when appropriate. Multinomial logistic regression was also applied to test the association between nutritional variables and CS.ResultsDifferences between CS groups were statistically significant for depressive symptomatology, vitamin A and D, albumin, selenium (Se), uric acid (UA), and BMI. The results of multinomial logistic regression found positive associations between groups with better CS and higher concentrations of vitamins A and D, transthyretin (TTR), albumin, Se, and UA, while negative associations were found for BMI.ConclusionHigher serum levels of vitamin A, vitamin D, TTR, albumin, Se, and UA could act as protective factors against cognitive decline, whereas higher BMI could act as a risk factor.

The alteration of epigenetic modifications often causes cancer onset and development. In a similar way, aberrant alternative splicing may result in oncogenic products. These issues have often been individually reviewed, but there is a growing body of evidence for the interconnection of both causes of cancer. Actually, aberrant splicing may result from abnormal epigenetic signalization and epigenetic factors may be altered by alternative splicing. In this way, the interrelation between epigenetic marks and alternative splicing form the base of a triangle, while cancer may be placed at the vertex. The present review centers on the interconnections at the triangle base, i.e., between alternative splicing and epigenetic modifications, which may result in neoplastic transformations. The effects of different epigenetic factors, including DNA and histone modifications, the binding of non-coding RNAs and the alterations of chromatin organization on alternative splicing resulting in cancer are first considered. Other less-frequently considered questions, such as the epigenetic regulation of the splicing machinery, the aberrant splicing of epigenetic writers, readers and erasers, etc., are next reviewed in their connection with cancer. The knowledge of the above-mentioned relationships has allowed increasing the collection of biomarkers potentially useful as cancer diagnostic and/or prognostic tools. Finally, taking into account on one hand that epigenetic changes are reversible, and some epigenetic drugs already exist and, on the other hand, that drugs intended for reversing aberrations in alternative splicing, therapeutic possibilities for breaking the mentioned cancer-related triangle are discussed.

In this work, we perform a first study of basic invariant sets of the spatial Hill's four-body problem, where we have used both analytical and numerical approaches. This system depends on a mass parameter mu in such a way that the classical Hill's problem is recovered when mu = 0. Regarding the numerical work, we perform a numerical continuation, for the Jacobi constant C and several values of the mass parameter mu by applying a classical predictor-corrector method, together with a high-order Taylor method considering variable step and order and automatic differentiation techniques, to specific boundary value problems related with the reversing symmetries of the system. The solution of these boundary value problems defines initial conditions of symmetric periodic orbits. Some of the results were obtained departing from periodic orbits within Hill's three-body problem. The numerical explorations reveal that a second distant disturbing body has a relevant effect on the stability of the orbits and bifurcations among these families. We have also found some new families of periodic orbits that do not exist in the classical Hill's three-body problem; these families have some desirable properties from a practical point of view.

Accumulation of human CD21low B cells in peripheral blood is a hallmark of chronic activation of the adaptive immune system in certain infections and autoimmune disorders. The molecular pathways underpinning the development, function, and fate of these CD21low B cells remain incompletely characterized. Here, combined transcriptomic and chromatin accessibility analyses supported a prominent role for the transcription factor T-bet in the transcriptional regulation of these T-bethighCD21low B cells. Investigating essential signals for generating these cells in vitro established that B cell receptor (BCR)/interferon-γ receptor (IFNγR) costimulation induced the highest levels of T-bet expression and enabled their differentiation during cell cultures with Toll-like receptor (TLR) ligand or CD40L/interleukin-21 (IL-21) stimulation. Low proportions of CD21low B cells in peripheral blood from patients with defined inborn errors of immunity (IEI), because of mutations affecting canonical NF-κB, CD40, and IL-21 receptor or IL-12/IFNγ/IFNγ receptor/signal transducer and activator of transcription 1 (STAT1) signaling, substantiated the essential roles of BCR- and certain T cell–derived signals in the in vivo expansion of T-bethighCD21low B cells. Disturbed TLR signaling due to MyD88 or IRAK4 deficiency was not associated with reduced CD21low B cell proportions. The expansion of human T-bethighCD21low B cells correlated with an expansion of circulating T follicular helper 1 (cTfh1) and T peripheral helper (Tph) cells, identifying potential sources of CD40L, IL-21, and IFNγ signals. Thus, we identified important pathways to target autoreactive T-bethighCD21low B cells in human autoimmune conditions, where these cells are linked to pathogenesis and disease progression.

La inmunoglobulina A (IgA) es el isotipo de anticuerpo más abundante en los humanos y fundamentalmente participa en la defensa contra las infecciones y el desarrollo de la tolerancia inmune en las mucosas. La deficiencia de IgA es la inmunodeficiencia más frecuente en humanos, pero comúnmente es asintomática y transitoria. Para diagnosticarla, se cuantifica la concentración de IgA en sangre y se evalúa la magnitud de su disminución. De acuerdo con esta evaluación se clasifica en deficiencia parcial (DPIgA) o deficiencia total (DTIgA). Adicionalmente, si solo se afectan los niveles de IgA sin alteraciones de otras inmunoglobulinas séricas como IgM e IgG o subclases de inmunoglobulina G, entonces se denomina como deficiencia selectiva de IgA (DSIgA). La deficiencia selectiva de IgA es de mayor relevancia clínica y considerada un error innato de la inmunidad, aunque su etiología aún es desconocida y clínicamente se asocia a infecciones de los tractos respiratorio y gastrointestinal, alergias y manifestaciones autoinmunes. Se realizó una búsqueda de artículos científicos en PubMed, Scopus, SciELO y Redalyc sobre la deficiencia selectiva de inmunoglobulina A, con el objetivo de realizar una revisión temática sobre las manifestaciones clínicas, el diagnóstico y el adecuado manejo clínico de los pacientes con esta inmunodeficiencia. Se propone un nuevo algoritmo clínico con el objetivo de mejorar el diagnóstico y brindar un adecuado manejo clínico de los pacientes con esta inmunodeficiencia. Un paciente con deficiencia selectiva de IgA se caracteriza por infecciones recurrentes de los tractos gastrointestinal y respiratorio, en asociación con manifestaciones alérgicas y autoinmunes en individuos mayores de cuatro años, con niveles de IgA sérica menores de 7 mg/dL y con niveles normales de IgG e IgM, y en quienes se hayan descartado defectos relacionados con los linfocitos T u otras causas de hipogammaglobulinemia. Con respecto al manejo clínico, se deben ajustar los esquemas de vacunación e implementar profilaxis antibiótica en las infecciones graves y recurrentes. Para mejorar el pronóstico se debe realizar una atención del paciente por un equipo médico interdisciplinario y un seguimiento continuo por un prolongado periodo de tiempo.

Skeletal muscle is the most abundant tissue in the human body and mechanical injuries are common; these are frequently of mechanical origins, such as contusion. However, the immediate mitochondrial response to injury and energetic substrate utilisation is still unclear. We evaluated the acute response in mitochondrial function after a single muscle contusion, either in fast twitch fibres (glycolytic metabolism), fast and slow twitch (oxidative and glycolytic metabolism), or slow twitch fibres (oxidative metabolism). Rats were assigned to two groups: control and Lesion (muscle contusion). We collected the gastrocnemius and soleus muscles. The fibres were analysed for mitochondrial respiration, lactate dehydrogenase (LDH), citrate synthase (CS) activity, Ca

Since 2013, the International Union of Immunological Societies (IUIS) expert committee (EC) on Inborn Errors of Immunity (IEI) has published an updated phenotypic classification of IEI, which accompanies and complements their genotypic classification into ten tables. This phenotypic classification is user-friendly and serves as a resource for clinicians at the bedside. There are now 430 single-gene IEI underlying phenotypes as diverse as infection, malignancy, allergy, autoimmunity, and autoinflammation. We herein report the 2019 phenotypic classification, including the 65 new conditions. The diagnostic algorithms are based on clinical and laboratory phenotypes for each of the ten broad categories of IEI.

Permethrin (PM) is one of the most used synthetic pyrethroid worldwide. Exposure to this compound during pregnancy and early childhood has been indicated as a risk factor for neurodevelopmental disorders. We evaluated the long-term effects of embryonic PM exposure in different stages of zebrafish development. Briefly, embryos (3 hpf) were exposed to sub-lethal concentrations of PM (25 and 50 μg.L−1) during 24 h and then behavioral parameters were evaluated during embryonic (28 hpf), eleutheroembryonic (3 dpf), larval (7 dpf), and adult stages (90 dpf). PM exposure decreased spontaneous movement at 28 hpf and decreased thigmotaxis in eleutheroembryos. The long-term effects of PM include changes in non-motor behaviors such as fear and anxiety in larva and adults. Adults embryonically exposed to PM also showed a significant increase in aggressiveness parameters. These results demonstrated that embryonic exposure to PM induces persistent neurotoxic effects in adulthood, which can impair the cognitive and behavioral fitness of non-target species contributing to a rise in neurodevelopmental disorders.

Background: LPS-responsive beige -like anchor protein (LRBA) deficiency is a primary immunodeficiency disease caused by loss of LRBA protein expression, due to biallelic mutations in LRBA gene. LRBA deficiency patients exhibit a clinically heterogeneous syndrome. The main clinical complication of LRBA deficiency is immune dysregulation. Furthermore, hypogammaglobulinemia is found in more than half of patients with LRBA-deficiency. To date, no patients with this condition have been reported in Colombia Objective: To evaluate the expression of the LRBA protein in patients from Colombia with clinical phenotype associated to LRBA-deficiency. Methods: In the present study the LRBA-expression in patients from Colombia with clinical phenotype associated to LRBA-deficiency was evaluated. After then, the clinical, the immunological characteristics and the possible genetic variants in LRBA or other genes associated with the immune system in patients that exhibit decrease protein expression was evaluated. Results: In total, 112 patients with different clinical manifestations associated to the clinical LRBA phenotype were evaluated. The LRBA expression varies greatly between different healthy donors and patients. Despite the great variability in the LRBA expression, six patients with a decrease in LRBA protein expression were observed. However, no pathogenic or possible pathogenic biallelic variants in LRBA, or in genes related with the immune system were found. Conclusion: LRBA expression varies greatly between different healthy donors and patients. Reduction LRBA-expression in 6 patients without homozygous mutations in LRBA or in associated genes with the immune system was observed. These results suggest the other genetic, epigenetic or environmental mechanisms, that might be regulated the LRBA-expression. Resumen Antecedentes: la deficiencia de LRBA (del inglés, LPS-responsive beige -like anchor protein) es una inmunodeficiencia primaria causada por la pérdida de la expresión de la proteína LRBA, debido a mutaciones bialélicas en el gen LRBA. Los pacientes con deficiencia de LRBA exhiben un síndrome clínicamente heterogéneo. La principal complicación clínica de la deficiencia de LRBA es la desregulación inmune. Además, la hipogammaglobulinemia se encuentra en más de la mitad de los pacientes con deficiencia de LRBA. Hasta la fecha, no se han reportado pacientes con esta afección en Colombia Objetivo: Evaluar la expresión de la proteína LRBA en pacientes de Colombia con fenotipo clínico asociado a deficiencia de LRBA Métodos: En el presente estudio se evaluó la expresión de LRBA en pacientes de Colombia con fenotipo clínico asociado a deficiencia de LRBA. Después de eso, se evaluaron las características clínicas, inmunológicas y las posibles variantes genéticas en LRBA o en otros genes asociadados con el sistema inmune en pacientes que exhiben una disminución de la expresión de la proteína. Resultados: En total, se evaluaron 112 pacientes con diferentes manifestaciones clínicas asociadas al fenotipo clínico LRBA. La expresión de LRBA varía mucho entre diferentes donantes sanos y pacientes. A pesar de la gran variabilidad en la expresión de LRBA, se observaron seis pacientes con una disminución en la expresión de la proteína LRBA. Sin embargo, no se encontraron variantes bialélicas patógenas o posibles patógenas en LRBA, o en genes relacionados con el sistema inmune. Conclusión: La expresión de LRBA varía mucho entre diferentes donantes sanos y pacientes. Se observó reducción de la expresión de LRBA en 6 pacientes sin mutaciones homocigotas en LRBA o en genes asociados. Estos resultados sugieren los otros mecanismos genéticos, por ejemplo epigenéticos o ambientales, que podrían estar regulados por la expresión de LRBA

El debate sobre la sostenibilidad del sistema sanitario público ha tenido una progresiva importancia debido a la reciente crisis económica. Entre las fórmulas más utilizadas para garantizar la sostenibilidad se encuentran las estrategias basadas en la colaboración público-privada. Este trabajo analiza diversas formas de gestión de hospitales públicos en un área de gestión homogénea, representativa y de elevada complejidad, como es la gestionada por el Servicio Madrileño de Salud (SERMAS). Se pretende conocer si la gestión basada en la colaboración público-privada obtiene mejores resultados de eficiencia técnica e investigadora.Se utiliza la metodología del análisis envolvente de datos (AED) desarrollada por Charnes et al (1978) orientada a outputs. La muestra está formada por los 25 hospitales generales gestionados por el SERMAS, con información obtenida de las memorias anuales de gestión de cada uno de los hospitales y relativa a los años 2009 a 2016. Los resultados evidenciaron una mayor eficiencia técnica de las formas de gestión de hospitales públicos basadas en la colaboración público-privada respecto a la gestión pública tradicional, que sin embargo, obtuvo resultados superiores en eficiencia investigadora a los obtenidos por las formas de gestión de hospitales basadas en la colaboración público-privada. Entre las causas de esta mayor eficiencia técnica, se encuentran la mayor flexibilidad en políticas organizativas y de gasto, así como una mayor independencia de la gerencia de los hospitales de gestión mixta, frente a los de gestión tradicional. En el caso de la eficiencia investigadora, la ausencia de incentivos económicos ligados a la obtención de resultados en investigación en los contratos de concesión de hospitales podría ser una de las principales causas de la menor eficiencia de los hospitales gestionados mediante colaboración público-privada. The debate on the sustainability of the public health system has had a growing importance due to the recent economic crisis. Among the most commonly used formulas to ensure sustainability we can find strategies based on public-private collaboration.This paper analyzes different models of hospital management in an area of homogeneous, representative and of high complexity management, such as managed by the Madrid Health Service (SERMAS).It is intended to know if the management models based in public-private collaboration achieve better results of technical and research efficiency of public hospitals.For the evaluation of the efficiency it is used the methodology of the data envelopment analysis (DEA) developed by Charnes et al (1978) aimed at outputs. The sample is composed of the 25 general hospitals managed by the SERMAS with information obtained from the annual reports for the management of each of the hospitals and relative to the years 2009 to 2016.The results showed a higher level of technical efficiency of the hospitals managed through models based in public-private collaboration with respect to traditional public management, which nevertheless obtained higher results in research efficiency than the hospitals managed through public-private collaboration forms of management. Among the causes of this greater technical efficiency are the greater flexibility in organizational and spending policies as well as greater independence of the management of mixed management hospitals, compared to those of traditional management. In the case of research efficiency, the absence of economic incentives linked to obtaining research results in hospital concession contracts could be one of the main causes of the lower efficiency of hospitals managed through public-private collaboration.

X-linked immunodeficiency with magnesium defect, EBV infection, and neoplasia (XMEN) disease are caused by deficiency of the magnesium transporter 1 (MAGT1) gene. We studied 23 patients with XMEN, 8 of whom were EBV naive. We observed lymphadenopathy (LAD), cytopenias, liver disease, cavum septum pellucidum (CSP), and increased CD4-CD8-B220-TCRαβ+ T cells (αβDNTs), in addition to the previously described features of an inverted CD4/CD8 ratio, CD4+ T lymphocytopenia, increased B cells, dysgammaglobulinemia, and decreased expression of the natural killer group 2, member D (NKG2D) receptor. EBV-associated B cell malignancies occurred frequently in EBV-infected patients. We studied patients with XMEN and patients with autoimmune lymphoproliferative syndrome (ALPS) by deep immunophenotyping (32 immune markers) using time-of-flight mass cytometry (CyTOF). Our analysis revealed that the abundance of 2 populations of naive B cells (CD20+CD27-CD22+IgM+HLA-DR+CXCR5+CXCR4++CD10+CD38+ and CD20+CD27-CD22+IgM+HLA-DR+CXCR5+CXCR4+CD10-CD38-) could differentially classify XMEN, ALPS, and healthy individuals. We also performed glycoproteomics analysis on T lymphocytes and show that XMEN disease is a congenital disorder of glycosylation that affects a restricted subset of glycoproteins. Transfection of MAGT1 mRNA enabled us to rescue proteins with defective glycosylation. Together, these data provide new clinical and pathophysiological foundations with important ramifications for the diagnosis and treatment of XMEN disease.

Chlorpyrifos (CP) is an organophosphate insecticide widely used in the control of agriculture and domestic pests. Occupational exposure is a major form of human poisoning by organophosphates and current therapies for these compounds are not completely efficient. Psidium guajava is a plant widely used in folk medicine and its antioxidant activity has been described. In this study we evaluated the antioxidant and protective potential of the hydroalcoholic extract of P. guajava (HEPG) against CP induced toxicity in the fruit fly Drosophila melanogaster. HEPG in vitro antioxidant activity was confirmed by ABTS, DPPH, Total Phenolics and FRAP assays. The exposure of flies to CP caused increased mortality, locomotor deficits and inhibition of acetylcholinesterase. Flies exposed to CP presented elevated ROS and lipid peroxidation which was accompanied by a significant decrease in mitochondrial viability. As a response to increased oxidative stress, CP exposed flies showed increased GST activity and GSH levels. The mRNA expression of NRF2 and MPK2 (which encodes D. melanogaster p38MAPK) was also significantly up-regulated. HEPG was able to restore all the damage and biochemical/molecular alterations caused by CP. Our results show for the first time the P. guajava potential protective effect against the toxicity caused by chlorpyrifos. Keywords: Organophosphate compound, Oxidative stress, Natural compounds, Protective effects

Dysregulated immune responses are essential underlying causes of a plethora of pathologies including cancer, autoimmunity, and immunodeficiency. We here investigated 4 patients from unrelated families presenting with immunodeficiency, autoimmunity, and malignancy. We identified 4 distinct homozygous mutations in TNFRSF9 encoding the tumor necrosis factor receptor superfamily member CD137/4-1BB, leading to reduced, or loss of, protein expression. Lymphocytic responses crucial for immune surveillance, including activation, proliferation, and differentiation, were impaired. Genetic reconstitution of CD137 reversed these defects. CD137 deficiency is a novel inborn error of human immunity characterized by lymphocytic defects with early-onset Epstein-Barr virus (EBV)-associated lymphoma. Our findings elucidate a functional role and relevance of CD137 in human immune homeostasis and antitumor responses.

El siguiente articulo hace una disertacion sobre los diferentes conceptos que han existido sobre la didactica, desde una vision de desarrollo historico, para luego aterrizar en un analisis de las practicas de ensenanza que han marcado al SENA, y de la importancia de la adaptacion de nuevos modelos que logren transformar las necesidades de formacion hoy en dia.ABSTRACTThe following article makes a dissertation on the different concepts that have existed on didactics, from a vision of historical development, to later land in an analysis of teaching practices that have marked the SENA, and the importance of adapting new models which transform the training needs nowadays.RESUMOO artigo a seguir faz uma dissertacao sobre os diferentes conceitos existentes sobre didatica, a partir de uma visao de desenvolvimento historico, para depois aterrar numa analise das praticas de ensino que marcaram o SENA, e a importância de adaptar novos modelos que transformem as necessidades de formacao hoje.

Llaima Volcano, one of the most active volcanoes in South America, has experienced intense activity during the last 100 years. The most recent eruptive activity occurred during the period 2007–2009 with at least six energetic eruptions, the January 1st 2008 (VEI 3) being the strongest episode. Most of the paroxysmal activity was characterized by a rapid increase in seismic energy (minutes to hours) and the absence of precursory signals, as well as by an accelerated drop of the seismic energy and eruption intensity at the end. Moreover, subtle changes in the increase of low-energy long-period (LP) seismicity and the occurrence of minor explosive activity (six months before the onset of the eruptive cycle), were the only remarkable changes observed in advance. This is the first study that includes a detailed description of the 2007–2009 eruptive period and is based on a temporal analysis of the seismic records, technical reports from the monitoring network and >2000 photos. This set allows a characterization of the coeval eruptive styles (including strombolian and hawaiian activity), morphological changes of the active vents inside the main crater and two fractures located in the SW and SE flanks. Ten phases were identified based on the eruptive style, Volcanic Explosivity Index (VEI) and the salient features of the seismic events. The seismicity that accompanied the eruptive phases was characterized by the predominance of a continuous tremor (TR) and discrete LP events, and a remarkable absence of volcano-tectonics (VT) earthquakes. A waveform cross-correlation analysis of LP events showed an overall low similarity between them, which suggests multiple sources. Our observations and analysis suggest that the plumbing system is composed of multiple independent structures, some of which reached the surface during this eruptive period, indicating that the upper part of the cone could be an unstable and essentially weak zone. The activity and seismicity observed are characteristic of an open-vent system in which the magma can ascend rapidly from several km depth, with little to no clear precursory activity. These results are in agreement with petrological studies of the products of these eruptions.

Circulating autoantibodies (auto-Abs) neutralizing high concentrations (10 ng/mL, in plasma diluted 1 to 10) of IFN-α and/or -ω are found in about 10% of patients with critical COVID-19 pneumonia, but not in subjects with asymptomatic infections. We detect auto-Abs neutralizing 100-fold lower, more physiological, concentrations of IFN-α and/or -ω (100 pg/mL, in 1/10 dilutions of plasma) in 13.6% of 3,595 patients with critical COVID-19, including 21% of 374 patients80 years, and 6.5% of 522 patients with severe COVID-19. These antibodies are also detected in 18% of the 1,124 deceased patients (aged 20 days-99 years; mean: 70 years). Moreover, another 1.3% of patients with critical COVID-19 and 0.9% of the deceased patients have auto-Abs neutralizing high concentrations of IFN-β. We also show, in a sample of 34,159 uninfected subjects from the general population, that auto-Abs neutralizing high concentrations of IFN-α and/or -ω are present in 0.18% of individuals between 18 and 69 years, 1.1% between 70 and 79 years, and 3.4%80 years. Moreover, the proportion of subjects carrying auto-Abs neutralizing lower concentrations is greater in a subsample of 10,778 uninfected individuals: 1% of individuals70 years, 2.3% between 70 and 80 years, and 6.3%80 years. By contrast, auto-Abs neutralizing IFN-β do not become more frequent with age. Auto-Abs neutralizing type I IFNs predate SARS-CoV-2 infection and sharply increase in prevalence after the age of 70 years. They account for about 20% of both critical COVID-19 cases in the over-80s, and total fatal COVID-19 cases.

International audience; In December of 2017, a lava dome emerged at the Nevados de Chillan volcanic complex in the southern Andean volcanic zone, Chile, at the base of a summit crater excavated by explosions during two preceding years of unrest. This posed a number of potential hazards to the surrounding touristic region, so the eruption was carefully monitored. Structure from Motion techniques were used to generate DEMs from satellite and aerial images, from which several useful measurements could be made. Dome growth was characterised at an unprecedented resolution, allowing for the calculation of discharge rates and effusion rates in near real time. A simple model fit to the distance between the dome and crater rim predicted relatively accurately the arrival of the dome toe at the crater rim and the onset of dome collapse outside the crater. Simulations of the path and extent that potential pyroclastic density currents (PDC) generated by dome collapse would follow showed that PDC were not directly threatening populated areas. Over its life cycle as of August 2019, the dome growth was punctuated by frequent explosions, averaging around 30 per day, one of which generated a minor 600 m long PDC on 13 to 15 of July 2018. There appears to be a positive correlation between explosion frequency and lava dome growth rate suggesting that both explosive and effusive processes can coexist, operating at different timescales but responding to the same driving force. A positive correlation is apparent between dome growth rate and seismic activity such as the frequency of tremor and long-period earthquakes suggesting that these might be used as proxies to estimate effusion rate. Initial lava dome effusion rates of 1730 ± 110 m3/day in January 2018 declined to 100 ± 150 m3/day in June 2019. These growth rates are extremely slow when compared to other lava domes, about 300 to 600 times slower than the lava domes at Mt Unzen (1992) and Mt. St. Helens (1980).

Orientador: Antônio Carlos Moretti Dissertação (mestrado) - Universidade Estadual de Campinas, Instituto de Matemática, Estatística e Computação Científica Resumo: Neste trabalho, foi desenvolvida uma aplicação prática de técnicas da pesquisa operacional para a resolução de um problema real de esquematização ou programação de máquinas. Este problema deriva de um flexible job shop scheduling, porém apresentando diversas características próprias, impossibilitando a aplicação de modelos disponíveis na literatura. O desempenho da utilização da combinação de um modelo de programação linear inteira mista com uma heurística de construção e uma heurística de melhoramento foi avaliado diante de cenários reais obtidos da indústria de produção de frascos plásticos. Estas técnicas provaram ser eficientes para a resolução dos casos propostos Abstract: In this work, a practical application of operational research techniques was developed to solve a real machine scheduling or programming problem. This problem derives from a flexible job shop scheduling framework, but presents several unique characteristics, which makes it impossible to apply models available in literature. The performance of using a combination of a mixed integer programming model with a construction heuristic and a improvement heuristic was evaluated using real world scenarios obtained from the plastic bottle production industry. Theses techniques were proven efficient in resolving the proposed cases Mestrado Pesquisa Operacional Mestre em Matemática Aplicada