Immune-mediated loss of transgene expression from virally transduced brain cells is irreversible, mediated by IFNγ, perforin, and TNFα, and due to the elimination of transduced cells

The adaptive immune response to viral vectors reduces vector-mediated transgene expression from the brain. It is unknown, however, whether this loss is caused by functional downregulation of transgene expression or death of transduced cells. Herein, we demonstrate that during the elimination of transgene expression, the brain becomes infiltrated with CD4 and CD8 T cells and that these T cells are necessary for transgene elimination. Further, the loss of transgene-expressing brain cells fails to occur in the absence of IFNγ, perforin, and TNFα receptor. Two methods to induce severe immune suppression in immunized animals also fail to restitute transgene expression, demonstrating the irreversibility of this process. The need for cytotoxic molecules and the irreversibility of the reduction in transgene expression suggested to us that elimination of transduced cells is responsible for the loss of transgene expression. A new experimental paradigm that discriminates between downregulation of transgene expression and the elimination of transduced cells demonstrates that transduced cells are lost from the brain upon the induction of a specific antiviral immune response. We conclude that the anti-adenoviral immune response reduces transgene expression in the brain through loss of transduced cellsFil: Zirger, Jeffrey M.. Cedars Sinai Medical Center; Estados Unidos. University of California at Los Angeles. School of Medicine; Estados UnidosFil: Puntel, Mariana. University of California at Los Angeles. School of Medicine; Estados Unidos. Cedars Sinai Medical Center; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Bergeron, Josee. Cedars Sinai Medical Center; Estados Unidos. University of California at Los Angeles. School of Medicine; Estados UnidosFil: Wibowo, Mia. University of California at Los Angeles. School of Medicine; Estados Unidos. Cedars Sinai Medical Center; Estados UnidosFil: Moridzadeh, Rameen. University of California at Los Angeles. School of Medicine; Estados Unidos. Cedars Sinai Medical Center; Estados UnidosFil: Bondale, Niyati. Cedars Sinai Medical Center; Estados Unidos. University of California at Los Angeles. School of Medicine; Estados UnidosFil: Barcia, Carlos. Cedars Sinai Medical Center; Estados Unidos. University of California at Los Angeles. School of Medicine; Estados UnidosFil: Kroeger, Kurt M.. University of California at Los Angeles. School of Medicine; Estados Unidos. Cedars Sinai Medical Center; Estados UnidosFil: Liu, Chunyan. University of California at Los Angeles. School of Medicine; Estados Unidos. Cedars Sinai Medical Center; Estados UnidosFil: Castro, Maria Graciela. University of California at Los Angeles. School of Medicine; Estados Unidos. Cedars Sinai Medical Center; Estados Unidos. University of Michigan; Estados UnidosFil: Lowenstein, Pedro R.. Cedars Sinai Medical Center; Estados Unidos. University of California at Los Angeles. School of Medicine; Estados Unidos. University of Michigan; Estados Unido

Theoretical study of the chemiluminescence of the Al + H2O reaction

We performed surface hopping simulations of Al + H2O collisions by a direct semiempirical method, reproducing the conditions of previous beam-gas experiments. We observed the formation of the HAlOH species, that dissociates to AlOH + H after a lifetime of about 0.6 ps. This species undergoes nonadiabatic transitions to its first excited state and is responsible for chemiluminescence in the visible range, while the Al−H2O complex emits in the infrared. The computed emission band in the visible is red-shifted with respect to the experimental one, because of slight inaccuracies of the potential energy surfaces. However, collisions with more water molecules and exciplex formation with excited Al(2S, 4P) atoms may also contribute to the short wavelength emission, as we show by accurate ab initio calculations

Demarcation of the included contents in tutoring plans in Europe

La acción tutorial es una parte esencial del trabajo de los docentes, especialmente el relacionado con la educación en valores. En España, este trabajo está determinado por el Plan de Acción Tutorial y por el esfuerzo conjunto de los docentes y los servicios de orientación en la escuela. Sin embargo en el entorno europeo, esta tarea difiere en los contenidos y métodos de trabajo. La presente comunicación tiene por objeto la determinación de los contenidos que se incluyen en la labor tutorial en el entorno europeo, a través del análisis de contenido de los Curriculums Nacionales español, inglés, irlandés, sueco y finlandés.Tutoring action is an essential part of the teachers work, specially the one referred to values teaching. In Spain, this work is determined by the Tutoring Action Plan and by the joint effort of teachers and the guidance services in school. However in european setting, this assignment differs in contents and working methods. The present communication´s aim is to demarcate the included contents in tutoring work in the european setting, through de content analysis of spanish, english, irish, swedish and finnish National Curriculums.peerReviewe

Increased mRNA expression of cytochrome oxidase in dorsal raphe nucleus of depressive suicide victims

Suicidal behavior is a problem with important social repercussions. Some groups of the population show a higher risk of suicide; for example, depression, alcoholism, psychosis or drug abuse frequently precedes suicidal behavior. However, the relationship between metabolic alterations in the brain and premorbid clinical symptoms of suicide remains uncertain. The serotonergic and noradrenergic systems have frequently been, implicated in suicidal behavior and the amount of serotonin in the brain and CSF of suicide victims has been found to be low compared with normal subjects. However, there are contradictory results regarding the role of noradrenergic neurons in the mediation of suicide attempts, possibly reflecting the heterogeneity of conditions that lead to a common outcome. In the present work we focus on the subgroup of suicide victims that share a common diagnosis of major depression. Based on post-mortem studies analyzing mRNA expression by in situ hybridization, serotonergic neurons from the dorsal raphe nucleus (DRN) from depressive suicide victims are seen to over-express cytochrome oxidase mRNA. However, no corresponding changes were found in the expression of tyrosine hydroxylase (TH) mRNA in the noradrenergic neurons of the Locus Coeruleus (LC). These results suggest that, despite of the low levels of serotonin described in suicide victims, the activity of DRN neurons could increase in the suicidally depressed, probably due to the over activation of serotonin re-uptake. No alteration was found in noradrenergic neurons, suggesting that they play no crucial role in the suicidal behavior of depressive patients

Coronavirus disease 2019 (COVID-19) and human pregnancy: a scoping review

The coronavirus disease 2019 (COVID-19) is caused by the infection with a coronavirus (SARS-CoV-2). Pregnants present mild or moderate symptoms, with 5% presenting as a severe pneumonia. Prevalence and evolution of COVID-19 in pregnancy is similar to that of the general population, including the risk of maternal death. Radiography, computed tomography or ultrasound imaging are pivotal for the diagnosis and given the clinical suspicion of COVID-19 pneumonia. Lab findings include lymphocytopenia, thrombocytopenia, leukopenia, and the elevation of D-dimer and ferritin. To date, there is no specific treatment or vaccination for COVID-19; yet clinical management in pregnants is also similar to that of the general population, with prophylactic antibiotic treatment for bacterial pneumonia and oxygen support. Thromboprophylaxis should be indicated in severe cases, given that pregnancy is a hypercoagulable state that may be exacerbated by COVID-19. Hospital management should focus on treating the mother and protecting the newborn and the health personnel. Regarding COVID-19 and perinatal outcomes, premature deliveries are mainly associated to iatrogenic pregnancy termination through cesarean section aimed conserving maternal well-being. To date, vertical transmission to the fetus has not been demonstrated, neither intrauterine, nor through the birth canal. The virus has not been detected in vaginal fluids, or in breast milk. Breastfeeding may be allowed depending on maternal and neonatal health status. There are still many unknown issues, although there is a continuous update of scientific information related to pregnancy and COVID-19

Identification and Visualization of CD8+ T Cell Mediated IFN-γ Signaling in Target Cells during an Antiviral Immune Response in the Brain

CD8+ T cells infiltrate the brain during an anti-viral immune response. Within the brain CD8+ T cells recognize cells expressing target antigens, become activated, and secrete IFNγ. However, there are no methods to recognize individual cells that respond to IFNγ. Using a model that studies the effects of the systemic anti-adenoviral immune response upon brain cells infected with an adenoviral vector in mice, we describe a method that identifies individual cells that respond to IFNγ. To identify individual mouse brain cells that respond to IFNγ we constructed a series of adenoviral vectors that contain a transcriptional response element that is selectively activated by IFNγ signaling, the gamma-activated site (GAS) promoter element; the GAS element drives expression of a transgene, Cre recombinase (Ad-GAS-Cre). Upon binding of IFNγ to its receptor, the intracellular signaling cascade activates the GAS promoter, which drives expression of the transgene Cre recombinase. We demonstrate that upon activation of a systemic immune response against adenovirus, CD8+ T cells infiltrate the brain, interact with target cells, and cause an increase in the number of cells expressing Cre recombinase. This method can be used to identify, study, and eventually determine the long term fate of infected brain cells that are specifically targeted by IFNγ. The significance of this method is that it will allow to characterize the networks in the brain that respond to the specific secretion of IFNγ by anti-viral CD8+ T cells that infiltrate the brain. This will allow novel insights into the cellular and molecular responses underlying brain immune responses

Learning styles and their relationship with the Technologies of Information and Communication (TIC) in the adaptation of pharmacy studies to the ESHE

Introducción: El conocimiento de los estilos de aprendizaje es fundamental para el docente a fin de comprender cómo aprenden sus alumnos y así modificar/reforzar su estilo de enseñanza. La aplicación de las nuevas Tecnologías de la Comunicación y de la Información (TIC) facilita la adaptación de las enseñanzas universitarias al Espacio Europeo de Educación Superior (EEES). Objetivo: Evaluar el estilo de aprendizaje de los alumnos de Farmacia de la Universidad Complutense de Madrid (UCM) y comparar dichos estilos con las TIC. Metodología: Alumnos de 4º curso de licenciatura en Farmacia y de postgrado. Todos respondieron al cuestionario CHAEA de estilos de aprendizaje. Además, se ha planteado un nuevo cuestionario para correlacionar estilos de aprendizaje y TIC. Discusión: Las puntuaciones positivas más elevadas correspondieron al estilo reflexivo seguido del teórico. Más del 80% de los alumnos muestran preferencia muy elevada por las clases magistrales (puntuaciones 4-5, siendo 5 la puntación de máxima preferencia). Este resultado estaría en concordancia con el estilo mayoritario de aprendizaje de los alumnos evaluados. Más del 90% de los alumnos valora de forma altamente positiva (4-5) la impartición de clases mediante la utilización de presentaciones en PowerPoint y, a continuación la utilización de la pizarra y la proyección de videos. Conclusiones: El estilo de aprendizaje de los alumnos de cuarto curso de Farmacia y de postgrado es fundamentalmente reflexivo aunque valoran de forma altamente positiva la utilización de las TIC, lo que confirma la importancia de su uso en la consecución de los objetivos del EEES.Introduction: knowledge of the learning styles of Pharmacy students is an important tool that can be used to improve teaching thereby reinforcing the use of appropriate and transferable teaching strategies. For this, the use of the Technologies of Information and Communication (TIC) may facilitate the implementation of the European Space for Higher Education (ESHE). Objective: To evaluate the learning styles of graduate and postgraduate pharmacy students at the Universidad Complutense of Madrid and, to compare the student´s learning styles with their preferences regarding the use of the TIC. Methods: The study was performed on fourth-year pharmacy students and postgraduate students. The instrument used to analyze the learning styles was the CHAEA questionnaire. Moreover, a new questionnaire was developed and implemented in order to establish a correlation between learning styles and TIC. Results: The preferred learning styles corresponded to reflexive and, in second place, theoretical learning. More than 80% of the students highly graded traditional lectures (4-5, being 5 the grade for maximum preference), with this result in accordance with the main learning style of the population assayed. More than 90% of the students also positively graded (4-5) multimedia presentations using PowerPoint software, followed by the use of blackboard and videos. Conclusions: The main learning style of fourth-year graduate students and postgraduate students at the School of Pharmacy (UCM) is reflexive. The populations assayed highly and positively graded the use of TIC, thereby stating their importance in the implementation of the ESHE

Diagnosis, Treatment, and Outcomes in Children With Congenital Nephrogenic Diabetes Insipidus: A Pediatric Nephrology Research Consortium Study

© Copyright © 2020 D\u27Alessandri-Silva, Carpenter, Ayoob, Barcia, Chishti, Constantinescu, Dell, Goodwin, Hashmat, Iragorri, Kaspar, Mason, Misurac, Muff-Luett, Sethna, Shah, Weng, Greenbaum and Mahan. Background and Objectives: Congenital or primary nephrogenic diabetes insipidus (NDI) is a rare genetic disorder that severely impairs renal concentrating ability, resulting in massive polyuria. There is limited information about prognosis or evidence guiding the management of these patients, either in the high-risk period after diagnosis, or long-term. We describe the clinical presentation, genetic etiology, treatment and renal outcomes in a large group of children (89%) and white (67%). Median age at diagnosis was 4.2 months interquartile range (IQR 1.1, 9.8). A desmopressin acetate loading test was administered to 46% of children at a median age of 4.8 months (IQR 2.8, 7.6); only 15% had a water restriction test. Genetic testing or a known family history was present in 70% of the patients; out of those genetically tested, 89 and 11% had mutations in AVPR2 and AQP2, respectively. No positive family history or genetic testing was available for 30%. The most common treatments were thiazide diuretics (74%), potassium-sparing diuretics (67%) and non-steroidal anti-inflammatory drugs (42%). At the time of first treatment, 70 and 71% of children were below −2 standard deviations (SD) for weight and height, respectively. At last follow-up, median age was 72.3 months (IQR 40.9, 137.2) and the percentage below −2 SD improved to 29% and 38% for weight and height, respectively. Adverse outcomes included inpatient hospitalizations (61%), urologic complications (37%), and chronic kidney disease (CKD) stage 2 or higher in 23%. Conclusion: We found the majority of patients were treated with thiazides with either a potassium sparing diuretic and/or NSAIDs. Hospitalizations, urologic complications, short stature, and CKD were common. Prospective trials to evaluate different treatment strategies are needed to attempt to improve outcomes

T Cells' Immunological Synapses Induce Polarization of Brain Astrocytes In Vivo and In Vitro: A Novel Astrocyte Response Mechanism to Cellular Injury

Astrocytes usually respond to trauma, stroke, or neurodegeneration by undergoing cellular hypertrophy, yet, their response to a specific immune attack by T cells is poorly understood. Effector T cells establish specific contacts with target cells, known as immunological synapses, during clearance of virally infected cells from the brain. Immunological synapses mediate intercellular communication between T cells and target cells, both in vitro and in vivo. How target virally infected astrocytes respond to the formation of immunological synapses established by effector T cells is unknown.Herein we demonstrate that, as a consequence of T cell attack, infected astrocytes undergo dramatic morphological changes. From normally multipolar cells, they become unipolar, extending a major protrusion towards the immunological synapse formed by the effector T cells, and withdrawing most of their finer processes. Thus, target astrocytes become polarized towards the contacting T cells. The MTOC, the organizer of cell polarity, is localized to the base of the protrusion, and Golgi stacks are distributed throughout the protrusion, reaching distally towards the immunological synapse. Thus, rather than causing astrocyte hypertrophy, antiviral T cells cause a major structural reorganization of target virally infected astrocytes.Astrocyte polarization, as opposed to hypertrophy, in response to T cell attack may be due to T cells providing a very focused attack, and thus, astrocytes responding in a polarized manner. A similar polarization of Golgi stacks towards contacting T cells was also detected using an in vitro allogeneic model. Thus, different T cells are able to induce polarization of target astrocytes. Polarization of target astrocytes in response to immunological synapses may play an important role in regulating the outcome of the response of astrocytes to attacking effector T cells, whether during antiviral (e.g. infected during HIV, HTLV-1, HSV-1 or LCMV infection), anti-transplant, autoimmune, or anti-tumor immune responses in vivo and in vitro

The ambivalent shadow of the pre-Wilsonian rise of international law

The generation of American international lawyers who founded the American Society of International Law in 1906 and nurtured the soil for what has been retrospectively called a “moralistic legalistic approach to international relations” remains little studied. A survey of the rise of international legal literature in the U.S. from the mid-19th century to the eve of the Great War serves as a backdrop to the examination of the boosting effect on international law of the Spanish American War in 1898. An examination of the Insular Cases before the US Supreme Court is then accompanied by the analysis of a number of influential factors behind the pre-war rise of international law in the U.S. The work concludes with an examination of the rise of natural law doctrines in international law during the interwar period and the critiques addressed.by the realist founders of the field of “international relations” to the “moralistic legalistic approach to international relation