Cohomology of classes of symbols and classi cation of traces on corresponding classes of operators with non positive order

This thesis is devoted to the classification issue of traces on classical pseudo-differential operators with fixed non positive order on closed manifolds of dimension $n>1$. We describe the space of homogeneous functions on a symplectic cone in terms of Poisson brackets of appropriate homogeneous functions, and we use it to find a representation of a pseudo-differential operator as a sum of commutators. We compute the cohomology groups of certain spaces of classical symbols on the $n$--dimensional Euclidean space with constant coefficients, and we show that any closed linear form on the space of symbols of fixed order can be written either in terms of a leading symbol linear form and the noncommutative residue, or in terms of a leading symbol linear form and the cut-off regularized integral. On the operator level, we infer that any trace on the algebra of classical pseudo-differential operators of order $a\in\Z$ can be written either as a linear combination of a generalized leading symbol trace and the residual trace when $-n+1\leq2a\leq0$, or as a linear combination of a generalized leading symbol trace and any linear map that extends the $L^2$--trace when $2a\leq-n\leq a$. In contrast, for odd class pseudo-differential operators in odd dimensions, any trace can be written as a linear combination of a generalized leading symbol trace and the canonical trace. We derive from these results the classification of determinants on the Fr\'echet Lie group associated to the algebras of classical pseudo-differential operators with non positive integer order

ZZW-115-dependent inhibition of NUPR1 nuclear translocation sensitizes cancer cells to genotoxic agents

Establishing the interactome of the cancer-associated stress protein Nuclear Protein 1 (NUPR1), we found that it binds to several hundreds of proteins, including proteins involved in nuclear translocation, DNA repair, and key factors of the SUMO pathway. We demonstrated that the NUPR1 inhibitor ZZW-115, an organic synthetic molecule, competes with importins for the binding to the NLS region of NUPR1, thereby inhibiting its nuclear translocation. We hypothesized, and then proved, that inhibition of NUPR1 by ZZW-115 sensitizes cancer cells to DNA damage induced by several genotoxic agents. Strikingly, we found that treatment with ZZW-115 reduced SUMOylation of several proteins involved in DNA damage response (DDR). We further report that the presence of recombinant NUPR1 improved the SUMOylation in a cell-free system, indicating that NUPR1 directly stimulates the SUMOylation machinery. We propose that ZZW-115 sensitizes cancer cells to genotoxic agents by inhibiting the nuclear translocation of NUPR1 and thereby decreasing the SUMOylation-dependent functions of key proteins involved in the DDR

Clonal chromosomal mosaicism and loss of chromosome Y in elderly men increase vulnerability for SARS-CoV-2

The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, COVID-19) had an estimated overall case fatality ratio of 1.38% (pre-vaccination), being 53% higher in males and increasing exponentially with age. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, we found 133 cases (1.42%) with detectable clonal mosaicism for chromosome alterations (mCA) and 226 males (5.08%) with acquired loss of chromosome Y (LOY). Individuals with clonal mosaic events (mCA and/or LOY) showed a 54% increase in the risk of COVID-19 lethality. LOY is associated with transcriptomic biomarkers of immune dysfunction, pro-coagulation activity and cardiovascular risk. Interferon-induced genes involved in the initial immune response to SARS-CoV-2 are also down-regulated in LOY. Thus, mCA and LOY underlie at least part of the sex-biased severity and mortality of COVID-19 in aging patients. Given its potential therapeutic and prognostic relevance, evaluation of clonal mosaicism should be implemented as biomarker of COVID-19 severity in elderly people. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, individuals with clonal mosaic events (clonal mosaicism for chromosome alterations and/or loss of chromosome Y) showed an increased risk of COVID-19 lethality

Precariedad, exclusión social y modelo de sociedad: lógicas y efectos subjetivos del sufrimiento social contemporáneo (IV). Innovación docente en Filosofía

El PIMCD “Precariedad, exclusión social y modelo de sociedad: lógicas y efectos subjetivos del sufrimiento social contemporáneo (IV). Innovación docente en Filosofía” constituye la cuarta edición de un PIMCD que ha recibido financiación en las últimas convocatorias de PIMCD UCM, de los que se han derivado actividades de formación para estudiantes de Grado, Máster y Doctorado y al menos 3 publicaciones colectivas publicadas por Ediciones Complutense, Siglo XXI y Palgrave McMillan

Classification of traces and hypertraces on spaces of classical pseudodifferential operators

Let M be a closed manifold and let CL(M) be the algebra of classical pseudodifferential operators. The aim of this note is to classify trace functionals on the subspaces CL^a(M) of CL(M) of operators of order a. CL^a(M) is a CL^0(M)-module for any real a; it is an algebra only if a is a non-positive integer. Therefore, it turns out to be useful to introduce the notions of pretrace and hypertrace. Our main result gives a complete classification of pre- and hypertraces on CL^a(M) for any real a, as well as the traces on CL^a(M) if a is a non-positive integer. We also extend these results to classical pseudodifferential operators acting on sections of a vector bundle. As a byproduct we give a new proof of the well-known uniqueness results for the Guillemin-Wodzicki residue trace and for the Kontsevich-Vishik canonical trace. The novelty of our approach lies in the calculation of the cohomology groups of homogeneous and log-polyhomogeneous differential forms on a symplectic cone. This allows to give an extremely simple proof of a generalization of a Theorem of Guillemin about the representation of homogeneous functions as sums of Poisson brackets.Comment: 39 pages; v2: acknowledgments and bibliographical remarks substantially expanded, minor corrections, bibliography updated and improved; v3: revision according to the referee's suggestions. The introduction is substantially expanded and now provides more explanations and motivations; v4: minor corrections, layout improvements; To appear in Journal of Noncommutative Geometr

Genetic polymorphisms among C57BL/6 mouse inbred strains

Mice from the inbred C57BL/6 strain have been commonly used for the generation and analysis of transgenic and knockout animal models. However, several C57BL/6 substrains exist, and these are genetically and phenotypically different. In addition, each of these substrains can be purchased from different animal providers and, in some cases, they have maintained their breeding stocks separated for a long time, allowing genetic differences to accumulate due to individual variability and genetic drift. With the aim of describing the differences in the genotype of several C57BL/6 substrains, we applied the Illumina® Mouse Medium Density Linkage Mapping panel, with 1,449 single nucleotide polymorphisms (SNPs), to individuals from ten C57BL/6-related strains: C57BL/6JArc, C57BL/6J from The Jackson Lab, C57BL/6J from Crl, C57BL6/JRccHsd, C57BL/6JOlaHsd, C57BL/6JBomTac, B6(Cg)-Tyrc-2j/J, C57BL/6NCrl, C57BL/6NHsd and C57BL/6NTac. Twelve SNPs were found informative to discriminate among the mouse strains considered. Mice derived from the original C57BL/6J: C57BL/6JArc, C57BL/6J from The Jackson Lab and C57BL/6J from Crl, were indistinguishable. Similarly, all C57BL/6N substrains displayed the same genotype, whereas the additional substrains showed intermediate cases with substrain-specific polymorphisms. These results will be instrumental for the correct genetic monitoring and appropriate mouse colony handling of different transgenic and knockout mice produced in distinct C57BL/6 inbred substrains. © 2010 Springer Science+Business Media B.V.This work was supported by funds from the Spanish Ministry of Science and Innovation (MICINN, BIO2009-1297) and from CIBERER (INTRA/09/756,1) to LM and Red de Trastornos Adictivos, RD06/0001/0011, Plan Nacional Sobre Drogas, PR61/08-16415, and Ministerio de Ciencia e Innovación, SAF2008-03763, to JALM.Peer Reviewe

Prevalencia del "síndrome de quemarse por el trabajo" (burnout) en pediatras de hospitales generales Burnout prevalence in pediatricians of general hospitals

OBJETIVO: Analizar la prevalencia del síndrome de quemarse por el trabajo (burnout) en pediatras de hospitales generales siguiendo criterios de diferentes países. MÉTODOS: Estudio transversal, no aleatorio, realizado en Buenos Aires, Argentina, en 2006. La muestra la formaron 123 pediatras que trabajaban en Servicios de Pediatría de hospitales generales, 89 fueron mujeres (72,4%) y 34 hombres (27,6%). Los datos fueron recogidos mediante un cuestionario anónimo y autoadministrado. El SQT fue diagnosticado utilizando el Maslach Burnout Inventory, con diferentes criterios para establecer su prevalencia. RESULTADOS: La prevalencia del SQT, varió en función del criterio utilizado: siguiendo los puntos de corte del manual de Estados Unidos, la prevalencia fue del 10,6% de 24,4 % siguiendo los criterios de España, 37,4% siguiendo los criterios de Argentina y considerando los criterios clínicos establecidos en Holanda, el porcentaje fue del 3,2%. CONCLUSIONES: Los niveles de prevalencia variaron significativamente en función de los criterios aplicados debido a influencias transculturales.<br>OBJETIVO: Analisar a prevalência da síndrome do esgotamento profissional (burnout) em pediatras de hospitais gerais segundo critérios de diversos países. MÉTODOS: Estudo transversal, não aleatório, realizado em Buenos Aires, Argentina, em 2006. A amostra foi formada por 123 pediatras que trabalhavam em serviços de pediatria de hospitais gerais, sendo 89 mulheres (72,4%) e 34 homens (27,6%). As informações foram coletadas com questionário anônimo e auto-administrado. A síndrome do esgotamento profissional foi diagnosticada utilizando o Maslach Burnout Inventory, com diferentes critérios para estabelecer sua prevalência. RESULTADOS: A prevalência da síndrome do esgotamento profissional variou em função do critério utilizado: seguindo os pontos de corte do manual dos Estados Unidos, a prevalência foi de 10,6%, de 24,4% segundo critérios na Espanha 37,4% pelos critérios da Argentina e considerando os critérios clínicos estabelecidos na Holanda, a percentagem foi de 3,2%. CONCLUSÕES: Os níveis de prevalência variaram significativamente em função dos critérios aplicados devido às influências transculturais.<br>OBJECTIVE: To assess the prevalence of burnout in pediatricians of general hospitals. METHODS: Non-randomized cross-sectional study carried out in the city of Buenos Aires, Argentina, in 2006. The study sample comprised 123 pediatricians working in pediatrics services of general hospitals, 89 women (72.4%) and 34 men (27.6%). Data were gathered through an anonymous, self-administered questionnaire. Burnout was measured using the Maslach Burnout Inventory, and different approaches were employed to estimate burnout prevalence. RESULTS: The prevalence of burnout was different according to the approach used: the prevalence was 10.6% by the United States criteria; 24.4% by the Spanish criteria; 37.4% by the Argentinean criteria and 3.25% by the Dutch clinical criteria. CONCLUSIONS: Burnout prevalences varied significantly depending on the approach used due to cross-cultural influences

Estudio CRONO: prevalencia del dolor irruptivo en pacientes con dolor crónico no oncológico en Andalucía, España

ABSTRACT Objective: The aim of this study was to evaluate the prevalence of breakthrough pain (BTP) in ambulatory patients with non-cancer chronic pain in Spain and to characterize physiopathology, location, intensity and frequency of BTP episodes. Methods: Prospective, non-interventional, observational study conducted in 16 pain units of hospitals of Andalusia and Ceuta. Eligible consecutive patients were are asked if they experience BTP defined as "a transient exacerbation of pain that occurs either spontaneously, or in relation to a specific predictable or unpredictable trigger, despite stable and controlled background pain". At each survey day, the first two patients reporting BTP were further interrogated on the clinical characteristics of their BTP (etiology, onset, intensity, frequency and treatment). Results: A total of 3,209 patients with non-cancer chronic pain were screened to identify 1,118 patients with BTP, which represented a prevalence of 36 %. BTP characteristics were retrieved from 350 patients: mean BTP intensity was 8.3 (± 1.4) on a Visual Analogue Scale (VAS), with a mean of 2 episodes/24 hour (range 1-5/24 h). Pain mechanism was mixed in 149 (42.6 %), neuropathic in 91 (26 %) and nociceptive in 72 in (20.6 %) of patients. Significant correlation was found between BTP intensity and both higher background pain (r = 0.243, p < 0.001), and daily BTP episodes frequency (r = 0.123, p = 0.003). 78 % of the patients were on opioid treatment. The most frequent were fentanyl citrate (52.6 %) and tramadol (17.4 %). Conclusions: The prevalence rate of BTP in patients with chronic non-oncologic pain is higher than one-third of the patients seen in outpatient hospital pain units in Spain. BTP causes reduced levels of functionality, psychological disorders, and an increase in health care expenditure. Individualization is the key to treatment.RESUMEN Objetivo: El objetivo de este estudio es evaluar la prevalencia de dolor irruptivo (DI) en pacientes ambulatorios con dolor crónico de origen no oncológico y caracterizar la fisiopatología, localización, intensidad y frecuencia de los episodios de DI. Material y métodos: Estudio observacional, prospectivo y no intervencionista realizado en 16 unidades de dolor ambulatorias de hospitales de Andalucía y Ceuta. Se preguntó a los pacientes consecutivos elegibles si experimentan DI definido como "una exacerbación transitoria del dolor que ocurre espontáneamente, o en relación con un desencadenante predecible o impredecible específico, a pesar del dolor de base estable y controlado". En cada día de la encuesta, los dos primeros pacientes que confirmaron DI fueron preguntados sobre las características clínicas de su PTP (etiología, inicio, intensidad, frecuencia y tratamiento). Resultados: Se realizó un cribaje a un total de 3209 pacientes con dolor crónico no oncológico para identificar a 1118 pacientes con DI, lo que representó una prevalencia del 36 %. Se obtuvieron las características del DI de 350 pacientes: la intensidad media fue de 8,3 (± 1,4) en una Escala Analógica Visual (EVA), con una media de 2 episodios/24 horas (rango 1-5/24 h). El mecanismo del dolor fue mixto en 149 (42,6 %), neuropático en 91 (26 %) y nociceptivo en 72 (20,6 %) de los pacientes. Se encontró correlación positiva entre una mayor intensidad de DI con el nivel de dolor basal (r = 0,243, p < 0,001), y el número de crisis diarias de DI (r = 0,123, p = 0,003), ambas estadísticamente significativas. El 78 % de los pacientes estaba en tratamiento con opioides. Los más frecuentes fueron el citrato de fentanilo (52,6 %) y el tramadol (17,4 %). Conclusiones: La tasa de prevalencia del DI en pacientes con dolor crónico no oncológico es superior a un tercio de los pacientes atendidos en las unidades ambulatorias de dolor hospitalario en España. El DI provoca niveles reducidos de funcionalidad, trastornos psicológicos y un aumento del gasto asistencial. La clave del tratamiento es la individualización

Recomendaciones para el manejo de los pacientes críticos con COVID-19 en las Unidades de Cuidados Intensivos.

The COVID-19 pandemic has led to the admission of a high number of patients to the ICU, generally due to severe respiratory failure. Since the appearance of the first cases of SARS-CoV-2 infection, at the end of 2019, in China, a huge number of treatment recommendations for this entity have been published, not always supported by sufficient scientific evidence or with methodological rigor necessary. Thanks to the efforts of different groups of researchers, we currently have the results of clinical trials, and other types of studies, of higher quality. We consider it necessary to create a document that includes recommendations that collect this evidence regarding the diagnosis and treatment of COVID-19, but also aspects that other guidelines have not considered and that we consider essential in the management of critical patients with COVID-19. For this, a drafting committee has been created, made up of members of the SEMICYUC Working Groups more directly related to different specific aspects of the management of these patients