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Background Idiopathic Pulmonary Fibrosis (IPF) is an age-associated progressive lung disease with accumulation of scar tissue impairing gas exchange. Previous high-throughput studies elucidated the role of cellular heterogeneity and molecular pathways in advanced disease. However, critical pathogenic pathways occurring in the transition of fibroblasts from normal to profibrotic have been largely overlooked. Methods We used single cell transcriptomics (scRNA-seq) from lungs of healthy controls and IPF patients (lower and upper lobes). We identified fibroblast subclusters, genes and pathways associated with early disease. Immunofluorescence assays validated the role of MOXD1 early in fibrosis. Results We identified four distinct fibroblast subgroups, including one marking the normal-to-profibrotic state transition. Our results show for the first time that global downregulation of ribosomal proteins and significant upregulation of the majority of copper-binding proteins, including MOXD1, mark the IPF transition. We find no significant differences in gene expression in IPF upper and lower lobe samples, which were selected to have low and high degree of fibrosis, respectively. Conclusions Early events during IPF onset in fibroblasts include dysregulation of ribosomal and copper-binding proteins. Fibroblasts in early stage IPF may have already acquired a profibrotic phenotype while hallmarks of advanced disease, including fibroblast foci and honeycomb formation, are still not evident. The new transitional fibroblasts we discover could prove very important for studying the role of fibroblast plasticity in disease progression and help develop early diagnosis tools and therapeutic interventions targeting earlier disease states.

As emoções têm um papel fundamental no desenvolvimento da criança pelo que é necessário criar um ambiente emocionalmente favorável para a aprendizagem. A arte no contexto educacional prepara as crianças para a cidadania consciente, crítica e participativa, a qual facilita a compreensão do mundo, reforçando e potencializando o crescimento das aptidões e competências de cada um dos alunos. As expressões artísticas permitem exteriorizar sentimentos e emoções, desenvolvendo a sensibilidade e a afetividade das crianças. A educação artística é indispensável ao desenvolvimento da expressão pessoal, social e cultural do aluno, articulando a imaginação com a razão e a emoção. O objetivo principal visa incentivar as crianças a expressar as suas emoções e entendê-las, utilizando a expressão plástica para tal. A metodologia utilizada neste estudo é de natureza qualitativa, inicialmente, através de observação direta e questionário de gostos e interesses no Centro Escolar, na turma do 4.º ano, composta por 23 alunos, com 9 anos de idade. Posteriormente, foi desenvolvido um projeto de intervenção pedagógica. Os resultados do projeto foram avaliados através de um questionário com 4 questões de resposta fechada. Concluiu-se que o projeto de intervenção pedagógica permitiu que a turma percebesse a importância da expressão das suas emoções e da facilidade em fazêlo.

A specific T-cell response persists in the majority of COVID-19 patients 6 months after hospital discharge. This response is more prominent in those who required critical care during the acute COVID-19 episode but is reduced in patients with lung sequelae.

Key evidence of human occupation in Africa during the Middle Palaeolithic (Middle Stone Age [MSA]) is available from the south and east of the continent, where semi-arid climate prevails. Rare evidence of MSA human occupation in the humid tropical region was recently reported from Equatorial Guinea. To identify if paleolithic human occupation occurred in the tropical forest, the stratigraphy of the recently discovered archaeological site “Mabewele I” was analyzed using a paleopedological approach. The properties evaluated along a vertical profile are: granulometry, magnetic susceptibility (K), free iron extractable with sodium dithionite (Fed), total organic carbon (TOC), chemical composition by X-ray fluorescence (XRF), X-ray diffraction mineralogy (XRD), ternary plot of the three main oxides (SiO2-Al2O3-Fe2O3), phytoliths and micromorphology. The predominant fraction is sand, with a significant clay content (> 30 %). The K and the Fed presented low values, as well as the TOC. XRF showed few variations along the sequence and XRD showed that the clays are mainly kaolinites, with a very low component of vermiculites. The phytoliths correspond to tropical vegetation with few changes in the vegetal composition between the deep and superficial zones. A charcoal from the lower part of the profile was dated between 12.57-12.24 ka cal BP, while the main artifact horizon was located at the bottom. The analytical results appear contradictory: on the one hand, there is evidence of intense chemical weathering under a humid tropical climate, but the clay cutans in the pores are very scarce and incipient and the iron nodules are mostly anorthic. This indicates that the sequence is composed of pedosediments associated with a high environmental dynamism, with short periods of erosion-sedimentation-pedogenesis. The results allow us to propose that humans inhabited the tropical forest during the MSA and that erosion-sedimentation processes could be related to anthropization processes.

We report a magnetic study of two preceramic hearths located at the southern region of Mexico City. Thermal demagnetization was applied between 200 to 540 °C to define the remanent magnetization components. The maximum unblocking temperature of the secondary magnetic component reached due to the last heating was identified in most samples. They were used to develop thermomagnetic anomaly source maps. The direction of this component was used to place the blocks to their last cooling spot and configurate a real and primal magnetic anomaly map produced by the thermoremanent magnetization acquired. A protocol to relocate blocks frame is proposed using geomagnetic secular variation curves. The thermomagnetic mapping revealed the position and temperature (220 to 460 °C) of the last heat sources. The distribution of these sources allowed to model an extensional zone of benefit and probable uses of the hearths.

espanolLas actividades realizadas por las sociedades agricolas prehispanicas poco complejas, no son usualmente consideradas como factores importantes de degradacion del suelo. Sin embargo, la repeticion de actividades cotidianas durante cientos de anos puede afectar sustancialmente sus caracteristicas. En el sitio de La Playa, las modificaciones del paisaje producidas por las actividades cotidianas, tales como la construccion de hornos de tierra para cocer alimentos, campos de maiz con un complejo sistema de canales de riego, y la practica de rituales mortuorios (crematorios, cremaciones e inhumaciones), juegan un papel importante en las transformaciones de los rasgos naturales del suelo. En este articulo se muestran las caracteristicas de los paleosuelos de La Playa, que constituyeron la superficie de ocupacion durante el Periodo de Agricultura Temprana (4500-1800 cal AP), y la influencia que las actividades de subsistencia diaria tuvieron en su configuracion. Para ello, se muestran los resultados obtenidos en campo y en laboratorio de tres perfiles de secuencias pedosedimentarias formadas durante el Holoceno tardio en La Playa, Sonora (NW de Mexico). Las caracteristicas evaluadas son: estructuracion, diferenciacion de horizontes, textura (a tacto y por separacion de fracciones), color, porosidad, pedregosidad, propiedades magneticas, contenido de carbono organico, carbonatacion, presencia de cutanes, nodulos y/o concreciones, entre otros rasgos pedologicos. Estudios previos muestran que los Fluvisoles de La Playa estan pobremente desarrollados y se formaron a partir de depositos aluviales (compuestos en gran medida por suelos redepositados). Las propiedades fisicas y quimicas indican periodos cortos de pedogenesis superpuestos, desarrollados bajo un clima arido durante los ultimos 4000 anos. Las caracteristicas de todos los perfiles son muy similares, indicando las mismas condiciones pedogeneticas; mientras que las propiedades micromorfologicas y magneticas muestran claramente que el suelo esta profundamente perturbado por las actividades humanas, principalmente quema en los hornos y cremaciones. EnglishThe activities carried out by preindustrial agricultural societies are not usually considered as important factors of soil degradation. Nonetheless, repetitive human daily activities for hundreds of years can substantially transform the natural properties of the soils. At the site of La Playa, Mexico, the activities of early farmers modified the landscape and had an important role in the physical transformations of the natural soil features. This paper depicts the characteristics of La Playa paleosols, which were the living surface of the Early Agriculture Period community (4000 - 1800 cal BP) and we discuss the influence of daily subsistence activities on the soil. The soil features (structuring, differentiation of horizons, texture-in field and laboratory, color, porosity, stoniness, magnetic properties, organic carbon content, carbonation, presence of cutans, nodules and/or concretions, among other pedological features) of three profiles with pedosediments (paleosols interbedded with sediments) formed during late Holocene are discussed. Our study suggests that La Playa Fluvisols are poorly developed and were formed with alluvial deposits (largely composed of reworked soils). The pedogenic properties indicate that overlapping developed during short time periods of stability, under arid conditions of the last 4000 years. The uniformity of the features in all the studied profiles indicate similar pedogenetic conditions across the site. The micromorphological and magnetic properties clearly show that the soil was deeply disturbed by human activities, mainly by roasting features to process food, crematories and grave digging to bury the dead, and removing soil for several agricultural activities.

Fibroblast-to-myofibroblast transdifferentiation and the acquisition of a senescent phenotype are hallmarks of fibrotic diseases. The study of the localization of senescent myofibroblasts as well as their interactions with other cell types in the fibrotic tissue has been hindered by the lack of methods to detect these cells in vivo. Here, we describe methods to detect tissue localization of senescent myofibroblasts in precision-cut lung slices (PCLS) by combining β-galactosidase staining with immunofluorescence techniques.

Rationale: Idiopathic Pulmonary Fibrosis (IPF) is a lethal disease with a mechanism of onset and progression that is not fully understood. Past genomic studies, focused on fibrotic lungs, provided valuable insights of its pathophysiology, but an important unanswered question remains: what are the cellular and molecular changes in the histologically normal looking parts of IPF lungs? The answer may help understand the early disease stages and unveil biological pathways that precede and likely lead to the histological changes in IPF. Methods: We reanalyzed our published single cell expression data from healthy controls and IPF patients (Morse et al, 2019, ERJ) . We used Seurat to identify cell types and perform all analyses. Results: We identified 20 cell types and further focused on 4 fibroblast sub-clusters. Two of the sub-clusters were significantly enriched for cells originating from the IPF lungs. Analysis of differentially expressed genes in each cluster identified unique expression profiles for IPF/control states. Interestingly, IPF upper non-fibrotic and lower fibrotic lobes didn’t show significant differences in these profiles. This result shows that fibroblast types such as myofibroblasts which have been associated with the IPF state, are present in parts of the lung that are histologically non-fibrotic. We also found an enrichment in multiple copper-binding proteins supporting the role of metal copper in IPF pathogenesis. Conclusion: We showed histologically normal tissue in IPF lungs is a profibrotic environment representing an earlier stage where many disease-associated cellular alterations have not yet occurred. This establishes a more appropriate environment to study early interventions.

Rationale: One of the features of IPF is the accumulation of senescent cells that produce the senescence-associated secretory phenotype (SASP) that modifies the lung microenvironment. We focus on the alteration of the lung immune response by the SASP, specifically on the natural killer (NK) lymphocytes cytotoxicity against senescence cells. Methods: Fresh lung samples were used for scRNAseq and flow. Blood was collected for the study of plasma cytokines and PBMCs. Results: There was decreased proportion of NK cells in the IPF lung, specifically of the circulatory/cytotoxic NK cells. Such NKs are more senescent, there is a higher proportion of IL6 producing cells and reduced expression of the chemokine receptor CCR2, which is involved in NK recruitment to the lung. scRNAseq analysis of the NK cluster in IPF patients revealed an impaired expression in some of the main NK genes and the fibroblast cluster revealed a profound decrease in the lung capacity to produce chemokines. There is an increase in the proportion of NK cells in the IPF blood with an increase of the circulating/cytotoxic NK population. Additionally, healthy blood NK cells have less migration capacity towards conditioned media (CM) from IPF lung fibroblasts and the culture with the IPF-CM reduces their cytotoxic capacity. Conclusions: Our data reveal that IPF patients have reduced numbers an impaired activity of NK cells in the lung, specifically of the circulating/cytotoxic subpopulation due to a deficiency in the lung capacity of the lung to recruit NKs, which results in their accumulation in the blood. This deficiency in the NK activity and senescence status in the lung could be one of the altered mechanisms perpetrating the accumulation of senescent cells in IPF lungs.

El problema del trabajo de investigación consiste en mejorar las habilidades comunicativas en los estudiantes del II ciclo de la especialidad de Industrias Alimentarias del I.E.S.T.P. “Manuel Arévalo Cáceres” ubicado en el distrito de Los Olivos, teniendo como punto principal la expresión oral que influye mucho en su desenvolvimiento como profesional técnico. El objetivo de la investigación es elaborar un programa de técnicas de expresión oral para mejorar las habilidades comunicativas. La hipótesis planteada como alternativa de solución al problema de la Institución Educativa es: Si se diseña un programa de técnicas de expresión oral entonces se mejoraría las habilidades comunicativas de los estudiantes. De acuerdo con la hipótesis y los objetivos propuestos en la presente tesis, el tipo de investigación es descriptivo siendo el diseño de investigación critico - propositivo; para la recolección de datos se aplicó una ficha de observación a los estudiantes. Así mismo para el análisis e interpretación de los datos recolectados se utilizó la estadística descriptiva, presentándolos en tablas estadísticas. Del análisis realizado se concluye que si se trabaja en desarrollar habilidades comunicativas en los estudiantes entonces es importante que los docentes identifiquen y desarrollen estrategias metodológicas basadas en técnicas de expresión oral, que permitan enseñarle al estudiante no solo aspectos teóricos, si no desarrollar destreza, métodos de aprendizaje y actitudes que son los cimientos para la transformación personal y social en un mundo en constante cambio. Tesis

Background Chronic Obstructive Pulmonary Disease (COPD) is associated with an abnormal pulmonary and systemic immune response to tobacco smoking. Yet, how do immune cells relate within and between these two biological compartments, how the pulmonary infiltrate influences the lung transcriptome, and what is the role of active smoking vs. presence of disease is unclear. Methods To investigate these questions, we simultaneously collected lung tissue and blood from 65 individuals stratified by smoking habit and presence of the disease. The immune cell composition of both tissues was assessed by flow cytometry, whole lung transcriptome was determined with Affymetrix arrays, and we used Weighted Gene Co-expression Network Analysis (WGCNA) to integrate results. Results Main results showed that: (1) current smoking and the presence of COPD were both independently associated with a reduction in the proportion of lung T cells and an increase of macrophages, specifically those expressing CD80 + CD163+; (2) changes in the proportion of infiltrating macrophages, smoking status or the level of airflow limitation were associated to different WGCNA modules, which were enriched in iron ion transport, extracellular matrix and cilium organization gene ontologies; and, (3) circulating white blood cells counts were correlated with lung macrophages and T cells. Conclusions Mild-moderated COPD lung immune infiltrate is associated with the active smoking status and presence of disease; is associated with changes in whole lung tissue transcriptome and marginally reflected in blood. Electronic supplementary material The online version of this article (10.1186/s12931-019-1105-z) contains supplementary material, which is available to authorized users.

Tobacco smoking is the main environmental risk factor for chronic obstructive pulmonary disease (COPD), but not all smokers develop the disease. A population of lung-resident mesenchymal stem cells (LR-MSCs) exist in healthy lungs, but how tobacco smoking affects them and their role in COPD have not been assessed yet. Using a sphere-based culture technique, we isolated LR-MSCs from lung tissue obtained from nonsmokers and current and former smokers with and without COPD (

Stable isotopes of carbon (δ 13 C) in terrestrial geological materials (paleosol humus and carbonates) as well as fossil bones (collagen and tooth enamel) are established as highly specific records on paleoenvironmental characteristics. It was assumed that comparing the results of different types of materials on regional or local scales provides more accurate and reliable reconstructions and even opens new aspects of interpretation. This was tested by the comparison of the data obtained from the late Pleistocene paleosols and/or remains of Pleistocene megafauna in various locations in Northwestern Mexico: Sonora (paleosols formed in MIS3, MIS2 and MIS1); Central-Northern Mexico: San Luis Potosi (teeth, corresponding to MIS2 and MIS1); and Central-Southern Mexico: Puebla (paleosols corresponding to MIS3 and MIS2, and teeth associated with these paleosols), and State of Mexico (teeth, corresponding to MIS2). The results of isotopic studies are complemented with other paleoenvironmental proxies. The δ 13 C values of paleosols of Sonora is −19.8 to −16.95‰ in organic matter, and shows little difference between paleosols and Holocene soils; δ 13 C values of pedogenic carbonates are −6.4 to −4.52‰. In San Luis Potosi, the δ 13 C values of paleosol are −12.16‰ in organic matter. In Puebla, they vary from −24.6‰ in paleosols to −15.16‰ in the modern surface soil, pointing to contrasting vegetation change. The δ 13 C values in fossils range from −10.7 to 1.2‰ in SLP; of −2.73 and −2.93‰ in Puebla; and −6.5 to −1.3‰ in State of Mexico. The δ 13 C values of paleosols and analysis of megafauna in Northwest and Central-Northern Mexico matched each other, indicating mixed C3–C4 vegetation; while for Central-Southern Mexico, paleosols indicated predominance of C3 plants and megafauna indicated mixed C3–C4 composition. In general, the results indicate that in northern Mexico environmental conditions were slightly wetter than at present, while for the central area there was a large change in the environmental conditions of high humidity in MIS3 and MIS2, with a trend to drier climates in MIS1.

Acute respiratory distress syndrome (ARDS) is a high-mortality syndrome that develops following an infection or trauma, leading to a dysregulated inflammatory response in the lung that can cause tissue remodeling, pulmonary dysfunction, and death [1]. ARDS is characterized by acute respiratory failure caused by an increase of fluids in the alveolar space. The breakdown of the immune response increases the permeability of the epithelial–endothelial barrier. This results in an increased filtration of protein-rich fluid from the vascular system into the alveolar spaces, with a subsequent lung edema and a decrease in the ability of gas exchange [2].

"The activities carried out by preindustrial agricultural societies are not usually considered as important factors of soil degradation. Nonetheless, repetitive human daily activities for hundreds of years can substantially transform the natural properties of the soils. At the site of La Playa, Mexico, the activities of early farmers modified the landscape and had an important role in the physical transformations of the natural soil features. This paper depicts the characteristics of La Playa paleosols, which were the living surface of the Early Agriculture Period community (4000 - 1800 cal BP) and we discuss the influence of daily subsistence activities on the soil. The soil features (structuring, differentiation of horizons, texture-in field and laboratory, color, porosity, stoniness, magnetic properties, organic carbon content, carbonation, presence of cutans, nodules and/or concretions, among other pedological features) of three profiles with pedosediments (paleosols interbedded with sediments) formed during late Holocene are discussed. Our study suggests that La Playa Fluvisols are poorly developed and were formed with alluvial deposits (largely composed of reworked soils). The pedogenic properties indicate that overlapping developed during short time periods of stability, under arid conditions of the last 4000 years. The uniformity of the features in all the studied profiles indicate similar pedogenetic conditions across the site. The micromorphological and magnetic properties clearly show that the soil was deeply disturbed by human activities, mainly by roasting features to process food, crematories and grave digging to bury the dead, and removing soil for several agricultural activities."

Background c-Kit + lung stem cells have been described in the human healthy lung. Their potential relation with smoking and/or chronic obstructive pulmonary disease (COPD) is unknown. Methods We characterized and compared c-Kit+ cells in lung tissue of 12 never smokers (NS), 15 smokers with normal spirometry (S) and 44 COPD patients who required lung resectional surgery. Flow cytometry (FACS) was used to characterize c-Kit+ cells in fresh lung tissue disaggregates, and immunofluorescence (IF) for further characterization and to determine their location in OCT- embedded lung tissue. Results We identified 4 c-Kit+ cell populations, with similar proportions in NS, S and COPD: (1) By FACS, c-Kithigh/CD45+ cells (4.03 ± 2.97% (NS), 3.96 ± 5.30% (S), and 5.20 ± 3.44% (COPD)). By IF, these cells were tryptase+ (hence, mast cells) and located around the airways; (2) By IF, c-Kitlow/CD45+/triptase- (0.07 ± 0.06 (NS), 0.03 ± 0.02 (S), and 0.06 ± 0.07 (COPD) cells/field), which likely correspond to innate lymphoid cells; (3) By FACS, c-Kitlow/CD45-/CD34+ (0.95 ± 0.84% (NS), 1.14 ± 0.94% (S) and 0.95 ± 1.38% (COPD)). By IF these cells were c-Kitlow/CD45-/CD31+, suggesting an endothelial lineage, and were predominantly located in the alveolar wall; and, (4) by FACS, an infrequent c-Kitlow/CD45-/CD34- population (0.09 ± 0.14% (NS), 0.08 ± 0.09% (S) and 0.08 ± 0.11% (COPD)) compatible with a putative lung stem cell population. Yet, IF failed to detect them and we could not isolate or grow them, thus questioning the existence of c-Kit+ lung stem-cells. Conclusions The adult human lung contains a mixture of c-Kit+ cells, unlikely to be lung stem cells, which are independent of smoking status and/or presence of COPD. Electronic supplementary material The online version of this article (10.1186/s12890-018-0688-3) contains supplementary material, which is available to authorized users.

La cubierta edafica del estado de Sonora, en el norte de Mexico, esta formada predominantemente por suelos rojos de desarrollo moderado, con procesos de intemperismo, humificacion, rubificacion, neoformacion de arcillas y carbonatacion, clasificados como Cambisoles segun la WRB, que constituyen una unidad edafica denominada Paleosuelo San Rafael (SRP). Sin embargo, en algunos sitios se han registrado suelos grises formados en cuencas semicerradas, con procesos de intemperismo, neoformacion de arcillas, reductomorfia y carbonatacion. Estos suelos se desarrollaron durante el Pleistoceno Superior bajo un clima semiarido y frio, un poco mas humedo que el actual, favorecido por las lluvias invernales y cambios estacionales marcados. Estos paleosuelos se encuentran asociados a restos de fauna pleistocenica rancholabreana de composicion diversa, asociada a climas tanto aridos como humedos, lo que muestra variaciones climaticas locales mucho mas complejas que en la actualidad. Con la intencion de establecer las caracteristicas particulares de los paleosuelos formados en cuencas semicerradas que pudieron permitir la acumulacion de agua y la formacion de estanques, se evaluaron las caracteristicas fisicas, quimicas y micromorfologicas de los paleosuelos localizados en los ranchos San Francisco y El Arenoso, en el norte de Sonora, en los cuales tambien se han hallado restos de megafauna pleistocenica. Los analisis permitieron evaluar las caracteristicas de los paleosuelos, identificar los procesos pedogeneticos principales y establecer las condiciones ambientales predominantes durante su formacion. Estos resultados se contrastaron con los estudios paleopedologicos previos y los antecedentes paleontologicos, lo que permitio enmarcarlos dentro de las tendencias paleoclimaticas regionales.

In Sonora, northwest Mexico, we have recognized the existence of paleosol units of Late Pleistocene/Early and Middle Holocene age (13,000 to 4,250 Cal years BP) at several archaeological sites with Paleo-indian occupations (e.g. La Playa, Fin del Mundo, El Bajio, El Aigame and El Arenoso). The few paleoenviromental reconstructions from the region indicate that the end of the Pleistocene was dominated by temperate climate that promoted the establishment of the first people in coexistence and interaction with the Pleistocene megafauna. The study of the spatial distribution of various soil units developed during late Pleistocene in the region provides information about local environmental settings of the initial peopling of Sonora. Several pedosedimentary sequences were analyzed in the different parts of Sonora, the age control in which was provided by archaeological and paleontological findings and/or by the radiocarbon dating of carbonates and paleosol humus. Two trends of the Late Pleistocene pedogenesis have been identified. The profiles located in the south, center and north of the state are dominated by red soils (earlier referred as Big Red in the archaeological literature) whose characteristics are represented by the Red San Rafael Paleosol (SRP). The properties of SRP in the lower part of the profile (rubification, clay accumulation, hig magnetic susceptibility, illuvial carbonates, and redoximorphic features) are indicative of a more humid environment. Above them is a late Holocene polycyclic sequence of soils with morphological characteristics displaying a more incipient development. In contrast with the sequence described above, El Arenoso, north of Caborca, show a sequence of gray soils. Two paleosols were formed in alluvial sediments. At the Cantera profile (CTP) and El Arenoso profile (ARP) paleosols are represented by Bgk horizons and evidence of weathering and clay neoformation, redoximorphic processes and illuvial accumulation of carbonates. We explain the differences of north-western profiles by specific geomorphic conditions which imply limited soil drainage and the possibility of over-wetting. These processes indicate alternating a humid environment (weathering, rubification, clay formation and redoximorphic processes); and dry periods (carbonates accumulation). Despite regional differences of the late Pleistocene paleosols, the comparison with the Holocene soils demonstrates clear trends towards desertification in the region. The first people that inhabited Sonora during the late Pleistocene found a more temperate and wetter climate than they encountered further to the north, but subsequent generations witnessed a rapid desiccation of the region with the formation of the Sonoran Desert in the early Holocene.

Rationale: Chronic Obstructive Pulmonary Disease (COPD) is a complex and heterogeneous disease whose pathobiology is not fully understood. Objectives: To characterize and contrast the pulmonary mRNA expression in former smokers with COPD (mild=15; severe-very severe=16) and healthy controls (never smokers=11). Methods: Lung tissue was obtained from individuals undergoing thoracic resectional surgery (mostly because of lung cancer) or lung transplantation explants. Paired end TruSEQ RNASeq libraries were constructed and analyzed with an Illumina HiSeq. Sequencing analysis and differential gene expression was done with DESeq2, and in order to find modules of co-expressed genes related to clinical traits (airflow limitation severity, BMI and PackYear) weighted correlation networks were constructed with the whole matrix. Measurements and Main Results: The number of differentially expressed genes was higher between non-smokers vs. severe COPD (n=675), followed by mild COPD vs. severe COPD (n=391), while the expression profile of non-smokers vs. mild COPD was the most similar. Network weighted co-expression analysis identified 19 modules, 5 of them were associated to the presence of airflow limitation and its severity but not smoking or BMI. Key genes are validated in a second cohort of individuals. Conclusions: Severe airflow limitation represents a distinctive transcriptomic signature in comparison to mild COPD and non-smokers. Transcriptomic changes of mild former smokers with COPD vs. non-smokers are more heterogeneous. Supported, in part, Instituto de Salud Carlos III (PI15/00799), CP (16/00039) and a grant from MSD.

Summary Red palaeosols of the late Pleistocene-early Holocene, both buried and non-buried, were studied recently in Sonora (NW Mexico) to reconstruct their pedogenesis as well as the palaeoenvironmental conditions. The alluvial palaeosol-sedimentary sequence of the La Playa archaeological site is a key locality for the buried San Rafael palaeosol, which exhibits a 2Ah-2Bw-2BCk-3Bgk profile and was defined as a Chromic Cambisol. Radiocarbon dates from pedogenic carbonates and charcoal set the soil formation interval between >18000 and 4300calibrated years before present (cal. year BP). Micro-morphological observations together with profile distribution of clay, carbonates, organic carbon, pedogenic iron oxides and rock magnetic properties indicated a strong eluvial-illuvial redistribution of carbonates, moderate silicate weathering and gleying in the lower horizon. Although this soil was much more developed than the overlying syn-sedimentary late Holocene Fluvisols, clay mineral composition and stable carbon isotope signatures of humus and carbonates were similar in both soils. We suggest that pedogenesis of the San Rafael palaeosol took place under a slightly more humid climate and relative geomorphic stability. This agrees with the regional palaeoclimate reconstruction, which indicates a moister climate during the Late Wisconsin glaciation (MIS 2). An abrupt termination of the San Rafael pedogenesis marked by disturbance and aridization features in the Ap horizon of the palaeosol could be linked to a global drought around 4200years cal. year BP. Surface Chromic Cambisols in northern Sonora show similar pedogenetic characteristics to the buried red palaeosols of La Playa. They appear to be a relict component of the present day soil mantle.

Chronic obstructive pulmonary disease (COPD) is a major public health problem because of its high prevalence, rising incidence and associated socio-economic cost. The inhalation of toxic particles and gases, mostly tobacco smoke, is the main risk factor for COPD. Yet, not all smokers are equally susceptible to these toxic effects and only a percentage of them develop the disease (so-called 'susceptible smokers'). This, in combination with the observation that COPD shows familial aggregation, suggests that the genetic background of the smoker is a key element in the pathogenesis of the disease. On the other hand, it is well established that 'susceptible' smokers exhibit an enhanced inflammatory response of the lung parenchyma as compared with 'resistant' smokers (i.e., those who manage to maintain lung function within the normal age range despite their habit). Importantly, in COPD patients this inflammatory response does not resolve after quitting smoking, again at variance with resistant smokers. All in all, these observations suggest that the pathogenesis of COPD may involve, in some patients, an autoimmune component which contributes to the enhanced and persistent inflammatory response that characterizes the disease. Here we: i) review briefly the pathobiology of COPD; ii) present the available scientific evidence supporting a potential role for autoimmunity in COPD; iii) propose a three-step pathogenic hypothesis in the transition from smoking to COPD; and iv) discuss potential implications for the diagnosis and treatment of this frequent, growing, devastating and costly disease.

Background Chronic Obstructive Pulmonary Disease (COPD) is characterized by pulmonary and systemic manifestations. Multiple studies have identified airway or blood biomarkers associated with the severity of airflow limitation, but it is not clear whether these biomarkers directly represent the pathobiology in the lung. Objective To identify pathobiological mechanisms shared between different compartments in COPD patients. Methods Weighted Gene Co-expression Network Analysis (WGCNA) was used to meta-analyse four gene expression datasets from Caucasian former smokers with COPD: two lung tissue datasets (n=70 and n=124), and one each of sputum (n=121) and peripheral blood (n=121). Results Eighteen (86%) of the twenty-one co-expression modules identified were preserved between the two lung tissue datasets; seven (33%) of them were preserved also in sputum, and five also (24%) in blood. One module (labelled “yellow”) was preserved across all datasets and associated with FEV 1 % in lung and sputum but not in blood. This module was enriched in ontologies related to mitochondrial function, cell cycle, ubiquitination and RNA processing. Two other modules (brown and magenta) were preserved and associated with FEV 1 % across lung and sputum datasets (but not in blood). These modules included genes related to ion homeostasis, T cell response, cytokine signalling and RNA processing. Conclusions Our study identified several biological functions in mRNA co-expression modules associated with FEV 1 % in lung and sputum but not in blood. These results suggest that the systemic manifestations of COPD likely constitute an independent component of the disease. Funding Unristricted grant form GSK, U.S. NIH P01 HL105339 and FIS PI15/00799.

Chronic obstructive pulmonary disease (COPD) is characterised by pulmonary and systemic inflammation that bursts during exacerbations of the disease (ECOPD). The NLRP3 inflammasome is a key regulatory molecule of the inflammatory response. Its role in COPD is unclear. We investigated the NLRP3 inflammasome status in: 1) lung tissue samples from 38 patients with stable COPD, 15 smokers with normal spirometry and 14 never-smokers; and 2) sputum and plasma samples from 56 ECOPD patients, of whom 41 could be reassessed at clinical recovery. We observed that: 1) in lung tissue samples of stable COPD patients, NLRP3 and interleukin (IL)-1β mRNA were upregulated, but both caspase-1 and ASC were mostly in inactive form, and 2) during infectious ECOPD, caspase-1, oligomeric ASC and associated cytokines (IL-1β, IL-18) were significantly increased in sputum compared with clinical recovery. The NLRP3 inflammasome is primed, but not activated, in the lungs of clinically stable COPD patients. Inflammasome activation occurs during infectious ECOPD. The results of this study suggest that the inflammasome participates in the inflammatory burst of infectious ECOPD., The NLRP3 inflammasome is primed in stable COPD lungs, then activated during infectious exacerbation http://ow.ly/Wopi300DXcT

Chronic obstructive pulmonary disease (COPD) is characterized by chronic airflow limitation caused by a combination of airways disease (bronchiolitis) and parenchymal destruction (emphysema), whose relative proportion varies from patient to patient.To explore and contrast the molecular pathogenesis of emphysema and bronchiolitis in COPD.We used network analysis of lung transcriptomics (Affymetrix arrays) in 70 former smokers with COPD to compare differential expression and gene coexpression in bronchiolitis and emphysema.We observed that in emphysema (but not in bronchiolitis) (1) up-regulated genes were enriched in ontologies related to B-cell homing and activation; (2) the immune coexpression network had a central core of B cell-related genes; (3) B-cell recruitment and immunoglobulin transcription genes (CXCL13, CCL19, and POU2AF1) correlated with emphysema severity; (4) there were lymphoid follicles (CD20(+)IgM(+)) with active B cells (phosphorylated nuclear factor-κB p65(+)), proliferation markers (Ki-67(+)), and class-switched B cells (IgG(+)); and (5) both TNFRSF17 mRNA and B cell-activating factor protein were up-regulated. These findings were by and large reproduced in a group of patients with incipient emphysema and when patients with emphysema were matched for the severity of airflow limitation of those with bronchiolitis.Our study identifies enrichment in B cell-related genes in patients with COPD with emphysema that is absent in bronchiolitis. These observations contribute to a better understanding of COPD pathobiology and may open new therapeutic opportunities for patients with COPD.

Self-renewing, multi-potent and clonogenic stem cells (ckit+/CD45-/tryptase-, CD34-) have been described in lung tissue of healthy adults. Whether they are present in smokers with and without chronic obstruc-tive pulmonary disease (COPD) is unknown.

Background Tobacco smoking is the main risk factor of chronic obstructive pulmonary disease (COPD) but not all smokers develop the disease. An abnormal pulmonary and systemic inflammatory response to smoking is thought to play a major pathogenic role in COPD, but this has never been tested directly. Methods We studied the systemic biomarker and leukocyte transcriptomic response (Affymetrix microarrays) to smoking exposure in 10 smokers with COPD and 10 smokers with normal spirometry. We also studied 10 healthy never smokers (not exposed to smoking) as controls. Because some aspects of COPD may differ in males and females, and the inflammatory response to other stressors (infection) might be different in man and women, we stratified participant recruitment by sex. Differentially expressed genes were validated by q-PCR. Ontology enrichment was evaluated and interaction networks inferred. Results Principal component analysis identified sex differences in the leukocyte transcriptomic response to acute smoking. In both genders, we identified genes that were differentially expressed in response to smoking exclusively in COPD patients (COPD related signature) or smokers with normal spirometry (Smoking related signature), their ontologies and interaction networks. Conclusions The use of an experimental intervention (smoking exposure) to investigate the transcriptomic response of peripheral leukocytes in COPD is a step beyond the standard case-control transcriptomic profiling carried out so far, and has facilitated the identification of novel COPD and Smoking expression related signatures which differ in males and females.