Quality assurance through laboratory reference materials (LRMs): dataset for non-certified elements (Al, Fe, Li, Mn and Pb) in estuarine sediment BCR-277R

Datasets for aluminium (Al), iron (Fe), lithium (Li), manganese (Mn) and lead (Pb) in the commercial estuarine sediment BCR-277RThree specialized laboratories examined the determination of non-certified trace elements (Al, Fe, Li, Mn and Pb) in a commercial CRM and therefore, produced a so-called laboratory reference material (LRM). The dataset (total mass fractions and their associated uncertainties) were estimated both using parametric and non-parametric methods. The results provided a coherent assessment for all except for Pb, in agreement with the results found by the CRM producer. We discuss the feasibility of the implementation of small-sized specialized laboratory comparisons to produce LRMs (from CRMs) for non-certified chemicals and strongly discourage attempts by a single laboratory

Typical support and Sanov large deviations of correlated states

Discrete stationary classical processes as well as quantum lattice states are asymptotically confined to their respective typical support, the exponential growth rate of which is given by the (maximal ergodic) entropy. In the iid case the distinguishability of typical supports can be asymptotically specified by means of the relative entropy, according to Sanov's theorem. We give an extension to the correlated case, referring to the newly introduced class of HP-states.Comment: 29 pages, no figures, references adde

Apolipoprotein E controls the development of monocyte-derived alveolar macrophages upon pulmonary inflammatory adaptation

The lung is constantly exposed to the outside world and optimal adaptation of immune responses is crucial for efficient pathogen clearance. However, mechanisms that lead to lung-associated macrophages' functional and developmental adaptation remain elusive. To reveal such mechanisms, we developed a reductionist model of environmental intranasal β-glucan exposure, allowing for the detailed interrogation of molecular mechanisms of pulmonary macrophage adaptation. Employing single-cell transcriptomics, high dimensional imaging, and flow cytometric characterization paired with in vivo and ex vivo challenge models, we reveal that pulmonary low-grade inflammation results in the development of Apolipoprotein E (ApoE) -dependent monocyte-derived alveolar macrophages (ApoE+CD11b+ AM). ApoE+CD11b+ AMs expressed high levels of CD11b, ApoE, Gpnmb, and Ccl6, were glycolytic, highly phagocytic, and produced large amounts of interleukin 6 upon restimulation. Functional differences were cell intrinsic and myeloid cell-specific ApoE ablation inhibited Ly6c+ monocyte to ApoE+CD11b+ AM differentiation dependent on M-CSF secretion, promoting ApoE+CD11b+ AM cell death and thus impeding ApoE+CD11b+ AM maintenance. In vivo, β-glucan-elicited ApoE+CD11b+ AMs limited the bacterial burden of Legionella pneumophilia post-infection and improved the disease outcome in vivo and ex vivo in a murine lung fibrosis model. Collectively these data identify ApoE+CD11b+ AMs generated uponenvironmental cues, under the control of ApoE signaling, as an essential determinant for lung adaptation enhancing tissue resilience

Tumor-Induced Cholesterol Efflux from Macrophages Drives IL-4 Mediated Reprogramming and Tumor Progression

Tumor-associated macrophages (TAM) have been shown to have important roles in the malignant progression of various cancers. However, macrophages also posses intrinsic tumoricidal activity and can promote the activity of cytotoxic lymphocytes, but they rapidly adopt an alternative phenotype within tumors, associated with immune-suppression and trophic functions that support tumor growth. The mechanisms that promote TAM polarization in the tumor-microenvironment remain poorly understood, these mechanisms may represent important therapeutic targets to block the tumor-promoting functions of TAM and restore their anti-tumor potential. Here we have characterized TAM in a mouse model of metastatic ovarian cancer. We show that ovarian cancer cells promote membrane-cholesterol efflux and the depletion of lipid rafts from macrophages. Increased cholesterol efflux promoted IL-4 mediated reprogramming while inhibiting IFNγ-induced gene expression. These studies reveal an unexpected role for tumor-induced membrane-cholesterol efflux in driving the IL-4 signaling and the tumor-promoting functions of TAM, while rendering them refractory to pro-inflammatory stimuli. Thus, preventing cholesterol efflux in TAM could represent a novel therapeutic strategy to block pro-tumor functions and restore anti-tumor immunity. Biopharmaceutic

Soluble mannose receptor induces proinflammatory macrophage activation and metaflammation

Proinflammatory activation of macrophages in metabolic tissues is critically important in the induction of obesity-induced metaflammation. Here, we demonstrate that the soluble mannose receptor (sMR) plays a direct functional role in both macrophage activation and metaflammation. We show that sMR binds CD45 on macrophages and inhibits its phosphatase activity, leading to an Src/Akt/ NF-kappa B-mediated cellular reprogramming toward an inflammatory phenotype both in vitro and in vivo. Remarkably, increased serum sMR levels were observed in obese mice and humans and directly correlated with body weight. Importantly, enhanced sMR levels increase serum proinflammatory cytokines, activate tissue macrophages, and promote insulin resistance. Altogether, our results reveal sMR as regulator of proinflammatory macrophage activation, which could constitute a therapeutic target for metaflammation and other hyperinflammatory diseases.Diabetes mellitus: pathophysiological changes and therap

Identification of drug candidates targeting monocyte reprogramming in people living with HIV

INTRODUCTION: People living with HIV (PLHIV) are characterized by functional reprogramming of innate immune cells even after long-term antiretroviral therapy (ART). In order to assess technical feasibility of omics technologies for application to larger cohorts, we compared multiple omics data layers. METHODS: Bulk and single-cell transcriptomics, flow cytometry, proteomics, chromatin landscape analysis by ATAC-seq as well as ex vivo drug stimulation were performed in a small number of blood samples derived from PLHIV and healthy controls from the 200-HIV cohort study. RESULTS: Single-cell RNA-seq analysis revealed that most immune cells in peripheral blood of PLHIV are altered in their transcriptomes and that a specific functional monocyte state previously described in acute HIV infection is still existing in PLHIV while other monocyte cell states are only occurring acute infection. Further, a reverse transcriptome approach on a rather small number of PLHIV was sufficient to identify drug candidates for reversing the transcriptional phenotype of monocytes in PLHIV. DISCUSSION: These scientific findings and technological advancements for clinical application of single-cell transcriptomics form the basis for the larger 2000-HIV multicenter cohort study on PLHIV, for which a combination of bulk and single-cell transcriptomics will be included as the leading technology to determine disease endotypes in PLHIV and to predict disease trajectories and outcomes

S100A8 and S100A9 are important for postnatal development of gut microbiota and immune system in mice and infants

BACKGROUND & AIMS: After birth, the immune system matures via interactions with microbes in the gut. The S100 calcium binding proteins S100A8 and S100A9, and their extracellular complex form, S100A8-A9, are found in high amounts in human breast milk. We studied levels of S100A8-A9 in fecal samples (also called fecal calprotectin) from newborns and during infancy, and their effects on development of the intestinal microbiota and mucosal immune system.background METHODS: We collected stool samples (n=517) from full-term (n=72) and preterm infants (n=49) at different timepoints over the first year of life (days 1, 3, 10, 30, 90, 180, and 360). We measured levels of S100A8-A9 by ELISA and analyzed fecal microbiomes by 16S sRNA gene sequencing. We also obtained small and large intestine biopsies from 8 adults and 10 newborn infants without inflammatory bowel diseases (controls) and 8 infants with necrotizing enterocolitis and measured levels of S100A8 by immunofluorescence microscopy. Children were followed for 2.5 years and anthropometric data and medical information on infections were collected. We performed studies with newborn C57BL/6J wild-type and S100a9(-/-) mice (which also lack S100A8). Some mice were fed or given intraperitoneal injections of S100A8 or subcutaneous injections of Staphylococcus aureus. Blood and intestine, mesenterial and celiac lymph nodes were collected; cells and cytokines were measured by flow cytometry and studied in cell culture assays. Colon contents from mice were analyzed by culture-based microbiology assays. RESULTS: Loss of S100A8 and S100A9 in mice altered the phenotypes of colonic lamina propria macrophages, compared with wildtype mice. Intestinal tissues from neonatal S100-knockout mice had reduced levels of CX3CR1 protein, and Il10 and Tgfb1 mRNAs, compared with wildtype mice, and fewer T-regulatory cells. S100-knockout mice weighed 21% more than wildtype mice at age 8 weeks and a higher proportion developed fatal sepsis during the neonatal period. S100-knockout mice had alterations in their fecal microbiomes, with higher abundance of Enterobacteriaceae. Feeding mice S100 at birth prevented the expansion of Enterobacteriaceae, increased numbers of T-regulatory cells and levels of CX3CR1 protein and Il10 mRNA in intestine tissues, and reduced body weight and death from neonatal sepsis. Fecal samples from term infants, but not preterm infants, had significantly higher levels of S100A8-A9 during the first 3 months of life than fecal samples from adults; levels decreased to adult levels after weaning. Fecal samples from infants born by cesarean section had lower levels of S100A8-A9 than from infants born by vaginal delivery. S100 proteins were expressed by lamina propria macrophages in intestinal tissues from infants, at higher levels than in intestinal tissues from adults. High fecal levels of S100 proteins, from 30 days to 1 year of age, were associated with higher abundance of Actinobacteria and Bifidobacteriaceae, and lower abundance of Gammaproteobacteria-particularly opportunistic Enterobacteriaceae. A low level of S100 proteins in infants' fecal samples associated with development of sepsis and obesity by age 2 years.results CONCLUSION: S100A8 and S100A9 regulate development of the intestinal microbiota and immune system in neonates. Nutritional supplementation with these proteins might aide in development of preterm infants and prevent microbiota-associated disorders in later years

Fighting post-COVID and ME/CFS - development of curative therapies

The sequela of COVID-19 include a broad spectrum of symptoms that fall under the umbrella term post-COVID-19 condition or syndrome (PCS). Immune dysregulation, autoimmunity, endothelial dysfunction, viral persistence, and viral reactivation have been identified as potential mechanisms. However, there is heterogeneity in expression of biomarkers, and it is unknown yet whether these distinguish different clinical subgroups of PCS. There is an overlap of symptoms and pathomechanisms of PCS with postinfectious myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). No curative therapies are available for ME/CFS or PCS. The mechanisms identified so far provide targets for therapeutic interventions. To accelerate the development of therapies, we propose evaluating drugs targeting different mechanisms in clinical trial networks using harmonized diagnostic and outcome criteria and subgrouping patients based on a thorough clinical profiling including a comprehensive diagnostic and biomarker phenotyping

Estudio de los Ecosistemas Marinos Vulnerables en aguas internacionales del Atlántico Sudoccidental

En este libro, basado en la mejor información científica disponible hasta la fecha, se presentan los resultados y conclusiones de una serie de trece campañas de investigación multidisciplinar realizadas entre octubre de 2007 y abril de 2010 por los componentes del Grupo ATLANTIS a bordo del B/O MIGUEL OLIVER, propiedad de la Secretaría General de Pesca (SGP). El estudio surge a raíz de la solicitud por parte de la SGP (anteriormente denominada Secretaría General del Mar) al Instituto Español de Oceanografía (IEO), para la realización de una serie de campañas de investigación multidisciplinar en aguas internacionales del Atlántico Sudoccidental, dirigidas al estudio de los Ecosistemas Marinos Vulnerables (EMVs) y de las posibles interacciones con las actividades pesqueras. El objetivo final de dichas campañas era el estudio y la identificación cuantitativa, cualitativa y geográfica de los EMVs y de los grupos taxonómicos de organismos sensibles que pudieran existir en la zona de estudio, incluyendo la propuesta de posibles zonas marinas a proteger, para una explotación sostenible de los recursos pesqueros en el ámbito del respeto a los EMVs. Los resultados que se presentan en este libro comprenden los obtenidos a través de los trabajos de geología, geomorfología, bentos, pesca, oceanografía física y análisis de contaminantes en la zona de aguas internacionales del Atlántico Sudoccidental comprendida entre los paralelos 42º y 48ºS, y la isobata de los 1500 m de profundidad (Figura 2.2). Entre estos resultados se incluye el cartografiado y una batimetría detallada de la zona, la descripción del substrato geológico y de los aspectos bentónicos, el análisis de la distribución y abundancia de las especies de mayor interés comercial, la huella de la pesquería, la identificación y descripción preliminar de los EMVs, y la propuesta de Zonas de Protección, basada en criterios Geológicos, Geomorfológicos y Biológicos. Toda esta información ha sido incorporada para su tratamiento en una plataforma SIG (Sistema de Información Geográfica) y los resultados obtenidos y presentados en este libro vienen acompañados de abundante información gráfica, como imágenes batimétricas en 3D, fotografías de bentos (infauna y epifauna), imágenes tomadas con un ROV (Remotely Operated Vehicle) y con una cámara digital submarina, así como una serie de mapas de distribución, capturas y densidad de las principales especies de interés pesquero. Se incluye también un mapa con la huella de la pesquería (1989-2010) que permita observar la incidencia de las Zonas de Protección propuestas en el área en la que faena habitualmente la flota española de arrastre de fondo. Como información adicional a la obtenida en las trece campañas de investigación, también se ha utilizado la base de datos creada con la información recogida por el Programa de Observadores del IEO entre los años 1989-2010, referente a datos comerciales, biológicos, oceanográficos y físicos (batimetría, temperatura superficial del mar y temperatura del fondo). Entre octubre de 2007 y abril de 2010 se han realizado un total de trece campañas de investigación multidisciplinar, que se han concretado en los siguientes trabajos: • 347 días efectivos de mar • Prospección de una superficie total de 59.105 km2 • Realización de un total de 91.905 km de perfiles geofísicos • 102 muestreos con draga de roca • 209 muestreos con draga box corer • 519 estaciones de CTD • 413 lances de pesca • 413 muestras de sedimentos con el colector de red • Recogida de varios miles de lotes de muestras de bentos que representan varios centenares de miles de especímenes y/o colonias • Realización de miles de fotografías de especies bentónicas, centenares de imágenes digitales de alta resolución y decenas de horas de vídeo realizadas con el ROV del barco Entre los principales resultados de los trabajos de investigación multidisciplinar presentados en este libro hay que destacar la identificación, descripción y delimitación de los EMVs, siguiendo criterios biológicos, geológicos y mixtos; la identificación de los principales grupos bentónicos indicadores de EMVs; la determinación de los valores que representan una captura significativa de los distintos taxones considerados como vulnerables según criterios de la ONU y OSPAR, y finalmente, la propuesta de áreas marinas que deberían ser consideradas como candidatas a ser protegidas. En total se proponen nueve polígonos de diferente superficie para su valoración como zonas de protección (Figura 7.5) y se hace referencia a la incidencia que el cierre de dichas zonas podría tener sobre la actividad de la flota, es decir, el grado de solapamiento entre las zonas de protección y la huella de la pesquería (Figura 7.6). Todos estos resultados se presentan acompañados de abundantes gráficas, figuras y mapas.Instituto Español de OceanografíaVersión del edito