Brucella abortus Uses a Stealthy Strategy to Avoid Activation of the Innate Immune System during the Onset of Infection

To unravel the strategy by which Brucella abortus establishes chronic infections, we explored its early interaction with innate immunity. Methodology/Principal Findings Brucella did not induce proinflammatory responses as demonstrated by the absence of leukocyte recruitment, humoral or cellular blood changes in mice. Brucella hampered neutrophil (PMN) function and PMN depletion did not influence the course of infection. Brucella barely induced proinflammatory cytokines and consumed complement, and was strongly resistant to bactericidal peptides, PMN extracts and serum. Brucella LPS (BrLPS), NH-polysaccharides, cyclic glucans, outer membrane fragments or disrupted bacterial cells displayed low biological activity in mice and cells. The lack of proinflammatory responses was not due to conspicuous inhibitory mechanisms mediated by the invading Brucella or its products. When activated 24 h post-infection macrophages did not kill Brucella, indicating that the replication niche was not fusiogenic with lysosomes. Brucella intracellular replication did not interrupt the cell cycle or caused cytotoxicity in WT, TLR4 and TLR2 knockout cells. TNF-α-induction was TLR4- and TLR2-dependent for live but not for killed B. abortus. However, intracellular replication in TLR4, TLR2 and TLR4/2 knockout cells was not altered and the infection course and anti-Brucella immunity development upon BrLPS injection was unaffected in TLR4 mutant mice. Conclusion/Significance We propose that Brucella has developed a stealth strategy through PAMPs reduction, modification and hiding, ensuring by this manner low stimulatory activity and toxicity for cells. This strategy allows Brucella to reach its replication niche before activation of antimicrobial mechanisms by adaptive immunity. This model is consistent with clinical profiles observed in humans and natural hosts at the onset of infection and could be valid for those intracellular pathogens phylogenetically related to Brucella that also cause long lasting infections

Role of age and comorbidities in mortality of patients with infective endocarditis

Purpose: The aim of this study was to analyse the characteristics of patients with IE in three groups of age and to assess the ability of age and the Charlson Comorbidity Index (CCI) to predict mortality. Methods: Prospective cohort study of all patients with IE included in the GAMES Spanish database between 2008 and 2015. Patients were stratified into three age groups:<65 years, 65 to 80 years, and = 80 years.The area under the receiver-operating characteristic (AUROC) curve was calculated to quantify the diagnostic accuracy of the CCI to predict mortality risk. Results: A total of 3120 patients with IE (1327 < 65 years;1291 65-80 years;502 = 80 years) were enrolled.Fever and heart failure were the most common presentations of IE, with no differences among age groups.Patients =80 years who underwent surgery were significantly lower compared with other age groups (14.3%, 65 years; 20.5%, 65-79 years; 31.3%, =80 years). In-hospital mortality was lower in the <65-year group (20.3%, <65 years;30.1%, 65-79 years;34.7%, =80 years;p < 0.001) as well as 1-year mortality (3.2%, <65 years; 5.5%, 65-80 years;7.6%, =80 years; p = 0.003).Independent predictors of mortality were age = 80 years (hazard ratio [HR]:2.78;95% confidence interval [CI]:2.32–3.34), CCI = 3 (HR:1.62; 95% CI:1.39–1.88), and non-performed surgery (HR:1.64;95% CI:11.16–1.58).When the three age groups were compared, the AUROC curve for CCI was significantly larger for patients aged <65 years(p < 0.001) for both in-hospital and 1-year mortality. Conclusion: There were no differences in the clinical presentation of IE between the groups. Age = 80 years, high comorbidity (measured by CCI), and non-performance of surgery were independent predictors of mortality in patients with IE.CCI could help to identify those patients with IE and surgical indication who present a lower risk of in-hospital and 1-year mortality after surgery, especially in the <65-year group

Role of age and comorbidities in mortality of patients with infective endocarditis

[Purpose]: The aim of this study was to analyse the characteristics of patients with IE in three groups of age and to assess the ability of age and the Charlson Comorbidity Index (CCI) to predict mortality. [Methods]: Prospective cohort study of all patients with IE included in the GAMES Spanish database between 2008 and 2015.Patients were stratified into three age groups:<65 years,65 to 80 years,and ≥ 80 years.The area under the receiver-operating characteristic (AUROC) curve was calculated to quantify the diagnostic accuracy of the CCI to predict mortality risk. [Results]: A total of 3120 patients with IE (1327 < 65 years;1291 65-80 years;502 ≥ 80 years) were enrolled.Fever and heart failure were the most common presentations of IE, with no differences among age groups.Patients ≥80 years who underwent surgery were significantly lower compared with other age groups (14.3%,65 years; 20.5%,65-79 years; 31.3%,≥80 years). In-hospital mortality was lower in the <65-year group (20.3%,<65 years;30.1%,65-79 years;34.7%,≥80 years;p < 0.001) as well as 1-year mortality (3.2%, <65 years; 5.5%, 65-80 years;7.6%,≥80 years; p = 0.003).Independent predictors of mortality were age ≥ 80 years (hazard ratio [HR]:2.78;95% confidence interval [CI]:2.32–3.34), CCI ≥ 3 (HR:1.62; 95% CI:1.39–1.88),and non-performed surgery (HR:1.64;95% CI:11.16–1.58).When the three age groups were compared,the AUROC curve for CCI was significantly larger for patients aged <65 years(p < 0.001) for both in-hospital and 1-year mortality. [Conclusion]: There were no differences in the clinical presentation of IE between the groups. Age ≥ 80 years, high comorbidity (measured by CCI),and non-performance of surgery were independent predictors of mortality in patients with IE.CCI could help to identify those patients with IE and surgical indication who present a lower risk of in-hospital and 1-year mortality after surgery, especially in the <65-year group

REQUITE: A prospective multicentre cohort study of patients undergoing radiotherapy for breast, lung or prostate cancer

Purpose: REQUITE aimed to establish a resource for multi-national validation of models and biomarkers that predict risk of late toxicity following radiotherapy. The purpose of this article is to provide summary descriptive data. Methods: An international, prospective cohort study recruited cancer patients in 26 hospitals in eight countries between April 2014 and March 2017. Target recruitment was 5300 patients. Eligible patients had breast, prostate or lung cancer and planned potentially curable radiotherapy. Radiotherapy was prescribed according to local regimens, but centres used standardised data collection forms. Pre-treatment blood samples were collected. Patients were followed for a minimum of 12 (lung) or 24 (breast/prostate) months and summary descriptive statistics were generated. Results: The study recruited 2069 breast (99% of target), 1808 prostate (86%) and 561 lung (51%) cancer patients. The centralised, accessible database includes: physician-(47,025 forms) and patient-(54,901) reported outcomes; 11,563 breast photos; 17,107 DICOMs and 12,684 DVHs. Imputed genotype data are available for 4223 patients with European ancestry (1948 breast, 1728 prostate, 547 lung). Radiation-induced lymphocyte apoptosis (RILA) assay data are available for 1319 patients. DNA (n = 4409) and PAXgene tubes (n = 3039) are stored in the centralised biobank. Example prevalences of 2-year (1-year for lung) grade >= 2 CTCAE toxicities are 13% atrophy (breast), 3% rectal bleeding (prostate) and 27% dyspnoea (lung). Conclusion: The comprehensive centralised database and linked biobank is a valuable resource for the radiotherapy community for validating predictive models and biomarkers. Patient summary: Up to half of cancer patients undergo radiation therapy and irradiation of surrounding healthy tissue is unavoidable. Damage to healthy tissue can affect short-and long-term quality-of-life. Not all patients are equally sensitive to radiation "damage" but it is not possible at the moment to identify those who are. REQUITE was established with the aim of trying to understand more about how we could predict radiation sensitivity. The purpose of this paper is to provide an overview and summary of the data and material available. In the REQUITE study 4400 breast, prostate and lung cancer patients filled out questionnaires and donated blood. A large amount of data was collected in the same way. With all these data and samples a database and biobank were created that showed it is possible to collect this kind of information in a standardised way across countries. In the future, our database and linked biobank will be a resource for research and validation of clinical predictors and models of radiation sensitivity. REQUITE will also enable a better understanding of how many people suffer with radiotherapy toxicity

A combination of ICT solutions with socio-ecological and economic indicators to evaluate the governance and improve the management of Posidonia oceanica in the Sierra Helada Marine Natural Park

Marine Protected Areas (MPAs) are essential tools in the protection and conservation of marine ecosystems. However, very few MPAs are effective and meet their conservation objectives mainly due to a lack of coordination, participation or resources. For instance, in the Mediterranean Sea there are about 1062 MPAs, but 72% of them do not have effective regulations to reduce human impacts on biodiversity and current efforts are insufficient in managing human uses for the conservation and protection of marine biodiversity. This makes necessary to seek new ways or instruments for their management. In this sense, digitalization and Information and Communication Technologies (ICT) can provide tools to facilitate the development of MPAs management in a more effective, participatory and efficient manner because automatic agents report their information and digest the data no matter the situation. In the specific case of Spain, one of the main problems identified for MPAs management is the overlapping of different kinds of protected areas in the same territory. In addition, these are managed by different administrations (Regional, National). An example of this situation is the Sierra Helada Marine Natural Park (SHMP) in Alicante. Within its territorial scope there are 3 MPAs with different protection figures that overlap each other, SHMP, the Natura 2000 site of Serra Gelada i la Marina Baixa and a fishing protected area. These MPAs are managed by different regional governmental bodies, and have a natural resources action plan in use, supported by a management collaboration agreement with the town councils in the area and the Altea Nautical Club. In the SHMP, Posidonia oceanica (PO) is one of the most important ecosystems and its presence prompted its creation and declaration. PO is a marine angiosperm endemic to the Mediterranean Sea that forms extensive meadows from the sea surface to 30–40 m depth and which provides essential goods and services: it improves water quality and protect beaches against erosion. PO meadows are recognized as biodiversity hotspots, and as major carbon sinks, but they are very sensitive to human activities. However, although many regulations protect PO, there are still significant threats to their conservation. In this regard, the research presented in this paper is the development of an ICT-based software tool, called Smart MPA, that includes an analysis framework based on management and governance indicators specific for PO and a database on PO that includes and combines different sources of information, including the results obtained of the evaluation of the analytical framework, input from information from citizens or MPA users, for example, by sending photos to report infractions in PO at specific points and from satellite images or underwater UAVs. The main objective of the Smart MPA tool is to offer services applied to PO management, either through the analysis of governance indicators or by facilitating the integration of citizen information to be used in management activities. The tool has been tested and used by the management staff of SHMP to be applied to an annual monitoring of management measures to develop an adaptive management of PO and the SHMP. After that, a semi-structured interview was carried out to collect information on the analytical framework co-developed and a survey was created where management staff of SHMP have given their perception on the usability of the tool and on the environmental problems affecting the conservation of PO in SHMP. According to the results obtained, the management of PO in SHMP is efficient, at a general level, with the lack of adequate funding being a limiting factor. The main threats are boat anchoring and organic pollution. In conclusion, the Smart MPA tool and the analytical framework are instruments that can facilitate the management and promote good environmental governance processes for the conservation of PO meadows in SHMP. At the same time, the importance of exploring mobile apps to increase citizen participation and mitigate threats and impacts on PO have been highlighted.This study forms part of: (1) ThinkInAzul project supported by Ministerio de Ciencia e Innovación with funding from European Union NextGenerationEU (PRTR-C17.I1) and by Comunidad Autónoma de la Región de Murcia-Fundación Seneca; (2) WATERMED4.0 project (Efficient use and management of conventional and non-conventional water resources through intelligent technologies applied to improve the quality and safety of Mediterranean agriculture in semi-arid areas) action 1821 of the PRIMA program of the European Union. The PRIMA program is an Art.185 initiative supported and funded by Horizon 2020 (https://www.watermed-project.eu); and (3) B-Blue (Building the Blue Biotechnology community in the Mediterranean) governance and innovation project co-financed by the European Regional Development Fund through the Interreg Med program (https://b-blue.interreg-med.eu)Peer reviewe

Provincias de Salta y Catamarca

Fil: Hongn, Fernando D. Ministerio de Economía. Subsecretaría de Minería. Servicio Geológico Minero Argentino (SEGEMAR); Argentina.Fil: Seggiaro, Raúl E. Ministerio de Economía. Subsecretaría de Minería. Servicio Geológico Minero Argentino (SEGEMAR); Argentina.Fil: Monaldi, César R. Ministerio de Economía. Subsecretaría de Minería. Servicio Geológico Minero Argentino (SEGEMAR); Argentina.Fil: Alonso, Ricardo N. Ministerio de Economía. Subsecretaría de Minería. Servicio Geológico Minero Argentino (SEGEMAR); Argentina.Fil: González, Raúl E. Ministerio de Economía. Subsecretaría de Minería. Servicio Geológico Minero Argentino (SEGEMAR); Argentina.Fil: Igarzábal, Antonio P. Ministerio de Economía. Subsecretaría de Minería. Servicio Geológico Minero Argentino (SEGEMAR); Argentina.Fil: Ramallo, Eulogio. Ministerio de Economía. Subsecretaría de Minería. Servicio Geológico Minero Argentino (SEGEMAR); Argentina.Fil: Godeas, Marta C. Ministerio de Economía. Subsecretaría de Minería. Servicio Geológico Minero Argentino (SEGEMAR); Argentina.Fil: Fuertes, Alfredo. Ministerio de Economía. Subsecretaría de Minería. Servicio Geológico Minero Argentino (SEGEMAR); Argentina.Fil: García, Rodolfo. Ministerio de Economía. Subsecretaría de Minería. Servicio Geológico Minero Argentino (SEGEMAR); Argentina.Fil: Moya, Federico. Ministerio de Economía. Subsecretaría de Minería. Servicio Geológico Minero Argentino (SEGEMAR); Argentina.Fil: González, Osvaldo. Ministerio de Economía. Subsecretaría de Minería. Servicio Geológico Minero Argentino (SEGEMAR); Argentina.La Hoja Geológica 2566-III, CACHI, está ubicada en las provincias de Salta y Catamarca, en el noroeste de Argentina. Esta cubre parte de dos provincias geológicas: la Puna en el oeste, la cual ocupa aproximadamente el 70% de la superficie de la Hoja, y la Cordillera Oriental o Subprovincia de las Cumbres Calchaquíes, en el este. Los pueblos de Payogasta, Cachi, Seclantas, Molinos y Angastaco constituyen las principales concentraciones urbanas en la parte oriental y las minas Tincalayu y Fénix son los centros de desarrollo más importantes de la región puneña. Las principales actividades económicas del sector oriental de la Hoja son la ganadería, agricultura y turismo, mientras que en el sector occidental es la minería. Las provincias geológicas tienen una diferente expresión morfológica. La Cordillera Oriental está caracterizada por un paisaje de sierras y valles por donde discurren los ríos principales de la región. La Puna corresponde a una altiplanicie con un nivel de base de aproximadamente 4.000 m s.n.m., con serranías y cerros volcánicos que separan extensas depresiones, muchas de ellas ocupadas por salares. La altura máxima corresponde al cerro Galán (5.912 m). Las rocas más antiguas pertenecen a un basamento metamórfico afectado por diferentes fases de deformación; este basamento está constituido por rocas sedimentarias y magmáticas neoproterozoicas (eocámbricas?), las cuales integran varias unidades: Formación Pachamama, Complejo Metamórfico Río Blanco y Metamorfita Antofallita en la Puna y Formaciones Puncoviscana y La Paya en la Cordillera Oriental. La Formación Cachi constituida por trondhjemitas, tonalitas y granitos de edad neoproterozoica-eocámbrica intruye el basamento de la Cordillera Oriental. Las unidades fanerozoicas aflorantes en la Puna y Cordillera Oriental son estratigráficamente diferentes. Las sedimentitas marinas de la Formación Tolillar y las turbiditas de la Formación Falda Ciénega, ambas del Ordovícico, afloran en la Puna. En el Paleozoico inferior tiene lugar una intensa actividad magmática representada por las granodioritas y granitos el Complejo Eruptivo Oire, aflorantes en el borde oriental de la Puna y, localmente, en la Cordillera Oriental. El granito de la Formación Cortaderas integra parte de los plutones ordovícicos del borde occidental de la Puna, mientras que La Tonalita Las Viñas de edad cámbrica? y los Granitos Angostura, Pucará y Altos del Cajón de edad ordovícica representan el magmatismo paleozoico en la Cordillera Oriental. Las sedimentitas cretácico-paleógenas del Grupo Salta afloran en la Cordillera Oriental. Esta unidad está integrada por los depósitos de sinrift del Subgrupo Pirgua, constituido por conglomerados y areniscas rojas, y las secuencias de postrift de los Subgrupos Balbuena y Santa Bárbara, integradas por areniscas, areniscas carbonáticas, pelitas y ocasionales calizas correspondientes a las Formaciones Lecho, Yacoraite, Mealla, Maíz Gordo y Lumbrera. El Paleógeno de la Puna está representado por la Formación Geste, compuesta por conglomerados y areniscas, cuya fauna registra condiciones de clima subtropical. La actividad del arco magmático andino y el acortamiento tectónico controlaron la naturaleza de las unidades neógenas en la Puna. Las rocas volcánicas consisten en unidades subvolcánicas (pórfidos de la Formación Inca Viejo) y lávicas (dacitas y andesitas de la Formación Tebenquicho). Los estratos depositados en cuencas orogénicas de antepaís se subdividen en distintas unidades formacionales, las cuales exhiben material proveniente del arco magmático terciario. Estas unidades son la Formación Catal integrada por conglomerados y areniscas con intercalaciones ignimbríticas; la Formación Batín constituida por conglomerados, areniscas y escasas tobas y la Formación Sijes integrada por pelitas y areniscas con intercalaciones evaporíticas y volcaniclásticas. Los estratos neógenos de la Cordillera Oriental integran el Grupo Payogastilla constituido por las Formaciones Quebrada de los Colorados, Angastaco, San Felipe y Palo Pintado. Estas unidades conforman secuencias clásticas de conglomerados, areniscas y escasas pelitas, con intercalaciones volcaniclásticas menores. La depositación de la Formación Angastaco es coetánea con la Ignimbrita Pucarilla, representando la manifestación distal del arco magmático mioceno. El registro plioceno está limitado a la actividad volcánica de la Puna, representado por la Andesita Ratones y por el Complejo Volcánico Galán; a este último se asocia una de las mayores calderas de los Andes. La porción superior del Grupo Payogastilla representa la sedimentación pliocena en la Cordillera Oriental. El Cuaternario comprende los depósitos de pie de monte y conos de deyección vinculados genéticamente al relieve estructural impuesto por la compresión plioceno-pleistocena. Asimismo, en la Puna sand tiene lugar el derrame de basaltos fisurales y de centros monogénicos, representado por la Formación Incahuasi, como así también el desarrollo de depósitos evaporíticos que configuran extensos salares. La estructura de la comarca es el resultado de la superposición de varios procesos de deformación ocurridos desde el Neoproterozoico. La actual configuración del relieve data del Mioceno, período en el cual se produce el engrosamiento cortical diferenciándose nítidamente la Puna de la Cordillera Oriental. Ambas regiones muestran fajas corridas y plegadas con fuertes anomalías geométricas, las cuales se deben en gran parte a cambios en la cinemática y velocidad de subducción del sistema de placas de Nazca y Sudamérica, y a la inversión de estructuras previas. Las distintas características topográficas y climáticas existentes en la Puna y Cordillera Orien tal controlan los procesos morfogenéticos resultantes. La acción fluvial es más activa en la Cordillera Oriental que en la Puna. En la región puneña se localizan los principales recursos minerales de la Hoja. La actividad minera consiste en la explotación de depósitos evaporíticos, fósiles o actuales. La mina Tincalayu explota boratos miocenos de la Formación Sijes y la mina Fénix extrae litio a partir de salmueras del Salar el Hombre Muerto. La extracción de ulexita de los salares de Diablillos, Ratones y Hombre Muerto constituyen explotaciones mineras menores. En la actualidad no se explotan minerales metalíferos. La mina Incahuasi consistente en vetas de cuarzo aurífero, fue trabajada hasta mediados de siglo. El área de Diablillos es el prospecto de mayor potencial descubierto al presente en la región

Paleoenvironmental variability and anthropic influence during the last 7300 years in the western Mediterranean based on the pollen record of Cartagena Bay, SE Spain

In this paper, we conduct a palynological analysis of a high-resolution Holocene record from Cartagena Bay, southeast of the Iberian Peninsula, to establish paleoenvironmental variability of coastal areas in the western Mediterranean region at a centennial-scale over the last 7300 years. Statistical analysis of four palynozones allows reconstruction of paleotemperature and paleohumidity conditions. Pinus, steppic, xerophilous, and Mediterranean taxa persisted continuously through the record, and only during periods of increased humidity did deciduous and Mediterranean taxa expand (Zones II, subzone IIIb). Cooler and dry conditions favored the development of Cupressaceae and scrubs between 7300 and 7000 yr cal BP. The mid-Holocene (Northgrippian) mesophytic optimum took place between 6800 and 4000 yr cal BP during which time a Mediterranean climate was present and open forest developed, predominantly consisting of Mediterranean taxa and deciduous trees. The gradual rise in aridity in the Meghalayan (4000–1700 yr cal BP) led to Mediterranean forest being replaced by steppic and xerophilous vegetation, a change related mostly to a decrease in summer insolation, with superimposed centennial-scale variability in humidity. In parallel with forest degradation caused by increasing aridity, the record shows marked evidence of human influence since 4000 yr cal BP, which accelerated the progression of open landscapes from the Chalcolithic onwards, this change being especially marked during the Roman period. Significant denudation of the landscape can be attributed to the use of fire, as well as due to agriculture and grazing, with a major contributor being intense metallurgical and mining activity in the area. The Cartagena Bay record reported herein shows centennial-scale oscillations in humidity and temperature that correlate with well-known climatic events during the late Holocene in the western Mediterranean region, synchronous with variability in solar and atmospheric dynamics. The alternation of persistent North Atlantic Oscillation modes is likely to have played a key role in regulating humid–arid periods.This paper was made possible by Grant HAR2017-85726-C2-2-P (Cambios ambientales y ocupación humana en el sector central del sureste ibérico) funded by MCIN/AEI/10.13039/501100011033 and by Grant HAR2017-85726-C2-1-P (Carthago Nova desde su entorno litoral: Paleotopografía y evolución medioambiental del Sector central del Sureste Ibérico. Dinámica poblacional y productiva) funded by MCIN/AEI/10.13039/501100011033Peer reviewe

Keys to discern the Phoenician, Punic and Roman mining in a typical coastal environment through the multivariate study of trace element distribution

Trace element concentrations in the Cartagena Bay coastal record reveal a contribution of natural processes. However, the influence of anthropogenic factors predominates in the last three millennia, particularly aerosol deposition linked to mining and industrial activities in the area. The coastal record of Cartagena can be considered a preserved environment, suitable to search for regional human activity fingerprinting, specifically that related to the deposition of heavy metals such as Pb and Cu. A multivariate statistical analysis was carried out to clarify the geochemical behaviour of trace and major elements. Our study design represents a novel approach to assign natural contributions, such as eolian and riverine input, to coastal deposits, and organic matter preservation under anoxic environments. Therefore, synergies obtained by the simultaneous study of multivariate statistics and enrichment factors allow robust conclusions about palaeoenvironmental evolution and human activities. Anthropogenic influence suggested that Pb mining and metallurgy began during the Chalcolithic period, with considerable inputs of Pb and Cu to atmospheric pollution during Phoenician, Punic and Roman times.This paper was made possible by funding from the Spanish Ministry of Science and Innovation projects: Cambios ambientales y ocupación humana en el sector central del sureste ibérico (HAR2017-85726-C2-2-P) and Carthago Nova desde su entorno litoral: Paleotopografía y evolución medioambiental del Sector central del Sureste Ibérico. Dinámica poblacional y productiva (HAR2017-85726-C2-1-P). XRF core scanner equipment was co-financed by the European Regional Development Fund via the Spanish National Plan for Scientific and Technical Research and Innovation 2013-2016 (IGME13-4E-2576).Peer reviewe