The activation mechanism of Irga6, an interferon-inducible GTPase contributing to mouse resistance against Toxoplasma gondii

Background: The interferon-inducible immunity-related GTPases (IRG proteins/p47 GTPases) are a distinctive family of GTPases that function as powerful cell-autonomous resistance factors. The IRG protein, Irga6 (IIGP1), participates in the disruption of the vacuolar membrane surrounding the intracellular parasite, Toxoplasma gondii, through which it communicates with its cellular hosts. Some aspects of the protein's behaviour have suggested a dynamin-like molecular mode of action, in that the energy released by GTP hydrolysis is transduced into mechanical work that results in deformation and ultimately rupture of the vacuolar membrane. Results: Irga6 forms GTP-dependent oligomers in vitro and thereby activates hydrolysis of the GTP substrate. In this study we define the catalytic G-domain interface by mutagenesis and present a structural model, of how GTP hydrolysis is activated in Irga6 complexes, based on the substrate-twinning reaction mechanism of the signal recognition particle (SRP) and its receptor (SRalpha). In conformity with this model, we show that the bound nucleotide is part of the catalytic interface and that the 3'hydroxyl of the GTP ribose bound to each subunit is essential for trans-activation of hydrolysis of the GTP bound to the other subunit. We show that both positive and negative regulatory interactions between IRG proteins occur via the catalytic interface. Furthermore, mutations that disrupt the catalytic interface also prevent Irga6 from accumulating on the parasitophorous vacuole membrane of T. gondii, showing that GTP-dependent Irga6 activation is an essential component of the resistance mechanism. Conclusions: The catalytic interface of Irga6 defined in the present experiments can probably be used as a paradigm for the nucleotide-dependent interactions of all members of the large family of IRG GTPases, both activating and regulatory. Understanding the activation mechanism of Irga6 will help to explain the mechanism by which IRG proteins exercise their resistance function. We find no support from sequence or G-domain structure for the idea that IRG proteins and the SRP GTPases have a common phylogenetic origin. It therefore seems probable, if surprising, that the substrate-assisted catalytic mechanism has been independently evolved in the two protein families

SchussenAktivplus: reduction of micropollutants and of potentially pathogenic bacteria for further water quality improvement of the river Schussen, a tributary of Lake Constance, Germany

The project focuses on the efficiency of combined technologies to reduce the release of micropollutants and bacteria into surface waters via sewage treatment plants of different size and via stormwater overflow basins of different types. As a model river in a highly populated catchment area, the river Schussen and, as a control, the river Argen, two tributaries of Lake Constance, Southern Germany, are under investigation in this project. The efficiency of the different cleaning technologies is monitored by a wide range of exposure and effect analyses including chemical and microbiological techniques as well as effect studies ranging from molecules to communities

ADHERENCE TO THERAPY BY ELDERLY PATIENTS WITH DIABETES MELLITUS: AN INTEGRATIVE REVIEW

The present study had the aim of identifying in the literature the factors that influence adherence to therapy by elderly individuals with diabetes mellitus. An integrative review with qualitative textual analysis was conducted. The search was conducted at the Portal of Periodicals of the Coordination for the Improvement of Higher Education Personnel and included Brazilian publications in eight databases between January 2002 and September 2016. A total of 12 studies was selected from the 187 that were found, generating two categories: factors that influence adherence to therapy by elderly individuals with diabetes mellitus positively; and factors that influence adherence to therapy by elderly individuals with diabetes mellitus negatively. The fact that only publications with low levels of evidence were found revealed the need for further studies on the theme and intensification of the awareness-raising dialogue with elderly individuals and their families in order to maximize and/or maintain their quality of life, autonomy, and independence.Objetivou-se identificar na literatura os fatores que influenciam a adesão do idoso com Diabetes Mellitus à terapêutica. Realizou-se revisão integrativa, com análise textual qualitativa. A busca ocorreu no Portal de Periódicos da Coordenação de Aperfeiçoamento de Pessoal de Nível Superior, por publicações brasileiras, em oito bases de dados, no período de janeiro de 2002 a setembro de 2016. Selecionou-se 12 estudos, dos 187 encontrados, originando duas categorias: Fatores que influenciam positivamente a adesão do idoso com Diabetes Mellitus à terapêutica, e Fatores que influenciam negativamente a adesão do idoso com Diabetes Mellitus à terapêutica. Conclui-se a necessidade de mais estudos sobre a temática, pois foram encontradas apenas publicações com baixos níveis de evidências e a premência da intensificação no diálogo conscientizador com os idosos e suas famílias, no intuito de maximizar e/ou manter sua qualidade de vida, autonomia e independência.Se objetivó identificar en la literatura los factores que influyen en adhesión del anciano con Diabetes Mellitus a la terapéutica. Se realizó revisión integrativa, con análisis textual cualitativo. Búsqueda efectuada en Portal de Periódicos de la Coordinación de Perfeccionamiento de Personal de Nivel Superior, por publicaciones brasileñas, en ocho bases de datos, de enero de 2002 a setiembre de 2016. Doce estudios fueron seleccionados de 187 hallados, determinando dos categorías: Factores que influyen positivamente en adhesión del anciano con Diabetes Mellitus a la terapéutica; y Factores que influyen negativamente en adhesión del anciano con Diabetes Mellitus a la terapéutica. Se concluye en que son necesarios más estudios sobre la temática, pues solo fueron encontradas publicaciones con bajos niveles de evidencias, y la urgencia de la identificación del diálogo de concientización con los ancianos y sus familias, para maximizar y/o mantener su calidad de vida, autonomía e independencia

Simultaneous measurements of aerosol size distributions at three sites in the European high Arctic

19 pages, 9 figures, 1 tableAerosols are an integral part of the Arctic climate system due to their direct interaction with radiation and indirect interaction through cloud formation. Understanding aerosol size distributions and their dynamics is crucial for the ability to predict these climate relevant effects. When of favourable size and composition, both long-rangetransported-and locally formed particles-may serve as cloud condensation nuclei (CCN). Small changes of composition or size may have a large impact on the low CCN concentrations currently characteristic of the Arctic environment. We present a cluster analysis of particle size distributions (PSDs; size range 8-500 nm) simultaneously collected from three high Arctic sites during a 3-year period (2013-2015). Two sites are located in the Svalbard archipelago: Zeppelin research station (ZEP; 474 m above ground) and the nearby Gruvebadet Observatory (GRU; about 2 km distance from Zeppelin, 67 m above ground). The third site (Villum Research Station at Station Nord, VRS; 30 m above ground) is 600 km west-northwest of Zeppelin, at the tip of northeastern Greenland. The GRU site is included in an inter-site comparison for the first time. K-means cluster analysis provided eight specific aerosol categories, further combined into broad PSD classes with similar characteristics, namely pristine low concentrations (12 %-14 % occurrence), new particle formation (16 %-32 %), Aitken (21 %-35 %) and accumulation (20 %-50 %). Confined for longer time periods by consolidated pack sea ice regions, the Greenland site GRU shows PSDs with lower ultrafine-mode aerosol concentrations during summer but higher accumulation-mode aerosol concentrations during winter, relative to the Svalbard sites. By association with chemical composition and cloud condensation nuclei properties, further conclusions can be derived. Three distinct types of accumulation-mode aerosol are observed during winter months. These are associated with sea spray (largest detectable sizes, > 400 nm), Arctic haze (main mode at 150 nm) and aged accumulation-mode (main mode at 220 nm) aerosols. In contrast, locally produced particles, most likely of marine biogenic origin, exhibit size distributions dominated by the nucleation and Aitken mode during summer months. The obtained data and analysis point towards future studies, including apportioning the relative contribution of primary and secondary aerosol formation pro cesses and elucidating anthropogenic aerosol dynamics and transport and removal processes across the Greenland Sea. In order to address important research questions in the Arctic on scales beyond a singular station or measurement events, it is imperative to continue strengthening international scientific cooperationThis research has been supported by the Spanish Ministry of Economy through project BIO-NUC (CGL2013-49020-R), PI-ICE (CTM2017-89117-R) and the Ramon y Cajal fellowship (RYC-2012-11922). The research leading to these results has received funding from the European Union's Horizon 2020 research and innovation programme under grant agreement no. 654109, the Danish Council for Independent Research (project NUMEN, DFF-FTP-4005-00485B) and previously from the European Union Seventh Framework Programme (FP7/2007-2013) under grant agreement no. 262254. The work at Villum Research Station, Station Nord, was financially supported by the Danish Environmental Protection Agency via the MIKA/DANCEA funds for Environmental Support to the Arctic Region. The Villum Foundation funded the construction of Villum Research Station, Station Nord. CCN measurements are supported by a KOPRI program (PN19081), funded by a National Research Foundation of Korea grant (NRF-2016M1A5A1901769). The authors acknowledge financial support (to David C. S. Beddows) from the Natural Environment Research Council's funding of the National Centre for Atmospheric Science (NCAS) (grant number R8/H12/83/011)Peer Reviewe

Lateglacial and Holocene climate and environmental change in the northeastern Mediterranean region: Diatom evidence from Lake Dojran (Republic of Macedonia/Greece)

The juncture between the west-east and north-south contrasting Holocene climatic domains across the Mediterranean is complex and poorly understood. Diatom analysis of Lake Dojran (Republic of Macedonia/Greece) provides a new insight into lake levels and trophic status during the Lateglacial and Holocene periods in the northeastern Mediterranean. Following a very shallow or even desiccated state at the core base at ca. 12,500 cal yr BP, indicated by sedimentological and hydro-acoustic data, diatoms indicate lake infilling, from a shallow state with abundant benthos to a plankton-dominated relatively high lake level and eutrophic state thereafter. Diatom-inferred shallowing between ca. 12,400 - 12,000 cal yr BP and a very low lake level and eutrophic, oligosaline state between ca. 12,000 - 11,500 cal yr BP provide strong evidence for Younger Dryas aridity. The earliest Holocene (ca. 11,500 - 10,700 cal yr BP) was characterised by a high lake level, followed by a lake-level reduction and increased trophic level between ca. 10,700-8,500 cal yr BP. The lake was relatively deep and exhibited peak Holocene trophic level between ca. 8,500-3,000 cal yr BP, becoming shallow thereafter. The diatom data provide more robust evidence and strengthen previous lake-level interpretation based on sedimentological and geochemical data during the earliest, mid and late Holocene, and also clarify previous uncertainty in interpretation of Lateglacial and early-Holocene lake-level change. Our results are also important in disentangling regional climate effects from local catchment dynamics during the Holocene, and to this end we exploit extant regional palynological evidence for vegetation change in the highlands and lowlands. The importance of seasonality in driving Holocene climate change is assessed by reference to the summer and winter latitudinal temperature gradient (LTG) model of Davis and Brewer (2009). We suggest that increased precipitation drove the high lake level during the earliest Holocene. The early- Holocene low lake level and relatively high trophic state may result climatically from high seasonality of precipitation and locally from limited, nutrient-rich catchment runoff. We argue that the mid- Holocene relatively deep and eutrophic state was driven mainly by local vegetation succession and associated changes in catchment processes, rather than showing a close relationship to climate change. The late-Holocene shallow state may have been influenced by a temperature-induced increase in evaporative concentration, but was coupled with clear evidence for intensified human impact. This study improves understanding of Lateglacial and Holocene climate change in the northeastern Mediterranean, suggests the important role of the LTG on moisture availability during the Holocene, and clarifies the influence of catchment processes on palaeohydrology

The DynaMine webserver: predicting protein dynamics from sequence.

Protein dynamics are important for understanding protein function. Unfortunately, accurate protein dynamics information is difficult to obtain: here we present the DynaMine webserver, which provides predictions for the fast backbone movements of proteins directly from their amino-acid sequence. DynaMine rapidly produces a profile describing the statistical potential for such movements at residue-level resolution. The predicted values have meaning on an absolute scale and go beyond the traditional binary classification of residues as ordered or disordered, thus allowing for direct dynamics comparisons between protein regions. Through this webserver, we provide molecular biologists with an efficient and easy to use tool for predicting the dynamical characteristics of any protein of interest, even in the absence of experimental observations. The prediction results are visualized and can be directly downloaded. The DynaMine webserver, including instructive examples describing the meaning of the profiles, is available at http://dynamine.ibsquare.be

EASL-ERN position paper on liver involvement in patients with Fontan-type circulation

Fontan-type surgery is the final step in the sequential palliative surgical treatment of infants born with a univentricular heart. The resulting long-term haemodynamic changes promote liver damage, leading to Fontan-associated liver disease (FALD), in virtually all patients with Fontan circulation. Owing to the lack of a uniform definition of FALD and the competitive risk of other complications developed by Fontan patients, the impact of FALD on the prognosis of these patients is currently debatable. However, based on the increasing number of adult Fontan patients and recent research interest, the European Association for The Study of the Liver and the European Reference Network on Rare Liver Diseases thought a position paper timely. The aims of the current paper are: (1) to provide a clear definition and description of FALD, including clinical, analytical, radiological, haemodynamic, and histological features; (2) to facilitate guidance for staging the liver disease; and (3) to provide evidence- and experience-based recommendations for the management of different clinical scenarios.</p

EASL-ERN position paper on liver involvement in patients with Fontan-type circulation

Fontan-type surgery is the final step in the sequential palliative surgical treatment of infants born with a univentricular heart. The resulting long-term haemodynamic changes promote liver damage, leading to Fontan-associated liver disease (FALD), in virtually all patients with Fontan circulation. Owing to the lack of a uniform definition of FALD and the competitive risk of other complications developed by Fontan patients, the impact of FALD on the prognosis of these patients is currently debatable. However, based on the increasing number of adult Fontan patients and recent research interest, the European Association for The Study of the Liver and the European Reference Network on Rare Liver Diseases thought a position paper timely. The aims of the current paper are: (1) to provide a clear definition and description of FALD, including clinical, analytical, radiological, haemodynamic, and histological features; (2) to facilitate guidance for staging the liver disease; and (3) to provide evidence- and experience-based recommendations for the management of different clinical scenarios.</p