Macrophage Migration Inhibitory Factor Deficiency Is Associated With Impaired Killing of Gram-Negative Bacteria by Macrophages and Increased Susceptibility to Klebsiella pneumoniae Sepsis.

The cytokine macrophage migration inhibitory factor (MIF) is an important component of the early proinflammatory response of the innate immune system. However, the antimicrobial defense mechanisms mediated by MIF remain fairly mysterious. In the present study, we examined whether MIF controls bacterial uptake and clearance by professional phagocytes, using wild-type and MIF-deficient macrophages. MIF deficiency did not affect bacterial phagocytosis, but it strongly impaired the killing of gram-negative bacteria by macrophages and host defenses against gram-negative bacterial infection, as shown by increased mortality in a Klebsiella pneumonia model. Consistent with MIF's regulatory role of Toll-like 4 expression in macrophages, MIF-deficient cells stimulated with lipopolysaccharide or Escherichia coli exhibited reduced nuclear factor κB activity and tumor necrosis factor (TNF) production. Addition of recombinant MIF or TNF corrected the killing defect of MIF-deficient macrophages. Together, these data show that MIF is a key mediator of host responses against gram-negative bacteria, acting in part via a modulation of bacterial killing by macrophages.

Evaluating the influence of spatial uncertainty in locality points for species distributional modeling

1. Species distribution modelling is used increasingly in both applied and theoretical research to predict how species are distributed and to understand attributes of species' environmental requirements. In species distribution modelling, various statistical methods are used that combine species occurrence data with environmental spatial data layers to predict the suitability of any site for that species. While the number of data sharing initiatives involving species' occurrences in the scientific community has increased dramatically over the past few years, various data quality and methodological concerns related to using these data for species distribution modelling have not been addressed adequately. 2. We evaluated how uncertainty in georeferences and associated locational error in occurrences influence species distribution modelling using two treatments: (1) a control treatment where models were calibrated with original, accurate data and (2) an error treatment where data were first degraded spatially to simulate locational error. To incorporate error into the coordinates, we moved each coordinate with a random number drawn from the normal distribution with a mean of zero and a standard deviation of 5 km. We evaluated the influence of error on the performance of 10 commonly used distributional modelling techniques applied to 40 species in four distinct geographical regions. 3. Locational error in occurrences reduced model performance in three of these regions; relatively accurate predictions of species distributions were possible for most species, even with degraded occurrences. Two species distribution modelling techniques, boosted regression trees and maximum entropy, were the best performing models in the face of locational errors. The results obtained with boosted regression trees were only slightly degraded by errors in location, and the results obtained with the maximum entropy approach were not affected by such errors. 4. Synthesis and applications. To use the vast array of occurrence data that exists currently for research and management relating to the geographical ranges of species, modellers need to know the influence of locational error on model quality and whether some modelling techniques are particularly robust to error. We show that certain modelling techniques are particularly robust to a moderate level of locational error and that useful predictions of species distributions can be made even when occurrence data include some error.

Subduction and obduction processes in the Swiss Alps

The significance of the Brianconnais domain in the Alpine orogen is reviewed in the light of data concerning its collision with the active Adriatic margin and the passive Helvetic margin. The Brianconnais which formerly belonged to the Iberian plate, was located on the northern margin of the Alpine Tethys (Liguro-Piemont ocean) since its opening in the early-Middle Jurassic. Together with the Iberian plate the Brianconnais terrane was separated from the European plate in the Late Jurassic-Early Cretaceous, following the northern Atlantic, Bay of Biscay, Valais ocean opening. This was accompanied by the onset of subduction along the northern margin of Adria and the closure of the Alpine Tethys. Stratigraphic and metamorphic data regarding this subduction and the geohistory of the Brianconnais allows the scenario of subduction-obduction processes during the Late Cretaceous-early Tertiary in the eastern and western Alps to be specified. HP-LT metamorphism record a long-lasting history of oceanic subduction-accretion, followed in the Middle Eocene by the incorporation of the Brianconnais as an exotic terrane into the accretionary prism. Middle to Late Eocene cooling ages of the Brianconnais basement and the presence of pelagic, anorogenic sedimentation lasting until the Middle Eocene on the Brianconnais preclude any sort of collision before that time between this domain and the active Adria margin or the Helvetic margin. This is confirmed by plate reconstructions constrained by magnetic anomalies in the Atlantic domain. Only a small percentage of the former Brianconnais domain was obducted, most of the crust and lithospheric roots were subducted. This applies also to domains formerly belonging to the southern Alpine Tethys margin (Austroalpine-inner Carpathian domain). It is proposed that there was a single Palaeogene subduction zone responsible for the Alpine orogen formation (from northern Spain to the East Carpathians), with the exception of a short-lived Late Cretaceous partial closure of the Valais ocean. Subduction in the western Tethyan domain originated during the closure of the Meliata ocean during the Jurassic incorporating the Austroalpine-Carpathian domain as terranes during the Cretaceous. The subduction zone propagated into the northern margin of Adria and then to the northern margin of the Iberian plate, where it gave birth to the Pyrenean-Provencal orogenic belt. This implies the absence of a separated Cretaceous subduction zone within the Austro-Carpathian Penninic ocean. Collision of Iberia with Europe forced the subduction to jump to the SE margin of Iberia in the Eocene, creating the Apenninic orogenic wedge and inverting the vergence of subduction from south- to north-directed. (C) 1998 Elsevier Science B.V. All rights reserved.

Bringing actors and violent conflict into forced migration literature. A model of the decision to return

Populations displaced as a result of mass violent conflict have become one of the most pressing humanitarian concerns of the last decades. They have also become one salient political issue as a perceived burden (in economic and security terms) and as an important piece in the shift towards a more interventionist paradigm in the international system, based on both humanitarian and security grounds. The saliency of these aspects has detracted attention from the analysis of the interactions between relocation processes and violent conflict. Violent conflict studies have also largely ignored those interactions as a result of the consideration of these processes as mere reaction movements determined by structural conditions. This article takes the view that individual’s agency is retained during such processes, and that it is consequential, calling for the need to introduce a micro perspective. Based on this, a model for the individual’s decision of return is presented. The model has the potential to account for the dynamics of return at both the individual and the aggregate level. And it further helps to grasp fundamental interconnections with violent conflict. Some relevant conclusions are derived for the case of Bosnia-Herzegovina and about the implications of the politicization of return.

On problems of calculating energy expenditure and substrate utilization from respiratory exchange data.

Indirect calorimetry based on respiratory exchange measurement has been successfully used from the beginning of the century to obtain an estimate of heat production (energy expenditure) in human subjects and animals. The errors inherent to this classical technique can stem from various sources: 1) model of calculation and assumptions, 2) calorimetric factors used, 3) technical factors and 4) human factors. The physiological and biochemical factors influencing the interpretation of calorimetric data include a change in the size of the bicarbonate and urea pools and the accumulation or loss (via breath, urine or sweat) of intermediary metabolites (gluconeogenesis, ketogenesis). More recently, respiratory gas exchange data have been used to estimate substrate utilization rates in various physiological and metabolic situations (fasting, post-prandial state, etc.). It should be recalled that indirect calorimetry provides an index of overall substrate disappearance rates. This is incorrectly assumed to be equivalent to substrate "oxidation" rates. Unfortunately, there is no adequate golden standard to validate whole body substrate "oxidation" rates, and this contrasts to the "validation" of heat production by indirect calorimetry, through use of direct calorimetry under strict thermal equilibrium conditions. Tracer techniques using stable (or radioactive) isotopes, represent an independent way of assessing substrate utilization rates. When carbohydrate metabolism is measured with both techniques, indirect calorimetry generally provides consistent glucose "oxidation" rates as compared to isotopic tracers, but only when certain metabolic processes (such as gluconeogenesis and lipogenesis) are minimal or / and when the respiratory quotients are not at the extreme of the physiological range. However, it is believed that the tracer techniques underestimate true glucose "oxidation" rates due to the failure to account for glycogenolysis in the tissue storing glucose, since this escapes the systemic circulation. A major advantage of isotopic techniques is that they are able to estimate (given certain assumptions) various metabolic processes (such as gluconeogenesis) in a noninvasive way. Furthermore when, in addition to the 3 macronutrients, a fourth substrate is administered (such as ethanol), isotopic quantification of substrate "oxidation" allows one to eliminate the inherent assumptions made by indirect calorimetry. In conclusion, isotopic tracers techniques and indirect calorimetry should be considered as complementary techniques, in particular since the tracer techniques require the measurement of carbon dioxide production obtained by indirect calorimetry. However, it should be kept in mind that the assessment of substrate oxidation by indirect calorimetry may involve large errors in particular over a short period of time. By indirect calorimetry, energy expenditure (heat production) is calculated with substantially less error than substrate oxidation rates.

Multimodel inference and multimodel averaging in empirical modeling of occupational exposure levels.

Empirical modeling of exposure levels has been popular for identifying exposure determinants in occupational hygiene. Traditional data-driven methods used to choose a model on which to base inferences have typically not accounted for the uncertainty linked to the process of selecting the final model. Several new approaches propose making statistical inferences from a set of plausible models rather than from a single model regarded as 'best'. This paper introduces the multimodel averaging approach described in the monograph by Burnham and Anderson. In their approach, a set of plausible models are defined a priori by taking into account the sample size and previous knowledge of variables influent on exposure levels. The Akaike information criterion is then calculated to evaluate the relative support of the data for each model, expressed as Akaike weight, to be interpreted as the probability of the model being the best approximating model given the model set. The model weights can then be used to rank models, quantify the evidence favoring one over another, perform multimodel prediction, estimate the relative influence of the potential predictors and estimate multimodel-averaged effects of determinants. The whole approach is illustrated with the analysis of a data set of 1500 volatile organic compound exposure levels collected by the Institute for work and health (Lausanne, Switzerland) over 20 years, each concentration having been divided by the relevant Swiss occupational exposure limit and log-transformed before analysis. Multimodel inference represents a promising procedure for modeling exposure levels that incorporates the notion that several models can be supported by the data and permits to evaluate to a certain extent model selection uncertainty, which is seldom mentioned in current practice.

What do we gain from simplicity versus complexity in species distribution models?

Species distribution models (SDMs) are widely used to explain and predict species ranges and environmental niches. They are most commonly constructed by inferring species' occurrence-environment relationships using statistical and machine-learning methods. The variety of methods that can be used to construct SDMs (e.g. generalized linear/additive models, tree-based models, maximum entropy, etc.), and the variety of ways that such models can be implemented, permits substantial flexibility in SDM complexity. Building models with an appropriate amount of complexity for the study objectives is critical for robust inference. We characterize complexity as the shape of the inferred occurrence-environment relationships and the number of parameters used to describe them, and search for insights into whether additional complexity is informative or superfluous. By building 'under fit' models, having insufficient flexibility to describe observed occurrence-environment relationships, we risk misunderstanding the factors shaping species distributions. By building 'over fit' models, with excessive flexibility, we risk inadvertently ascribing pattern to noise or building opaque models. However, model selection can be challenging, especially when comparing models constructed under different modeling approaches. Here we argue for a more pragmatic approach: researchers should constrain the complexity of their models based on study objective, attributes of the data, and an understanding of how these interact with the underlying biological processes. We discuss guidelines for balancing under fitting with over fitting and consequently how complexity affects decisions made during model building. Although some generalities are possible, our discussion reflects differences in opinions that favor simpler versus more complex models. We conclude that combining insights from both simple and complex SDM building approaches best advances our knowledge of current and future species ranges.

The stabilizing effects of the acquired immunity on the schistosomiasis transmission modeling - the sensitivity Analysis

A mathematical model is proposed to analyze the effects of acquired immunity on the transmission of schistosomiasis in the human host. From this model the prevalence curve dependent on four parameters can be obtained. These parameters were estimated fitting the data by the maximum likelihood method. The model showed a good retrieving capacity of real data from two endemic areas of schistosomiasis: Touros, Brazil (Schistosoma mansoni) and Misungwi, Tanzania (S. haematobium). Also, the average worm burden per person and the dispersion of parasite per person in the community can be obtained from the model. In this paper, the stabilizing effects of the acquired immunity assumption in the model are assessed in terms of the epidemiological variables as follows. Regarded to the prevalence curve, we calculate the confidence interval, and related to the average worm burden and the worm dispersion in the community, the sensitivity analysis (the range of the variation) of both variables with respect to their parameters is performed.

Studies on Procamallanus (Spirocamallanus) pereirai Annereaux, 1946 (Nematoda: Camallanidae), with new host records and new morphological data on the larval stages

Larval stages and adults of Procamallanus (Spirocamallanus) pereirai Annereaux, 1946 are described from naturally infected Paralonchurus brasiliensis (Steindachner) (Sciaenidae) from the coast of the State of Rio de Janeiro, Brazil. The translucent first-stage larvae have a denticulate process at the anterior end, no buccal capsule or esophagus undifferentiated into anterior muscular and posterior glandular parts and an elongate tail; third-stage larvae have a tail with three terminal projections, a buccal capsule divided into an anterior portion with 12-20 ridges running to the left and a posterior smooth portion, and an esophagus with muscular and glandular regions. Fourth-stage larvae exhibit a buccal capsule lacking a distinct basal ring with ridges running to the right and a tail with two terminal processes, as in adults. New host records are reported and their role in its life-cycle are discussed.

Population genetic structure and demography analysis in palinurus elephas populations from atlantic and mediterranean waters

Report for the scientific sojourn at the University of Reading, United Kingdom, from January until May 2008. The main objectives have been firstly to infer population structure and parameters in demographic models using a total of 13 microsatellite loci for genotyping approximately 30 individuals per population in 10 Palinurus elephas populations both from Mediterranean and Atlantic waters. Secondly, developing statistical methods to identify discrepant loci, possibly under selection and implement those methods using the R software environment. It is important to consider that the calculation of the probability distribution of the demographic and mutational parameters for a full genetic data set is numerically difficult for complex demographic history (Stephens 2003). The Approximate Bayesian Computation (ABC), based on summary statistics to infer posterior distributions of variable parameters without explicit likelihood calculations, can surmount this difficulty. This would allow to gather information on different demographic prior values (i.e. effective population sizes, migration rate, microsatellite mutation rate, mutational processes) and assay the sensitivity of inferences to demographic priors by assuming different priors.

Preliminary regional rockfall hazard mapping using LIDAR-based slope frequency distribution and CONEFALL modeling

A factor limiting preliminary rockfall hazard mapping at regional scale is often the lack of knowledge of potential source areas. Nowadays, high resolution topographic data (LiDAR) can account for realistic landscape details even at large scale. With such fine-scale morphological variability, quantitative geomorphometric analyses become a relevant approach for delineating potential rockfall instabilities. Using digital elevation model (DEM)-based ?slope families? concept over areas of similar lithology and cliffs and screes zones available from the 1:25,000 topographic map, a susceptibility rockfall hazard map was drawn up in the canton of Vaud, Switzerland, in order to provide a relevant hazard overview. Slope surfaces over morphometrically-defined thresholds angles were considered as rockfall source zones. 3D modelling (CONEFALL) was then applied on each of the estimated source zones in order to assess the maximum runout length. Comparison with known events and other rockfall hazard assessments are in good agreement, showing that it is possible to assess rockfall activities over large areas from DEM-based parameters and topographical elements.

Functional analysis and structural modeling of human APOBEC3G reveal the role of evolutionarily conserved elements in the inhibition of human immunodeficiency virus type 1 infection and Alu transposition.

Retroelements are important evolutionary forces but can be deleterious if left uncontrolled. Members of the human APOBEC3 family of cytidine deaminases can inhibit a wide range of endogenous, as well as exogenous, retroelements. These enzymes are structurally organized in one or two domains comprising a zinc-coordinating motif. APOBEC3G contains two such domains, only the C terminal of which is endowed with editing activity, while its N-terminal counterpart binds RNA, promotes homo-oligomerization, and is necessary for packaging into human immunodeficiency virus type 1 (HIV-1) virions. Here, we performed a large-scale mutagenesis-based analysis of the APOBEC3G N terminus, testing mutants for (i) inhibition of vif-defective HIV-1 infection and Alu retrotransposition, (ii) RNA binding, and (iii) oligomerization. Furthermore, in the absence of structural information on this domain, we used homology modeling to examine the positions of functionally important residues and of residues found to be under positive selection by phylogenetic analyses of primate APOBEC3G genes. Our results reveal the importance of a predicted RNA binding dimerization interface both for packaging into HIV-1 virions and inhibition of both HIV-1 infection and Alu transposition. We further found that the HIV-1-blocking activity of APOBEC3G N-terminal mutants defective for packaging can be almost entirely rescued if their virion incorporation is forced by fusion with Vpr, indicating that the corresponding region of APOBEC3G plays little role in other aspects of its action against this pathogen. Interestingly, residues forming the APOBEC3G dimer interface are highly conserved, contrasting with the rapid evolution of two neighboring surface-exposed amino acid patches, one targeted by the Vif protein of primate lentiviruses and the other of yet-undefined function.

Paper 3: EUROCAT data quality indicators for population-based registries of congenital anomalies.

The European Surveillance of Congenital Anomalies (EUROCAT) network of population-based congenital anomaly registries is an important source of epidemiologic information on congenital anomalies in Europe covering live births, fetal deaths from 20 weeks gestation, and terminations of pregnancy for fetal anomaly. EUROCAT's policy is to strive for high-quality data, while ensuring consistency and transparency across all member registries. A set of 30 data quality indicators (DQIs) was developed to assess five key elements of data quality: completeness of case ascertainment, accuracy of diagnosis, completeness of information on EUROCAT variables, timeliness of data transmission, and availability of population denominator information. This article describes each of the individual DQIs and presents the output for each registry as well as the EUROCAT (unweighted) average, for 29 full member registries for 2004-2008. This information is also available on the EUROCAT website for previous years. The EUROCAT DQIs allow registries to evaluate their performance in relation to other registries and allows appropriate interpretations to be made of the data collected. The DQIs provide direction for improving data collection and ascertainment, and they allow annual assessment for monitoring continuous improvement. The DQI are constantly reviewed and refined to best document registry procedures and processes regarding data collection, to ensure appropriateness of DQI, and to ensure transparency so that the data collected can make a substantial and useful contribution to epidemiologic research on congenital anomalies.

Macrophage migration inhibitory factor: a counter-regulator of glucocorticoid action and critical mediator of septic shock.

Recent studies have led to the discovery of a mediator that acts as an endogenous counter-regulator of glucocorticoid action within the immune system. Isolated as a product of anterior pituitary cells, this protein was found to have the sequence of macrophage migration inhibitory factor (MIF), one of the first cytokine activities to be described. Macrophages and T cells release MIF in response both to various inflammatory stimuli and upon incubation with low concentrations of glucocorticoids. The glucocorticoid-induced secretion of MIF is tightly regulated and decreases at high, anti-inflammatory steroid concentrations. Once secreted, MIF "overrides" the anti-inflammatory and immunosuppressive effects of steroids on macrophage and T-cell cytokine production. The physiological role of MIF thus appears to be to counter-balance steroid inhibition of the inflammatory response. Anti-MIF antibodies fully protect animals from experimentally induced gram-negative or gram-positive septic shock, an effect that may be the result of the increased anti-inflammatory effects of glucocorticoids after neutralization of endogenous MIF. Anti-MIF therapeutic strategies are presently under development and may prove to be a means to modulate cytokine production in septic shock as well as in other inflammatory disease states.

Deciding where to belong: gender differences in educational trajectories and migration in a rural Spanish town

From an anthropological perspective, formal post-secondary schooling is not an abstractentity with an intrinsic value that everyone finds desirable, but rather one alternative among many that young people evaluate from their different positions in the social field. The problem discussed in this paper is the diverging life trajectories that young men and women in a concrete rural context, at the end of the 20th century, shape for themselves at the ages of 14-16, a moment of decision created by national legislation regarding mandatory education (LGE, 1970, General Education Law, and LOGSE, 1990, General Organic Law of the Education System). Despite a strong cultural norm of equal inheritance divided among all children, male and female, and despite the equal educational opportunities provided by the Spanish State, different meanings of possession and use-rights over land and the resulting culturally accepted gendered division of work converge to orient men and women differently towards post-secondary schooling. Observation of the age, gender, and civil status structure of the population led to the preliminary query: Why do men and women, in this town, behave differently with respect to migration and marriage? The main hypothesis was that women’s longer school trajectories and resulting migration and men’s anchoring in the town and their higher rates of celibacy were not drastic changes in values, in the positional-relational sense of Bourdieu (1988, 2002), but the current outcome of previously existing dissimilar relations to property that produce dissimilar mobility. Through their schooling and work choices, young men and women, at very early ages, locate themselves in, or decide to belong to, different contexts that later reveal very different possibilities of finding marriage partners. This paper is based on an ethnographic study of a small rural town (302 inhabitants in 1950; 193 in 2000) near Leon. Although this paper deals with the situation in the final decades of the 20th century, we must also consider the first half of the century, where some elements that shape this situation have their roots. Fieldwork was carried out between 1988 and 2001, in periods of differing length and intensity. The social subjects discussed here are the domestic unit and its component members. They were studied in conjunction, analyzing the life-trajectory decisions of specific persons in the framework of the domestic unit and the relations among people and property which comprise it. The tried-and-true methods of ethnographic research –participant observation, interviews, and life-histories, etc.- were employed. Archival research was also important for producing demographic data. Demographic analysis, the analysis of the composition and transformation of domestic units, and the creation of life trajectories were among the principal techniques used. The theoretical analysis was oriented by Bourdieu’s (2002) framework of the social field, habitus, and difference.