Cross-neutralization of four paramyxoviruses by a human monoclonal antibody.

Broadly neutralizing antibodies reactive against most and even all variants of the same viral species have been described for influenza and HIV-1 (ref. 1). However, whether a neutralizing antibody could have the breadth of range to target different viral species was unknown. Human respiratory syncytial virus (HRSV) and human metapneumovirus (HMPV) are common pathogens that cause severe disease in premature newborns, hospitalized children and immune-compromised patients, and play a role in asthma exacerbations. Although antisera generated against either HRSV or HMPV are not cross-neutralizing, we speculated that, because of the repeated exposure to these viruses, cross-neutralizing antibodies may be selected in some individuals. Here we describe a human monoclonal antibody (MPE8) that potently cross-neutralizes HRSV and HMPV as well as two animal paramyxoviruses: bovine RSV (BRSV) and pneumonia virus of mice (PVM). In its germline configuration, MPE8 is HRSV-specific and its breadth is achieved by somatic mutations in the light chain variable region. MPE8 did not result in the selection of viral escape mutants that evaded antibody targeting and showed potent prophylactic efficacy in animal models of HRSV and HMPV infection, as well as prophylactic and therapeutic efficacy in the more relevant model of lethal PVM infection. The core epitope of MPE8 was mapped on two highly conserved anti-parallel β-strands on the pre-fusion viral F protein, which are rearranged in the post-fusion F protein conformation. Twenty-six out of the thirty HRSV-specific neutralizing antibodies isolated were also found to be specific for the pre-fusion F protein. Taken together, these results indicate that MPE8 might be used for the prophylaxis and therapy of severe HRSV and HMPV infections and identify the pre-fusion F protein as a candidate HRSV vaccine.

Common Variable Immunodeficiency: molecular pathways and clinical manifestations

Common variable immunodeficiency (CVID), is a disease that is characterized by hypogammaglobulinemia as well as a defect in T, B and dendritic cells. This leads to recurrent bacterial infection mainly caused by Streptococcus pneumoniae, Klebsiella pneumoniae and Haemophilus influenzae, as well as inflammatory manifestations, i.e. granulomateous disease, gastro-intestinal disorders and chronic lung disease. Intravenous Immunoglobulin (IVIg) therapy reduces CVID susceptibility to bacterial infections to some extend. We analyzed clinical aspects of patients from our database. We recently showed that bacteria-specific CD4 T cells of CVID patients were impaired. We therefor postulated that CVID patients may harbor an acquired T-cell deficiency also called exhaustion. To test this hypothesis, we performed a comprehensive investigation of the functional profiles of bacteria-specific CD4 T cells isolated from 31 healthy individuals and 30 CVID patients. In the present study, we demonstrated that bacteria-specific but not virus-specific CD4 T cells in CVID patients harbored reduced proliferation capacity and expressed high level of PD-1. Interestingly, the blockade of PD-1/PD-1 ligands interactions restored partially bacteria but not virus-specific CD4 T-cell proliferation. Finally, we showed that 1) the level of endotoxins inversely correlates with IgG concentration, 2) IVIG treated CVID patients harbored reduced endotoxemia and 3) IgG concentration exceeding 7 mg/mL strongly reduces both the proportion of CVID patients with detectable endotoxemia and the concentration of endotoxins in plasma. Taken together our observations, suggest that primary B-cell defect(s) in CVID patients leads to recurrent bacterial infections that are associated to an acquired (secondary) impairment of CD4 T cells which may in turn exacerbate the lack of protection against extracellular bacteria.

On making causal claims: A review and recommendations

Social scientists often estimate models from correlational data, where the independent variable has not been exogenously manipulated; they also make implicit or explicit causal claims based on these models. When can these claims be made? We answer this question by first discussing design and estimation conditions under which model estimates can be interpreted, using the randomized experiment as the gold standard. We show how endogeneity--which includes omitted variables, omitted selection, simultaneity, common methods bias, and measurement error--renders estimates causally uninterpretable. Second, we present methods that allow researchers to test causal claims in situations where randomization is not possible or when causal interpretation is confounded, including fixed-effects panel, sample selection, instrumental variable, regression discontinuity, and difference-in-differences models. Third, we take stock of the methodological rigor with which causal claims are being made in a social sciences discipline by reviewing a representative sample of 110 articles on leadership published in the previous 10 years in top-tier journals. Our key finding is that researchers fail to address at least 66 % and up to 90 % of design and estimation conditions that make causal claims invalid. We conclude by offering 10 suggestions on how to improve non-experimental research.

Diversity and efficiency of bradyrhizobium strains isolated from soil samples collected from around sesbania virgata roots using cowpea as trap species

The genetic diversity of ten Bradyrhizobium strains was evaluated for tolerance to high temperatures, to different salinity levels and for the efficiency of symbiosis with cowpea plants (Vigna unguiculata (L.) Walp.). Eight of these strains were isolated from nodules that appeared on cowpea after inoculation with suspensions of soil sampled from around the root system of Sesbania virgata (wand riverhemp) in ecosystems of South Minas Gerais. The other two strains used in our analyses as references, were from the Amazon and are currently recommended as cowpea inoculants. Genetic diversity was analyzed by amplifying repetitive DNA elements with the BOX primer, revealing high genetic diversity with each strain presenting a unique band profile. Leonard jar assays showed that the strains UFLA 03-30 and UFLA 03-38 had the highest N2-fixing potentials in symbiosis with cowpea. These strains had more shoot and nodule dry matter, more shoot N accumulation, and a higher relative efficiency than the strains recommended as inoculants. All strains grew in media of pH levels ranging from 4.0 to 9.0. The strains with the highest N2-fixing efficiencies in symbiosis with cowpea were also tolerant to the greatest number of antibiotics. However, these strains also had the lowest tolerance to high salt concentrations. All strains, with the exceptions of UFLA 03-84 and UFLA 03-37, tolerated temperatures of up to 40 ºC. The genetic and phenotypic characteristics of the eight strains isolated from soils of the same region were highly variable, as well as their symbiotic efficiencies, despite their common origin. This variability highlights the importance of including these tests in the selection of cowpea inoculant strains.

Selection methods regulate evolution of cooperation in digital evolution.

A key, yet often neglected, component of digital evolution and evolutionary models is the 'selection method' which assigns fitness (number of offspring) to individuals based on their performance scores (efficiency in performing tasks). Here, we study with formal analysis and numerical experiments the evolution of cooperation under the five most common selection methods (proportionate, rank, truncation-proportionate, truncation-uniform and tournament). We consider related individuals engaging in a Prisoner's Dilemma game where individuals can either cooperate or defect. A cooperator pays a cost, whereas its partner receives a benefit, which affect their performance scores. These performance scores are translated into fitness by one of the five selection methods. We show that cooperation is positively associated with the relatedness between individuals under all selection methods. By contrast, the change in the performance benefit of cooperation affects the populations' average level of cooperation only under the proportionate methods. We also demonstrate that the truncation and tournament methods may introduce negative frequency-dependence and lead to the evolution of polymorphic populations. Using the example of the evolution of cooperation, we show that the choice of selection method, though it is often marginalized, can considerably affect the evolutionary dynamics.

Selecting statistical models to study the relationship between soybean yield and soil physical properties

Statistical models allow the representation of data sets and the estimation and/or prediction of the behavior of a given variable through its interaction with the other variables involved in a phenomenon. Among other different statistical models, are the autoregressive state-space models (ARSS) and the linear regression models (LR), which allow the quantification of the relationships among soil-plant-atmosphere system variables. To compare the quality of the ARSS and LR models for the modeling of the relationships between soybean yield and soil physical properties, Akaike's Information Criterion, which provides a coefficient for the selection of the best model, was used in this study. The data sets were sampled in a Rhodic Acrudox soil, along a spatial transect with 84 points spaced 3 m apart. At each sampling point, soybean samples were collected for yield quantification. At the same site, soil penetration resistance was also measured and soil samples were collected to measure soil bulk density in the 0-0.10 m and 0.10-0.20 m layers. Results showed autocorrelation and a cross correlation structure of soybean yield and soil penetration resistance data. Soil bulk density data, however, were only autocorrelated in the 0-0.10 m layer and not cross correlated with soybean yield. The results showed the higher efficiency of the autoregressive space-state models in relation to the equivalent simple and multiple linear regression models using Akaike's Information Criterion. The resulting values were comparatively lower than the values obtained by the regression models, for all combinations of explanatory variables.

Density modes in spherical 4He shells

We compute the density-fluctuation spectrum of spherical 4HeN shells adsorbed on the outer surface of Cn fullerenes. The excitation spectrum is obtained within the random-phase approximation, with particle-hole elementary excitations and effective interaction extracted from a density-functional description of the shell structure. The presence of one or two solid helium layers adjacent to the adsorbing fullerene is phenomenologically accounted for. We illustrate our results for a selection of numbers of adsorbed atoms on C20, C60, and C120. The hydrodynamical model that has proven successful to describe helium excitations in the bulk and in restricted geometries permits to perform a rather exhaustive analysis of various fluid spherical systems, namely, spheres, cavities, free bubbles, and bound shells of variable size.

Essays on the measurement of school efficiency

Measuring school efficiency is a challenging task. First, a performance measurement technique has to be selected. Within Data Envelopment Analysis (DEA), one such technique, alternative models have been developed in order to deal with environmental variables. The majority of these models lead to diverging results. Second, the choice of input and output variables to be included in the efficiency analysis is often dictated by data availability. The choice of the variables remains an issue even when data is available. As a result, the choice of technique, model and variables is probably, and ultimately, a political judgement. Multi-criteria decision analysis methods can help the decision makers to select the most suitable model. The number of selection criteria should remain parsimonious and not be oriented towards the results of the models in order to avoid opportunistic behaviour. The selection criteria should also be backed by the literature or by an expert group. Once the most suitable model is identified, the principle of permanence of methods should be applied in order to avoid a change of practices over time. Within DEA, the two-stage model developed by Ray (1991) is the most convincing model which allows for an environmental adjustment. In this model, an efficiency analysis is conducted with DEA followed by an econometric analysis to explain the efficiency scores. An environmental variable of particular interest, tested in this thesis, consists of the fact that operations are held, for certain schools, on multiple sites. Results show that the fact of being located on more than one site has a negative influence on efficiency. A likely way to solve this negative influence would consist of improving the use of ICT in school management and teaching. Planning new schools should also consider the advantages of being located on a unique site, which allows reaching a critical size in terms of pupils and teachers. The fact that underprivileged pupils perform worse than privileged pupils has been public knowledge since Coleman et al. (1966). As a result, underprivileged pupils have a negative influence on school efficiency. This is confirmed by this thesis for the first time in Switzerland. Several countries have developed priority education policies in order to compensate for the negative impact of disadvantaged socioeconomic status on school performance. These policies have failed. As a result, other actions need to be taken. In order to define these actions, one has to identify the social-class differences which explain why disadvantaged children underperform. Childrearing and literary practices, health characteristics, housing stability and economic security influence pupil achievement. Rather than allocating more resources to schools, policymakers should therefore focus on related social policies. For instance, they could define pre-school, family, health, housing and benefits policies in order to improve the conditions for disadvantaged children.

Promoter IV of the class II transactivator gene is essential for positive selection of CD4+ T cells.

Major histocompatibility complex class II (MHCII) expression is regulated by the transcriptional coactivator CIITA. Positive selection of CD4(+) T cells is abrogated in mice lacking one of the promoters (pIV) of the Mhc2ta gene. This is entirely due to the absence of MHCII expression in thymic epithelia, as demonstrated by bone marrow transfer experiments between wild-type and pIV(-/-) mice. Medullary thymic epithelial cells (mTECs) are also MHCII(-) in pIV(-/-) mice. Bone marrow-derived, professional antigen-presenting cells (APCs) retain normal MHCII expression in pIV(-/-) mice, including those believed to mediate negative selection in the thymic medulla. Endogenous retroviruses thus retain their ability to sustain negative selection of the residual CD4(+) thymocytes in pIV(-/-) mice. Interestingly, the passive acquisition of MHCII molecules by thymocytes is abrogated in pIV(-/-) mice. This identifies thymic epithelial cells as the source of this passive transfer. In peripheral lymphoid organs, the CD4(+) T-cell population of pIV(-/-) mice is quantitatively and qualitatively comparable to that of MHCII-deficient mice. It comprises a high proportion of CD1-restricted natural killer T cells, which results in a bias of the V beta repertoire of the residual CD4(+) T-cell population. We have also addressed the identity of the signal that sustains pIV expression in cortical epithelia. We found that the Jak/STAT pathways activated by the common gamma chain (CD132) or common beta chain (CDw131) cytokine receptors are not required for MHCII expression in thymic cortical epithelia.

Clonal deletion and the fate of autoreactive thymocytes that survive negative selection.

Clonal deletion of autoreactive thymocytes is important for self-tolerance, but the intrathymic signals that induce clonal deletion have not been clearly identified. We now report that clonal deletion during negative selection required CD28-mediated costimulation of autoreactive thymocytes at the CD4(+)CD8(lo) intermediate stage of differentiation. Autoreactive thymocytes were prevented from undergoing clonal deletion by either a lack of CD28 costimulation or transgenic overexpression of the antiapoptotic factors Bcl-2 or Mcl-1, with surviving thymocytes differentiating into anergic CD4(-)CD8(-) double-negative thymocytes positive for the T cell antigen receptor αβ subtype (TCRαβ) that 'preferentially' migrated to the intestine, where they re-expressed CD8α and were sequestered as CD8αα(+) intraepithelial lymphocytes (IELs). Our study identifies costimulation by CD28 as the intrathymic signal required for clonal deletion and identifies CD8αα(+) IELs as the developmental fate of autoreactive thymocytes that survive negative selection.

Comment on "Selection of the Saffman-Taylor finger width in the absence of surface tension: an exact result"

A Comment on the Letter by Mark Mineev-Weinstein, Phys. Rev. Lett. 80, 2113 (1998). The authors of the Letter offer a Reply.