TACI, unlike BAFF-R, is solely activated by oligomeric BAFF and APRIL to support survival of activated B cells and plasmablasts.

The cytokine BAFF binds to the receptors TACI, BCMA, and BAFF-R on B cells, whereas APRIL binds to TACI and BCMA only. The signaling properties of soluble trimeric BAFF (BAFF 3-mer) were compared with those of higher-order BAFF oligomers. All forms of BAFF bound BAFF-R and TACI, and elicited BAFF-R-dependent signals in primary B cells. In contrast, signaling through TACI in mature B cells or plasmablasts was only achieved by higher-order BAFF and APRIL oligomers, all of which were also po-tent activators of a multimerization-dependent reporter signaling pathway. These results indicate that, although BAFF-R and TACI can provide B cells with similar signals, only BAFF-R, but not TACI, can respond to soluble BAFF 3-mer, which is the main form of BAFF found in circulation. BAFF 60-mer, an efficient TACI agonist, was also detected in plasma of BAFF transgenic and nontransgenic mice and was more than 100-fold more active than BAFF 3-mer for the activation of multimerization-dependent signals. TACI supported survival of activated B cells and plasmablasts in vitro, providing a rational basis to explain the immunoglobulin deficiency reported in TACI-deficient persons.

Tax reforms and inequality: theoretical and empirical implications

In this paper we examine the effect of tax policy on the relationship between inequality and growth in a two-sector non-scale model. With non-scale models, the longrun equilibrium growth rate is determined by technological parameters and it is independent of macroeconomic policy instruments. However, this fact does not imply that fiscal policy is unimportant for long-run economic performance. It indeed has important effects on the different levels of key economic variables such as per capita stock of capital and output. Hence, although the economy grows at the same rate across steady states, the bases for economic growth may be different.The model has three essential features. First, we explicitly model skill accumulation, second, we introduce government finance into the production function, and we introduce an income tax to mirror the fiscal events of the 1980¿s and 1990¿s in the US. The fact that the non-scale model is associated with higher order dynamics enables it to replicate the distinctly non-linear nature of inequality in the US with relative ease. The results derived in this paper attract attention to the fact that the non-scale growth model does not only fit the US data well for the long-run (Jones, 1995b) but also that it possesses unique abilities in explaining short term fluctuations of the economy. It is shown that during transition the response of the relative simulated wage to changes in the tax code is rather non-monotonic, quite in accordance to the US inequality pattern in the 1980¿s and early 1990¿s.More specifically, we have analyzed in detail the dynamics following the simulation of an isolated tax decrease and an isolated tax increase. So, after a tax decrease the skill premium follows a lower trajectory than the one it would follow without a tax decrease. Hence we are able to reduce inequality for several periods after the fiscal shock. On the contrary, following a tax increase, the evolution of the skill premium remains above the trajectory carried on by the skill premium under a situation with no tax increase. Consequently, a tax increase would imply a higher level of inequality in the economy

Development of an Fn14 agonistic antibody as an anti-tumor agent.

TWEAK, a TNF family ligand with pleiotropic cellular functions, was originally described as capable of inducing tumor cell death in vitro. TWEAK functions by binding its receptor, Fn14, which is up-regulated on many human solid tumors. Herein, we show that intratumoral administration of TWEAK, delivered either by an adenoviral vector or in an immunoglobulin Fc-fusion form, results in significant inhibition of tumor growth in a breast xenograft model. To exploit the TWEAK-Fn14 pathway as a therapeutic target in oncology, we developed an anti-Fn14 agonistic antibody, BIIB036. Studies described herein show that BIIB036 binds specifically to Fn14 but not other members of the TNF receptor family, induces Fn14 signaling, and promotes tumor cell apoptosis in vitro. In vivo, BIIB036 effectively inhibits growth of tumors in multiple xenograft models, including colon (WiDr), breast (MDA-MB-231), and gastric (NCI-N87) tumors, regardless of tumor cell growth inhibition response observed to BIIB036 in vitro. The anti-tumor activity in these cell lines is not TNF-dependent. Increasing the antigen-binding valency of BIB036 significantly enhances its anti-tumor effect, suggesting the contribution of higher order cross-linking of the Fn14 receptor. Full Fc effector function is required for maximal activity of BIIB036 in vivo, likely due to the cross-linking effect and/or ADCC mediated tumor killing activity. Taken together, the anti-tumor properties of BIIB036 validate Fn14 as a promising target in oncology and demonstrate its potential therapeutic utility in multiple solid tumor indications.

Signatures of CP violation in the presence of multiple b-pair production at hadron colliders

We calculate the production of two b-quark pairs in hadron collisions. Sources of multiple pairs are multiple interactions and higher order perturbative QCD mechanisms. We subsequently investigate the competing effects of multiple b-pair production on measurements of CP violation: (i) the increase in event rate with multiple b-pair cross sections which may reach values of the order of 1 b in the presence of multiple interactions and (ii) the dilution of b versus b tagging efficiency because of the presence of events with four B mesons. The impact of multiple B-meson production is small unless the cross section for producing a single pair exceeds 1 mb. We show that even for larger values of the cross section the competing effects (i) and (ii) roughly compensate so that there is no loss in the precision with which CP-violating CKM angles can be determined.

MSSM Higgs boson decays to bottom quark pairs reexamined

We present an update of neutral Higgs boson decays into bottom quark pairs in the minimal supersymmetric extension of the standard model. In particular the resummation of potentially large higher-order corrections due to the soft supersymmetry (SUSY) breaking parameters Ab and is extended. The remaining theoretical uncertainties due to unknown higher-order SUSY-QCD corrections are analyzed quantitatively.

The ability model of emotional intelligence: Searching for valid measures

Current measures of ability emotional intelligence (EI)--including the well-known Mayer-Salovey-Caruso Emotional Intelligence Test (MSCEIT)--suffer from several limitations, including low discriminant validity and questionable construct and incremental validity. We show that the MSCEIT is largely predicted by personality dimensions, general intelligence, and demographics having multiple R's with the MSCEIT branches up to .66; for the general EI factor this relation was even stronger (Multiple R = .76). As concerns the factor structure of the MSCEIT, we found support for four first-order factors, which had differential relations with personality, but no support for a higher-order global EI factor. We discuss implications for employing the MSCEIT, including (a) using the single branches scores rather than the total score, (b) always controlling for personality and general intelligence to ensure unbiased parameter estimates in the EI factors, and (c) correcting for measurement error. Failure to account for these methodological aspects may severely compromise predictive validity testing. We also discuss avenues for the improvement of ability-based tests.

On the relationship between connections and the asymptotic properties of predictive distributions

In a recent paper, Komaki studied the second-order asymptotic properties of predictive distributions, using the Kullback-Leibler divergence as a loss function. He showed that estimative distributions with asymptotically efficient estimators can be improved by predictive distributions that do not belong to the model. The model is assumed to be a multidimensional curved exponential family. In this paper we generalize the result assuming as a loss function any f divergence. A relationship arises between alpha connections and optimal predictive distributions. In particular, using an alpha divergence to measure the goodness of a predictive distribution, the optimal shift of the estimate distribution is related to alpha-covariant derivatives. The expression that we obtain for the asymptotic risk is also useful to study the higher-order asymptotic properties of an estimator, in the mentioned class of loss functions.

An efficient algorithm to perform multiple testing in epistasis screening

Background: Research in epistasis or gene-gene interaction detection for human complex traits has grown over the last few years. It has been marked by promising methodological developments, improved translation efforts of statistical epistasis to biological epistasis and attempts to integrate different omics information sources into the epistasis screening to enhance power. The quest for gene-gene interactions poses severe multiple-testing problems. In this context, the maxT algorithm is one technique to control the false-positive rate. However, the memory needed by this algorithm rises linearly with the amount of hypothesis tests. Gene-gene interaction studies will require a memory proportional to the squared number of SNPs. A genome-wide epistasis search would therefore require terabytes of memory. Hence, cache problems are likely to occur, increasing the computation time. In this work we present a new version of maxT, requiring an amount of memory independent from the number of genetic effects to be investigated. This algorithm was implemented in C++ in our epistasis screening software MBMDR-3.0.3. We evaluate the new implementation in terms of memory efficiency and speed using simulated data. The software is illustrated on real-life data for Crohn’s disease. Results: In the case of a binary (affected/unaffected) trait, the parallel workflow of MBMDR-3.0.3 analyzes all gene-gene interactions with a dataset of 100,000 SNPs typed on 1000 individuals within 4 days and 9 hours, using 999 permutations of the trait to assess statistical significance, on a cluster composed of 10 blades, containing each four Quad-Core AMD Opteron(tm) Processor 2352 2.1 GHz. In the case of a continuous trait, a similar run takes 9 days. Our program found 14 SNP-SNP interactions with a multiple-testing corrected p-value of less than 0.05 on real-life Crohn’s disease (CD) data. Conclusions: Our software is the first implementation of the MB-MDR methodology able to solve large-scale SNP-SNP interactions problems within a few days, without using much memory, while adequately controlling the type I error rates. A new implementation to reach genome-wide epistasis screening is under construction. In the context of Crohn’s disease, MBMDR-3.0.3 could identify epistasis involving regions that are well known in the field and could be explained from a biological point of view. This demonstrates the power of our software to find relevant phenotype-genotype higher-order associations.

The novel proteins Rng8 and Rng9 regulate the myosin-V Myo51 during fission yeast cytokinesis.

The myosin-V family of molecular motors is known to be under sophisticated regulation, but our knowledge of the roles and regulation of myosin-Vs in cytokinesis is limited. Here, we report that the myosin-V Myo51 affects contractile ring assembly and stability during fission yeast cytokinesis, and is regulated by two novel coiled-coil proteins, Rng8 and Rng9. Both rng8Δ and rng9Δ cells display similar defects as myo51Δ in cytokinesis. Rng8 and Rng9 are required for Myo51's localizations to cytoplasmic puncta, actin cables, and the contractile ring. Myo51 puncta contain multiple Myo51 molecules and walk continuously on actin filaments in rng8(+) cells, whereas Myo51 forms speckles containing only one dimer and does not move efficiently on actin tracks in rng8Δ. Consistently, Myo51 transports artificial cargos efficiently in vivo, and this activity is regulated by Rng8. Purified Rng8 and Rng9 form stable higher-order complexes. Collectively, we propose that Rng8 and Rng9 form oligomers and cluster multiple Myo51 dimers to regulate Myo51 localization and functions.

Why should we care about soil fauna?

The reasons why we care about soil fauna are related to their intrinsic, utilitarian and functional values. The intrinsic values embrace aesthetic or moral reasons for conserving below-ground biodiversity. Unfortunately, the protection of soil invertebrates has rarely been a criterion for avoiding changes in land use and management. Utilitarian, or direct use values, have been investigated more extensively for fungi, bacteria and marine invertebrates than for soil fauna. However, some traditional remedies, novel enzymes and pharmaceutical compounds have been derived from earthworms, termites and other groups, and gut symbionts may provide microbial strains with interesting properties for biotechnology. The functional importance of soil invertebrates in ecosystem processes has been a major focus of research in recent decades. It is suggested herein that it is rarely possible to identify the role of soil invertebrates as rate determinants of soil processes at plot and ecosystem scales of hectares and above because other biophysical controls override their effects. There are situations, however, where the activities of functional groups of soil animals, even of species, are synchronised in space or time by plant events, resource inputs, seasonality or other perturbations to the system, and their emergent effects are detectable as higher order controls.

Simulation of surface waves in porous media

We present a novel numerical algorithm for the simulation of seismic wave propagation in porous media, which is particularly suitable for the accurate modelling of surface wave-type phenomena. The differential equations of motion are based on Biot's theory of poro-elasticity and solved with a pseudospectral approach using Fourier and Chebyshev methods to compute the spatial derivatives along the horizontal and vertical directions, respectively. The time solver is a splitting algorithm that accounts for the stiffness of the differential equations. Due to the Chebyshev operator the grid spacing in the vertical direction is non-uniform and characterized by a denser spatial sampling in the vicinity of interfaces, which allows for a numerically stable and accurate evaluation of higher order surface wave modes. We stretch the grid in the vertical direction to increase the minimum grid spacing and reduce the computational cost. The free-surface boundary conditions are implemented with a characteristics approach, where the characteristic variables are evaluated at zero viscosity. The same procedure is used to model seismic wave propagation at the interface between a fluid and porous medium. In this case, each medium is represented by a different grid and the two grids are combined through a domain-decomposition method. This wavefield decomposition method accounts for the discontinuity of variables and is crucial for an accurate interface treatment. We simulate seismic wave propagation with open-pore and sealed-pore boundary conditions and verify the validity and accuracy of the algorithm by comparing the numerical simulations to analytical solutions based on zero viscosity obtained with the Cagniard-de Hoop method. Finally, we illustrate the suitability of our algorithm for more complex models of porous media involving viscous pore fluids and strongly heterogeneous distributions of the elastic and hydraulic material properties.

Impulse response recovery of linear systems through weighted cumulant slice

Identifiability of the so-called ω-slice algorithm is proven for ARMA linear systems. Although proofs were developed in the past for the simpler cases of MA and AR models, they were not extendible to general exponential linear systems. The results presented in this paper demonstrate a unique feature of the ω-slice method, which is unbiasedness and consistency when order is overdetermined, regardless of the IIR or FIR nature of the underlying system, and numerical robustness.

Designing online interaction to address disciplinary competencies: A cross-country comparison of faculty perspectives

This study was conducted at colleges in three countries (United States, Venezuela, and Spain) and across three academic disciplines (engineering, education, and business), to examine how experienced faculty define competencies for their discipline, and design instructional interaction for online courses. A qualitative research design employing in-depth interviews was selected. Results show that disciplinary knowledge takes precedence when faculty members select competencies to be developed in online courses for their respective professions. In all three disciplines, the design of interaction to correspond with disciplinary competencies was often influenced by contextual factors that modify faculty intention. Therefore, instructional design will vary across countries in the same discipline to address the local context, such as the needs and expectations of the learners, faculty perspectives, beliefs and values, and the needs of the institution, the community, and country. The three disciplines from the three countries agreed on the importance of the following competencies: knowledge of the field, higher order cognitive processes such as critical thinking, analysis, problem solving, transfer of knowledge, oral and written communication skills, team work, decision making, leadership and management skills, indicating far more similarities in competencies than differences between the three different applied disciplines. We found a lack of correspondence between faculty¿s intent to develop collaborative learning skills and the actual development of them. Contextual factors such as faculty prior experience in design, student reluctance to engage in collaborative learning, and institutional assessment systems that focus on individual performance were some of these reasons.

Different concentrations of Mg++ ions affect nuclear matrix protein distribution during thermal stabilization of isolated nuclei.

The nuclear matrix, a proteinaceous network believed to be a scaffolding structure determining higher-order organization of chromatin, is usually prepared from intact nuclei by a series of extraction steps. In most cell types investigated the nuclear matrix does not spontaneously resist these treatments but must be stabilized before the application of extracting agents. Incubation of isolated nuclei at 37C or 42C in buffers containing Mg++ has been widely employed as stabilizing agent. We have previously demonstrated that heat treatment induces changes in the distribution of three nuclear scaffold proteins in nuclei prepared in the absence of Mg++ ions. We studied whether different concentrations of Mg++ (2.0-5 mM) affect the spatial distribution of nuclear matrix proteins in nuclei isolated from K562 erythroleukemia cells and stabilized by heat at either 37C or 42C. Five proteins were studied, two of which were RNA metabolism-related proteins (a 105-kD component of splicing complexes and an RNP component), one a 126-kD constituent of a class of nuclear bodies, and two were components of the inner matrix network. The localization of proteins was determined by immunofluorescent staining and confocal scanning laser microscope. Mg++ induced significant changes of antigen distribution even at the lowest concentration employed, and these modifications were enhanced in parallel with increase in the concentration of the divalent cation. The different sensitivity to heat stabilization and Mg++ of these nuclear proteins might reflect a different degree of association with the nuclear scaffold and can be closely related to their functional or structural role.

Dynamic analysis of belt-drives using the absolute nodal coordinate formulation

Belt-drive systems have been and still are the most commonly used power transmission form in various applications of different scale and use. The peculiar features of the dynamics of the belt-drives include highly nonlinear deformation,large rigid body motion, a dynamical contact through a dry friction interface between the belt and pulleys with sticking and slipping zones, cyclic tension of the belt during the operation and creeping of the belt against the pulleys. The life of the belt-drive is critically related on these features, and therefore, amodel which can be used to study the correlations between the initial values and the responses of the belt-drives is a valuable source of information for the development process of the belt-drives. Traditionally, the finite element models of the belt-drives consist of a large number of elements thatmay lead to computational inefficiency. In this research, the beneficial features of the absolute nodal coordinate formulation are utilized in the modeling of the belt-drives in order to fulfill the following requirements for the successful and efficient analysis of the belt-drive systems: the exact modeling of the rigid body inertia during an arbitrary rigid body motion, the consideration of theeffect of the shear deformation, the exact description of the highly nonlinear deformations and a simple and realistic description of the contact. The use of distributed contact forces and high order beam and plate elements based on the absolute nodal coordinate formulation are applied to the modeling of the belt-drives in two- and three-dimensional cases. According to the numerical results, a realistic behavior of the belt-drives can be obtained with a significantly smaller number of elements and degrees of freedom in comparison to the previously published finite element models of belt-drives. The results of theexamples demonstrate the functionality and suitability of the absolute nodal coordinate formulation for the computationally efficient and realistic modeling ofbelt-drives. This study also introduces an approach to avoid the problems related to the use of the continuum mechanics approach in the definition of elastic forces on the absolute nodal coordinate formulation. This approach is applied to a new computationally efficient two-dimensional shear deformable beam element based on the absolute nodal coordinate formulation. The proposed beam element uses a linear displacement field neglecting higher-order terms and a reduced number of nodal coordinates, which leads to fewer degrees of freedom in a finite element.