ANOVA kernels and RKHS of zero mean functions for model-based sensitivity analysis

Given a reproducing kernel Hilbert space (H,〈.,.〉)(H,〈.,.〉) of real-valued functions and a suitable measure μμ over the source space D⊂RD⊂R, we decompose HH as the sum of a subspace of centered functions for μμ and its orthogonal in HH. This decomposition leads to a special case of ANOVA kernels, for which the functional ANOVA representation of the best predictor can be elegantly derived, either in an interpolation or regularization framework. The proposed kernels appear to be particularly convenient for analyzing the effect of each (group of) variable(s) and computing sensitivity indices without recursivity.

Kernels and Designs for Modelling Invariant Functions: From Group Invariance to Additivity

We focus on kernels incorporating different kinds of prior knowledge on functions to be approximated by Kriging. A recent result on random fields with paths invariant under a group action is generalised to combinations of composition operators, and a characterisation of kernels leading to random fields with additive paths is obtained as a corollary. A discussion follows on some implications on design of experiments, and it is shown in the case of additive kernels that the so-called class of “axis designs” outperforms Latin hypercubes in terms of the IMSE criterion.

Tree-level contribution to B[over ¯]→X_{d}γ using fragmentation functions

We evaluate the most important tree-level contributions connected with the b→uu ¯ ¯ dγ transition to the inclusive radiative decay B ¯ ¯ ¯ →X d γ using fragmentation functions. In this framework the singularities arising from collinear photon emission from the light quarks (u , u ¯ ¯ , and d ) can be absorbed into the (bare) quark-to-photon fragmentation function. We use as input the fragmentation function extracted by the ALEPH group from the two-jet cross section measured at the large electron positron (LEP) collider, where one of the jets is required to contain a photon. To get the quark-to-photon fragmentation function at the fragmentation scale μ F ∼m b , we use the evolution equation, which we solve numerically. We then calculate the (integrated) photon energy spectrum for b→uu ¯ ¯ dγ related to the operators P u 1,2 . For comparison, we also give the corresponding results when using nonzero (constituent) masses for the light quarks.

Calculating track thrust with track functions

In e+e− event shapes studies at LEP, two different measurements were sometimes performed: a “calorimetric” measurement using both charged and neutral particles and a “track-based” measurement using just charged particles. Whereas calorimetric measurements are infrared and collinear safe, and therefore calculable in perturbative QCD, track-based measurements necessarily depend on nonperturbative hadronization effects. On the other hand, track-based measurements typically have smaller experimental uncertainties. In this paper, we present the first calculation of the event shape “track thrust” and compare to measurements performed at ALEPH and DELPHI. This calculation is made possible through the recently developed formalism of track functions, which are nonperturbative objects describing how energetic partons fragment into charged hadrons. By incorporating track functions into soft-collinear effective theory, we calculate the distribution for track thrust with next-to-leading logarithmic resummation. Due to a partial cancellation between nonperturbative parameters, the distributions for calorimeter thrust and track thrust are remarkably similar, a feature also seen in LEP data.

Influence of Gestational Age and Parental Education on Executive Functions of Children Born Very Preterm

Background: Children born very preterm (<32 weeks’ gestational age; VPT) and/or very low birth weight (<1500 g; VLBW) are at high risk of deficits in executive functions, namely inhibition, working memory, and shifting. Both, gestational age and socioeconomic factors, such as parental education, are known to influence executive functions, with children born at lower gestational age and with lower educated parents displaying worse executive skills. This study aimed to investigate if maternal and paternal education moderated the relationship between gestational age and executive functions in VPT/VLBW children aged 8-12 years. It was hypothesised that the disadvantageous effect of low gestational age could be buffered more easily in families with higher educational background. Methods: Sixty VPT/VLBW children born in the cohort of 1998-2003 were recruited. All children completed executive function tasks (inhibition, working memory, and shifting). Results: There was a significant dose-response-relationship between gestational age and inhibition, with children being born at earlier gestational age showing worse inhibition. However, neither maternal nor paternal education moderated the relationship between gestational age and executive functions significantly. Conclusion: children than parental education. The disadvantageous effect of low gestational age was equal in children with higher and lower educated parents. However, the impact of gestational age and parental education on executive functions may differ depending on the socioeconomic spectrum of the study sample.

Executive functions and their differential contribution to sustained attention in 5- to 8-year-old children

ABSTRACT Everyday routine in general and school settings in particular make high demands on children's abilities to sustain their focus of attention over longer time periods. School tasks thus require the child to accomplish the task on an appropriate level of performance while maintaining the focus of attention even under repetitious or distracting conditions. However, sustained attention (SA) may be a more heterogeneous construct than commonly assumed as it requires the individual not only to sustain attentional capacities but also to store and maintain the task rule (working memory), to inhibit inappropriate responses (inhibition), and to switch according to requirements (switching). It might thus involve processes counted among executive functions (EF). In the present study, performance in EF tasks (covering the core components inhibition, switching, and working memory) and in a SA task was assessed in 118 children, aged between 5;0 and 8;11 years. Similar age-dependent performance trajectories were found in EF components and SA, indicating ongoing performance improvements between 5 until at least 8 years of age in SA and in EF. Interrelations between single EF components and SA showed to be small to moderate. Finally, different patterns of SA performance predictions were found in age-homogeneous subgroups with inhibition being crucial for SA performance in the youngest and switching in the oldest age group. Taken as a whole, even though similarities in assumed developmental trajectories and substantial interrelations point to common underlying processes in EF and SA, age-dependent patterns of explained variance indicate clear discriminability.

Personality factors in elementary school children: Contributions to academic performance over and above executive functions?

Unique contributions of Big Five personality factors to academic performance in young elementary school children were explored. Extraversion and Openness (labeled “Culture” in our study) uniquely contributed to academic performance, over and above the contribution of executive functions in first and second grade children (N = 446). Well established associations between Conscientiousness and academic performance, however, could only be replicated with regard to zero-order correlations. Executive functions (inhibition, updating, and shifting), for their part, proved to be powerful predictors of academic performance. Results were to some extent dependent on the criterion with which academic performance was measured: Both personality factors had stronger effects on grades than on standardized achievement tests, whereas the opposite was true for executive functions. Finally, analyses on gender differences revealed that Extraversion and Openness/Culture played a more dominant role in girls than in boys, but only regarding grades.

Executive functions in 5- to 8-year olds: Developmental changes and relationship to academic achievement

Pronounced improvements in executive functions (EF) during preschool years have been documented in cross-sectional studies. However, longitudinal evidence on EF development during the transition to school and predictive associations between early EF and later school achievement are still scarce. This study examined developmental changes in EF across three time-points, the predictive value of EF for mathematical, reading and spelling skills and explored children's specific academic attainment as a function of early EF. Participants were 323 children following regular education; 160 children were enrolled in prekindergarten (younger cohort: 69 months) and 163 children in kindergarten (older cohort: 78.4 months) at the first assessment. Various tasks of EF were administered three times with an interval of one year each. Mathematical, reading and spelling skills were measured at the last assessment. Individual background characteristics such as vocabulary, non-verbal intelligence and socioeconomic status were included as control variables. In both cohorts, changes in EF were substantial; improvements in EF, however, were larger in preschoolers than school-aged children. EF assessed in preschool accounted for substantial variability in mathematical, reading and spelling achievement two years later, with low EF being especially associated with significant academic disadvantages in early school years. Given that EF continue to develop from preschool into primary school years and that starting with low EF is associated with lower school achievement, EF may be considered as a marker or risk for academic disabilities.

Interferon-α antagonizes IL-3-mediated immunoregulatory functions of human basophils

Human basophils are major inflammatory cells in maintaining chronic allergic asthma. It has been published that interferon-α (IFN-α) improves clinical symptoms of asthma patients. In contrast, IL-3 exacerbates airway inflammation by inducing IL-4, IL-8 and IL-13 secretion from human basophils thus regulating their immunoregulatory functions. Furthermore, IL-3 exceptionally promotes survival of basophils. Here, we assessed cellular response of human basophils treated with IFN-α alone or in combination with IL-3. Our data show that IFN-α enhances apoptosis in purified human blood basophils compared to spontaneous apoptosis of controls or IFN-γ treated cells. Furthermore, we demonstrate that both IFN-α and FasL enhance apoptosis in human basophils with similar efficiency in a rather additive than synergistic way. IFN-α inhibits IL-3-induced survival to a minor degree. Particularly however, it suppresses IL-3-induced de-novo production of IL-8 and IL-13 up to 80%. In contrast, the production of IL-4 is not affected. Analyses of signaling pathways reveal that IFN-α promotes prolonged phosphorylation of STAT1/STAT2. By using a pan-JAK inhibitor the phosphorylation of STAT1/STAT2 is inhibited and most importantly the pro-apoptotic effect of IFN-α is abolished. Although the phosphorylation of p38-MAPK in IFN-α-treated cells is comparable to non-treated cells, inhibition of p-p38 activity abrogates IFN-α-enhanced apoptosis as well. We conclude that IFN-α-enhanced apoptosis is tightly regulated by the cooperation of JAK/STAT and p38-MAPK pathways. Our study identifies IFN-α as a novel inhibitor of IL-3-induced IL-8 and IL-13 production of human basophils. Taken together our study may explain the improved clinical symptoms of asthma patients treated with IFN-α.

Prospective memory, executive functions and metacognitive control: An empirical approach to their structural interrelations in young elementary school children

Introduction Prospective memory (PM), the ability to remember to perform intended activities in the future (Kliegel & Jäger, 2007), is crucial to succeed in everyday life. PM seems to improve gradually over the childhood years (Zimmermann & Meier, 2006), but yet little is known about PM competences in young school children in general, and even less is known about factors influencing its development. Currently, a number of studies suggest that executive functions (EF) are potentially influencing processes (Ford, Driscoll, Shum & Macaulay, 2012; Mahy & Moses, 2011). Additionally, metacognitive processes (MC: monitoring and control) are assumed to be involved while optimizing one’s performance (Krebs & Roebers, 2010; 2012; Roebers, Schmid, & Roderer, 2009). Yet, the relations between PM, EF and MC remain relatively unspecified. We intend to empirically examine the structural relations between these constructs. Method A cross-sectional study including 119 2nd graders (mage = 95.03, sdage = 4.82) will be presented. Participants (n = 68 girls) completed three EF tasks (stroop, updating, shifting), a computerised event-based PM task and a MC spelling task. The latent variables PM, EF and MC that were represented by manifest variables deriving from the conducted tasks, were interrelated by structural equation modelling. Results Analyses revealed clear associations between the three cognitive constructs PM, EF and MC (rpm-EF = .45, rpm-MC = .23, ref-MC = .20). A three factor model, as opposed to one or two factor models, appeared to fit excellently to the data (chi2(17, 119) = 18.86, p = .34, remsea = .030, cfi = .990, tli = .978). Discussion The results indicate that already in young elementary school children, PM, EF and MC are empirically well distinguishable, but nevertheless substantially interrelated. PM and EF seem to share a substantial amount of variance while for MC, more unique processes may be assumed.

THE DOMAINS OF THE CATALYTIC SUBUNIT OF THE EUKARYOTIC RNA DEGRADING EXOSOME, RRP44P, HAVE DISTINCT FUNCTIONS

The exosome is a 3’ to 5’ exoribonuclease complex that consists of ten essential subunits. In the cytoplasm, the exosome degrades mRNA in a general mRNA turnover pathway and in several mRNA surveillance pathways. In the nucleus, the exosome processes RNA precursors to form small, stable, mature RNA species, including rRNA, snRNA, and snoRNA. In addition to processing these RNAs, the nuclear exosome is also involved in degrading aberrantly processed forms of these RNAs, and others, including mRNA. The 3’ to 5’ exoribonuclease activity of the exosome is contributed by the RNB domain of the only catalytically active subunit, Rrp44p, a member of the RNase II family of enzymes. In addition to the RNB domain, Rrp44p consists of three putative RNA binding domains and has an uncharacterized N-terminus, which includes a CR3 region and PIN domain. In an effort to characterize the cellular functions of the domains of Rrp44p, this study identified a second nuclease active site in the PIN domain. Specifically, the PIN domain exhibits endoribonuclease activity in vitro and is essential for exosome function. Further analysis of the nuclease activities of Rrp44p indicate a role for the exoribonuclease activity of Rrp44p in the cytoplasmic and nuclear exosome. This work has also characterized the CR3 region of Rrp44p, a region that has not yet been characterized in any other protein. This region is needed for the majority, if not all, of the cytoplasmic exosome functions as well as for interaction with the exosome. The CR3 region, along with a histidine residue in the N-terminus of Rrp44p, may coordinate a zinc atom. Preliminary evidence supports a role for this coordination in exosome function. Further investigation, however, is needed to determine the molecular dependence of the exosome on the CR3 region of Rrp44p. Despite its initial discovery thirteen years ago, the essential function of Rrp44p, and the exosome, is not yet known. The studies presented here, however, indicate that the essential function of Rrp44p and the exosome is in the nucleus and depends on the nuclease activities of Rrp44p.

FUNCTIONS OF DEADENYLATION FACTORS IN MRNA DECAY AND MRNA PROCESSING BODY FORMATION

Most newly synthesized messenger RNAs possess a 5’ cap and a 3’ poly(A) tail. The process of poly(A) tail shortening, also termed deadenylation, is important for post-transcriptional gene regulation, because deadenylation not only leads to mRNA translational inhibition but also is the first step of major mRNA degradation. Translationally inhibited mRNAs can be stored and/or degraded in dynamic cytoplasmic foci termed mRNA processing bodies, or P bodies, which are conserved in eukaryotes. To shed new light on the mechanisms of P body formation and P body functions, I focused on the link between deadenylation factors and P bodies. I found that the two major deadenylation complexes, Pan3-Pan2 and Ccr4-Caf1, can both be enriched in P bodies. The deadenylase activity of the Ccr4-Caf1 complex is prerequisite for P body formation. Pan3, but not the deadenylase Pan2, is essential for P body formation. While the C-terminal domain of Pan3 is important for interaction with Pan2, Pan3 N-terminal domain is important for Pan3 to form cytoplasmic foci colocalizing with P bodies and to promote mRNA decay. Interestingly, Pan3 N-terminal domain may be phosphorylated to regulate Pan3 localization and functions. Aside from the functions of the two deadenylation complexes in P bodies, I also studied all reported human P body proteins as a whole using bioinformatics. This effort not only has generated a comprehensive picture of the functions of and interactions among human P body proteins, but also has predicted proteins that may regulate P body formation and/or functions. In summary, my study has established a direct link between mRNA deadenylation and P body formation and has also led to new hypotheses to guide future research on how P body dynamics are controlled.

THE ROLE OF TYROSINE PHOSPHORYLATION IN THE FUNCTIONS OF THE TUMOR SUPPRESSOR GPRC5A

The retinoic acid inducible G protein coupled receptor family C group 5 type A (GPRC5A) is expressed preferentially in normal lung tissue but its expression is suppressed in the majority of human non-small cell lung cancer cell lines and tissues. This differential expression has led to the idea that GPRC5A is a potential tumor suppressor. This notion was supported by the finding that mice with a deletion of the Gprc5a gene develop spontaneous lung tumors. However, there are various tumor cell lines and tissue samples, including lung, that exhibit higher GPRC5A expression than normal tissues and some reports by other groups that GPRC5A transfection increased cell growth and colony formation. Obviously, GPRC5A has failed to suppress the development of the tumors and the growth of the cell lines where its expression is not suppressed. Since no mutations were detected in the coding sequence of GPRC5A in 20 NSCLC cell lines, it’s possible that GPRC5A acts as a tumor suppressor in the context of some cells but not in others. Alternatively, we raised the hypothesis that the GPRC5A protein may be inactivated by posttranslational modification(s) such as phosphorylation. It is well established that Serine/Threonine phosphorylation of G protein coupled receptors leads to their desensitization and in a few cases Tyrosine phosphorylation of GPCRs has been linked to internalization. Others reported that GPRC5A can undergo tyrosine phosphorylation in the cytoplasmic domain after treatment of normal human mammary epithelial cells (HMECs) with epidermal growth factor (EGF) or Heregulin. This suggested that GPRC5A is a substrate of EGFR. Therefore, we hypothesized that tyrosine phosphorylation of GPRC5A by activation of EGFR signaling may lead to its inactivation. To test this hypothesis, we transfected human embryo kidney (HEK) 293 cells with GPRC5A and EGFR expression vectors and confirmed that GPRC5A can be tyrosine phosphorylated after activation of EGFR by EGF. Further, we found that EGFR and GPRC5A can interact either directly or through other proteins and that inhibition of the EGFR kinase activity decreased the phosphorylation of GPRA5A and the interaction between GPRC5A and EGFR. In c-terminal of GPRC5A, There are four tyrosine residues Y317, Y320, Y347, Y350. We prepared GPRC5A mutants in which all four tyrosine residues had been replaced by phenylalanine (mutant 4F) or each individual Tyr residue was replaced by Phe and found that Y317 is the major site for EGFR mediated phosphorylation in the HEK293T cell line. We also found that EGF can induce GPRC5A internalization both in H1792 transient and stable cell lines. EGF also partially inactivates the suppressive function of GPRC5A on cell invasion activity and anchorage-independent growth ability of H1792 stable cell lines. These finding support our hypothesis that GPRC5A may be inactivated by posttranslational modification- tyrosine phosphorylation.