HOW BUSINESS INTELLIGENCE CREATES VALUE

Assessing IT business value has long been recognized as a major challenge, stemming largely from the considerable variability in the role and contribution of IT. This study examines the business value associated with business intelligence (BI) systems, suggesting that business value assessment is largely contingent on system type and should consider its unique contribution. The study adopts a process-oriented approach to evaluating the value contribution of BI, arguing that it stems from the improvement of business processes. The study develops and tests a research model that explains the unique mechanisms through which BI creates business value. The model draws on the resource-based view to identify key resources and capabilities that determine the impact of BI on business processes and, consequently, on organizational performance. Furthermore, the research model seeks to analyse the manner in which the organizational approach to innovation moderates the business value of BI. Analysis of data collected from 159 managers and IT/BI experts, using Structural Equations Modelling (SEM) techniques, shows that BI largely contributes to business value by improving both operational and strategic business processes. Further, it highlights the effect of the organizational approach toward exploration on transforming BI resources into capabilities and further into business value

The flavor of a light charged Higgs

The ATLAS Collaboration has recently reported a search for light-charged Higgs in $t\to H^+ b$ decay, with $H^+\to c\bar b$. An excess with a local significance of approximately $3\sigma$ is found at $m_{H^+}\approx130$ GeV, with a best-fit value of ${\rm BR}(t\to H^+b)\times {\rm BR}(H^+\to c\bar b)=(1.6\pm0.6)\times10^{-3}$. We study the implications of such a hypothetical signal in multi-Higgs doublet models. We take into account constraints from searches for other charged Higgs decays and from flavor-changing neutral current processes. Two Higgs doublet models with flavor structure dictated by natural flavor conservation (NFC), minimal flavor violation (MFV), or the Froggatt-Nielsen (FN) mechanism cannot account for such excess. A three-Higgs doublet model with NFC can account for the signal. The Yukawa couplings of the neutral pseudoscalar $A$ in the down sector, $\hat Y_A^D$, should be larger by a factor of $4-6$ compared to the corresponding Yukawa couplings of the Higgs $h$, $\hat Y_h^D$. We further present two minimal scenarios, one in which a single Yukawa coupling in the down sector, $(\hat Y_A^D)_{bb}$, gives the only significant contribution, and one in which two Yukawa couplings in the up sector, $(\hat Y_A^U)_{tt}$ and $(\hat Y_A^U)_{tc}$, give the only significant contributions, and we discuss possible tests of these scenarios.Comment: 19 pages, 4 figure

Tolerance without clonal expansion: Self-antigen-expressing B cells program self-reactive T cells for future deletion

B cells have been shown in various animal models to induce immunological tolerance leading to reduced immune responses and protection from autoimmunity. We show that interaction of B cells with naive T cells results in T cell triggering accompanied by the expression of negative costimulatory molecules such as PD-1, CTLA-4, B and T lymphocyte attenuator, and CD5. Following interaction with B cells, T cells were not induced to proliferate, in a process that was dependent on their expression of PD-1 and CTLA-4, but not CD5. In contrast, the T cells became sensitive to Ag-induced cell death. Our results demonstrate that B cells participate in the homeostasis of the immune system by ablation of conventional self-reactive T cells

TGF-β inhibitor Smad7 regulates dendritic cell-induced autoimmunity

TGF-β is an anti-inflammatory cytokine whose signaling is negatively controlled by Smad7. Previously, we established a role for Smad7 in the generation of autoreactive T cells; however, the function of Smad7 in dendritic cells (DCs) remains elusive. Here, we demonstrate that DC-specific Smad7 deficiency resulted in elevated expression of the transcription factors Batf3 and IRF8, leading to increased frequencies of CD8(+)CD103(+) DCs in the spleen. Furthermore, Smad7-deficient DCs expressed higher levels of indoleamine 2,3-dioxygenase (IDO), an enzyme associated with tolerance induction. Mice devoid of Smad7 specifically in DCs are resistant to the development of experimental autoimmune encephalomyelitis (EAE) as a result of an increase of protective regulatory T cells (Tregs) and reduction of encephalitogenic effector T cells in the central nervous system. In agreement, inhibition of IDO activity or depletion of Tregs restored disease susceptibility. Intriguingly, when Smad7-deficient DCs also lacked the IFN-γ receptor, the mice regained susceptibility to EAE, demonstrating that IFN-γ signaling in DCs mediates their tolerogenic function. Our data indicate that Smad7 expression governs splenic DC subset differentiation and is critical for the promotion of their efficient function in immunity

A novel microglial subset plays a key role in myelinogenesis in developing brain

Microglia are resident macrophages of the central nervous system that contribute to homeostasis and neuroinflammation. Although known to play an important role in brain development, their exact function has not been fully described. Here, we show that in contrast to healthy adult and inflammation-activated cells, neonatal microglia show a unique myelinogenic and neurogenic phenotype. A CD11c(+) microglial subset that predominates in primary myelinating areas of the developing brain expresses genes for neuronal and glial survival, migration, and differentiation. These cells are the major source of insulin-like growth factor 1, and its selective depletion from CD11c(+) microglia leads to impairment of primary myelination. CD11c-targeted toxin regimens induced a selective transcriptional response in neonates, distinct from adult microglia. CD11c(+) microglia are also found in clusters of repopulating microglia after experimental ablation and in neuroinflammation in adult mice, but despite some similarities, they do not recapitulate neonatal microglial characteristics. We therefore identify a unique phenotype of neonatal microglia that deliver signals necessary for myelination and neurogenesis

Executive Function and Falls in Older Adults: New Findings from a Five-Year Prospective Study Link Fall Risk to Cognition

Background: Recent findings suggest that executive function (EF) plays a critical role in the regulation of gait in older adults, especially under complex and challenging conditions, and that EF deficits may, therefore, contribute to fall risk. The objective of this study was to evaluate if reduced EF is a risk factor for future falls over the course of 5 years of follow-up. Secondary objectives were to assess whether single and dual task walking abilities, an alternative window into EF, were associated with fall risk. Methodology/Main Results We longitudinally followed 256 community-living older adults (age: 76.4±4.5 yrs; 61% women) who were dementia free and had good mobility upon entrance into the study. At baseline, a computerized cognitive battery generated an index of EF, attention, a closely related construct, and other cognitive domains. Gait was assessed during single and dual task conditions. Falls data were collected prospectively using monthly calendars. Negative binomial regression quantified risk ratios (RR). After adjusting for age, gender and the number of falls in the year prior to the study, only the EF index (RR: .85; CI: .74–.98, p = .021), the attention index (RR: .84; CI: .75–.94, p = .002) and dual tasking gait variability (RR: 1.11; CI: 1.01–1.23; p = .027) were associated with future fall risk. Other cognitive function measures were not related to falls. Survival analyses indicated that subjects with the lowest EF scores were more likely to fall sooner and more likely to experience multiple falls during the 66 months of follow-up (p<0.02). Conclusions/Significance: These findings demonstrate that among community-living older adults, the risk of future falls was predicted by performance on EF and attention tests conducted 5 years earlier. The present results link falls among older adults to cognition, indicating that screening EF will likely enhance fall risk assessment, and that treatment of EF may reduce fall risk

Smad7 in T cells drives T helper 1 responses in multiple sclerosis and experimental autoimmune encephalomyelitis

Autoreactive CD4+ T lymphocytes play a vital role in the pathogenesis of multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis. Since the discovery of T helper 17 cells, there is an ongoing debate whether T helper 1, T helper 17 or both subtypes of T lymphocytes are important for the initiation of autoimmune neuroinflammation. We examined peripheral blood CD4+ cells from patients with active and stable relapsing–remitting multiple sclerosis, and used mice with conditional deletion or over-expression of the transforming growth factor-β inhibitor Smad7, to delineate the role of Smad7 in T cell differentiation and autoimmune neuroinflammation. We found that Smad7 is up-regulated in peripheral CD4+ cells from patients with multiple sclerosis during relapse but not remission, and that expression of Smad7 strongly correlates with T-bet, a transcription factor defining T helper 1 responses. Concordantly, mice with transgenic over-expression of Smad7 in T cells developed an enhanced disease course during experimental autoimmune encephalomyelitis, accompanied by elevated infiltration of inflammatory cells and T helper 1 responses in the central nervous system. On the contrary, mice with a T cell-specific deletion of Smad7 had reduced disease and central nervous system inflammation. Lack of Smad7 in T cells blunted T cell proliferation and T helper 1 responses in the periphery but left T helper 17 responses unaltered. Furthermore, frequencies of regulatory T cells were increased in the central nervous system of mice with a T cell-specific deletion and reduced in mice with a T cell-specific over-expression of Smad7. Downstream effects of transforming growth factor-β on in vitro differentiation of naïve T cells to T helper 1, T helper 17 and regulatory T cell phenotypes were enhanced in T cells lacking Smad7. Finally, Smad7 was induced during T helper 1 differentiation and inhibited during T helper 17 differentiation. Taken together, the level of Smad7 in T cells determines T helper 1 polarization and regulates inflammatory cellular responses. Since a Smad7 deletion in T cells leads to immunosuppression, Smad7 may be a potential new therapeutic target in multiple sclerosis

Exploring the function of IL-10, BTLA and DCs as regulators of immune responses

This thesis focuses on different aspects of immune regulation, both at the cellular and molecular levels. More specifically, this work concentrates on the importance of Interleukin-10, B and T Lymphocyte Attenuator (BTLA), and dendritic cells in respect to immune regulation, with special emphasis on autoimmunity. In this thesis, we show that the cellular source of IL10 production can dramatically influence the outcome of an autoimmune response. We show that T cell-derived IL10 plays an important role in controlling the viability of recently activated T cells, allowing them to become fully functional T effector cells. T cell-specific IL10-deficient mice failed to induce EAE when immunized with MOG peptide. Furthermore, when re-challenged with MOG or other stimuli, these T cells exhibited increased apoptosis rates. Here we report for the first time the generation of a novel mouse model that allows the conditional over-expression of BTLA. We show that BTLA can negatively regulate CD4+ T cells responses, when expressed by the T cells themselves. BTLA over-expression by CD8+ T cells or dendritic cells, however, resulted in enhanced viral clearance. In this study, we show that depletion of DCs, either early on from birth or later in adulthood, does not prevent EAE induction, but instead leads to a lower state of tolerance and stronger immune response. We also show that DCs are responsible for the upregulation of PD-1 on antigen-specific T cells and subsequently induce the formation of Tregs during immune responses.Diese Arbeit behandelt verschiedene Aspekte der Immunregulation auf zellulärer und molekularer Ebene. Dabei liegt der Fokus auf der Rolle des Cytokins Interleukin 10, des Proteins BTLA (B and T Lymphocyte Attenuator) als auch der Funktion von dendritischen Zellen in der Regulation der Immunantwort und im speziellen der Autoimmunantwort. In der vorliegenden Arbeit zeigen wir, dass IL10 einen großen Einfluss auf den Ausgang einer Autoimmunantwort hat. T-Zell-sekretiertes IL10 reguliert die Viabilität kürzlich aktivierter T Zellen und ermöglicht deren Entwicklung zu funktionalen Effektor T Zellen. Mäuse, deren T Zellen kein IL10 produzieren können zeigten sich resistent gegen EAE (Experimentelle autoimmune Enzephalomyelitis, ein Modell für Multiple Sklerose) nach einer Immunisierung mit dem MOG-Peptid. Nach erneuter Verabreichung des MOG-Peptids oder eines anderen Stimulus, zeigten die T Zellen eine erhöhte Apoptoserate. In dieser Arbeit wird ebenfalls ein neues Mausmodell vorgestellt, dass eine konditionale Überexpression des Proteins BTLA ermöglicht. Wir zeigen, dass BTLA einen negativen autoregulatorischen Einfluss auf die CD4 T-Zellantwort hat. BTLA-Überexpression in CD8 T Zellen oder denritischen Zellen führte zu einer beschleunigten Virusbekämpfung (viral clearance). Des Weiteren zeigen wir, dass die Depletion von dendritischen Zellen von Geburt an oder auch zu einem späteren Zeitpunkt EAE nicht verhindert, sondern sogar eine niedrigere Toleranz und stärkere Immunantwort verursacht. Wie liefern weitere Beweise dafür, dass dendritische Zellen die PD-1 Expression auf antigen-spezifischen T-Zellen induzieren und somit die Bildung regulatorischer T Zellen während einer Immunantwort herbeiführen