Cbl-b Positively Regulates Btk-mediated Activation of Phospholipase C-γ2 in B Cells

Genetic studies have revealed that Cbl-b plays a negative role in the antigen receptor–mediated proliferation of lymphocytes. However, we show that Cbl-b–deficient DT40 B cells display reduced phospholipase C (PLC)-γ2 activation and Ca2+ mobilization upon B cell receptor (BCR) stimulation. In addition, the overexpression of Cbl-b in WEHI-231 mouse B cells resulted in the augmentation of BCR-induced Ca2+ mobilization. Cbl-b interacted with PLC-γ2 and helped the association of PLC-γ2 with Bruton's tyrosine kinase (Btk), as well as B cell linker protein (BLNK). Cbl-b was indispensable for Btk-dependent sustained increase in intracellular Ca2+. Both NH2-terminal tyrosine kinase-binding domain and COOH-terminal half region of Cbl-b were essential for its association with PLC-γ2 and the regulation of Ca2+ mobilization. These results demonstrate that Cbl-b positively regulates BCR-mediated Ca2+ signaling, most likely by influencing the Btk/BLNK/PLC-γ2 complex formation

Wie nicht-lineare Zeitrepräsentationen zukunftsbezogene Urteile und Entscheidungen beeinflussen können : ein entwicklungspsychologischer Ansatz

Die vorliegende Arbeit untersuchte in drei Experimenten den Einfluss der Zeit auf Bewertungen und Entscheidungen in unterschiedlichen Altersstufen. Experiment 1 beschäftigte sich mit dem Einfluss des Zeithorizontes auf die Beurteilung der Riskantheit einer Investition sowie auf das Investitionsverhalten bei 12-Jährigen. Im Gegensatz zu typischen Ergebnissen von Erwachsenen führte bei den Kindern eine lange Zeitspanne zwischen Investition und Erfolgsfeedback zur Annahme eines höheren Risikos und damit zu geringeren Investitionen. In Experiment 2 wurde die Bewertung materieller und nicht-materieller Werte, deren Erhalt verzögert war, bei 12-Jährigen und Erwachsenen untersucht. Dabei zeigte sich, dass Erwachsene Geld als materiellen Wert und Hilfe als nicht-materiellen Wert in ähnlicher Weise mit zunehmender Verzögerung abwerteten. Die Kinder hingegen werteten das verzögerte Geld deutlich stärker ab als Erwachsene, die Hilfe jedoch gar nicht. In Experiment 3 wurde die Entwicklung des Wissens über exponentielles Mengenwachstum in verschiedenen Altersgruppen untersucht. So schätzten 13-Jährige ein solches Wachstum normativ, doch bereits 9-Jährige unterschieden in ihren Schätzungen bedeutsam zwischen exponentiellem und linearem Wachstum, was für ein frühes intuitives Wissen in diesem Bereich spricht. Im Anschluss wurde ein Modell zur altersabhängigen Zeitrepräsentation entwickelt, das versucht, den Einfluss der Zeitrepräsentation in allen drei Experimenten zu erklären. Three experiments were conducted to examine the role of time on judgments and decisions in different age groups. Experiment 1 investigated the influence of the time horizon on 12-year-olds judgments of riskiness and amount of investment into an endeavour. In contrast to typical results of adults, a long time span between the investment and a feedback about its success yielded judgments of higher riskiness and, thus, lower investments in children. Experiment 2 assessed 12-year-olds and adults evaluation of material and immaterial values, whose receipt was either immediate or delayed. Results showed similar subjective discount rates for delayed money (i.e. material value) and delayed help (i.e. immaterial value) in adults. However, children discounted the delayed money more than adults, but they devaluated the delayed help not at all. Experiment 3 investigated the development of knowledge about exponential growth in children, aged 7 to 13 years, and adults. Only 13-year-olds showed a normative estimation of exponential growth. However, 9-year-olds already differentiated between exponential and linear growth in their estimations. This result points to an early intuitive knowledge in this domain. Finally, a model of age-related time representation was proposed to explain the role of time representation in the three experiments

Effectiveness of an erbium-doped:yttrium, aluminum and garnet laser for treatment of peri-implant disease : clinical, microbiological, and biochemical marker analyses

The effectiveness of an erbium-doped: yttrium, aluminum and garnet (Er: YAG) laser (EYL) for the treatment of peri-implant disease (PID) remains unclear. The aim of this study was to compare non-surgical EYL therapy for PID with locally delivered minocycline hydrochloride (MC) ointment therapy by evaluating clinical, microbiological, and biochemical markers. Thirty-seven patients with PID were randomly assigned to either the EYL group (n = 18) or the MC group (n = 19). The clinical, microbiological, and biochemical markers at baseline and at 1 and 3 months after treatment were compared between the two groups. Subgingival plaque and peri-implant crevicular fluid (PICF) were collected from the diseased pockets. In the EYL group, probing pocket depth (PPD) was significantly decreased after treatment when compared with baseline. On the other hand, in the MC group, there was no significant decrease in PPD after treatment. Specific bacteria associated with PID were not determined. The counts of both Gram-positive and -negative species did not significantly decrease in the EYL group at 3 months after treatment. In the MC group, the counts of almost all bacterial species were significantly decreased after treatment. Biochemical marker analysis of PICF revealed significantly lower levels of metalloproteinase (MMP)-9 in the EYL group, as compared with the MC group at 3 months after treatment (p= 0.009). Non-surgical therapy with an EYL for PID was clinically effective, with decreased MMP-9 levels in PICF, which may lead to reduced peri-implant tissue destruction

Measurement of a Phase of a Radio Wave Reflected from Rock Salt and Ice Irradiated by an Electron Beam for Detection of Ultra-High-Energy Neutrinos

We have found a radio-wave-reflection effect in rock salt for the detection of ultra-high energy neutrinos which are expected to be generated in Greisen, Zatsepin, and Kuzmin (GZK) processes in the universe. When an UHE neutrino interacts with rock salt or ice as a detection medium, a shower is generated. That shower is formed by hadronic and electromagnetic avalanche processes. The energy of the UHE neutrino shower converts to thermal energy through ionization processes. Consequently, the temperature rises along the shower produced by the UHE neutrino. The refractive index of the medium rises with temperature. The irregularity of the refractive index in the medium leads to a reflection of radio waves. This reflection effect combined with the long attenuation length of radio waves in rock salt and ice would yield a new method to detect UHE neutrinos. We measured the phase of the reflected radio wave under irradiation with an electron beam on ice and rock salt powder. The measured phase showed excellent consistence with the power reflection fraction which was measured directly. A model taking into account the temperature change explained the phase and the amplitude of the reflected wave. Therefore the reflection mechanism was confirmed. The power reflection fraction was compared with that calculated with the Fresnel equations, the ratio between the measured result and that obtained with the Fresnel equations in ice was larger than that of rock salt.Comment: 6 Pages, 5th International Workshop on Acoustic and Radio EeV Neutrino Detection Activitie

Dok-1 and Dok-2 are negative regulators of lipopolysaccharide-induced signaling

Endotoxin, a bacterial lipopolysaccharide (LPS), causes fatal septic shock via Toll-like receptor (TLR)4 on effector cells of innate immunity like macrophages, where it activates nuclear factor κB (NF-κB) and mitogen-activated protein (MAP) kinases to induce proinflammatory cytokines such as tumor necrosis factor (TNF)-α. Dok-1 and Dok-2 are adaptor proteins that negatively regulate Ras–Erk signaling downstream of protein tyrosine kinases (PTKs). Here, we demonstrate that LPS rapidly induced the tyrosine phosphorylation and adaptor function of these proteins. The stimulation with LPS of macrophages from mice lacking Dok-1 or Dok-2 induced elevated Erk activation, but not the other MAP kinases or NF-κB, resulting in hyperproduction of TNF-α and nitric oxide. Furthermore, the mutant mice showed hyperproduction of TNF-α and hypersensitivity to LPS. However, macrophages from these mutant mice reacted normally to other pathogenic molecules, CpG oligodeoxynucleotides, poly(I:C) ribonucleotides, or Pam3CSK4 lipopeptide, which activated cognate TLRs but induced no tyrosine phosphorylation of Dok-1 or Dok-2. Forced expression of either adaptor, but not a mutant having a Tyr/Phe substitution, in macrophages inhibited LPS-induced Erk activation and TNF-α production. Thus, Dok-1 and Dok-2 are essential negative regulators downstream of TLR4, implying a novel PTK-dependent pathway in innate immunity