SerpinB1 is critical for neutrophil survival through cell-autonomous inhibition of cathepsin G

Bone marrow (BM) holds a large reserve of polymorphonuclear neutrophils (PMNs) that are rapidly mobilized to the circulation and tissues in response to danger signals. SerpinB1 is a potent inhibitor of neutrophil serine proteases neutrophil elastase (NE) and cathepsin G (CG). SerpinB1 deficiency (sB1(-/-)) results in a severe reduction of the BM PMN reserve and failure to clear bacterial infection. Using BM chimera, we found that serpinB1 deficiency in BM cells was necessary and sufficient to reproduce the BM neutropenia of sB1(-/-) mice. Moreover, we showed that genetic deletion of CG, but not NE, fully rescued the BM neutropenia in sB1(-/-) mice. In mixed BM chimera and in vitro survival studies, we showed that CG modulates sB1(-/-) PMN survival through a cell-intrinsic pathway. In addition, membrane permeabilization by lysosomotropic agent l-leucyl-l-leucine methyl ester that allows cytosolic release of granule contents was sufficient to induce rapid PMN death through a CG-dependent pathway. CG-mediated PMN cytotoxicity was only partly blocked by caspase inhibition, suggesting that CG cleaves a distinct set of targets during apoptosis. In conclusion, we have unveiled a new cytotoxic function for the serine protease CG and showed that serpinB1 is critical for maintaining PMN survival by antagonizing intracellular CG activity.

Von der Volksschule in den Beruf: Ein integratives Modell der beruflichen Motivation beim Übertritt in das Erwerbsleben

Ziel Motivation ist ein Kernkonzept für das Verständnis von arbeitsbezogenem Verhalten. In der bisherigen Forschung wurde Motivation jedoch meist fragmentarisch untersucht. Mit dem Ziel, die theoretischen Grundlagen weiterzuentwickeln, schlagen wir einen neuen theoretischen Rahmen zur Erklärung der arbeitsbezogenen Motivation vor. Theoretischer Rahmen und Forschungsstand Als theoretische Grundlage nutzen wir die Motivational Systems Theorie sowie ein Modell der proaktiven Motivation. Basierend auf diesen Modellen verstehen wir arbeitsbezogene Motivation als ein System sich gegenseitig verstärkender Komponenten: Zielen, Emotionen, sowie persönlichen Wirkungsüberzeugungen (Ford & Smith, 2007). Methoden Aufgrund einer Integration von Literatur zur Berufswahl, proaktiven Motivation sowie Karrieremanagement wenden wir das Motivationsmodell auf den Übergang von der Schule in das Berufsleben an. Wir postulieren, dass dieses motivationale System durch soziale, persönliche und Umwelt-Variablen beeinflusst wird (z.B. erlebte soziale Unterstützung, berufliche Vorbilder, Persönlichkeitsvariablen, schulische Leistung). Wir erwarten, dass Schüler und Schülerinnen einen erfolgreicheren Übergang von der Schule in das Berufsleben haben, wenn sie autonom verankerte Ziele, die Erwartung von positiven affektiven Zuständen am zukünftigen Arbeitsplatz, weniger Hindernisse in ihrer Berufswahl sowie eine höhere berufliche Selbstwirksamkeit aufweisen. Daten Die Hypothesen werden zwischen 2013 und 2015 mit einer Multi-Kohorten Studie von ca. 800 Schweizer Jugendlichen längsschnittlich mit etablierten Messinstrumenten untersucht. Die erste Welle der Datenerhebung findet aktuell statt und an der AEPF-Tagung 2013 werden erste Ergebnisse daraus vorliegen. Geplante Analysen Mit Hilfe einer konfirmatorischen Faktorenanalyse werden wir die empirische Realität des theoretischen Modells überprüfen. Multiple Mediationsanalysen werden eingesetzt, um die direkten und mediierten Effekte von Person- und Umwelt-Variablen auf Motivation und Berufserfolg zu evaluieren. Wissenschaftliche Bedeutsamkeit der Studie Ein integratives Konzept der Motivation im Übergang von der Schule in den Beruf erweitert das theoretische Verständnis wichtiger Prädiktoren eines erfolgreichen Übergangs. Zudem bietet es vielfältige Implikationen für Praxisanwendungen in den Bereichen Berufsberatung und Berufswahlunterricht.

A study of factors regulating the autonomous proliferation of the steroid hormone-induced LJ6195 murine reproductive tract tumor

Neonatal estrogen treatment of BALB/c mice results in the unregulated proliferation of the cervicovaginal epithelium and eventually tumorigenesis. The conversion of the normally estrogen responsive cyclic proliferation of the vaginal epithelium to a continuous estrogen-independent pattern of growth is a complex phenomenon. The aim of this study was to gain an understanding of the mechanism(s) by which steroid hormone administration during a critical period of development alters the cyclic proliferation of vaginal epithelium, ultimately leading to carcinogenesis in the adult animal.^ The LJ6195 murine cervicovaginal tumor was induced by treating newborn female BALB/c mice with 20 $\mu$g 17$\beta$-estradiol plus 100 $\mu$g progesterone for the first 5 days after birth. In contrast to proliferation of the normal vaginal epithelium, proliferation of LJ6195 is not regulated by estradiol. Northern blot analysis of RNA from vaginal tracts of normal mice, neonatal-estrogen treated mice, and LJ6195 indicate that there is an alteration in the expression of several genes such as the estrogen receptor, c-fos, and HER2/neu. In response to neonatal estrogen treatment, the estrogen receptor is down regulated in the murine vaginal tract. Therefore, the estrogen-independent nature of this tissue is established as early as 3 months after treatment. There is strong evidence that the proliferation of LJ6195 is regulated through an autocrine growth pathway. The LJ6195 tumor expresses mRNA for the epidermal growth factor receptor. In addition, conditioned medium from the LJ6195 tumor cell line contains a growth factor(s) with epidermal growth factor-like activity. Conditioned medium from the LJ6195 cell line stimulated the proliferation of the EGF-dependent COMMA D mouse mammary gland cell line in a dose-dependent manner. The addition of an anti-mEGF-antibody to LJ6195 cell cultures significantly decreased growth. These results suggest that the EGF-receptor mediated growth pathway may play a role in regulating the estrogen-independent proliferation of the LJ6195 tumor. ^

Motivation as a predictor of drinking outcomes after residential treatment programs for alcohol dependence

OBJECTIVES: Patients' motivation to change their substance use is usually viewed as a crucial component of successful treatment. The objective of this study was to examine whether motivation contributes to drinking outcomes after residential treatment for alcohol dependence. METHODS: Our sample included 415 Swiss patients from 12 residential alcohol treatment programs. We statistically controlled for important predictors, such as sex, employment, alcohol consumption before admission, severity of alcohol dependence, severity of psychiatric symptoms at admission, and alcohol-related self-efficacy at discharge. Abstinence, alcohol consumption, and time to first drink were used as primary outcome measures and were assessed 1 year after discharge from treatment. RESULTS: Action-oriented motivation to change substance use had a modest impact on drinking outcomes. At the 1-year follow-up, only the Taking Steps subscale of the Stages of Change Readiness and Treatment Eagerness Scale and alcohol-related self-efficacy were found to be significant predictors of abstinence and the number of standard drinks. CONCLUSIONS: The impact of action-oriented motivation at admission to residential treatment is modest but still relevant, compared with other outcome predictors. It may be useful to focus treatment on improving action-oriented motivation to reduce substance use

Relations between adolescents' self-evaluations, time perspectives, motivation for school and their achievement in different countries and at different ages

The present study focused on the relations between the self-efficacy, social self-concept, time perspectives, school investment and academic achievement of students in four different European countries and in different adolescence periods. A total of 1623 students completed questionnaires. The relations between the concepts proved not to be specific to the Western or to the former Communist bloc countries studied. The expected general decline in investment and academic achievement over the adolescence period showed up in all four countries studied. Contrary to our hypothesis, however, this decline could not be explained by growing influences of either social self-concept or time perspectives regarding personal development on their investment. In fact, the effects of social self-concept were strongest for the youngest adolescence group. Students’ social self-concept was the best predictor for their investment, while self-efficacy proved to predict academic achievement best in all adolescence periods.