Vitamin D analogs differentially control antimicrobial peptide/"alarmin" expression in psoriasis

Antimicrobial peptides (AMPs) are strongly expressed in lesional skin in psoriasis and play an important role as proinflammatory "alarmins" in this chronic skin disease. Vitamin D analogs like calcipotriol have antipsoriatic effects and might mediate this effect by changing AMP expression. In this study, keratinocytes in lesional psoriatic plaques showed decreased expression of the AMPs beta-defensin (HBD) 2 and HBD3 after topical treatment with calcipotriol. At the same time, calcipotriol normalized the proinflammatory cytokine milieu and decreased interleukin (IL)-17A, IL-17F and IL-8 transcript abundance in lesional psoriatic skin. In contrast, cathelicidin antimicrobial peptide expression was increased by calcipotriol while psoriasin expression remained unchanged. In cultured human epidermal keratinocytes the effect of different vitamin D analogs on the expression of AMPs was further analyzed. All vitamin D analogs tested blocked IL-17A induced HBD2 expression by increasing IkappaB-alpha protein and inhibition of NF-kappaB signaling. At the same time vitamin D analogs induced cathelicidin through activation of the vitamin D receptor and MEK/ERK signaling. These studies suggest that vitamin D analogs differentially alter AMP expression in lesional psoriatic skin and cultured keratinocytes. Balancing AMP "alarmin" expression might be a novel goal in treatment of chronic inflammatory skin diseases.

Macrophage migration inhibitory factor contributes to the immune escape of ovarian cancer by down-regulating NKG2D

The proinflammatory cytokine macrophage migration inhibitory factor (MIF) stimulates tumor cell proliferation, migration, and metastasis; promotes tumor angiogenesis; suppresses p53-mediated apoptosis; and inhibits antitumor immunity by largely unknown mechanisms. We here describe an overexpression of MIF in ovarian cancer that correlates with malignancy and the presence of ascites. Functionally, we find that MIF may contribute to the immune escape of ovarian carcinoma by transcriptionally down-regulating NKG2D in vitro and in vivo which impairs NK cell cytotoxicity toward tumor cells. Together with the additional tumorigenic properties of MIF, this finding provides a rationale for novel small-molecule inhibitors of MIF to be used for the treatment of MIF-secreting cancers.

Deliberative Perfectionism: Why We Can and Should Talk about the Good

In contemporary political theory, perfectionists believe that the state should promote substantive conceptions of the good through its legislation. Supporters of neutrality, instead, claim that the state should refrain from doing so. In this article I analyse perfectionism in relation to Jürgen Habermas’ theory of discourse and deliberative politics (1996) and critique Habermas’ distinction between ‘ethical’ and ‘moral’ discourses (1984, 1990). By relating Habermas’ theory to George Sher’s account of perfectionism (1997), I argue that we can establish the meta-ethical grounds for a model of deliberation encompassing ethical matters (that is, questions concerning the good life) not confined to the limits of specific communities. I conclude by arguing that ethical deliberation is not only feasible but also desirable. Given the fact of ethical pluralism, and in order to show respect towards their fellow citizens, political perfectionists ought to be ready to show how their ethical claims (which they want to see translated into state policy) relate to deeper meta-ethical human goals on which we can ideally find a consensus through deliberation.

Defining the role of common variation in the genomic and biological architecture of adult human height

Using genome-wide data from 253,288 individuals, we identified 697 variants at genome-wide significance that together explained one-fifth of the heritability for adult height. By testing different numbers of variants in independent studies, we show that the most strongly associated 1/42,000, 1/43,700 and 1/49,500 SNPs explained 1/421%, 1/424% and 1/429% of phenotypic variance. Furthermore, all common variants together captured 60% of heritability. The 697 variants clustered in 423 loci were enriched for genes, pathways and tissue types known to be involved in growth and together implicated genes and pathways not highlighted in earlier efforts, such as signaling by fibroblast growth factors, WNT/I 2-catenin and chondroitin sulfate-related genes. We identified several genes and pathways not previously connected with human skeletal growth, including mTOR, osteoglycin and binding of hyaluronic acid. Our results indicate a genetic architecture for human height that is characterized by a very large but finite number (thousands) of causal variants.

Cognitive amplify-and-forward relay networks with beamforming under primary user power constraint over Nakagami-m fading channels

In this paper, we analyze the performance of cognitive amplify-and-forward (AF) relay networks with beamforming under the peak interference power constraint of the primary user (PU). We focus on the scenario that beamforming is applied at the multi-antenna secondary transmitter and receiver. Also, the secondary relay network operates in channel state information-assisted AF mode, and the signals undergo independent Nakagami-m fading. In particular, closed-form expressions for the outage probability and symbol error rate (SER) of the considered network over Nakagami-m fading are presented. More importantly, asymptotic closed-form expressions for the outage probability and SER are derived. These tractable closed-form expressions for the network performance readily enable us to evaluate and examine the impact of network parameters on the system performance. Specifically, the impact of the number of antennas, the fading severity parameters, the channel mean powers, and the peak interference power is addressed. The asymptotic analysis manifests that the peak interference power constraint imposed on the secondary relay network has no effect on the diversity gain. However, the coding gain is affected by the fading parameters of the links from the primary receiver to the secondary relay network

New genetic loci link adipose and insulin biology to body fat distribution

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms.

Genetic studies of body mass index yield new insights for obesity biology

Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci (P < 5 × 10(-8)), 56 of which are novel. Five loci demonstrate clear evidence of several independent association signals, and many loci have significant effects on other metabolic phenotypes. The 97 loci account for ∼2.7% of BMI variation, and genome-wide estimates suggest that common variation accounts for >20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis.

Gender and Cosmopolitanism in Europe: A Feminist Perspective

Gender and Cosmopolitanism in Europe combines a feminist critique of contemporary and prominent approaches to cosmopolitanism with an in-depth analysis of historical cosmopolitanism and the manner in which gendered symbolic boundaries of national political communities in two European countries are drawn. Exploring the work of prominent scholars of new cosmopolitanism in Britain and Germany, including Held, Habermas, Beck and Bhabha, it delivers a timely intervention into current debates on globalisation, Europeanisation and social processes of transformation in and beyond specific national societies.

A rigorous examination of the emancipatory potential of current debates surrounding cosmopolitanism in Europe, this book will be of interest to sociologist and political scientists working on questions of identity, inclusion, citizenship, globalisation, cosmopolitanism and gender.
Contents: Introduction: gendered cosmopolitanism: the scope of this book; Who belongs? Who is the Other?; Recognition, social equality and the current EU anti-discrimination policy; Kulturnation and the homogenised notion of community belonging: Jürgen Habermas's and Ulrich Beck's approaches to 'European' cosmopolitanism; Global trade, the city and commercial cosmopolitanism: David Held's and Homi K. Bhabha's approaches to new cosmopolitanism; About dead-ends, one-way streets and critical crossroads; Transversal conversations on the scope of new cosmopolitanism beyond the Eurocentric framework; Bibliography; Index.

Dissection of the early steps in the assembly of the 20S proteasome in Saccharomyces cerevisiae

Tese de dout., Bioquímica (Biologia Celular e Molecular), Faculdade de Ciências e Tecnologia, Univ. do Algarve, 2010

Evaluation an der FH Bund - Konzepte und Ergebnisse aus den Fachbereichen

Dulisch, Linssen und Reiter (2001) legten ein umfassendes Evaluationskonzept für die FH Bund vor. In den zehn Fachbereichen und im Zentralbereich der FH Bund erfolgt/e eine Diskussion, Modifikation und konkrete Anpassung an die Belange vor Ort. Dieser Prozess wurde in einer Evaluationtagung an der FH Bund im Juni 2003 gebündelt. Die Tagung zeigte, dass alle Fachbereiche und der Zentralbereich Fortschritte machen, wenn auch in unterschiedlichem Tempo. Dieser Band dokumentiert den Status Quo der Evaluation in den Fachbereichen und dem Zentralbereich und folgt damit § 6 Hochschulrahmengesetz (HRG), wonach die Arbeit der Hochschulen bewertet und das Ergebnis der Bewertung veröffentlicht werden soll. Inhaltsübersicht: - Evaluation an Fachhochschulen - Überblick - Empfehlungen des Benchmarking Clubs - Evaluationstagung der FH Bund 2003 - Zentralbereich - Allgemeine und Innere Verwaltung - Arbeitsverwaltung - Auswärtige Angelegenheiten - Bundesgrenzschutz - Bundeswehrverwaltung - Finanzen - Landwirtschaftliche Sozialversicherung - Öffentliche Sicherheit - Gesamtkonzept - Öffentliche Sicherheit - Abteilung Kriminalpolizei - Sozialversicherung - Wetterdienst

Modellierung und Analyse lastinduzierter Speicherfehler

Ein sehr großer Anteil der in Rechensystemen auftretenden Fehler ereignet sich im Speicher. In dieser Arbeit wird ein zerlegungsorientiertes Modell entwickelt, das die Wechselwirkungen zwischen Speicherfehlern und Systemleistung untersucht. Zunächst wird das Speicherverhalten eines Auftrags durch ein mehrphasiges Independent-Reference-Modell charakterisiert. Dies dient als Grundlage eines Modells zum Auftreten von Störungen, in das Lastcharakteristika wie die Auftrags-Verweildauer, die Seitenzugriffs-Rate und die Paging-Rate eingehen. Anschließend kann die Wahrscheinlichkeit, mit der ein Speicherfehler entdeckt wird, berechnet werden. Die zur Behandlung von Speicherfehlern erforderlichen Maßnahmen bestimmen die mittlere durch Fehler induzierte Last. Die Wechselwirkungen zwischen Fehler- und Leistungsverhalten werden durch ein System nichtlinearer Gleichung beschrieben, für dessen Lösung ein iteratives Verfahren abgeleitet wird. Abschließend wird mit ausführlichen Beispielen das Modell erläutert und der Einfluß einiger Modell-Parameter auf Leistungs- und Zuverlässigkeitskenngrößen untersucht.

Speicher- und Prozessverwaltung

Das Kapitel (aus dem Buch "Mikrorechner-Systeme : Mikroprozessoren, Speicher, Peripherie", siehe Quelle) behandelt verschiedene Konzepte der Speicherverwaltung und stellt Bausteine vor, die diese Verwaltung hardwaremäßig durchführen. Außerdem werden verschiedene Maßnahmen zur Hardware-Unterstützung von Mikroprozessor-Betriebssystemen beschrieben.

Leitfaden zur strukturierten Anhörung von Kindern im forensischen Kontext

Der Leitfaden dient als Wegweiser für eine strukturierte Anhörung von Kindern im Alter von drei bis 14 Jahren im forensischen Kontext. Ziel soll es sein, kindgerecht möglichst umfangreiche und zuverlässige Informationen zu erhalten. Er gliedert sich in 1) Beispielformulierungen und prägnante Informationen sowie Erklärungen zur praktischen Befragung von Kindern, die in Form von einzelnen, aufeinanderfolgenden Karten präsentiert werden und 2) einen theoretischen Teil, der entwicklungspsychologische Aspekte, rechtliche Rahmenbedingungen, sowie Lösungsansätze für häufig aufkommende Fragen und Probleme bei der Anhörung von Kindern beinhaltet. Die Karten folgen dem typischen Verlauf einer strukturierten Anhörung: Belehrung, Themenneutrales Training zur Befragung, Tatrelevante Anhörung, Verständnisfragen. Sie können am Bildschirm eingeblendet, oder in ausgedruckter Form verwendet werden. Zu jeder Karte finden sich entsprechende Erklärungen zur Vertiefung. Der gesamte Leitfaden orientiert sich an neuesten wissenschaftlichen Erkenntnissen aus dem Bereich der Vernehmungs‐ und Entwicklungspsychologie sowie an relevanten gesetzlichen Grundlagen. Er eignet sich für Polizeibeamte, Richter, Staatsanwälte, Anwälte, forensische Gutachter und andere Personen, die Befragungen von Kindern im forensischen Kontext durchführen.

O contributo das representações numéricas básicas e da função executiva no desempenho de operações aritméticas : um estudo exploratório

Tese de mestrado, Psicologia (Secção de Cognição Social Aplicada), Universidade de Lisboa, Faculdade de Psicologia, 2014