Infectious diseases are the second leading cause of deaths in the world with malaria being responsible for approximately the same amount of deaths as cancer in 2012. Despite the success in malaria prevention and control measures decreasing the disease mortality rate by 45% since 2000, the development of single-dose therapeutics with radical cure potential is required to completely eradicate this deadly disease. Targeting multiple stages of the malaria parasite is becoming a primary requirement for new candidates in antimalarial drug discovery and development. Recently, 4(1H)-pyridone, 4(1H)-quinolone, 1,2,3,4-tetrahydroacridone, and phenoxyethoxy-4(1H)-quinolone chemotypes have been shown to be antimalarials with blood stage activity, liver stage activity, and transmission blocking activity. Advancements in structure-activity relationship and structure-property relationship studies, biological evaluation in vitro and in vivo, as well as pharmacokinetics of the 4(1H)-pyridone and 4(1H)-quinolone chemotypes is discussed in the first chapter of the dissertation. Convenient synthetic approaches to 3-aryl-4(1H)-quinolones via metal-catalyzed and metal-free arylation of β-keto carbonyl compounds is addressed in Chapter 2. A clean arylation protocol of ethyl acetoacetate was developed by using hypervalent diaryl iodonium salts under mild and metal-free conditions. The scope of the reaction, using symmetric and unsymmetric iodonium salts varying in sterics and electronics was examined. This method has been applied for the synthesis of antimalarial compound ELQ-300, which is currently in preclinical development. Additionally, a first gram scale synthesis of ELQ-300 and its structurally related 4(1H)-quinolone P4Q-391 using operationally simple and highly yielding metal-catalyzed conditions have been shown. Despite of 3-aryl-4(1H)-quinolone chemotypes displaying potent antimalarial activities against Plasmodium species in vitro and in vivo, their development is also associated with risks. 4(1H)-quinolones are known to be poorly soluble and thus represent challenging drug candidates for pharmacokinetic and bioavailability reasons. Disrupting of molecular crystal packing and prodrug approaches were employed to overcome solubility and bioavailability issues in current series. Quantum mechanics torsion profile calculations, 13C T1 spin-lattice relaxation experiments as well as X-ray studies were conducted with the objective to determine possible effects improving key physicochemical properties such as solubility and stability. As a backup strategy, a prodrug approach was developed enabling the 4(1H)-quinolone scaffold to be functionalized at the quinolone's oxygen. In order to avoid any enzymatic dependences, an approach was developed in which the prodrug moiety was removed via a pH-triggered decay. Additionally, phosphate prodrugs regenerating the active compound via extrahepatic enzymes such as the ubiquitous alkaline phosphatase were investigated. The development of orally bioavailable prodrugs enabled an advance overcoming in vivo efficacy limitations and has been confirmed by pharmacokinetic profiling studies. The herein presented approaches present viable options for any pyridone quinolone antimalarial chemotype which are currently studied.

Der Transkriptionsfaktor Stat6 vermittelt zentrale Wirkungen von IL-4 und IL-13, die in der Pathologie atopischer Erkrankungen eine Rolle spielen. Seine Spezifität für diese beiden allergieassoziierten Cytokine ist eine wesentliche Motivation ihn näher zu untersuchen. In dieser Arbeit sollte mehr über die Funktion von Stat6 herausgefunden werden. Außerdem wurden Möglichkeiten untersucht dieses Verhalten zu beinflussen. Einen Schwerpunkt der Arbeit bildete die Regulation des Eotaxin-1-Promotors. Eotaxin-1 ist einer der stärksten Rekrutierungsfaktoren für Eosinophile, die eine zentrale Rolle bei der Immunpathologie allergischer Erkrankungen spielen. Mit Hilfe der Daten konnte eine neue Hypothese zur Regulation des Eotaxin-1-Promotors entwickelt werden. Zum Vergleich wurde mit der Untersuchung des Promotors eines weiteren Chemokins, des MCP-4, begonnen. In Zusammenarbeit mit Dr. Sascha Stolzenberger wurde ein Weg untersucht den Stat6-Signalweg zu hemmen. Dabei wurden mit Hilfe des Antennapedia-Peptides Stat6-Bindepeptide in die Zelle transportiert, um dort über eine kompetitive Hemmung die Signaltransduktion zu unterbinden. Ergebnis dieser Arbeiten ist ein hochspezifischer, aber nur transient wirkender Stat6 Inhibitor. Die Stat6/DNA-Wechselwirkung wurde mit der Magnetobead-Technik untersucht. Dabei werden Promotorfragmente an Magnetkügelchen gekoppelt und unter Ausnutzung der Magnetisierung an die DNA bindende Proteine isoliert und über SDS-PAGE/Immunoblotanalyse untersucht. Mit dem Verfahren konnte die Stat6-Bindung an acht verschiedene Promotoren nachgewiesen werden. In Zusammenarbeit mit der Arbeitsgruppe Pallardy aus Paris wurde die Wechselwirkung von Stat6 mit dem Glucocorticoid-Rezeptor untersucht. Glucocorticoide kontrollieren Entzündungen und Interaktionen des aktivierten Rezeptors mit anderen Proteinen aus der Stat-Familie sind seit längerem bekannt. Wie in dieser Arbeit gezeigt wurde, interagiert Stat6 mit dem Glucocorticoidrezeptor unabhängig von einer Bindung an DNA. Zusätzlich wurde der Mucin-2-Promotor auf Stat6-Regulierung untersucht. Mucine sind wichtige Bestandteile des Schleimes. Verstärkte Schleim-Sekretion ist ein klinisches Symptom asthmatischer Erkrankungen und trägt zur Zerstörung der Lunge bei. Ein potentiell Stat6 reguliertes Fragment aus dem Mucinpromoter wurde mit Hilfe von PCR-Techniken isoliert und in Reportergenvektoren kloniert. / The transcriptionfactor Stat6 mediates central effects of the interleukins (IL)-4 and -13, that play important roles in the pathology of Allergy and Asthma. The specificity of these both Allergy-associated cytokines is a strong motivation to investigate the detailed functions of Stat6 and to search for possibilities to influence the behaviour of this transcriptionfactor. The main focus of this work was the regulation of the Eotaxin-1-promoter. The Eotaxin-1 chemokine is one of the most potent recruiting factors for eosinophils, that play a central role in the immunopathology of allergic diseases. On the basis of these data a new model for the regulation was created. In addition to this the investigation of another chemokine promoter, the MCP-4-promoter, was started. In another part of this work a specific Stat6-binding-peptide to inhibit the IL-4 signaltransduction pathway was established. Using the Antennapedia-carrier-peptide allowed to shuttle Stat6-binding peptides into cells where they prevented Stat6 mediated signalling by competitive inhibition. Thus the Stat6-binding-peptide came out to be a transient Stat6 inhibitor with high specificity. The Stat6/DNA-interaction was investigated by DNA-pull-down assays with magnetobeads. Fragments of different promoters are linked to magnetobeads and by using magnetic forces the DNA binding proteins are isolated. This application was used to show Stat6-binding to 8 different promoters. Another subject of this work was the interaction of Stat6 with the glucocorticoid receptor. It is well known that glucocorticoids control inflammation and that the activated receptor interacts with different proteins of the Stat-family. In collaboration with the group of Marc Pallardy in Paris we were able to show that Stat6 interacts with the glucocorticoid receptor independently of DNA binding. In association with Stat6 the regulation of the Mucin-2-promoter seemed to be an interesting aspect. Mucins are essential components of mucus (slime). Enhanced mucus-secretion is a symptom of asthmatic diseases and contributes to the destruction of the lung. A potentially Stat6 regulated fragment was isolated by PCR-techniques and cloned into reportergene vectors.

Protein-bound 3,4-dihydroxyphenylalanine (PB-DOPA), a long-lived, redox-active product of protein oxidation, is capable of functioning as both a pro- and anti-oxidant. A number of in vitro and in vivo studies have demonstrated a toxic, non-toxic or even beneficial effect of free DOPA, however little investigation has examined the physiological activity of PB-DOPA. Furthermore, as free DOPA is currently the major treatment available for Parkinson?s disease, most studies have focused on the effect of DOPA within neurological cells or tissues, although the presence of PB-DOPA in other locations, for example within atherosclerotic plaques, suggests that broader research is needed to fully understand the physiological effects of both free and PB-DOPA. The hypothesis presented in this thesis is that under physiological conditions, when little redox active transition metal is available, PB-DOPA can function as a redox signalling molecule, triggering an enhancement of cellular antioxidant defences, with a potentially specific role in the regulation of defences targeted against protein oxidation. Physiological levels of PB-DOPA are very low, however the level on individual proteins can change to a proportionally large degree during oxidative stress, an appropriate property for a signalling molecule. In addition, remarkably elevated levels occur in some pathologies, including atherosclerosis. As an initial and commonly formed product of protein oxidation, PB-DOPA is well placed for a signalling role, promoting a significant up-regulation of antioxidant defences in the early stages of oxidative stress, before extensive damage has occurred. As an initiator of antioxidant defences, PB-DOPA would be potentially useful as a therapeutic for the treatment of diseases involving oxidative stress or the accumulation of oxidative damage. The main objective of this thesis was, therefore, to examine the effect of PB-DOPA on the cellular antioxidant defence system using monocytic and macrophage-like cells, key cells involved in the formation of atherosclerotic plaques. The incorporation of free DOPA into protein during protein synthesis, a process previously shown to occur both in vitro and in vivo, was used to generate PB-DOPA. Neither free nor PB-DOPA were found to be toxic to monocytic or macrophage-like cells in culture, but rather were both capable of protecting these cells from oxidative stress. Free DOPA was shown to be capable of directly scavenging radicals, a process that was thought to be in part responsible for the protection induced during oxidative stress. The presence of free and PB-DOPA up-regulated the activity of catalase and NAD(P)H:quinone oxidoreductase, two enzymatic antioxidants, however the activity of superoxide dismutase and the concentration of oxidised and reduced glutathione were not affected. Whilst it was thought that PB-DOPA would have a specific effect on the activity of antioxidant defences targeted against protein oxidation, proteolysis and bulk chaperone activity were not affected by a combination of free and PB-DOPA. Oxidatively-induced protein aggregation, however, was inhibited by the presence of free and PB-DOPA, suggesting that a more specific chaperone regulation may be taking place. The regulation of gene and protein expression was thought to be one possible mechanism by which PB-DOPA could function as a signalling molecule. To test this hypothesis, the effect of free and PB-DOPA on transcription factor activation and protein expression were investigated. Free and PB-DOPA did not induce the expression or activation of Nrf2, AP-1 or NFJB, three transcription factors thought to be involved in the expressional regulation of genes involved in the antioxidant defence system. However, the expression of a number of proteins, including antioxidants, chaperones and proteins involved in cell cycle progression, were regulated in monocytic and macrophage-like cells following the administration of free DOPA under conditions that resulted in either a high or low level of PB-DOPA generation. The regulated proteins differed between the two conditions, suggesting that the level of PB-DOPA may be a key factor in determining the specific defences targeted. The results presented in this thesis support the hypothesis that PB-DOPA can function as a signalling molecule, triggering an enhancement of cellular antioxidant defences, with a specific role in the regulation of the chaperone system, a key defence targeted against protein oxidation. This thesis may provide the basis for the potential use of free or PB-DOPA as a therapeutic for diseases known to involve oxidative stress or oxidative damage, however more research will be required to determine if the effects demonstrated in this thesis are also capable of occurring in vivo.

Uncertainty is pervasive in risk assessment. In ecotoxicological risk assessments, it arises from such sources as a lack of data, the simplification and abstraction of complex situations, and ambiguities in assessment endpoints (Burgman 2005; Suter 1993). When evaluating and managing risks, uncertainty needs to be explicitly considered in order to avoid erroneous decisions and to be able to make statements about the confidence that we can place in risk estimates. Although informative, previous approaches to dealing with uncertainty in ecotoxicological modelling have been found to be limited, inconsistent and often based on assumptions that may be false (Ferson & Ginzburg 1996; Suter 1998; Suter et al. 2002; van der Hoeven 2004; van Straalen 2002a; Verdonck et al. 2003a). In this thesis a Generalised Linear Modelling approach is proposed as an alternative, congruous framework for the analysis and prediction of a wide range of ecotoxicological effects. This approach was used to investigate the results of toxicity experiments on the effect of 2,4-Dichlorophenoxyacetic Acid (2,4-D) formulations and 4-Chlorophenol (4-CP, an associated breakdown product) on Daphnia carinata. Differences between frequentist Maximum Likelihood (ML) and Bayesian Markov-Chain Monte-Carlo (MCMC) approaches to statistical reasoning and model estimation were also investigated. These approaches are inferentially disparate and place different emphasis on aleatory and epistemic uncertainty (O'Hagan 2004). Bayesian MCMC and Probability Bounds Analysis methods for propagating uncertainty in risk models are also compared for the first time. For simple models, Bayesian and frequentist approaches to Generalised Linear Model (GLM) estimation were found to produce very similar results when non-informative prior distributions were used for the Bayesian models. Potency estimates and regression parameters were found to be similar for identical models, signifying that Bayesian MCMC techniques are at least a suitable and objective replacement for frequentist ML for the analysis of exposureresponse data. Applications of these techniques demonstrated that Amicide formulations of 2,4-D are more toxic to Daphnia than their unformulated, Technical Acid parent. Different results were obtained from Bayesian MCMC and ML methods when more complex models and data structures were considered. In the analysis of 4-CP toxicity, the treatment of 2 different factors as fixed or random in standard and Mixed-Effect models was found to affect variance estimates to the degree that different conclusions would be drawn from the same model, fit to the same data. Associated discrepancies in the treatment of overdispersion between ML and Bayesian MCMC analyses were also found to affect results. Bayesian MCMC techniques were found to be superior to the ML ones employed for the analysis of complex models because they enabled the correct formulation of hierarchical (nested) datastructures within a binomial logistic GLM. Application of these techniques to the analysis of results from 4-CP toxicity testing on two strains of Daphnia carinata found that between-experiment variability was greater than that within-experiments or between-strains. Perhaps surprisingly, this indicated that long-term laboratory culture had not significantly affected the sensitivity of one strain when compared to cultures of another strain that had recently been established from field populations. The results from this analysis highlighted the need for repetition of experiments, proper model formulation in complex analyses and careful consideration of the effects of pooling data on characterising variability and uncertainty. The GLM framework was used to develop three dimensional surface models of the effects of different length pulse exposures, and subsequent delayed toxicity, of 4-CP on Daphnia. These models described the relationship between exposure duration and intensity (concentration) on toxicity, and were constructed for both pulse and delayed effects. Statistical analysis of these models found that significant delayed effects occurred following the full range of pulse exposure durations, and that both exposure duration and intensity interacted significantly and concurrently with the delayed effect. These results indicated that failure to consider delayed toxicity could lead to significant underestimation of the effects of pulse exposure, and therefore increase uncertainty in risk assessments. A number of new approaches to modelling ecotoxicological risk and to propagating uncertainty were also developed and applied in this thesis. In the first of these, a method for describing and propagating uncertainty in conventional Species Sensitivity Distribution (SSD) models was described. This utilised Probability Bounds Analysis to construct a nonparametric 'probability box' on an SSD based on EC05 estimates and their confidence intervals. Predictions from this uncertain SSD and the confidence interval extrapolation methods described by Aldenberg and colleagues (2000; 2002a) were compared. It was found that the extrapolation techniques underestimated the width of uncertainty (confidence) intervals by 63% and the upper bound by 65%, when compared to the Probability Bounds (P3 Bounds) approach, which was based on actual confidence estimates derived from the original data. An alternative approach to formulating ecotoxicological risk modelling was also proposed and was based on a Binomial GLM. In this formulation, the model is first fit to the available data in order to derive mean and uncertainty estimates for the parameters. This 'uncertain' GLM model is then used to predict the risk of effect from possible or observed exposure distributions. This risk is described as a whole distribution, with a central tendency and uncertainty bounds derived from the original data and the exposure distribution (if this is also 'uncertain'). Bayesian and P-Bounds approaches to propagating uncertainty in this model were compared using an example of the risk of exposure to a hypothetical (uncertain) distribution of 4-CP for the two Daphnia strains studied. This comparison found that the Bayesian and P-Bounds approaches produced very similar mean and uncertainty estimates, with the P-bounds intervals always being wider than the Bayesian ones. This difference is due to the different methods for dealing with dependencies between model parameters by the two approaches, and is confirmation that the P-bounds approach is better suited to situations where data and knowledge are scarce. The advantages of the Bayesian risk assessment and uncertainty propagation method developed are that it allows calculation of the likelihood of any effect occurring, not just the (probability)bounds, and that the same software (WinBugs) and model construction may be used to fit regression models and predict risks simultaneously. The GLM risk modelling approaches developed here are able to explain a wide range of response shapes (including hormesis) and underlying (non-normal) distributions, and do not involve expression of the exposure-response as a probability distribution, hence solving a number of problems found with previous formulations of ecotoxicological risk. The approaches developed can also be easily extended to describe communities, include modifying factors, mixed-effects, population growth, carrying capacity and a range of other variables of interest in ecotoxicological risk assessments. While the lack of data on the toxicological effects of chemicals is the most significant source of uncertainty in ecotoxicological risk assessments today, methods such as those described here can assist by quantifying that uncertainty so that it can be communicated to stakeholders and decision makers. As new information becomes available, these techniques can be used to develop more complex models that will help to bridge the gap between the bioassay and the ecosystem.

The search for a reliable and non-invasive technique for the dating of rock art has produced an array of different, localised, and limited techniques. This is one of them. Still in its experimental stage, the recognition of quartz microdebitage produced by the pecking of engravings is the aim of this project. This investigation aims to establish whether microdebitage from rock engravings can be distinguished from other sediments. Analysis of microdebitage from rock engraving experiments was used to determine the difference between experimental and naturally derived particles. This research discusses methodology, and applications for the recognition of quartz grain features, derived from experimental and natural material from Mutawintji National Park (Broken Hill, NSW, Australia) and the Sydney region (NSW Australia). A three-step process was devised for this research: What features occur on non-cultural quartz grains? What features occur on rock engraving quartz grains? Are they different? Can rock engraving quartz microdebitage be identified under natural conditions? Microdebitage from rock engravings was examined using optical and scanning electron microscopy to identify diagnostic attributes, with the objective of assessing the potential of microdebitage for spatial and temporal archaeological investigation. Characteristics of the quartz grains in the microdebitage were compared with quartz from differing environments. The observation of diagnostic features on quartz grains made it possible to discriminate between microdebitage from rock engravings and the natural soil background. This knowledge may be applied to excavated material from archaeological sites, for identifying episodes of rock engraving and other lithic activity in temporal relation to other evidence of cultural activity.

Copies of author's previously published articles inserted. / Bibliography: leaves 112-166. / 179, [38] leaves, [29] leaves of plates : ilol. ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Aims to contribute to the understanding of the mechanisms of peroxisomal assembly in human hepatocytes by investigating the nature of the ultrastructural changes in peroxisomes in those patients where peroxisomal biogenesis or function is impaired. / Thesis (Ph.D.)--University of Adelaide, Dept. of Paediatrics, 1994

<p>Att eleverna får lära sig att skriva är ett av grundskolans viktigaste uppdrag. Under vår verksamhetsförlagda utbildning under tiden på Lärarhögskolan har vi sett att mycket av undervisningen under de första åren i grundskolan ägnas åt att läsa, samtala och skriva. Det har fått oss att fundera kring hur lärare fortsätter att arbeta med skrivandet. Vårt syfte med den här studien är att fördjupa förståelsen för och utveckla kunskaper om hur lärare ser på den fortsatta skrivutvecklingen i skolår 4-6. Syftet är också att utveckla förståelse för vad lärare anser vara viktig kunskap i ämnet. Vi har använt oss av en kvalitativ undersökningsmetod i form av intervjuer med lärare verksamma i skolår 4-6. I bearbetningen av våra intervjuer har vi funnit åtta tema-områden som berör olika aspekter av skrivutveckling. I den vidare analysen presenterar vi, av oss konstruerade, lärartyper som representerar skilda sätt att se på skrivande i skolan. Utöver detta har vi fördjupat oss i teorier och begrepp som berör ämnet. Resultatet har visat att lärarna anser att skrivandet är betydelsefullt och lägger stor vikt vid att eleverna får möjlighet att fortsätta utveckla detta. För att eleverna ska kunna utveckla sitt skrivande menar alla lärarna att undevisningen på olika sätt måste utgå från att göra skrivandet till något meningsfullt, lustfyllt och inspirerande. Däremot har vi sett skillnader i vad lärarna betonar som viktigt i undervisningens form och innehåll.</p><p>One of the most important tasks of schools is to teach the students how to write. During our education at Lärarhögskolan we have had the opportunity to spend some time working at schools. During this time, we have seen that a great emphasis is put at reading, talking and writing during the first school years. This has made us think about how teachers continue working with writing in the later school years. Our objective with this study is to deepen the understanding for and develop knowledge about how teachers look upon the writing development in school years 4-6. The objective is also to develop an understanding for what teachers consider to be important knowledge in this subject. We have used a qualitative method by interviewing teachers working with school years 4-6. While going through our interviews, we have found seven themes that touch upon different aspects on writing development. In the further analysis, we relate the results to the three theoretical conceptions scaffolding, the zone of proximal development and dialogism. Moreover, we have studied theories and conceptions about the subject. The results show that teachers consider writing to be meaningful and put a lot of emphasis on that the students get the opportunity to continue to develop their skills. In order for the students to continue their development, all teachers in the study point out that the teaching must make writing something meaningful, enjoyable and inspiring. However, we have seen differences in what the teachers consider as important content and how the teaching is done.</p>

<p>A closed Riemann surface which can be realized as a 3-sheeted covering of the Riemann sphere is called trigonal, and such a covering is called a trigonal morphism. Accola showed that the trigonal morphism is unique for Riemann surfaces of genus g ≥ 5. This thesis will characterize the Riemann surfaces of genus 4 wiht non-unique trigonal morphism. We will describe the structure of the space of cyclic trigonal Riemann surfaces of genus 4.</p> / Report code: LiU-Tek-Lic-2004:54. The electronic version of the printed licentiate thesis is a corrected version where errors in the calculations have been corrected. See Errata below for a list of corrections.

<p>SAAB Support and Services, som är servicecenter för flygplanskomponenter, utför idag huvuddelar av sina mätningar manuellt, mätningar som ibland kan ta upp till fyra dagar. För att höja noggrannheten samt öka effektiviteten köpte de år 2007 in ett automatiskt testkoncept från MK Test systems.</p><p>I examensarbetet har vi först undersökt den inköpta utrustningen.</p><p>Sedan har vi tagit fram rutiner för kalibrering av utrustningen som klarar SAAB:s krav. Därefter har vi arbetat fram kravspecifikationer och instruktioner för hur utrustningen ska användas. Under arbetets gång har vi samlat in information för att kunna göra en utvärdering av hur lämplig utrustningen är att använda för att testa flygplanskomponenter.</p><p>Arbetet resulterade huvudsakligen i tre st manualer som går igenom tre olika områden; kalibrering, kablagetest och ett standardtest för t.ex.</p><p>paneler och styrboxar.</p> / <p>SAAB Support & Services, a service centre for air plane components, perform most of their measurements manually. These measurements can sometimes take up to four days to perform. In 2007 an automatic concept for testing from MK Test systems was purchased in order to enhance the accuracy and increase the efficiency.</p><p>In our thesis we have initially examined the automatic concept for testing and then developed standards for how to calibrate this equipment, standards that meets SAAB:s requirements. Thereafter we have developed specifications and instructions on how to use the equipment. During our work we have gathered information for an evaluation of how fitting it is to use the F1500 for testing air plane components.</p><p>The main outcome of our work consists of three manuals for three different areas; calibration, harness test and a standard test for example panels and controller units.</p>

<p>Cytokines play important roles in bone metabolism, participating in the complex interplay necessary for normal bone formation and turnover. The aim of the present thesis was to investigate the effects of two anti-inflammatory cytokines, interleukin-4 (IL-4) and interleukin-13 (IL-13) on bone. </p><p>Influence of pro- and anti-inflammatory cytokines on interleukin-6 (IL-6) formation in cultured human osteoblasts (hOBs) was investigated. IL-4 and IL-13 as well as interleukin-1 (IL-1) and tumour necrosis factor alpha and beta (TNF-α/β) stimulated IL-6 secretion in hOBs. Also, IL-4 and IL-13 synergistically potentiated the effect of IL-1 and TNFs on IL-6 secretion. </p><p>Effects of IL-4 and IL-13 on markers of osteoblastic activity in hOBs were investigated. IL-4 and IL-13 induced a dose-dependent increase in the formation of alkaline phosphatase (ALP) and pro-collagen type I carboxy-peptide (PICP) together with enhanced mineralization rate in hOBs. Formation of osteocalcin (OC) was unaffected. </p><p>The mechanism behind inhibited proliferation by IL-4 and IL-13 in hOBs was investigated. IL-4 and IL-13 caused a dose-dependent increase in DNA-fragmentation together with escalating Caspase-3 activity in hOBs, reflecting induced apoptosis. Osteoblast apoptosis was also confirmed by TNF-α, dexamethasone and by serum starvation.</p><p>The skeletal phenotype of IL-13^-/-, IL-4^-/-IL-13^-/- and WT mice was compared. An altered cortical bone mass was detected in adult male IL-4^-/-IL-13^-/- mice. They displayed a reduction in cortical bone mineral content (BMC) secondary to reduced cortical thickness. Mechanical strength of the cortical bone was reduced in level with the reduction detected in BMC. Trabecular bone mineral density (tvBMD) was unaffected. </p><p>Callus formation in IL-4^-/-IL-13^-/- and WT male mice was compared. No differences were found concerning radiological healing, biomechanical properties, callus parameters or histology. Heterotopic bone formation in IL-4^-/-IL-13^-/- and WT mice was compared using DXBM implants. No differences were found concerning mineralization of implants. Immuno-histology showed inhibition of autonomic nerves and lack of implant vascularization in IL-4^-/-IL-13^-/- mice. </p><p>In summery, the two anti-inflammatory cytokines IL-4 and IL-13 influence osteoblast activity and apoptosis <i>in vitro</i>. They also selectively influence cortical bone formation <i>in vivo</i>. These findings suggest a role for IL-4 and IL-13 in osteoblast differentiation, in bone metabolism and in bone formation. </p>