Unpredictability, invisibility and vulnerability: Unaccompanied asylum-seeking minors’ journeys to Australia

This qualitative study investigated the refugee journey of 17 males who arrived in Australia as unaccompanied asylum-seeking minors between 2009 and 2013, and were granted protection visas. The paper focuses on the four conceptual challenges of refugee journeys, as identified recently by BenEzer and Zetter: temporal characteristics; drivers and destinations; the process/content of the journey; and the characteristics of the wayfarers. The findings indicate that their mental journey has not yet ended and transcends the physical departure-arrival voyage. Although the primary drivers for the refugee journey were protection reasons, their desire to find a “better life” free from violence and exclusion also played an important role. The irregular character of the journey made it highly unpredictable, exposed these minors to extreme levels of vulnerability and the need to remain invisible, prompted short lived friendships with other asylum seekers, and created a pervasive feeling of mistrust towards smugglers and other people they met along the way. The study has highlighted the need for interventions to protect unaccompanied minors during their refugee journey.

Transcriptional regulation by the orphan nuclear receptor ERRgamma

The nuclear receptor (NR) superfamily is comprised of receptors for small lipopfilic ligands such as steroid hormones, thyroid hormone, retinoids, and vitamin D. NRs are ligand-inducible transcription factors capable of both activating and repressing their target gene expression. They control a wide range of biological functions connected to growth, development, and homeostasis. In addition to the ligand-regulated receptors, the family includes a large group of receptors whose physiological ligands are unknown. These receptors are referred to as orphan NRs. Estrogen-related receptor gamma (ERRgamma) belongs to the ERR subfamily of orphan NRs together with the related ERRalpha and ERRbeta. ERRs share amino acid sequence homology with the classical estrogen receptors (ERs) but they are unable to bind natural estrogenic ligands. ERRgamma is expressed in several embryonic and adult tissues but its biological role is still largely unknown. ERRgamma activates reporter gene expression in transfected cells independently of added hormones implying that ERRgamma harbors constitutive activity. However, the intrinsic activity of ERRgamma can be inhibited by synthetic compounds such as the selective estrogen receptor modulator 4-hydroxytamoxifen (4-OHT). Ligands of NRs can act as agonists that activate transcription, as antagonists that prevent activation of transcription, or as inverse agonists that antagonize the constitutive transcriptional activity of receptor. Most of the synthetic ERRgamma ligands act as inverse agonists but recently, a synthetic ERRgamma agonist GSK4716 was identified. This demonstrates that it is possible to design and identify agonists for ERRgamma. Prior to this thesis work, the structural and functional characteristics of ERRgamma were largely unknown. The aim of this study was to define the functional requirements for ERRgamma-mediated transcriptional regulation and to examine the cross-talk between ERRgamma and other NRs. Due to the fact that natural physiological ligands of ERRgamma are unknown, another aim of this study was to seek new natural compounds that may affect transcriptional activity of ERRgamma. Plant-derived phytoestrogens have previously been shown to act as ligands for ERs and ERRalpha, and therefore the effects of these compounds were also studied on ERRgamma-mediated transcriptional regulation. This work demonstrated that ERRgamma-mediated transcriptional regulation was dependent on DNA-binding, dimerization and activation function-2. Heterodimerization with ERRalpha inhibited the transcriptional activity of ERRgamma. In addition to 4-OHT, another anti-estrogen, 4-hydroxytoremifene (4-OHtor), was identified as an inverse agonist of ERRgamma. Interestingly, ERRgamma activated transcription in the presence of 4-OHT and 4-OHtor on activator protein-1 binding sites. ERRgamma was found to interact with another orphan NR Nurr1 by repressing the ability of Nurr1 to activate transcription of the osteopontin gene. Transcriptional activity of ERRgamma was shown to be stimulated by the phytoestrogen equol. Structural model analysis and mutational experiments indicated that equol was able to bind to the ligand binding domain of ERRgamma. The growth inhibitory effect of ERRgamma on prostate cancer cells was found to be enhanced by equol. In summary, this study demonstrates that despite the absence of an endogenous physiological ligand, the activity of ERRgamma can be modulated in other ways such as dimerization with related receptors or by cross-talk with other transcription factors as well as by binding some synthetic or natural compounds.

Orphan nuclear receptor subfamily NR4A their interplay with other nuclear receptors and functions in osteoblasts

Nurr1, NGFI-B and Nor1 (NR4A2, NR4A1 and NR4A3, respectively) belong to the NR4A subfamily of nuclear receptors. The NR4A receptors are orphan nuclear receptors which means that activating or repressing ligands for these receptors have not been found. NR4A expression is rapidly induced in response to various stimuli including growth factors and the parathyroid hormone (PTH). The studies concerning the NR4A receptors in the central nervous system have demonstrated that they have a major role in the development and function of the dopaminergic neurons of the midbrain and in regulating hypothalamus-pituitary-adrenal-axis. However, the peripheral functions of the NR4A family are largely unknown. Cultured mouse primary osteoblasts, a preosteoblastic cell line and several osteoblastic cell lines were used to investigate the role of NR4A receptors in osteoblasts. NR4A receptors were shown to directly bind to and activate the promoter of the osteopontin gene (OPN) in osteoblastic cells, thus regulating its expression. OPN is a major bone matrix protein expressed throughout the differentiation of preosteoblastic cells into osteoblasts. The activation of the OPN promoter was shown to be dependent on the activation function-1 located in the N-terminal part of Nurr1 and to occur in both monomeric and RXR heterodimeric forms of NR4A receptors. Furthermore, PTH was shown to upregulate OPN expression through the NR4A family. It was also demonstrated that the fibroblast growth factor-8b (FGF-8b) induces the expression of NR4A receptors in osteoblasts as immediate early genes. This induction involved phosphatidylinositol-3 kinase, protein kinase C, and mitogen activated protein kinase, which are all major pathways of FGF signalling. Nurr1 and NGFI-B were shown to induce the proliferation of preosteoblastic cells and to reduce their apoptosis. FGF-8b was shown to stimulate the proliferation of osteoblastic cells through the NR4A receptors. These results suggest that NR4A receptors have a role both in the differentiation of osteoblasts and in the proliferation and apoptosis of preosteoblast. The NR4A receptors were found to bind to the same response element on OPN as the members of the NR3B family of orphan receptors do. Mutual repression was observed between the NR4A receptors and the NR3B receptors. This repression was shown to be dependent on the DNA-binding domains of both receptor families, but to result neither from the competition of DNA binding nor from the competition for coactivators. As the repression was dependent on the relative expression levels of the NR4As and NR3Bs, it seems likely that the ratio of the receptors mediates their activity on their response elements. Rapid induction of the NR4As in response to various stimuli and differential expression of the NR3Bs can effectively control the gene activation by the NR4A receptors. NR4A receptors can bind DNA as monomers, and Nurr1 and NGFI-B can form permissive heterodimers with the retinoid X receptor (RXR). Permissive heterodimers can be activated with RXR agonists, unlike non-permissive heterodimers, which are formed by RXR and retinoic acid receptor or thyroid hormone receptor (RAR and TR, respectively). Non-permissive heterodimers can only be activated by the agonists of the heterodimerizing partner. The mechanisms behind differential response to RXR agonists have remained unresolved. As there are no activating or repressing ligands for the NR4A receptors, it would be important to find out, how they are regulated. Permissiviness of Nurr1/RXR heterodimers was linked to the N-terminal part of Nurr1 ligand-binding domain. This region has previously been shown to mediate the interaction between NRs and corepressors. Non-permissive RAR and TR, permissive Nurr1 and NGFI-B, and RXR were overexpressed with corepressors silencing mediator for retinoic acid and thyroid hormone receptors (SMRT), and with nuclear receptor corepressor in several cell lines. Nurr1 and NGFI-B were found to be repressed by SMRT. The interaction of RXR heterodimers with corepressors was weak in permissive heterodimers and much stronger in non-permissive heterodimers. Non-permissive heterodimers also released corepressors only in response to the agonist of the heterodimeric partner of RXR. In the permissive Nurr1/RXR heterodimer, however, SMRT was released following the treatment with RXR agonists. Corepressor release in response to ligands was found to differentiate permissive heterodimers from non-permissive ones. Corepressors were thus connected to the regulation of NR4A functions. In summary, the studies presented here linked the NR4A family of orphan nuclear receptors to the regulation of osteoblasts. Nurr1 and NGFI-B were found to control the proliferation and apoptosis of preosteoblasts. The studies also demonstrated that cross-talk with the NR3B receptors controls the activity of these orphan receptors. The results clarified the mechanism of permissiviness of RXR-heterodimers. New information was obtained on the regulation and functions of NR4A receptors, for which the ligands are unknown.

Fritz Loewenthal at Abendschule (night school) with unidentified classmates; Philadelphia.

Father of Steven Lowell Loewenthal

Harry Greenberg; Philadelphia.

The Greenbergs were relatives from Philadelphia who provided the entry papers to the United States for the Lowell Loewenthal family

Fritz Loewenthal at Abendschule (night school) with unidentified classmates; Philadelphia.

Father of Steven Lowell Loewenthal

Steven Lowell Loewenthal with members of the Greenberg family; Philadelphia.

The Greenbergs were relatives from Philadelphia who provided the entry papers to the United States for the Lowell Loewenthal family

Leo Baeck (sitting second from left) on stage at Dropsie College in Philadelphia to receive honorary Doctorate of Hebrew Letters Ceremonies; Commemorative

Page 14 of the "American Jewish Cavalcade" scrapbook of Leo Baeck in New York found in ROS 10 Folder 3

Franks family papers, 1711-1821, [1965-1968].

Contains business correspondence, accounts and documents relating to Jacob Franks of New York, his two sons, Moses and David, a nephew, Isaac, and a John Franks of Halifax, possibly a member of the family.

Letter introducing Mark Solomons, shochet, from Philadelphia

Digital image

The function of NR3B and NR4A orphan nuclear receptors in osteoblasts

Nuclear receptors (NRs) comprise a large family of proteins that mediate the effects of small lipophilic molecules such as steroid hormones. In addition, there are a group of NRs which lack identified natural ligands and are referred as orphan NRs. In this thesis, the function of two such orphan NR families, the NR3B (ERRα, ERRβ and ERRγ) and the NR4A family (NGFI-B, Nurr1 and Nor1), was studied. NR3B and NR4A receptors regulate many biological processes such as energy metabolism and carcinogenesis. In addition, NR3B and NR4A receptors are expressed in bone. Therefore, the signaling and function of NR3B and NR4A orphan nuclear receptors was studied specifically in osteoblasts. NR4A receptors were found to be regulated by NR3B receptors and the Wnt/β-catenin signaling pathway as ERRα, ERRγ and β-catenin repressed the transcriptional activity of NR4A receptors in U2-OS cells. NGFI-B was found to repress the transcriptional activity of ERRγ in HeLa cells. The phytoestrogen equol was identified as a new agonist for ERRγ and ERRβ in PC-3, U2-OS, and SaOS-2 cells. Equol increased the transcriptional activity of ERRγ by increasing ERRγ co-activator binding and by inducing a conformational change in the ligand binding pocket of ERRγ. The growth inhibitory effect of equol on PC-3 prostate cancer cells was decreased by blocking ERRγ expression by siRNA. Therefore, ERRγ could mediate some of the beneficial health effects of equol. The Wnt/β-catenin signaling pathway is important for the differentiation and function of osteoblasts. NR3B and NR4A receptors were found to repress the transcriptional activity mediated by β-catenin in U2-OS cells. The mesenchymal stem cells (MSCs) isolated from ERRα knockout (KO) mice showed diminished proliferation and osteoblastic differentiation compared to the wild-type cells. The overexpression of ERRα in osteoblastic MC3T3-E1 cell line increased their mineralization. Bone sialoprotein (BSP) was shown to be a direct target gene for ERRα and ERRγ as the BSP promoter was activated by ERRα or ERRγ and PGC-1α in HeLa cells. The adipogenic differentiation of ERRα KO MSCs was also decreased and they expressed less adipogenic marker genes. In conclusion, the studies described in this thesis demonstrated that the transcriptional activity of NR3B and NR4A receptors can be regulated by other orphan NRs and signaling pathways in osteoblasts. NR3B receptors can also be regulated by ligands and a new agonist, equol, was identified for ERRβ and ERRγ. New roles for NR3B and NR4A were also identified as they were shown to converge with the Wnt signaling pathway in osteoblasts, ERRγ was shown to mediate the growth inhibitory effect of equol in prostate cancer cells, and ERRα was shown to regulate positively MSC proliferation, osteoblastic differentiation and adipogenesis.

Evidence in European Asylum Procedures

This thesis explores the particular framework of evidentiary assessment of three selected appellate national asylum procedures in Europe and discusses the relationship between these procedures, on the one hand, and between these procedures and other legal systems, including the EU legal order and international law, on the other. A theme running throughout the thesis is the EU strivings towards approximation of national asylum procedures and my study analyses the evidentiary assessment of national procedures with the aim of pinpointing similarities and differences, and the influences which affect these distinctions. The thesis first explores the frames construed for national evidentiary solutions by studying the object of decision-making and the impact of legal systems outside the national. Second, the study analyses the factual evidentiary assessment of three national procedures - German, Finnish and English. Thirdly, the study explores the interrelationship between these procedures and the legal systems influencing them and poses questions in relation to the strivings of EU and methods of convergence. The thesis begins by stating the framework and starting points for the research. It moves on to establish keys of comparison concerning four elements of evidentiary assessment that are of importance to any appellate asylum procedure, and that can be compared between national procedures, on the one hand, and between international, regional and national frameworks, on the other. Four keys of comparison are established: the burden of proof, demands for evidentiary robustness, the standard of proof and requirements for the methods of evidentiary assessment. These keys of comparison are then identified in three national appellate asylum procedures, and in order to come to conclusions on the evidentiary standards of the appellate asylum procedures, relevant elements of the asylum procedures in general are presented. Further, institutional, formal and procedural matters which have an impact on the evidentiary standards in the national appellate procedures are analysed. From there, the thesis moves on to establish the relationship between national evidentiary standards and the legal systems which affect them, and gives reasons for similarities and divergences. Further, the thesis studies the impact of the national frameworks on the regional and international level. Lastly, the dissertation makes a de lege ferenda survey of the relationship between EU developments, the goal of harmonization in relation to national asylum procedures and the particular feature of evidentiary standards in national appellate asylum procedures. Methodology The thesis follows legal dogmatic methods. The aim is to analyse legal norms and legal constructions and give them content and context. My study takes as its outset an understanding of the purposes for legal research also regarding evidence and asylum to determine the contents of valid law through analysis and systematization. However, as evidentiary issues traditionally are normatively vaguely defined, a strict traditional normative dogmatic approach is not applied. For the same reason a traditionalist and strict legal positivism is not applied. The dogmatics applied to the analysis of the study is supported by practical analysis. The aim is not only to reach conclusions concerning the contents of legal norms and the requirements of law, but also to study the use and practical functioning of these norms, giving them a practcial context. Further, the study relies on a comparative method. A functionalist comparative method is employed and keys of comparison are found in evidentiary standards of three selected national appellate asylum procedures. The functioning equivalences of German, Finnish and English evidentiary standards of appellate asylum procedures are compared, and they are positioned in an European and international legal setting. Research Results The thesis provides results regarding the use of evidence in national appellate asylum procedures. It is established that evidentiary solutions do indeed impact on the asylum procedure and that the results of the procedure are dependent on the evidentiary solutions made in the procedures. Variations in, amongst other things, the interpretation of the burden of proof, the applied standard of proof and the method for determining evidentiary value, are analysed. It is established that national impacts play an important role in the adaptation of national appellate procedures to external requirements. Further, it is established that the impact of national procedures on as well the international framework as on EU law varies between the studied countries, partly depending on the position of the Member State in legislative advances at the EU level. In this comparative study it is, further, established that the impact of EU requirements concerning evidentiary issues may be have positive as well as negative effects with regard to the desired harmonization. It is also concluded that harmonization using means of convergence that primaly target legal frameworks may not in all instances be optimal in relation to evidentiary standards, and that more varied and pragmatic means of convergence must be introduced in order to secure harmonization also in terms of evidence. To date, legal culture and traditions seem to prevail over direct efforts at procedural harmonization.

Liminal Belonging: West African male asylum seekers’ narratives of the asylum experience whilst in Finland

The dominant discourses on the issue of asylum have placed it on a uniquely higher level of scrutiny as a politically very sensitive area for social research. Today, member states within the EU have implemented stricter policies to control new arrivals, whilst instituting statutory procedures to manage the existing asylum claims. In 2010, the number of applicants for asylum in Finland totalled 5988, out of which 1784 were given positive decisions. This thesis endeavour to highlight asylum seekers in the discourses about them by adding their voices to the discussions of them in contemporary Finland. Studies, which has concentrated on asylum seekers in Finland, uses the living conditions within asylum reception centres to assess the impacts of structural barriers on asylum seekers’ efforts to deal with the asylum process. By highlighting the impacts of the entire asylum process, which I believe starts from the country of origin; I focus on examining narratives of dealing with the experience of liminality whilst waiting for asylum, and then explore areas of possible participation within informal social networks for West African asylum seekers in Finland. The overall aim is to place the current research within the broader sociological discussion of ‘belonging’ for asylum seekers who are yet to be recognized as refugees, and who exist in a state of limbo. Methodologically, oral interviews, self-written autobiographical narratives, and ethnographic field work are qualitatively combined as data in this thesis for an empirical study of West African male asylum seekers in Finland. Narrative analysis is employed to analyze the data for this thesis. The ethnographic research data for the study began in May 2009 and ended in August of 2010. Altogether, ten interviews and four self-written narratives were collected as data. In total seven hours of audio recording were made, along eleven pages of hand-written autobiographical narratives. Field observation notes are employed in the study to provide contexts to the active interactional processes of interpretation throughout the analysis. Findings from the study suggest that within the experience of liminality, which surrounds the entire asylum process, participations within informal social networks are found to be important to the process of re-making place and the sense of belonging. My study shows that this is necessary to countering the experience of boredom, stress and social isolation, which permeate all aspects of life for West African asylum seekers, whilst they wait for asylum decisions in Finland.

Predicting gene ontology annotations of orphan GWAS genes using protein-protein interactions

Background: The number of genome-wide association studies (GWAS) has increased rapidly in the past couple of years, resulting in the identification of genes associated with different diseases. The next step in translating these findings into biomedically useful information is to find out the mechanism of the action of these genes. However, GWAS studies often implicate genes whose functions are currently unknown; for example, MYEOV, ANKLE1, TMEM45B and ORAOV1 are found to be associated with breast cancer, but their molecular function is unknown. Results: We carried out Bayesian inference of Gene Ontology (GO) term annotations of genes by employing the directed acyclic graph structure of GO and the network of protein-protein interactions (PPIs). The approach is designed based on the fact that two proteins that interact biophysically would be in physical proximity of each other, would possess complementary molecular function, and play role in related biological processes. Predicted GO terms were ranked according to their relative association scores and the approach was evaluated quantitatively by plotting the precision versus recall values and F-scores (the harmonic mean of precision and recall) versus varying thresholds. Precisions of similar to 58% and similar to 40% for localization and functions respectively of proteins were determined at a threshold of similar to 30 (top 30 GO terms in the ranked list). Comparison with function prediction based on semantic similarity among nodes in an ontology and incorporation of those similarities in a k nearest neighbor classifier confirmed that our results compared favorably. Conclusions: This approach was applied to predict the cellular component and molecular function GO terms of all human proteins that have interacting partners possessing at least one known GO annotation. The list of predictions is available at http://severus.dbmi.pitt.edu/engo/GOPRED.html. We present the algorithm, evaluations and the results of the computational predictions, especially for genes identified in GWAS studies to be associated with diseases, which are of translational interest.