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SMYD3 (SET and MYND domain-containing protein 3) is a protein lysine methyltransferase that was initially described as an H3K4 methyltransferase involved in transcriptional regulation. SMYD3 has been reported to methylate and regulate several nonhistone proteins relevant to cancer, including mitogen-activated protein kinase kinase kinase 2 (MAP3K2), vascular endothelial growth factor receptor 1 (VEGFR1), and the human epidermal growth factor receptor 2 (HER2). In addition, overexpression of SMYD3 has been linked to poor prognosis in certain cancers, suggesting SMYD3 as a potential oncogene and attractive cancer drug target. Here we report the discovery of a novel SMYD3 inhibitor. We performed a thermal shift assay (TSA)-based high-throughput screening (HTS) with 410,000 compounds and identified a novel benzodiazepine-based SMYD3 inhibitor series. Crystal structures revealed that this series binds to the substrate binding site and occupies the hydrophobic lysine binding pocket via an unprecedented hydrogen bonding pattern. Biochemical assays showed substrate competitive behavior. Following optimization and extensive biophysical validation with surface plasmon resonance (SPR) analysis and isothermal titration calorimetry (ITC), we identified BAY-6035, which shows nanomolar potency and selectivity against kinases and other PKMTs. Furthermore, BAY-6035 specifically inhibits methylation of MAP3K2 by SMYD3 in a cellular mechanistic assay with an IC50

Objective: The key objective of this research is to investigate the aroma profle of Kaffir lime (Citrus hystrix) leaves grown under greenhouse and peatlite soilless substrate conditions using the electronic nose system. Methodology: Fresh Citrus hystrix samples of recently matured (RML) and old (OL) leaves were analyzed using electronic nose. A total of 79 volatiles were identified and those equivalent to 90% were reported. Results: The RML and OL leaves had similar volatiles such as Citronellal, N-Nonanal, Myrcene, Pentyl Octanoate and γ-Terpinene with no significant difference in the concentration. Citronellal was the major volatile found more than 20% in both recently matured and old leaves. Recently matured and old leaves also had dissimilar volatiles such as 5-Propyldihydro-2(3H)-Furanone(32.9%), β-Pinene (7.6%), Terpinen-4-ol (2.4%), 1-Hexanol (1.3%) and (Z)-3-Hexen-1-ol-Acetate (1.0%) were only found in the recently matured leaves, whereas 1-Nonanol (30.8%), 3-Methyl Butanoic Acid(4.6%), p-Methyl Acetophenone (1.5%), Trans-Hex-2-Enyl Acetate (1.4%) and Methyl Eugenol (1.1%) were detected only in OL. Conclusion: The results are very useful in food and cosmetics industries to develop innovative products based on kaffirlime leaves/oil.

Here, we report the fragment-based discovery of BI-9321, a potent, selective and cellular active antagonist of the NSD3-PWWP1 domain. The human NSD3 protein is encoded by the WHSC1L1 gene located in the 8p11-p12 amplicon, frequently amplified in breast and squamous lung cancer. Recently, it was demonstrated that the PWWP1 domain of NSD3 is required for the viability of acute myeloid leukemia cells. To further elucidate the relevance of NSD3 in cancer biology, we developed a chemical probe, BI-9321, targeting the methyl-lysine binding site of the PWWP1 domain with sub-micromolar in vitro activity and cellular target engagement at 1 µM. As a single agent, BI-9321 downregulates Myc messenger RNA expression and reduces proliferation in MOLM-13 cells. This first-in-class chemical probe BI-9321, together with the negative control BI-9466, will greatly facilitate the elucidation of the underexplored biological function of PWWP domains. A chemical probe BI-9321 for the PWWP1 domain of NSD3 and its inactive analog were identified. BI-9321 binds to the methyl-lysine binding site, reduces the association of NSD3 with chromatin and inhibits proliferation of acute myeloid leukemia cells.

BCDIN3D is an RNA-methyltransferase that O-methylates the 5' phosphate of RNA and regulates microRNA maturation. To discover small-molecule inhibitors of BCDIN3D, a suite of biochemical assays was developed. A radiometric methyltransferase assay and fluorescence polarization-based S-adenosylmethionine and RNA displacement assays are described. In addition, differential scanning fluorimetry and surface plasmon resonance were used to characterize binding. These assays provide a comprehensive package for the development of small-molecule modulators of BCDIN3D activity.

SET domain bifurcated protein 1 (SETDB1) is a human histone-lysine methyltransferase, which is amplified in human cancers and was shown to be crucial in the growth of non-small and small cell lung carcinoma. In addition to its catalytic domain, SETDB1 harbors a unique tandem tudor domain which recognizes histone sequences containing both methylated and acetylated lysines, and likely contributes to its localization on chromatin. Using X-ray crystallography and NMR spectroscopy fragment screening approaches, we have identified the first small molecule fragment hits that bind to histone peptide binding groove of the TTD of SETDB1. Herein, we describe the binding modes of these fragments and analogues and the biophysical characterization of key compounds. These confirmed small molecule fragments will inform the development of potent antagonists of SETDB1 interaction with histones.

N(6)-methyladenosine (m(6)A) is the most common reversible internal modification in mammalian RNA. Changes in m(6)A levels have been implicated in a variety of cellular processes, including nuclear RNA export, control of protein translation, and protein splicing, and they have been linked to obesity, cancer, and other human diseases. METTL3 and METTL14 are N(6)-adenosine methyltransferases that work more efficiently in a stable METTL3-METTL14 heterodimer complex (METTL3-14). ALKBH5 is an m(6)A-RNA demethylase that belongs to the AlkB family of dioxygenases. We report the development of radioactivity-based assays for kinetic characterization of m(6)A-RNA modifications by METTL3-14 complex and ALKBH5 and provide optimal assay conditions suitable for screening for ligands in a 384-well format with Z' factors of 0.78 and 0.77, respectively.

Here we present a virtual docking screen of 1648 commercially available covalent fragments, and identified covalent inhibitors of cysteine protease cathepsin L. These inhibitors did not inhibit closely related protease cathepsin B. Thus, we have established virtual docking of covalent fragments as an approach to discover covalent enzyme inhibitors.

[Image: see text] Protein arginine methyltransferase 5 (PRMT5) is a type II arginine methyltransferase that catalyzes the formation of symmetric dimethylarginine in a number of nuclear and cytoplasmic proteins. Although the cellular functions of PRMT5 have not been fully unraveled, it has been implicated in a number of cellular processes like RNA processing, signal transduction, and transcriptional regulation. PRMT5 is ubiquitously expressed in most tissues and its expression has been shown to be elevated in several cancers including breast cancer, gastric cancer, glioblastoma, and lymphoma. Here, we describe the identification and characterization of a novel and selective PRMT5 inhibitor with potent in vitro and in vivo activity. Compound 1 (also called LLY-283) inhibited PRMT5 enzymatic activity in vitro and in cells with IC(50) of 22 ± 3 and 25 ± 1 nM, respectively, while its diastereomer, compound 2 (also called LLY-284), was much less active. Compound 1 also showed antitumor activity in mouse xenografts when dosed orally and can serve as an excellent probe molecule for understanding the biological function of PRMT5 in normal and cancer cells.

The protein arginine methyltransferases PRMT7 and PRMT5, respectively, monomethylate and symmetrically dimethylate arginine side-chains of proteins involved in diverse cellular mechanisms, including chromatin-mediated control of gene transcription, splicing, and the RAS to ERK transduction cascade. It is believed that PRMT5 and PRMT7 act in conjunction to methylate their substrates, and genetic deletions support the notion that these enzymes derepress cell proliferation and migration in cancer. Using available structures of PRMT5, we designed DS-437, a PRMT5 inhibitor with an IC50 value of 6 μM against both PRMT5 and PRMT7 that is inactive against 29 other human protein-, DNA-, and RNA-methyltransferases and inhibits symmetrical dimethylation of PRMT5 substrates in cells. This compound behaves as a cofactor competitor and represents a valid scaffold to interrogate the potential of the PRMT5-PRMT7 axis as a target for therapy.

PRMT3 catalyzes the asymmetric dimethylation of arginine residues of various proteins. It is essential for maturation of ribosomes, may have a role in lipogenesis, and is implicated in several diseases. A potent, selective, and cell- active PRMT3 inhibitor would be a valuable tool for further investigating PRMT3 biology. Here we report the discovery of the first PRMT3 chemical probe, SGC707, by structure-based optimization of the allosteric PRMT3 inhibitors we reported previously, and thorough characterization of this probe in biochemical, biophysical, and cellular assays. SGC707 is a potent PRMT3 inhibitor (IC50 = 31 ± 2 nm, KD = 53 ± 2 nm) with outstanding selectivity (selective against 31 other methyltransferases and more than 250 non-epigenetic targets). The mechanism of action studies and crystal structure of the PRMT3-SGC707 complex confirm the allosteric inhibition mode. Importantly, SGC707 engages PRMT3 and potently inhibits its methyltransferase activity in cells. It is also bioavailable and suitable for animal studies. This well- characterized chemical probe is an excellent tool to further study the role of PRMT3 in health and disease.

SET domain containing (lysine methyltransferase) 7 (SETD7) is implicated in multiple signaling and disease related pathways with a broad diversity of reported substrates. Here, we report the discovery of (R)-PFI-2-a first-in-class, potent (Ki (app) = 0.33 nM), selective, and cell-active inhibitor of the methyltransferase activity of human SETD7-and its 500-fold less active enantiomer, (S)-PFI-2. (R)-PFI-2 exhibits an unusual cofactor-dependent and substrate-competitive inhibitory mechanism by occupying the substrate peptide binding groove of SETD7, including the catalytic lysine-binding channel, and by making direct contact with the donor methyl group of the cofactor, S-adenosylmethionine. Chemoproteomics experiments using a biotinylated derivative of (R)-PFI-2 demonstrated dose-dependent competition for binding to endogenous SETD7 in MCF7 cells pretreated with (R)-PFI-2. In murine embryonic fibroblasts, (R)-PFI-2 treatment phenocopied the effects of Setd7 deficiency on Hippo pathway signaling, via modulation of the transcriptional coactivator Yes-associated protein (YAP) and regulation of YAP target genes. In confluent MCF7 cells, (R)-PFI-2 rapidly altered YAP localization, suggesting continuous and dynamic regulation of YAP by the methyltransferase activity of SETD7. These data establish (R)-PFI-2 and related compounds as a valuable tool-kit for the study of the diverse roles of SETD7 in cells and further validate protein methyltransferases as a druggable target class.

Lysine acetyltransferases (KATs) are key mediators of cell signaling. Methods capable of providing new insights into their regulation thus constitute an important goal. Here we report an optimized platform for profiling KAT-ligand interactions in complex proteomes using inhibitor-functionalized capture resins. This approach greatly expands the scope of KATs, KAT complexes, and CoA-dependent enzymes accessible to chemoproteomic methods. This enhanced profiling platform is then applied in the most comprehensive analysis to date of KAT inhibition by the feedback metabolite CoA. Our studies reveal that members of the KAT superfamily possess a spectrum of sensitivity to CoA, and highlight NAT10 as a novel KAT that may be susceptible to metabolic feedback inhibition. This platform provides a powerful tool to define the potency and selectivity of reversible stimuli, such as small molecules and metabolites, that regulate KAT-dependent signaling.

Sequential and simultaneous bilateral cochlear implants are emerging as appropriate treatment options for Australian adults with sensory deficits in both cochleae. Current funding of Australian public hospitals does not provide for simultaneous bilateral cochlear implantation (CI) as a separate surgical procedure. Previous cost-effectiveness studies of sequential and simultaneous bilateral CI assumed 100% of unilaterally treated patients' transition to a sequential bilateral CI. This assumption does not place cochlear implantation in the context of the generally treated population. When mutually exclusive treatment options exist, such as unilateral CI, sequential bilateral CI, and simultaneous bilateral CI, the mean costs of the treated populations are weighted in the calculation of incremental cost-utility ratios. The objective was to evaluate the cost-utility of bilateral hearing aids (HAs) compared with unilateral, sequential, and simultaneous bilateral CI in Australian adults with bilateral severe to profound sensorineural hearing loss.Cost-utility analysis of secondary sources input to a Markov model.Australian health care perspective, lifetime horizon with costs and outcomes discounted 5% annually.Bilateral HAs as treatment for bilateral severe to profound sensorineural hearing loss compared with unilateral, sequential, and simultaneous bilateral CI.Incremental costs per quality adjusted life year (AUD/QALY).When compared with bilateral hearing aids the incremental cost-utility ratio for the CI treatment population was AUD11,160/QALY. The incremental cost-utility ratio was weighted according to the number of patients treated unilaterally, sequentially, and simultaneously, as these were mutually exclusive treatment options.No peer-reviewed articles have reported the incremental analysis of cochlear implantation in a continuum of care for surgically treated populations with bilateral severe to profound sensorineural hearing loss. Unilateral, sequential, and simultaneous bilateral CI were cost-effective when compared with bilateral hearing aids. Technologies that reduce the total number of visits for a patient could introduce additional cost efficiencies into clinical practice.

SMYD3 (SET and MYND domain-containing protein 3) is a protein lysine methyltransferase (PKMT) which was initially described as H3K4 methyltransferase involved in transcriptional regulation. SMYD3 has recently been reported to methylate and regulate several non-histone cancer relevant proteins such as mitogen-activated protein kinase kinase kinase 2 (MAP3K2), vascular endothelial growth factor receptor 1 (VEGFR1), and the human epidermal growth factor receptor 2 (HER2). In addition overexpression of SMYD3 has been linked to poor prognosis in certain cancers, thus supporting a possible oncogenic role for SMYD3 and making it an attractive target for anticancer drug development. Here we report the discovery of a novel potent and selective SMYD3 inhibitor series. We performed a thermal shift assay based (TSA) high throughput screening followed by extensive biophysical validation resulting in identification of a benzodiazepine-based SMYD3 inhibitor series. The co-crystallization structures revealed that this series binds to the substrate binding site and occupies the hydrophobic pocket for lysine binding using an unprecedented hydrogen bond pattern. The competitive behavior of the inhibitor in biochemical assays was consistent with the binding mode observed in the crystal structure. Further optimization generated BAY-6035, which showed improved nanomolar potency and was selective against kinases and other PKMTs. Furthermore, BAY-6035 specifically inhibited methylation of MAP3K2 by SMYD3 in a cellular assay with similar potency. In summary, BAY-6035 is a novel selective and potent SMYD3 inhibitor probe and will foster the exploration of the biologic role of SMYD3 in diseased and non-diseased tissues. Citation Format: Stefan Gradl, Holger Steuber, Jörg Weiske, Norbert Schmees, Stephan Siegel, Detlef Stoeckigt, Clara D. Christ, Fengling Li, Shawna Organ, Dalia Barsyte-Lovejoy, Magdalena M. Szewczyk, Steven Kennedy, Viacheslav Trush, Masoud Vedadi, Cheryl H. Arrowsmith, Peter J. Brown, Manfred Husemann, Amaury E. Fernandez-Montalvan, Volker Badock, Marcus Bauser, Andrea Haegebarth, Ingo V. Hartung, Carlo Stresemann. Discovery and characterization of BAY-6035, a novel benzodiazepine-based SMYD3 inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1646.

This paper compares the health of Australian immigrants with that of the Australian-born population and examines the extent to which differences vary with time since migration. Health is measured using self-reports of chronic diseases from three national health surveys. Probit models are used to estimate the health effects of immigrant arrival cohorts, years since migration and country of birth. We find that the health of Australian immigrants is better than the Australian-born population, but the longer immigrants spend in Australia, the closer their health approximates that of the Australian-born population. There are variations for different immigrant groups and for particular chronic diseases.

A lack of useful small molecule tools has precluded thorough interrogation of the biological function of SMYD2, a lysine methyltransferase with known tumor-suppressor substrates. Systematic exploration of the structure–activity relationships of a previously known benzoxazinone compound led to the synthesis of A-893, a potent and selective SMYD2 inhibitor (IC50: 2.8 nM). A cocrystal structure reveals the origin of enhanced potency, and effective suppression of p53K370 methylation is observed in a lung carcinoma (A549) cell line.

In this paper we examine how the stresses associated with the transition to a new country combined with additional stress arising from a period of unemployment affect the mental health of immigrants. Australian immigrants are found to have poorer mental health at 6 months after arrival in Australia compared with 18 and 42 months. Furthermore, unemployment, and especially a long duration of unemployment, is found to be associated with poor mental health. We found that although immigrant women appear unaffected by their spouses’ labour force status, there is evidence that immigrant men's mental health is affected by spouse labour force status.

Equivalence scales attempt to control for family size and composition, as well as the relative costs of maintaining various family types. The 1995 National Health Survey is used to examine how variations in the assumptions underlying equivalence scales, such as household composition and economies of size, affect poverty measures for Indigenous and non-Indigenous Australians. The main finding is that the assumptions about the costs of children can increase Indigenous poverty by a factor of two- and-a-half. Another finding is that the choice of equivalence scales can induce large threshold effects that influence the composition of poverty.

Indigenous families experience substantial and multiple forms of economic burden arising from the size and structure of their families and households. Indigenous households are more likely to have more than one family in residence than other Australian households and are more likely to be multigenerational with older Indigenous people living with younger people in extended family households. This paper seeks to characterise the economies of household size in Indigenous and other Australian households using equivalence scales that cover the range of feasible values and 1995 National Health Survey data.

This paper examines the wage curve in Australia. Regressions for weekly earnings are estimated on a pooled cross-section data set for 1982 to 1994/95. Using the preferred regression specification it is found that the elasticity of weekly earnings with respect to state-level rates of unemployment is -0.07 to -0.09. These findings are robust to a variety of modifications to the regression specification. A comparison of Australia, the US and UK is undertaken to examine how differences in wage-setting institutions between those countries might affect wage curve estimates.

This chapter discusses the role of cell cycle machinery in initiation and progression of pancreatic cancer. Normal pancreatic cells—their types, organization, and functions—are first described to characterize the environment in which cellular transformation and tumor expansion occurs. The epidemiology and histology of pancreatic cancer is then briefly presented to emphasize the urgent need for earlier diagnosis and more effective treatments. Current efforts towards this goal are focused on understanding the disease at the molecular level, so the hallmarks of cancerous cells are discussed with respect to the progression model of pancreatic cancer development. Because the pancreas is composed of various cell types with different genetic backgrounds and regulatory systems, identifying the cell in which cancer originates is of utmost importance. Molecular mechanisms of normal proliferative control are then presented so that mechanisms by which they are disrupted can be appreciated. Particular attention is paid to how signaling transduction pathways and the cell cycle machinery cooperate to make cell fate decisions at the Restriction point. This analysis sets the stage for evaluating the role of cell cycle control mechanisms in transformation of the initiating cell in pancreatic cancer. The chapter concludes by arguing that genetic alterations associated with pancreatic cancer indicate disrupted cell cycle control mechanisms play a central role in disease development and progression.

The existence of a healthy immigrant effect – where immigrants are on average healthier than the native-born – is now a well accepted phenomenon. There are many competing explanations for this phenomenon including health screening by recipient countries, healthy behaviour prior to migration followed by the steady adoption of new country (less) healthy behaviours, and immigrant self-selection where healthier and wealthier people tend to be migrants. We explore the last two of these explanations for the healthy immigrant effect by examining the health outcomes, health behaviours, and socio-economic characteristics of immigrants from a range of source countries in the US, Canada, UK and Australia. We find evidence of strong positive selection effects for immigrants from all regions of origin in terms of education. However, we also find evidence that self-selection in terms of unobservable factors is an important determinant of the better health of recent immigrants.

Interest in pandemics has increased dramatically in recent times with the emergence of Avian Influenza and conditions conducive to a global flu outbreak. While understandably most of the focus is on public health policies that might prevent or ameliorate the effects of a pandemic, there is often reference to the possible economic effects. This paper discusses the pathways through which a pandemic might affect the Australian economy. The Treasury macro-econometric model (TRYM) is used to illustrate these pathways. The paper finds that confidence effects and the (large) short term withdrawal of labour are probably the dominant mechanisms through which a pandemic adversely affects the economy. The macroeconomic policy implications flow naturally from these potential economic effects. In particular, policies that restore confidence and consumption, support business in the short term, and promote a quick return to work are likely to be most effective in offsetting the adverse economic consequences of a pandemic.

Over the past five years, the labour force participation rate of older Australian men has risen after declining for over 25 years. In combination with ongoing increases in older women’s participation, the participation rate of older persons is now at its highest level on record. We describe some of the trends in older persons’ participation with a focus on older men and discuss some possible reasons why older men’s participation has reversed its long decline. We find that improved labour market conditions for older workers is the most likely explanation for the recent increase in participation but that the increase is supported by long-lived improvements in health and education.

Introduction: Canada's annual immigrant intake is increasingly composed of visible minorities, with 59% of immigrants arriving in 1996-01 coming from Asia. However, only a small number of studies have used population health surveys to examine Canadian women's use of cancer screening. We use recent population health surveys to analyze immigrant and native-born women's use of Pap smears, breast exams, breast self-exams, and mammograms. Methods: We study women aged 21-65 drawn from the National Population Health Survey and Canadian Community Health Surveys that together yield a sample size of 105,000 observations. Results: We find that for most forms of cancer screening, recent immigrants have markedly lower utilization rates, but these rates slowly increase with years in Canada. However, there is wide variation in rates of cancer screening by ethnicity. Screening rates for white immigrants approach Canadian-born women's utilization rates after 15-20 years in Canada, but screening rates for immigrants from Asia remain significantly below native-born Canadian levels. Discussion: Health authorities need to tailor their message about the importance of these forms of cancer screening to reflect the perceptions and beliefs of particular minority groups if the objective of universal use of preventative cancer screening is to be achieved.

This note examines trends in labour force participation for people with different levels of educational attainment. The note offers insights into the labour market behaviour of people with different skill attributes and discusses the possible implications of a more highly educated workforce. Using census data, we find that while the labour force participation rates of prime age males have fallen for all educational attainment groups between 1981 and 2001, the fall for those males with no post-school qualifications was particularly dramatic. In contrast, female participation rose for all educational attainment categories and for most age groups, though at a slower rate in the 1990s than in the 1980s.

It is well accepted that education is positively related to health. However, there is considerably less agreement as to the explanation of this relationship. I examine the strength of the empirical relationship between education and health for Australia and Canada. I find that education is indeed related to health and to a very similar extent in both countries. I discuss three important explanations of the education and health relationship: technical efficiency, allocative efficiency and time preference explanations. Empirical analysis is presented which attempts to distinguish between the alternative explanations. I find evidence for all three explanations.

The objective of this research is to assess whether stress associated with the transition to a new country combined with additional stress arising from unemployment affects the mental health of immigrants. I use the Longitudinal Survey of Immigrants to Australia (LSIA) to examine the effect of labour force status on the mental health of immigrants. By using a rich longitudinal data set, I am able to control for individual immigrant differences whilst examining whether changes in mental health cause changes in labour force status rather than changes in labour force status causing changes in mental health. I find that causality runs from unemployment to mental health and that unemployment significantly adversely affects the mental health of immigrants. Other characteristics associated with poor mental health include; age, gender, visa category, marital status and educational attainment.

This article examines trends in labour force participation for people with different levels of educational attainment. The article offers insights into the labour market behaviour of people with different skill attributes and discusses the possible implications of a more highly educated workforce.

A number of anionic adducts of H2Os3(CO)10 have been prepared. Potassium hydride reacts with H2Os3(CO)10 in a 1 : 1 molar ratio in THF to yield K[H3Os3(CO)10]. When a 2 : 1 molar ratio of KH to H2Os3(CO)10 is employed, one mole of H2 is given off and K2[H2Os3(CO)10] is formed. Effectively two electrons have added to H2Os3(CO)10. In the presence of an electron carrier, (C6H5)2CO, potassium reacts with H2Os3(CO)10 to give K2[H2Os3(CO)10] which is spectroscopically identical to K2[H2Os3(CO)10] obtained from the reaction of 2 KH with 1 H2Os3(CO)10. Halide ions as [(C6H5)3P]2N+ salts readily add to H2Os3(CO)10, forming [H2Os3(CO)10X]−, where X− = Cl−, Br−, and I−. Metallocarbonylates react with H2Os3(CO)10 in a analogous to the reaction of halide ions with this cluster. The following mixed metal ions habe been prepared: [H2Os3(CO)10Mn(CO)5]−, [H2Os3(CO)10Fe(CO)4]2−, [H2Os3(CO)10Mo(η5-C5H5(CO) 3]−, [H2Os3(CO)10V(η5-C5H5)(CO)3]2−, and [H2Os3(CO)10Fe(η-C5H5)(CO)2]−.

This book examines the role of immigration policy, and of economic and social policies involved in promoting the settlement of immigrants to Australia. It is based on research of two groups of recent immigrants who arrived six years apart during the 1990s holding a range of family reunion, skill and humanitarian visas.

Despite a rich literature on the political and constitutional development of the Canadian territorial North, few scholars have examined the post-devolution environment in Yukon. This lacuna is surprising since devolution is frequently cited as being crucial to the well-being of Northerners, leading both the Government of Nunavut and the Government of the Northwest Territories to lobby the federal government to devolve lands and resources to them. This paper provides an updated historical account of devolution in Yukon and assesses its impact on the territory since 2003. Relying mainly on written sources and 16 interviews with Aboriginal, government, and industry officials in the territory, it highlights some broad effects of devolution and specifically analyzes the processes of obtaining permits for land use and mining. Our findings suggest that devolution has generally had a positive effect on the territory, and in particular has led to more efficient and responsive land use and mining permit processes.