The Effects of Settlement Policy on Refugee Political Activism: Sudanese Refugees in Australia and the US

South Sudanese refugees are strongly motivated to effect change in South Sudan. After resettlement to the US, this motivation has resulted in much transnational political activism on their part. In Australia, Sudanese refugees have concentrated primarily on domestic political and social integration. Why? In this project I examine the possible causes of this difference, including the institutions, the policies, and the agents who implement settlement programs. I argue that refugee settlement policies of host countries directly shape the political activities of their refugees. When a host country provides assistance to integrate refugees, the government\u27s policies and the individuals who implement policy (professional service providers and volunteers) influence what activities refugee leaders are likely to pursue. I find evidence that professional service providers are more likely to channel refugees toward domestic political goals, especially when they are implementing specific refugee capacity building programs. In contrast, volunteers are more likely to support refugee leaders in the political activities that the leaders themselves are eager to pursue. Due to different levels of centralization and institutionalization across these two host country contexts, they have different compositions of policy implementers and utilize capacity building programs to differing degrees. These factors play a significant role in shaping the direction of South Sudanese political activities. I use evidence from examination of institutional policies and semi-structured interviews of Sudanese refugees, professional and volunteer service providers, and government officials in the USA and Australia

Systematics and population structure of Amblyomma maculatum group ticks and Rickettsia parkeri, an emerging human pathogen in southern Arizona, USA

The recent discovery of Amblyomma maculatum sensu lato (s. l.) ticks in southern Arizona has renewed discussions around species designations for members of the Amblyomma maculatum tick group. Amblyomma maculatum s. l. from Arizona appear to be morphologically intermediate between A. maculatum sensu stricto (s. s.) and A. triste s. s. At present there is no conclusive species designation for the ticks from Arizona. My research focused on analyzing the systematics of both A. maculatum s. l. and Rickettsia parkeri, a common bacterial pathogen transmitted by these ticks. In the laboratory, A. maculatum s. l. from Arizona and A. maculatum s. s. from Georgia readily mated on experimental animals to produce F1 hybrid ticks; there was no difference in fertility with these two populations when compared with homologous populations. However, the F1 hybrids produced during these experiments exhibited diminished fitness and did not produce a viable F2 generation. These results suggest that A. maculatum s. l. and A. maculatum s. s. represent separate biological species. Results of the crossbreeding experiment conflict with recent genetic analyses of A. maculatum s. l. and A. maculatum s. s. suggesting they are a single species. Thus, I developed and optimized 14 microsatellite loci that amplify both A. maculatum s. s. and A. maculatum s. l. These novel microsatellite markers can be used in future analyses of A. maculatum s. l. and A. maculatum s. s. to further test for conspecificity between the two. I also investigated the genetic relationships within geographically distinct R. parkeri strains through development and implementation of a multi-locus sequence typing analysis. I showed that while there is no consistent genetic delineation of strains isolated from A. maculatum s. l. versus A. maculatum s. s., there is a subset of R. parkeri strains from A. maculatum s. l. that appear to represent an intermediate genotype between the North and South American strains. While the biological causes for these results are not immediately clear, coevolution of R. parkeri and A. maculatum s. l. may account for the detection of the intermediate genotype only found in association with A. maculatum s. l

Multistate Survey of American Dog Ticks \u3ci\u3e(Dermacentor variabilis)\u3c/i\u3e for \u3ci\u3eRickettsia\u3c/i\u3e Species

Dermacentor variabilis, a common human-biting tick found throughout the eastern half and along the west coast of the United States, is a vector of multiple bacterial pathogens. Historically, D. variabilis has been considered a primary vector of Rickettsia rickettsii, the causative agent of Rocky Mountain spotted fever. A total of 883 adult D. variabilis, collected between 2012 and 2017 from various locations in 12 states across the United States, were screened for rickettsial DNA. Tick extracts were evaluated using three real-time PCR assays; an R. rickettsii-specific assay, a Rickettsia bellii-specific assay, and a Rickettsia genus-specific assay. Sequencing of ompA gene amplicons generated using a seminested PCR assay was used to determine the rickettsial species present in positive samples not already identified by species-specific real-time assays. A total of 87 (9.9%) tick extracts contained R. bellii DNA and 203 (23%) contained DNA of other rickettsial species, including 47 (5.3%) with Rickettsia montanensis, 11 (1.2%) with Rickettsia amblyommatis, 2 (0.2%) with Rickettsia rhipicephali, and 3 (0.3%) with Rickettsia parkeri. Only 1 (0.1%) tick extract contained DNA of R. rickettsii. These data support multiple other contemporary studies that indicate infrequent detection of R. rickettsii in D. variabilis in North America

A mutation in the viral sensor 2'-5'-oligoadenylate synthetase 2 causes failure of lactation.

We identified a non-synonymous mutation in Oas2 (I405N), a sensor of viral double-stranded RNA, from an ENU-mutagenesis screen designed to discover new genes involved in mammary development. The mutation caused post-partum failure of lactation in healthy mice with otherwise normally developed mammary glands, characterized by greatly reduced milk protein synthesis coupled with epithelial cell death, inhibition of proliferation and a robust interferon response. Expression of mutant but not wild type Oas2 in cultured HC-11 or T47D mammary cells recapitulated the phenotypic and transcriptional effects observed in the mouse. The mutation activates the OAS2 pathway, demonstrated by a 34-fold increase in RNase L activity, and its effects were dependent on expression of RNase L and IRF7, proximal and distal pathway members. This is the first report of a viral recognition pathway regulating lactation

ELF5 Drives Lung Metastasis in Luminal Breast Cancer through Recruitment of Gr1+ CD11b+ Myeloid-Derived Suppressor Cells.

During pregnancy, the ETS transcription factor ELF5 establishes the milk-secreting alveolar cell lineage by driving a cell fate decision of the mammary luminal progenitor cell. In breast cancer, ELF5 is a key transcriptional determinant of tumor subtype and has been implicated in the development of insensitivity to anti-estrogen therapy. In the mouse mammary tumor virus-Polyoma Middle T (MMTV-PyMT) model of luminal breast cancer, induction of ELF5 levels increased leukocyte infiltration, angiogenesis, and blood vessel permeability in primary tumors and greatly increased the size and number of lung metastasis. Myeloid-derived suppressor cells, a group of immature neutrophils recently identified as mediators of vasculogenesis and metastasis, were recruited to the tumor in response to ELF5. Depletion of these cells using specific Ly6G antibodies prevented ELF5 from driving vasculogenesis and metastasis. Expression signatures in luminal A breast cancers indicated that increased myeloid cell invasion and inflammation were correlated with ELF5 expression, and increased ELF5 immunohistochemical staining predicted much shorter metastasis-free and overall survival of luminal A patients, defining a group who experienced unexpectedly early disease progression. Thus, in the MMTV-PyMT mouse mammary model, increased ELF5 levels drive metastasis by co-opting the innate immune system. As ELF5 has been previously implicated in the development of antiestrogen resistance, this finding implicates ELF5 as a defining factor in the acquisition of the key aspects of the lethal phenotype in luminal A breast cancer

ELF5 suppresses estrogen sensitivity and underpins the acquisition of antiestrogen resistance in luminal breast cancer.

We have previously shown that during pregnancy the E-twenty-six (ETS) transcription factor ELF5 directs the differentiation of mammary progenitor cells toward the estrogen receptor (ER)-negative and milk producing cell lineage, raising the possibility that ELF5 may suppress the estrogen sensitivity of breast cancers. To test this we constructed inducible models of ELF5 expression in ER positive luminal breast cancer cells and interrogated them using transcript profiling and chromatin immunoprecipitation of DNA followed by DNA sequencing (ChIP-Seq). ELF5 suppressed ER and FOXA1 expression and broadly suppressed ER-driven patterns of gene expression including sets of genes distinguishing the luminal molecular subtype. Direct transcriptional targets of ELF5, which included FOXA1, EGFR, and MYC, accurately classified a large cohort of breast cancers into their intrinsic molecular subtypes, predicted ER status with high precision, and defined groups with differential prognosis. Knockdown of ELF5 in basal breast cancer cell lines suppressed basal patterns of gene expression and produced a shift in molecular subtype toward the claudin-low and normal-like groups. Luminal breast cancer cells that acquired resistance to the antiestrogen Tamoxifen showed greatly elevated levels of ELF5 and its transcriptional signature, and became dependent on ELF5 for proliferation, compared to the parental cells. Thus ELF5 provides a key transcriptional determinant of breast cancer molecular subtype by suppression of estrogen sensitivity in luminal breast cancer cells and promotion of basal characteristics in basal breast cancer cells, an action that may be utilised to acquire antiestrogen resistance

A mutation in the viral sensor 2’-5’-oligoadenylate synthetase 2 causes failure of lactation

We identified a non-synonymous mutation in Oas2 (I405N), a sensor of viral double-stranded RNA, from an ENU-mutagenesis screen designed to discover new genes involved in mammary development. The mutation caused post-partum failure of lactation in healthy mice with otherwise normally developed mammary glands, characterized by greatly reduced milk protein synthesis coupled with epithelial cell death, inhibition of proliferation and a robust interferon response. Expression of mutant but not wild type Oas2 in cultured HC-11 or T47D mammary cells recapitulated the phenotypic and transcriptional effects observed in the mouse. The mutation activates the OAS2 pathway, demonstrated by a 34-fold increase in RNase L activity, and its effects were dependent on expression of RNase L and IRF7, proximal and distal pathway members. This is the first report of a viral recognition pathway regulating lactation.Samantha R. Oakes, David Gallego-Ortega, Prudence M. Stanford, Simon Junankar, Wendy Wing Yee Au ... Moira K. O’Bryan ... et al

ELF5 suppresses estrogen sensitivity and underpins the acquisition of antiestrogen resistance in luminal breast cancer

We have previously shown that during pregnancy the E-twenty-six (ETS) transcription factor ELF5 directs the differentiation of mammary progenitor cells toward the estrogen receptor (ER)-negative and milk producing cell lineage, raising the possibility that ELF5 may suppress the estrogen sensitivity of breast cancers. To test this we constructed inducible models of ELF5 expression in ER positive luminal breast cancer cells and interrogated them using transcript profiling and chromatin immunoprecipitation of DNA followed by DNA sequencing (ChIP-Seq). ELF5 suppressed ER and FOXA1 expression and broadly suppressed ER-driven patterns of gene expression including sets of genes distinguishing the luminal molecular subtype. Direct transcriptional targets of ELF5, which included FOXA1, EGFR, and MYC, accurately classified a large cohort of breast cancers into their intrinsic molecular subtypes, predicted ER status with high precision, and defined groups with differential prognosis. Knockdown of ELF5 in basal breast cancer cell lines suppressed basal patterns of gene expression and produced a shift in molecular subtype toward the claudin-low and normal-like groups. Luminal breast cancer cells that acquired resistance to the antiestrogen Tamoxifen showed greatly elevated levels of ELF5 and its transcriptional signature, and became dependent on ELF5 for proliferation, compared to the parental cells. Thus ELF5 provides a key transcriptional determinant of breast cancer molecular subtype by suppression of estrogen sensitivity in luminal breast cancer cells and promotion of basal characteristics in basal breast cancer cells, an action that may be utilised to acquire antiestrogen resistance