Journal articles on the topic 'Autonomous Fire Suppression'

<span lang="EN-US">Robots is one of the most important devices in the world that work automatically without human intervention. Robot can work for long hours without feeling tired and can be performed work that can be dangerous to human life. Autonomous robots are used today in many areas in our daily lives, for example, industry, Agriculture, Health, Education, scientific explorations and many other fields. Therefore in this research we will going to design autonomous robot that able to find and extinguish fires. In some cases, the dense flames very dangerous to humans live and therefore require intervention of robot. Fire tracking and suppression robot is a robot can automatically find and fighting fire. In this project a camera and flame sensor based on an rotary base was used. It can detect fire in an angle of rotation of 1600. ATmega328 microcontroller based on Arduino Uno board have been used, to control the robot to do the right work without mistakes, ATmega328 based on Arduini Uno board have been used, and it can be programmed using C language by using arduino IDE.</span>

Traditional uses of the forest (timber, forage) have been giving way to other uses more in demand (recreation, ecosystem services). An observable consequence of this process of forest land use conversion is an increase in more difficult and extreme wildfires. Wildland forest management and protection program budgets are limited, and managers are requesting help in finding ways to objectively assign their limited protection resources based on the intrinsic environmental characteristics of a site and the site’s interrelationship with available firefighting resources and existing infrastructure. A Fire Suppression Priority Index, integrating information on both the potential fire behaviour risk (Potential Fire Behaviour Index) and the fire suppression difficulty (Suppression Difficulty Index), provides managers with fundamental information for strategic planning and development of tactical operations to protect the natural environment. Results in the Córdoba Province, Andalusia’s autonomous region, Spain, showed a statistically significant relationship between wildfire size and all three indices, demonstrating the utility of the methodology to identify and prioritise forest areas for strategic and tactical fire management operations. In addition, the methodology was tested and validated by trained and qualified wildfire management personnel in Chile and Israel, obtaining similar results as in Spain.

Abstract Background: Jod-Basedow phenomenon is a rare cause of thyrotoxicosis due to excess iodine intake. Herbal supplements containing sea-moss have high iodine amount which may precipitate thyrotoxicosis in patients with underlying Grave’s disease or autonomous thyroid nodules. Clinical Case: A seemingly healthy 28-year-old female presented to the ED with chief complaint of fatigue with associated anxiety, palpitations and weight loss. On admission her temperature was 100.4 F, pulse 126 bpm and blood pressure 116/56 mmHg. Exam was unremarkable for thyroid goiter or orbitopathy. Labs revealed WBC count 3.4 x103/µL (ref range 4.0-11.0) with neutropenia, hemoglobin 4.3 g/dL (11.7-15.7), platelet 49 x103/µL (150-450). Liver transaminases (AST, ALT, and alkaline phosphatase) were elevated with levels up to 4 times the upper limit of normal. She was diagnosed with hemolytic anemia secondary to severe Vitamin B12 deficiency due to pernicious anemia. TSH was &lt;0.01 mIU/L (0.27-4.20), free T4 2.46 ng/dL (0.8-1.9) and total T3 139 ng/dL (76-181). The patient subsequently endorsed remote history of hyperthyroidism diagnosed 7 years ago however she could not recall the underlying etiology or the name of medication she was treated with. She reportedly stopped this medication after 1 month due to developing goiter. She also endorsed intermittent use of store-bought supplement of Irish sea moss and bladderwrack in last 2 years. Further workup revealed elevated TSI and TBII antibody titers establishing diagnosis of Grave’s disease. Thyroid ultrasound showed normal sized heterogeneous hypervascular gland with no nodules. I-123 thyroid uptake and scan showed diffuse moderately elevated radioiodine uptake of 16.8% and 40.8% at 4 and 24 hours, respectively. Thionamide therapy was withheld due to concern of neutropenia and transaminitis. She was treated with beta-blocker after which her vital signs normalized. Labs 1 week after stopping sea moss showed TSH 0.01 mIU/L and free T4 1.4 ng/dL. Conclusion: Irish sea moss is a readily available herbal supplement with high, variable amounts of iodine. Despite little scientific evidence, it is often marketed to improve goiter amongst other health benefits. The recommended daily iodine intake per the FDA is 150 mcg. Higher amounts are expected to initially cause a short-lived suppression of thyroid function; the Wolff-Chaikoff effect, followed by “escape” and accelerated production of thyroid hormone in abnormal thyroid gland, known as Jod-Basedow phenomenon. In our case, the patient unknowingly worsened her underlying Grave’s disease due to the Jod-Basedow effect. Of note, apparantly she had a longer than expected course of Wolff-Chaikoff effect preceding the thyrotoxic state due to sporadic irregular intake of sea moss. Discontinuing sea moss led to clinical and biochemical improvement of hyperthyroidism without requiring thionamide therapy.

На основе актов и книг учета лесных пожаров, а также статистической отчетности проанализированы показатели фактической горимости лесов за 2016–2020 гг. Установлено, что за 2020 г. на территории Уральского федерального округа зафиксировано 2182 лесных пожара. При этом пройденная огнем площадь составила 167,2 тыс. га. Указанные показатели несколько превышают значения количества и пройденной огнем площади по округу за последние 5 лет: 1961 случай и 124,6 тыс. га соответственно. Наибольшее количество лесных пожаров зафиксировано в 2020 г. в челябинской области – 587 случаев, а наименьшее – в Ямало-Ненецком автономном округе – 111 случаев. При этом максимальной пройден- ной огнем лесных пожаров площадью в 2020 г. характеризуется Ханты-Мансийский автономный округ – Югра – 144,7 тыс. га. Минимальная пройденная огнем площадь зафиксирована в Тюменской области – 1,6 тыс. га. Площадь среднего пожара за 2020 г. по округу составила 76,64 га, при этом в Ханты-Мансийском авто- номном округе – Югре она равнялась 308,0 га, а в Тюменской области – 6,98 га. Экономический ущерб от лесных пожаров составил по округу 4 109 793, 16 тыс. руб., при этом на тушение было затрачено 575 481,57 тыс. руб. Значительный размер ущерба от лесных пожаров, а также экологический ущерб вызывают необходи- мость дальнейшего совершенствования охраны лесов. On the bases and books of forest fire accounting, as well as statistical reporting the indicators of actual forest fire rates for 2016–2020 were and lyzed. It was established that in 2020 2182 forest fires were recorded in the Ural Federal Distict. While the area covered by fire was 167,2 th/ga. These indicators slightly exceed the value of the number and the area covered by fire over the past five years in the district. The latter account for 1961 cases and 124,6 thousands of ha respectively. The largest number of forest fires was recorded in 2020 in Chelyabinsk region – 587 cases, the least in the Yamalonenets autonomous okrug – 111 cases. At the same time the maximum area covered by forest fires in 2020 is charaiterized by the Khanty-Mansiysk autonomous okrug – Yugra – 144,7 thousands of has. The minimum area covered by the fire was recorded in the Tyumen region – 1,6 th. ha. The average fire area in 2020 around the Okrug was 76,64 ha, at the same time in the Khanty-Mansiysk autonomous okrug – Yugra, it is 308,0 ha, but in the Tyumen region – 6,98 ha. The economic damage from forest fires amounted to 4 109 793,16 th of roubes, at the same time 575 481,57 th of ronbes were spent fire suppressing significant damage from forest fires as well as environmental damage necessitates futher forest protection improvement.

Tumorigenesis can be induced by various stresses that cause aberrant DNA mutations and unhindered cell proliferation. Under such conditions, normal cells autonomously induce defense mechanisms, thereby stimulating tumor suppressor activation. ARF, encoded by the CDKN2a locus, is one of the most frequently mutated or deleted tumor suppressors in human cancer. The safeguard roles of ARF in tumorigenesis are mainly mediated via the MDM2-p53 axis, which plays a prominent role in tumor suppression. Under normal conditions, low p53 expression is stringently regulated by its target gene, MDM2 E3 ligase, which induces p53 degradation in a ubiquitin-proteasome-dependent manner. Oncogenic signals induced by MYC, RAS, and E2Fs trap MDM2 in the inhibited state by inducing ARF expression as a safeguard measure, thereby activating the tumor-suppressive function of p53. In addition to the MDM2-p53 axis, ARF can also interact with diverse proteins and regulate various cellular functions, such as cellular senescence, apoptosis, and anoikis, in a p53-independent manner. As the evidence indicating ARF as a key tumor suppressor has been accumulated, there is growing evidence that ARF is sophisticatedly fine-tuned by the diverse factors through transcriptional and post-translational regulatory mechanisms. In this review, we mainly focused on how cancer cells employ transcriptional and post-translational regulatory mechanisms to manipulate ARF activities to circumvent the tumor-suppressive function of ARF. We further discussed the clinical implications of ARF in human cancer.

Although animals eliminate apoptotic cells using macrophages, plants use cell corpses throughout development and disassemble cells in a cell-autonomous manner by vacuolar cell death. During vacuolar cell death, lytic vacuoles gradually engulf and digest the cytoplasmic content. On the other hand, acute stress triggers an alternative cell death, necrosis, which is characterized by mitochondrial dysfunction, early rupture of the plasma membrane, and disordered cell disassembly. How both types of cell death are regulated remains obscure. In this paper, we show that vacuolar death in the embryo suspensor of Norway spruce requires autophagy. In turn, activation of autophagy lies downstream of metacaspase mcII-Pa, a key protease essential for suspensor cell death. Genetic suppression of the metacaspase–autophagy pathway induced a switch from vacuolar to necrotic death, resulting in failure of suspensor differentiation and embryonic arrest. Our results establish metacaspase-dependent autophagy as a bona fide mechanism that is responsible for cell disassembly during vacuolar cell death and for inhibition of necrosis.

Abstract FoxP3+ regulatory T cells (Tregs) suppress GVHD while preserving graft-versus-tumor effects, making them an attractive target for GVHD therapy. The donor-derived Treg pool can potentially be derived from the expansion of preexisting natural Tregs (nTregs) or from de novo generation of inducible Tregs (iTregs) from donor Tconvs in the transplantation recipient. Using an MHC-mismatched model of acute GVHD, in the present study we found that the Treg pool was comprised equally of donor-derived nTregs and iTregs. Experiments using various combinations of T cells from wild-type and FoxP3-deficient mice suggested that both preexisting donor nTregs and the generation of iTregs in the recipient mice contribute to protection against GVHD. Surprisingly, CD8+FoxP3+ T cells represented approximately 70% of the iTreg pool. These CD8+FoxP3+ T cells shared phenotypic markers with their CD4+ counterparts and displayed suppressive activity, suggesting that they were bona fide iTregs. Both CD4+ and CD8+ Tregs appeared to be protective against GVHD-induced lethality and required IL-2 and TGFβ receptor expression for their generation. These data illustrate the complex makeup of the donor-derived FoxP3+ Treg pool in allogeneic recipients and their potential role in protection against GVHD.

ObjectiveHepatic steatosis accompanying obesity is a major health concern, since it may initiate non-alcoholic fatty liver disease (NAFLD) and associated complications like cirrhosis or cancer. Intestinal gluconeogenesis (IGN) is a recently described function that contributes to the metabolic benefits of specific macronutrients as protein or soluble fibre, via the initiation of a gut-brain nervous signal triggering brain-dependent regulations of peripheral metabolism. Here, we investigate the effects of IGN on liver metabolism, independently of its induction by the aforementioned macronutrients.DesignTo study the specific effects of IGN on hepatic metabolism, we used two transgenic mouse lines: one is knocked down for and the other overexpresses glucose-6-phosphatase, the key enzyme of endogenous glucose production, specifically in the intestine.ResultsWe report that mice with a genetic overexpression of IGN are notably protected from the development of hepatic steatosis and the initiation of NAFLD on a hypercaloric diet. The protection relates to a diminution of de novo lipogenesis and lipid import, associated with benefits at the level of inflammation and fibrosis and linked to autonomous nervous system. Conversely, mice with genetic suppression of IGN spontaneously exhibit increased hepatic triglyceride storage associated with activated lipogenesis pathway, in the context of standard starch-enriched diet. The latter is corrected by portal glucose infusion mimicking IGN.ConclusionWe conclude that IGN per se has the capacity of preventing hepatic steatosis and its eventual evolution toward NAFLD.

Abstract Abstract 4015 FoxP3+ regulatory T cells (Tregs) suppress graft-versus-host disease (GVHD) while preserving graft-versus-tumor effects, making them an attractive target for GVHD therapy. The donor-derived Treg pool can potentially be derived from expansion of pre-existing natural Tregs (nTregs) or from de novo generation of inducible Tregs (iTregs) from donor conventional T cells (Tconvs) in the transplant recipient. Although the co-adoptive transfer of nTregs or in vitro -derived iTregs has been shown to prevent the development of GVHD, the relative contribution of these two Treg subsets in protection against GVHD has been unclear. To investigate the contribution of the different FoxP3+ Treg subsets, we used a MHC-mismatched mouse model of acute GVHD. Lethally irradiated (500cGy × 2) B6D2F1.SJL (H-2bxd) host mice were injected with T cell-depleted bone marrow cells and FACS-sorted Tconvs (WT or Foxp3-deficient) with or without FACS-sorted Tregs of C57BL/6 (H-2b) mouse origin. Weight loss in mice receiving Foxp3-deficient Tconvs alone was significantly more pronounced compared to other groups. The presence of either donor-derived nTregs or iTregs alone protected against GVHD-induced weight loss but was suboptimal compared to the presence of both donor-derived nTregs and iTregs. Next, we sought to determine how the donor-derived Treg pool was established during acute GVHD and tracked the appearance of Tregs in the secondary lymphoid organs at different time points post transplant. On Day 8 post GVHD induction, ∼5% of the donor-derived CD4+ T cells in the spleen were FoxP3+. We found that the Treg pool was comprised equally of donor-derived nTregs and iTregs. Unexpectedly, we found a significant fraction of CD8+FoxP3+ T cells (1–3% of all CD8+ T cells) in the spleen and in the lymph nodes. These CD8+FoxP3+ T cells representing ∼70% of the iTreg pool on Day 8 post GVHD induction. These CD8+FoxP3+ T cells shared phenotypic markers with their CD4+ counterparts and displayed suppressive activity, suggesting that they were bona fide iTregs. Both CD4+ and CD8+ Tregs expanded in vivo with IL-2 treatment and required IL-2 and TGFβ receptor expression for their generation. In summary, we found that donor derived-iTregs are generated during GVHD and contribute to suppression of acute GVHD induced-weight loss. Surprisingly, CD8+Foxp3+T cells were a major contributor to the donor derived-iTreg pool after transplantation. The generation of CD8+ and CD4+ iTregs occurred at least in part by a cell autonomous IL-2 and TGFβ receptor-dependent mechanism. Thus, our data suggest that in addition to increasing nTregs, concomitant strategies aimed at enhancing the conversion of donor-derived Tconvs to iTregs for example by engaging the IL-2 and TGFβ signaling pathways might be beneficial for the treatment of GVHD. Disclosures: No relevant conflicts of interest to declare.

Abstract Abstract 2392 Poster Board II-369 Introduction: Cancer entities frequently exhibiting constitutive Myc expression, such as aggressive B-cell lymphomas, typically display significant amounts of apoptotic cell death. So far, cellular senescence as another cell-autonomous oncogene-inducible safeguard program has been recognized in RAS/BRAF-driven scenarios but not as a bona fide Myc-evoked anti-cancer mechanism. Understanding how oncogenic Myc may provoke not only apoptosis but cellular senescence as a failsafe mechanism to counter tumor development has broad implications for the clinical presentation and therapeutic strategies in frequently Myc-driven lymphoma entities such as Burkitt's lymphoma and diffuse large B-cell lymphoma (DLBCL). Results: Using the Burkitt's like Eμ-myc transgenic mouse lymphoma model, we show here that cellular senescence serves as another crucial anti-neoplastic barrier during Myc-driven tumorigenesis in addition to apoptosis. Eμ-myc lymphomas harbor a substantial fraction of senescent tumor cells, that stain positive for histone H3 lysine 9 (H3K9)-trimethylation. Lymphomas lacking the H3K9 methyltransferase Suv39h1 display no senescence and develop significantly faster, although apoptosis is not affected by Suv39h1 deficiency. While Myc, unlike other Ras-type oncogenes, shows rather modest pro-senescent activity in vitro, we identified the cytostatic cytokine TGF-β as the main paracrine senescence trigger in vivo. When neutralizing TGF-β action during Myc-driven lymphomagenesis utilizing a secretable TGF-β receptor II ecto-domain, senescence is completely blunted and tumor latency is significantly shortened. We identify macrophages, but not lymphoma cells, as the main source of exogenous TGF-β, that is secreted upon phagocytosis of apoptotic lymphoma cells. Lymphomas harboring a Bcl2-mediated apoptotic block presented with a much lower frequency of both infiltrating macrophages and senescent cells in vivo, suggesting that there is a functional link between cell-autonomous Myc-triggered apoptosis and non-cell-autonomous, macrophage-induced senescence. Both pharmacological suppression of TGF-β production in macrophages via the angiotensin-converting enzyme (ACE) inhibitor lisinopril and depletion of macrophages in Eμ-myc lymphoma-harboring mice by systemic exposure to clodronate resulted in a profound reduction of senescence, thereby underscoring the important role for tumor-infiltrating macrophages in TGF-β-mediated senescence in vivo. We recapitulated components of such a mechanism in human aggressive B-cell lymphomas, a frequently Myc-activated entity where TGF-β1 signaling has previously been identified as a component of the prognostically favourable “stromal-1” signature (Lenz-G et al., NEJM, 2008). A panel of 30 DLBCL samples was sub-divided based on Ki67 immunoreactivity into a very high proliferation (Ki67hi; ≥80% Ki67-positive cells) and a lower proliferation (Ki67lo; <80% Ki67-positive cells) group. Ki67lo samples exhibited a higher frequency of H3K9me3-positive cells, indicative of cellular senescence. Importantly, the Ki67lo group also presented with a higher fraction of apoptotic cells, more lymphoma-infiltrating macrophages, and a stronger reactivity for the TGF-β signaling mediator Smad3-P, thereby representing a subgroup in DLBCL that displays features highly reminiscent of the macrophage-derived mechanism of senescence induction. Conclusions: Our study expands the relevance of oncogene-induced senescence to Myc-driven cancers and demonstrates that different tumor suppressor programs - such as apoptosis and senescence - are enforced in an interdependent fashion between the tumor- and non-malignant stroma cells during lymphomagenesis. Utilizing the Eμ-myc transgenic mouse lymphoma model and furthermore supported by evidence from human aggressive B-cell lymphoma samples, this study establishes a novel network of heterotypic cell-cell interactions within a tumor in which apoptotic tumor cells induce a paracrine response in non-malignant bystander cells that limits lymphomagenesis by cellular senescence. Given the anti-cancer relevance of senescence and the demonstrated inducibility of senescence by a non-DNA damaging cytokine, such as TGF-β, these findings open the exciting perspective to utilize Suv39h1/H3K9me3-mimicking approaches for future cancer therapies. Disclosures: No relevant conflicts of interest to declare.

Abstract A remarkable feature of erythropoiesis is the coordination of proliferation, differentiation and apoptosis of erythroid cells to precisely achieve erythropoietic homeostasis to avoid anemia and polycythemia. Anemia is a common disease arising from various causes, including Myelodysplastic syndromes, thalassemia, cancer chemotherapy, chronic kidney disease and hemorrhage. The pro-erythropoietic factor erythropoietin (EPO) is often employed for anemia therapy. However, questions have been raised about the safety of EPO given its potential for tumor promotion in cancer-related anemia. Moreover, many acute and chronic anemias, including hemolysis, sepsis and genetic bone marrow failure diseases such as Diamond-Blackfan anemia are untreatable with EPO. To overcome these hurdles, new molecular mechanisms need to be identified that physiologically restrain erythropoiesis by acting as molecular brakes to prevent over-active erythropoiesis caused by pro-erythropoietic signals. Inhibiting these restraining mechanisms could provide alternative approaches to treat anemia in an EPO-independent fashion. P38 MAPK (Mitogen-activated protein kinase) is an important pathway involved in diverse biological processes. P38 modulates cell proliferation, controls cell survival and decides cell fate during differentiation. P38 pathway functions mainly by phosphorylating and activating important transcription factors in response to different stimuli, including ATF2, CREB, and MEF2. There are four members within the P38 MAPK family, including P38α, P38β, P38γ, and P38δ. These members are encoded by different genes and have different tissue expression patterns. Among them, P38α is ubiquitously expressed. P38α modulates the function of different cell types. There are two distinct developmental defects reported in global P38α knockout mice by two separate groups using different mouse strains. One displayed embryonic death with highly anemic appearance due to reduced EPO production and another showed even earlier embryonic lethality due to placental developmental defects. In a P38α conditional mice model in which Cre recombinase was expressed in the whole mouse embryo but not in the placenta by crossing to MORE-Cre mice, no anemia or EPO defects were observed. However, the intrinsic and cell autonomous role of P38α in adult steady-state or stressful erythropoiesis has not been established. Loss of P38α causes activation of JNK in the liver. P38 inhibitors are in clinical trials and have the potential for the treatment of human disease. Therefore, it is important to understand the down-stream targets and functional outcomes induced by P38α deficiency. Using primary human erythroblasts derived from human CD34+ hematopoietic stem and progenitor cells (HSPCs) and P38α conditional knockout mice, we find that P38α acts as a molecular brake during anemia recovery through integrating apoptotic signals and by shortening the lifespan of erythroblasts to prevent potential over-active erythropoiesis caused by pro-erythropoietic signaling. Loss of P38α in erythroblasts activates JNK through augmented Map3k4 via a negative feedback circuit revealed by gene expression profiling. Functionally, JNK serves as a pro-survival signal independent of EPO by compromising Bim expression via stabilizing the epigenetic silencer Ezh2 in erythroblasts. JNK-controlled Cdk1 activity modulates full interaction of Ezh2 to the E3 ligase Smurf2 through multiple threonine phosphorylation sites within Ezh2. Our findings identify a key signaling cascade involving P38α/JNK/Cdk1/smurf2/Ezh2/Bim in fine tuning stress erythropoiesis. We propose that inhibition of P38α may provide an alternative strategy for the treatment of anemia. Disclosures No relevant conflicts of interest to declare.

Abstract Abstract 2618 Rho family small GTPases are critical regulators of multiple functions of blood cells, including adhesion, migration, proliferation, survival and gene expression. Elucidation of their roles in hematopoiesis could be fundamental for understanding the mechanisms of various blood diseases and improving therapeutic outcomes for hematopoietic abnormalities. The Rho GTPases Rac1, Rac2 and Cdc42 have been found essential in maintaining hematopoietic stem cell (HSC) niche residency and regulating myelopoiesis and lymphopoiesis in previous mouse gene targeting studies. Using a dominant-negative mutant overexpression approach, an earlier study showed that suppression of RhoA activity enhanced HSC proliferation and engraftment potential; however, the bone fide role of RhoA in blood development remains unknown given limitations of such a mutant overexpression approach in specificity, dosage effect, and physiological relevance. Here, we stringently define the function of RhoA in HSC maintenance and hematopoiesis using an interferon inducible RhoA conditional knockout mouse model (Mx-cre+; RhoAloxp/loxp). Systematic deletion of RhoA caused lethality of the mice 7 days post polyIC induction due to hematopoietic failure that was accompanied by drastically decreased bone marrow (BM) cellularity (to ∼1/3 of wild type controls), a loss of splenocytes, and a significant reduction of cell counts of most cell lineages in peripheral blood, suggesting RhoA is required for multiple blood cell lineage differentiation and production. Syngenic transplant experiments yielded similar results, demonstrating that these effects are intrinsic to the hematopoietic compartment. The observed cytopenia resulting from RhoA loss was associated with the exhaustion of BM phenotypic HSPC (Lin−Sca1+c-kit+, LSK) and the hierarchical progenitor cells (Lin−c-kit+, LK) in number and frequency, a complete loss of colony forming activities, and a total engraftment failure. In addition, BrdU chase labeling and Annexin V/7-AAD staining revealed that RhoA deletion caused a transient increase of proliferation (1.7 fold increase in S phase) and reduction of survival (16.8 fold reduction in Annexin V− 7-AAD−) of remaining LSK in the BM. These results indicate that RhoA plays an indispensible, cell autonomous role in HSPC maintenance and hematopoiesis. In a competitive transplantation model where Mx-cre+;RhoAloxp/loxp or Mx-cre−;RhoAloxp/loxp CD45.2+ BM cells and WT CD45.1+ competitor cells were transplanted at 1:1 ratio into syngenic CD45.1+ recipients prior to polyIC induction, RhoA deletion also caused a complete extinction of donor derived (CD45.2+) Mac1+Gr1+ myeloid cells, B220+ B cells, as well as CD3+ T cells, in the peripheral. Interestingly, distinct from these more differentiated lineages, BM CD45.2+ LSK population was only marginally affected (88.9 % of pre-polyIC induction level) while the CD45.2+ LK cells and later hierarchical lineages were rapidly eliminated after RhoA deletion in this competitive transplant model. This was associated with increased apoptosis in CD45.2+ RhoA−/− LK, but not LSK, cells, suggesting a specific requirement of RhoA in the myeloid progenitor cell survival. Further, the CD45.2+ RhoA−/− LSK and LSKCD150+ cell populations, not differentiated donor-derived progenitors, from the primary competitive transplant BM, were able to be maintained in secondary transplant recipients 5 months post-transplantation, indicating that RhoA serves as a key regulator at an early progenitor differentiation step. Interestingly, RhoA deletion did not affect lin− cell p-MLC and p-cofilin contents and in vitro expansion in response to SCF stimulation, suggesting that RhoA is not required for actomyosin signaling nor SCF induced proliferation. Taken together, our results implicate RhoA as a unique and essential regulator of multipotent progenitor differentiation and survival that controls multi-lineage hematopoiesis. Disclosures: No relevant conflicts of interest to declare.

Abstract Over the last years, numerous studies have dissected the mutational landscape of T-cell acute lymphoblastic leukemia (T-ALL) resulting in the identification of numerous oncogenes and tumor suppressors implicated in T-cell transformation. However, most genetic abnormalities found in cancer are located in intergenic regions, whose role in cancer development, if any, remains poorly understood. Here we hypothesized that recurrent cancer-associated intergenic mutations, amplifications and deletions may implicate strong transcriptional regulatory sequences responsible for the activation of key oncogenic factors in the pathogenesis of T-ALL. To address this question, we first used ChIPseq analysis to map the genomic landscape of enhancer sequences controlled by NOTCH1, a critical T-ALL oncogene activated by mutations in over 60% of human T-ALLs. In addition, we performed high resolution aCGH analysis of somatic chromosomal amplifications and deletions in a comprehensive series of 160 T-ALL samples. These analyses revealed recurrent focal duplications at chromosome 8q24 in 8/160 (5%) T-ALL cases in an area devoid of protein-coding genes containing a prominent 1 kb NOTCH1-binding peak. Strikingly, this putative oncogenic element is located +1,427 kb 3’ from the MYC locus and chromatin configuration 3C analysis demonstrated its direct association with the MYC proximal promoter. Multispecies DNA sequence alignment revealed remarkable conservation of this region in mammals, birds and reptiles and local ChIP analysis revealed bona fide active enhancer features including P300 occupancy and high levels of H3K4me1 with low levels of H3K4me3. In addition, detailed analysis of epigenetic marks across 64 hematopoietic and non-hematopoietic cell lines and tissues revealed that his regulatory element is located within a major superenhancer specifically active in T-cells. Based on these results, we proposed that this regulatory sequence, hereby named N-Me for NOTCH-bound MYCenhancer, could function as an important regulatory element driving the activation of MYC downstream of NOTCH1 in T-ALL. Consistently, luciferase reporter assays showed strong, orientation-independent and NOTCH-dependent activation of reporter constructs containing N-Me in association with a -2.5 kb MYC proximal promoter in JURKAT T-ALL cells. Next and to formally test the functional relevance of this enhancer in T-cell development and transformation we generated and characterized N-Me knockout and conditional knockout mice. N-Me null animals were viable and showed a marked and selective reduction in thymus size and cellularity as their only developmental alteration. Detailed immunophenotypic analysis of N-Me knockout thymocytes demonstrated accumulation of double negative 3 (DN3) T cells and marked reductions in double positive and CD4+ and CD8+ single positive cells. Mechanistically, this phenotype was associated with a marked reduction in Myc expression in DN3, DN4 and ISP cells. Moreover, transplantation of N-Me knockout bone marrow hematopoietic progenitors demonstrated that this phenotype is cell autonomous, and can be rescued upon retroviral expression of MYC. Next, we analyzed the role of N-Me in the induction of NOTCH-driven leukemias by transplanting mice with N-Me wild-type and knockout hematopoietic progenitors infected with retroviruses expressing a mutant constitutively active form of NOTCH1 (ΔE-NOTCH1). In this context, mice transplanted with ΔE-NOTCH1-infected N-Me wild type cells developed T-ALL with 100% penetrance 6 weeks after transplant. In contrast, mice transplanted with ΔE-NOTCH1-N-Me knockout cells showed complete resistance to NOTCH1-induced transformation remaining 100% leukemia-free at 15 weeks post-transplant. In addition, secondary deletion of N-Me in established NOTCH1 induced leukemias from tamoxifen-inducible N-Me conditional knockout mice (Rosa26TMCre N-Meflox/flox) induced profound antileukemic effects with extended survival and almost complete suppression of leukemia initiating cell activity. Altogether, these results identify N-Me as the first long range oncogenic enhancer directly implicated in the pathogenesis of human leukemia. Disclosures No relevant conflicts of interest to declare.

Abstract Somatic mutations and chromosomal translocations of genes have emerged as major drivers in a range of hematopoietic malignancies. While ASXL1 is mutated in all forms of myeloid malignancies, ASXL2 is specifically mutated in t(8;21) AML patients. ASXL1 and ASXL2 mutations are mutually exclusive in t(8;21) AML. Despite the importance of ASXL2 mutations in clinical, it's role in leukemogenesis remain unknown. In the current study, we sought to dissect the role of ASXL2 in normal hematopoiesis and to identify the molecular mechanisms by which Asxl2 loss contributes to myeloid malignancies. In the current study, we utilized a mouse model of Asxl2 to characterize the hematopoietic features of in vivo. Asxl2-/- mice were characterized by pancytopenia and dysplastic features, including hyposegmented (bilobed) neutrophils with fine nuclear bridging (consistent with pseudo Pelger-Huët) and increased number of polychromatophilic red blood cells (RBCs), reminiscent of myelodysplastic syndrome (MDS). Flow cytometric analyses revealed that Asxl2-/- mice had an increased proportion of granulocytic/monocytic cells (Gr-1+/Mac1+) in the PB, BM and spleens compared to WT mice. The histologic analysis of the Asxl2+/- and Asxl2-/- spleen sections showed disrupted splenic architecture with an increased proportion of myeloid cells and massive accumulation of myeloperoxidase (MPO) positive cells in WT spleens. Asxl2-/- mice had an increased long-term (LH)-HSCs and granulocyte-macrophage progenitor (GMP) cells compared to WT mice.Consistently, the paired-daughter cell assays revealed that Asxl2-/- CD34-LSK BM cells had a higher proportion of cells with symmetric self-renewal capacity (SS, 62%) than WT cells (33%). In contrast, a significant reduction in the cells with symmetric differentiation potential was observed in Asxl2-/- HSCs (18%) compared to WT HSCs (40%), indicating a critical role of ASXL2 in the balance between the symmetric and asymmetric division of HSCs. Transplantation assays revealed that recipients transplanted with Asxl2-/- and Asxl2+/- bone marrow cells had shortened lifespan due to the development of MDS or AML, suggesting a cell-autonomous effect of Asxl2-loss in HSC/HPC functions. Furthermore, Asxl2-loss further increase the colony-forming potential and colony replating capacity of AML1-ETO expressing HSCs in vitro, suggesting a cooperative effect between AML1/ETO9a and Asxl2+/-to promote HSC self-renewal. RNA-seq analysis showed a unique signature of Asxl2-/- LK cells compared to WT LK cells. Gene set enrichment analysis revealed that altered expressed genes in Asxl2-/-LK cells were enriched in myeloid cell differentiation, hematopoiesis, apoptosis, and chromatin/nucleosome assembly signature. ChIP-seq analysis showed that differentially expressed genes were associated with dysregulated histone enhancer markers, including H3K27ac, H3K4me1, and H3K4me2. Further analysis demonstrated that the alteration of H3K27ac enrichment had a greater impact on gene expression, in comparison to H3K4me1/2. KEGG pathway analysis showed that genes with differential H3K27ac signals were enriched for hematopoietic cell lineage, cancer signaling pathway and myeloid leukemia development. IPA analysis further confirmed that genes with altered enrichment levels of were enriched in myeloid cell differentiation and apoptosis pathways. Altogether, these data suggest that ASXL2 regulates gene expression mainly through enhancer markers. Our results demonstrate that ASXL2 plays an important role in normal hematopoiesis, and Asxl2-loss in mice is sufficient to cause MDS-like disease and leukemia transformation. These results indicate that ASXL2 functions as a tumor suppressor in myelopoiesis. The Asxl2 knock-out mice present an ideal model for unveiling the mechanisms underlying the Asxl2-loss mediated multiple-step pathogenesis of myeloid malignancies and for testing novel therapeutic agents for myeloid malignant patients with ASXL2 alterations. Further studies to dissect the possible roles of ASXL2alterations in leukemogenesis and to identify therapeutic vulnerabilities they may create are ongoing. Disclosures No relevant conflicts of interest to declare.

Abstract Background: Hyperfunctioning papillary thyroid carcinoma (PTC) is a rare tumor and accounts for less than 0.1% of all thyroid tumors. Information about its driver mutations is limited. Our literature search yielded 16 cases wherein a mutational analysis was conducted. Thyrotropin receptor (TSHR) mutations were identified in 11 of these cases. One case revealed a combination of TSHR and KRAS mutations. No mutations were identified in the other four cases. BRAFV600E is a prominent oncogene in PTC; however, hyperfunctioning PTC with this mutation has not yet been reported. Clinical Case: In a 48-year-old man, ultrasonography (US) during an annual medical checkup revealed a nodule at the right lobe of the thyroid gland. He visited the outpatient clinic for further evaluation. Thyroid function tests indicated that he was hyperthyroid with TSH level of 0.01 mIU/L (reference range: 0.05-5.00), free thyroxine level of 1.8 ng/dL (reference range: 0.9-1.7), and free triiodothyronine level of 4.3 pg/mL (reference range: 2.3-4.0). Serum thyroglobulin was 62.1 ng/mL (reference range: &lt;33.7) and TSHR autoantibodies (TRAb) was &lt;0.8 IU/L (reference range: &lt;2.0 IU/L). B-mode US revealed a hypoechoic, heterogeneous nodule with largest diameter of 25 mm, and it had a jagged border and microcalcification. Color Doppler US revealed increased intranodular vascularity. The 99mTc thyroid scintigram revealed a round, right-sided focus of tracer uptake by the nodule with suppression in the remainder of the gland. These findings were consistent with an autonomously-functioning thyroid nodule. The patient underwent total thyroidectomy because fine-needle aspiration cytology revealed a malignant cytological diagnosis. The histopathological diagnosis of the patient was PTC, tall cell variant, pT2, pEx0, pN1b, and M0. Subsequent mutational analysis of BRAF (exon 15), TSHR (exons 9 and 10), GNAS (exons 7-10), KRAS, NRAS, HRAS (codons 12, 13, and 61), and TERT promoter (C250T and C228T) only identified a heterozygous point mutation in BRAFV600E in tissue samples. Conclusion: We report for the first time a case of hyperfunctioning papillary thyroid carcinoma with a BRAF mutation.

Abstract Introduction: Thyroid nodules are less common among children than adults but are more likely to be malignant. Among all the thyroid nodules, autonomous functioning thyroid nodules (AFTN) are generally considered to be a benign entity, with malignancy found in less than 1 %. AFTN are very rare in the pediatric population, and the optimal treatment is not well defined. We present a 14-year-old female patient with an AFTN treated with surgical resection and found to contain papillary thyroid carcinoma, despite a previous biopsy which did not demonstrate malignancy. Case presentation: A 14-year-old girl presented with left-sided palpable thyroid lesion for four months. The patient had no symptoms at that time, and the physical exam was notable for a palpable left thyroid nodule measuring 3x 2.2 cm. Thyroid studies were remarkable for a suppressed thyroid-stimulating hormone (TSH) of 0.056uIU/mL (0.350–4.94), normal free thyroxine (FT4): 1.1 ng/dL (0.7–1.5), and positive anti-thyroglobulin antibodies: 9.0 IU/ml (0.0 - 4.1) with negative anti peroxidase antibodies and negative thyroid-stimulating immunoglobulin. Initial ultrasound (US) showed a left complex cystic and solid nodule measuring 3.4 cm x 1.8 cm x 2.3 cm. Fine needle aspiration (FNA) of the nodule revealed a benign aspirate. An I-123 scan revealed a hyperfunctioning nodule with suppression of uptake in surrounding thyroid parenchyma. The patient was then lost to follow up, presenting to our clinic over a year later due to difficulty breathing when supine and increased nodule size. Thyroid studies were notable for a suppressed TSH of 0.005 and slightly elevated FT4:1.8. Thyroid US showed a mixed cystic and solid nodule measuring 4.7 x3 x 4cm, with no calcification. Given the increased size of the lesion, her age, and difficulty breathing when supine, a decision was made to proceed with left hemithyroidectomy for definitive diagnosis and treatment. Pathology of the specimen revealed an encapsulated papillary thyroid carcinoma with focal capsular invasion. Right hemithyroidectomy was performed three weeks later, followed by I-131 ablation one month after surgery. The patient is currently doing well and euthyroid on thyroid hormone replacement therapy, with no evidence of disease. She is undergoing surveillance with ultrasound imaging and laboratory evaluation. Conclusion: This is a rare case of AFTN harboring papillary thyroid carcinoma. Although the majority of cases of AFTN are benign, an FNA was performed and was negative for malignancy. Due to an increase in size, new symptoms and ultrasound changes, surgery was performed and revealed the final diagnosis. The behavior of thyroid nodules in pediatric patients can be different than adult patients. Even though the majority of AFTN are benign, we should still keep malignancy in our differential when the nodule has a growth pattern, new US findings or patient develops worsening symptoms.

IntroductionTransformation, claims McCracken, is the expression of consumer agency and individual freedom in which consumers, as “co-creators of culture,” are empowered to creatively construct new improved selves (xvi). No longer an “extraordinary event for extraordinary creatures,” transformation today is routine and accessible (McCracken xxi). Contemporary consumer culture encourages individuals to enact these transformations by turning to the market to purchase the resources they require to achieve their desired identity (Ellis et al. 179). This market model of transformation embraces the concept of the marketplace exchange where the one party satisfies the needs of the other in a mutually beneficial exchange relationship. For consumers, the market enables transformation through the purchase and consumption of the desired products and services which support identity building.Critics, however, argue that markets have less positive effects. While it is too simplistic to claim that markets manipulate consumers, marketing exchanges constitute an enduring shaping force on individuals and society (Laczniak and Murphy). Markets shape consumer identities by homogenising them and suppressing their self-expressive capabilities (Kozinets 22). As producers become more powerful, “the market is transformed from a consumer-driven mechanism to a sphere where the producers assimilate consumers’ needs to their own through commercial activity” (Sassatelli 76) (my italics). Marketing and promotion have a persuasive influence and their role in the transformation process is a crucial element in understanding the consumer’s impetus to transform. Consumer identity is of course neither fully a “liberatory act” nor “wholly dictated by the market” (Ellis et al. 182), but there is a relationship between consumer autonomy and the dictates of the market which can be explored through focusing on the transformation of identity through the consumption of cosmetic surgery. Cosmetic surgery is an important site of enquiry as a social practice which “merges the attention given to the body by an individual person with the values and priorities of the consumer society” (Martinez Lirola and Chovanec 490). The body, as Kathy Davis highlighted, has long been seen as a commodity which can be endlessly transformed (Davis, Reshaping the Female Body), and the market for cosmetic surgery is at the forefront of this commodification process (Aizura 305). What is new, however, is the increasing marketisation and commercialisation of the cosmetic surgery industry combined with rising consumerism in which surgical transformation can be purchased simply as a “lifestyle choice alongside fashion, fitness and therapy” (Elliott 7). In the cosmetic surgery market, “patients” are consumers. Rather than choosing cosmetic surgery in order to feel whole or normal, contemporary consumers see surgery as a grooming practice which is part of a body maintenance routine (Jones).As the cosmetic surgery market becomes progressively more competitive, it relies more and more on marketing and promotion for its survival. The intense rivalry between providers drives them, in some cases, to aggressive and often unethical promotional practices. In the related field of pharmaceuticals for example, marketers have been charged with explicitly manipulating social understanding of disease in order to increase profits (Brennan, Eagle, and Rice 17). Unlike TV make-over shows whose primary purpose is to entertain, or celebrity culture which influences indirectly through example, cosmetic surgery promotion sets out with intent to persuade consumers to choose surgical transformation. Cosmetic surgery is presented to consumers “through the neoliberal prism of choice,” encouraging women (mostly) to choose surgery as a self-improvement practice in order to “feel good or pamper herself” (Gurrieri, Brace-Govan, and Previte 534). In a promotional culture which valorises external values and ‘the new’ (Fatah 1), the cost, risk, and pain of surgery are downplayed as an increasing array of self-transformative possibilities are presented as consumption choices. This scenario sees the impetus to transform as driven as much by marketing imperatives as by consumers’ free choice. Indeed in mobilising the rhetoric of choice, the “autonomous” consumer, it seems, plays into the hands of the cosmetic surgery industry.This paper explores consumer transformation through cosmetic surgery by focusing on the tension between the rhetoric of consumer autonomy, freedom, and choice and that of the industry’s marketing and promotional practices in the United Kingdom (UK). I argue that while the consumer is an active player, expressing their freedom and agency in choosing self-transformation through surgery, that autonomy is influenced and constrained by the marketing and promotional practices of the industry. I focus on the inherent paradox in the discourse of transformation in consumer culture which advocates individual consumer freedom and creativity yet limits these freedoms to “acceptable” bodily forms constructed as the norm by promotional images of the cosmetic surgery industry. To paraphrase Susan Bordo, those promotions which espouse consumer choice and self-determination simultaneously eradicate individual difference and circumscribe choice (Unbearable Weight 250). Here I explore how ideals of autonomy, freedom, and choice are utilised to support consumer surgical transformation. Drawing on market research, professional publications, blogs and industry webpages used by UK consumers as they search for information, I demonstrate how marketing and promotion adopt these ideals to provide a visual reference and a language for consumer transformation, which has the effect of shaping and limiting consumer freedom and creativity. Consumer Transformation as Expression of Freedom Contemporary consumers need not be content just to admire the appearance of celebrities and film stars, but can actively engage in the creative construction of new improved selves through surgical transformation (McCracken). This transformation is often expressed by consumers as a liberatory act, as is illustrated by the women surveyed for a UK Department of Health report. As one respondent explains, “I think it’s just the fact that they can . . . and I think over the years, women have a battle with their bodies, as they change, different ages, they do, they struggle with trying to accept it over different years and the fact that you can, it’s like ‘wow, so what, it’s a bit of money, let’s just change ourselves’” (UK Department of Health 32). Even young consumers see cosmetic surgery as an easily available transformative option, such as this 16-year-old female research respondent who describes surgery as “Things that you don’t really need but you just feel you want to have them” (UK Department of Health 33). As these women attest, cosmetic surgery is seen as an increasingly normal and everyday practice. By rhetorically constructing the possibility of transformation as an expression of individual consumer empowerment (“wow, so what, it’s a bit of money, let’s just change ourselves”), they distance the practice “from negative associations with vanity” and oppression (Tait 131). This postmodern consumer is no dupe or victim but a “conscious subject who modifies their body as a project of identity” (Gibson 51) and for whom cosmetic surgery transformation is “the route to happiness and personal empowerment” (Tait 119). Surgical transformation is not a way to strive narcissistically after “an elusive beauty ideal” (Heyes 93). Instead, it is expressed as something they choose to do just for themselves—which Bordo calls the “for me” argument (“Braveheart, Babe, and the Contemporary Body”). In an increasingly visual culture, the accessibility and affordability of cosmetic surgery enable consumers, who are already accustomed to digitally editing their photographical images, to “edit” their physical bodies. This is candidly expressed by Singaporean blogger Ang Chiew Ting who writes, "When I learnt how to use Photoshop, the things that I edited about myself, those have now all been done in real life through plastic surgery. Whatever I wanted to change about my face, I have done." Yet, as I illustrate later, the emphasis on transformation as empowerment through exercising choice (“Whatever I wanted to change about my face, I have done"), plays into the hands of the industry as it “reproduces the logic of surgical industries” (Tait 121). In the politics of consumption, driven by neo-liberal ideologies, consumer choice is sovereign (Sassatelli 184), and it is in the ability to exercise choice, choosing surgery and taking responsibility for that choice, that agency and empowerment are expressed (Leve, Rubin, and Pusic). Blogger Stella Lee explains her decision as “I don't want to say I encourage plastic surgery, this is just my personal choice. It is like saying if I dye my hair purple then I want everyone to have purple hair too. It is simply just for me only. If you wish to do so, go ahead. If you're satisfied with what you have, go ahead.” This consumer is a “discerning and knowledgeable consumer” who researches information about potential surgical procedures and practitioners (Gimlin, “Imagining” 58) and embraces the ideology of self-determinism (Heyes). Consumers considering surgery may visit recommended doctors, research doctors online, and peruse beauty magazines (Leve, Rubin, and Pusic). Tatler magazine, for example, publishes an annual Beauty and Cosmetic Surgery Guide which celebrates “the newest, niftiest ways to reclaim your face and your figure” (Tatler nd). In taking responsibility for themselves, the contemporary consumer reflects the neoliberal agenda “that promotes empowerment through consumer choice and responsibility for self-care” (Leve, Rubin, and Pusic 131). Yet, consumer information on the suitability of surgery and alternative providers is often partial. As one research respondent recalled, “I just typed it into Google and then worked through whatever came up; you're trying to go for the names of companies that are a bit more reputable” (UK Department of Health 28). Internet searches most frequently identify promotional information from the surgery providers themselves including customer stories and testimonials, which seem informative in nature but which have persuasive intent to influence choice. Therefore although seemingly exerting agency by undertaking a process of search in order to make an informed choice, that choice is made within a promotional context that the consumer may not be fully aware exists.Consumer Transformation as Marketing ImperativeThe aim of marketing and promotion, as medicine meets consumerism, is to secure clients for cosmetic surgery (Mirivel). As a consequence, the discourse of cosmetic surgery is highly persuasive and commercially motivated, promoting the need for surgery by mobilising the existing ideological link between identity and physical appearance for commercial ends (Martinez Lirola and Chovanec 489). Promotional strategies include drawing attention to possible deficiencies in appearance, creating opportunities for surgery by problematising normal bodily states, promising intangible benefits, and normalising surgery by positioning it within a consumerist vision of success. Consumer transformation can be driven by perceived lack, inadequacy, or deficit, where a part of the body or face does not stand up to scrutiny when compared to media images. Marketing and promotion draw attention to this lack and imply that any deficiency in appearance can be remedied by consumption practices such as the purchase of hair dye, make-up, or, more drastically, cosmetic surgery. As one research respondent considering surgery explains, “I think people want to look their best and media portrays ‘perfect’ looking people or they portray a certain image and then because it’s what you see all the time, it almost feels like if you don't look like that, then it’s wrong” (UK Department of Health 18). The influence of media on the impetus to transform is explored elsewhere (see Wegenstein), so is not addressed further here. However, the insecurity which results from such media images is further exploited by the marketing and promotional strategies adopted by cosmetic surgery providers in an increasingly competitive marketplace. This does not go unnoticed by consumers: as one research respondent noted, “They pick out your insecurities as a tactic for making you purchase stuff . . . it was supposed to be a free consultation but they definitely do pressure you into having stuff” (UK Department of Health 19). In this deficiency model of transformation, the cosmetic surgery consumer is insecure, lacking in power and volition, and convinced of her inadequacy. This is exacerbated by the promotional images of models featured on cosmetic surgery websites against which consumers evaluate their own looks in a process of social comparisons (Markey and Markey 210). This reflects Bernadette Wegenstein’s notion of the cosmetic gaze, a circular process whereby “the act of looking at our bodies and those of others is informed by the techniques, expectations, and strategies of bodily modification” (2). In comparing themselves with the transformed images on surgery websites, consumers are drawn into a process of comparison that tells them how they should look. At the same time as convincing consumers of their inadequacies, providers also tell consumers that they are in control and can act autonomously to transform themselves. For example, a TV advert for The Hospital Group which shows three smiling “transformed” customers claims “If you’re unhappy with your appearance you could change it. If it affects your confidence you could overcome it. If it makes you feel self-conscious, you could take control with cosmetic surgery or dentistry from The Hospital Group” (my italics). In this way marketers marshal the neo-liberal rhetoric of consumer empowerment to encourage the consumption of cosmetic surgery and normalise the practice through the emphasis on choice. Marketing and promotional messages contribute further to these perceived deficits by problematising “normal” bodily conditions resulting from “normal” life experiences such as ageing and pregnancy. Surgeon Ran Rubinstein, for example, draws attention in his blog to thinning lips as an opportunity for lip augmentation: “Lip augmentation might seem like a trend among the younger crowd, but it’s something that people of any age can benefit from getting. As you get older, some areas of your body thin out while some thicken. You might find that you’re gaining weight around your stomach, while your lips and face are getting thin.” Problematising frames a real or perceived physical state as “as a medical problem that requires a medical solution,” subtly implying that cosmetic surgery is “an unavoidable necessity” which is medically justified (Martinez Lirola and Chovanec 503). For example, Jules’s testimonial for facial fillers frames natural, and even positive, features such as smile lines as problematic: “I smile a lot and noticed some smile lines coming through.” Indeed as medicine has historically defined the female body as “deficient and in need of repair,” cosmetic surgery can be legitimately proposed as a solution for “women’s problems with their appearance” (Davis, “A Dubious Equality” 55). Promotional messages emphasise the intrinsic benefits of external transformation, encouraging consumers to opt for surgery in order to align their external appearance with how they feel inside. Much of this discourse calls on consumers’ perceptions of a disparity between how they feel inside and their external body image (Gibson 54). For example, a testimonial from “Carole Anne 69” claims that facial fillers “make me feel like I’m the best version of myself.” (Note that Carole Anne, like all the women providing testimonials for this website, including Carol 50, Jules 38, or Pamela 59, is defined by her looks and by her age.) Although Gimlin’s research suggests that the notions of the “body reflecting the ‘true’ self or re-creating one’s ‘genuine’ appearance” have become less important (“Too Good” 930), they continue to dominate in customer testimonials on surgery websites. For example, Transform breast enlargement client Rebecca exclaims, “I’m still me, but it has completely transformed how I feel about myself on the inside, how I hold and present myself on the outside.” A typical promotional strategy is to emphasise the intangible benefits of cosmetic surgery, such as happiness or confidence. This is encapsulated in a 2011 print advert for Transform Cosmetic Surgery Group which shows a smiling young girl in a bikini holding a placard which reads, “I’ve just had my breasts done, but the biggest change you’ll see is on my face.” In promising happiness or self-confidence, intangible effects which are impossible to measure, marketers avoid the reality of surgery—where a cut is made, what is added or removed, how many stitches are required. Consumers know the world through shopping (Elliott 43), and marketers draw on this behaviour to associate surgery with any other purchase in the life of a successful consumer. Consumers are encouraged to choose from a gallery of looks, to “Browse through our Before and After Gallery for inspiration,” and the purchase is rendered more accessible through the use of discounts, offers, and incentives, which consumers are accustomed to seeing in familiar shopping contexts. Sales intent can be blatant, such as this appeal to disposable income on Realself.com: “Now that your 2015 taxes are (hopefully) filed and behind you, were you fortunate enough to get a refund? If it just so happens that the government will be returning some of your hard-earned cash, what will you be using it for? Electronic gadgets, an island vacation, a shopping spree . . . or plastic surgery?” Providers reduce perceived risk by implying that interventions such as facial fillers are considered normal practice for others, claiming that “Millions of women choose facial fillers, so that they can age exactly the way they want to” and by providing online interactive tools which consumers can use to manipulate facial features to see the potential effect of surgery (This-is-me.com).ConclusionThe aim of this article was to explore the tension between two different views of transformation, one which emphasised consumer autonomy, freedom, and market choice and the other which claims a more restrictive and manipulative influence of the market and its promotional practices. I argue that McCracken’s explanation of transformation as “the expression of consumer agency and individual freedom” (xvi) offers an overly optimistic view of consumer transformation. In the cosmetic surgery market, the expression of consumer autonomy and freedom rests on the discourse of choice. This same discourse is adopted by surgery providers in their persuasive strategies to secure new clients so that the market’s promotional language (e.g. a whole new you) becomes part of the consumer’s understanding of and articulation of cosmetic surgery transformation. I argue that marketing and promotion work to progress consumers along the path to surgery, by giving them reasons to do so. This is achieved by reflecting existing consumer anxieties as deficiencies, by creating new reasons for surgery by problematising normal conditions, by promising intangible benefits, and by normalising the purchase. These promotional practices also regulate and restrict consumers by presenting visual images of transformation which influence how others understand “the perfect you.” The gallery of looks on surgery websites constrains choice by signifying which looks are desirable, and “before and after” rhetoric emphasises the pivotal role of cosmetic surgery in achieving this transformation. ReferencesAizura, Aren. “Where Health and Beauty Meet: Femininity and Racialisation in Thai Cosmetic Surgery Clinics.” Asian Studies Review 33.3 (2009): 303–17.Bordo, Susan. “Braveheart, Babe, and the Contemporary Body.” 3 June 2016 <www.public.iastate.edu/~jwcwolf/Papers/Bordo>.———. Unbearable Weight: Feminism, Western Culture, and the Body. Berkeley: U of California P, 1993.Brennan, Ross, Lynn Eagle, and David Rice. “Medicalization and Marketing.” Journal of Macromarketing 30.1 (2010): 8–22.Davis, Kathy. “‘A Dubious Equality’: Men, Women and Cosmetic Surgery.” Body & Society 8.1 (2002): 49–65.———. 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Introduction How do we measure intimacy? What are its impacts on our social, political and personal lives? Can we claim a politics to our intimate lives that escapes the normative confines of archaic institutions, while making social justice claims for relationship recognition? Negotiating some of these disparate questions requires us to think more broadly in contemporary public debates on equality and relationship recognition. Specifically, by outlining the impacts of the popular "gay marriage" debate, this paper examines the impacts of queer theory in association with public policy and community lobbying for relationship equality. Much of the debate remains polarised: eliminating discrimination is counterposed to religious or reproductive narratives that suggest such recognition undermines the value of the "natural" heterosexual family. Introducing queer theory into advocacy that oscillates between rights and reproduction problematises indexing intimacy against normative ideas of monogamy and family. While the arguments circulated by academics, lawyers, politicians and activists have disparate political and ethical impacts, when taken together, they continue to define marriage as a public regulation of intimacy and citizenship. Citizenship, measured in democratic participation and choice, however, can only be realised through reflexive politics that value difference. Encouraging critical dialogue across disparate areas of the marriage equality debate will have a significant impact on how we make ethical claims for recognising intimacy. (Re)defining Marriage In legislative terms, marriage remains the most fundamental means through which the relationship between citizenship and intimacy is crystallised in Australia. For example, in 2004 the Federal Liberal Government in Australia passed a legislative amendment to the Marriage Act 1961 and expressly defined marriage as a union between a man and a woman. By issuing a public legislative amendment, the Government intended to privilege monogamous (in this case understood as heterosexual) intimacy by precluding same-sex or polygamous marriage. Such an exercise had rhetorical rather than legal significance, as common law principles had previously defined the scope of marriage in gender specific terms for decades (Graycar and Millbank 41). Marriage as an institution, however, is not a universal or a-historical discourse limited to legal or political constructs. Socialist feminist critiques of marriage in the 1950s conceptualised the legal and gender specific constructs in marriage as a patriarchal contract designed to regulate female bodies (Hannam 146). However, Angela McRobbie notes that within a post-feminist context, these historical realities of gendered subjugation, reproduction or domesticity have been "disarticulated" (26). Marriage has become a more democratic and self-reflexive expression of intimacy for women. David Shumway elaborates this idea and argues that this shift has emerged in a context of "social solidarity" within a consumer environment of social fragmentation (23). What this implies is that marriage now evokes a range of cultural choices, consumer practices and affective trends that are incommensurable to a singular legal or historical term of reference. Debating the Politics of Intimacy and Citizenship In order to reflect on this shifting relationship between choice, citizenship and marriage as a concept, it is necessary to highlight that marriage extends beyond private articulations of love. It is a ritualised performance of heterosexual individual (or coupled) citizenship as it entrenches economic and civil rights and responsibilities. The private becomes public. Current neo-liberal approaches to same-sex marriage focus on these symbolic and economic questions of how recognising intimacy is tied to equality. In a legal and political context, marriage is defined in s5 Marriage Act as "the union between a man and a woman to the exclusion of all others, voluntarily entered into for life." While the Act does not imbue marriage with religious or procreative significance, such a gender dichotomous definition prevents same-sex and gender diverse partners from entering into marriage. For Morris Kaplan, this is a problem because "full equality for lesbian and gay citizens requires access to the legal and social recognition of our intimate associations" (201). Advocates and activists define the quest for equal citizenship by engaging with current religious dogma that situates marriage within a field of reproduction, whereby same-sex marriage is seen to rupture the traditional rubric of monogamous kinship and the biological processes of "gender complementarity" (Australian Christian Lobby 1). Liberal equality arguments reject such conservative assertions on the basis that desire, sexuality and intimacy are innate features of human existence and hence always already implicated in public spheres (Kaplan 202). Thus, legal visibility or state recognition becomes crucial to sustaining practices of intimacy. Problematising the broader social impact of a civil rights approach through the perspective of queer theory, the private/public distinctions that delineate citizenship and intimacy become more difficult to negotiate. Equality and queer theory arguments on same-sex marriage are difficult to reconcile, primarily because they signify the different psychic and cultural investments in the monogamous couple. Butler asserts that idealisations of the couple in legal discourse relates to norms surrounding community, family and nationhood (Undoing 116). This structured circulation of sexual norms reifies the hetero-normative forms of relationships that ought to be recognised (and are desired) by the state. Butler also interrogates this logic of marriage, as a heterosexual norm, and suggests it has the capacity to confine rather than liberate subjects (Undoing 118-20). The author's argument relies upon Michel Foucault's notion of power and subjection, where the subject is not an autonomous individual (as conceived in neo liberal discourses) but a site of disciplined discursive production (Trouble 63). Butler positions the heterosexuality of marriage as a "cultural and symbolic foundation" that renders forms of kinship, monogamy, parenting and community intelligible (Undoing 118). In this sense, marriage can be a problematic articulation of state interests, particularly in terms of perpetuating domesticity, economic mobility and the heterosexual family. As former Australian Prime Minister John Howard opines: Marriage is … one of the bedrock institutions of our society … marriage, as we understand it in our society, is about children … providing for the survival of the species. (qtd. in Wade) Howard's politicisation of marriage suggests that it remains crucial to the preservation of the nuclear family. In doing so, the statement also exemplifies homophobic anxieties towards non-normative kinship relations "outside the family". The Prime Ministers' words characterise marriage as a framework which privileges hegemonic ideas of monogamy, biological reproduction and gender dichotomy. Butler responds to these homophobic terms by alluding to the discursive function of a "heterosexual matrix" which codes and produces dichotomous sexes, genders and (hetero)sexual desires (Trouble 36). By refusing to accept the binary neo-liberal discourse in which one is either for or against gay marriage, Butler asserts that by prioritising marriage, the individual accepts the discursive terms of recognition and legitimacy in subjectifying what counts as love (Undoing 115). What this author's argument implies is that by recuperating marital norms, the individual is not liberated, but rather participates in the discursive "trap" and succumbs to the terms of a heterosexual matrix (Trouble 56). In contradistinction to Howard's political rhetoric, engaging with Foucault's broader theoretical work on sexuality and friendship can influence how we frame the possibilities of intimacy beyond parochial narratives of conjugal relationships. Foucault emphasises that countercultural intimacies rely on desires that are relegated to the margins of mainstream (hetero)sexual culture. For example, the transformational aesthetics in practices such as sadomasochism or queer polyamorous relationships exist due to certain prohibitions in respect to sex (Foucault, History (1) 38, and "Sex" 169). Foucault notes how forms of resistance that transgress mainstream norms produce new experiences of pleasure. Being "queer" (though Foucault does not use this word) becomes identified with new modes of living, rather than a static identity (Essential 138). Extending Foucault, Butler argues that positioning queer intimacies within a field of state recognition risks normalising relationships in terms of heterosexual norms whilst foreclosing the possibilities of new modes of affection. Jasbir Puar argues that queer subjects continue to feature on the peripheries of moral and legal citizenship when their practices of intimacy fail to conform to the socio-political dyadic ideal of matrimony, fidelity and reproduction (22-28). Puar and Butler's reluctance to embrace marriage becomes clearer through an examination of the obiter dicta in the recent American jurisprudence where the proscription on same-sex marriage was overturned in California: To the extent proponents seek to encourage a norm that sexual activity occur within marriage to ensure that reproduction occur within stable households, Proposition 8 discourages that norm because it requires some sexual activity and child-bearing and child-rearing to occur outside marriage. (Perry vs Schwarzenegger 128) By connecting the discourse of matrimony and sex with citizenship, the court reifies the value of marriage as an institution of the family, which should be extended to same-sex couples. Therefore, by locating the family in reproductive heterosexual terms, the court forecloses other modes of recognition or rights for those who are in non-monogamous relationships or choose not to reproduce. The legal reasoning in the case evinces the ways in which intimate citizenship or legitimate kinship is understood in highly parochial terms. As Kane Race elaborates, the suturing of domesticity and nationhood, with the rhetoric that "reproduction occur within stable households", frames heterosexual nuclear bonds as the means to legitimate sexual relations (98). By privileging a familial kinship aesthetic to marriage, the state implicitly disregards recognising the value of intimacy in non-nuclear communities or families (Race 100). Australia, however, unlike most foreign nations, has a dual model of relationship recognition. De facto relationships are virtually indistinguishable from marriage in terms of the rights and entitlements couples are able to access. Very recently, the amendments made by the Same-Sex Relationships (Equal Treatment in Commonwealth Laws - General Reform) Act 2008 (Cth) has ensured same-sex couples have been included under Federal definitions of de facto relationships, thereby granting same-sex couples the same material rights and entitlements as heterosexual married couples. While comprehensive de facto recognition operates uniquely in Australia, it is still necessary to question the impact of jurisprudence that considers only marriage provides the legitimate structure for raising children. As Laurent Berlant suggests, those who seek alternative "love plots" are denied the legal and cultural spaces to realise them ("Love" 479). Berlant's critique emphasises how current "progressive" legal approaches to same-sex relationships rely on a monogamous (heterosexual) trajectory of the "love plot" which marginalises those who are in divorced, single, polyamorous or multi-parent situations. For example, in the National Year of Action, a series of marriage equality rallies held across Australia over 2010, non-conjugal forms of intimacy were inadvertently sidelined in order to make a claim for relationship recognition. In a letter to the Sydney Star Observer, a reader laments: As a gay man, I cannot understand why gay people would want to engage in a heterosexual ritual called marriage … Why do gay couples want to buy into this ridiculous notion is beyond belief. The laws need to be changed so that gays are treated equal under the law, but this is not to be confused with marriage as these are two separate issues... (Michael 2) Marriage marks a privileged position of citizenship and consumption, to which all other gay and lesbian rights claims are tangential. Moreover, as this letter to the Sydney Star Observer implies, by claiming sexual citizenship through the rubric of marriage, discussions about other campaigns for legislative equality are effectively foreclosed. Melissa Gregg expands on such a problematic, noting that the legal responses to equality reiterate a normative relationship between sexuality and power, where only couples that subscribe to dyadic, marriage-like relationships are offered entitlements by the state (4). Correspondingly, much of the public activism around marriage equality in Australia seeks to achieve its impact for equality (reforming the Marriage Act) by positioning intimacy in terms of state legitimacy. Butler and Warner argue that when speaking of legitimacy a relation to what is legitimate is implied. Lisa Bower corroborates this, asserting "legal discourse creates norms which universalise particular modes of living…while suppressing other practices and identities" (267). What Butler's and Bower's arguments reveal is that legitimacy is obtained through the extension of marriage to homosexual couples. For example, Andrew Barr, the current Labor Party Education Minister in the Australian Capital Territory (ACT), noted that "saying no to civil unions is to say that some relationships are more legitimate than others" (quoted in "Legal Ceremonies"). Ironically, such a statement privileges civil unions by rendering them as the normative basis on which to grant legal recognition. Elizabeth Povinelli argues the performance of dyadic intimacy becomes the means to assert legal and social sovereignty (112). Therefore, as Jenni Millbank warns, marriage, or even distinctive forms of civil unions, if taken alone, can entrench inequalities for those who choose not to participate in these forms of recognition (8). Grassroots mobilisation and political lobbying strategies around marriage equality activism can have the unintentional impact, however, of obscuring peripheral forms of intimacy and subsequently repudiating those who contest the movement towards marriage. Warner argues that those who choose to marry derive pride from their monogamous commitment and "family" oriented practice, a privilege afforded through marital citizenship (82). Conversely, individuals and couples who deviate from the "normal" (read: socially palatable) intimate citizen, such as promiscuous or polyamorous subjects, are rendered shameful or pitiful. This political discourse illustrates that there is a strong impetus in the marriage equality movement to legitimate "homosexual love" because it mimics the norms of monogamy, stability, continuity and family by only seeking to substitute the sex of the "other" partner. Thus, civil rights discourse maintains the privileged political economy of marriage as it involves reproduction (even if it is not biological), mainstream social roles and monogamous sex. By defining social membership and future life in terms of a heterosexual life-narrative, same-sex couples become wedded to the idea of matrimony as the basis for sustainable intimacy and citizenship (Berlant and Warner 557). Warner is critical of recuperating discourses that privilege marriage as the ideal form of intimacy. This is particularly concerning when diverse erotic and intimate communities, which are irreducible to normative forms of citizenship, are subject to erasure. Que(e)rying the Future of Ethics and Politics By connecting liberal equality arguments with Butler and Warner's work on queer ethics, there is hesitation towards privileging marriage as the ultimate form of intimacy. Moreover, Butler stresses the importance of a transformative practice of queer intimacy: It is crucial…that we maintain a critical and transformative relation to the norms that govern what will not count as intelligible and recognisable alliance and kinship. (Undoing 117) Here the author attempts to negotiate the complex terrain of queer citizenship and ethics. On one hand, it is necessary to be made visible in order to engage in political activism and be afforded rights within a state discourse. Simultaneously, on the other hand, there is a need to transform the prevailing hetero-normative rhetoric of romantic love in order to prevent pathologising bodies or rendering certain forms of intimacy as aberrant or deviant because, as Warner notes, they do not conform to our perception of what we understand to be normal or morally desirable. Foucault's work on the aesthetics of the self offers a possible transformational practice which avoids the risks Warner and Butler mention because it eludes the "normative determinations" of moralities and publics, whilst engaging in an "ethical stylization" (qtd. in Race 144). Whilst Foucault's work does not explicitly address the question of marriage, his work on friendship gestures to the significance of affective bonds. Queer kinship has the potential to produce new ethics, where bodies do not become subjects of desires, but rather act as agents of pleasure. Negotiating the intersection between active citizenship and transformative intimacy requires rethinking the politics of recognition and normalisation. Warner is quite ambivalent as to the potential of appropriating marriage for gays and lesbians, despite the historical dynamism of marriage. Rather than acting as a progressive mechanism for rights, it is an institution that operates by refusing to recognise other relations (Warner 129). However, as Alexander Duttmann notes, recognition is more complex and a paradoxical means of relation and identification. It involves a process in which the majority neutralises the difference of the (minority) Other in order to assimilate it (27). However, in the process of recognition, the Other which is validated, then transforms the position of the majority, by altering the terms by which recognition is granted. Marriage no longer simply confers recognition for heterosexual couples to engage in reproduction (Secomb 133). While some queer couples may subscribe to a monogamous relationship structure, these relationships necessarily trouble conservative politics. The lamentations of the Australian Christian Lobby regarding the "fundamental (anatomical) gender complementarity" of same-sex marriage reflect this by recognising the broader social transformation that will occur (and already does with many heterosexual marriages) by displacing the association between marriage, procreation and parenting (5). Correspondingly, Foucault's work assists in broadening the debate on relationship recognition by transforming our understanding of choice and ethics in terms of "queer friendship." He describes it as a practice that resists the normative public distinction between romantic and platonic affection and produces new aesthetics for sexual and non-sexual intimacy (Foucault, Essential 170). Linnell Secomb argues that this "double potential" alluded to in Foucault and Duttman's work, has the capacity to neutralise difference as Warner fears (133). However, it can also transform dominant narratives of sexual citizenship, as enabling marriage equality will impact on how we imagine traditional heterosexual or patriarchal "plots" to intimacy (Berlant, "Intimacy" 286). Conclusion Making an informed impact into public debates on marriage equality requires charting the locus of sexuality, intimacy and citizenship. Negotiating academic discourses, social and community activism, with broader institutions and norms presents political and social challenges when thinking about the sorts of intimacy that should be recognised by the state. The civil right to marriage, irrespective of the sex or gender of one's partner, reflects a crucial shift towards important democratic participation of non-heterosexual citizens. However, it is important to note that the value of such intimacy cannot be indexed against a single measure of legal reform. While Butler and Warner present considered indictments on the normalisation of queer intimacy through marriage, such arguments do not account for the impacts of que(e)rying cultural norms and practices through social and political change. Marriage is not a singular or a-historical construction reducible to state recognition. Moreover, in a secular democracy, marriage should be one of many forms of diverse relationship recognition open to same-sex and gender diverse couples. In order to expand the impact of social and legal claims for recognition, it is productive to rethink the complex nature of recognition, ritual and aesthetics within marriage. 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