Journal articles on the topic 'Failsafe mechanism'

Autonomous Aerial Refueling (AAR) is vulnerable to various failures and involves cooperation among autonomous receivers, tankers and remote pilots. Dangerous flight maneuvers may be executed when unexpected failures or command conflicts happen. To solve this problem, a failsafe mechanism based on State Tree Structures (STS) is proposed. The failsafe mechanism is a control logic that guides what subsequent actions the autonomous receiver should take, by observing real-time information of internal low-level subsystems such as guidance and drogue&probe and external instructions from tankers and pilots. To generate such a controller using STS, the AAR procedure is decomposed into several modes, and safety issues related with seven low-level subsystems are summarized. Then common functional demands and safety requirements are textually described. On this basis, the AAR plants and specifications are modeled by STS, and a supervisor is synthesized to control the AAR model. To prove its feasibility and correctness, a simulation environment incorporating such a logic supervisor is built and tested. The design procedures presented in this paper can be used in decision-making strategies for similar flight tasks. Supporting materials can be downloaded in Github, [ https://github.com/KevinDong0810/Failsafe-Design-for-AAR-using-STS ] including related software, input documents and output files.

The opportunistic pathogenPseudomonas aeruginosais capable of establishing severe and persistent infections in various eukaryotic hosts. It encodes a wide array of virulence factors and employs several strategies to evade immune detection. In the present study, we screened the Harvard Medical School transposon mutant library ofP. aeruginosaPA14 for bacterial factors that modulate interleukin-8 responses in A549 human airway epithelial cells. We found that in addition to the previously identified alkaline protease AprA, the elastase LasB is capable of degrading exogenous flagellin under calcium-replete conditions and prevents flagellin-mediated immune recognition. Our results indicate that the production of two proteases with anti-flagellin activity provides a failsafe mechanism forP. aeruginosato ensure the maintenance of protease-dependent immune-modulating functions.

We profiled soybean and Arabidopsis methylomes from the globular stage through dormancy and germination to understand the role of methylation in seed formation. CHH methylation increases significantly during development throughout the entire seed, targets primarily transposable elements (TEs), is maintained during endoreduplication, and drops precipitously within the germinating seedling. By contrast, no significant global changes in CG- and CHG-context methylation occur during the same developmental period. An Arabidopsis ddcc mutant lacking CHH and CHG methylation does not affect seed development, germination, or major patterns of gene expression, implying that CHH and CHG methylation does not play a significant role in seed development or in regulating seed gene activity. By contrast, over 100 TEs are transcriptionally de-repressed in ddcc seeds, suggesting that the increase in CHH-context methylation may be a failsafe mechanism to reinforce transposon silencing. Many genes encoding important classes of seed proteins, such as storage proteins, oil biosynthesis enzymes, and transcription factors, reside in genomic regions devoid of methylation at any stage of seed development. Many other genes in these classes have similar methylation patterns, whether the genes are active or repressed. Our results suggest that methylation does not play a significant role in regulating large numbers of genes important for programming seed development in both soybean and Arabidopsis. We conclude that understanding the mechanisms controlling seed development will require determining how cis-regulatory elements and their cognate transcription factors are organized in genetic regulatory networks.

Bovine adrenal zona fasciculata (AZF) cells express bTREK-1 K+ channels that set the resting membrane potential and function pivotally in the physiology of cortisol secretion. Inhibition of these K+ channels by adrenocorticotropic hormone (ACTH) or cAMP is coupled to depolarization and Ca2+ entry. The mechanism of ACTH and cAMP-mediated inhibition of bTREK-1 was explored in whole cell patch clamp recordings from AZF cells. Inhibition of bTREK-1 by ACTH and forskolin was not affected by the addition of both H-89 and PKI(6–22) amide to the pipette solution at concentrations that completely blocked activation of cAMP-dependent protein kinase (PKA) in these cells. The ACTH derivative, O-nitrophenyl, sulfenyl-adrenocorticotropin (NPS-ACTH), at concentrations that produced little or no activation of PKA, inhibited bTREK-1 by a Ca2+-independent mechanism. Northern blot analysis showed that bovine AZF cells robustly express mRNA for Epac2, a guanine nucleotide exchange protein activated by cAMP. The selective Epac activator, 8-pCPT-2′-O-Me-cAMP, applied intracellularly through the patch pipette, inhibited bTREK-1 (IC50 = 0.63 μM) at concentrations that did not activate PKA. Inhibition by this agent was unaffected by PKA inhibitors, including RpcAMPS, but was eliminated in the absence of hydrolyzable ATP. Culturing AZF cells in the presence of ACTH markedly reduced the expression of Epac2 mRNA. 8-pCPT-2′-O-Me-cAMP failed to inhibit bTREK-1 current in AZF cells that had been treated with ACTH for 3–4 d while inhibition by 8-br-cAMP was not affected. 8-pCPT-2′-O-Me-cAMP failed to inhibit bTREK-1 expressed in HEK293 cells, which express little or no Epac2. These findings demonstrate that, in addition to the well-described PKA-dependent TREK-1 inhibition, ACTH, NPS-ACTH, forskolin, and 8-pCPT-2′-O-Me-cAMP also inhibit these K+ channels by a PKA-independent signaling pathway. The convergent inhibition of bTREK-1 through parallel PKA- and Epac-dependent mechanisms may provide for failsafe membrane depolarization by ACTH.

During Drosophila melanogaster metamorphosis, arrested immature neurons born during larval development differentiate into their functional adult form. This differentiation coincides with the downregulation of two zinc-finger transcription factors, Chronologically Inappropriate Morphogenesis (Chinmo) and the Z3 isoform of Broad (Br-Z3). Here, we show that br-Z3 is regulated by two microRNAs, let-7 and miR-125, that are activated at the larval-to-pupal transition and are known to also regulate chinmo. The br-Z3 3′UTR contains functional binding sites for both let-7 and miR-125 that confers sensitivity to both of these microRNAs, as determined by deletion analysis in reporter assays. Forced expression of let-7 and miR-125 miRNAs leads to early silencing of Br-Z3 and Chinmo and is associated with inappropriate neuronal sprouting and outgrowth. Similar phenotypes were observed by the combined but not separate depletion of br-Z3 and chinmo. Because persistent Br-Z3 was not detected in let-7-C mutants, this work suggests a model in which let-7 and miR-125 activation at the onset of metamorphosis may act as a failsafe mechanism that ensures the coordinated silencing of both br-Z3 and chinmo needed for the timely outgrowth of neurons arrested during larval development. The let-7 and miR-125 binding site sequences are conserved across Drosophila species and possibly other insects as well, suggesting that this functional relationship is evolutionarily conserved.

Bacterial cell division and peptidoglycan (PG) synthesis are orchestrated by the coordinated dynamic movement of essential protein complexes. Recent studies show that bidirectional treadmilling of FtsZ filaments/bundles is tightly coupled to and limiting for both septal PG synthesis and septum closure in some bacteria, but not in others. Here we report the dynamics of FtsZ movement leading to septal and equatorial ring formation in the ovoid-shaped pathogen, Streptococcus pneumoniae. Conventional and single-molecule total internal reflection fluorescence microscopy (TIRFm) showed that nascent rings of FtsZ and its anchoring and stabilizing proteins FtsA and EzrA move out from mature septal rings coincident with MapZ rings early in cell division. This mode of continuous nascent ring movement contrasts with a failsafe streaming mechanism of FtsZ/FtsA/EzrA observed in a ΔmapZ mutant and another Streptococcus species. This analysis also provides several parameters of FtsZ treadmilling in nascent and mature rings, including treadmilling velocity in wild-type cells and ftsZ(GTPase) mutants, lifetimes of FtsZ subunits in filaments and of entire FtsZ filaments/bundles, and the processivity length of treadmilling of FtsZ filament/bundles. In addition, we delineated the motion of the septal PBP2x transpeptidase and its FtsW glycosyl transferase-binding partner relative to FtsZ treadmilling in S. pneumoniae cells. Five lines of evidence support the conclusion that movement of the bPBP2x:FtsW complex in septa depends on PG synthesis and not on FtsZ treadmilling. Together, these results support a model in which FtsZ dynamics and associations organize and distribute septal PG synthesis, but do not control its rate in S. pneumoniae.

Abstract Background: Cellular senescence has been recognized as a failsafe mechanism against hyperproliferation and might thus be induced by DNA replicative stress and oncogenic signaling, commonly termed oncogene-induced senescence (OIS). OIS has been described in several premalignant conditions such as colon adenomas and melanocytic nevi, with impaired OIS capabilities found in their malignant counterparts. Here, we analyze the possible impact of cellular senescence on malignant transformation in plasma cell disorders. Methods: Bone marrow and soft tissue biopsies from 125 patients with different stages of plasma cell disorders (16 monoclonal gammopathy of undetermined significance (MGUS), 32 smoldering multiple myeloma (SMM), 56 symptomatic multiple myeloma (MM), 21 extramedullary MM) as well as from 10 healthy donors were analyzed. Expression of OIS associated proteins p16INK4A, p21Cip1/Waf1, p27Kip1, phospho-Chk2, the DNA double-strand break marker γH2AX, as well as the proliferation marker Ki67 were assessed on plasma cells by immunohistochemistry. Additionally, double staining experiments for p21 and Ki67 were performed applying immunofluorescence confocal microscopy. Levels of protein expression were compared between different disease stages using the Kruskal-Wallis test. Results: A differential expression pattern was found for p21 in various stages of plasma cell disorders with peak expression of p21 in SMM compared to both healthy controls (p<0.001) and MGUS (p=0.02), as well as compared to symptomatic multiple myeloma (MM) (p=0.007) (see Figure 1a). Median p21 expression was 0.63% of plasma cells from healthy subjects, 6.67% in MGUS, 13.81% in SMM, 2.37% in MM, and 0% in EMM. Plasma cells of SMM patients expressing p21 were negative for Ki67 consistent with a potentially senescent phenotype. In contrast, p27 was highly expressed in healthy controls, MGUS and SMM but decreased significantly in MM patients (p=0.02) (see Figure 1b). p16 showed no nuclear expression in healthy controls, MGUS or SMM and was expressed only in few patients with MM. In addition, we found low expression of p21, p27 and phospho-Chk2 in extramedullary MM compared to medullary MM samples, accompanied by increased expression of γH2AX and high levels of proliferation (Ki67 58%). Conclusions: We found indication of induction of OIS in SMM compared to symptomatic MM, mainly mediated by increased expression of p21. Further disease progression to extramedullary MM was characterized by almost complete absence of OIS markers and increased signs of DNA damage and proliferation. These observations are consistent with the hypothesis of OIS as a breakpoint mechanism against malignant transformation in plasma cell disorders and should be further explored mechanistically and as a possible therapeutic target. Figure 1 Expression levels of p21 and p27in different stages of plasma cell disorders. Semiquantitative assessment of plasma cells positive for p21 (a) and p27 (b) is shown in healthy controls, MGUS, SMM, MM, and EMM patients. Significant differences in expression levels between cohorts are indicated by their respective p-values with * p-value < 0.05, ** < 0.01, *** < 0.001. Figure 1. Expression levels of p21 and p27in different stages of plasma cell disorders. Semiquantitative assessment of plasma cells positive for p21 (a) and p27 (b) is shown in healthy controls, MGUS, SMM, MM, and EMM patients. Significant differences in expression levels between cohorts are indicated by their respective p-values with * p-value < 0.05, ** < 0.01, *** < 0.001. Disclosures Goldschmidt: Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Chugai: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium: Membership on an entity's Board of Directors or advisory committees, Research Funding; Onyx: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Raab:Novartis: Consultancy, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Consultancy.

This article contains the analysis of the performance of interface hoses for the thermal conditioning system of a Cyclone-4 space rocket in extreme operating conditions. thermal conditioning system interfaces with rubber hoses must ensure a tightness of a hose at a rocket’s inlet with easy detachment, involving little to no force impact on the rocket during its start on its one end, and rigid connection with a pipeline of the thermal conditioning system ground part, ensuring the hose tightness and retaining after the launch of a rocket on its other end, under any abnormal operating conditions. As it is shown in the article, this goal is attained by inducing contact stresses on surfaces adjacent to the rubber hose, originating from a designed radial compressive stress and coarseness of the contact surfaces. At the same time, the detachable part is subjected to lower radial deformation than the fixed one. To prevent any operating pressure excess in the thermal conditioning system ground part that might lead to extreme operating conditions, the retaining and release mechanism has been designed in such a way that under the operating conditions of pressing the hose’s sealing part, a proper stable gap would be ensured between the external radius of the rocket’s inlet protrusion and the internal diameter of its rim, so that the hose's sealing part could act as a safety valve. In such case, upon an excess of the permissible operating pressure, the hose’s sealing part would protrude through the gap mentioned by expanding and getting thinner, thus leading to detachment of the hose from the rocket’s inlet in the course of its launch or launch abort. In case of the retaining and release mechanism’s pin failure, the thermal conditioning system interface design would ensure the guaranteed failsafe detachment of the thermal conditioning system hoses with minimum stress on both the rocket and the thermal conditioning system ground part. As in a case of a critical pressure excess in the thermal conditioning system, the hose’s sealing part would act as a safety valve thanks to its axial extension under stresses from the rocket’s launch, the transportation and erection installation’s boom movement, or both factors at the same time. The hose’s sealing part, having a smaller cross-section in the area of the groove for retaining and release mechanism, would shrink in thickness during stretching and expand through the gap between the outer diameter of the rocket’s inlet protrusion and the internal diameter of the retaining and release mechanism’s rim, which was proven experimentally on a special test bench simulating operating conditions close to the real ones. At the same time, the stresses of the hose detachment from the rocket’s inlet are less than the hose’s rupture stresses in the axial direction by several orders during stretching.

Abstract As a barrier against malignant transformation, checkpoint-mediated failsafe mechanisms such as apoptosis or cellular senescence may be activated in response to mitogenic oncogenes. Acute induction of oncogenic Ras has been shown to provoke a senescence-like cell-cycle arrest that involves the retinoblastoma (Rb) pathway. Recently, Rb-mediated formation of heterochromatin was identified as a critical feature of cellular senescence. Since methylation of histone H3 lysine 9 by the Rb-bound histone methyltransferase Suv39h1 contributes to the transcriptional repression of growth promoting genes, we asked whether inactivation of Suv39h1 may disable cellular senescence as a suppressor mechanism against malignant transformation by oncogenic Ras. To investigate the role of Suv39h1 in Ras-driven lymphomagenesis, Eμ-N-ras-transgenic mice were crossbred to mice harboring targeted deletions in the Suv39h1 locus, as well as to p53 knockout mice. Ras-transgenic mice with no additional defined genetic lesion - hereafter referred to as controls - developed a terminal condition mostly due to a neoplastic histiocytic infiltration of the liver with a median latency of about 250 days. In stark contrast, ras-transgenic mice lacking Suv39h1, or carrying heterozygous defects in the Suv39h1 or p53 locus, respectively, entered a final disease stage significantly earlier, i.e. at a median age of 50 to 100 days, due to aggressive T cell lymphomas that were virtually absent or only sporadically found in the control group. Importantly, similar to p53+/− mice which typically lost the remaining wild-type allele in lymphoma cells, Suv39h1 heterozygous mice produced tumors that invariably lacked Suv39h1 expression, rendering these lymphomas in fact Suv39h1 null. Suv39h1 null cells propagated as primary cultures grew readily in an exponential fashion, surpassed only by the growth potential of p53 null cells. In short-term cytotoxicity assays, the anticancer agent adriamycin efficiently killed both control and Suv39h1 null lymphoma cells, whereas p53 null cells were resistant, indicating no overt apoptotic defect in Suv39h1 null cells. While non-neoplastic ras-transgenic Suv39h1+/+ cells exhibited heterochromatin foci reminiscent of cellular senescence, this phenotype was completely lost in Suv39h1 null lymphoma cells. In the presence of Bcl2 - introduced to block apoptotic cell death - adriamycin-treated control cells entered cellular senescence, whereas Suv39h1 null cells failed to display a senescent phenotype in response to therapy, demonstrating that stress-inducible senescence is a Suv39h1-dependent program. The data unveil the fundamental role of cellular senescence as a tumor suppressor principle by establishing a novel link between Ras-driven transformation and deregulated histone modification in vivo. Impaired cellular senescence due to inactivation of the histone H3 lysine 9 methyltransferase Suv39h1 promotes malignant transformation by oncogenic Ras, leading to a dramatic acceleration of Ras-driven lymphoma formation. Moreover, the observation that a full-blown malignancy may arise as a consequence of disabled senescence but without an apparent apoptotic defect has important therapeutic implications.

Abstract Activation of the DNA damage response (DDR) was recently claimed to serve as a critical anti−cancer barrier in early human tumorigenesis (Bartkova−J et al., and Gorgoulis−VG et al., Nature, 2005). As a consequence, deregulation of the DDR machinery may be required for tumor manifestation. Myc activation is an oncogenic event frequently detected in malignant lymphomas. It is known that constitutive Myc expression provokes apoptosis via the ARF/p53 pathway as a cellular failsafe mechanism to counteract malignant transformation, but the potential role of Myc signaling to the DDR machinery, mediated via the Atm (ataxia telangiectasia mutated) kinase, as another putative tumor suppressive restraint remains still elusive. Utilizing a tamoxifen−regulatable Myc system as well as RNA interference in vitro, we found in cell−based models that acute induction of Myc, associated with an increased production of reactive oxygen species (ROS) and marks of DNA strand breaks, leads to p53 activation which is mainly mediated by Atm and its upstream regulator PP5. To further examine the role of Atm during Myc−driven tumorigenesis in vivo, we intercrossed Atm knockout mice to Eμ−myc transgenic mice that develop B−cell lymphomas. Lymphomas formed significantly faster in the absence of Atm, mostly due to a significant apoptotic defect in Atm−/− lymphomas compared to Atm+/+ derived (referred to as ‘control’) lymphomas. In accordance with our in vitro findings, we detected significantly elevated levels of ROS−induced oxidative DNA damage and γ−H2AX foci in Myc−driven lymphomas. Importantly, constitutive expression of Myc selected against components of the Atm−governed DDR in a subset of control lymphomas. Like Atm deficiency, these lesions predetermined a poor response in subsequent cytotoxicity assays in vitro and anticancer therapy in vivo, since DNA damaging treatments also produce apoptosis via PP5/Atm. The role for ROS as inducers of DNA damage during the execution of Myc−induced apoptosis was further substantiated by the finding that Eμ−myc transgenic mice continuously exposed to the ROS scavenger N−acetylcysteine (starting prenatally) developed lymphomas with significantly reduced levels of spontaneous apoptosis and with less marks of DNA damage (i.e. γ−H2AX foci), but a retained ability to respond to anticancer therapy in vitro and in vivo. Hence, Atm eliminates pre−neoplastic lesions by converting oncogenic signaling into apoptosis, while selection for an attenuated Atm response permits lymphoma formation, and, in turn, has profound implications for reduced efficacy of DNA damaging therapies.

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 Abstract 107 Introduction: Premature senescence is a cellular failsafe mechanism which is induced upon various cellular insults, such as oncogene activation or exposure to DNA damaging chemotherapy. It suppresses tumor formation and acts as a barrier to tumor progression in vivo. In contrast to apoptotic cells, senescent cells are viably arrested in the G1 phase of the cell cycle. They continue to take up nutrients and interact with tumor and host cells. To what extent senescent cells alter the tumor environment and tumor-host interactions remains largely unsolved. Here, we analyze lymphoma cells with defined genetic lesions, e.g. deletion of the histone H3 lysine 9 methyltransferase Suv39h1 (controlling senescence) and p53 (mediating both apoptosis and senescence), for their influence on immunological tumor-host interactions as a consequence of therapy-induced senescence (TIS) in the Eμ-myc mouse lymphoma model. Our data demonstrate for the first time a senescence-primed T-cell response against lymphoma cells in vitro and in vivo. Methods: Lymphoma cells (LCs) from different genetic were retrovirally transduced with the bcl2 gene to block apoptosis. Subsequently, they were treated with the DNA damaging anticancer agent adriamycin in vitro or the alkylating agent cyclophosphamide upon lymphoma formation in normal immunocompetent mice in vivo. Therapy-inducible senescence (TIS) was detected based on senescence-associated b-galactosidase activity (SA-b-gal), Ki67 staining and BrdU incorporation. The cytokine profile of senescent LCs was analysed by gene expression and protein arrays. Infiltration and activation of immune cells in TIS lymphomas was analysed by immunohistochemistry and flow cytometry with leukocyte-specific antibodies. Immune responses elicited upon TIS induction in vivo were further analysed in gld (generalized lymphoproliferative disease) mice, which lack functional FasL and by systemic depletion of macrophages after clodronate administration. Pharmaceutical inhibitors of FasL and perforin and IFNg knockout mice were used to analyze T-cell mediated cytotoxity in vitro. Results: TIS lymphoma cells, but not Suv39h1- or p53-deficient LCs, upregulate the secretion of pro-inflammatory cytokines, such as IL6 and IL12, with pro-inflammatory on tumor and bystander cells. In vivo, TIS correlates with the attraction of immune cells, particularly macrophages and T cells, to the tumor site. Senescent LCs became sensitive to both macrophage engulfment and death receptor (Fas)-mediated apoptosis. Activation of both CD4 and CD8 T cells leads to production of IFNg and clearing of senescent cells. Clearance can be attenuated by systemic depletion of macrophages and interference with T cell-mediated programmed cell death. T-cells specifically primed by TIS cells in vivo potently killed both senescent and proliferating LCs after isolation and co-incubation in vitro. In vivo clearance of TIS LCs was attenuated by systemic depletion of macrophages or by interference with T-cell-mediated programmed cell death. Lymphoma-bearing gld mice presented with a reduced overall survival when compared to wild-type host mice. Discussion: This study demonstrates that therapy-induced senescence drives a profound remodeling of the tumor site after therapy and unveils functional interactions of senescent LCs with different immune cell subsets in vitro and in vivo. Senescent cells secrete a cytokine program, which stimulates immune cell attraction and an adaptive and presumably lastingly protective immune response. Thus, TIS is a highly dynamic and interdependent process whose paracrine effects and immune cell interactions account for regression of the senescent mass and present an attractive target network for novel therapeutic strategies. Disclosures: No relevant conflicts of interest to declare.

Superficially, screening programmes may seem relatively straightforward to organize. However they are much more complicated than appears at first sight. The UK National Screening Committee, set up in 1996, advises all four nations on the introduction of new screening programmes and the improvement or, less commonly, cessation of an established programme. Most of the established programmes have a Programme Centre which advises on the running of the programme and sets standards. Because true outcomes may be some years hence, these standards usually relate to the process, rather than health improvement. There are many different stages in the programmes from ascertaining the target population to timely diagnosis and prompt management. This means there are a number of places where the system might fail. Therefore, part of the advice offered by the Programme Centres relates to failsafe mechanisms. These are backup systems, designed to make sure that no child slips through the net and all are correctly assigned to high or low risk groups. These systems may be expensive, but are necessary and cost effective. A missed diagnosis causes unnecessary disability to the child and distress to the parents, and may be very costly to the health service.

The regulation of infection and inflammation by a variety of host peptides may represent an evolutionary failsafe in terms of functional degeneracy and it emphasizes the significance of host defense in survival. Neuropeptides have been demonstrated to have similar antimicrobial activities to conventional antimicrobial peptides with broad-spectrum action against a variety of microorganisms. Neuropeptides display indirect anti-infective capacity via enhancement of the host’s innate and adaptive immune defense mechanisms. However, more recently concerns have been raised that some neuropeptides may have the potential to augment microbial virulence. In this review we discuss the dual role of neuropeptides, perceived as a double-edged sword, with antimicrobial activity against bacteria, fungi, and protozoa but also capable of enhancing virulence and pathogenicity. We review the different ways by which neuropeptides modulate crucial stages of microbial pathogenesis such as adhesion, biofilm formation, invasion, intracellular lifestyle, dissemination, etc., including their anti-infective properties but also detrimental effects. Finally, we provide an overview of the efficacy and therapeutic potential of neuropeptides in murine models of infectious diseases and outline the intrinsic host factors as well as factors related to pathogen adaptation that may influence efficacy.

Aust G, Lehmann I, Laue S, Scherbaum WA. Activated and interferon-γ producing thyroid-derived T cells are detected in Graves' disease, thyroid autonomy as well as in non-toxic multinodular goiter. Eur J Endocrinol 1996;135:60–8. ISSN 0804–4643 The relative numbers of activated and interferon gamma (IFN-γ)-producing peripheral blood lymphocytes (PBL) and thyroid-derived lymphocytes (TL) were determined using double surface and intracellular labeling techniques in flow cytometry. Cells were analyzed from 10 patients with Graves' disease (GD), eight patients with thyroid autonomy (TA) and five patients with non-toxic multinodular goiter (NTG). A maximum of 1% IFN-γ+ cells were detected both in unstimulated PBL and TL. Stimulation caused a two- to threefold higher number of IFN-γ+ cells in TL (GD, 48 ± 12%; TA, 48 ± 11%; NTG, 50± 15%) as compared to PBL (GD, 15 ± 7%: TA, 16 ± 8%; NTG, 18 ± 10%) of the same patients. Nearly all IFN-γ+ TL in GD were CD3+ T cells, whereas 10–20% of IFN-γ+ TL in TA and NTG were NK cells. In PBL 80% and in TL almost 100% of IFN-γ+ cells were antigenprimed CD45RO+ cells. Only 25–35% of IFN-γ+ thyroid-derived T cells expressed the CD4 antigen. About 42 ± 10% thyroid-derived T cells in GD, 33 ± 11% in TA and 34 ± 13% in NTG expressed the HLA-DR molecule but not the interleukin 2 (CD25) or the transferrin receptor (CD71). Forty per cent of these HLA-DR+ T cells showed an intracellular staining for IFN-γ and half of them co-expressed the activation antigen CD69. Immunofluorescence double labeling on thyroid cryostat sections demonstrated that HLA-DR+ T cells were also present in situ. The presence of activation antigens on thyroid-derived T cells not only in patients with GD but also in TA and NTG suggests failsafe mechanisms such as anergy, suppression or cytokine regulation in so-called non-immunogenic goiter. Gabriela Aust, Department of Internal Medicine III, Endocrinology, University of Leipzig, Ph.-Rosenthal-Str. 27, Leipzig, D-04103, Germany

ABSTRACT Mammalian cells have established mechanisms to reduce the abundance of mRNAs that harbor a nonsense codon and prematurely terminate translation. In the case of the human triosephosphate isomerase (TPI gene), nonsense codons located less than 50 to 55 bp upstream of intron 6, the 3′-most intron, fail to mediate mRNA decay. With the aim of understanding the feature(s) of TPI intron 6 that confer function in positioning the boundary between nonsense codons that do and do not mediate decay, the effects of deleting or duplicating introns have been assessed. The results demonstrate that TPI intron 6 functions to position the boundary because it is the 3′-most intron. Since decay takes place after pre-mRNA splicing, it is conceivable that removal of the 3′-most intron from pre-mRNA “marks” the 3′-most exon-exon junction of product mRNA so that only nonsense codons located more than 50 to 55 nucleotides upstream of the “mark” mediate mRNA decay. Decay may be elicited by the failure of translating ribosomes to translate sufficiently close to the mark or, more likely, the scanning or looping out of some component(s) of the translation termination complex to the mark. In support of scanning, a nonsense codon does not elicit decay if some of the introns that normally reside downstream of the nonsense codon are deleted so the nonsense codon is located (i) too far away from a downstream intron, suggesting that all exon-exon junctions may be marked, and (ii) too far away from a downstream failsafe sequence that appears to function on behalf of intron 6, i.e., when intron 6 fails to leave a mark. Notably, the proposed scanning complex may have a greater unwinding capability than the complex that scans for a translation initiation codon since a hairpin structure strong enough to block translation initiation when inserted into the 5′ untranslated region does not block nonsense-mediated decay when inserted into exon 6 between a nonsense codon residing in exon 6 and intron 6.

Online user activities are tracked for many purposes. In e-commerce, cross-domain tracking is used to quantify and pay for web-traffic generation. Our previous research studies have shown that HTTP cookie-based tracking process, though reliable, can fail due to technical reasons, as well as through fraudulent manipulation by traffic generators. In this research study, we evaluate which of the previously published tracking mechanisms are still functional. We assess the efficacy and utility of those methods to create a robust tracking mechanism for e-commerce. A failsafe and robust tracking mechanism does not need to translate into further privacy intrusions. Many countries are rushing to introduce new regulations, which can have a negative impact on the development of robust technologies in an inherently stateless eco-system. We used a multi-domain, purpose-built simulation environment to experiment common tracking scenarios, and to describe the parameters that define the minimum tracking requirement use-cases, and practices that result in invading privacy of users. This study will help practitioners in their implementations, and policy developers and regulators to draw up policies that would not curtail the development of robust tracking technologies that are needed in e-commerce activities, while safeguarding the privacy of internet users.

Introduction The current social climate of Western societies understands fatness as the self-inflicted disease ‘obesity’; a chronic illness of epidemic proportions that carries accompanying risks of additional disease and that will eventually lead to death. In recent years, the stigmatisation and general negative societal evaluation of fatness and thus fat identities has increased (Sobal). Primarily, fatness has become a sign of medical deviance in that it is perceived to be a product of unhealthy eating behaviours and physical inactivity (Rothman). As a result, to be fat has become a barrier to entry in terms of employment opportunities, and has restricted the availability of health and insurance services for many (Sobal). Recently there has been a drastic increase in the availability of radical weight-loss solutions that strictly regulate and police fat-bodied deviants, namely in the form of surgery. Bariatric surgery, or weight-loss surgery, physically enforces the achievement of ‘health’ by curing obesity by reducing the size and functionality of the stomachs of the morbidly obese. However, bariatric ‘post-ops’ (short for post-operative) often encounter harmful consequences following their surgery in the form of increased self-surveillance, regulation and control in order to maintain their health through thinness. This article seeks to examine these consequences of surgery as a way to problematise the achievement of health through thinness overall. In order to address this issue, this article first establishes a framework of obesity discourse which enables us to understand how obesity is perceived as a self-inflicted disease in need of medical intervention within modern Western societies. From this position, we can begin to understand the purpose of interventions such as bariatric surgery. While it is acknowledged that surgery provides the morbidly obese with a gateway to health through the achievement of thinness and an escape from a heavily stigmatised identity, it is argued that this is done at the expense of placing increased regulations and surveillance upon individuals. Finally, in drawing on post-op experiences collected for research examining the life impacts of bariatric surgery, this article will examine how post-ops are subjected to intense policing, monitoring and regulating from themselves and others as a result of achieving and maintaining ‘health’ through body size. Obesity Discourse: Establishing a FrameworkScholars Evans, Rich, Davies and Allwood argue that contemporary Western responses to obesity can be conceptualised as operating within an ‘obesity discourse’ which provides a framework of “thought, talk and action concerning the body in which ‘weight’ is privileged not only as a primary determinant but as a manifest index of well-being” (13). Predominantly, this framework draws upon two key assumptions; that obesity is a legitimate and measurable disease that poses significant medical risks to populations, and that both the cause of and solution to obesity are individual lifestyle choices (Rich, Monaghan and Aphramor). More specifically, the obesity discourse is the result of the combined efforts of an extensive process of medicalisation in conjunction with an increasingly neoliberal approach to healthcare. Since the 1950s, fatness has been widely regarded as the disease ‘obesity’. Sobal argues that this occurred through an extensive process of medicalisation, which can be defined as when non-medical issues and behaviour are redefined and understood as medical problems through the use of medical jargon and medical solutions (Conrad). In particular, fat was portrayed as pathological and requiring medical intervention through “frequent, powerful and persuasive claims that [medicine] should exercise social control over fatness” (Sobal 69). In particular this has been exercised through the widespread implementation of the body mass index [BMI] into healthcare settings, as it is seen as an accessible, practical and affordable measure of ‘health’ (Ministry of Health). Unlike other markers of health, body weight is highly visible, and thus using it as an overall indicator of health increases surveillance of the self and others within populations. In this way we can see how the medicalisation of fatness works to produce what Bordo refers to as:one of the most powerful normalizing mechanisms of our century, insuring the production of self-monitoring and self-disciplining ‘docile bodies’ sensitive to any departure from social norms and habituated to self-improvement and self-transformation in the service of these norms. (186)Primarily, this is created through a construction of a ‘normal’ body shape or an ‘ideal’ weight, which can be specified using the BMI, and acts as a health imperative for individuals to achieve and maintain (Rich and Evans). However, these constructions do not factor in individual variations in body composition and thus represent a medically defined ‘thin ideal’, in that they are unobtainable and unrealistic for most people (Metzl 5). Consequently, the idea of a ‘normal weight’ strengthens contemporary body ideals (Burns and Gavey).The recent move in contemporary Western societies towards a neoliberal model of healthcare has significantly impacted societal attitudes towards fatness. The neoliberal healthcare model emphasises an individual’s choice and responsibility with respect to their health, and the privatisation of healthcare systems overall (Fries). While there is a general belief that this change gives patients more autonomy and input within the medical encounter (Lupton), the move towards a ‘democratisation’ of healthcare in reality further entrenches self-surveillance behaviours within populations by asserting that the responsibility for achieving and maintaining ‘health’ lies at the feet of the individual (Fox, Ward and O’Rourke). In particular, there is an assumption that ‘health’ can be ‘unproblematically’ achieved through individual efforts to discipline and regulate body size (Crawford) and thus individuals are obliged to engage in acts of self-discipline as both a personal and public service (Throsby, War). In this way, those who are labelled as ‘obese’ are not only questioned on their ability to appropriately care for themselves, but also their ability to be a good citizen (Throsby, War). Overall, the obesity discourse has intensified the stigmatisation of the obese in that they are portrayed as morally bad and weak-willed (Sobal) and ultimately reinforced the need for external regulatory bodies such as the weight-loss industry to monitor and control the obese. The combined efforts of the medical and weight-loss industry have produced a single message which suggests that if individuals want to maintain ‘health’ and prevent disease, there must be an enduring commitment to a ‘lifestyle change’. A ‘lifestyle change’ implies that in order to achieve successful weight loss and thus ‘health’, there needs to be enduring amendments to diet and exercise that are perceived as a ‘way of life’ rather than the ‘means to an end’ message marketed by other diet regimes (Fullagar). These changes are necessitated through an assumption that excess body weight is a sign of laziness and poor personal habits (Evans and Colls). Similar to the causes of obesity, there is a definitive notion that individual choices predicate the outcomes of weight loss endeavours. Thus, weight-loss successes and failures directly reflect how well individuals adhered to their ‘lifestyle change’ rather than the reliability and validity of the weight-loss regimes themselves (Saguy and Riley).Addressing Bariatric Surgery: The Solution to Morbid ObesityOver the past decade there has been a drastic increase in the availability of radical weight-loss solutions that strictly regulate and police fat-bodied deviants, namely in the form of surgery. While there appears to be support from the medical community for the effectiveness of a ‘lifestyle change’ as the primary solution to obesity, it should be highlighted that a ‘lifestyle change’ is only seen as a realistic option for certain obesity cohorts. In particular, surgery is reserved for the very highest of obesity cohorts – the morbidly obese – and is presented as their only viable option. ‘Morbid obesity’ is defined as having a BMI of 40 or higher and is associated with the most risk of comorbid diseases such as type II diabetes, cardiovascular disease and hypertension (Foo et al.). According to the Ministry of Health, for individuals classified as morbidly obese, clinicians in New Zealand should strongly recommend bariatric surgery. Bariatric surgery describes a group of surgical procedures that physically restrict and redesign the stomachs of morbidly obese patients to achieve weight-loss as most procedures are permanent, and are associated with the greatest long-term weight loss in patients (Ministry of Health). Bariatric surgical procedures became popular due to their long-term effectiveness in weight-loss, and cost-effectiveness particularly for countries with public healthcare, through the drastic reduction in public health expenditure for co-morbid diseases such as diabetes and cardiovascular disease (Sampalis et al.). These procedures are considered the only effective treatment option for morbid obesity or a ‘last resort’ (Cranwell and Seymour-Smith; Ogden, Clementi and Aylwin), and consequently the amount of surgeries performed annually within Australasia has increased at an exponential rate (Buchwald and Williams).What makes bariatric surgery so important as a weight-loss method is that it offers the ‘morbidly obese’, who are seen as persistently deviating from idealised body norms and unable or unwilling to conform to standardised forms of self-regulation, a reprieve from their stigmatising identity. Indeed, many morbidly obese individuals who are seeking weight loss state that bariatric surgery is their only ‘hope’ or choice, or the ‘right’ choice for them (Morgan; Ogden, Clementi and Aylwin). In particular, the fear of, or the onset of, illnesses associated with obesity can be a major factor in their decision to undergo surgery (Ogden, Clementi and Aylwin). In this way, motivations to have surgery are heavily reflective of obesity discourse in that the presence of body fat is a marker of ‘impending doom’ (Rich, Monaghan and Aphramor). Indeed as Wann highlights:I really do understand why someone would consider this extreme option. The stigma attached to even the slightest amount of body fat can be daunting, and the surgeon’s sales pitch can be very slick. (41)However, as Morgan argues, more must be done to critique bariatric surgery as it largely exemplifies the social forces that control and regulate modern societies. Bariatric surgery physically enforces weight-loss and adherence to acceptable eating practices, and makes dissent both punishable and difficult (203). The removal of a large portion of the stomach means that, bariatric surgery imposes “corporeal order and discipline” (Morgan 203) upon individuals. The stomach not only enforces strict self-surveillance protocols but also an unyielding control over the individual through the “forceful prohibition or ejection” (Morgan 202) of substances. Thus, if individuals fail to regulate and govern their intake, the surgical intervention does it for them. The side-effects of vomiting and dumping syndrome act as a regulation failsafe and a form of punishment – an ‘internal policeman’ (Morgan) – that rejects deviant behaviour and punishes the individual through unpleasant and often painful experience. In this way, bariatric surgery can be viewed as the ‘ultimate weapon’ in the war against obesity as it is a means through which deviant individuals and bodies can be controlled and normalised (Glenn, McGannon and Spence).Bariatric Surgery: For Better or for Worse?In order to interrogate the dominant notion perpetuated through obesity discourse that fatness is a disease and body weight more generally is a legitimate way of measuring ‘health’ overall, this article will now draw on key findings generated from recent research examining the life impacts of bariatric surgery conducted with a support group for bariatric surgery in Auckland, New Zealand. While bariatric surgery is portrayed as a gateway to health, Throsby (Re-Birthday) argues that ultimately it is constructed as a ‘tool’ for weight-loss, rather than a cure-all ‘magic pill’ (130). This means that users are required to engage in normative dieting practices in the midst of developing new techniques of discipline that are specific to the post-surgery experience. In this way bariatric surgery creates new levels of self-surveillance that are unique to post-surgery life (Throsby, Re-Birthday 120). Self-surveillance and policing are methods in which bariatric post-ops are subjected to critique, monitoring and maintenance by both themselves and others. A key aspect of this involves the moral construction of ‘good’ and ‘bad’ foods, which often influenced eating behaviours and narratives whereby bariatric post-ops adhere to normalised understandings of diet, nutrition and health (Simpson 84). This dichotomy of good and bad foods reflects dominant understandings of the causal relationship between food, health and body size. Researchers have noted that there is a significant change in the relationship individuals have with food following surgery, and that often this comes with a serious fear of weight regain, and thus an intense policing of food (Cranwell & Seymour-Smith; Ogden, Clementi and Aylwin). Often, further restrictions are placed on an already restricted diet in order to achieve thinness, which emphasises the importance of achieving and maintaining thinness through the micromanagement of food intake (Simpson). In part, this reflects the way that the rhetoric that equates obesity with individual responsibility can equally ascribe blame to patients for any subsequent weight gain following surgery (Throsby, Re-Birthday 130) and indeed previous research has highlighted extensive fear of weight regain, particularly when users encounter fluctuations in their weight (Cranwell and Seymour-Smith). This is arguably what makes discussions around the concept of ‘maintenance’ so important. Maintenance refers to the monitoring process post-ops enter into after losing a significant portion of their weight and reaching a ‘plateau’, or a point where they stop losing weight; in essence it involves discussions around how to maintain and manage a ‘healthy’ weight (Simpson 79). Largely this draws on the assumption that despite being treated for obesity through a surgical intervention, one can never be recovered or truly ‘cured’ of obesity and thus individuals must engage in consistent monitoring as a preventative measure through ‘maintenance’ (Throsby, Re-Birthday). Maintenance is a complex process for bariatric post-ops; it is inextricably linked to weight management and is therefore a visible and moral indicator as to how ‘well’ post-ops are doing in their weight loss endeavours (Simpson). In this way maintenance is heavily couched in obesity discourse as individuals are expected to integrate self-surveillance and regulation practices into a ‘lifestyle change’ in order to prevent future weight gain (Cranwell and Seymour-Smith). For most, maintenance is difficult, and is understood to require a consistent consciousness of food related behaviours in order to be successful. In the observed support group, participants discussed the observations that they had made about their difficulties with resisting ‘crave’ or ‘bad’ foods (primarily those associated with high calories) that they enjoy, as well as revealing the ways in which they had altered their behaviour to address maintenance concerns (Simpson 79). One participant revealed that recent weight gain was making maintenance ‘very hard’, and it was clear that they attributed this weight gain to personal failings despite admitting that there had been no change to their ‘healthy’ eating behaviour (80). In order to address this issue, the participant admitted that they had resorted to traditional dieting rhetoric and removed dairy from their diet (83). Other support group members encouraged the participant to also remove carbohydrates from their diet (83), which further reinforced the notion that weight is a product of personal choice and individual responsibility (Crawford; Donaghue and Clemitshaw). As a result of the rapid weight loss achieved through bariatric surgery, many post-ops struggle to adjust to their ‘new’ bodies. This makes maintenance increasingly difficult as many individuals continue to see themselves as ‘fat’ despite having achieved a ‘normal’ weight (Simpson). Arguably a key factor in their misinterpretation of their body size and composition is the abundance of excess skin that is left over after rapid weight-loss. Excess skin, which has to be surgically removed and cannot be lost through diet or exercise, is a sore issue for bariatric post-ops, as it is a reminder of their former ‘fat’ selves, and thus a source of continuous dissatisfaction and lowered self-esteem (Groven, Råheim and Engelsrud). This is a common problem for many bariatric post-ops, with many citing that their low-hanging stomach or ‘apron’ is a primary source of anguish. Indeed, one post-op admitted that it was “even harder now because … it doesn’t seem to be going anywhere” (Simpson 63), and another revealed that while they consciously understood that their ‘apron’ was excess skin and not fat, they still used it as a sign that they must continue to lose weight. In this way, the reduction of the ‘apron’ has become a dangerous fixation for this post-op and the way in which they measure their success (Simpson 63). Further, post-ops were monitored by family and friends, primarily through concerns over their small portion sizes, which led them to develop techniques to escape the scrutiny of others (Simpson 78). One technique that was particularly popular was the use of a smaller side plate during dinner time (Simpson 78). A smaller plate was both an easy way for post-ops to monitor and regulate their portions, and a method of avoiding criticism and monitoring from others as it effectively masked their reduced portions from the gaze of others. Indeed many post-ops lamented over the consistent external pressures from friends and family to increase their intake and discussed further masking techniques such as moving food around the plate to convince others that they were eating (Simpson 78). These behaviours are troubling as they mimic many primarily observed within the eating disorder community (Prestwood) and indeed Rich and Evans highlight that the level of stigmatisation surrounding fat and body size may push obese individuals into disordered relationships with food, exercise and the body (354). This would suggest that the discourses surrounding the bariatric and the eating disorder communities have lines of similarity in that weight and in particular, thinness is privileged as the primary method in which health and overall personal success is measured (Burns and Gavey; Rich and Evans). Concluding RemarksThe existence of behaviours such as maintenance, food policing and body fixation forces us to question the extent to which bariatric surgery is a gateway at all to ‘health’. While bariatric surgery enables morbidly obese individuals to escape stigmatisation by achieving the appearance of health, often this comes at the expense of increased surveillance, regulation and control of the individual. In this way it would seem that solutions to obesity only serve to extend and intensify behaviours of regulation and control promoted through obesity discourse. Ultimately the reality of the post-op existence problematises the very foundational assumptions that the pursuit of thinness is a legitimate pursuit of health.ReferencesBordo, Susan. Unbearable Weight: Feminism, Western Culture and the Body. Los Angeles: University of California Press, 1993. Burns, Maree, and Nicola Gavey. “‘Healthy Weight’ at What Cost? ‘Bulimia’ and a Discourse of Weight Control.” Journal of Health Psychology 9.4 (2004): 549-65.Buchwald, Henry, and Stanley E. 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