GDF15 Provides an Endocrine Signal of Nutritional Stress in Mice and Humans.

GDF15 is an established biomarker of cellular stress. The fact that it signals via a specific hindbrain receptor, GFRAL, and that mice lacking GDF15 manifest diet-induced obesity suggest that GDF15 may play a physiological role in energy balance. We performed experiments in humans, mice, and cells to determine if and how nutritional perturbations modify GDF15 expression. Circulating GDF15 levels manifest very modest changes in response to moderate caloric surpluses or deficits in mice or humans, differentiating it from classical intestinally derived satiety hormones and leptin. However, GDF15 levels do increase following sustained high-fat feeding or dietary amino acid imbalance in mice. We demonstrate that GDF15 expression is regulated by the integrated stress response and is induced in selected tissues in mice in these settings. Finally, we show that pharmacological GDF15 administration to mice can trigger conditioned taste aversion, suggesting that GDF15 may induce an aversive response to nutritional stress.This work and authors were funded by the NIHR Cambridge Biomedical Research Centre; NIHR Rare Disease Translational Research Collaboration; Medical Research Council [MC_UU_12012/2 and MRC_MC_UU_12012/3]; MRC Metabolic Diseases Unit [MRC_MC_UU_12012/5 and MRC_MC_UU_12012.1]; Wellcome Trust Strategic Award [100574/Z/12/Z and 100140]; Wellcome Trust [107064 , 095515/Z/11/Z , 098497/Z/12/Z, 106262/Z/14/Z and 106263/Z/14/Z]; British Heart Foundation [RG/12/13/29853]; Addenbrooke’s Charitable Trust / Evelyn Trust Cambridge Clinical Research Fellowship [16-69] US Department of Agriculture: 2010-34323-21052; EFSD project grant and a Royal College of Surgeons Research Fellowship, Diabetes UK Harry Keen intermediate clinical fellowship (17/0005712). European Research Council, Bernard Wolfe Health Neuroscience Endowment, Experimental Medicine Training Initiative/AstraZeneca and Medimmune

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

The human dimensions of marine mammal management in a time of rapid change: comparing policies in Canada, Finland and the United States

Arctic coastal populations share a close relationship with their environment consisting of linkages among communities, landscapes and seascapes, and the social institutions developed to sustain the system. This cultural-biogeophysical dynamic is termed throughout the section as a social-ecological system (SES). Marine mammals constitute a large portion of the subsistence diet for these communities, and as such represent key ecological services provided by the system. At the same time, marine mammals have gained iconic status as symbols for climate change in the North. A tension results between the demands of balancing on one hand good policy optics consistent with national and international norms and, on the other hand, flexible and adaptive institutions able to take on the task of managing resources in a dynamic, changing North. This tension and associated policy solutions such as co-management are explored in a series of papers focusing on marine mammal management dilemmas and policy practices around the circumpolar North. This introduction communicates the problem context and describes the five papers making up this special section. A guiding premise to this work is that new international pressures to implement moratoria on marine mammal hunting in the North ignore critical human dimensions of marine mammal management. Such policy proposals are unlikely to succeed in areas that require collaboration across scales. Simultaneously, new local-scale participation in multi-level management regimes holds promise for creating more resilient marine mammal SESs.Marine mammals Human dimensions Policy Climate change Social-ecological systems Arctic

Building resilience through interlocal relations: Case studies of polar bear and walrus management in the Bering Strait

Arctic coastal communities in the Bering Strait region of Alaska (USA) and Chukotka (Russia) share a close relationship with their natural environments that can be characterized as a social-ecological system. This system is complex, featuring changing ecosystem conditions, multiple jurisdictions, migratory animal populations, and several cultures. We argue that linkages between communities in both countries enhance the effectiveness of transborder polar bear and walrus conservation. We find that locally embedded bilateral institutions can provide effective management venues that persist despite slow or lacking processes of international law because they provide a better fit between rules for managing and the true system state.Social-ecological systems Transborder conservation Wildlife management Cross-scale interactions Co-management Marine mammals

The role of a Williams-Beuren syndrome-associated helix–loop–helix domain-containing transcription factor in activin/nodal signaling

We investigated the regulation of the activin/nodal-inducible distal element (DE) of the Xenopus goosecoid (gsc) promoter. On the basis of its interaction with the DE, we isolated a Xenopus homolog of the human Williams-Beuren syndrome critical region 11 (XWBSCR11), and further, show that it interacts with pathway-specific Smad2 and Smad3 in a ligand-dependent manner. Interestingly, we also find that XWBSCR11 functions cooperatively with FoxH1 (Fast-1) to stimulate DE-dependent transcription. We propose a mechanism in which FoxH1 functions together with Smads as a cofactor for the recruitment of transcription factors like XWBSCR11 in the process of activin/nodal-mediated gsc-specific induction. This mechanism provides considerable opportunities for modulation of transcription across a variety of activin/nodal-inducible genes, increasing diversity in promoter selection, thus leading to the differential induction of activin/nodal target genes

Adaptive governance and the human dimensions of marine mammal management: Implications for policy in a changing North

As climate change has driven dramatic changes in Northern sea ice regimes, marine mammals have gained iconic status around the world reflecting the perils of global warming. There is a tension between policies that have international support like a ban on seal hunting or whaling, and the adoption of adaptive, flexible rules that are likely to work in Northern places. Whereas most wildlife policy focuses on biological information to inform policy strategy, this analysis focuses on the "human dimensions" of Northern marine mammal management. This research examines ways in which human relationships and modes of governance affect conservation success. Standard analyses of risk to animal populations focused on direct sources of take are inadequate to address multi-causal, complex problems such as climate-induced habitat loss or increased industrialization of the Arctic Ocean. Early conservation policy strategies focusing on the moratorium of take have eliminated or reduced such practices as commercialized hunting and high levels of fisheries bycatch, but may be less relevant in an era in which habitats and climate changes are key drivers of population dynamics. This paper argues that effective adaptive policy requires new ways of learning about and governing human interactions with marine mammals. Through an exploration of marine mammal management in three Northern regions (Alaska, Nunavut, and the Finnish Baltic Sea coast), the paper analyzes the extent to which these marine mammal management regimes are practicing adaptive governance, that is, building cross-scale (local to international) understanding while allowing actors at the local scale the flexibility to direct the creation of rules that are ecologically robust and likely to succeed. Lessons are taken from these examples and used to propose selected policy and research recommendations for the marine mammal policy community.Marine mammals Adaptive governance Institutional performance Climate change Arctic governance

Microarray optimizations: increasing spot accuracy and automated identification of true microarray signals

In this paper, fluorescent microarray images and various analysis techniques are described to improve the microarray data acquisition processes. Signal intensities produced by rarely expressed genes are initially correctly detected, but they are often lost in corrections for background, log or ratio. Our analyses indicate that a simple correlation between the mean and median signal intensities may be the best way to eliminate inaccurate microarray signals. Unlike traditional quality control methods, the low intensity signals are retained and inaccurate signals are eliminated in this mean and median correlation. With larger amounts of microarray data being generated, it becomes increasingly more difficult to analyze data on a visual basis. Our method allows for the automatic quantitative determination of accurate and reliable signals, which can then be used for normalization. We found that a mean to median correlation of 85% or higher not only retains more data than current methods, but the retained data is more accurate than traditional thresholds or common spot flagging algorithms. We have also found that by using pin microtapping and microvibrations, we can control spot quality independent from initial PCR volume

Microarray optimizations: increasing spot accuracy and automated identification of true microarray signals

In this paper, fluorescent microarray images and various analysis techniques are described to improve the microarray data acquisition processes. Signal intensities produced by rarely expressed genes are initially correctly detected, but they are often lost in corrections for background, log or ratio. Our analyses indicate that a simple correlation between the mean and median signal intensities may be the best way to eliminate inaccurate microarray signals. Unlike traditional quality control methods, the low intensity signals are retained and inaccurate signals are eliminated in this mean and median correlation. With larger amounts of microarray data being generated, it becomes increasingly more difficult to analyze data on a visual basis. Our method allows for the automatic quantitative determination of accurate and reliable signals, which can then be used for normalization. We found that a mean to median correlation of 85% or higher not only retains more data than current methods, but the retained data is more accurate than traditional thresholds or common spot flagging algorithms. We have also found that by using pin microtapping and microvibrations, we can control spot quality independent from initial PCR volume