Glucocorticoid Compounds Modify Smoothened Localization and Hedgehog Pathway Activity

The Hedgehog signaling pathway is linked to a variety of diseases, notably a range of cancers. The first generation of drug screens identified Smoothened (Smo), a membrane protein essential for signaling, as an attractive drug target. Smo localizes to the primary cilium upon pathway activation, and this transition is critical for the response to Hedgehog ligands. In a high content screen directly monitoring Smo distribution in Hedgehog-responsive cells, we identified different glucocorticoids as specific modulators of Smo ciliary accumulation. One class promoted Smo accumulation, conferring cellular hypersensitivity to Hedgehog stimulation. In contrast, a second class inhibited Smo ciliary localization and signaling activity by both wild-type Smo, and mutant forms of Smo, SmoM2, and SmoD473H, that are refractory to previously identified Smo antagonists. These findings point to the potential for developing glucocorticoid-based pharmacological modulation of Smo signaling to treat mutated drug-resistant forms of Smo, an emerging problem in long-term cancer therapy. They also raise a concern about potential crosstalk of glucocorticoid drugs in the Hedgehog pathway, if therapeutic administration exceeds levels associated with on-target transcriptional mechanisms of glucocorticoid action.Chemistry and Chemical BiologyMolecular and Cellular BiologyStem Cell and Regenerative Biolog

COP21 climate negotiators' responses to climate model forecasts

Policymakers involved in climate change negotiations are key users of climate science. It is therefore vital to understand how to communicate scientific information most effectively to this group. We tested how a unique sample of policymakers and negotiators at the Paris COP21 conference update their beliefs on year 2100 global mean temperature increases in response to a statistical summary of climate models' forecasts. We randomized the way information was provided across participants using three different formats similar to those used in Intergovernmental Panel on Climate Change reports. In spite of having received all available relevant scientific information, policymakers adopted such information very conservatively, assigning it less weight than their own prior beliefs. However, providing individual model estimates in addition to the statistical range was more effective in mitigating such inertia. The experiment was repeated with a population of European MBA students who, despite starting from similar priors, reported conditional probabilities closer to the provided models' forecasts than policymakers. There was also no effect of presentation format in the MBA sample. These results highlight the importance of testing visualization tools directly on the population of interest

Business Case for Energy Efficiency in Support of Climate Change Mitigation, Economic and Societal Benefits in India

This study seeks to provide policymakers and other stakeholders with actionable information towards a road map for reducing energy consumption cost-effectively. We focus on individual end use equipment types (hereafter referred to as appliance groups) that might be the subject of policies - such as labels, energy performance standards, and incentives - to affect market transformation in the short term, and on high-efficiency technology options that are available today. the high efficiency or Business Case scenario is constructed around a model of cost-effective efficiency improvement. Our analysis demonstrates that a significant reduction in energy consumption and emissions is achievable at net negative cost, that is, as a profitable investment for consumers. Net savings are calculated assuming no additional costs to energy consumption such as carbon taxes. Savings relative to the base case as calculated in this way is often referred to as “economic savings potential”. So far, the Indian market has responded favorably to government efficiency initiatives, with Indian manufacturers producing a higher fraction of high-efficiency equipment than before program implementation. This study highlights both the financial benefit and the scope of potential impact for adopting this equipment, all of which is already readily available on the market. The approach of the study is to assess the impact of short-term actions on long-term impacts. “Short-term” market transformation is assumed to occur by 2015, while “long-term” energy demand reduction impacts are assessed in 2030. In the intervening years, most but not all of the equipment studied will turn over completely. The Business Case concentrates on technologies for which cost-effectiveness can be clearly demonstrated

Business Case for Energy Efficiency in Support of Climate Change Mitigation, Economic and Societal Benefits in the United States

This study seeks to provide policymakers and other stakeholders with actionable information towards a road map for reducing energy consumption in the most cost-effective way. A major difference between the current study and some others is that we focus on individual equipment types that might be the subject of policies - such as labels, energy performance standards, and incentives - to affect market transformation in the short term, and on high-efficiency technology options that are available today. The approach of the study is to assess the impact of short-term actions on long-term impacts. “Short term” market transformation is assumed to occur by 2015, while “long-term” energy demand reduction impacts are assessed in 2030. In the intervening years, most but not all of the equipment studied will turn over completely. The 15-year time frame is significant for many products however, indicating that delay of implementation postpones impacts such as net economic savings and mitigation of emissions of carbon dioxide. Such delays would result in putting in place energy-wasting technologies, postponing improvement until the end of their service life, or potentially resulting in expensive investment either in additional energy supplies or in early replacement to achieve future energy or emissions reduction targets

Business Case for Energy Efficiency in Support of Climate Change Mitigation, Economic and Societal Benefits in India

This study seeks to provide policymakers and other stakeholders with actionable information towards a road map for reducing energy consumption cost-effectively. We focus on individual end use equipment types (hereafter referred to as appliance groups) that might be the subject of policies - such as labels, energy performance standards, and incentives - to affect market transformation in the short term, and on high-efficiency technology options that are available today. the high efficiency or Business Case scenario is constructed around a model of cost-effective efficiency improvement. Our analysis demonstrates that a significant reduction in energy consumption and emissions is achievable at net negative cost, that is, as a profitable investment for consumers. Net savings are calculated assuming no additional costs to energy consumption such as carbon taxes. Savings relative to the base case as calculated in this way is often referred to as “economic savings potential”. So far, the Indian market has responded favorably to government efficiency initiatives, with Indian manufacturers producing a higher fraction of high-efficiency equipment than before program implementation. This study highlights both the financial benefit and the scope of potential impact for adopting this equipment, all of which is already readily available on the market. The approach of the study is to assess the impact of short-term actions on long-term impacts. “Short-term” market transformation is assumed to occur by 2015, while “long-term” energy demand reduction impacts are assessed in 2030. In the intervening years, most but not all of the equipment studied will turn over completely. The Business Case concentrates on technologies for which cost-effectiveness can be clearly demonstrated

Business Case for Energy Efficiency in Support of Climate Change Mitigation, Economic and Societal Benefits in China

This study seeks to provide policymakers and other stakeholders with actionable information towards a road map for reducing energy consumption cost-effectively. We focus on individual end use equipment types (hereafter referred to as appliance groups) that might be the subject of policies - such as labels, energy performance standards, and incentives - to affect market transformation in the short term, and on high-efficiency technology options that are available today. As the study title suggests, the high efficiency or Business Case scenario is constructed around a model of cost-effective efficiency improvement. Our analysis demonstrates that a significant reduction in energy consumption and emissions is achievable at net negative cost, that is, as a profitable investment for consumers. Net savings are calculated assuming no additional costs to energy consumption such as carbon taxes. Savings relative to the base case as calculated in this way is often referred to as 'economic savings potential'. Chinese energy demand has grown dramatically over the last few decades. While heavy industry still plays a dominant role in greenhouse gas emissions, demand from residential and commercial buildings has also seen rapid growth in percentage terms. In the residential sector this growth is driven by internal migration from the countryside to cities. Meanwhile, income in both urban and rural subsectors allows ownership of major appliances. While residences are still relatively small by U.S. or European standards, nearly all households own a refrigerator, a television and an air conditioner. In the future, ownership rates are not expected to grow as much as in other developing countries, because they are already close to saturation. However, the gradual turnover of equipment in the world's largest consumer market provides a huge opportunity for greenhouse gas mitigation. In addition to residences, commercial floor space has expanded rapidly in recent years, and construction continues at a rapid pace. Growth in this sector means that commercial lighting and HVAC will play an increasingly important role in energy demand in China. The outlook for efficiency improvement in China is encouraging, since the Chinese national and local governments have implemented significant policies to contain energy intensity and announced their intention to continue and accelerate these. In particular, the Chinese appliance standards program, first established in 1989, was significantly strengthened and modernized after the passage of the Energy Conservation Law of 1997. Since then, the program has expanded to encompass over 30 equipment types (including motor vehicles). The current study suggests that, in spite of these efforts, there is significant savings to be captured through wide adoption of technologies already available on the Chinese market. The approach of the study is to assess the impact of short-term actions on long-term impacts. 'Short-term' market transformation is assumed to occur by 2015, while 'long-term' energy demand reduction impacts are assessed in 2030. In the intervening years, most but not all of the equipment studied will turn over completely. Early in 2011, the Chinese government announced a plan to reduce carbon dioxide emissions intensity (per unit GDP) by 16% by 2015 as part of the 12th five year plan. These targets are consistent with longer term goals to reduce emissions intensity 40-45% relative to 2005 levels by 2020. The efforts of the 12th FYP focus on short-term gains to meet the four-year targets, and concentrate mainly in industry. Implementation of cost-effective technologies for all new equipment in the buildings sector thus is largely complementary to the 12th FYP goals, and would provide a mechanism to sustain intensity reductions in the medium and long term. The 15-year time frame is significant for many products, in the sense that delay of implementation postpones economic benefits and mitigation of emissions of carbon dioxide. Such delays would result in putting in place energy-wasting technologies, postponing improvement until the end of their service life, or potentially resulting in expensive investment either in additional energy supplies or in early replacement to achieve future energy or emissions reduction targets

Prioritization of zoonotic diseases in Kenya, 2015

INTRODUCTION:Zoonotic diseases have varying public health burden and socio-economic impact across time and geographical settings making their prioritization for prevention and control important at the national level. We conducted systematic prioritization of zoonotic diseases and developed a ranked list of these diseases that would guide allocation of resources to enhance their surveillance, prevention, and control. METHODS:A group of 36 medical, veterinary, and wildlife experts in zoonoses from government, research institutions and universities in Kenya prioritized 36 diseases using a semi-quantitative One Health Zoonotic Disease Prioritization tool developed by Centers for Disease Control and Prevention with slight adaptations. The tool comprises five steps: listing of zoonotic diseases to be prioritized, development of ranking criteria, weighting criteria by pairwise comparison through analytical hierarchical process, scoring each zoonotic disease based on the criteria, and aggregation of scores. RESULTS:In order of importance, the participants identified severity of illness in humans, epidemic/pandemic potential in humans, socio-economic burden, prevalence/incidence and availability of interventions (weighted scores assigned to each criteria were 0.23, 0.22, 0.21, 0.17 and 0.17 respectively), as the criteria to define the relative importance of the diseases. The top five priority diseases in descending order of ranking were anthrax, trypanosomiasis, rabies, brucellosis and Rift Valley fever. CONCLUSION:Although less prominently mentioned, neglected zoonotic diseases ranked highly compared to those with epidemic potential suggesting these endemic diseases cause substantial public health burden. The list of priority zoonotic disease is crucial for the targeted allocation of resources and informing disease prevention and control programs for zoonoses in Kenya

Search for New Physics Using Quaero: A General Interface to D0 Event Data

We describe Quaero, a method that i) enables the automatic optimization of searches for physics beyond the standard model, and ii) provides a mechanism for making high energy collider data generally available. We apply Quaero to searches for standard model WW, ZZ, and ttbar production, and to searches for these objects produced through a new heavy resonance. Through this interface, we make three data sets collected by the D0 experiment at sqrt(s)=1.8 TeV publicly available.Comment: 7 pages, submitted to Physical Review Letter