Conformational change and enhanced stabilization of the vitamin D receptor by the 1,25-dihydroxyvitamin D3 analog KH1060.

The 1,25-dihydroxyvitamin D3 [1,25-(OH)2vitamin D3] analog KH1060 exerts very potent effects on cell proliferation and cell differentiation via the vitamin D receptor (VDR). However, the activities of KH1060 are not associated with an increased affinity for the VDR. We now show that increased stabilization of the VDR-KH1060 complex could be an explanation for its high potencies. VDR half-life studies performed with cycloheximide-translational blocked rat osteoblast-like ROS 17/2.8 cells demonstrated that, in the absence of ligand, VDR levels rapidly decreased. After 2 hr, less than 10% of the initial VDR level could be measured. In the presence of 1,25-(OH)2vitamin D3, the VDR half-life was 15 hr. After 24 hr. less than 20% of the initial VDR content was detectable, whereas, at this time-point, when the cells were incubated with KH1060 80% of the VDR was still present. Differences in 1,25-(OH)2vitamin D3- and KH1060-induced conformational changes of the VDR could underlie the increased VDR stability. As assessed by limited proteolytic digestion analysis, both 1,25-(OH)2vitamin D3 and KH1060 caused a specific conformational change of the VDR. Compared with 1,25-(OH)2vitamin D3, KH1060 induced a conformational change that led to a far more dramatic protection of the VDR against proteolytic degradation. In conclusion, the altered VDR stability and the possibly underlying change in VDR conformation caused by KH1060 could be an explanation for its enhanced bioactivity.

Point mutation of the autophosphorylation site or in the nuclear location signal causes protein kinase A RII beta regulatory subunit to lose its ability to revert transformed fibroblasts.

The RII beta regulatory subunit of cAMP-dependent protein kinase (PKA) contains an autophosphorylation site and a nuclear location signal, KKRK. We approached the structure-function analysis of RII beta by using site-directed mutagenesis. Ser114 (the autophosphorylation site) of human RII beta was replaced with Ala (RII beta-P) or Arg264 of KKRK was replaced with Met (RII beta-K). ras-transformed NIH 3T3 (DT) cells were transfected with expression vectors for RII beta, RII beta-P, and RII beta-K, and the effects on PKA isozyme distribution and transformation properties were analyzed. DT cells contained PKA-I and PKA-II isozymes in a 1:2 ratio. Over-expression of wild-type or mutant RII beta resulted in an increase in PKA-II and the elimination of PKA-I. Only wild-type RII beta cells demonstrated inhibition of both anchorage-dependent and -independent growth and phenotypic change. The growth inhibitory effect of RII beta overexpression was not due to suppression of ras expression but was correlated with nuclear accumulation of RII beta. DT cells demonstrated growth inhibition and phenotypic change upon treatment with 8-Cl-cAMP. RII beta-P or RII beta-K cells failed to respond to 8-Cl-cAMP. These data suggest that autophosphorylation and nuclear location signal sequences are integral parts of the growth regulatory mechanism of RII beta.

Specific mutations in the estrogen receptor change the properties of antiestrogens to full agonists.

The estrogen receptor (ER) stimulates transcription of target genes by means of its two transcriptional activation domains, AF-1 in the N-terminal part of the receptor and AF-2 in its ligand-binding domain. AF-2 activity is dependent upon a putative amphipathic alpha-helix between residues 538 and 552 in the mouse ER. Point mutagenesis of conserved hydrophobic residues within this region reduces estrogen-dependent transcriptional activation without affecting hormone and DNA binding significantly. Here we show that these mutations dramatically alter the pharmacology of estrogen antagonists. Both tamoxifen and ICI 164,384 behave as strong agonists in HeLa cells expressing the ER mutants. In contrast to the wild-type ER, the mutant receptors maintain nuclear localization and DNA-binding activity after ICI 164,384 treatment. Structural alterations in AF-2 caused by gene mutations such as those described herein or by estrogen-independent signaling pathways may account for the insensitivity of some breast cancers to tamoxifen treatment.

The impact of a future solar minimum on climate change projections in the Northern Hemisphere

Solar variability represents a source of uncertainty in the future forcings used in climate model simulations. Current knowledge indicates that a descent of solar activity into an extended minimum state is a possible scenario. With aid of experiments from a state-of-the-art Earth system model, we investigate the impact of a future solar minimum on Northern Hemisphere climate change projections. This scenario is constructed from recent 11 year solar-cycle minima of the solar spectral irradiance, and is therefore more conservative than the 'grand' minima employed in some previous modeling studies. Despite the small reduction in total solar irradiance (0.36 W m^-2), relatively large responses emerge in the winter Northern Hemisphere, with a reduction in regional-scale projected warming by up to 40%. To identify the origin of the enhanced regional signals, we assess the role of the different mechanisms by performing additional experiments forced only by irradiance changes at different wavelengths of the solar spectrum. We find that a reduction in visible irradiance drives changes in the stationary wave pattern of the North Pacific and sea-ice cover. A decrease in UV irradiance leads to smaller surface signals, although its regional effects are not negligible. These results point to a distinct but additive role of UV and visible irradiance in the Earth's climate, and stress the need to account for solar forcing as a source of uncertainty in regional scale projections.

Climate Change Policy & the Natural Gas Transmission Sector

Various emission reduction strategies are proposed to manage climate change in the U.S. This applied capstone evaluates the most likely policy options considering impacts and benefits to the natural gas transmission sector (NGT). It examines a case-study including a comparison of policy options to recommend the most beneficial program to the NGT sector. Two conclusions of major importance are: a federally preempted cap-and-trade program would be the most cost-effective for the NGT sector and the NGT sector should not be the point of regulation of any climate policy. Recommendations, strategies, and costs for implementation of a compliance plan for a federally preempted cap-and-trade program were developed as a tool for NGT companies as part of this applied capstone project.

Semantic change and intersubjectification: The origin of reprise evidential conditional in Old Catalan

The reprise evidential conditional (REC) is nowadays not very usual in Catalan: it is restricted to journalistic language and to some very formal genres (such as academic or legal language), it is not present in spontaneous discourse. On the one hand, it has been described among the rather new modality values of the conditional. On the other, the normative tradition tended to reject it for being a gallicism, or to describe it as an unsuitable neologism. Thanks to the extraction from text corpora, we surprisingly find this REC in Catalan from the beginning of the fourteenth century to the contemporary age, with semantic and pragmatic nuances and different evidence of grammaticalization. Due to the current interest in evidentiality, the REC has been widely studied in French, Italian and Portuguese, focusing mainly on its contemporary uses and not so intensively on the diachronic process that could explain the origin of this value. In line with this research, that we initiated studying the epistemic and evidential future in Catalan, our aim is to describe: a) the pragmatic context that could have been the initial point of the REC in the thirteenth century, before we find indisputable attestations of this use; b) the path of semantic change followed by the conditional from a ‘future in the past’ tense to the acquisition of epistemic and evidential values; and c) the role played by invited inferences, subjectification and intersubjectification in this change.

Lynn to Halibut Point, Rockport, Massachusetts, Atlantic Coast, 1873 (Raster Image)

This layer is a georeferenced raster image of the historic paper map entitled: Eldridge's new chart from Lynn to Halibut Point : with the harbors of Salem, Beverly, Marblehead, Manchester, Gloucester & Rockport, compiled from the latest surveys, [by George Eldridge] ; G.W. Boynton, sc. It was published by S. Thaxter & Son, 1873. Scale [ca. 1:58,370]. This map is a nautical chart covering the Atlantic Coast of Massachusetts from Lynn to Halibut Point, Rockport, Massachusetts. The image inside the map neatline is georeferenced to the surface of the earth and fit to the Massachusetts State Plane Coordinate System, Mainland Zone (in Feet) (Fipszone 2001). All map collar and inset information is also available as part of the raster image, including any inset maps, profiles, statistical tables, directories, text, illustrations, or other information associated with the principal map. This map shows coastal features such as lighthouses, buoys, beacons, rocks, channels, points, coves, islands, and more. Depths are shown by soundings and shading. Includes sailing directions and table of tides. This layer is part of a selection of digitally scanned and georeferenced historic maps of Massachusetts from the Harvard Map Collection. These maps typically portray both natural and manmade features. The selection represents a range of regions, originators, ground condition dates (1755-1922), scales, and purposes. The digitized selection includes maps of: the state, Massachusetts counties, town surveys, coastal features, real property, parks, cemeteries, railroads, roads, public works projects, etc.

Eastern Point, East Gloucester, Massachusetts, 1888 (Raster Image)

This layer is a georeferenced raster image of the historic paper map entitled: Lands of The Eastern Point Associates, East Gloucester, Mass., [by] William H. Foss, engr. and supt. It was published by Forbes Co., Mar. 1st, 1888. Scale [ca. 1:3,550]. Cadastral map showing roads, property lot numbers, dimensions, and areas. Covers Eastern Point and part of East Gloucester, Gloucester, Massachusetts. Relief is shown by hachures. It includes two vignettes. The image inside the map neatline is georeferenced to the surface of the earth and fit to the Massachusetts State Plane Coordinate System, Mainland Zone (in Feet) (Fipszone 2001). All map collar and inset information is also available as part of the raster image, including any inset maps, profiles, statistical tables, directories, text, illustrations, or other information associated with the principal map. This layer is part of a selection of digitally scanned and georeferenced historic maps of Massachusetts from the Harvard Map Collection. These maps typically portray both natural and manmade features. The selection represents a range of regions, originators, ground condition dates (1755-1922), scales, and purposes. The digitized selection includes maps of: the state, Massachusetts counties, town surveys, coastal features, real property, parks, cemeteries, railroads, roads, public works projects, etc.

An Assessment of US Progress towards its Pledge on Climate Change Mitigation. CEPS ECP Report No. 12, 15 October 2012

In 2009, President Obama pledged that, by 2020, the United States would achieve reductions in greenhouse gas emissions of 17% from 2005 levels. With the failure of Congress to adopt comprehensive climate legislation in 2010, the feasibility of the pledge was put in doubt. However, we find that the United States is near to reaching this goal: the country is currently on course to achieve reductions of 16.3% from 2005 levels in 2020. Three factors contribute to this outcome: greenhouse gas regulations under the Clean Air Act, secular trends including changes in relative fuel prices and energy efficiency and sub-national efforts. Perhaps even more surprising, domestic emissions are probably lower than would have been the case if the Waxman-Markey cap-and-trade proposal had become law in 2010. At this point, however, the United States is expected to fail to meet its financing commitments under the Copenhagen Accord for 2020.

Brazilian climate policy since 2005: continuity, change and prospective. CEPS Working Document No. 373, February 2013

In the five-year period 2005-09, Brazil has dramatically reduced carbon emissions by around 25% and at the same time has kept a stable economic growth rate of 3.5% annually. This combination of economic growth and emissions reduction is unique in the world. The driver was a dramatic reduction in deforestation in the Amazonian forest and the Cerrado Savannah. This shift empowered the sustainability social forces in Brazil to the point that the national Congress passed (December 2009) a very progressive law internalising carbon constraints and promoting the transition to a low-carbon economy. The transformation in Brazil’s carbon emissions profile and climate policy has increased the potentialities of convergence between the European Union and Brazil. The first part of this paper examines the assumption on which this paper is based, mainly that the trajectory of carbon emissions and climate/energy policies of the G20 powers is much more important than the United Nations multilateral negotiations for assessing the possibility of global transition to a low-carbon economy. The second part analyses Brazil’s position in the global carbon cycle and public policies since 2005, including the progressive shift in 2009 and the contradictory dynamic in 2010-12. The final part analyses the potential for a transition to a low-carbon economy in Brazil and the impact in global climate governance.

EU actorness and effectiveness under political pressure at the Copenhagen climate change negotiations

This paper analyses the extent of European Union (EU) actorness and effectiveness at the fifteenth United Nations Framework Convention on Climate Change (UNFCCC) Conference of the Parties (COP) meeting in Copenhagen in December 2009. For over a decade the European Union has been characterised as a leader in international climate policy-making and as an important actor in international climate change negotiations. The COP15 meeting in Copenhagen has overall brought about disappointing outcomes, especially from the perspective of the European Union. This casts doubts on EU leadership and begs the question of what has happened to EU actorness and effectiveness in this field. In terms of actorness we take Jupille and Caporaso (1998) as a point of departure and then specify a more parsimonious actorness framework that consists of cohesion and autonomy. Effectiveness (i.e. goal attainment) is seen as conceptually separate from actorness. Effectiveness is conceptualised as the result of actorness conditioned by the ‘opportunity structure’, i.e. the external context (of other actors, events and ideas) that enables or constrains EU actions. We hold that the EU’s actorness has been only moderate, especially given somewhat limited preference cohesion. In terms of the opportunity structure in Copenhagen we argue that the high degree of politicisation constrained the EU’s ability to negotiate and thus to attain its goals. Another external factor that had a substantial adverse impact on the EU’s effectiveness at the Copenhagen negotiations was the strong involvement of other actors with rather different positions, namely the United States (US) and the BASIC countries (Brazil, South Africa, India, and China).

Making the impossible possible: the prospects for visa-free movement between the EU and its eastern partners. OSW Point of View Number 27, May 2012

To make the abolition of visas in relations between the EU and the Eastern European countries possible, the ”spell cast” must be broken on this issue. With the present levels of mobility and people-to-people, business and political contacts the introduction of a visa-free regime will be a natural consequence of the liberalisation processes which have been at work for years.Moreover, the decision to lift the visa requirement is unlikely to significantly stimulate an increase in migration pressure from Eastern European countries but could reduce the operating costs of expanded Schengen consular network. Lifting the visa requirement for Eastern European citizens can be temporary and conditional and allow for actual implementation of an increased conditionality rule. In political terms, making visa liberalisation a key issue would fundamentally change the partners’ approach to the Eastern Partnership and would provide a link to the Partnership for Modernisation targeted at Russia.

On the periphery of global jihad. The North Caucasus: the illusion of stabilisation. OSW Point of View Number 45, November 2014

The situation in the North Caucasus has stabilised, in comparison with previous years, mainly as regards the activity of the Islamic military underground. This is an effect of ideological changes among the militants which have led to a dilution of the Caucasian armed struggle and its marginalisation in global jihad, since top priority has been granted to the Middle Eastern front. The factors which have contributed to this stabilisation are the organisational crisis in the Caucasus Emirate and the outflux of militants to the Middle East, as well the successful ‘carrot and stick’ policy adopted by Moscow. However, the partial stabilisation in the Caucasus is inherently precarious, being a contingent outcome of the situation rather than the result of systemic change. The region’s pressing problems remain unresolved; and these problems are generating chronic instability and cauing the Caucasus to drift away from Russia in civilisational terms. An economic or political crisis in the Russian Federation may result in the conflicts in the Caucasus unfreezing, including a reactivation of the idea of Chechen independence as well as the idea of the Caucasus Emirate, which is a part of global jihad.

Breaking the boundaries. The transformation of Central European gas markets. OSW Point of View Number 46, December 2014

According to the European Council decision of February 2011, the process of creating the European Union’s internal gas market should be completed by the end of 2014. Therefore, it is worth summarising the changes which have taken place in the gas markets of Central Europe so far. The past few years have seen not only a period of gradual ‘marketisation’ of the national gas sectors, but also the building of new gas infrastructure, a redrawing of the gas flow map, and changes in the ownership of the Central European gas companies. Another change in Central Europe is the fact that individual states and companies are moving away from their traditional focus on their national gas markets; instead, they are beginning to develop a variety of concepts for the regional integration of Central European markets. This publication attempts to grasp the main elements of the ongoing transformation of Central Europe’s gas markets, with particular emphasis on the situation in Poland, the Czech Republic, Slovakia and Hungary.

Coalitions, Power and Institutional Change in Global Patent Politics. IES WORKING PAPER 2/2013

With the 1995 Agreement on Trade - related Aspects of Intellectual Property Rights (TRIPS), a centralised rule - system for the international governance of patents was put in place under the general framework of the World Trade Organisation (WTO). Since then, the number of patent – related institutions has increased monotonically on the multilateral, plurilateral and bilateral levels. I will explain this case of institutional change by focusing on the norm – setting activities of both industrialised and developing countries, arguing that both groups constitute internally highly cohesive coalitions in global patent politics, while institutional change occurs when both coalitions engage in those negotiating settings in which they enjoy a comparative advantage over the other coalition. Specifically, I make the point that industrialised countries’ norm – setting activities take place on the plurilateral and bilateral level, where economic factors can be effectively translated into political outcomes while simultaneously avoiding unacceptably high legitimacy costs; whereas developing countries, on the other hand, use various multilateral United Nations (UN) forums where their claims possess a high degree of legitimacy, but cannot translate into effective political outcomes. The paper concludes with some remarks on how this case yields new insights into ongoing debates in institutionalist International Relations (IR), as pertaining to present discussions on “regime complexity”.