Transcriptional regulation of human inducible nitric oxide synthase (NOS2) gene by cytokines: initial analysis of the human NOS2 promoter.

The expression of inducible nitric oxide synthase (NOS2) is complex and is regulated in part by gene transcription. In this investigation we studied the regulation of NOS2 in a human liver epithelial cell line (AKN-1) which expresses high levels of NOS2 mRNA and protein in response to tumor necrosis factor alpha, interleukin 1 beta, and interferon gamma (cytokine mix, CM). Nuclear run-on analysis revealed that CM transcriptionally activated the human NOS2 gene. To delineate the cytokine-responsive regions of the human NOS2 promoter, we stimulated AKN-1 cells with CM following transfection of NOS2 luciferase constructs. Analysis of the first 3.8 kb upstream of the NOS2 gene demonstrated basal promoter activity but failed to show any cytokine-inducible activity. However, 3- to 5-fold inductions of luciferase activity were seen in constructs extending up to -5.8 and -7.0 kg, and a 10-fold increase was seen upon transfection of a -16 kb construct. Further analysis of various NOS2 luciferase constructs ligated upstream of the thymidine kinase promoter identified three regions containing cytokine-responsive elements in the human NOS2 gene: -3.8 to -5.8, -5.8 to -7.0, and -7.0 to -16 kb. These results are in marked contrast with the murine macrophage NOS2 promoter in which only 1 kb of the proximal 5' flanking region is necessary to confer inducibility to lipopolysaccharide and interferon gamma. These data demonstrate that the human NOS2 gene is transcriptionally regulated by cytokines and identify multiple cytokine-responsive regions in the 5' flanking region of the human NOS2 gene.

How the first biopolymers could have evolved.

In this work, we discuss a possible origin of the first biopolymers with stable unique structures. We suggest that at the prebiotic stage of evolution, long organic polymers had to be compact to avoid hydrolysis and had to be soluble and thus must not be exceedingly hydrophobic. We present an algorithm that generates such sequences for model proteins. The evolved sequences turn out to have a stable unique structure, into which they quickly fold. This result illustrates the idea that the unique three-dimensional native structures of first biopolymers could have evolved as a side effect of nonspecific physicochemical factors acting at the prebiotic stage of evolution.

Antibodies against specific extracellular epitopes of the glucagon receptor block glucagon binding.

Polyclonal antibodies were prepared against synthetic peptides corresponding to four different extramembrane segments of the rat glucagon receptor. The antibodies bound specifically to native glucagon receptor as judged by immunofluorescence microscopy of cultured cells expressing a synthetic gene for the receptor. Antibodies to peptides designated PR-15 and DK-12 were directed against amino acid residues 103-117 and 126-137, respectively, of the extracellular N-terminal tail. Antibody to peptide KD-14 was directed against residues 206-219 of the first extracellular loop, and antibody to peptide ST-18, against the intracellular C-terminal tail, residues 468-485. The DK-12 and KD-14 antibodies, but not the PR-15 and ST-18 antibodies, could effectively block binding of 125I-labeled glucagon to its receptor in liver membranes. Incubation of these antibodies with rat liver membranes resulted in both a decrease in the maximal hormonal binding capacity and an apparent decrease in glucagon affinity for its receptor. These effects were abolished in the presence of excess specific peptide antigen. In addition, DK-12 and KD-14 antibodies, but not PR-15 and ST-18 antibodies, interfered with glucagon-induced adenylyl cyclase activation in rat liver membranes and behaved as functional glucagon antagonists. These results demonstrate that DK-12 and KD-14 antibodies are pharmacologically active glucagon antagonists and strongly suggest that residues 126-137 of the N-terminal tail and residues 206-219 of the first extracellular loop contain determinants of ligand binding and may comprise the primary ligand-binding site on the glucagon receptor.

The site of action of neuronal acidic fibroblast growth factor is the organ of Corti of the rat cochlea.

Here we show that the mature cochlear neurons are a rich source of acidic fibroblast growth factor (aFGF), which is expressed in the neuronal circuitry consisting of afferent and efferent innervation. The site of action of neuronal aFGF is likely to reside in the organ of Corti, where one of the four known FGF receptor (FGFR) tyrosine kinases--namely, FGFR-3 mRNA--is expressed. Following acoustic overstimulation, known to cause damage to the organ of Corti, a rapid up-regulation of FGFR-3 is evident in this sensory epithelium, at both mRNA and protein levels. The present results provide in vivo evidence for aFGF being a sensory neuron-derived, anterogradely transported factor that may exert trophic effects on a peripheral target tissue. In this sensory system, aFGF, rather than being a neurotrophic factor, seems to promote maintenance of the integrity of the organ of Corti. In addition, aFGF, released from the traumatized nerve endings, may be one of the first signals initiating protective recovery and repair processes following damaging auditory stimuli.

Role of the monkey ventrolateral prefrontal cortex in the integration of contextual information for the selection and understanding of goal-directed actions

Action selection and organization are very complex processes that need to exploit contextual information and the retrieval of previously memorized information, as well as the integration of these different types of data. On the basis of anatomical connection with premotor and parietal areas involved in action goal coding, and on the data about the literature it seems appropriate to suppose that one of the most candidate involved in the selection of neuronal pools for the selection and organization of intentional actions is the prefrontal cortex. We recorded single ventrolateral prefrontal (VLPF) neurons activity while monkeys performed simple and complex manipulative actions aimed at distinct final goals, by employing a modified and more strictly controlled version of the grasp-to-eat(a food pellet)/grasp-to-place(an object) paradigm used in previous studies on parietal (Fogassi et al., 2005) and premotor neurons (Bonini et al., 2010). With this task we have been able both to evaluate the processing and integration of distinct (visual and auditory) contextual sequentially presented information in order to select the forthcoming action to perform and to examine the possible presence of goal-related activity in this portion of cortex. Moreover, we performed an observation task to clarify the possible contribution of VLPF neurons to the understanding of others’ goal-directed actions. Simple Visuo Motor Task (sVMT). We found four main types of neurons: unimodal sensory-driven, motor-related, unimodal sensory-and-motor, and multisensory neurons. We found a substantial number of VLPF neurons showing both a motor-related discharge and a visual presentation response (sensory-and-motor neurons), with remarkable visuo-motor congruence for the preferred target. Interestingly the discharge of multisensory neurons reflected a behavioural decision independently from the sensory modality of the stimulus allowing the monkey to make it: some encoded a decision to act/refraining from acting (the majority), while others specified one among the four behavioural alternatives. Complex Visuo Motor Task (cVMT). The cVMT was similar to the sVMT, but included a further grasping motor act (grasping a lid in order to remove it, before grasping the target) and was run in two modalities: randomized and in blocks. Substantially, motor-related and sensory-and-motor neurons tested in the cVMTrandomized were activated already during the first grasping motor act, but the selectivity for one of the two graspable targets emerged only during the execution of the second grasping. In contrast, when the cVMT was run in block, almost all these neurons not only discharged during the first grasping motor act, but also displayed the same target selectivity showed in correspondence of the hand contact with the target. Observation Task (OT). A great part of the neurons active during the OT showed a firing rate modulation in correspondence with the action performed by the experimenter. Among them, we found neurons significantly activated during the observation of the experimenter’s action (action observation-related neurons) and neurons responding not only to the action observation, but also to the presented cue stimuli (sensory-and-action observation-related neurons. Among the neurons of the first set, almost the half displayed a target selectivity, with a not clear difference between the two presented targets; Concerning to the second neuronal set, sensory-and-action related neurons, we found a low target selectivity and a not strictly congruence between the selectivity exhibited in the visual response and in the action observation.

The first extrasolar planet discovered with a new-generation high-throughput Doppler instrument

We report the detection of the first extrasolar planet, ET-1 (HD 102195b), using the Exoplanet Tracker (ET), a new-generation Doppler instrument. The planet orbits HD 102195, a young star with solar metallicity that may be part of the local association. The planet imparts radial velocity variability to the star with a semiamplitude of 63.4 ± 2.0 m s^-1 and a period of 4.11 days. The planetary minimum mass (m sin i) is 0.488MJ ± 0.015M_J. The planet was initially detected in the spring of 2005 with the Kitt Peak National Observatory (KPNO) 0.9 m coudé feed telescope. The detection was confirmed by radial velocity observations with the ET at the KPNO 2.1 m telescope and also at the 9 m Hobby-Eberly Telescope (HET) with its High Resolution Spectrograph. This planetary discovery with a 0.9 m telescope around a V = 8.05 magnitude star was made possible by the high throughput of the instrument: 49% measured from the fiber output to the detector. The ET's interferometer-based approach is an effective method for planet detection. In addition, the ET concept is adaptable to multiple-object Doppler observations or very high precision observations with a cross-dispersed echelle spectrograph to separate stellar fringes over a broad wavelength band. In addition to spectroscopic observations of HD 102195, we obtained brightness measurements with one of the automated photometric telescopes at Fairborn Observatory. Those observations reveal that HD 102195 is a spotted variable star with an amplitude of ~0.015 mag and a 12.3 ± 0.3 day period. This is consistent with spectroscopically observed Ca II H and K emission levels and line-broadening measurements but inconsistent with rotational modulation of surface activity as the cause of the radial velocity variability. Our photometric observations rule out transits of the planetary companion.

Updating the marine biostratigraphy of the Granada Basin (central Betic Cordillera). Insight for the Late Miocene palaeogeographic evolution of the Atlantic – Mediterranean seaway

The marine stratigraphic record of the Granada Basin (central Betic Cordillera, Spain) is composed of three Late Miocene genetic units deposited in different sea-level contexts (from base to top): Unit I (sea-level rise), Unit II (high sea-level), and Unit III (low sea-level). The latter mainly consists of evaporites precipitated in a shallow-basin setting. Biostratigraphic analyses based on planktonic foraminifera and calcareous nannoplankton indicate four late Tortonian bioevents (PF1-CN1, PF2, PF3, and PF4), which can be correlated with astronomically-dated events in other sections of the Mediterranean. PF1-CN1 (7.89 Ma) is characterized by the influx of the Globorotalia conomiozea group (including typical forms of Globorotalia mediterranea) and by the first common occurrence of Discoaster surculus; PF2 (7.84 Ma) is marked by the first common occurrence of Globorotalia suterae; PF3 (7.69 Ma) is typified by the influx of dextral Neogloboquadrina acostaensis; and PF4 (7.37 Ma) is defined by the influx of the Globorotalia menardii group II (dextral forms). The PF1 event occurred in the upper part of Unit I, whereas PF2 to PF4 events occurred successively within Unit II. The age of Unit III (evaporites) can only be estimated in its lower part based on the presence of dextral Globorotalia scitula, which, together with the absence of the first common occurrence of the G. conomiozea group (7.24 Ma), points to the latest Tortonian. Comparisons with data from the other Betic basins indicate that the evaporitic phase of the Granada Basin (7.37–7.24 Ma) is not synchronous with those from the Lorca Basin (7.80 Ma) and the Fortuna Basin (7.6 Ma). In the Bajo Segura Basin (easternmost Betic Cordillera), no evaporite deposition occurred during the late Tortonian. The evaporitic unit of the Granada Basin (central Betics) records the late Tortonian restriction of the Betic seaway (the marine connection between the Atlantic and Mediterranean). The diachrony in the restriction of the Betic seaway is related to differing tectonic movements in the central and eastern sectors of the Betic Cordillera.

A Coppe of the Plan of Cambridge New Meeting House which was excepted by the people, 1752

The floor plan details the proposed interior of the New Meeting House of the First Parish in Cambridge to be built near the College, in the present area of Lehman Hall. This land became Harvard property in 1833. The drawing includes space allotted for the pulpit, pews, and center aisle. The document is fragile.

A collection of the most approved pieces of music from various authors: transcribed while member of Harvard University, from July 1789 to July 1793

John Pierce kept this journal while he was a student at Harvard College. It consists of manuscript musical scores with annotations indicating the occasions at which the music was performed. These occasions included commencements, public exhibitions and Dudleian lectures. A note indicates that one anthem was prepared by Samuel Holyoke at Pierce's request, to be performed at Pierce's class commencement exercises, held on July 13, 1793. Several annotations were made in May 1794, the year following Pierce's graduation. There is a table of contents on the last page.

Account book of the executors of the Henry Flynt estate, 1760-1767

The volume contains acknowledgements of the disbursements of Harvard Tutor Henry Flynt's estate written in the hands of the respective beneficiaries. The entries begin on February 27, 1760 following Flynt's death on February 13, 1760, and continue through May 9, 1767. Each receipt includes the date, name of the executors, description of the property, beneficiary's name, and signature. The beneficiaries include the wife of Sol. Davy, Dorothy Jackson, Edmund Quincy, J. Henry Quincy, Esther and Stephen Richard (received by attorney Nicholas Boylston), Dorothy Skinner (also received for her by her husband Richard Skinner), John Wendell, Edmund Wendell, Katherine Wendell, and Oliver Wendell, as well as Harvard College (received by Harvard Treasurer Thomas Hubbard), and the Deacons of the First Church of Cambridge. The volume also includes a loose document titled "Account from Messrs Edmund & Josiah Quincy Settled & Ballanced March 31, 1749."

Various Shiite devotional texts to be recited in religious assemblies (majālis) commemorating the events leading to the martyrdom of the Shii Imam Ḥusain b. ʻAlī (d. 860)] : manuscript, 1900?

Various Shiite devotional texts to be recited in religious assemblies (majālis) commemorating the events leading to the martyrdom of the Shii Imam Ḥusain b. ʻAlī (d. 680). Each majlis (there is twenty) begins with a synoptic heading. The beginning of 17th majlis suggests that some of these texts are based on Mahdī b. Abī Zarr al-Kāshānī an-Niraqī's "Muḥarriq al-qulub (a Shiite history of the martyrs of the Prophet's family).

Application and Reliability of the Retrospective Interview Procedure to Trace Physical Activity

This paper reports the results of two studies. The purpose of the first study was to determine if lifestyle variables and past involvement in physical activity was related to current activity levels in master athletes and sedentary older adults. Retrospective interviews were conducted with 12 master athletes and 12 sedentary older adults. Results demonstrated that education level, spouse participation, smoking, and recent physical activity levels were indicators of current involvement. The second study investigated the reliability of the data collected in the retrospective interviews. Similar to results with younger samples, we confirm that lifestyle variables and physical activity involvement could be accurately recalled for a period of 25 years, making this tool a useful addition for the study of physical activity in older adults.

The ‘Lisbonisation’ of the European Parliament: Assessing progress, shortcomings and challenges for democratic accountability in the area of freedom, security and justice. CEPS Paper on Liberty and Security in Europe No. 58, September 2013

This paper examines the performance of the European Parliament in EU AFSJ law and policy-making from the entry into force of the Lisbon Treaty until the end of the first half of 2013. The paper situates the EP in the new post-Lisbon institutional setting, documenting its transition to ‘AFSJ decision-maker’, and its new powers to shape and make policy covering the EU’s internal and external security agenda. While the paper finds that the EP has become an active co-owner of the EU AFSJ post-Lisbon, with the Parliament demonstrating a dynamic adjustment to its new post-Lisbon role and powers, the authors identify a set of new developments and challenges that have arisen in the conduct of democratic accountability by the EP in the AFSJ since 2009, which call for critical reflection ahead of the new parliamentary term 2014-2019 and the post-2014 phase of the EU’s AFSJ.

Iceland’s contested European Policy: The Footprint of the Past - A Small and Insular Society. Jean Monnet Occasional Paper 01/2013

Introduction. Iceland’s domestic politics and foreign affairs are undergoing drastic changes. After an economic crash, violent protests on the streets of Reykjavik for the first time in Iceland’s history contributed to the defeat of the government. The party system has been altered. A turn has been taken towards Europe after the United States left the island, first by closing its military base in 2006 and then by its clear stance not to assist the country in its economic difficulties. The former close relations with the superpower are unlikely ever to be restored. The EU membership application is placing severe constraints on political parties which are split on the issue and has put in jeopardy the unity of the first left majority in the Icelandic parliament, the Althingi. Society is in a state of flux after an unprecedented economic downscaling and the collapse of almost its entire financial sector – which had boomed rapidly beginning in the mid-1990s. The credibility of politicians, the parliament and the media is in ruins. Iceland’s smallness and its location on the geographical map – one could also say the geopolitical map – has had a profound influence on its domestic and foreign affairs. Iceland is closely associated with the other Nordic states and has adopted many of their domestic characteristics, with important exceptions. On the other hand, the country has come under American influence – geographically, it straddles the Mid-Atlantic rift – and has limited its participation in the European project. Its geographical location in the middle of the North Atlantic has led to a notion that the country’s culture is unique and should be protected by all available means. Politicians continue to play the ‘nationalistic uniqueness’ card with considerable success even though the country has been swept by globalization. Rapid modernization (which only really began in the Second World War with British and American occupations) and sudden engagement with the outside world (which only extended to the general public in the last quarter of the twentieth century) are still slowly but steadily making their mark on the country’s foreign policy. The country’s political discourse and foreign policy still bear the hallmark of the past, i.e. of a small and insular society This paper will address the political developments in Iceland since the 2008 economic crash and place it in a historical context. The aim is to understand Iceland’s present foreign policy and, in particular, the highly contested decision by its government in 2009 to apply for membership of the European Union. The paper is divided into five sections in addition to this introduction and the concluding remarks. First, it starts by explaining the importance in Iceland of a political discourse based on the concept of independence which dates back to the historical narrative of the settlement period. This section will also examine Iceland’s close relations with the other Nordic states – despite important differences between it and the others. Second, the paper will analyse the importance of the party system, i.e. the dominance of the centre-right in Icelandic politics, and the changed nature of the system. Third, it examines how Iceland further distinguishes itself from the other Nordic states in many important features. Fourthly, the paper analyses the country’s three main foreign policy priorities in the post-war period, i.e. extensions of the Exclusive Economic Zone, firm defence arrangements with the US and membership of NATO, and the drive for better market access for marine products – including a partial engagement in the European project. Fifthly, the paper examines how the country’s smallness, in terms of its central administrative capacity, has affected its domestic and foreign policy-making. The concluding section summarizes the main findings concerning the political and historical obstacles that the Social Democratic Alliance faces in its hard-fought battle to change the country’s European Policy.

Between energy security and energy market integration. Guidelines for the future development of the EU’s external energy policy in Europe’s neighbourhood. OSW Report, June 2011

For many years the European Union has been improving the efficient use of energy resources and yet the demand for energy in the EU continues to increase. When Europe belonged to one of the world’s key energy markets with relatively easy access to energy resources, growing energy needs were not seen as a source of concern. Today, however, as the competition for energy resources is intensifying and the global position of the EU energy market is being challenged by growing economies in the developing countries, above all China and India, the EU needs to adopt bold policies to guarantee the sustainable supply of energy. This report argues the EU needs to develop a fully-fledged external energy policy; i.e. a common, coherent, strategic approach that build bridges between the interests and needs of the EU integrated energy market on the one hand and supplier countries on the other. The EU’s external energy policy has two main objectives. The first one is to ensure a sustainable, stable and cost-effective energy supply. The second is to promote energy market integration and regulatory convergence with neighbouring countries (often but not always this supports the achievement of the first objective). However, in order to improve its effectiveness, the EU’s external energy policy needs to be seen in a broader economic and political context. Any progress in energy cooperation with third countries is contingent upon the EU’s general stance and offer to those countries.