Impaired hippocampal plasticity in mice lacking the Cbeta1 catalytic subunit of cAMP-dependent protein kinase.

Neural pathways within the hippocampus undergo use-dependent changes in synaptic efficacy, and these changes are mediated by a number of signaling mechanisms, including cAMP-dependent protein kinase (PKA). The PKA holoenzyme is composed of regulatory and catalytic (C) subunits, both of which exist as multiple isoforms. There are two C subunit genes in mice, Calpha and Cbeta, and the Cbeta gene gives rise to several splice variants that are specifically expressed in discrete regions of the brain. We have used homologous recombination in embryonic stem cells to introduce an inactivating mutation into the mouse Cbeta gene, specifically targeting the Cbeta1-subunit isoform. Homozygous mutants showed normal viability and no obvious pathological defects, despite a complete lack of Cbeta1. The mice were analyzed in electrophysiological paradigms to test the role of this isoform in long-term modulation of synaptic transmission in the Schaffer collateral-CA1 pathway of the hippocampus. A high-frequency stimulus produced potentiation in both wild-type and Cbeta1-/- mice, but the mutants were unable to maintain the potentiated response, resulting in a late phase of long-term potentiation that was only 30% of controls. Paired pulse facilitation was unaffected in the mutant mice. Low-frequency stimulation produced long-term depression and depotentiation in wild-type mice but failed to produce lasting synaptic depression in the Cbeta1 -/- mutants. These data provide direct genetic evidence that PKA, and more specifically the Cbeta1 isoform, is required for long-term depression and depotentiation, as well as the late phase of long-term potentiation in the Schaffer collateral-CA1 pathway.

Ovulation efficiency is reduced in mice that lack plasminogen activator gene function: functional redundancy among physiological plasminogen activators.

Several lines of indirect evidence suggest that plasminogen activation plays a crucial role in degradation of the follicular wall during ovulation. However, single-deficient mice lacking tissue-type plasminogen activator (tPA), urokinase-type plasminogen activator (uPA), or PA inhibitor type 1(PAI-1) gene function were recently found to have normal reproduction, although mice with a combined deficiency of tPA and uPA were significantly less fertile. To investigate whether the reduced fertility of mice lacking PA gene function is due to a reduced ovulation mechanism, we have determined the ovulation efficiency in 25-day-old mice during gonadotropin-induced ovulation. Our results reveal that ovulation efficiency is normal in mice with a single deficiency of tPA or uPA but reduced by 26% in mice lacking both physiological PAs. This result suggests that plasminogen activation plays a role in ovulatory response, although neither tPA nor uPA individually or in combination is obligatory for ovulation. The loss of an individual PA seems to be functionally complemented by the remaining PA but this compensation does not appear to involve any compensatory up-regulation. Our data imply that a functionally redundant mechanism for plasmin formation operates during gonadotropin-induced ovulation and that PAs together with other proteases generate the proteolytic activity required for follicular wall degradation.

An investigative and interpretive study, with paintings, drawings and prints, of "All Saints' Day" and "All Souls" Day" in Mexico

"In Mexico, the first two days of November are set aside each year for the commemoration of the dead. This fete, called All Saints' Day and All Souls' Day, is observed throughout the world; however, in Mexico, it is celebrated in a manner peculiar to that country and to the various localities within that country . This holiday is sanctioned by both government and church; and is celebrated by practically all Mexicans, whether they be Catholic, pagan, relilious or irreligious. These are the two days when that contrast which is the essence of Mexico becomes obvious: the "triste~alegria" (sad-happiness). During these days , art objects are abundant and arresting ; and religious ceremonies, rites and fiestas blossom forth! Urban and folk arts, in every field, find full expression at this time. The religious, social, political, and artistic manifestations of the holiday are not only stimulating in themselves, but are exciting as subjects for painting, drawings, prints, and any other form of artistic expression!"

Women Of India: Developmental setbacks of gender inequity

This project examines rural Indian women and discusses the strong correlation between gender inequity and the setbacks that have crippled development. The embedded caste system has created a distinct social hierarchy, which has incidentally deprived women of their freedom and voice. Gender inequity and social stratification are direct causes of the AIDS epidemic, research revealing a contingency between lack of empowerment and exposure to the disease. Additionally, the HIV/AIDS virus carries a strong cultural stigma, which influences whether or not women will seek treatment if infected, since AIDS victims face extreme social isolation and discrimination, in India. This project discusses several cause-and-effect frameworks related to gender inequity, which have stunted the growth and success of India.

Gender analysis of moxifloxacin clinical trials

Purpose: To determine the inclusion of women and the sex-stratification of results in moxifloxacin Clinical Trials (CTs), and to establish whether these CTs considered issues that specifically affect women, such as pregnancy and use of hormonal therapies. Previous publications about women’s inclusion in CTs have not specifically studied therapeutic drugs. Although this type of drug is taken by men and women at a similar rate, adverse effects occur more frequently in the latter. Methods: We reviewed 158 published moxifloxacin trials on humans, retrieved from MedLine and the Cochrane Library (1998–2010), to determine whether they complied with the gender recommendations published by U.S. Food and Drug Administration Guideline. Results: Of a total of 80,417 subjects included in the moxifloxacin CTs, only 33.7% were women in phase I, in contrast to phase II, where women accounted for 45%, phase III, where they represented 38.3% and phase IV, where 51.3% were women. About 40.9% (n = 52) of trials were stratified by sex and 15.3% (n = 13) and 9% (n = 7) provided data by sex on efficacy and adverse effects, respectively. We found little information about the influence of issues that specifically affect women. Only 3 of the 59 journals that published the moxifloxacin CTs stated that authors should stratify their results by sex. Conclusions: Women are under-represented in the published moxifloxacin trials, and this trend is more marked in phase I, as they comprise a higher proportion in the other phases. Data by sex on efficacy and adverse effects are scarce in moxifloxacin trials. These facts, together with the lack of data on women-specific issues, suggest that the therapeutic drug moxifloxacin is only a partially evidence-based medicine.

Trade relations between the Mycenaean Greeks and the civilizations of the Eastern Mediterranean in the Late Bronze Age

The Mycenaean Greeks are often assumed to have been in contact with the civilizations of the Mediterranean throughout the Late Bronze Age. The extent of this contact however is not as clearly understood, and the archaeological evidence that has survived provides a sample of what must have exchanged hands. This thesis will examine the archaeological, textual and iconographic evidence from a number of sites and sources, from the Anatolian plains to the Kingdom of Egypt and major settlements in-between during the Late Bronze Age to examine what trade may have looked like for the Mycenaeans. Due to the extensive finds in some regions and a lack of evidence in others, this paper will also try to understand the relationship between the Mycenaeans and other cultures to determine whether a trade embargo was enacted on the Mycenaeans by the Central Anatolian Hittites during this period, or whether other factors contributed to the paucity of objects in Central Anatolia.

Regional business cycles and the emergence of sheltered economies in the southern periphery of Europe. Bruges European Economic Research (BEER) Papers 7/November 2006

Recent research has highlighted that in the last few years the evolution of regional disparities in many European states has become pro-cyclical. This represents a change with respect to the predominantly anti-cyclical pattern of the 1960s and 1970s. This paper addresses the question of whether and when this change has taken place in the southern periphery of Europe, before analyzing the factors that may have played a role in such a change. The analysis relies on a regional database that includes the evolution of the GDP per capita of NUTS II regions in five European countries (France, Greece, Italy, Portugal, and Spain) between 1980 and 2000. The results of the analysis support the hypothesis of a change towards a pro-cyclical evolution of regional disparities in the cases of Italy, Portugal, and Spain, but not in those of Greece and France. A relationship between these pro-cyclical patters and the emergence of less dynamic sheltered economies is also detected in peripheral regions. This lack of dynamism is related to the fact that numerous peripheral areas in southern Europe have become increasingly dependent on factors such as transfers or public investment and employment, and therefore are less exposed to changes in market conditions.

The Cost of Servicing Greece’s Debt: A Sisyphean task? CEPS Commentary, 4 February 2015

Following the victory of Syriza in the Greek elections on January 25th, policy-makers, economists and concerned EU citizens are scrambling to understand the causes, modalities and consequences of a possible Greek default in order to anticipate and prepare for what is likely to unfold in the coming weeks and months. The debate on the sustainability of Greek public finances has often been characterised by a lack of clarity and even a certain degree of confusion. This brief note focuses first on the cost that Greece faces in servicing its debt and then asks whether this is a manageable or a Sisyphean task. It concludes by reflecting on the political implications of the new government’s announced intentions and whether these are being taken into account in the current debate over debt restructuring.

The sense and nonsense of Eurozone level Democracy. Egmont Paper No. 70, October 2014

The democratic functioning of the EU is frequently called into question. Increasingly, the focus of this criticism is the perceived lack of legitimacy in eurozone policymaking. The eurozone has gained a firmer grip on national policymaking in recent years, but has not adapted its democratic structure to reflect this. To tackle this problem, European and national policymakers have committed to improving the eurozone’s legitimacy and accountability. One of the rare concrete proposals by policymakers is the institution of parliamentary control that deals specifically with eurozone matters. This Egmont Paper examines whether it would be beneficial to have eurozone level democracy. This is defined as parliamentary scrutiny of, by and for the eurozone. It would deal with issues that solely concern the eurozone, and decisions would be made solely by parliamentarians from the eurozone.

The Catholic Question in Contemporary Portuguese Civil Society: A Case of Muted Vibrancy? CES Papers - Open Forum #14, 2012

The ‘Catholic question’ in contemporary Portugal obliges us to consider whether Catholicism will remain a force in Portuguese associational life in the next century, or whether it faces a future of slow and steady decline. On the one hand, an overall statistical drop of church membership, and the lack of religious practice by almost half of self-identified Roman Catholics, suggests that the future of the Catholic Church in Portugal will probably be very different than the past. On the other hand, the church’s support for democratic processes, the important social services it provides, and its educational establishment, have certainly been a positive factor in Portuguese associational life, and helped the larger process of democratic-regime consolidation since the Carnation Revolution of 1974. This paper suggests that social scientists need to move beyond the lens normally applied to the question of Catholicism in contemporary Europe (i.e. it is a dying, anti-modern, anti-rational, conservative institution), and instead consider the complex interplay of its demographic challenges combined with the popular sources of its theological and spiritual strength, as well as its vital societal contributions, to assess whether or not it will remain a force in Portuguese associational life in the future.

Mineral and chemical composition of hydrothermally altered rocks and sediments from the Middle Valley, ODP Leg 139 data

The Middle Valley segment at the northern end of the Juan de Fuca Ridge is a deep extensional rift blanketed with 200-500 m of Pleistocene turbiditic sediment. Sites 857 and 858 were drilled during Ocean Drilling Program Leg 139 to determine whether these two sites were hydrologically linked end members of an active hydrothermal circulation system. Site 858 was placed in an area of active hydrothermal discharge with fluids up to 270°C venting through anhydrite-bearing mounds on top of altered sediment. The shallow basement of fine-grained basalt that underlies the vents at Site 858 is interpreted as a seamount that was subsequently buried by turbidites. Site 857 was placed 1.6 km south of the Site 858 vents in a zone of high heat flow and numerous seismically imaged ridge-parallel faults. Drilling at Site 857 encountered sediments that are increasingly altered with depth and that overlie a series of mafic sills at depths of 460-940 m below sea floor. Sill margins and adjacent baked sediment are highly altered to magnesian chlorite and crosscut with veins filled with quartz, chlorite, sulfides, epidote, and wairakite. The sill interiors vary from slightly altered, with unaltered plagioclase and clinopyroxene in a mesostasis replaced by chlorite, to local zones of intense alteration and brecciation. In these latter zones, the sill interiors are pervasively replaced by chlorite, epidote, quartz, pyrite, titanite, and rare actinolite. The most complete replacement is associated with brecciated horizons with low recovery and slickensides on fracture surfaces, which we interpret as intersections between faults and the sills. Geochemically, the alteration of the sill complex is reflected in significant whole-rock depletions in Ca, Sr, and Na with corresponding enrichments in Mg, Al, and most metals. The latter results from the formation of conspicuous sulfide poikiloblasts. In contrast, metamorphism of the Site 858 seamount includes incomplete albitization of plagioclase phenocrysts and replacement of sparse mafic phenocrysts. Much of the basement alteration at Site 858 is confined to crosscutting veins except for a highly altered and veined horizon at the contact between basaltic basement and the overlying sediment. The sill complex at Site 857 is more highly depleted in 18O (d18O = 2.4 per mil - 4.7 per mil) and more pervasively replaced by secondary minerals relative to the extrusives at Site 858 (d18O = 4.5 per mil - 5.5 per mil). There is no evidence of significant albitization of the plagioclase at Site 857, suggesting high Ca/Na in the pore fluids. Fluid-inclusion data from hydrothermal minerals in altered mafic rocks and veins at Sites 857 and 858 show a consistency of homogenization temperatures, varying from 245 to 270°C, which is within the range of temperatures observed for the fluids venting at Site 858. The consistency of the fluid inclusion temperatures, the lack of albitization within the Site 857 sills, and the apparently low water/rock ratio collectively suggest that the sill complex at Site 857 is in thermal equilibrium and being altered by a highly evolved Ca-rich fluid similar to the fluids now venting at Site 858. The alteration evident in these two deep crustal drillsites is a result of the ongoing hydrothermal circulation and is consistent with downhole logging results, instrumented borehole results, and hydrothermal fluid chemistry. The pervasive alteration of the laterally extensive sill-sediment complex at Site 857 determines the chemistry of the fluids that are venting at Site 858. The limited alteration of the Site 858 lavas suggests that this basement edifice acts as a penetrator or ventilator for the regional hydrothermal reservoir with much of the flow focussed at the highly altered and veined sediment-basalt contact.

The Role of IL-25 in Colitis-Associated Colon Cancer and Pulmonary Inflammation

Thesis (Ph.D.)--University of Washington, 2016-06

Local Actors in Donor-Funded Rule of Law Assistance in Indonesia: Owners, Partners, Agents?

Thesis (Ph.D.)--University of Washington, 2016-06

The role of morphine-6-glucuronide (M6G) in pain control

Morphine-6beta-D-glucuronide (M6G) is an analgesically active metabolite of morphine, accounting for approximate to10% of the morphine dose when administered by systemic routes to humans. Although M6G is more hydrophilic than morphine, it crosses the blood-brain barrier, albeit relatively slowly. For this reason, it is generally thought that, after chronic dosing, M6G contributes significantly to the analgesic effects of systemically administered morphine. Owing to its polar nature, M6G is cleared from the systemic circulation primarily via renal elimination. As M6G accumulates in patients with renal impairment, there is an increased risk of M6G-induced respiratory depression in renal failure patients who are being dosed chronically with systemic morphine. Consistent with its analgesic and respiratory depressant properties, M6G binds to the p-opioid receptor in a naloxone-reversible manner. Although the affinity of M6G for the mu-opioid receptor is similar to or slightly less than that of morphine, preclinical studies in rodents show that M6G is one to two orders of magnitude more potent than morphine when administered by central routes. This major discrepancy between the markedly higher intrinsic antinociceptive potency of M6G relative to morphine, despite their similar p-opioid receptor binding affinities, is difficult to reconcile. It has been proposed that M6G mediates its pain-relieving effects through a novel 'M6G opioid receptor', while others have argued that M6G may have higher efficacy than morphine for transduction of intracellular events. When administered by parenteral routes to rodents, M6G's antinociceptive potency is no more than twofold higher than morphine. In humans, the analgesic efficacy and respiratory depressant potency of M6G relative to morphine have been assessed in a number of short-term studies involving the intrathecal or intravenous routes of administration. For example, in hip replacement patients, intrathecal M6G provided excellent postoperative analgesia but the occurrence of late respiratory depression in 10% of these patients raised serious concern about safety. In postoperative patients, intravenous M6G administered by means of patient-controlled analgesia (PCA), or bolus plus PCA, produced no analgesia in one study and limited analgesia in another. Similarly, there was a lack of significant analgesia in healthy volunteers who received intravenous M6G for the alleviation of experimental pain (carbon dioxide applied to the nasal mucosa). In contrast, satisfactory analgesia was produced by bolus doses of intravenous M6G administered to patients with cancer pain, and to healthy volunteers with experimentally-induced ischaemic, electrical or thermal (ice water) pain. Studies to date in healthy volunteers suggest that intravenous M6G may be a less potent respiratory depressant and have a lower propensity for producing nausea and vomiting than morphine. However, it is unclear whether equi-analgesic doses of M6G and morphine were compared. Clearly, more extensive short-term trials, together with studies involving chronic M6G administration, are necessary before the potential clinical utility of M6G as an analgesic drug in its own right can be determined.

Out of the generosity of your heart: Are we creating active citizens through compulsory volunteer programmes for young people in Australia?

Using governmentality as a theoretical framework, we examine two Australian policy areas where young people are disciplined into becoming good, active citizens. These policies-mutual obligation through the work for the dole programme, and school-based active citizenship programmes similar to American service learning programmes-both mirror volunteer-ope activities, in a social context where volunteers are viewed as good citizens. In this study, we present findings from a qualitative study that addresses the question of whether young people will develop active citizenship through compulsory volunteer-type programmes. The findings show that first, young people are very conscious of the lack of choice involved in these programmes and that this weakened their sense of agency. Second, the programmes failed to develop positive community attitudes and active social behaviours. These results suggest that policies that compel individuals to contribute to society may actually weaken their citizenship identities.