An investigation into the effects of metabolic disturbance on monocyte inflammatory response and regulation

The presence of chronic inflammation is associated with increased nutrient availability during obesity or type 2 diabetes which contributes to the development of complications such as atherosclerosis, stroke and myocardial infarction. The link between increased nutrient availability and inflammatory response remains poorly understood. The functioning of monocytes, the primary instigators of the inflammatory response was assessed in response to obesity and increased glucose availability. Monocyte microRNA expression was assessed in obese individuals prior to and up to one year after bariatric surgery. A number of microRNAs were identified to be dysregulated in obesity, some of which have previously been linked to the regulation of monocyte inflammatory responses including the microRNAs 146a-5p and 424-5p. Weight loss in response to bariatric surgery lead to the reversal of microRNA changes towards control values. In vitro treatments of THP-1 monocytes with high concentrations of D-glucose resulted in decreased intracellular NAD+:NADH ratio, decreased SIRT1 deacetylase activity and increased P65 acetylation. However the increased osmotic concentration inhibited LPS induced inflammatory response and TNFα mRNA expression. In vitro treatment of primary human monocytes with increased concentrations of D-glucose resulted in increased secretion of a number of inflammatory cytokines and increased expression of TNFα mRNA. Treatment also resulted in decreased intracellular NAD+:NADH ratio and increased binding of acetylated P65 to the TNFα promoter region. In vitro treatments of primary monocytes also replicated the altered expression of the microRNAs 146a-5p and miR-424-5p, as seen in obese individuals. In conclusion a number of changes in monocyte function were observed in response to obesity and treatment with high concentrations of D-glucose. These may lead to the dysregulation of inflammatory responses contributing to the development of co-morbidities.

Jurors' use of social framework evidence

Monahan and Walker (1988) delineated three uses of social science evidence within the courts: social authority, social fact, and social framework. Social authority evidence is social science evidence used in making policy or law. Social fact evidence is social science evidence that describes research undertaken expressly for the case at hand. Social framework evidence involves providing conclusions from previously conducted social science research to assist jurors in evaluating the other evidence in the case. Although this type of evidence has traditionally been presented via expert testimony, Monahan and Walker (1988) have suggested that, because the social science research involved comes from the extant literature and is not the province of any particular expert, it would be more economical to have the judge present this information as part of the judicial instructions to the jury. This study tested the implicit assumption that the presentation of the social framework evidence by the judge will have the same impact on juror verdicts as presentation of this evidence by an expert. ^ Two hundred mock jurors watched a videotaped hostile work environment sexual harassment trial. The social framework evidence consisted of the discussion of factors that have been found to increase the likelihood of sex stereotyping of women by men. The trial included either no social framework evidence, social framework evidence presented by the expert, or social framework evidence presented in judicial instructions. ^ Results indicated that men who heard the social framework evidence from the judge were more likely to vote for the defendant than men who heard no social framework evidence. Men who heard the judicial instruction with the social framework evidence also rated the plaintiff as less credible than the other men and women in the study. Thus, it appears that, for men, social framework evidence presented by the judge harms the plaintiff's case by reducing ratings of her credibility, but the same evidence presented by an expert does not affect men's verdicts. For women, however, social framework evidence, irrespective of who presents it, enhances the plaintiff's case. ^

Factors predicting recommendations for civil commitment of sexually violent predators under Florida's Jimmy Ryce Act

This study investigated the factors considered by forensic examiners when evaluating sexually violent predators (SVP) for civil commitment under Florida's “Jimmy Ryce Act.” The project was funded by a pre-doctoral research grant awarded by the Association for the Treatment of Sexual Abusers (ATSA). ^ This study proposed two specific research questions. First, what is the direct relationship between actuarial risk assessment scores and recommendations for sex offender civil commitment? Second, which other variables are likely to influence SVP commitment decisions, and to what degree? The purpose of the study was to determine if risk assessment practices are evidence-based, and whether offenders selected for commitment meet statutory criteria. ^ The purposive sample of 450 SVPs was drawn from the population of sex offenders evaluated for civil commitment in Florida between July 1, 2000 and June 30, 2001. Data were extracted from SVP evaluations provided by the Florida Department of Children and Families. Using multivariate logistic regression, this correlational research design examined the relationship between the dependent variable, commitment decision, and several sets of independent variables. The independent variables were derived from a review of the literature, and were grouped conceptually according to their degree of correlation with sex offense recidivism. Independent variables included diagnoses, actuarial risk assessment scores, empirically validated static and dynamic risk factors, consensus based risk factors, evaluator characteristics, and demographics. This study investigated the degree to which the identified variables predicted civil commitment decisions. ^ Logistic regression results revealed that the statistically significant predictors of recommendations for sex offender civil commitment were actuarial risk assessment scores, diagnoses of Pedophilia and Paraphilia NOS, psychopathy, younger age of victim, and non-minority race. Discriminant function analysis confirmed that these variables correctly predicted commitment decisions in 90% of cases. ^ It appears that civil commitment evaluators in Florida used empirically-based assessment procedures, and did not make decisions that were heavily influenced by extraneous factors. SVPs recommended for commitment consistently met the criteria set forth by the U.S. Supreme Court in Hendricks v. Kansas (1997): they suffered from a mental abnormality predisposing them to sexual violence, and risk assessment determined that they were likely to reoffend. ^

Perceived and actual sex differences in attributional style for affiliative behavior

The objectives of this thesis were threefold: (1) to review the concept of attributional style, (2) to demonstrate its applicability to affiliative behavior, and (3) to document the existence of actual and perceived sex differences in attributional style for affiliative behavior. To fulfill the first two objectives the development of attributional theory was traced from the Abramson, Seligman, and Teasdale (1978) presentation of the reformulated learned helplessness model through Weiner's (1979) examination of attributional style as a motivational feature of achievement behavior to the application of attribution theory to affiliative behavior. To fulfill the third objective the evidence detailing the sex differences in achievement and affiliative attributional styles was reviewed within the framework of perceptions of sex appropriate behavior. A study was then designed to assess both actual and perceived affiliative attributional sex differences. The Escovar, Brown, and Rodriguez Attributional Style Questionnaire for Affiliative Behavior was administered to 107 male and female University of Miami and Florida International University students. Each subject answered the questionnaire twice, once for themselves and once as if they were a member of the opposite sex. The results indicated that the EBR-ASQ maintained previous levels of internal consistency and reliability. Analyses performed on the covariate of the order of perspective presentation were negative; all further analyses were performed without a covariate. The data were analyzed using a 2(Sex) X 2(Perspective) X 2(Outcome) factorial, multivariate, repeated measures design with the three attributional dimensions serving as the dependent variable repeated measures. As expected all multivariate tests revealed that each of the three factors was a significant influence over all three of the dependent variables. Of the 21 univariate tests 12 of the main effect and two-way interactions were significant and one approached significance. Examination of the means revealed that of the eight significant main effects six were in the expected direction; of the four significant two-way interactions three were in the expected direction. Although the results were not totally supportive of the hypotheses they did support the thesis that affiliation is the female sex-role appropriate analogue to male achievement behavior.

The mermaid series of Elizabethan and Jacobean dramatists (1887-1909): a literary and critical history

The Mermaid Series (1887-1909) edited by Havelock Ellis was a major watershed in appreciation of Elizabethan and Jacobean drama. Before it appeared plays were available to general readers in scattered anthologies, large expensive collected editions or in expurgated selections which included only the more lyrical speeches and memorable scenes. Criticism of the drama followed suit; the majority of critics concentrated on the sections which appealed to the romantic and sentimental tastes of nineteenthcentury readers. The two men who conceived the Mermaid Series, John Addington Symonds and Havelock Ellis, approached the drama differently from their contemporaries; Symonds studied a play as a whole work of art and Ellis concentrated on its view of life. Both were unsatisfied with the "select beauties", fragmented approach and wanted readers to have the best plays in their entirety easily available in handy, inexpensive editions. Symonds's awareness of the drama as theatre was combined with a historical perspective allowing him to judge the drama in relation to its own time. He made a lasting but hitherto underestimated contribution to study of Beaumont and Fletcher, Dekker, Marlowe, and Ford. Ellis's work on the drama is overshadowed today by his studies of sex but his concentration on ideas and appreciation of unconventional behaviour enabled him to formulate new views on Ford, Middleton and Chapman. The two other major editors to work on the series, A. C. Swinburne and Arthur Symons had more conventional nineteenth-century approaches. Both were impressionistic critics who were most attracted to the l~nguage of the drama. Swinburne, however, occasionally transcended his fragmented approach and offered significant interpretations of Tourneur, Massinger; 'The .Changeling, Heywood. Symons's range was more limited but his form of impressionism was valuable for its concentration on the aesthetic experience at the heart of a work of art. His most important contributions were the study of Middleton and Massinger. Besides these four major critics numerous lesser writers worked on the series. Their editorial work was valuable and some, notably Ernest Rhys, c. H. Herford and Thomas Dickinson offered criticism of enduring importance. In my first chapter I consider the general availability of texts of the Elizabethan and Jacobean drama in the nineteenth century, the general attitudes towards the drama, and the critical approaches of each of the editors. The subsequent chapters are organized around the volumes of the series. I consider the climate of opinion in which each appeared, assess its critical and editorial contribution and evaluate the work of the other Mermaid editors on the dramatist included in the volume. My study shows that the concept of the Mermaid Series and the work of its editors helped to revolutionize study of the Elizabethan and Jacobean dramatists by providing good texts and by pointing the way to our present view of the plays as whole works of art.

Development and Characterization of Monovalent and Bivalent RNA Aptamers Targeting the Common Pathway of Coagulation

Anticoagulant agents are commonly used drugs to reduce blood coagulation in acute and chronic clinical settings. Many of these drugs target the common pathway of coagulation because it is critical for thrombin generation and disruption of this portion of the pathway has profound effects on the hemostatic process. Currently available drugs for these indications struggle with balancing desired activity with immunogenicity and poor reversibility or irreversibility in the event of hemorrhage. While improvements are being made with the current drugs, new drugs with better therapeutic indices are needed for surgical intervention and chronic indications to prevent thrombosis from occurring.

A class of therapeutics known as aptamers may be able to meet the need for safer anticoagulant agents. Aptamer are short single-stranded RNA oligonucleotides that adopt specific secondary and tertiary structures based upon their sequence. They can be generated to both enzymes and cofactors because they derive their inhibitory activity by blocking protein-protein interactions, rather than active site inhibition. They inhibit their target proteins with a high level of specificity and bind with high affinity to their target. Additionally, they can be reversed using two different antidote approaches, specific oligonucleotide antidotes, or with cationic, “universal” antidotes. The reversal of their activity is both rapid and durable.

The ability of aptamers to be generated to cofactors has been conclusively proven by generating an aptamer targeting the common pathway coagulation cofactor, Factor V (FV). We developed two aptamers with anticoagulant ability that bind to both FV and FVa, the active cofactor. Both aptamers were truncated to smaller functional sizes and had specific point mutant aptamers developed for use as controls. The anticoagulant activity of both aptamer-mutant pairs was characterized using plasma-based clotting assays and whole blood assays. The mechanism of action resulting in anticoagulant activity was assessed for one aptamer. The aptamer was found to block FVa docking to membrane surfaces, a mechanism not previously observed in any of our other anticoagulant aptamers.

To explore development of aptamers as anticoagulant agents targeting the common pathway for surgical interventions, we fused two anticoagulant aptamers targeting Factor X and prothrombin into a single molecule. The bivalent aptamer was truncated to a minimal size while maintaining robust anticoagulant activity. Characterization of the bivalent aptamer in plasma-based clotting assays indicated we had generated a very robust anticoagulant therapeutic. Furthermore, we were able to simultaneously reverse the activity of both aptamers with a single oligonucleotide antidote. This rapid and complete reversal of anticoagulant activity is not available in the antithrombotic agents currently used in surgery.

Sex offender risk assessment and management in Ireland

This research examined sex offender risk assessment and management in Ireland. It focused on the statutory agencies with primary responsibility (Garda Síochána and the Probation Service). The goal was to document the historical, contextual and current systems, in addition to identifying areas of concern/improvements. The research was a mixed-methods approach. Eight studies were conducted. This incorporated documentary reviews of four Commission to Inquire Reports, qualitative interviews/focus groups with Garda staff, Probation Service staff, statutory agencies, community stakeholders, various Non-Governmental Organisations (NGOs) and sex offenders. Quantitative questionnaires were also administered to Garda staff. In all over 70 interviews were conducted and questionnaires were forwarded to 270 Garda members. The overall findings are: •Sex offender management in Ireland has become formal only since 2001. Knowledge, skills and expertise is in its infancy and is still evolving. •Mixed reviews and questions regarding fitness for purpose of currently used risk assessments tools were noted. •The Sex Offender Act 2001 requires additional elements to ensure safe sex offender monitoring and public protection. A judicial review of the Sex Offender Act 2001 was recommended by many respondents. •Interagency working under SORAM was hugely welcomed. The sharing of information has been welcomed by managing agencies as the key benefit to improving sex offender management. •Respondents reported that in practice, sex offender management in Ireland is fragmented and unevenly implemented. The research concluded that an independent National Sex Offender Authority should be established as an oversight and regulatory body for policy, strategy and direction in sex offender management. Further areas of research were also highlighted: ongoing evaluation and audits of the joint agency process and systems in place; recidivism studies tracking the risk assessment ratings and subsequent offending; and an evaluation of the current status of sex offender housing in Ireland.

Relative abundance of anaerobic methanotrophic archaea in bacterial mat Cascadia margin off Oregon

The microbially mediated anaerobic oxidation of methane (AOM) is the major biological sink of the greenhouse gas methane in marine sediments (doi:10.1007/978-94-009-0213-8_44) and serves as an important control for emission of methane into the hydrosphere. The AOM metabolic process is assumed to be a reversal of methanogenesis coupled to the reduction of sulfate to sulfide involving methanotrophic archaea (ANME) and sulfate-reducing bacteria (SRB) as syntrophic partners which were describes amongst others in Boetius et al. (2000; doi:10.1038/35036572). In this study, 16S rRNA-based methods were used to investigate the distribution and biomass of archaea in samples from sediments above outcropping methane hydrate at Hydrate Ridge (Cascadia margin off Oregon) and (ii) massive microbial mats enclosing carbonate reefs (Crimea area, Black Sea). Sediment samples from Hydrate Ridge were obtained during R/V SONNE cruises SO143-2 in August 1999 and SO148-1 in August 2000 at the crest of southern Hydrate Ridge at the Cascadia convergent margin off the coast of Oregon. The second study area is located in the Black Sea and represents a field in which there is active seepage of free gas on the slope of the northwestern Crimea area. Here, a field of conspicuous microbial reefs forming chimney-like structures was discovered at a water depth of 230 m in anoxic waters. The microbial mats were sampled by using the manned submersible JAGO during the R/V Prof. LOGACHEV cruise in July 2001. At Hydrate Ridge the surface sediments were dominated by aggregates consisting of ANME-2 and members of the Desulfosarcina-Desulfococcus branch (DSS) (ANME-2/DSS aggregates), which accounted for >90% of the total cell biomass. The numbers of ANME-1 cells increased strongly with depth; these cells accounted 1% of all single cells at the surface and more than 30% of all single cells (5% of the total cells) in 7- to 10-cm sediment horizons that were directly above layers of gas hydrate. In the Black Sea microbial mats ANME-1 accounted for about 50% of all cells. ANME-2/DSS aggregates occurred in microenvironments within the mat but accounted for only 1% of the total cells. FISH probes for the ANME-2a and ANME-2c subclusters were designed based on a comparative 16S rRNA analysis. In Hydrate Ridge sediments ANME-2a/DSS and ANME-2c/DSS aggregates differed significantly in morphology and abundance. The relative abundance values for these subgroups were remarkably different at Beggiatoa sites (80% ANME-2a, 20% ANME-2c) and Calyptogena sites (20% ANME-2a, 80% ANME-2c), indicating that there was preferential selection of the groups in the two habitats.

Electrophysiological study of the effects of arginine vasopressin in the rat juxtacapsular nucleus of the bed nucleus of the stria terminalis

Arginine vasopressin (AVP), a nine amino acid neuropeptide (CYFQNCPRG- NH2) fulfills a dual function: (i) in the periphery, AVP acts as a peptide hormone and (ii) in the CNS, AVP is a neuromodulatory peptide. AVP produces its effects through 3 AVP receptors (AVPRs). AVPR1a and AVPR1b are expressed in the CNS and periphery, whilst AVPR2 is not found centrally but instead solely expressed in the kidneys. Recent evidence revealed a high density of AVP-binding sites in the juxtacapsular nucleus of the bed nucleus of the stria terminalis (jxBNST). While in other regions of the brain, AVP acts at AVPRs to regulate an array of biological processes, including male-typical social behaviours, social memory, stress adaptation, fear, anxiety, and fluid homeostasis, its role in the jxBNST remains elusive. Furthermore, the neurophysiological properties of AVP in the jxBNST are unknown so this study aimed to examine how AVP modulates synaptic transmission in the rat jxBNST. The BNST being one of the most notable sexually dimorphic brain regions and AVPR expression being influenced by gonadal steroids, we investigated the putative influence of sex on the modulatory effects of AVP in the jxBNST. Finally, due to AVP being released at a substantially higher concentration following periods of water deprivation, we examined changes in AVPs modulatory role following water deprivation. Male and female Long Evans rats were euthanized and brain slice whole-cell voltage-clamp electrophysiology was done in the jxBNST to measure the effects of AVP on synaptic transmission of GABA synapses. Exogenous application of AVP produced three responses; either postsynaptic long-term potentiation (LTP) of GABAA-inhibitory postsynaptic currents (IPSC), postsynaptic long-term depression (LTD) of GABAA-IPSC, or no change in GABAA-IPSC amplitudes. Interestingly, the proportion of neurons responding in each of these ways did not differ between sexes and within females was not estrous cycle-dependent. Finally, although not statistically significant, 24-hour water deprivation abolished GABAA-LTD, an effect that was not a consequence of social isolation. Taken together, our data show that AVP modulates GABAA synaptic transmission in the jxBNST in fluid homeostasis- but not sex-dependent manner.

Reverberations: The Philosophy, Aesthetics, and Politics of Noise

A publication emerging out of a successful international conference I co-organised on noise in 2010. The first of two volumes, this one focuses on noise as an aesthetic, political and cultural concept, and a range of noise practices beyond purely sonic ones, such as audiovisual noise and noise in communication theory. It argues that noise is fundamental to contemporary communication practices and facilitates a reversal of perspective in how these practices can be understood

Who needs evidence? Radical Feminism, the Christian Right and sex work research in Northern Ireland

This chapter describes my experiences of conducting research on commercial sex in Belfast, Northern Ireland which was conducted as part of a larger British Academy – Leverhulme Trust funded study that examined the policing and legal regulation of commercial sex in Belfast (Northern Ireland) along with three other cities: Manchester (England), Berlin (Germany) and Prague (Czech Republic). This study provided the first empirical analysis of commercial sex in the jurisdiction and was instrumental in shedding light on prevalence rates for those involved in the industry as well as providing demographic information on the age, nationality and sexual orientation of sex workers along with the sector worked in, whether on-street or off-street. In the chapter I consider my role as a researcher and highlight some of the difficulties that I experienced conducting what was seen as controversial research in the politically, socially and culturally conservative context of Northern Ireland.

Commercial sex, clients, and Christian morals: Paying for sex in Ireland

This article reports on the results of a study on men who pay for sex across Ireland. In presenting a detailed picture of the diverse group of sex workers’ clients, their motives and attitudes, we debunk the prevalent stereotypes about men who pay for sex, as continuously used in the public discourse about sex work on both sides of the Irish border: we show that the majority of clients do not fit the image of violent, careless misogynists. We argue that these debates about commercial sex as well as the experiences of those who pay for sex are shaped and nurtured by the specific local context, by conservative Christian morals and the dominant sex-negative culture across Ireland. Finally, we argue that the criminalization of paying for sex which came into effect in Northern Ireland in 2015 and is being discussed in the Republic of Ireland will likely not stop the majority of clients from paying for sex and thus fail to achieve its aim to reduce or abolish sex work.

The Strange Revival of Bicameralism

The turn of the twenty-first century witnessed a surprising reversal of the long-observed trend towards the disappearance of second chambers in unitary states, with 28 countries – all but one of them unitary – adopting the bicameral system. This article explores this development by first setting it in the context of the historical evolution of second chambers and the arguments that support bicameralism, and then exploring the characteristics that distinguish today’s second chambers from first chambers. A ‘census’ of second chambers in 2014 is used to provide data on second chambers in federal and unitary states, to facilitate comparison with earlier data, and to distinguish between ‘new’ and longer-established second chambers. The article concludes that newly established second chambers are concentrated predominantly in political systems where liberal democratic principles are not established, suggesting that the debate over their role in democratic states is set to continue.

Gender mismatch between donor and recipient is a factor of morbidity but does not condition survival after cardiac transplantation

We intended to evaluate the influence of sex mismatch between donor and recipient, which is still under much debate, on survival and comorbidities after cardiac transplantation. From November 2003 to December 2013, a total of 258 patients were transplanted in our center. From these, 200 receptors were male (77.5%) and constituted our study population, further divided into those who received the heart from a female donor (Group A) - 44 patients (22%) and those who received it from a male donor (Group B) - 156 (78%). Median follow-up was 4.2 ± 3.0 years (1-10 years). The two groups were quite comparable with each other, except for body mass index, systolic pulmonary artery pressure, and transpulmonary gradient, which were significantly lower in Group A. A low donor/recipient weigh ratio (<0.8) was avoided whenever possible. Hospital mortality was not different in the two groups. During follow-up, global survival was similar, as was survival free from acute cellular rejection and cardiac allograft vasculopathy. However, patients in Group A had decreased survival free from serious infections and malignant tumors. Allocation of female donors to male receptors can be done safely, at least in receptors without pulmonary hypertension and when an adequate donor/recipient weigh ratio is ensured.

Evolutionary dynamics under various modes of reproduction

Thesis (Ph.D.)--University of Washington, 2016-08