A nonantisense sequence-selective effect of a phosphorothioate oligodeoxynucleotide directed against the epidermal growth factor receptor in A431 cells

The overexpression of epidermal growth factor receptor (EGFr) has been implicated as a causative factor and a poor prognostic marker in a number of carcinomas. Therefore, strategies that down-regulate EGFr expression may be therapeutically useful. We designed antisense ODNs complementary to the initiation codon region of the EGFr mRNA and evaluated their efficacy in several tumor-derived cells, including the A431 cell line that express amplified levels of EGFr. A 15-mer phosphorothioate (PS) antisense ODN (erbB1AS15) induced a concentration-dependent reduction in proliferation that was accompanied by a change in the morphology of A431 cells into more tightly clustered and discrete colonies. A 15-mer sense (PS) control oligodeoxynucleotide (ODN) and a phosphodiester (PO) version of erbB1AS15 had little or no effect on cell number of morphology, and erbB1AS15 (PS) did not induce these effects in control cell lines expressing lower levels of EGFr. The effects of erbB1AS15 (PS) on A431 cells were not mediated by a true antisense mechanism in that there was no reduction in the level of EGFr mRNA or protein over a 24-hr period, as determined by Northern and Western blotting, respectively. However, autophosphorylation of the receptor was significantly reduced by erbB1AS15 (PS) and not by control ODNs. The results of further studies suggested that this effect was mediated by a direct, dose-dependent inhibition of the EGFr tyrosine kinase enzyme and was not due to impairment of either ligand-binding or receptor dimerization. These data suggest that erbB1AS15 (PS) can inhibit proliferation and alter the morphology of A431 cells by a sequence-selective, but nonantisense mechanism affecting receptor tyrosine kinase activity.

Monopoly in the UK:what determines whether the MMC finds against the investigated firms?

This paper draws on data from 73 UK Monopolies and Mergers Commission reports on monopoly between 1973 and 1995. It shows that there is a roughly two in three chance that the Commission will come to an adverse conclusion against the investigated firms in a given case. 75–80% of decisions can be explained purely in terms of the market share of the leading firm and knowledge of the broad nature of the alleged anti-competitive practice. An adverse finding is most likely in cases involving exclusive dealing, and least likely where other vertical restraints are involved.

Length, lexicality, and articulatory suppression in immediate recall:evidence against the articulatory loop

Influential models of short-term memory have attributed the fact that short words are recalled better than longer words in serial recall (the length effect) to articulatory rehearsal. Crucial for this link is the finding that the length effect disappears under articulatory suppression. We show, instead, that, under suppression, the length effect is abolished or reversed for real words but remains robust for nonwords. The latter finding is demonstrated in a variety of conditions: with lists of three and four nonwords, with nonwords drawn from closed and open sets, with spoken and written presentation, and with written and spoken output. Our interpretation is that the standard length effect derives from the number of phonological units to be retained. The length effect is abolished or reversed under suppression because this condition encourages reliance on lexical-semantic representations. Using these representations, longer words can more easily be reconstructed from degraded phonology than shorter words. © 2005 Elsevier Inc. All rights reserved.

Language against the odds, or rather not:the weak central coherence hypothesis and language

EV is a child with a talent for learning language combined with Asperger syndrome. EV’s talent is evident in the unusual circumstances of her acquisition of both her first (Bulgarian) and second (German) languages and the unique patterns of both receptive and expressive language (in both the L1 and L2), in which she shows subtle dissociations in competence and performance consistent with an uneven cognitive profile of skills and abilities. We argue that this case provides support for theories of language learning and usage that require more general underlying cognitive mechanisms and skills. One such account, the Weak Central Coherence (WCC) hypothesis of autism, provides a plausible framework for the interpretation of the simultaneous co-occurrence of EV’s particular pattern of cognitive strengths and weaknesses. Furthermore, we show that specific features of the uneven cognitive profile of Asperger syndrome can help explain the observed language talent displayed by EV. Thus, rather than demonstrating a case where language learning takes place despite the presence of deficits, EV’s case illustrates how a pattern of strengths within this profile can specifically promote language learning.

Have the GIPSI settled down? Breaks and multivariate stochastic volatility models for, and not against, the European financial integration

We investigate the integration of the European peripheral financial markets with Germany, France, and the UK using a combination of tests for structural breaks and return correlations derived from several multivariate stochastic volatility models. Our findings suggest that financial integration intensified in anticipation of the Euro, further strengthened by the EMU inception, and amplified in response to the 2007/2008 financial crisis. Hence, no evidence is found of decoupling of the equity markets in more troubled European countries from the core. Interestingly, the UK, despite staying outside the EMU, is not worse integrated with the GIPSI than Germany or France. © 2013 Elsevier B.V.

Evaluation of DNA enzymes targeted against the RNA component of human telomerase

Glioblastoma Multiforme (GBM) is a highly malignant form of brain cancer for which there is currently no effective cure. Consequently, developing new therapies and elucidating effective targets is crucial for this fatal disease. In recent years, DNA enzymes, deoxyribonucleic acid molecules with enzymatic activity, have emerged. In the same manner as ribozymes, DNA enzymes are able to effect cleavage of RNA in a sequence-specific manner, and operate with catalytic efficiency. In this study, two DNA enzymes were designed to target the template region of human telomerase RNA (hTR), utilising the 10-23 and 8-17 catalytic motifs elucidated by Santoro and Joyce (1997). Telomerase is an RNA-dependent DNA polymerase, which stabilises telomere lengths by adding hexameric repeats (TTAGGG in humans) to chromosome termini, thus preventing the telomere shortening that usually occurs during mitotic cell division. Telomerase activity, whilst absent in normal somatic tissues, is present in almost 90% of all tumours. Thus, there is speculation that telomerase may be the much sought universal target for therapeutic intervention in cancer. In vitro cleavage assays showed both DNA enzymes to be catalytically competent. Unmodified phosphodiester (PO) backbone DNA enzymes were rapidly degraded in the presence of serum, with a half-life of 10 minutes. The common approach of introducing phosphorothioate (PS) linkages was used in an effort to overcome this instability. As a result of concurrent activity and stability studies on the DNA enzymes with various numbers of PS linkages, the DNA enzymes with a PO core and PS arms were chosen for use in further cell work. The cleavage activity of both was shown to be specific and affected by temperature, pH, MgCI2 concentration and enzyme concentration. Both DNA enzyme motifs reduced telomerase activity in cell lysates, as assessed by the telomerase repeat amplification protocol (TRAP) with an IC50 of 100nM. DNA enzymes being polyanionic molecules do not readily cross biological barriers. Cellular association of naked DNA enzyme was inefficient at less than 2%. Cellular delivery of the DNA enzymes was effectively improved using commercial cationic lipid formulations. However, the lipid-mediated delivery of DNA enzymes to U87-MG cells over a 4-hour period did not significantly inhibit cell proliferation compared to controls. This is possibly due to an expected lag period between the inhibition of telomere maintenance and cell death. Therefore, biodegradable polymer microspheres were investigated as a potential delivery option for prolonged and sustained delivery. In vitro release profiles showed that after an initial burst, sustained release of DNA enzymes was observed over 35 days. Finally, the efficacy and specificity of the DNA enzymes were demonstrated in a luciferase based reporter assay. Specific inhibition of luciferase expression was displayed at 10nM. Thus DNA enzymes have potential against endogenous cellular targets.

Trading democracy for security? The effects of the international drug war on the quality of democracy in the Dominican Republic, 1996–2008

The purpose of the research is to study the relationship between international drug interdiction policies and domestic politics in fragile democracies, and to demonstrate how international drug control policies and the use of force fit the rhetoric of war, are legitimized by the principles of a just war, but may also cause collateral damage and negative unintended consequences. The method used is a case study of the Dominican Republic. The research has found that international drug control regimes, primarily led by the U.S. and narrowly focused on interdiction, have influenced an increasingly militarized approach to domestic law enforcement in the Dominican Republic. The collateral damage caused by militarized enforcement comes in the form of negative perceptions of citizen security, loss of respect for the rule of law and due process, and low levels of civil society development. The drug war has exposed the need for significant reform of the institutions charged with carrying out enforcement, the police force and the judicial system in particular. The dissertation concludes that the extent of drug trafficking in the Dominican Republic is beyond the scope of domestic reform efforts alone, but that the programs implemented do show some potential for future success. The dissertation also concludes that the framework of warfare is not the most appropriate for the international problems of drug traffic and abuse. A broader, multipronged approach should be considered by world policy makers in order to address all conditions that allow drugs to flourish without infringing upon democratic and civil rights in the process.

Swimming against the tide: A study of a youth enrichment program seeking to empower inner-city Black youth

Serious inequities in our K-12 public education system, particularly in regard to the quality of education in predominately Black inner-city schools, are well-documented in the literature (Freeman, 1998; Ross, 1998). Moreover, there is general agreement that the most effective means of ameliorating that situation is through well-thought-out after-school programs and partnership initiatives (Beck, 1993; Gardner et al., 2001). ^ The purpose of this qualitative study was to examine the programmatic interventions of a youth enrichment program for inner-city Black youth currently in place at the Overtown Youth Center (OYC) in Miami, Florida, in order to: (a) discern those factors that support its claim that it is making a difference in students’ lives, (b) explore how any such factors are implemented, and (c) determine whether its interventions have served to equalize the playing field for these youth. ^ Two primary methods of data collection were used for this study. The first was participant observation conducted over the course of two years through a partnership initiative established and led by this author. The second was through in-depth interviews of the Center’s founder, staff, and students. Secondary methods used were the recording of informal conversations and the analysis of written documents. ^ Analysis of the data yielded four features of the Center that are indispensible to the students’ growth. The center provides the youth with (a) physical and psychological safety, (b) supportive relationships, (c) exposure to cultural and educational opportunities, and (d) assistance in building self-esteem. ^ The most significant finding of the study was that OYC has been successful at making a difference in students’ lives and at increasing their aspirations to attend college. By addressing the full spectrum of their needs, the Center has given them many of the necessary tools with which to compete and thereby helped equalize their opportunities to succeed in school and in life. ^ The study also noted a number of challenges for the Center to examine. The main issues that need to be addressed more seriously are staff turnover, staff indifference, nepotism, inconsistent student attendance, and insufficient focus on racial issues and African-American-centered education. Meeting those challenges would engender even greater positive outcomes.^

From Bilingualism to Interlinguistics: The Case Against the Deficit Model of Language Acquisition

The article argues against an ahistorical deficit model of Spanish/English bilingualism in educational practice based on interlinguistic research. The bidirectional facilitative effects of Hispanic bilingualism allow Spanish-speaking minorities to exploit their language background while learning academic English and integrating their language and culture into the American mainstream.

The Spanish Civil War in the twenty -first century peninsular narrative: Narrative endeavors towards a national reconciliation?

This dissertation analyzes six twenty-first century novels that reflect Spain's current intellectual trends on the Spanish Civil War, Francoism and the transition to a democratic system. These novels deal with the complex correlation between memory and amnesia caused by the traumatic events of the Civil War. Despite the abundance of literature on this topic, these writers insist on the need for the recovery of historical and collective memory in order to halt the negative historical revisionism of recent years. Beginning with the death of Francisco Franco, this work focuses on the historical-theoretical framework that leads to the development of this mnemonic narrative and outlines the politics of memory effectuated during the transitional period, a lieu de mémoire frequently revisited and examined by new generations of writers. The novels analyzed also call for the retelling of history from the perspective of everyday people and address the need to pay overdue homage to victims of the post-war era.^ This work concludes that, while the texts may be considered settings for posthumous tributes, they could likewise advocate for a national reconciliation. Thus, as this narrative reveals, by focusing more on the need for a work on memory than on political and ideological polarizations, the memory of restitution does not interfere with the memory of reconciliation. The writers in question are nonetheless aware that reconciliation cannot be based on a spurious amnesia. The first step, therefore, towards reconciliation is to achieve a legitimate dialogue with regard to the traumatic past, and literary works may offer a tenable path. ^

"To hold the world in contempt": The British Empire, war, and the Irish and Indian nationalist press, 1899–1914

The era between the close of the nineteenth century and the onset of the First World War witnessed a marked increase in radical agitation among Indian and Irish nationalists. The most outspoken political leaders of the day founded a series of widely circulated newspapers in India and Ireland, placing these editors in the enviable position of both reporting and creating the news. Nationalist journalists were in the vanguard of those pressing vocally for an independent India and Ireland, and together constituted an increasingly problematic contingent for the British Empire. The advanced-nationalist press in Ireland and the nationalist press in India took the lead in facilitating the exchange of provocative ideas--raising awareness of perceived imperial injustices, offering strategic advice, and cementing international solidarity. Irish and Indian press coverage of Britain's imperial wars constituted one of the premier weapons in the nationalists' arsenal, permitting them to build support for their ideology and forward their agenda in a manner both rapid and definitive. Directing their readers' attention to conflicts overseas proved instructive in how the Empire dealt with those who resisted its policies, and also showcased how it conducted its affairs with its allies. As such, critical press coverage of the Boxer Rebellion, Boer War, Russo-Japanese War, and World War I bred disaffection for the Empire, while attempts by the Empire to suppress the critiques further alienated the public. This dissertation offers the first comparative analysis of the major nationalist press organs in India and Ireland, using the prism of war to illustrate the increasingly persuasive role of the press in promoting resistance to the Empire. It focuses on how the leading Indian and Irish editors not only fostered a nationalist agenda within their own countries, but also worked in concert to construct a global anti-imperialist platform. By highlighting the anti-imperial rhetoric of the nationalist press in India and Ireland and illuminating their strategies for attaining self-government, this study deepens understanding of the seeds of nationalism, making a contribution to comparative imperial scholarship, and demonstrating the power of the media to alter imperial dynamics and effect political change.

Betting Against the Glass Ceiling: Supervisor Gender & Employee Job Satisfaction in the Casino-Entertainment Industry

This exploratory study expands on hospitality management literature, specifically on the influence of a supervisor’s gender in regards to employee job satisfaction within the casino-entertainment sector. Employee job satisfaction was analyzed using company, department, and supervisor variables based on 961 surveys. The study’s results suggest that employees with male supervisors have a higher employee satisfaction level than employees with supervisors that are female. Hospitality organizations are therefore encouraged to create leadership programs to ensure women are a part of corporate leadership’s success formula for the future.

Don't Get Mad, Get Even: How Employees Abused by Their Supervisor Retaliate Against the Organization and Undermine Their Spouses

My study investigated the effects of abusive supervision on work and family outcomes including supervisor-directed and organization-directed deviance and spousal undermining. Using a moderated-mediation model, the relationship of abusive supervision on outcome variables was proposed to be mediated by moral courage and moderated by leader-member exchange (a-path) and work and family role quality (b-path). Two separate studies were conducted using a sample (N=200) recruited through Amazon’s Mechanical Turk and through relatives of students at a large US public southeastern university (N=150 dyads). Results confirm the effects of abusive supervision on work and family outcomes while analyses of contextual and conditional factors are mixed. Confirmatory factor analyses, factor loadings, and model fit statistics are provided and implications for research and practice are discussed.