The scaffold protein KSR1, a novel therapeutic target for the treatment of Merlin-deficient tumors

Merlin has broad tumor-suppressor functions as its mutations have been identified in multiple benign tumors and malignant cancers. In all schwannomas, the majority of meningiomas and 1/3 of ependymomas Merlin loss is causative. In neurofibromatosis type 2, a dominantly inherited tumor disease because of the loss of Merlin, patients suffer from multiple nervous system tumors and die on average around age 40. Chemotherapy is not effective and tumor localization and multiplicity make surgery and radiosurgery challenging and morbidity is often considerable. Thus, a new therapeutic approach is needed for these tumors. Using a primary human in vitro model for Merlin-deficient tumors, we report that the Ras/Raf/mitogen-activated protein, extracellular signal-regulated kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) scaffold, kinase suppressor of Ras 1 (KSR1), has a vital role in promoting schwannomas development. We show that KSR1 overexpression is involved in many pathological phenotypes caused by Merlin loss, namely multipolar morphology, enhanced cell-matrix adhesion, focal adhesion and, most importantly, increased proliferation and survival. Our data demonstrate that KSR1 has a wider role than MEK1/2 in the development of schwannomas because adhesion is more dependent on KSR1 than MEK1/2. Immunoprecipitation analysis reveals that KSR1 is a novel binding partner of Merlin, which suppresses KSR1's function by inhibiting the binding between KSR1 and c-Raf. Our proteomic analysis also demonstrates that KSR1 interacts with several Merlin downstream effectors, including E3 ubiquitin ligase CRL4DCAF1. Further functional studies suggests that KSR1 and DCAF1 may co-operate to regulate schwannomas formation. Taken together, these findings suggest that KSR1 serves as a potential therapeutic target for Merlin-deficient tumors.

The theory-practice divide:thoughts from the Editors and Senior Advisory Board of EJM

Purpose – The purpose of this editorial is to bring together thoughts and opinions from the Editors and Senior Advisory Board of EJM regarding the nature of the long-debated “theory-practice divide” in marketing scholarship. Design/methodology/approach – The authors synthesise diverse opinions from senior academics in order both to inspire further debate in marketing scholarship, and to draw some important conclusions for marketing academia as a whole. Findings – The authors propose that, for marketing scholarship to mature and progress, room must be found for those who wish to focus both on practical and on pure marketing scholarship. Career advancement from both routes is vital. Research limitations/implications – The topic of the theory-practice gap is complex. Many diverse opinions are cited and, due to space constraints, the coverage of many issues is necessarily brief. Practical implications – Scholars should find the thoughts contained in the paper of significant interest. Originality/value – The paper appears to be the first to bring together such a set of diverse opinions on the subject, and to try to draw some overall pragmatic conclusions, while still recognising the multiplicity of valid thought in the area.

Mechanisms of altered cortical excitability in photosensitive epilepsy

Despite the multiplicity of approaches and techniques so far applied for identifying the pathophysiological mechanisms of photosensitive epilepsy, a generally agreed explanation of the phenomenon is still lacking. The present thesis reports on three interlinked original experimental studies conducted to explore the neurophysiological correlates and the phatophysiological mechanism of photosensitive epilepsy. In the first study I assessed the role of the habituation of the Visual Evoked Response test as a possible biomarker of epileptic visual sensitivity. The two subsequent studies were designed to address specific research questions emerging from the results of the first study. The findings of the three intertwined studies performed provide experimental evidence that photosensitivity is associated with changes in a number of electrophysiological measures suggestive of altered balance between excitatory and inhibitory cortical processes. Although a strong clinical association does exist between specific epileptic syndromes and visual sensitivity, results from this research indicate that photosensitivity trait seems to be the expression of specific pathophysiological mechanisms quite distinct from the “epileptic” phenotype. The habituation of Pattern Reversal Visual Evoked Potential (PR-VEP) appears as a reliable candidate endo-phenotype of visual sensitivity. Interpreting the findings of this study in the context of the broader literature on visual habituation we can hypothesise the existence of a shared neurophysiological background between photosensitive epilepsy and migraine. Future studies to elucidate the relationship between the proposed indices of cortical excitability and specific polymorphisms of excitatroy and inhibitory neurotransmission will need to be conducted to assess their potential role as biomarkers of photosensitivity.

Oxygen tension modulates the cytokine response of oral epithelium to periodontal bacteria

Background: There is an inverse relationship between pocket depth and pocket oxygen tension with deep pockets being associated with anaerobic bacteria. However, little is known about how the host tissues respond to bacteria under differing oxygen tensions within the periodontal pocket. Aim: To investigate the effect of different oxygen tensions upon nuclear factor-kappa B (NF-?B) activation and the inflammatory cytokine response of oral epithelial cells when exposed to nine species of oral bacteria. Materials and Methods: H400 oral epithelial cells were equilibrated at 2%, 10% or 21% oxygen. Cells were stimulated with heat-killed oral bacteria at multiplicity of infection 10:1, Escherichia coli lipopolysaccharide (15 µg/ml) or vehicle control. Interleukin-8 (IL-8) and tumour necrosis factor-alpha (TNF-a) levels were measured by enzyme-linked immunosorbent assay and NF-?B activation was measured by reporter vector or by immunohistochemical analysis. Results: Tannerella forsythensis, Porphyromonas gingivalis and Prevotella intermedia elicited the greatest epithelial NF-?B activation and cytokine responses. An oxygen-tension-dependent trend in cytokine production was observed with the highest IL-8 and TNF-a production observed at 2% oxygen and lowest at 21% oxygen. Conclusions: These data demonstrate a greater pro-inflammatory host response and cell signalling response to bacteria present in more anaerobic conditions, and hypersensitivity of epithelial cells to pro-inflammatory stimuli at 2% oxygen, which may have implications for disease pathogenesis and/or therapy.

On the Hyperbolicity Domain of the Polynomial x^n + a1x^(n-1) + 1/4+ an

∗ Partially supported by INTAS grant 97-1644

On a Variational Approach to some Quasilinear Problems

We prove some multiplicity results concerning quasilinear elliptic equations with natural growth conditions. Techniques of nonsmooth critical point theory are employed.

On a Stratification Defined by Real Roots of Polynomials

2000 Mathematics Subject Classification: 12D10

Queer sex work

Sex work is a subject of significant contestation across academic disciplines, as well as within legal, medical, moral, feminist, political and socio-cultural discourses. A large body of research exists, but much of this focuses on the sale of sex by women to men and ignores other performances, practices, meanings and embodiments in the contemporary sex industry. A queer agenda is important in order to challenge hetero-centric gender norms and to develop new insights into how gender, sex, power, crime, work, migration, space/place, health and intimacy are understood in the context of commercial sexual encounters. Queer Sex Work explores what it might mean to 'be', 'do' and 'think' queer(ly) in the study and practice of commercial sex. It brings together a multiplicity of empirical case studies - including erotic dance venues, online sex working, pornography, grey sexual economies, and BSDM - and offers a variety of perspectives from academic scholars, policy practitioners, activists and sex workers themselves. In so doing, the book advances a queer politics of sex work that aims to disrupt heteronormative logics whilst also making space for different voices in academic and political debates about commercial sex. This unique and multidisciplinary volume will be indispensable for scholars and students of the global sex trade and of gender, sexuality, feminism and queer theory more broadly, as well as policymakers, activists and practitioners interested in the politics and practice of sex work in local, national and international contexts.

Dynamical Resonances and SSF Singularities for a Magnetic Schrödinger Operator

We consider the Hamiltonian H of a 3D spinless non-relativistic quantum particle subject to parallel constant magnetic and non-constant electric field. The operator H has infinitely many eigenvalues of infinite multiplicity embedded in its continuous spectrum. We perturb H by appropriate scalar potentials V and investigate the transformation of these embedded eigenvalues into resonances. First, we assume that the electric potentials are dilation-analytic with respect to the variable along the magnetic field, and obtain an asymptotic expansion of the resonances as the coupling constant ϰ of the perturbation tends to zero. Further, under the assumption that the Fermi Golden Rule holds true, we deduce estimates for the time evolution of the resonance states with and without analyticity assumptions; in the second case we obtain these results as a corollary of suitable Mourre estimates and a recent article of Cattaneo, Graf and Hunziker [11]. Next, we describe sets of perturbations V for which the Fermi Golden Rule is valid at each embedded eigenvalue of H; these sets turn out to be dense in various suitable topologies. Finally, we assume that V decays fast enough at infinity and is of definite sign, introduce the Krein spectral shift function for the operator pair (H+V, H), and study its singularities at the energies which coincide with eigenvalues of infinite multiplicity of the unperturbed operator H.

On strongly regular graphs with m2 = qm3 and m3 = qm2

2010 Mathematics Subject Classification: 05C50.

Development and implementation of a tool to assess the micro/macro elements in an organization

This study examines the congruency of planning between organizational structure and process, through an evaluation and planning model known as the Micro/Macro Dynamic Planning Grid. The model compares day-to-day planning within an organization to planning imposed by organizational administration and accrediting agencies. A survey instrument was developed to assess the micro and macro sociological analysis elements utilized by an organization.^ The Micro/Macro Dynamic Planning Grid consists of four quadrants. Each quadrant contains characteristics that reflect the interaction between the micro and macro elements of planning, objectives and goals within an organization. The Over Macro/Over Micro, Quadrant 1, contains attributes that reflect a tremendous amount of action and ongoing adjustments, typical of an organization undergoing significant changes in either leadership, program and/or structure. Over Macro/Under Micro, Quadrant 2, reflects planning characteristics found in large, bureaucratic systems with little regard given to the workings of their component parts. Under Macro/Under Micro, Quadrant 3, reflects the uncooperative, uncoordinated organization, one that contains a multiplicity of viewpoints, language, objectives and goals. Under Macro/Under Micro, Quadrant 4 represents the worst case scenario for any organization. The attributes of this quadrant are very reactive, chaotic, non-productive and redundant.^ There were three phases to the study: development of the initial instrument, pilot testing the initial instrument and item revision, and administration and assessment of the refined instrument. The survey instrument was found to be valid and reliable for the purposes and audiences herein described.^ In order to expand the applicability of the instrument to other organizational settings, the survey was administered to three professional colleges within a university.^ The first three specific research questions collectively answered, in the affirmative, the basic research question: Can the Micro/Macro Dynamic Planning Grid be applied to an organization through an organizational development tool? The first specific question: Can an instrument be constructed that applies the Micro/Macro Dynamic Planning Grid? The second specific research question: Is the constructed instrument valid and reliable? The third specific research question: Does an instrument that applies the Micro/Macro Dynamic Planning Grid assess congruency of micro and macro planning, goals and objectives within an organization? The fourth specific research question: What are the differences in the responses based on roles and responsibilities within an organization? involved statistical analysis of the response data and comparisons obtained with the demographic data. (Abstract shortened by UMI.) ^

Improving resource management in virtualized data centers using application performance models

The rapid growth of virtualized data centers and cloud hosting services is making the management of physical resources such as CPU, memory, and I/O bandwidth in data center servers increasingly important. Server management now involves dealing with multiple dissimilar applications with varying Service-Level-Agreements (SLAs) and multiple resource dimensions. The multiplicity and diversity of resources and applications are rendering administrative tasks more complex and challenging. This thesis aimed to develop a framework and techniques that would help substantially reduce data center management complexity.^ We specifically addressed two crucial data center operations. First, we precisely estimated capacity requirements of client virtual machines (VMs) while renting server space in cloud environment. Second, we proposed a systematic process to efficiently allocate physical resources to hosted VMs in a data center. To realize these dual objectives, accurately capturing the effects of resource allocations on application performance is vital. The benefits of accurate application performance modeling are multifold. Cloud users can size their VMs appropriately and pay only for the resources that they need; service providers can also offer a new charging model based on the VMs performance instead of their configured sizes. As a result, clients will pay exactly for the performance they are actually experiencing; on the other hand, administrators will be able to maximize their total revenue by utilizing application performance models and SLAs. ^ This thesis made the following contributions. First, we identified resource control parameters crucial for distributing physical resources and characterizing contention for virtualized applications in a shared hosting environment. Second, we explored several modeling techniques and confirmed the suitability of two machine learning tools, Artificial Neural Network and Support Vector Machine, to accurately model the performance of virtualized applications. Moreover, we suggested and evaluated modeling optimizations necessary to improve prediction accuracy when using these modeling tools. Third, we presented an approach to optimal VM sizing by employing the performance models we created. Finally, we proposed a revenue-driven resource allocation algorithm which maximizes the SLA-generated revenue for a data center.^

Middle -class immigrant identities: Dominican-Americans in South Florida

Identity studies of immigrants are complex because of multiple influences affecting identity reconstruction during immigration and acculturation: nationality, socio-cultural differences, occupations, education, spatial and geographic locations, age, gender, and personal attributes. Most immigrant identity studies deal with lower-income immigrants, who do not have the resources of middle- and upper-middle-class immigrants. South Florida is “home” to many middle-class immigrants, including Dominican-Americans. This dissertation interviewed sixty-six Dominican immigrants in South Florida, in order to determine their reconstructed identities after immigration/resettlement and to discover what influences contributed to these changes in identities. ^ The research design of this dissertation utilized an inductive, qualitative model, with the “grounded theory” method of data collection, categorization, and analysis. Participants were selected by a snowball sampling and interviewed with an informal questionnaire. Results were transcribed, categorized, tabulated, and analyzed for conclusions and theorization on immigrant identity. ^ The dissertation addressed numerous influences relating to identity reconstruction: the differing circumstances of immigration, the unique resources of middle- and higher-class immigrants, the nurturing environment of South Florida for immigrants with education and professional skills, and the boundary protection offered by suburban spaces. The interviewees displayed a wide range of age, length of residence in the United States, reasons for immigration, entry ports, settlement, relocations, occupations, and claimed identities. Identity was cross-tabulated with the various influences, as a means of invalidating certain influences and indicating possible trends. ^ The dissertation concluded that middle-class immigrant identities are diverse and multiple, as are the related influences. None of these immigrants had become totally assimilated, nor have they retained dual, non-overlapping attachments or frames of reference. Instead, many of the immigrants seemed to have developed or negotiated two or more identities, according to need, context, and personal interest. A cosmopolitan community such as South Florida seems to have encouraged such multiplicity of identity. However, rather than forming free-flowing identities, most of these immigrants eventually developed diverse and hybrid identities that have bounded attachments to various networks, groups, and places in South Florida. ^

3D navigation with six degrees-of-freedom using a multi-touch display

With the introduction of new input devices, such as multi-touch surface displays, the Nintendo WiiMote, the Microsoft Kinect, and the Leap Motion sensor, among others, the field of Human-Computer Interaction (HCI) finds itself at an important crossroads that requires solving new challenges. Given the amount of three-dimensional (3D) data available today, 3D navigation plays an important role in 3D User Interfaces (3DUI). This dissertation deals with multi-touch, 3D navigation, and how users can explore 3D virtual worlds using a multi-touch, non-stereo, desktop display. ^ The contributions of this dissertation include a feature-extraction algorithm for multi-touch displays (FETOUCH), a multi-touch and gyroscope interaction technique (GyroTouch), a theoretical model for multi-touch interaction using high-level Petri Nets (PeNTa), an algorithm to resolve ambiguities in the multi-touch gesture classification process (Yield), a proposed technique for navigational experiments (FaNS), a proposed gesture (Hold-and-Roll), and an experiment prototype for 3D navigation (3DNav). The verification experiment for 3DNav was conducted with 30 human-subjects of both genders. The experiment used the 3DNav prototype to present a pseudo-universe, where each user was required to find five objects using the multi-touch display and five objects using a game controller (GamePad). For the multi-touch display, 3DNav used a commercial library called GestureWorks in conjunction with Yield to resolve the ambiguity posed by the multiplicity of gestures reported by the initial classification. The experiment compared both devices. The task completion time with multi-touch was slightly shorter, but the difference was not statistically significant. The design of experiment also included an equation that determined the level of video game console expertise of the subjects, which was used to break down users into two groups: casual users and experienced users. The study found that experienced gamers performed significantly faster with the GamePad than casual users. When looking at the groups separately, casual gamers performed significantly better using the multi-touch display, compared to the GamePad. Additional results are found in this dissertation.^

(Santa) Rita de Cássia na boca do povo de Santa Cruz/RN: identidades culturais em construção

The purpose of this study is to investigate the cultural identities of Santa Rita de Cassia constructed from the representations contained in the speech of Santa Cruz urban area residents, which is located in a harsh part of the State of Rio Grande do Norte. These residents make the story of the Saint full of meaning for themselves, in their daily lives, as well as to the society. This is observed in the narration of Rita de Cassia’s story which has been told in the city over the past one hundred and eighty years, the number of women's names and commercial establishments named “Santa Rita”. In 2010, with the inauguration of the Alto de Santa Rita – a space for worshiping the saint –, the amount of visitors increased in the city, due to the construction and inauguration of a colossal monument representing the image of Rita de Cassia. Then, new social, cultural, religious and political aspects became part of the local reality of the city of Santa Cruz, what made residents have something in common to talk about. According to the interdisciplinary approach of Applied Linguistics, our theoretical background is based on the socio-historical language concept, which understands language as discursive practice. Still theoretically speaking, this study establishes an interface with cultural studies, taking into account the concept of cultural identity in post-modernity society. Discourse analysis proved plural, with a multiplicity of cultural identities ranging from very obedient daughter to wife who suffered because of the husband, from very religious woman to the widow who entered the convent, on to the Saint of the miracles and healings interceding in the lives of the ones who seek for help. It was also observed in the above mentioned investigative path that these identities can be constructed and reconstructed if immersed in a different set of social practices historically determined