Spatial Dynamics and the Mechanoresponse in CD4+ T Cell Activation

The activation of naïve CD4+ T cells by antigen presenting cells is a critical step in the response of the immune system to foreign pathogens and in its acclimation to host tissues. Activation of naïve T cells proceeds through TCR engagement and is further augmented by CD28 costimulation: ensuring T cell survival and conferring numerous functional capabilities. The work in this dissertation highlights the spatial and temporal dynamics that regulate the initial coupling of CD28 with TCR signaling and also dissects the mechanical properties conferred by downstream effectors that are required to relay CD28 costimulation. A reaction-diffusion model that describes the spatial regulation of costimulation in activating human T cells is developed. The Src kinase Lck, though predominantly cytosolic, is an ideal candidate for the coupling of the TCR and CD28 pathways. Membrane associations bring Lck in contact with these receptors, where mediation of its active state by kinase activity and regulation of its spatial dynamics dictate its capacity to integrate early TCR and CD28 signaling. This developed reaction-diffusion model focusing on Lck is then extrapolated to mouse cells that do not share similar sensitivity to segregation of TCR and CD28 triggering: indicating that while Lck is essential for costimulation, it does not confer spatial sensitivity in activating mouse T cells. A comparison of human and mouse cells demonstrate underlying differences in the diffusivity of Lck across the membrane and the enrichment of the cytoskeleton at the interface. The role of the cytoskeleton in generating TCR-driven contractile forces is then investigated through use of micropillar arrays. This approach also enables the quantification of forces generated by T cells during cellular activation. The impact of CD28 costimulation on TCR-driven force generation is assessed and noted to increase cellular forces by 80% beyond what is induced through TCR triggering. By manipulating the presentation of CD28 activation, CD28 is determined to be a mechanoresponsive receptor that is not directly responsible for mechanosensitivty. Rather, CD28 mediates a change in cellular forces through PI3 kinase, whose inhibition normalizes force generation in T cells activated by TCR and those costimulated with TCR and CD28. Downstream of PI3 kinase, PDK1 is identified as being essential in both TCR and CD28 costimulatory force generation; inhibition of PDK1 fully abrogates cellular forces. Lastly, we qualitatively characterize T cell activation on micropillar arrays, where their complex topology reveals a multiphasic behavior during activation. Whereas T cells activated on planar surfaces are relatively stationary, T cells activated on micropillars slowly migrate towards the base of the array. Forces exerted during this migration are substantially greater than those previously measured, and the slow migration leads to the characterization of multiple phases and the relocalization of key cellular proteins

The Intrinsic Dimensionality of Attractiveness: A Study in Face Profiles

The study of human attractiveness with pattern analysis techniques is an emerging research field. One still largely unresolved problem is which are the facial features relevant to attractiveness, how they combine together, and the number of independent parameters required for describing and identifying harmonious faces. In this paper, we present a first study about this problem, applied to face profiles. First, according to several empirical results, we hypothesize the existence of two well separated manifolds of attractive and unattractive face profiles. Then, we analyze with manifold learning techniques their intrinsic dimensionality. Finally, we show that the profile data can be reduced, with various techniques, to the intrinsic dimensions, largely without loosing their ability to discriminate between attractive and unattractive face

Rapid Breast Cancer Disease Progression Following Cyclin Dependent Kinase 4 and 6 Inhibitor Discontinuation.

Background: CDK 4 and 6 inhibitors (CDK4/6i), which arrest unregulated cancer cell proliferation, show clinical efficacy in breast cancer. Unexpectedly, a patient treated on a CDK4/6i-based trial, as first-line therapy in metastatic breast cancer, developed rapid disease progression following discontinuation of study drug while receiving standard second-line therapy off trial. We thus sought to expand this observation within a population of patients treated similarly at The University of Texas MD Anderson Cancer Center. Methods: Using an IRB-approved protocol, 4 patients previously enrolled on CDK4/6i trials were analyzed for outcomes after discontinuing study drug. These patients were treated on a randomized trial of first-line endocrine therapy +/- a CDK4/6i. Rapid disease progression was defined as progression occurring within 4 months of CDK4/6i discontinuation. Results: In total, 4 patients developed rapid disease progression and died; 2 of whom died within 6 months of CDK4/6i discontinuation. Conclusion: This case series suggests a potential for rapid disease progression following CDK4/6i discontinuation. However, the clinical course following progression must be validated in large CDK4/6i clinical trials and standard-of-care cohorts. If confirmed, such observations may alter the algorithm for subsequent therapy in patients with disease progression on CDK4/6i. Nevertheless, the need remains to define a mechanistic basis for this rapid progression and formulate alternative therapeutic strategies

The analysis of facial beauty: an emerging area of research in pattern analysis

Much research presented recently supports the idea that the human perception of attractiveness is data-driven and largely irrespective of the perceiver. This suggests using pattern analysis techniques for beauty analysis. Several scientific papers on this subject are appearing in image processing, computer vision and pattern analysis contexts, or use techniques of these areas. In this paper, we will survey the recent studies on automatic analysis of facial beauty, and discuss research lines and practical application

Refugee and Migrant Women's Views of Antenatal Ultrasound on the Thai Burmese Border: A Mixed Methods Study

Antenatal ultrasound suits developing countries by virtue of its versatility, relatively low cost and safety, but little is known about women's or local provider's perspectives of this upcoming technology in such settings. This study was undertaken to better understand how routine obstetric ultrasound is experienced in a displaced Burmese population and identify barriers to its acceptance by local patients and providers.Qualitative (30 observations, 19 interviews, seven focus group discussions) and quantitative methods (questionnaire survey with 644 pregnant women) were used to provide a comprehensive understanding along four major themes: safety, emotions, information and communication, and unintended consequences of antenatal ultrasound in refugee and migrant clinics on the Thai Burmese border. One of the main concerns expressed by women was the danger of childbirth which they mainly attributed to fetal malposition. Both providers and patients recognized ultrasound as a technology improving the safety of pregnancy and delivery. A minority of patients experienced transitory shyness or anxiety before the ultrasound, but reported that these feelings could be ameliorated with improved patient information and staff communication. Unintended consequences of overuse and gender selective abortions in this population were not common.The results of this study are being used to improve local practice and allow development of explanatory materials for this population with low literacy. We strongly encourage facilities introducing new technology in resource poor settings to assess acceptability through similar inquiry

Clients' reasons for prenatal ultrasonography in Ibadan, South West of Nigeria

<p>Abstract</p> <p>Background</p> <p>Prenatal ultrasonography has remained a universal tool but little is known especially from developing countries on clients' reasons for desiring it. Then aim was to determine the reasons why pregnant women will desire a prenatal ultrasound.</p> <p>Methods</p> <p>It was a cross-sectional survey of consecutive 222 women at 2 different ultrasonography facilities in Ibadan, South-west Nigeria.</p> <p>Results</p> <p>The mean age of the respondents was 30.1 ± 4.5 years. The commonest reason for requesting for prenatal ultrasound scans was to check for fetal viability in 144 women (64.7%) of the respondents, followed by fetal gender determination in 50 women (22.6%. Other reasons were to check for number of fetuses, fetal age and placental location. Factors such as younger age, artisans profession and low level of education significantly influenced the decision to check for fetal viability on bivariate analysis but all were not significant on multivariate analysis. Concerning fetal gender determination, older age, Christianity, occupation and gravidity were significant on bivariate analysis, however, only gravidity and occupation remained significant independent predictor on logistic regression model. Women with less than 3 previous pregnancies were about 4 times more likely to request for fetal sex determination than women with more than 3 previous pregnancies, (OR 3.8 95%CI 1.52 – 9.44). The professionals were 7 times more likely than the artisans to request to find out about their fetal sex, (OR 7.0 95%CI 1.47 – 333.20).</p> <p>Conclusion</p> <p>This study shows that Nigerian pregnant women desired prenatal ultrasonography mostly for fetal viability, followed by fetal gender determination. These preferences were influenced by their biosocial variables.</p

Vision-related quality of life and Appearance concerns are associated with anxiety and depression after eye enucleation: A cross-sectional study

© 2015 Ye et al. Aims: To investigate the association of demographic, clinical and psychosocial variables with levels of anxiety and depression in participants wearing an ocular prosthesis after eye enucleation. Methods: This cross-sectional study included 195 participants with an enucleated eye who were attending an ophthalmic clinic for prosthetic rehabilitation between July and November 2014. Demographic and clinical data, and self-reported feelings of shame, sadness and anger were collected. Participants also completed the National Eye Institute Visual Function Questionnaire, the Facial Appearance subscale of the Negative Physical Self Scale, and the Hospital Anxiety and Depression Scale. Regression models were used to identify the factors associated with anxiety and depression. Results: The proportion of participants with clinical anxiety was 11.8% and clinical depression 13.8%. More anxiety and depression were associated with poorer vision-related quality of life and greater levels of appearance concerns. Younger age was related to greater levels of anxiety. Less educated participants and those feeling more angry about losing an eye are more prone to experience depression. Clinical variables were unrelated to anxiety or depression. Conclusions: Anxiety and depression are more prevalent in eye-enucleated patients than the general population, which brings up the issues of psychiatric support in these patients. Psychosocialrather than clinical characteristics were associated with anxiety and depression. Longitudinal studies need to be conducted to further elucidate the direction of causality before interventions to improve mood states are developed. Copyright

Behaviour change techniques and contraceptive use in low and middle income countries: a review

We aimed to identify effective behaviour change techniques to increase modern contraceptive use in low and middle income countries (LMICs). Literature was identified in Global Health, Web of Science, MEDLINE, PsycINFO and Popline, as well as peer reviewed journals. Articles were included if they were written in English, had an outcome evaluation of contraceptive use, modern contraceptive use, contraceptive initiation/uptake, contraceptive adherence or continuation of contraception, were a systematic review or randomised controlled trial, and were conducted in a low or middle income country. We assessed the behaviour change techniques used in each intervention and included a new category of male partner involvement. We identified six studies meeting the inclusion criteria. The most effective interventions were those that involve male partner involvement in the decision to initiate contraceptive use. The findings also suggest that providing access to contraceptives in the community promotes their use. The interventions that had positive effects on contraceptive use used a combination of behaviour change techniques. Performance techniques were not used in any of the interventions. The use of social support techniques, which are meant to improve wider social acceptability, did not appear except in two of the interventions. Our findings suggest that when information and contraceptives are provided, contraceptive use improves. Recommendations include reporting of behaviour change studies to include more details of the intervention and techniques employed. There is also a need for further research to understand which techniques are especially effective

p21-Activated Kinases Are Required for Transformation in a Cell-Based Model of Neurofibromatosis Type 2

NF2 is an autosomal dominant disease characterized by development of bilateral vestibular schwannomas and other benign tumors in central nervous system. Loss of the NF2 gene product, Merlin, leads to aberrant Schwann cell proliferation, motility, and survival, but the mechanisms by which this tumor suppressor functions remain unclear. One well-defined target of Merlin is the group I family of p21-activated kinases, which are allosterically inhibited by Merlin and which, when activated, stimulate cell cycle progression, motility, and increased survival. Here, we examine the effect of Pak inhibition on cells with diminished Merlin function.Using a specific peptide inhibitor of group I Paks, we show that loss of Pak activity restores normal cell movement in cells lacking Merlin function. In addition, xenografts of such cells form fewer and smaller tumors than do cells without Pak inhibition. However, in tumors, loss of Pak activity does not reduce Erk or Akt activity, two signaling proteins that are thought to mediate Pak function in growth factor pathways.These results suggest that Pak functions in novel signaling pathways in NF2, and may serve as a useful therapeutic target in this disease