Selection Of A Novel Aptamer Against Vitronectin Using Capillary Electrophoresis And Next Generation Sequencing

Breast cancer (BC) results in ≃40,000 deaths each year in the United States and even among survivors treatment of the disease may have devastating consequences, including increased risk for heart disease and cognitive impairment resulting from the toxic effects of chemotherapy. Aptamer-mediated drug delivery can contribute to improved treatment outcomes through the selective delivery of chemotherapy to BC cells, provided suitable cancer-specific antigens can be identified. We report here the use of capillary electrophoresis in conjunction with next generation sequencing to develop the first vitronectin (VN) binding aptamer (VBA-01; Kd 405 nmol/l, the first aptamer to vitronectin (VN; Kd = 405 nmol/l), a protein that plays an important role in wound healing and that is present at elevated levels in BC tissue and in the blood of BC patients relative to the corresponding nonmalignant tissues. We used VBA-01 to develop DVBA-01, a dimeric aptamer complex, and conjugated doxorubicin (Dox) to DVBA-01 (7:1 ratio) using pH-sensitive, covalent linkages. Dox conjugation enhanced the thermal stability of the complex (60.2 versus 46.5°C) and did not decrease affinity for the VN target. The resulting DVBA-01-Dox complex displayed increased cytotoxicity to MDA-MB-231 BC cells that were cultured on plasticware coated with VN (1.8 × 10⁻⁶mol/l) relative to uncoated plates (2.4 × 10⁻⁶ mol/l), or plates coated with the related protein fibronectin (2.1 × 10⁻⁶ mol/l). The VBA-01 aptamer was evaluated for binding to human BC tissue using immunohistochemistry and displayed tissue specific binding and apparent association with BC cells. In contrast, a monoclonal antibody that preferentially binds to multimeric VN primarily stained extracellular matrix and vessel walls of BC tissue. Our results indicate a strong potential for using VN-targeting aptamers to improve drug delivery to treat BC

Experimental Signatures of Critically Balanced Turbulence in MAST

Beam Emission Spectroscopy (BES) measurements of ion-scale density fluctuations in the MAST tokamak are used to show that the turbulence correlation time, the drift time associated with ion temperature or density gradients, the particle (ion) streaming time along the magnetic field and the magnetic drift time are consistently comparable, suggesting a "critically balanced" turbulence determined by the local equilibrium. The resulting scalings of the poloidal and radial correlation lengths are derived and tested. The nonlinear time inferred from the density fluctuations is longer than the other times; its ratio to the correlation time scales as $\nu_{*i}^{-0.8\pm0.1}$, where $\nu_{*i}=$ ion collision rate/streaming rate. This is consistent with turbulent decorrelation being controlled by a zonal component, invisible to the BES, with an amplitude exceeding the drift waves' by $\sim \nu_{*i}^{-0.8}$.Comment: 6 pages, 4 figures, submitted to PR

(e,2e) study of two-center interference effects in the ionization of N(2)

A number of previous studies have suggested the possibility of two-center interference effects in the single ionization of diatomic molecules such as H2 and N2. While interference effects have been successfully observed in the ionization of H2, to date evidence for interference in N2 ionization has yet to be conclusively demonstrated. This study presents triply differential cross sections for electron impact ionization of N2, measured using the (e,2e) technique. The data are probed for signatures of two-center interference effects. Evidence for interference manifesting in the cross sections is observed.L. R. Hargreaves, C. Colyer, M. A. Stevenson, B. Lohmann, O. Al-Hagan, D. H. Madison and C. G. Nin

Theorising interprofessional pedagogic evaluation: framework for evaluating the impact of interprofessional CPD on practice change

This paper outlines the development of a conceptual framework to guide the evaluation of the impact of the pedagogy employed in continuing professional development for professionals in education, health and social care. The work is developed as part of the Centre for Excellence in Teaching and Learning: Interprofessional Learning across the Public Sector (CETL: IPPS) at the University of Southampton. The paper briefly outlines the field for pedagogic research and comments on the underpinning theories that have so far been used to guide research into interprofessional learning (IPL). It maps out the development of interprofessional CPD in its specific context as part of the CETL: IPPS with its links to a local authority undergoing service reorganisation and the role of the continuing professional development (CPD) in effecting change. It then brings together a theoretical framework with the potential toexplore, explain and evaluate the essential features of the model of pedagogy used in interprofessional CPD, in which professionals from education have for the first time been included alongside those from health and social care. The framework draws upon elements of situated learning theory, Activity Theory and Dreier’s work (2002, 1999) on trajectories of participation, particularly Personal Action Potency. By combining the resulting analytic framework with an adapted version of an established evaluation model, a theoretically-driven, practicable evaluation matrix is developed. The matrix has potential use in evaluating the impact of pedagogic input on practice change. The paper models a process for developing a conceptual framework to steer pedagogic evaluation. Such a process and the resulting matrix may be of use to other researchers who are similarly developing pedagogic evaluation

Cultural Orientations of sport managers

Various interpretations of sport management are cultural constructs underpinned by core assumptions and values held by members of professional communities. Sport managers world wide share common problems, but differ in how they resolve them. These universal differences emerge from the relationships they form with other people, and their attitude to time, activities and the natural environment. This paper examines the role of sport managers’ cultural orientations in the interpretation and practice of sport management. Using a multiple dimension model (Hampden-Turner and Trompenaars, 2000) it sketches the cultural profiles of fifteen sport managers from seven countries. A combination of methods was employed including questionnaires, interviews and participant observation. It is contended that the culture of sport management concerns a social process by which managers get involved in reconciling seven fundamental cultural dilemmas in order to perform tasks and achieve certain ends. Thus, a knowledge of the cultural meaning of sport management in a particular country would equip sport managers with a valuable tool in managing both the cultural diversity of their own work forces and in developing appropriate cross-cultural skills needed for running international events, marketing campaigns, sponsorship deals and joint ventures

Genome-wide profiling of methylation identifies novel targets with aberrant hyper-methylation and reduced expression in low-risk myelodysplastic syndromes

Gene expression profiling signatures may be used to classify the subtypes of Myelodysplastic syndrome (MDS) patients. However, there are few reports on the global methylation status in MDS. The integration of genome-wide epigenetic regulatory marks with gene expression levels would provide additional information regarding the biological differences between MDS and healthy controls. Gene expression and methylation status were measured using high-density microarrays. A total of 552 differentially methylated CpG loci were identified as being present in low-risk MDS; hypermethylated genes were more frequent than hypomethylated genes. In addition, mRNA expression profiling identified 1005 genes that significantly differed between low-risk MDS and the control group. Integrative analysis of the epigenetic and expression profiles revealed that 66.7% of the hypermethylated genes were underexpressed in low-risk MDS cases. Gene network analysis revealed molecular mechanisms associated with the low-risk MDS group, including altered apoptosis pathways. The two key apoptotic genes BCL2 and ETS1 were identified as silenced genes. In addition, the immune response and micro RNA biogenesis were affected by the hypermethylation and underexpression of IL27RA and DICER1. Our integrative analysis revealed that aberrant epigenetic regulation is a hallmark of low-risk MDS patients and could have a central role in these diseases. © 2013 Macmillan Publishers Limited All rights reserved

The Use of Preoperative Prophylactic Systemic Antibiotics for the Prevention of Endopthalmitis in Open Globe Injuries:A Meta-Analysis

Topic:This study reports the effect of systemic prophylactic antibiotics (and their route) on the risk of endophthalmitis after open globe injury. Clinical relevance:Endophthalmitis is a major complication of open globe injury, it can lead to rapid sight loss in the affected eye. The administration of systemic antibiotic prophylaxis is common practice in some health care systems, although there is no consensus on their use. PubMed, CENTRAL, Web of Science, CINAHL and Embase were searched. This was completed 6th July 2021 and updated 10th Dec 2022. We included randomised and non-randomised prospective studies which reported the rate of post-open globe injury endophthalmitis, when systemic pre-operative antibiotic prophylaxis (via the oral or intravenous route) was given. The Cochrane Risk of Bias tool and ROBINS-I tool were used for assessing the risk of bias. Where meta-analysis was performed results were reported as odds ratio. PROSPERO registration: CRD42021271271. Three studies were included. One prospective observational study compared outcomes of patients who had received systemic or no systemic pre-operative antibiotics. The endophthalmitis rates reported were 3.75% and 4.91% in the systemic and no systemic pre-operative antibiotics groups, a non-significant difference (p = 0.68). Two randomised controlled trials were included (1,555 patients). The rates of endophthalmitis were 17 events in 751 patients (2.26%) and 17 events in 804 patients (2.11%) in the oral antibiotics and intravenous (+/- oral) antibiotics groups, respectively. Meta-analysis demonstrated no significant differences between groups (OR 1.07 [95% confidence interval 0.54 – 2.12]). The incidences of endophthalmitis after open globe injury were low with and without systemic antibiotic prophylaxis, although high risk cases were excluded in the included studies. When antibiotic prophylaxis is considered, there is moderate evidence that oral antibiotic administration is non-inferior to intravenous

Functional Characterization of the Dendritically Localized mRNA Neuronatin in Hippocampal Neurons

Local translation of dendritic mRNAs plays an important role in neuronal development and synaptic plasticity. Although several hundred putative dendritic transcripts have been identified in the hippocampus, relatively few have been verified by in situ hybridization and thus remain uncharacterized. One such transcript encodes the protein neuronatin. Neuronatin has been shown to regulate calcium levels in non-neuronal cells such as pancreatic or embryonic stem cells, but its function in mature neurons remains unclear. Here we report that neuronatin is translated in hippocampal dendrites in response to blockade of action potentials and NMDA-receptor dependent synaptic transmission by TTX and APV. Our study also reveals that neuronatin can adjust dendritic calcium levels by regulating intracellular calcium storage. We propose that neuronatin may impact synaptic plasticity by modulating dendritic calcium levels during homeostatic plasticity, thereby potentially regulating neuronal excitability, receptor trafficking, and calcium dependent signaling