The Level of NMDA Receptor in the Membrane Modulates Amyloid-β Association and Perforation

Alzheimer’s disease is a neurodegenerative disorder that affects mostly the elderly. The main histopathological markers are the senile plaques formed by amyloid-β peptide (Aβ) aggregates that can perforate the plasma membrane of cells, increasing the intracellular calcium levels and releasing synaptic vesicles that finally lead to a delayed synaptic failure. Several membrane proteins and lipids interact with Aβ affecting its toxicity in neurons. Here, we focus on NMDA receptors (NMDARs) as proteins that could be modulating the association and neurotoxic perforation induced by Aβ on the plasma membrane. In fact, our results showed that decreasing NMDARs, using enzymatic or siRNA approaches, increased the association of Aβ to the neurons. Furthermore, overexpression of NMDARs also resulted in an enhanced association between NMDA and Aβ. Functionally, the reduction in membrane NMDARs augmented the process of membrane perforation. On the other hand, overexpressing NMDARs had a protective effect because Aβ was now unable to cause membrane perforation, suggesting a complex relationship between Aβ and NMDARs. Because previous studies have recognized that Aβ oligomers are able to increase membrane permeability and produce amyloid pores, the present study supports the conclusion that NMDARs play a critical protective role on Aβ actions in hippocampal neurons. These results could explain the lack of correlation between brain Aβ burden and clinically observed dementia

On the pharmacogenetics of non-small cell lung cancer treatment

Abstract: Introduction. Despite many clinical efforts, non-small-cell lung cancer (NSCLC) has a dismal 5-year survival rate of 16%, and high incidence of recurrence. The success of biologically targeted agents, as well as the activity of well-established chemotherapeutic regimens, has been limited by inherited/acquired resistance, and biomarkers to adapt the prescription of anticancer drugs to patients' features are urgently warranted. Areas covered. In oncology, pharmacogenetics should provide the way to select patients who may benefit from a specific therapy that best match the individual and tumor genetic profile, thus allowing maximum activity and minimal toxicity. The present review summarizes the main findings on NSCLC pharmacogenetics, critically reappraising the most important studies on polymorphisms correlated with outcome of pemetrexed and EGFR-inhibitors, and provides perspective on clinical application of genomic tests for treatment decision-making. Expert Opinion. A major challenge in NSCLC is the identification of subgroups of diseases/patients that will truly benefit from specific treatments. Ideally, convenient and minimally invasive tests to decipher biomarkers of chemosensitivity/resistance and toxicity should be developed alongside novel anticancer treatments. Integration with the latest generation of whole-genome analyses and liquid biopsies as well as prospective validation in large cohorts of patients will overcome the limitations of the traditional pharmacogenetic approaches

Web information systems : a study of maintenance, change and flexibility

Information Systems (IS’s) have provided organisations with huge efficiency gains and benefits over the years; however an outstanding problem that is yet to be successfully tackled is that of the troublesome maintenance phase. Consuming vast resources and thwarting business progression in a competitive global market place, system maintenance has been recognised as one of the key areas where IS is failing organisations. Organisations are too often faced with the dilemma of either replacement or the continual upkeep of an unwieldy system. The ability for IS’s to be able to adapt to exogenous influences is even more acute today than at any time in the past. This is due to IS’s namely, Web Information Systems (WIS’s) increasingly and continually having to accommodate the needs of organisations to interconnect with a plethora of additional systems as well as supporting evolving business models. The richness of the interconnectivity, functionalities and services WIS’s now offer are shaping social, cultural and economic behaviour on a truly global scale, making the maintenance of such systems and evermore pertinent issue. The growth and proliferation of WIS’s shows no sign of abating which leads to the conclusion that what some have termed as the ‘maintenance iceberg’ should not be ignored. The quandary that commercial organisations face is typically driven by two key aspects; firstly, systems are built on the cultural premise of using fixed requirements, with not enough thought or attention being paid to systems abilities to deviate from these requirements. Secondly, systems do not generally cope well with adapting to unpredictable change arising from outside of the organisations environment. Over the recent past, different paradigms, approaches and methods have attempted to make software development more predictable, controllable and adaptable, however, the benefits of such measures in relation to the maintenance dilemma have been limited. The concept of flexible systems that are able to cope with such change in an efficient manner is currently an objective that few can claim to have realised successfully. The primary focus of the thesis was to examine WIS post-development change in order to empirically substantiate and understand the nature of the maintenance phase. This was done with the intention to determine exactly ‘where’ and ‘how’ flexibility could be targeted to address these changes. This study uses an emergent analytical approach to identify and catalogue the nature of change occurring within WIS maintenance. However, the research framework design underwent a significant revision as the initial results indicated that a greater emphasis and refocus was required to achieve the research objective. To study WIS’s in an appropriate and detailed context, a single case study was conducted in a web development software house. In total the case study approach was used to collect empirical evidence from four projects that investigated post-development change requests in order to identify areas of the system susceptible to change. The maintenance phases of three WIS projects were considered in-depth, resulting in the collection of over four hundred change requests. The fourth project served as a validation case. The results are presented and the findings are used to identify key trends and characteristics that depict WIS maintenance change. The analytical information derived from the change requests is consolidated and shown diagrammatically for the key areas of change using profile models developed in this thesis. Based on the results, the thesis concludes and contributes to the ongoing debate that there is a discernable difference when considering WIS maintenance change compared to that of traditional IS maintenance. The detailed characteristics displayed in the profile models are then used to map specific flexibility criteria that ultimately are required to facilitate change. This is achieved using the Flexibility Matrix of Change (FMoC) tool which was developed within the remit of this research. This tool is a qualitative measurement scheme that aligns WIS maintenance changes to a reciprocal flexibility attribute. Thus, the wider aim of this thesis is to also expand the awareness of flexibility and its importance as a key component of the WIS lifecycle.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Search for unbound 15Be states in the 3n+12Be channel

15Be is expected to have low-lying 3/2+ and 5/2+ states. A first search did not observe the 3/2+ [A. Spyrou et al., Phys. Rev. C 84, 044309 (2011)], however, a resonance in 15Be was populated in a second attempt and determined to be unbound with respect to 14Be by 1.8(1) MeV with a tentative spin-parity assignment of 5/2+ [J. Snyder et al., Phys. Rev. C 88, 031303(R) (2013)]. Search for the predicted 15Be 3/2+ state in the three-neutron decay channel. A two-proton removal reaction from a 55 MeV/u 17C beam was used to populate neutron-unbound states in 15Be. The two-, three-, and four-body decay energies of the 12Be + neutron(s) detected in coincidence were reconstructed using invariant mass spectroscopy. Monte Carlo simulations were performed to extract the resonance and decay properties from the observed spectra. The low-energy regions of the decay energy spectra can be described with the first excited unbound state of 14Be (E_x=1.54 MeV, E_r=0.28 MeV). Including a state in 15Be that decays through the first excited 14Be state slightly improves the fit at higher energies though the cross section is small. A 15Be component is not needed to describe the data. If the 3/2+ state in 15Be is populated, the decay by three-neutron emission through 14Be is weak, less than or equal to 11% up to 4 MeV. In the best fit, 15Be is unbound with respect to 12Be by 1.4 MeV (unbound with respect to $14Be by 2.66 MeV) with a strength of 7%.Comment: 6 pages, 5 figures, accepted in Physical Review