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

This thesis was submitted for the degree of Doctor of Philosophy and awarded by Brunel University.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

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

The Sixth Transmembrane Segment Is a Major Gating Component of the TMEM16A Calcium-Activated Chloride Channel.

Calcium-activated chloride channels (CaCCs) formed by TMEM16A or TMEM16B are broadly expressed in the nervous system, smooth muscles, exocrine glands, and other tissues. With two calcium-binding sites and a pore within each monomer, the dimeric CaCC exhibits voltage-dependent calcium sensitivity. Channel activity also depends on the identity of permeant anions. To understand how CaCC regulates neuronal signaling and how CaCC is, in turn, modulated by neuronal activity, we examined the molecular basis of CaCC gating. Here, we report that voltage modulation of TMEM16A-CaCC involves voltage-dependent occupancy of calcium- and anion-binding site(s) within the membrane electric field as well as a voltage-dependent conformational change intrinsic to the channel protein. These gating modalities all critically depend on the sixth transmembrane segment

Generation of three dimensional retinal tissue with functional photoreceptors from human iPSCs

Many forms of blindness result from the dysfunction or loss of retinal photoreceptors. Induced pluripotent stem cells (iPSC) hold great potential for the modeling of these diseases or as potential therapeutic agents. However, to fulfill this promise, a remaining challenge is to induce human iPSC to recreate in vitro key structural and functional features of the native retina, in particular the presence of photoreceptors with outer-segment discs and light-sensitivity. Here we report that hiPSC can, in a highly autonomous manner, recapitulate spatiotemporally each of the main steps of retinal development observed in vivo and form 3-dimensional retinal cups that contain all major retinal cell types arranged in their proper layers. Moreover, the photoreceptors in our hiPSC-derived retinal tissue achieve advanced maturation, showing the beginning of outer-segment-disc formation and photosensitivity. This success brings us one step closer to the anticipated use of hiPSC for disease modeling and open possibilities for future therapies

Association studies of up to 1.2 million individuals yield new insights into the genetic etiology of tobacco and alcohol use.

Tobacco and alcohol use are leading causes of mortality that influence risk for many complex diseases and disorders1. They are heritable2,3 and etiologically related4,5 behaviors that have been resistant to gene discovery efforts6-11. In sample sizes up to 1.2 million individuals, we discovered 566 genetic variants in 406 loci associated with multiple stages of tobacco use (initiation, cessation, and heaviness) as well as alcohol use, with 150 loci evidencing pleiotropic association. Smoking phenotypes were positively genetically correlated with many health conditions, whereas alcohol use was negatively correlated with these conditions, such that increased genetic risk for alcohol use is associated with lower disease risk. We report evidence for the involvement of many systems in tobacco and alcohol use, including genes involved in nicotinic, dopaminergic, and glutamatergic neurotransmission. The results provide a solid starting point to evaluate the effects of these loci in model organisms and more precise substance use measures

Targeting the tumor mutanome for personalized vaccination in a TMB low non-small cell lung cancer.

BackgroundCancer is characterized by an accumulation of somatic mutations, of which a significant subset can generate cancer-specific neoepitopes that are recognized by autologous T cells. Such neoepitopes are emerging as important targets for cancer immunotherapy, including personalized cancer vaccination strategies.MethodsWe used whole-exome and RNA sequencing analysis to identify potential neoantigens for a patient with non-small cell lung cancer. Thereafter, we assessed the autologous T-cell reactivity to the candidate neoantigens using a long peptide approach in a cultured interferon gamma ELISpot and tracked the neoantigen-specific T-cells in the tumor by T-cell receptor (TCR) sequencing. In parallel, identified gene variants were incorporated into a Modified Vaccinia Ankara-based vaccine, which was evaluated in the human leucocyte antigen A*0201 transgenic mouse model (HHD).ResultsSequencing revealed a tumor with a low mutational burden: 2219 sequence variants were identified from the primary tumor, of which 23 were expressed in the transcriptome, involving 18 gene products. We could demonstrate spontaneous T-cell responses to 5/18 (28%) mutated gene variants, and further analysis of the TCR repertoire of neoantigen-specific CD4+ and CD8+ T cells revealed TCR clonotypes that were expanded in both blood and tumor tissue. Following vaccination of HHD mice, de novo T-cell responses were generated to 4/18 (22%) mutated gene variants; T cells reactive against two variants were also evident in the autologous setting. Subsequently, we determined the major histocompatibility complex restriction of the T-cell responses and used in silico prediction tools to determine the likely neoepitopes.ConclusionsOur study demonstrates the feasibility of efficiently identifying tumor-specific neoantigens that can be targeted by vaccination in tumors with a low mutational burden, promising successful clinical exploitation, with trials currently underway