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Neuronal dendritic and synaptic pruning are early features of neurodegenerative diseases, including Alzheimer’s disease. In addition to brain pathology, amyloid plaque deposition, microglial activation, and cell loss occur in the retinas of human patients and animal models of Alzheimer’s disease. Retinal ganglion cells, the output neurons of the retina, are vulnerable to damage in neurodegenerative diseases and are a potential opportunity for non-invasive clinical diagnosis and monitoring of Alzheimer’s progression. However, the extent of retinal involvement in Alzheimer’s models and how well this reflects brain pathology is unclear. Here we have quantified changes in retinal ganglion cells dendritic structure and hippocampal dendritic spines in three well-studied Alzheimer’s mouse models, Tg2576, 3xTg-AD and APP NL-G-F . Dendritic complexity of DiOlistically labelled retinal ganglion cells from retinal explants was reduced in all three models in an age-, gender-, and receptive field-dependent manner. DiOlistically labelled hippocampal slices showed spine loss in CA1 apical dendrites in all three Alzheimer’s models, mirroring the early stages of neurodegeneration as seen in the retina. Morphological classification showed that loss of thin spines predominated in all. The demonstration that retinal ganglion cells dendritic field reduction occurs in parallel with hippocampal dendritic spine loss in all three Alzheimer’s models provide compelling support for the use of retinal neurodegeneration. As retinal dendritic changes are within the optical range of current clinical imaging systems (for example optical coherence tomography), our study makes a case for imaging the retina as a non-invasive way to diagnose disease and monitor progression in Alzheimer’s disease.

We studied adaptive evolution of gene expression using long-term experimental evolution of Saccharomyces cerevisiae in ammonium-limited chemostats. We found repeated selection for non-synonymous variation in the DNA binding domain of the transcriptional activator, GAT1, which functions with the repressor, DAL80 in an incoherent type-1 feedforward loop (I1-FFL) to control expression of the high affinity ammonium transporter gene, MEP2. Missense mutations in the DNA binding domain of GAT1 reduce its binding to the GATAA consensus sequence. However, we show experimentally, and using mathematical modeling, that decreases in GAT1 binding result in increased expression of MEP2 as a consequence of properties of I1-FFLs. Our results show that I1-FFLs, one of the most commonly occurring network motifs in transcriptional networks, can facilitate adaptive tuning of gene expression through modulation of transcription factor binding affinities. Our findings highlight the importance of gene regulatory architectures in the evolution of gene expression.

This article reviews some issues associated with the way in which academic research into marketing is evaluated by UK education authorities using their research excellence framework (REF), in particular the impact component of the assessment. It discusses the extent to which research by marketing academics published in leading academic journals is relevant to the concerns of marketing management and how this relevance or lack of it may be reflected in the relative paucity of impact submissions in marketing. It considers the model of impact assessment used in the REF and how this differs from how marketing academics work in practice, giving three examples of significant impact that would not be acceptable under current rules. It concludes by suggesting that alternative models for impact should be investigated and suggests that using more practical models might result in better engagement of marketing academics with business, leading to greater relevance in teaching and employability of marketing graduates.

Purpose Resource integration is a central idea within service-dominant logic (S-D logic), but there has been little scholarly research on this aspect of theory. This paper aims to explore resource integration between marketing agencies and their clients. Design/methodology/approach In total, nine case studies have been developed using a dyadic approach of interviewing clients and members of their agency teams. This is followed-up with presentations and workshops with over 200 practitioners who validated the findings and added new perspectives. Findings The key operant resources in the client/agency context have been identified. The ways the operant resources of the actors developed during the course of resource integration, building potential resources for future co-creation are shown. The differing perspectives of the actors to each other’s contribution are highlighted. Research limitations/implications This study suggests that resource enhancement and development, as a result of integration, is important. For agency/client research, resource integration and development brings new perspectives complementing existing relationship approaches to research. The findings have implications for relationship marketing theory across business-to-business (B2B) contexts. Practical implications The findings suggest a resource integration approach that could be jointly addressed between agency and client in improving the way they work together. The discourse of co-creation suggests a way for them to talk about how to work together effectively. Suggestions are made for teaching. Originality/value This study develops the S-D logic theory through exploring resource enhancement and development in a B2B co-creation context. The dyadic nature of the research is novel in studying how marketing agencies and clients work together and new perspectives emerge from the approach.

Purpose – Employees have traditionally played a major role in the customer ' s service experience. Yet self-service technology (SST) replaces the customer-service employee experience with a customer-technology experience. This paper seeks to use a service-dominant logic lens to gain fresh insight into the consumer experience of SST. In particular, it aims to consider the resources that are integrated when consumers use SSTs, their co-production role and what might constitute value. Design/methodology/approach – The paper presents findings from 24 semi-structured interviews that focus on the everyday experiences of consumers in using SST. Both genders and all socio-economic categories within all adult age groups from 18 to 65+ were included. Findings – There is a danger that organizations embrace SST as an economic and efficient mechanism to “co-create” value with consumers when they are merely shifting responsibility for service production. The paper identifies risks when customers become partial employees and concludes that customers should perceive the value they gain from using SST to be at least commensurate with their co-production role. Research limitations/implications – The qualitative study was confined to the consumer perspective. Future research within organizations and among employees who support consumers using SST would extend understanding, as would research within the business-to-business (B2B) context. Quantitative studies could measure the frequency and extent of the phenomena the authors report and assist with market segmentation strategies. Practical implications – The application of service-dominant logic highlights potential risks and managerial challenges as self-service, and consequent value co-creation, relies on the operant resources of customers, who lack the tacit knowledge of employees and are less easy to manage. There is also the need to manage a new employee role: “self-service education, support and recovery”. Originality/value – The paper draws attention to managerial challenges for organizations to ensure that SST adoption enhances and does not destroy value. Additionally, it highlights the importance of distinguishing between co-production and co-creation.

Purpose - This paper seeks to concern itself with the implications for the management of customer relationships of pursuing a multi-channel approach.Design methodology approach - The case study method is used in analysing the situation of four organizations from the UK financial services industry. A conceptual framework covering structural, people and process elements is utilized to examine the challenges to be overcome in providing an integrated approach to customer management.Findings - The addition of new channels alongside those already in existence opens up new areas of the organization to customer contact and creates significant challenges in relation to staff roles and existing processes for interacting with customers. Channel integration is a strategic issue potentially requiring structural changes to the organization and changes in the behaviour of customers.Research limitations implications - This exploratory research suggests the need for studies in relationship marketing to take cross-disciplinary approaches in investigating what organizational forms operate most effectively in multi-channel environments. There is also a need to develop a better understanding of how different groups of customers use different channels and of how service quality dimensions operate in this environment.Practical implications - Multi-channel customer management adds another dimension to traditional methods of segmenting customers and requires sophisticated understanding of the way that customers use channels. The addition of new channels offers a range of opportunities for interacting directly with the customer, raising new questions about how best to manage customer communications holistically.Originality value - The paper contributes to one's understanding of the implications for organizations in managing customers in a multi-channel environment.

Purpose – Value co-creation thinking is reshaping the understanding of markets and marketing and presents a significant opportunity to develop the theory and practice of social marketing. However, whilst value co-creation offers thought-provoking new directions for the field, applying this theory and its core concepts in social marketing is not without significant challenges. The paper aims to discuss these issues. Design/methodology/approach – This is a conceptual paper that seeks to integrate lessons from social marketing practice with the value co-creation discourse from commercial marketing. Drawing upon two projects that have applied principles of collaboration and co-design, the paper provides a critical perspective on the adoption of value co-creation in social marketing. Findings – The collaborative and emancipatory ambitions of co-creation seem highly compatible with social marketing. However, the paper notes some significant conceptual, ethical and practical obstacles in the path of a workable theory of value co-creation for social marketing. Originality/value – While representation of value co-creation and other collaborative approaches is increasing in the social marketing literature, this is the first attempt to provide an integrated and critical review of their compatibility with social marketing at a conceptual, ethical and theoretical level. The analysis shows that value co-creation theory can simultaneously offer opportunities and present obstacles for social marketing.

This paper seeks to concern itself with the implications for the management of customer relationships of pursuing a multi-channel approach. A case study method is used in analyzing the situation of four organizations from the UK financial services industry. A conceptual framework covering structural, people and process elements is utilized to examine the challenges to be overcome in providing an integrated approach to customer management. The findings indicate that the addition of new channels alongside those already in existence opens up new areas of the organization to customer contact and creates significant challenges in relation to staff roles and existing processes for interacting with customers. Channel integration is a strategic issue potentially requiring structural changes to the organization and changes in the behavior of customers.

Abstract Machine learning models are increasingly being used to estimate ‘brain age’ from neuroimaging data. The gap between chronological age and the estimated brain age (BAG) is potentially a measure of accelerated/resilient brain aging, and we estimated BAG based on an elastic net regression approach. Here, we report associations between this brain age measure and plasma protein levels (measured using an aptamer-based proteomic platform) in the Atherosclerosis Risk in Communities (ARIC) Study to determine whether BAG was associated with proteins linked to biologic aging. We used brain MRI scans from 1507 ARIC visit 5 participants: 938 were Cognitively Normal (CN), 495 had mild cognitive impairment (MCI) and 74 had dementia. The proteomic dataset contains 4877 plasma proteins in these same individuals. We fitted univariate linear regression models adjusting for age, race, smoking, education, sex, diabetes, hypertension and intra-cranial volume. A Bonferroni correction was applied to account for multiple testing to maintain an analysis-wise α=0.05. In total 31 proteins were significantly associated with BAG. Among these SEVP1, GDF-15, pleiotrophin, MMP7, Natriuretic-peptides and Hsp70 were found to be associated with accelerated BAG, whereas EGF-receptor, mast/stem-cell-growth-factor-receptor (KIT), Coagulation-factor-VII and cGMP-dependent-protein-kinase-1 were associated to resilient BAG. The analysis based only on CN participants produced 3 significant proteins: retinoblastoma-2 and SEVP1, which were associated with accelerated BAG and Coagulation-factor-VII, which was associated to resilient BAG. These results suggest circulating proteins implicated in biological aging, cellular senescence, angiogenesis and coagulation are associated with a neuroimaging measure of accelerated brain aging.

Measurement of the transcripts of BCR-ABL, the key molecular abnormality in chronic myeloid leukemia (CML), provides an estimate of the burden of leukemic cells in a given patient. A profound reduction in blood levels of BCR-ABL transcripts was much more frequent among patients treated with imatinib than among those treated with interferon alfa plus cytarabine. Responses superior to those with interferon plus cytarabine. Chronic myeloid leukemia (CML) is a clonal disease of the hematopoietic stem cell in which a reciprocal translocation, t(9;22)(q34;q11), forms the Philadelphia chromosome (Ph) and creates a novel fusion gene, BCR-ABL . 1 This gene expresses an activated tyrosine kinase that is central to the pathogenesis of CML. 2 , 3 The median survival among patients with CML is three to six years, with most deaths resulting from progression of the disease into a blastic phase. Survival among patients treated with interferon alfa is superior to that among patients treated with hydroxyurea. 4 The addition of cytarabine to interferon alfa may further improve median . . .