Explore the vast range of titles available.

Neuronal activity generates DNA double-strand breaks (DSBs) at specific loci in vitro and this facilitates the rapid transcriptional induction of early response genes (ERGs). Physiological neuronal activity, including exposure of mice to learning behaviors, also cause the formation of DSBs, yet the distribution of these breaks and their relation to brain function remains unclear. Here, following contextual fear conditioning (CFC) in mice, we profiled the locations of DSBs genome-wide in the medial prefrontal cortex and hippocampus using γH2AX ChIP-Seq. Remarkably, we found that DSB formation is widespread in the brain compared to cultured primary neurons and they are predominately involved in synaptic processes. We observed increased DNA breaks at genes induced by CFC in neuronal and non-neuronal nuclei. Activity-regulated and proteostasis-related transcription factors appear to govern some of these gene expression changes across cell types. Finally, we find that glia but not neurons have a robust transcriptional response to glucocorticoids, and many of these genes are sites of DSBs. Our results indicate that learning behaviors cause widespread DSB formation in the brain that are associated with experience-driven transcriptional changes across both neuronal and glial cells.

Formalin-fixed paraffin-embedded (FFPE) samples are valuable but underutilized in single-cell omics research due to their low RNA quality. In this study, leveraging a recent advance in single-cell genomic technology, we introduce snPATHO-seq, a versatile method to derive high-quality single-nucleus transcriptomic data from FFPE samples. We benchmarked the performance of the snPATHO-seq workflow against existing 10x 3’ and Flex assays designed for frozen or fresh samples and highlighted the consistency in snRNA-seq data produced by all workflows. The snPATHO-seq workflow also demonstrated high robustness when tested across a wide range of healthy and diseased FFPE tissue samples. When combined with FFPE spatial transcriptomic technologies such as FFPE Visium, the snPATHO-seq provides a multi-modal sampling approach for FFPE samples, allowing more comprehensive transcriptomic characterization. A combination of an FFPE nuclei preparation protocol and a probe-based transcriptomic profiling technique enables snRNA-seq characterization of archival human FFPE tissues, holding promise for retrospective studies involving aged clinical cohorts.

Immunosenescence predisposes the elderly to infectious and autoimmune diseases and impairs the response to vaccination. We recently demonstrated that ageing also impedes development of transplantation tolerance. Unlike their young counterparts (8-12 weeks of age) aged male recipients (greater than 12 months of age) transplanted with a full MHC-mismatched heart are resistant to tolerance mediated by anti-CD45RB antibody. Surprisingly, either chemical or surgical castration restored tolerance induction to levels observed using young recipients. Based on the strong impact of endocrine modulation on transplant tolerance, we explored the impact of ageing and castration on the immune system. Here we report a significant increase in the percentage of T cells that produce interferon-γ (IFN-γ) in aged male versus young male animals and that the overall increase in IFN-γ production was due to an expansion of IFN-γ-producing memory T cells in aged animals. In contrast to IFN-γ production, we did not observe differences in IL-10 expression in young versus old male mice. We hypothesized that endocrine modulation would diminish the elevated levels of IFN-γ production in aged recipients, however, we observed no significant reduction in the percentage of IFN-γ+ T cells upon castration. Furthermore, we neutralized interferon-γ by antibody and did not observe an effect on graft survival. We conclude that while elevated levels of interferon-γ serves as a marker of tolerance resistance in aged mice, other as yet to be identified factors are responsible for its cause. Defining these factors may be relevant to design of tolerogenic strategies for aged recipients.

BackgroundFFPE tissues are the most commonly generated sample type in clinical settings. They provide valuable diagnostic information about disease etiology. However, many existing technologies for profiling gene expression at the RNA level are either incompatible with FFPE tissues due to formaldehyde crosslinking and RNA degradation or lack the ability to resolve expression patterns at single cell resolution.MethodsThe new and highly sensitive Chromium Single Cell Gene Expression Flex assay (Flex) from 10x Genomics uses a probe-based approach to profile the whole transcriptome in fixed samples, including FFPE tissues. The Flex assay enables single cell sequencing of FFPE tissues (scFFPE-Seq) with highly sensitive detection of whole transcriptome gene expression.ResultsTo demonstrate the robustness of the Flex assay, we separately dissociated FFPE sections from 38 human tissue blocks containing both healthy and diseased/cancer samples derived from a variety of tissues including Alzheimer’s brain, glioblastoma, breast, colon, heart, liver, lung, ovary, prostate, and skin. Data derived from these samples provided important biological insights including distinct cell clustering along with identification of representative cell types. Additionally, consistent data quality observed across different sections from the same FFPE block highlights the reproducibility and reliability of the assay.The ability to integrate Flex single cell data with Visium CytAssist spatial data from the same FFPE block through spot deconvolution allows for a more comprehensive understanding of biology. Each spot in Visium CytAssist data may include multiple cells. Using spot deconvolution methods that annotate scFFPE data as reference, the proportion of different cell types in each Visium spot can be determined to further refine cell heterogeneity for spatial visualization. After data integration for a colon cancer sample, we identified distinct tumor stroma with plasma cells expressing MZB1 surrounding tumor regions with high expression of BRCA1, nicely overlapping the H&E images. The integration of both platforms opens opportunities to leverage single cell resolution while preserving spatial context.ConclusionsIn summary, Chromium Single Cell Gene Expression Flex enables characterization of the biology preserved in human FFPE tumor samples at a single cell level. The assay expands the capabilities of 10x Genomics’ Chromium platform, enabling cross-assay compatibility with Visium CytAssist Spatial Gene Expression for FFPE samples and serves as a powerful tool to facilitate discoveries in disease progression and therapeutic target development.

Purpose The purpose of this research is to identify how managers can apply the results of academic research into the concept of business models for creating and evaluating possible models for their businesses. Design/methodology/approach A review of the literature is followed by two case studies, from the airline and logistics industries, followed by recommendations based on both. Findings The findings are that there is relatively weak consensus among academics as to the definition and meaning of a business model and its components, and that the notion of generic business model applies better within rather than between industries, but that the discussion is a very fertile one for developing recommendations for managers. Practical implications The managerial implications of the study are that in their planning and strategizing, managers should factor in a proper analysis of the business model they currently use and one that they could use. Originality/value The study provides a useful addition to the literature on the practical implications of business models.

Purpose The purpose of this paper is to explain how ecosystems and platforms have evolved to manage customer information and to identify the management, research and teaching implications of this evolution. Design/methodology/approach This paper is based on research and industrial experience of two of the co-authors in customer relationship management, further developed with other co-authors in the field of business models, the research and teaching experience of the university authors and cross-functional literature reviews in the areas of strategy, marketing, economics, organizational behaviour and information management. Findings This paper shows that digitalization, cloud computing and new information-based platforms are beginning to change how customer information is being managed, creating new opportunities for improving marketing, customer relationship management and business strategy. Research limitations/implications The impact of platforms on the management of customer information needs to be confirmed by primary empirical research. Practical implications This paper identifies the need for senior marketing management to examine closely how internal and external/public customer information platforms may enhance their capability for managing customers and setting new strategic directions. Social implications The emergence of giant multi-sided platforms has clear implications for data protection and privacy, which need to be explored more in research. Originality/value This paper highlights the move to customer information platforms and identifies how senior managers should consider them as an option for better customer information management and as a basis for new business strategies.

Neuronal activity generates DNA double-strand breaks (DSBs) in the brain. Topoisomerase IIb (TOP2B), important for relieving transcription-associated DNA supercoiling, was implicated as the source of these neuronal activity-induced DSBs, facilitating rapid transcriptional induction of immediate early genes (IEGs). However, the locations of these DSBs in vivo and their relation to brain function was unclear. In Chapter 2, following contextual fear conditioning (CFC) of wild type mice, we profiled the locations of DSBs genome-wide through gH2AX ChIP-Seq, along with transcriptomic changes in neuronal and glial-enriched nuclei in two brain regions. We found DSB-susceptible genes were involved in synaptic processes, while both activity-regulated and proteostasis-related transcription factors appeared to govern gene expression changes across cell types at some sites of gH2AX. Finally, we found that glia have a robust transcriptional response to glucocorticoids and some of these genes are sites of brain DSBs. In Chapter 3, we examined the relationship between brain DNA breaks and TOP2B function. We utilized a mouse forebrain excitatory neuron-specific functional knockout of Top2b. We found that neuronal loss of Top2b in the medial prefrontal cortex (mPFC) impairs both the expression of long genes and gene induction following exposure to a learning paradigm. Ultimately, loss of Top2b leads to abnormal learning and cognition.

Purpose The purpose of this paper is to show how the business model of the information and communications technology (ICT) industry has evolved and the general differences that evolution has made to information management. Design/methodology/approach Literature review was carried out accompanied by conceptual analysis. Findings It shows that changes in the business model of the ICT industry have been quite dramatic and have led to significant changes in the structure of the industry. Research limitations/implications This research is based on analysis of the ICT industry. The analysis could be broadened to include other industries. Research into business model change should consider adopting the evolutionary approach taken in this paper. Practical implications Managers in the ICT industry should factor the likely evolution of business models in their industry into their planning. Social implications Government policymakers considering how to stimulate the development of the ICT industry in their country should be aware of the moving nature of their target. Originality/value This is one of the first papers to apply the evolutionary approach to business model change.

Purpose The purpose of this paper is to explore the role of analysts in providing information to support business model innovation. Design/methodology/approach This paper is based on initial research by two of the co-authors on business models (Stott et al., 2016), to which is added the experience of members of the team in working in strategic analyst firms or in working closely with clients of business analyst firms and further secondary data. Findings The findings of this paper show that analysts could do more to help their clients capture the opportunities and meet the threats of business model innovation, but this may require business leaders and analyst firms to think differently about their mutual relationship, particularly the briefs that clients provide analysts and how analysts aggregate information to provide a clearer picture of business model choices and their likely consequences. Research limitations/implications This paper needs confirmation of views by primary empirical research. Practical implications This study identifies the need for firms to brief their analysts to provide much enhanced information concerning business model opportunities and threats, and for teachers and researchers in marketing to become more closely acquainted with the business model literature and analyst reports and processes. Social implications As the idea of business model change becomes a more acceptable part of the strategic armoury of firms, the understanding of the information requirements to support such change to become more widely understood, and business model change to be consequently more common can be expected. This paper contributes to the understanding of the information requirements involved in such changes. Originality/value This study highlights the gap in the discussion of information provision to business leaders concerning business model innovation requirements and threats.

This chapter investigates how the adoption of different business models affects what marketing researchers do. After defining the concept of business model, it explores the dependence of different business models on marketing research and customer insight. It investigates the implications for analysis of how business leaders use information to review and/or change business models. It identifies that although many large firms have made large investments in customer data and customer insight, they may not use this information appropriately, particularly if a firm's current business model is under threat, whether due to denial by senior management, the problems of changing or adapting business models or the extent to which the firm's financial situation is based upon exploiting its current business model.