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SNPs associated with human stroke risk have been identified in the intergenic region between Forkhead family transcription factors FOXF2 and FOXQ1 , but we lack a mechanism for the association. FoxF2 is expressed in vascular mural pericytes and is important for maintaining pericyte number and stabilizing small vessels in zebrafish. The stroke-associated SNPs are located in a previously unknown transcriptional enhancer for FOXF2 , functional in human cells and zebrafish. We identify critical enhancer regions for FOXF2 gene expression, including binding sites occupied by transcription factors ETS1, RBPJ, and CTCF. rs74564934, a stroke-associated SNP adjacent to the ETS1 binding site, decreases enhancer function, as does mutation of RPBJ sites. rs74564934 is significantly associated with the increased risk of any stroke, ischemic stroke, small vessel stroke, and elevated white matter hyperintensity burden in humans. Foxf2 has a conserved function cross-species and is expressed in vascular mural pericytes of the vessel wall. Thus, stroke-associated SNPs modulate enhancer activity and expression of a regulator of vascular stabilization, FOXF2 , thereby modulating stroke risk.

Digital technologies and information systems have played a pivotal role during the past SARS pandemic and continue to assist with the recovery process during the ongoing COVID-19 pandemic. Nonetheless, the technologies themselves have advanced significantly and allow ready access and ease of use to individuals, organizations, and communities. We focus on a set of such technologies – Readily Available Digital Technologies (RADT) – and show how they assist during various phases of management of the ongoing crisis. We utilize an existing crisis management framework and emphasize the role and impact of RADTs. Furthermore, we extend the crisis management framework to include a resilience phase and explore examples from extant academic and practitioner literature to demonstrate its applicability in the current context. We invite future researchers to build further on our exploratory framework and highlight its potential contributions.

Images contain a wealth of information that is often under analyzed in biological studies. Developmental models of vascular disease are a powerful way to quantify developmentally regulated vessel phenotypes to identify the roots of the disease process. We present vessel Metrics, a software tool specifically designed to analyze developmental vascular microscopy images that will expedite the analysis of vascular images and provide consistency between research groups.We developed a segmentation algorithm that robustly quantifies different image types, developmental stages, organisms, and disease models at a similar accuracy level to a human observer. We validate the algorithm on confocal, lightsheet, and two photon microscopy data in zebrafish. The tool accurately segments data taken by multiple scientists on varying microscopes. We validate vascular parameters such as vessel density, network length, and diameter, across developmental stages, genetic mutations, and drug treatments, and show a favorable comparison to other freely available software tools. Vessel Metrics reduces the time to analyze experimental results, improves repeatability within and between institutions, and expands the percentage of a given vascular network analyzable in experiments.Summary statementVessel Metrics is an automated software tool designed to standardize and streamline the analysis of vascular microscopy images.

Unless there are systemic investments in digitization of rural economies, rural entrepreneurs will suffer, and digital innovation activity will remain modest. Nonetheless, the authors do find examples of digital innovation practiced by firms in rural economies. These firms successfully fostered growth and revitalization due to co-evolution of business and digital strategies, investments in technology, and digitization of business processes. In this chapter, using three such small, rural firms in Ontario, Canada, the co-evolution of business and digital technology strategies and related performance impacts are described by using the lens of “digital ecodynamics,” which is defined as the holistic confluence among environmental factors, capabilities, and digital technologies—and their fused dynamic interactions unfolding as an ecosystem. The focus on the development of resources and capabilities that are critical for the survival of the firms and the local ecosystem centered around a business incubator that supports and sustains them.

Digital platforms are changing the nature of business across the world. Firms orchestrate digital innovations and break traditional business boundaries through participation in ecosystems enabled by digital platforms. This chapter focuses on a specific type of ecosystem called a frugal ecosystem. A frugal ecosystem is an entrepreneurial ecosystem usually found in the developing world and is highly constrained by resources, poor infrastructure, and scarcity. Therefore, firms focus on low-cost, sustainable, and social innovation to succeed. Using a case study approach, the chapter provides insights from two frugal digital platform ecosystems in India: 1) the JobMatch platform that is used to orchestrate informal, low-skilled job seekers, connecting them with potential employers; 2) the IGG platform that orchestrates a community of waste management workers to integrate them into the recycling ecosystem of the city. The chapter extends the discussion on digital platform ecosystems in a frugal context and brings new insights. It also leverages literature on digital and spatial affordances to interrelate constraints, institutional voids, and frugal innovation. The novelty of the findings will guide future research in this area.

Frugal innovation (FI) is an emerging paradigm of innovation, mainly practiced in developing countries such as India, China, Brazil, and Kenya. In both developing and advanced countries, platform firms such as Uber and AirBnB have disrupted traditional business models by leveraging the capabilities provided by digital technologies such as social media, mobility, analytics, and cloud computing. Digital innovation results from the digitalisation of resources, capabilities, processes, products, services, and business models. Digitalisation moves beyond digitisation and involves additional socio-technical aspects that impact the socio-economic context of the organisation. The complexities of the relationships and the physical and digital orchestration of resources, services, and processes that take place in a FI ecosystem are difficult to operationalise and visualise. The lower half extrapolates the top layers and highlights “digitalisation” through the digital platform. The ecosystem consists of several “digital platform participants” and policy and regulations that can shape the environment with respect to socio-economic and political issues including resource constraints and institutional voids.

The atrioventricular canal (AVC) connects the atrial and ventricular chambers of the heart and its formation is critical for the development of the cardiac valves, chamber septation and formation of the cardiac conduction system. Consequently, problems in AVC formation can lead to congenital defects ranging from cardiac arrhythmia to incomplete cardiac septation. While our knowledge about early heart tube formation is relatively comprehensive, much remains to be investigated about the genes that regulate AVC formation. Here we identify a new role for the basic helix-loop-helix factor Id4 in zebrafish AVC valve development and function. id4 is first expressed in the AVC endocardium and later becomes more highly expressed in the atrial chamber. TALEN induced inactivation of id4 causes retrograde blood flow at the AV canal under heat induced stress conditions, indicating defects in AV valve function. At the molecular level, we found that id4 inactivation causes misexpression of several genes important for AVC and AV valve formation including bmp4 and spp1. We further show that id4 appears to control the number of endocardial cells that contribute to the AV valves by regulating Wnt signaling in the developing AVC endocardium.

Increasingly, firms embark on digital journeys that involve changing business models, strategies, and processes that straddle industries and geographies, and create complex ecosystems. In this symp...

The ultimate formation of a four-chambered heart allowing the separation of the pulmonary and systemic circuits was key for the evolutionary success of tetrapods. Complex processes of cell diversification and tissue morphogenesis allow the left and right cardiac compartments to become distinct but remain poorly understood. Here, we describe an unexpected laterality in the single zebrafish atrium analogous to that of the two atria in amniotes, including mammals. This laterality appears to derive from an embryonic antero-posterior asymmetry revealed by the expression of the transcription factor gene meis2b. In adult zebrafish hearts, meis2b expression is restricted to the left side of the atrium where it controls the expression of pitx2c, a regulator of left atrial identity in mammals. Altogether, our studies suggest that the multi-chambered atrium in amniotes arose from a molecular blueprint present before the evolutionary emergence of cardiac septation and provide insights into the establishment of atrial asymmetry., SCOPUS: ar.j, info:eu-repo/semantics/published

Zebrafish regenerate damaged myocardial tissue very effectively. Hence, insights into the molecular networks underlying zebrafish heart regeneration might help develop alternative strategies to restore human cardiac performance. While TGF-β signaling has been implicated in zebrafish cardiac regeneration, the role of its individual ligands remains unclear. Here, we report the opposing expression response during zebrafish heart regeneration of two genes, mstnb and inhbaa, which encode TGF-β family ligands. Using gain-of-function (GOF) and loss-of-function (LOF) approaches, we show that these ligands mediate inverse effects on cardiac regeneration and specifically on cardiomyocyte (CM) proliferation. Notably, we find that Inhbaa functions as a CM mitogen and that its overexpression leads to accelerated cardiac recovery and scar clearance after injury. In contrast, mstnb GOF and inhbaa LOF both lead to unresolved scarring after cardiac injury. We further show that Mstnb and Inhbaa inversely control Smad2 and Smad3 transcription factor activities through alternate Activin type 2 receptors., Zebrafish can regenerate damaged myocardial tissue but it is unclear how this is regulated. Here, the authors show that two TGF-β family members, Mstnb and Inhbaa, have opposite effects in regeneration, with mstnb overexpression or inhbaa loss-of-function causing cardiac scarring after injury.

Congenital heart disease is a major health issue, accounting for a third of all congenital defects. Improved early surgical management has led to a growing population of adults with congenital heart disease, including patients with defects affecting the right ventricle, which are often classified as severe. Defects affecting the right ventricle often cause right ventricular volume or pressure overload and affected patients are at high risk for complications such as heart failure and sudden death. Recent insights into the developmental mechanisms and distinct developmental origins of the left ventricle, right ventricle, and the outflow tract have shed light on the common features and distinct problems arising in specific defects. Here, we provide a comprehensive overview of the current knowledge on the development into the normal and congenitally malformed right heart and the clinical consequences of several congenital heart defects affecting the right ventricle.

Regulation of gene expression is central to cell growth, differentiation and diseases. Context specific and signal dependent regulation of gene expression is achieved to a large part by transcription factors. Cardiac transcription factors regulate heart development and are also involved in stress regulation of the adult heart, which may lead to cardiac hypertrophy. Hypertrophy of cardiac myocytes is an outcome of the imbalance between prohypertrophic factors and anti-hypertrophic factors. This is initially a compensatory mechanism but sustained hypertrophy may lead to heart failure. The growing knowledge of transcriptional control mechanisms is helpful in the development of novel therapies. This review summarizes the role of cardiac transcription factors in cardiac hypertrophy, emphasizing their potential as attractive therapeutic targets to prevent the onset of heart failure and sudden death as they can be converging targets for current therapy.

In this conceptual paper, we examine how digital platforms foster innovation in resource constrained environments. We use the context of frugal ecosystems, where lack of infrastructure, resource sc...

Objectives This study was designed to evaluate the effect of curcumin on H9c2 cardiac cell line and primary rat cardiac myocytes, using purified noradrenaline as a hypertrophy-inducing agent. Methods The concentration of curcumin at which cells were treated was determined by MTT (3-(4,5-dimethyl-thiazol-2-yl)-2,5-diphenyl tetrazolium bromide) assay. The effect of this safe dose in preventing noradrenaline-induced cardiac hypertrophy was assessed by biochemical analysis (estimating total protein content), molecular analysis (using RT-PCR to study the expression of fetal genes like ANF), immunological analysis (by determining the nuclear localization of GATA-4) and electrophoretic mobility shift assay (EMSA; to study DNA binding activity of GATA-4). Key findings Curcumin at a concentration of 8 µm was found to suppress the increase in cell size, protein content and enhanced marker gene expression (ANF) caused by noradrenaline. Immunocytochemistry and Western blot analysis showed that curcumin suppressed the localization of transcription factor GATA-4 in the nucleus. It also showed a reduced DNA-binding activity in the presence of noradrenaline as confirmed by EMSA. Conclusions These findings suggest that curcumin reduces the hypertrophic marker gene expression by inhibiting nuclear localization and DNA binding activity of GATA-4. Thus it has a great anti-hypertrophic potential.

The purpose of this chapter is to present an integrated framework that addresses the need for organizational information security requirements as well as alignment between business, IT and information security strategies. This is achieved via the integrated use of control objectives for Information Technology (COBIT) and balanced scorecard (BSC) frameworks, in conjunction with Systems Security Engineering Capability Maturity Model (SSE-CMM) as a tool for performance measurement and evaluation, in order to ensure the adoption of a continuous improvement approach for successful sustainability. This integrated framework has been presented at the IEEE Symposium on Security & Privacy (2009) and the International Conference on Business/IT Alignment (2009). The goal is to investigate the strengths, implementation techniques, and potential benefits of such an integrated approach. The integrated use of COBIT, BSC, and SSE-CMM can provide a more comprehensive mechanism for strategic information security management–one that is fully aligned with business, IT, and information security strategies.