Galactokinase is a Novel Modifier of Calcineurin-Induced Cardiomyopathy in Drosophila

<p>Calcineurin is both necessary and sufficient to induce cardiac hypertrophy, an independent risk factor for arrhythmia, dilated cardiomyopathy, heart failure, and sudden cardiac death. However, current knowledge of the downstream effectors of calcineurin is limited. My study utilizes <italic>Drosophila melanogaster</italic> to 1) establish a reliable model for discovering novel modifiers of calcineurin-induced cardiomyopathy; and 2) discover and characterize novel modifiers of calcineurin-induced cardiomyopathy.</p><p>In this study, I generated sensitized <italic>Drosophila</italic> lines expressing constitutively active calcineurin (CanA<super>act</super>) that was either fused to yellow fluorescent protein (YFP) or a Flag epitope (Flag-tagged) specifically in the heart using the cardiac-specific tinC driver (<italic>tinC-CanA<super>act</super></italic>). These sensitized lines displayed significant cardiac enlargement as assayed via optical coherence tomography (OCT), histology, and confocal microscopy. The feasibility of this method was established by testing <italic>Drosophila</italic> expressing deficiency of a known calcineurin modifier, Mef2. </p><p>Employing a targeted deficiency screen informed by calcineurin modifier screens in the eye and mesoderm, Galactokinase (<italic>Galk</italic>) was discovered as a novel modifier of calcineurin-induced cardiomyopathy in the fly through 1) genetic deficiencies, transposable elements, and RNAi disrupting <italic>Galk</italic> expression rescued <italic>tinC-CanA<super>act</super></italic>-induced cardiomyopathy; and 2) transposable element in <italic>Galk</italic> rescued <italic>tinC-CanA<super>act</super></italic>-induced decreased life span. Further characterization identified that the genetic disruption of <italic>Galk</italic> rescued CanA<super>act</super>-induced phenotypes driven in the posterior wing, but not ectodermaly, mesodermaly, or ubiquitously driven phenotypes. In a separate region, genetic disruption of the galactoside-binding lectin, galectin, was also found to rescue <italic>tinC-CanA<super>act</super></italic>-induced cardiac enlargement.</p><p>Together, these results characterize <italic>tinC-CanA<super>act</super></italic>-induced cardiac enlargement in the fly, establish that the <italic>tinC-CanA<super>act</super></italic> sensitized line is a reliable model for discovering novel calcineurin regulators and suggest that galactokinase and galectin-regulated glycosylation is important for calcineurin-induced cardiomyopathy. These results have the potential to provide insight into new treatments for cardiac hypertrophy.</p>Dissertatio

Classifying E-Commerce Trust Seals: An Analytical Framework

Trust seals are business assurance service in e-commerce. Vendors apply for trust seals to increase their trustworthiness. In this paper, we classify trust seals in five different categories: (1) comprehensive certificate provider, (2) seller evaluation service, (3) market evaluator, (4) market assurance service, and (5) niche service. We derive the five categories through three steps: (1) reviewing literature, (2) examining c-commerce processes, and (3) reviewing seal providers’ documents. Our framework and analytical process can help e-commerce consumer to differentiate different types of seals and inspire seal provider to develop new services. We also identify many research opportunities for academics

Understanding E-Commerce Assurance Seals: An Analytical Framework

Trust seals provide a business assurance service in e-commerce. Vendors employ trust seals to increase the perception of their trustworthiness. In this paper, we create an analytical framework that we use to group trust seals into five categories: (1) comprehensive certificate provider, (2) seller evaluation service, (3) market evaluator, (4) market assurance service, and (5) niche service. Our framework provides an easy means for online shoppers to differentiate trust seals and motivate seal providers to develop new services.

The English language, multilingualism, and the politics of location

Drawing on Pennycook&apos;s frameworks for understanding the global role of English, we discuss the paradoxes of English language usage in what Canagarajah terms &apos;periphery communities&apos; internationally. This analysis is complemented by Canagarajah&apos;s work on a &apos;politics of location&apos;, which provides powerful insights into a periphery community&apos;s local and global investments in English. This notion is explored with particular reference to Norton&apos;s work in South Africa and Pakistan, which suggests that creative responses to the dominance of English, whether through codeswitching, appropriation, or subversion, defy essentialist analysis. We argue further that the notion of a politics of location can provide insights into English language usage not only in periphery communities, but also in center communities as well. In this regard, there is urgent need for the ongoing research of such scholars as Cummins, who has sought to better understand the challenges to bilingualism and multilingualism in center communities

Exploring the intersections of immigrant seniors’ digital literacies and social connectedness: a Canadian study

Seniors’ adoption of emerging technologies is crucial to their social connectedness, well-being, and digital participation in society. This article presents a Canadian study on how immigrant seniors established and sustained social connections through their engagement with digital technologies during the COVID-19 pandemic. Specifically, we aim to (1) deepen understandings of how immigrant seniors’ learning through and about technologies can shed light on our conceptualization of seniors’ digital literacies and (2) suggest programs and pedagogies that could foster lifelong learning for seniors. Data were collected through interviews, observations, and digital artifacts from a sample of immigrant seniors (N:16). Through narrative, we stitch together the personal and sociocultural perspectives from four seniors’ stories for holistic insights into their learning and engagement with technologies. Their stories also emphasize possibilities for dynamic and interconnected digital engagement and the inseparable link between community support and developing seniors’ digital literacy. Social interaction plays a pivotal role in facilitating, fostering, promoting, and enhancing seniors’ digital literacies. Our findings challenge preconceived notions about how seniors navigate digital technologies and offer strategies for supporting community service agencies in designing and implementing senior-friendly digital literacy programs

On the Effects of Local Environment on Active Galactic Nucleus (AGN) in the Horizon Run 5 Simulation

We use the Horizon Run 5 cosmological simulation to study the effect of galaxy intrinsic properties and the local environment on active galactic nuclei (AGNs) characterized by their threshold of the accretion rate. We select galaxies in the stellar mass range 10 9.5 ≤ M * / M ⊙ ≤ 10 10.5 in the snapshot at redshift z = 0.625. Among various intrinsic properties, we find that the star formation rate of the host galaxy is most correlated to the AGN activity. To quantify the environment, we use background galaxy number density (large-scale environment) and distance and morphological type of the nearest neighbors (small-scale environment), and study their relative effects on the AGN properties. We find that, compared to the background density, the nearest neighbor environment is the dominant quantity determining the bolometric luminosity, star formation rate, and kinematic properties of AGNs and better dictates the gas mass of the host galaxy. We show that the cold gas content in the host galaxies is crucial in triggering AGN activity. However, when the nearest neighbor environment effects start to act at the neighbor distance of less than about half the virial radius of the neighbor, the neighbor environmental effects are the most dominant factor for quasar activity

Twenty-one lessons: preventing domestic violence in the Caribbean

Domestic violence infringes the basic right to security of the individual and affects society as a whole – it impacts on demography, education and health systems, the economy, political participation and the overall security of a country. Domestic violence is a universal problem which affects all parts of the social fabric; it transcends ethnic, gender, religious, generational and economic lines. In Barbados and the Eastern Caribbean, beyond the ratification of a number of international instruments, domestic violence is widely recognised as a persistent challenge. On average, more than one in three women in the Caribbean experience gender-based violence in their lifetime; child sexual abuse is also a concern. The causes behind domestic violence in Barbados and the Eastern Caribbean are complex and deeply entrenched in cultural and behavioural norms. The prevention of domestic violence is vital if protection rights are to be effectively safeguarded. To this end, a sustainable and community driven approach -involving civil society and the various stakeholders - is crucial in effecting changes in cultural attitudes towards domestic violence. Early and continuous education about gender based violence and a focus on the prosecution and rehabilitation of perpetrators are both necessary to address the problem at its root. In addition, it is important that the relevant legal framework - and accompanying measures - is fortified and effectively enforced, so that the safety of victims and their families is adequately provided for. A co-ordinated approach between the various stakeholders is important to allow public and private mitigation and response mechanisms toward both protective and restorative safety nets (European Instrument for Democracy and Human Rights (EIDHR), ‘Towards a Future Free from Domestic Violence’, Guidelines for grant applicants 2014)

Sebaceous Hyperplasia of the Scrotum and Penile Shaft

Sebaceous hyperplasia (SH) is a proliferative abnormality of sebaceous glands, most often seen in elderly individuals. It consists of single or multiple, asymptomatic, small yellow papules with a central depression. The face is most commonly affected, but there have been reports of SH on the chest or genitalia. A lobular array of well-differentiated mature sebaceous lobules is noted on histological preparations. In this report, we describe a patient with SH on the penile shaft and parts of the scrotum

Melanoma NOS1 expression promotes dysfunctional IFN signaling.

In multiple forms of cancer, constitutive activation of type I IFN signaling is a critical consequence of immune surveillance against cancer; however, PBMCs isolated from cancer patients exhibit depressed STAT1 phosphorylation in response to IFN-α, suggesting IFN signaling dysfunction. Here, we demonstrated in a coculture system that melanoma cells differentially impairs the IFN-α response in PBMCs and that the inhibitory potential of a particular melanoma cell correlates with NOS1 expression. Comparison of gene transcription and array comparative genomic hybridization (aCGH) between melanoma cells from different patients indicated that suppression of IFN-α signaling correlates with an amplification of the NOS1 locus within segment 12q22-24. Evaluation of NOS1 levels in melanomas and IFN responsiveness of purified PBMCs from patients indicated a negative correlation between NOS1 expression in melanomas and the responsiveness of PBMCs to IFN-α. Furthermore, in an explorative study, NOS1 expression in melanoma metastases was negatively associated with patient response to adoptive T cell therapy. This study provides a link between cancer cell phenotype and IFN signal dysfunction in circulating immune cells

Vitamin D Binding Protein, Total and Free Vitamin D Levels in Different Physiological and Pathophysiological Conditions.

This review focuses on the biologic importance of the vitamin D binding protein (DBP) with emphasis on its regulation of total and free vitamin D metabolite levels in various clinical conditions. Nearly all DBP is produced in the liver, where its regulation is influenced by estrogen, glucocorticoids and inflammatory cytokines but not by vitamin D itself. DBP is the most polymorphic protein known, and different DBP alleles can have substantial impact on its biologic functions. The three most common alleles-Gc1f, Gc1s, Gc2-differ in their affinity with the vitamin D metabolites and have been variably associated with a number of clinical conditions. Although DBP has a number of biologic functions independent of vitamin D, its major biologic function is that of regulating circulating free and total levels of vitamin D metabolites. 25 hydroxyvitamin D (25(OH)D) is the best studied form of vitamin D as it provides the best measure of vitamin D status. In a normal non-pregnant individual, approximately 0.03% of 25(OH)D is free; 85% is bound to DBP, 15% is bound to albumin. The free hormone hypothesis postulates that only free 25(OH)D can enter cells. This hypothesis is supported by the observation that mice lacking DBP, and therefore with essentially undetectable 25(OH)D levels, do not show signs of vitamin D deficiency unless put on a vitamin D deficient diet. Similar observations have recently been described in a family with a DBP mutation. This hypothesis also applies to other protein bound lipophilic hormones including glucocorticoids, sex steroids, and thyroid hormone. However, tissues expressing the megalin/cubilin complex, such as the kidney, have the capability of taking up 25(OH)D still bound to DBP, but most tissues rely on the free level. Attempts to calculate the free level using affinity constants generated in a normal individual along with measurement of DBP and total 25(OH)D have not accurately reflected directly measured free levels in a number of clinical conditions. In this review, we examine the impact of different clinical conditions as well as different DBP alleles on the relationship between total and free 25(OH)D, using only data in which the free 25(OH)D level was directly measured. The major conclusion is that a number of clinical conditions alter this relationship, raising the question whether measuring just total 25(OH)D might be misleading regarding the assessment of vitamin D status, and such assessment might be improved by measuring free 25(OH)D instead of or in addition to total 25(OH)D