Mutant Neurogenin-3 in congenital malabsorptive diarrhea

Background: Neurogenin-3 (NEUROG3) is expressed in endocrine progenitor cells and is required for endocrine-cell development in the pancreas and intestine. The NEUROG3 gene (NEUROG3) is therefore a candidate for the cause of a newly discovered autosomal recessive disorder characterized by generalized malabsorption and a paucity of enteroendocrine cells. Methods: We screened genomic DNA from three unrelated patients with sparse enteroendocrine cells for mutations of NEUROG3. We then tested the ability of the observed mutations to alter NEUROG3 function, using in vitro and in vivo assays. Results: The patients had few intestinal enteroendocrine cells positive for chromogranin A, but they had normal numbers of Paneth\u27s, goblet, and absorptive cells. We identified two homozygous mutations in NEUROG3, both of which rendered the NEUROG3 protein unable to activate NEUROD1, a downstream target of NEUROG3, and compromised the ability of NEUROG3 to bind to an E-box element in the NEUROD1 promoter. The injection of wild-type but not mutant NEUROG3 messenger RNA into xenopus embryos induced NEUROD1 expression. Conclusions: A newly discovered disorder characterized by malabsorptive diarrhea and a lack of intestinal enteroendocrine cells is caused by loss-of-function mutations in NEUROG3. Copyright © 2006 Massachusetts Medical Society

Understanding Technology as Situated Practice: Everyday use of Voice User Interfaces Among Diverse Groups of Users in Urban India

Abstract: As smartphones have become ubiquitous across urban India, voice user interfaces (VUIs) are increasingly becoming part of diverse groups of users’ daily experiences. These technologies are now generally accessible as a result of improvements in mobile Internet access, [-8.5pc]Biography is Required. Please provide. introduction of low-cost smartphones and the ongoing process of their localisation into Indian languages. However, when people engage with technologies in their everyday lives, they not only enact the material attributes of the artifact but also draw on their skills, social positions, prior experience and societal norms and expectations to make use of the artifact. Drawing on Orlikowski’s analytical framework of “technologies-in-practice” we engage in an interview-based exploratory study among diverse groups of users in urban India to understand use of VUIs as situated practice. We identify three technologies-in-practice emerging through enactment of VUIs on users’ smartphones: looking up, learning and leisure. We argue that – instead of asking why and how users appropriate VUIs – identifying different kinds of enactments of VUIs present researchers and practitioners with a more nuanced understanding of existing and potential use of VUIs across varied contexts

Out of the Panopticon and into Exile:Visibility and Control in Distributed New Culture Organizations

This paper builds a theoretical argument for exile as an alternative metaphor to the panopticon, for conceptualizing visibility and control in the context of distributed “new culture” organizations. Such organizations emphasize team relationships between employees who use digital technologies to stay connected with each other and the organization. I propose that in this context, a fear of exile – that is a fear of being left out, overlooked, ignored or banished – can act as a regulating force that inverts the radial spatial dynamic of the panopticon and shifts the responsibility for visibility, understood both in terms of competitive exposure and existential recognition, onto workers. As a consequence these workers enlist digital technologies to become visible at the real or imagined organizational centre. A conceptual appreciation of exile, as discussed in existential philosophy and postcolonial theory, is shown to offer productive grounds for future research on how a need for visibility in distributed, digitised, and increasingly precarious work environments regulates employee subjectivity, in a manner that is not captured under traditional theories of ICT-enabled surveillance in organizations

A systematic review of the literature on digital transformation: insights and implications for strategy and organizational change

In this article we provide a systematic review of the extensive yet diverse and fragmented literature on digital transformation (DT), with the goal of clarifying boundary conditions to investigate the phenomenon from the perspective of organizational change. On the basis of 279 articles, we provide a multi-dimensional framework synthesizing what is known about DT and discern two important thematical patterns: DT is moving firms to malleable organizational designs that enable continuous adaptation, and this move is embedded in and driven by digital business ecosystems. From these two patterns, we derive four perspectives on the phenomenon of DT: technology impact, compartmentalized adaptation, systemic shift and holistic co-evolution. Linking our findings and interpretations to existing work, we find that the nature of DT is only partially covered by conventional frameworks on organizational change. On the basis of this analysis, we derive a research agenda and provide managerial implications for strategy and organizational change.info:eu-repo/semantics/publishedVersio

Enhancing organisational competitiveness via social media - a strategy as practice perspective

The affordances, popularity and pervasive use of social media platforms such as Facebook, Twitter and Instagram have made these platforms attractive to organisations for enhancing their competitiveness and creating business value. Despite this apparent significance of social media for businesses, they are struggling with the development of a social media strategy as well as understanding the implications of social media on practice within their organisations. This paper explores how social media has become a tool for competitiveness and its influence on organisational strategy and practice. Using the 'strategy as practice' lens and guided by the interpretivist philosophy, this paper uses the empirical case of a telecom organisation in Tanzania. The findings show that social media is influencing competitiveness through imitation and product development. Also, the findings indicate how social media affects the practices within an organisation, consequently making the social media strategy an emergent phenomenon

Neonatal presentation of ventricular tachycardia and a Reye-like syndrome episode associated with disturbed mitochondrial energy metabolism

BACKGROUND: Hyperammonemia, hypoglycemia, hepatopathy, and ventricular tachycardia are common presenting features of carnitine-acylcarnitine translocase deficiency (Mendelian Inheritance in Man database: *212138), a mitochondrial fatty acid oxidation disorder with a lethal prognosis. These features have not been identified as the presenting features of mitochondrial cytopathy in the neonatal period. CASE PRESENTATION: We describe an atypical presentation of mitochondrial cytopathy in a 2 day-old neonate. She presented with a Reye-like syndrome episode, premature ventricular contractions and ventricular tachycardia. Initial laboratory evaluation exhibited a large amount of 3-methylglutaconic acid on urine organic acid analysis, mild orotic aciduria and a nonspecific abnormal acylcarnitine profile. The evaluation for carnitine-acylcarnitine translocase deficiency and other fatty acid oxidation disorders was negative. The patient later developed a hypertrophic cardiomyopathy and continued to be affected by recurrent Reye-like syndrome episodes triggered by infections. A muscle biopsy exhibited signs of a mitochondrial cytopathy. During the course of her disease, her Reye-like syndrome episodes have subsided; however, cardiomyopathy has persisted along with fatigue and exercise intolerance. CONCLUSIONS: This case illustrates that, in the neonatal period, hyperammonemia and ventricular tachycardia may be the presenting features of a lethal carnitine-acylcarnitine translocase deficiency or of a mitochondrial cytopathy, associated with a milder clinical course. This association broadens the spectrum of presenting phenotypes observed in patients with disturbed mitochondrial energy metabolism. Also, the presence of 3-methylglutaconic aciduria suggests mitochondrial dysfunction and mild orotic aciduria could potentially be used as a marker of mitochondrial disease

Molecular changes in the expression of human colonic nutrient transporters during the transition from normality to malignancy

Healthy colonocytes derive 60–70% of their energy supply from short-chain fatty acids, particularly butyrate. Butyrate has profound effects on differentiation, proliferation and apoptosis of colonic epithelial cells by regulating expression of various genes associated with these processes. We have previously shown that butyrate is transported across the luminal membrane of the colonic epithelium via a monocarboxylate transporter, MCT1. In this paper, using immunohistochemistry and in situ hybridisation histochemistry, we have determined the profile of MCT1 protein and mRNA expression along the crypt to surface axis of healthy human colonic tissue. There is a gradient of MCT1 protein expression in the apical membrane of the cells along the crypt-surface axis rising to a peak in the surface epithelial cells. MCT1 mRNA is expressed along the crypt-surface axis and is most abundant in cells lining the crypt. Analysis of healthy colonic tissues and carcinomas using immunohistochemistry and Western blotting revealed a significant decline in the expression of MCT1 protein during transition from normality to malignancy. This was reflected in a corresponding reduction in MCT1 mRNA expression, as measured by Northern analysis. Carcinoma samples displaying reduced levels of MCT1 were found to express the high affinity glucose transporter, GLUT1, suggesting that there is a switch from butyrate to glucose as an energy source in colonic epithelia during transition to malignancy. The expression levels of MCT1 in association with GLUT1 could potentially be used as determinants of the malignant state of colonic tissue