Notch signalling in context.

The highly conserved Notch signalling pathway functions in many different developmental and homeostatic processes, which raises the question of how this pathway can achieve such diverse outcomes. With a direct route from the membrane to the nucleus, the Notch pathway has fewer opportunities for regulation than do many other signalling pathways, yet it generates exquisitely patterned structures, including sensory hair cells and branched arterial networks. More confusingly, its activity promotes tissue growth and cancers in some circumstances but cell death and tumour suppression in others. Many different regulatory mechanisms help to shape the activity of the Notch pathway, generating functional outputs that are appropriate for each context. These mechanisms include the receptor-ligand landscape, the tissue topology, the nuclear environment and the connectivity of the regulatory networks

A population of adult satellite-like cells in Drosophila is maintained through a switch in RNA-isoforms.

Adult stem cells are important for tissue maintenance and repair. One key question is how such cells are specified and then protected from differentiation for a prolonged period. Investigating the maintenance of Drosophila muscle progenitors (MPs) we demonstrate that it involves a switch in zfh1/ZEB1 RNA-isoforms. Differentiation into functional muscles is accompanied by expression of miR-8/miR-200, which targets the major zfh1-long RNA isoform and decreases Zfh1 protein. Through activity of the Notch pathway, a subset of MPs produce an alternate zfh1-short isoform, which lacks the miR-8 seed site. Zfh1 protein is thus maintained in these cells, enabling them to escape differentiation and persist as MPs in the adult. There, like mammalian satellite cells, they contribute to muscle homeostasis. Such preferential regulation of a specific RNA isoform, with differential sensitivity to miRs, is a powerful mechanism for maintaining a population of poised progenitors and may be of widespread significance

SWI/SNF chromatin remodeling controls Notch-responsive enhancer accessibility.

Notch signaling plays a key role in many cell fate decisions during development by directing different gene expression programs via the transcription factor CSL, known as Su(H) in Drosophila Which target genes are responsive to Notch signaling is influenced by the chromatin state of enhancers, yet how this is regulated is not fully known. Detecting a specific increase in the histone variant H3.3 in response to Notch signaling, we tested which chromatin remodelers or histone chaperones are required for the changes in enhancer accessibility to Su(H) binding. We show a crucial role for the Brahma SWI/SNF chromatin remodeling complex, including the actin-related BAP55 subunit, in conferring enhancer accessibility and enabling the transcriptional response to Notch activity. The Notch-responsive regions have high levels of nucleosome turnover which depend on the Brahma complex, increase in magnitude with Notch signaling, and primarily involve histone H3.3. Together these results highlight the importance of SWI/SNF-mediated nucleosome turnover in rendering enhancers responsive to Notch

Notch after cleavage.

The discovery that Notch activation involves a proteolytic cleavage to release the intracellular domain (NICD) revolutionized the field of Notch signaling. It resulted in a simple model whereby the cleaved NICD enters the nucleus and activates expression of genes by forming a DNA bound complex with CSL. However, is it really this simple? The realization that the outcome from activating Notch varies greatly from cell to cell raised many questions about what governs the target gene selections in different cell types. Insights have come from recent genome-wide studies, which highlight the importance of tissue-specific transcription factors and epigenetics. Co-factors also have been identified that participate in the regulation of enhancers. Finally, it is generally assumed that once cleaved, NICD goes on to do its job, but with a burgeoning number of post-translations, it may not be that simple

Changes in objectively measured BMI in children aged 4-11 years: Data from the National Child Measurement Programme

© 2015 The Author 2015. Published by Oxford University Press on behalf of Faculty of Public Health. All rights reserved. For permissions, please e-mail: [email protected]. Background This study looked at the degree of weight gain between the first (Reception) and last year (Year 6) of primary school and how weight status in Reception predicts becoming overweight/obese by Year 6. Methods A longitudinal sample of 1863 children was created using two time points (2006/7, 2012/13) from the National Child Measurement Programme (NCMP) in South Gloucestershire. T-test and logistic regression were used to test the difference between the BMI z-scores and BMI percentiles, and predict the probability of being overweight (BMI ≥ 85th) or obese (≥95th) at Year 6 based on BMI percentile in Reception. Results Of those children who were obese at Reception age, 68% were obese at Year 6. Compared with children with a BMI in the 2nd to 49th percentile range, children between the 75th and 84th percentiles of BMI at Reception age were 10 times more likely (odds ratio (OR) = 10.18, P < 0.01), and those with a BMI between the 85th and 94th percentiles were 13 times more likely (OR = 13.38, P < 0.01), to become obese by Year 6. Boys were more likely than girls to revert to a healthy weight. Conclusions This is the first study to link data from the NCMP. It provides estimates of prevalence and offers new evidence on obesity emergence and gender differences

Enabling healthy food choices in the workplace: the canteen operators’ perspective.

Purpose: Employees eat regularly in workplace foodservice settings, thus the food served can significantly impact their overall diet. Workplace foodservice providers are facing several challenges, including changing consumer demands, partial blame for high levels of obesity and the delivery of accessible information that can encourage healthier food choices. This paper explores the industry perspective on consumer information needs and will assess the challenges faced by foodservice providers in terms of responding to these in a workplace setting. Methodology: A qualitative approach was adopted, involving ten in-depth semi-structured interviews with contract catering managers in the UK and Germany. Findings: Canteen operators have a sound understanding of what is important to their customers. However, the amount of dish information currently provided is limited, and the reasons for this are discussed. The menu remains the traditional medium of communication of information on dishes, but there is openness to technical platforms, which not only reduce information overload but also increase customer engagement. Practical Implications: Technological solutions are discussed as a way to overcome barriers to information provision providing Workplace caterers with a clear approach to effectively communicate enhanced dish information. Social Implications: The provision of enhanced dish information has been found to influence consumers’ to make more healthful selections. This is an important public health issue given the growing rates of obesity and diabetes type 2. Originality: This study makes an original contribution by exploring the industry perspective on consumer needs for information and on how this information can be provided

Is there law in a post-zombie world? a critical discourse analysis of power, authority, and governance in AMC's The walking dead

v, 247 leaves ; 29 cm.Includes abstract and appendix.Includes bibliographical references (leaves 207-226).Using one of AMC’s “original series",The Walking Dead, as a narrative frame, this thesis offers a qualitative critical analysis of different and competing discourses of power, authority, gender, race, class, the law, governance, risk, and the body in the first two seasons of the series. I critically examine and analyze these discourses to demonstrate how the power and authority to govern, the management of risk, and the control of the body are brought into being in the text as well as how these discourses produce régimes of truth in the series. In particular, I argue that the power and authority to govern are gendered, raced, and classed, overwhelmingly falling in the purview of those who are male, white, middle-class, and heterosexual; I also argue that discursively the able, clean, and living body is privileged as normal in the text and that the body is governed through the management of risk, more so than through overt physical violence or force. I draw on Jacques Derrida’s vocabulary of deconstruction, Michel Foucault’s concepts of discourse, knowledge, power, truth, governance, normalization, resistance, and the body, and Julia Kristeva’s theory of abjection to compile the conceptual tools and language I need to deconstruct, critically analyze, and speak about this text

Notch directly regulates the cell morphogenesis genes Reck, talin and trio in adult muscle progenitors.

There is growing evidence that activation of the Notch pathway can result in consequences on cell morphogenesis and behaviour, both during embryonic development and cancer progression. In general, Notch is proposed to coordinate these processes by regulating expression of key transcription factors. However, many Notch-regulated genes identified in genome-wide studies are involved in fundamental aspects of cell behaviour, suggesting a more direct influence on cellular properties. By testing the functions of 25 such genes we confirmed that 12 are required in developing adult muscles, consistent with roles downstream of Notch. Focusing on three, Reck, rhea/talin and trio, we verify their expression in adult muscle progenitors and identify Notch-regulated enhancers in each. Full activity of these enhancers requires functional binding sites for Su(H), the DNA-binding transcription factor in the Notch pathway, validating their direct regulation. Thus, besides its well-known roles in regulating the expression of cell-fate-determining transcription factors, Notch signalling also has the potential to directly affect cell morphology and behaviour by modulating expression of genes such as Reck, rhea/talin and trio. This sheds new light on the functional outputs of Notch activation in morphogenetic processes.This is the author's accepted manuscript. The final version is available from the Journal of Cell Science at http://dx.doi.org/10.1242/​jcs.15178

Drosophila Reporter Vectors Compatible with ΦC31 Integrase Transgenesis Techniques and Their Use to Generate New Notch Reporter Fly Lines

Complex spatial and temporal regulation of gene activity is fundamental to development and homeostasis. The ability to decipher the DNA sequences that accurately coordinate gene expression is, therefore, of primary importance. One way to assess the functions of DNA elements entails their fusion to fluorescent reporter genes. This powerful approach makes it possible to visualize their regulatory capabilities when reintroduced into the developing animal. Transgenic studies in Drosophila have recently advanced with the introduction of site-specific, ΦC31 integrase–mediated approaches. However, most existing Drosophila reporter vectors are not compatible with this new approach and have become obsolete. Here we describe a new series of fluorescent reporter vectors optimized for use with ΦC31 transgenesis. By using these vectors to generate a set of Notch reporter fly lines, we demonstrate their efficacy in reporting the function of gene regulatory elements