A Transgenic Rat for Investigating the Anatomy and Function of Corticotrophin Releasing Factor Circuits.

Corticotrophin-releasing factor (CRF) is a 41 amino acid neuropeptide that coordinates adaptive responses to stress. CRF projections from neurons in the central nucleus of the amygdala (CeA) to the brainstem are of particular interest for their role in motivated behavior. To directly examine the anatomy and function of CRF neurons, we generated a BAC transgenic Crh-Cre rat in which bacterial Cre recombinase is expressed from the Crh promoter. Using Cre-dependent reporters, we found that Cre expressing neurons in these rats are immunoreactive for CRF and are clustered in the lateral CeA (CeL) and the oval nucleus of the BNST. We detected major projections from CeA CRF neurons to parabrachial nuclei and the locus coeruleus, dorsal and ventral BNST, and more minor projections to lateral portions of the substantia nigra, ventral tegmental area, and lateral hypothalamus. Optogenetic stimulation of CeA CRF neurons evoked GABA-ergic responses in 11% of non-CRF neurons in the medial CeA (CeM) and 44% of non-CRF neurons in the CeL. Chemogenetic stimulation of CeA CRF neurons induced Fos in a similar proportion of non-CRF CeM neurons but a smaller proportion of non-CRF CeL neurons. The CRF1 receptor antagonist R121919 reduced this Fos induction by two-thirds in these regions. These results indicate that CeL CRF neurons provide both local inhibitory GABA and excitatory CRF signals to other CeA neurons, and demonstrate the value of the Crh-Cre rat as a tool for studying circuit function and physiology of CRF neurons

When the guardian sleeps: Reactivation of the p53 pathway in cancer

The p53 tumor suppressor is inactivated in most cancers, thus suggesting that loss of p53 is a prerequisite for tumor growth. Therefore, its reintroduction through different means bears great clinical potential. After a brief introduction to current knowledge of p53 and its regulation by the ubiquitin-ligases MDM2/MDMX and post-translational modifications, we will discuss small molecules that are able to reactivate specific, frequently observed mutant forms of p53 and their applicability for clinical purposes. Many malignancies display amplification of MDM genes encoding negative regulators of p53 and therefore much effort to date has concentrated on the development of molecules that inhibit MDM2, the most advanced of which are being tested in clinical trials for sarcoma, glioblastoma, bladder cancer and lung adenocarcinoma. These will be discussed as will recent findings of MDMX inhibitors: these are of special importance as it has been shown that cancers that become resistant to MDM2 inhibitors often amplify MDM4. Finally, we will also touch on gene therapy and vaccination approaches; the former of which aims to replace mutated TP53 and the latter whose goal is to activate the body's immune system toward mutant p53 expressing cells. Besides the obvious importance of MDM2 and MDMX expression for regulation of p53, other regulatory factors should not be underestimated and are also described. Despite the beauty of the concept, the past years have shown that many obstacles have to be overcome to bring p53 reactivation to the clinic on a broad scale, and it is likely that in most cases it will be part of a combined therapeutic approach. However, improving current p53 targeted molecules and finding the best therapy partners will clearly impact the future of cancer therapy.This study was supported by an EU Marie Curie Actions Innovative Training Network grant (ALKATRAS 675712). We are also grateful to collaborators of the European Research Initiative of ALK-related malignancies (www.erialcl.net). We thank the Jubiläumsfond der Österreichischen Nationalbank (Grant No. 14856, to OM) and the Fonds der Stadt Wien für innovative interdisziplinäre Krebsforschung (The role of Brg1 in Anaplastic Large Cell Lymphoma, to OM) as well as the Austrian Science Funds (FWF; Grant Nos P 26011 and P 29251, to LK). SDT is a Senior Lecturer supported by funding from Bloodwise. RM was supported by grants SFB F47 (SFB F4707-B20) from the Austrian Science Fund

Where two worlds meet: language policing in mainstream and complementary schools in England

We compare language policing in two educational contexts in England: mainstream schools and complementary schools. We draw on a varied dataset (policy documents, in-class observations, interviews) collected from mainstream schools and Greek complementary schools in London. We find similarities in how the two types of schools control, regulate, monitor and suppress the language of school students. Both settings hierarchise standardised and non-standardised varieties in institutional policies that delegitimise the non-standardised varieties. Teachers become vehicles for language ideologies in enacting monovarietal policies drawing on discourses around academic success and the primacy of written language over spoken language, including regional varieties such as Cypriot Greek. Our findings suggest that multilingual and multidialectal students in England who attend both mainstream and complementary schools are exposed to similar kinds of prescriptive discourses across the whole spectrum of their educational experiences, which can have a range of negative effects on their learning and the construction of their self-image. We argue that more links need to be forged between the two educational settings and that these should include the development of integrated pedagogies and policies that legitimise students’ whole linguistic repertoires, encompassing both their standardised and their non-standardised varieties as well as their other linguistic resources

Global nomads, cultural chameleons, strange ones or immigrants? An exploration of Third Culture Kid terminology with reference to the United Arab Emirates

© The Author(s) 2019. The term ‘Third Culture Kid’ (TCK) is commonly used to denote children living in a host culture other than their passport culture during their developmental years. However, its meaning in relation to other terminology referring to a similar concept is a source of interest for many stakeholders. This paper opens up opportunities for further exploring and critiquing the definition of TCK, and opening this up to case studies within the context of the United Arab Emirates and more widely. It is critical to clarify the terminology in light of unprecedented levels of international migration throughout the world. This paper reviews the meaning of culture in relation to TCKs, and explores the meaning of the TCK concept as well as a number of other terms used as alternatives to TCK. A contextualization of the literature follows in relation to the researchers’ own lived experiences in the United Arab Emirates. The term TCK can be seen as part of the general stock of theoretical concepts. This paper acknowledges that it cannot catch all nuances of migrant children in the global context

Complexity of the Tensegrity Structure for Dynamic Energy and Force Distribution of Cytoskeleton during Cell Spreading

Cytoskeleton plays important roles in intracellular force equilibrium and extracellular force transmission from/to attaching substrate through focal adhesions (FAs). Numerical simulations of intracellular force distribution to describe dynamic cell behaviors are still limited. The tensegrity structure comprises tension-supporting cables and compression-supporting struts that represent the actin filament and microtubule respectively, and has many features consistent with living cells. To simulate the dynamics of intracellular force distribution and total stored energy during cell spreading, the present study employed different complexities of the tensegrity structures by using octahedron tensegrity (OT) and cuboctahedron tensegrity (COT). The spreading was simulated by assigning specific connection nodes for radial displacement and attachment to substrate to form FAs. The traction force on each FA was estimated by summarizing the force carried in sounding cytoskeletal elements. The OT structure consisted of 24 cables and 6 struts and had limitations soon after the beginning of spreading by declining energy stored in struts indicating the abolishment of compression in microtubules. The COT structure, double the amount of cables and struts than the OT structure, provided sufficient spreading area and expressed similar features with documented cell behaviors. The traction force pointed inward on peripheral FAs in the spread out COT structure. The complex structure in COT provided further investigation of various FA number during different spreading stages. Before the middle phase of spreading (half of maximum spreading area), cell attachment with 8 FAs obtained minimized cytoskeletal energy. The maximum number of 12 FAs in the COT structure was required to achieve further spreading. The stored energy in actin filaments increased as cells spread out, while the energy stored in microtubules increased at initial spreading, peaked in middle phase, and then declined as cells reached maximum spreading. The dynamic flows of energy in struts imply that microtubules contribute to structure stabilization

Co-constructing bilingual learning: an equal exchange of strategies between complementary and mainstream teachers

Teachers in complementary schools are often assumed to be using outmoded teaching strategies and an authoritarian approach to discipline. However, it is rare for mainstream teachers to have visited these community-run after-school or weekend classes, which remain on the margins of educational provision. This paper argues that complementary teachers’ knowledge has been ‘doubly devalued’: firstly because of their location in the informal learning sector, and secondly because their work focuses on languages and cultures that are ignored or viewed negatively by the wider society. Our action research study with complementary teachers in East London challenges mainstream preconceptions in showing the creative range of teaching strategies devised to meet the needs of multi-level, mixed-age classes in under-resourced conditions. Uniquely, the research set up partnerships between these complementary teachers and local primary school teachers, in which they visited each other's settings and jointly planned topic-based lessons adapted to each context. Findings demonstrate that mainstream teachers had much to learn from their complementary colleagues about negotiating teacher–student relationships, the child as independent learner and as leader within a learning community, and the use of bilingual strategies. Partnership teaching created mutual respect for each other's expertise, crucial to the equal valuing of shared knowledge