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Rapid alterations in protein expression are commonly regulated by adjusting translation. In addition to cap-dependent translation, which is e.g. induced by pro-proliferative signaling via the mammalian target of rapamycin (mTOR)-kinase, alternative modes of translation, such as internal ribosome entry site (IRES)-dependent translation, are often enhanced under stress conditions, even if cap-dependent translation is attenuated. Common stress stimuli comprise nutrient deprivation, hypoxia, but also inflammatory signals supplied by infiltrating immune cells. Yet, the impact of inflammatory microenvironments on translation in tumor cells still remains largely elusive. In the present study, we aimed at identifying translationally deregulated targets in tumor cells under inflammatory conditions. Using polysome profiling and microarray analysis, we identified cyp24a1 (1,25-dihydroxyvitamin D3 24-hydroxylase) to be translationally upregulated in breast tumor cells co-cultured with conditioned medium of activated monocyte-derived macrophages (CM). Using bicistronic reporter assays, we identified and validated an IRES within the 5′ untranslated region (5′UTR) of cyp24a1, which enhances translation of cyp24a1 upon CM treatment. Furthermore, IRES-dependent translation of cyp24a1 by CM was sensitive to phosphatidyl-inositol-3-kinase (PI3K) inhibition, while constitutive activation of Akt sufficed to induce its IRES activity. Our data provide evidence that cyp24a1 expression is translationally regulated via an IRES element, which is responsive to an inflammatory environment. Considering the negative feedback impact of cyp24a1 on the vitamin D responses, the identification of a novel, translational mechanism of cyp24a1 regulation might open new possibilities to overcome the current limitations of vitamin D as tumor therapeutic option.
This volume is an attempt to provide this intersectional and reflexive space. The thinking behind the book began in Lamu in mid-2010. It was a time when growing community resistance emerged towards the Kenyan government's plan to build a second seaport under a trans-frontier infrastructural project known as the Lamu Port- South Sudan-Ethiopia Transport Corridor (LAPSSET). The editors agreed that a book that draws community activists, academics, researchers and policy makers into a discussion of the predicament of indigenous rights and development against the backdrop of the Endorois case was timely and needed. Assembled here are the original contributions of some of the leading contemporary thinkers in the area of indigenous and human rights in Africa. The book is an interdisciplinary effort with the single purpose of thinking through indigenous rights after the Endorois case but it is not a singular laudatory remark on indigenous life in Africa. The discussion begins by framing indigenous rights and claims to indigeneity as found in the Endorois decision and its related socio-political history. Subsequent chapters provide deeper contextual analysis by evaluating the tense relationship between indigenous peoples and the post-colonial nation-state. Overall, the book makes a peering and provocative contribution to the relational interests between state policies and the developmental intersections of indigeneity, indigenous rights, gender advocacy, environmental conservation, chronic trauma and transitional justice.
It has long been observed that subjects cross-linguistically have topic properties: they are typically definite, referential and/or generic (Givón 1976). Bantu languages are said to illustrate this generalization: preverbal position for NPs is equated with both subject and topic status and postverbal position with focus (and non-subject). However, there is a growing body of work showing that preverbal subjects are not necessarily syntactically or semantically equivalent to topics. For example, Zerbian’s (2006) careful study of preverbal position in Northern Sotho shows that preverbal subjects meet few of the semantic tests for aboutness topics. The study of restrictions on preverbal subjects in Durban Zulu presented in this paper builds on Zerbian (2006) and Halpert (2012). In particular, we investigate the interpretational properties of preverbal indefinite subjects. These subjects show us that preverbal subjects carry a presupposition of existence. We explore an analysis connecting the "strong reading" of preverbal subjects with how high the verb moves in Zulu (following Tsai’s 2001 work on Mandarin).
The Eurozone fiscal crisis has created pressure for institutional harmonization, but skeptics argue that cultural predispositions can prevent convergence in behavior. Our paper derives a robust cultural classification of European countries and utilizes unique data on natives and immigrants to Sweden. Classification based on genetic distance or on Hofstede’s cultural dimensions fails to identify a single ‘southern’ culture but points to a ‘northern’ culture. Significant differences in financial behavior are found across cultural groups, controlling for household characteristics. Financial behavior tends to converge with longer exposure to common institutions, but is slowed down by longer exposure to original institutions.
The history of people with disabilities has been dominated by their isolation and exclusion. The long fight towards inclusion - and inclusive education in particular - started not many years ago. Most were powerless to control their own destiny. Their participation in society has been the object of other's actions. In many countries their disability policies have a substantial element of protection and charity but not the right to equalisation of opportunities. This book highlights the process of change that is underway internationally. The equalisation of opportunities requires new processes through which the various systems of society such as health services and education are delivered. It means the right for people with disabilities to remain in their communities and to receive the schooling and social supports they need within the ordinary structures available in local communities. Strong advocacy is needed for this to happen. In particular parents need to be empowered, communities mobilised and professionals trained in new ways of working: hence this book. Drawing on experiences in Africa, the book describes the issues to be considered when it comes to implementing inclusive strategies: the processes to be followed and the roles of different sectors, such as people with disabilities, parents, policy makers, educationalists, health and community development professionals and crucially, society at large.
This paper examines the effect of imperfect labor market competition on the efficiency of compensation schemes in a setting with moral hazard, private information and risk-averse agents. Two vertically differentiated firrms compete for agents by offering contracts with fixed and variable payments. Vertical differentiation between firms leads to endogenous, type-dependent exit options for agents. In contrast to screening models with perfect competition, we find that existence of equilibria does not depend on whether the least-cost separating allocation is interim efficient. Rather, vertical differentiation allows the inferior firm to offer (cross-)subsidizing fixed payments even above the interim efficient level. We further show that the efficiency of variable pay depends on the degree of competition for agents: For small degrees of competition, low-ability agents are under-incentivized and exert too little effort. For large degrees of competition, high-ability agents are over-incentivized and bear too much risk. For intermediate degrees of competition, however, contracts are second-best despite private information.
Many QCD based and phenomenological models predict changes of hadron properties in a strongly interacting environment. The results of these models differ significantly and the experimental determination of hadron properties in nuclear matter is essential. In this paper we present a review of selected physics results obtained at GSI Helmholtzzentrum für Schwerionenforschung GmbH by HADES (High-Acceptance Di-Electron Spectrometer). The e+e− pair emission measured for proton and heavy-ion induced collisions is reported together with results on strangeness production. The future HADES activities at the planned FAIR facility are also discussed.
In vitro investigation of genes identified by genome-wide association studies of Parkinson's disease
(2014)
Fibrous tissue growth and loss of residual hearing after cochlear implantation can be reduced by application of the glucocorticoid dexamethasone-21-phosphate-disodium-salt (DEX). To date, sustained delivery of this agent to the cochlea using a number of pharmaceutical technologies has not been entirely successful. In this study we examine a novel way of continuous local drug application into the inner ear using a refillable hydrogel functionalized silicone reservoir. A PEG-based hydrogel made of reactive NCO-sP(EO-stat-PO) prepolymers was evaluated as a drug conveying and delivery system in vitro and in vivo. Encapsulating the free form hydrogel into a silicone tube with a small opening for the drug diffusion resulted in delayed drug release but unaffected diffusion of DEX through the gel compared to the free form hydrogel. Additionally, controlled DEX release over several weeks could be demonstrated using the hydrogel filled reservoir. Using a guinea-pig cochlear trauma model the reservoir delivery of DEX significantly protected residual hearing and reduced fibrosis. As well as being used as a device in its own right or in combination with cochlear implants, the hydrogel-filled reservoir represents a new drug delivery system that feasibly could be replenished with therapeutic agents to provide sustained treatment of the inner ear.
South African poetry today is charged with restlessness, burstng with diversity. Gone is the intense inward focus required to deal with a situation of systematic oppression, the enclosing effort of concentration on a single predicament. While politics and identity continue to be central themes, the poetry since the late 1990s reveals a richer investigation of ancestors and history, alongside more experimentation with language and translation; and enduring concern with the touchstones of love, loss, memory, and acts of witnessing. In the Heat of Shadows: South African Poetry 1996-2013 presents work by 33 poets and includes some translations from Afrikaans, isiXhosa, isiZulu, Sesotho and Xitsonga. This collection follows on from Denis Hirson's 1997 anthology The Lava of this Land: South African Poetry 1960-1996.