Current perspectives of the signaling pathways directing neural crest induction

The neural crest is a migratory population of embryonic cells with a tremendous potential to differentiate and contribute to nearly every organ system in the adult body. Over the past two decades, an incredible amount of research has given us a reasonable understanding of how these cells are generated. Neural crest induction involves the combinatorial input of multiple signaling pathways and transcription factors, and is thought to occur in two phases from gastrulation to neurulation. In the first phase, FGF and Wnt signaling induce NC progenitors at the border of the neural plate, activating the expression of members of the Msx, Pax, and Zic families, among others. In the second phase, BMP, Wnt, and Notch signaling maintain these progenitors and bring about the expression of definitive NC markers including Snail2, FoxD3, and Sox9/10. In recent years, additional signaling molecules and modulators of these pathways have been uncovered, creating an increasingly complex regulatory network. In this work, we provide a comprehensive review of the major signaling pathways that participate in neural crest induction, with a focus on recent developments and current perspectives. We provide a simplified model of early neural crest development and stress similarities and differences between four major model organisms: Xenopus, chick, zebrafish, and mouse

Practical guidelines for rigor and reproducibility in preclinical and clinical studies on cardioprotection

The potential for ischemic preconditioning to reduce infarct size was first recognized more than 30 years ago. Despite extension of the concept to ischemic postconditioning and remote ischemic conditioning and literally thousands of experimental studies in various species and models which identified a multitude of signaling steps, so far there is only a single and very recent study, which has unequivocally translated cardioprotection to improved clinical outcome as the primary endpoint in patients. Many potential reasons for this disappointing lack of clinical translation of cardioprotection have been proposed, including lack of rigor and reproducibility in preclinical studies, and poor design and conduct of clinical trials. There is, however, universal agreement that robust preclinical data are a mandatory prerequisite to initiate a meaningful clinical trial. In this context, it is disconcerting that the CAESAR consortium (Consortium for preclinicAl assESsment of cARdioprotective therapies) in a highly standardized multi-center approach of preclinical studies identified only ischemic preconditioning, but not nitrite or sildenafil, when given as adjunct to reperfusion, to reduce infarct size. However, ischemic preconditioning—due to its very nature—can only be used in elective interventions, and not in acute myocardial infarction. Therefore, better strategies to identify robust and reproducible strategies of cardioprotection, which can subsequently be tested in clinical trials must be developed. We refer to the recent guidelines for experimental models of myocardial ischemia and infarction, and aim to provide now practical guidelines to ensure rigor and reproducibility in preclinical and clinical studies on cardioprotection. In line with the above guideline, we define rigor as standardized state-of-the-art design, conduct and reporting of a study, which is then a prerequisite for reproducibility, i.e. replication of results by another laboratory when performing exactly the same experiment

Codeswitching in the Irish-Latin Leabhar Breac: Mediæval homiletic culture

An Leabhar Breac ('The Speckled Book'; c.1410) is a manuscript containing a collection of mostly religious material in both Latin and Irish, now housed in Dublin at the Royal Irish Academy. The present publication explores the make-up of the manuscript, focusing on the question which languages are used where and for which texts, and singling out individual texts which use a combination of languages within the same speech act, a process called codeswitching. Special attention is paid to the genre of the homily, a moral commentary on religious themes. The use of Latin and Irish in such texts can shed light on the intellectual culture of Ireland, an important centre of learning in mediaeval Europe. The Leabhar Breac manuscript is a composite piece of various sources, most of which date to about 1100, though some may be dated as late as 1350. By studying the languages of these texts, one can hypothesise about the languages and dates of their sources, and thus about the availability and level of Latin learning in Irish intellectual society through time. For this purpose it is important to study not only individual texts but also the quires in which they occur. The hierarchy and juxtaposition of texts and languages is an indication of their intended manner of composition, while the level of compositional ability on the part of the author or scribe is a reflection of bilingual education. Such a bilingual education can then be compared to similar circumstances such as Latin-English sermons in England