microRNA-184 induces a commitment switch to epidermal differentiation

miR-184 is a highly evolutionary conserved microRNA (miRNA) from fly to human. The importance of miR-184 was underscored by the discovery that point mutations in miR-184 gene led to corneal/lens blinding disease. However, miR-184-related function in vivo remained unclear. Here, we report that the miR-184 knockout mouse model displayed increased p63 expression in line with epidermal hyperplasia, while forced expression of miR-184 by stem/progenitor cells enhanced the Notch pathway and induced epidermal hypoplasia. In line, miR-184 reduced clonogenicity and accelerated differentiation of human epidermal cells. We showed that by directly repressing cytokeratin 15 (K15) and FIH1, miR-184 induces Notch activation and epidermal differentiation. The disease-causing miR-184C57U mutant failed to repress K15 and FIH1 and to induce Notch activation, suggesting a loss-of-function mechanism. Altogether, we propose that, by targeting K15 and FIH1, miR-184 regulates the transition from proliferation to early differentiation, while mis-expression or mutation in miR-184 results in impaired homeostasis

The RESET project: constructing a European tephra lattice for refined synchronisation of environmental and archaeological events during the last c. 100 ka

This paper introduces the aims and scope of the RESET project (. RESponse of humans to abrupt Environmental Transitions), a programme of research funded by the Natural Environment Research Council (UK) between 2008 and 2013; it also provides the context and rationale for papers included in a special volume of Quaternary Science Reviews that report some of the project's findings. RESET examined the chronological and correlation methods employed to establish causal links between the timing of abrupt environmental transitions (AETs) on the one hand, and of human dispersal and development on the other, with a focus on the Middle and Upper Palaeolithic periods. The period of interest is the Last Glacial cycle and the early Holocene (c. 100-8 ka), during which time a number of pronounced AETs occurred. A long-running topic of debate is the degree to which human history in Europe and the Mediterranean region during the Palaeolithic was shaped by these AETs, but this has proved difficult to assess because of poor dating control. In an attempt to move the science forward, RESET examined the potential that tephra isochrons, and in particular non-visible ash layers (cryptotephras), might offer for synchronising palaeo-records with a greater degree of finesse. New tephrostratigraphical data generated by the project augment previously-established tephra frameworks for the region, and underpin a more evolved tephra 'lattice' that links palaeo-records between Greenland, the European mainland, sub-marine sequences in the Mediterranean and North Africa. The paper also outlines the significance of other contributions to this special volume: collectively, these illustrate how the lattice was constructed, how it links with cognate tephra research in Europe and elsewhere, and how the evidence of tephra isochrons is beginning to challenge long-held views about the impacts of environmental change on humans during the Palaeolithic. © 2015 Elsevier Ltd.RESET was funded through Consortium Grants awarded by the Natural Environment Research Council, UK, to a collaborating team drawn from four institutions: Royal Holloway University of London (grant reference NE/E015905/1), the Natural History Museum, London (NE/E015913/1), Oxford University (NE/E015670/1) and the University of Southampton, including the National Oceanography Centre (NE/01531X/1). The authors also wish to record their deep gratitude to four members of the scientific community who formed a consultative advisory panel during the lifetime of the RESET project: Professor Barbara Wohlfarth (Stockholm University), Professor Jørgen Peder Steffensen (Niels Bohr Institute, Copenhagen), Dr. Martin Street (Romisch-Germanisches Zentralmuseum, Neuwied) and Professor Clive Oppenheimer (Cambridge University). They provided excellent advice at key stages of the work, which we greatly valued. We also thank Jenny Kynaston (Geography Department, Royal Holloway) for construction of several of the figures in this paper, and Debbie Barrett (Elsevier) and Colin Murray Wallace (Editor-in-Chief, QSR) for their considerable assistance in the production of this special volume.Peer Reviewe

Deglacial landscapes and the Late Upper Palaeolithic of Switzerland

The presence of people in Switzerland in recently deglaciated landscapes after the Last Glacial Maximum represents human utilisation of newly available environments. Understanding these landscapes and the resources available to the people who exploited them is key to understanding not only Late Upper Palaeolithic settlement in Switzerland, but more broadly human behavioural ecology in newly inhabited environmental settings. By applying bone collagen stable isotope analysis (δ13C, δ15N and δ34S) to faunal remains from Late Upper Palaeolithic localities in Switzerland, we investigate animal ecology and environmental conditions during periods of human occupation. High and relatively uniform δ34S values indicate that landscapes north of the Jura Mountains provided comparatively stable environmental conditions, while lower and more variable δ34S values on the Swiss Plateau suggest a dynamic landscape with diverse hydrological and pedological conditions, potentially linked to regionally different patterns of permafrost thaw. This contrasts with the archaeological record that appears relatively uniform between the two regions, suggesting people were employing similar subsistence behaviours across a range of environmental settings. The pattern of change in δ15N across the deglacial period appears consistent between areas that remained ice-free throughout the LGM and those that were glaciated. Most notable is a period of exclusively low δ15N values between 15,200 and 14,800 cal. BP, which could relate a regional expansion of floral biomass in response to environmental change

Supplementary Material for: Multicenter Experience with Stenting for Symptomatic Carotid Web

<b><i>Background:</i></b> A carotid web (CaW) is a shelf-like lesion in the posterior aspect of the internal carotid bulb and represents an intimal variant of fibromuscular dysplasia. CaW has been associated with recurrent strokes and conventionally treated with surgical excision. We report a multicenter experience of stenting in patients with symptomatic CaWs. <b><i>Methods:</i></b> Retrospective review of consecutive patients admitted to 5 comprehensive stroke centers who were identified to have a symptomatic CaW and treated with carotid stenting. A symptomatic CaW was defined by the presence of a shelf-like/linear, smooth filling defect in the posterior aspect of the carotid bulb diagnosed by neck CT angiography (CTA) and confirmed with conventional angiography in patients with negative stroke workup. <b><i>Results:</i></b> Twenty-four patients with stented symptomatic CaW were identified (stroke in 83% and transient ischemic attack in 17%). Their median age was 47 years (IQR 41–61), 14 (58%) were female, and were 17 (71%) black. The degree of stenosis by NASCET was 0% (range 0–11). All patients were placed on dual antiplatelets and stented at a median of 9 days (IQR 4–35) after the last event. Closed-cell stents were used in 18 (75%) of the cases. No periprocedural events occurred with the exception of 2 cases of asymptomatic hypotension/bradycardia. Clinical follow-up after stent placement occurred for a median of 12 months (IQR 3–19) with no new cerebrovascular events noted. Functional independence at 90 days was achieved in 22 (91%) patients. Follow-up vascular imaging (ultrasound <i>n</i> = 18/CTA <i>n</i> = 5) was performed at a median of 10 months (IQR 3–18) and revealed no stenosis. <b><i>Conclusions:</i></b> Stenting for symptomatic CaW appears to be a safe and effective alternative to surgical resection. Further studies are warranted