Neuropilin-mediated neural crest cell guidance is essential to organise sensory neurons into segmented dorsal root ganglia

The peripheral nervous system (PNS) of higher vertebrates is segmented to align the spinal nerve roots with the vertebrae. This co-patterning is set up during embryogenesis, when vertebrae develop from the sclerotome layer of the metameric somites, and PNS neurons and glia differentiate from neural crest cells (NCCs) that preferentially migrate into the anterior sclerotome halves. Previous analyses of mice deficient in the class 3 semaphorin (SEMA3) receptors neuropilin (NRP) 1 or 2 raised the possibility that each controlled a distinct aspect of trunk NCC migration. We now demonstrate that both pathways act sequentially in distinct NCC subpopulations and thereby cooperate to enforce segmental NCC migration. Specifically, SEMA3A/NRP1 signalling first directs one population of NCCs from the intersomitic path into the sclerotome, and SEMA3F/NRP2 signalling acts subsequently to restrict a second population to the anterior half of the sclerotome. NCC exclusion from either the posterior sclerotome or the intersomitic boundary is sufficient to enforce the separation of neighbouring NCC streams and the segregation of sensory NCC progeny into metameric dorsal root ganglia (DRG). By contrast, the combined loss of both guidance pathways leads to ectopic invasion of the intersomitic furrows and posterior sclerotome halves, disrupting metameric NCC streaming and DRG segmentation

Neuropilin 1 signaling guides neural crest cells to coordinate pathway choice with cell specification

Neural crest cells (NCCs) are highly motile embryonic stem cells that delaminate from the neuroectoderm early during vertebrate embryogenesis and differentiate at defined target sites into various essential cell types. To reach their targets, NCCs follow 1 of 3 sequential pathways that correlate with NCC fate. The firstborn NCCs travel ventrally alongside intersomitic blood vessels to form sympathetic neuronal progenitors near the dorsal aorta, while the lastborn NCCs migrate superficially beneath the epidermis to give rise to melanocytes. Yet, most NCCs enter the somites to form the intermediate wave that gives rise to sympathetic and sensory neurons. Here we show that the repulsive guidance cue SEMA3A and its receptor neuropilin 1 (NRP1) are essential to direct the intermediate wave NCC precursors of peripheral neurons from a default pathway alongside intersomitic blood vessels into the anterior sclerotome. Thus, loss of function for either gene caused excessive intersomitic NCC migration, and this led to ectopic neuronal differentiation along both the anteroposterior and dorsoventral axes of the trunk. The choice of migratory pathway did not affect the specification of NCCs, as they retained their commitment to differentiate into sympathetic or sensory neurons, even when they migrated on an ectopic dorsolateral path that is normally taken by melanocyte precursors. We conclude that NRP1 signaling coordinates pathway choice with NCC fate and therefore confines neuronal differentiation to appropriate locations

Molecular mechanisms controlling neurovascular patterning

The vascular system delivers oxygen and nutrients to tissues throughout the developing organism, including the nervous system. Vice versa, the nervous system innervates resistance arteries to modulate vascular function. The two systems share several guidance cues and cell-­‐surface receptors. One receptor is neuropilin 1 (NRP1), which is present on blood vessels and neurons. The sympathetic nervous system is a neural crest cell (NCC)-­‐derived structure that innervates the heart and blood vessels to modulate heart rate and vasoconstriction. Semaphorin3A (SEMA3A) signals through NRP1 to pattern the axonal projections of sympathetic nerves. I show here that this signalling pathway also controls the earliest stage of sympathetic nervous system development -­‐ sympathetic NCC migration through the somites. Accordingly, sympathetic NCCs stray into ectopic territories and differentiate into sympathetic neurons in mice with disrupted NRP1/SEMA3A signalling. I also show that NRP2/SEMA3F signalling provides a backup pathway for NRP1/SEMA3A signalling in sympathetic NCC guidance. I further show defective sympathetic innervation of the heart and dorsal aorta in postnatal mice with disrupted NRP1/SEMA3A signalling and describe a previously unidentified role for NRP2 in sympathetic axon guidance. I found that the recently discovered SEMA3G does not play a part in sympathetic axon guidance to target arteries, despite its unique arterial expression. The alternative NRP1 ligand, a vascular endothelial growth factor isoform termed VEGF164, is essential for the sprouting of new blood vessels from existing ones in a process called angiogenesis. A large body of in vitro evidence suggests that heparan sulphate proteoglycans (HSPGs) are required for VEGF164 -­‐driven angiogenesis by promoting its interaction with its receptors VEGFR1, VEGFR2 and NRP1. In vivo data supporting the idea that HSPGs are essential for angiogenesis, however, are sparse. I here found that mouse embryos lacking enzymes required for the sulphation of HSPGs, or lacking enzymes essential for HSPG production in specific cells, had no obvious vascular branching defects in the hindbrain and do not phenocopy mutants lacking VEGF164. These observations suggest that HSPGs are not essential for VEGF164-­‐driven angiogenesis. In contrast, I found that the VEGF164/NRP1 guided migration of facial branchiomotor neurons was dependent on the presence of HSPGs. Taken together, these results provide evidence for the differential requirement of HSPGs in VEGF164-­‐driven neural, but not endothelial cell patterning in the hindbrain

¹⁴C AMS at SUERC: improving QA data from the 5 MV tandem AMS and 250 kV SSAMS

In 2003, a National Electrostatics Corporation (NEC) 5MV tandem accelerator mass spectrometer was installed at SUERC, providing the radiocarbon laboratory with 14C measurements to 4–5‰ repeatability. In 2007, a 250kV single-stage accelerator mass spectrometer (SSAMS) was added to provide additional 14C capability and is now the preferred system for 14C analysis. Changes to the technology and to our operations are evident in our copious quality assurance data: typically, we now use the 134-position MC-SNICS source, which is filled to capacity. Measurement of standards shows that spectrometer running without the complication of on-line δ13C evaluation is a good operational compromise. Currently, 3‰ 14C/13C measurements are routinely achieved for samples up to nearly 3 half-lives old by consistent sample preparation and an automated data acquisition algorithm with sample random access for measurement repeats. Background and known-age standard data are presented for the period 2003–2008 for the 5MV system and 2007–2008 for the SSAMS, to demonstrate the improvements in data quality

Cosmogenic 10Be chronology of the last deglaciation of western Ireland, and implications for sensitivity of the Irish Ice Sheet to climate change

Accelerator mass spectrometry (AMS) 14C dates of fossiliferous marine mud identify a readvance of the Irish Ice Sheet from the north and central lowlands of Ireland into the northern Irish Sea Basin during the Killard Point Stadial at ca. 16.5 cal k.y. B.P., with subsequent deglaciation occurring by ca. 15.0–15.5 cal k.y. B.P. Killard Point Stadial moraines have been mapped elsewhere in Ireland but have previously remained undated. Here, we report sixteen 10Be surface exposure dates that constrain the age of retreat of the Killard Point Stadial ice margin from western Ireland. Eight 10Be dates from the Ox Mountains (13.9–18.1 ka) indicate that fi nal deposition of the moraine occurred at 15.6 ± 0.5 ka (mean age, standard error). Eight 10Be dates from Furnace Lough (14.1–17.3 ka, mean age of 15.6 ± 0.4 ka) are statistically indistinguishable from the Ox Mountain samples, suggesting that the moraines were deposited during the same glacial event. Given the agreement between the two age groups, and their common association with a regionally signifi cant moraine system, we combine them to derive a mean age of 15.6 ± 0.3 ka (15.6 ± 1.0 ka with external uncertainty). This age is in excellent agreement with the timing of deglaciation from the Irish Sea Basin (at or older than 15.3 ± 0.2 cal k.y. B.P.) and suggests the onset of near-contemporaneous retreat of the Irish Ice Sheet from its maximum Killard Point Stadial limit. A reconstruction of the ice surface indicates that the Irish Ice Sheet reached a maximum surface elevation of ~500 m over the central Irish Lowlands during the Killard Point Stadial, suggesting a high sensitivity of the ice sheet to small changes in climate

Cosmogenic 10Be chronology of the last deglaciation of western Ireland, and implications for sensitivity of the Irish Ice Sheet to climate change

Accelerator mass spectrometry (AMS) 14C dates of fossiliferous marine mud identify a readvance of the Irish Ice Sheet from the north and central lowlands of Ireland into the northern Irish Sea Basin during the Killard Point Stadial at ca. 16.5 cal k.y. B.P., with subsequent deglaciation occurring by ca. 15.0–15.5 cal k.y. B.P. Killard Point Stadial moraines have been mapped elsewhere in Ireland but have previously remained undated. Here, we report sixteen 10Be surface exposure dates that constrain the age of retreat of the Killard Point Stadial ice margin from western Ireland. Eight 10Be dates from the Ox Mountains (13.9–18.1 ka) indicate that fi nal deposition of the moraine occurred at 15.6 ± 0.5 ka (mean age, standard error). Eight 10Be dates from Furnace Lough (14.1–17.3 ka, mean age of 15.6 ± 0.4 ka) are statistically indistinguishable from the Ox Mountain samples, suggesting that the moraines were deposited during the same glacial event. Given the agreement between the two age groups, and their common association with a regionally signifi cant moraine system, we combine them to derive a mean age of 15.6 ± 0.3 ka (15.6 ± 1.0 ka with external uncertainty). This age is in excellent agreement with the timing of deglaciation from the Irish Sea Basin (at or older than 15.3 ± 0.2 cal k.y. B.P.) and suggests the onset of near-contemporaneous retreat of the Irish Ice Sheet from its maximum Killard Point Stadial limit. A reconstruction of the ice surface indicates that the Irish Ice Sheet reached a maximum surface elevation of ~500 m over the central Irish Lowlands during the Killard Point Stadial, suggesting a high sensitivity of the ice sheet to small changes in climate

Evaluating the impact of clinical librarian services in the North West

BackgroundClinical librarians “provide quality assured information to health professionals at the point of need to support clinical decision making”, (Hill, 2008) and in the UK tend to follow an outreach model which delivers services such as literature searching and training across hospital Trusts (Brettle et al 2011). A number of systematic reviews have examined the effectiveness of clinical librarians (Weightman, Urquhart, Spink, & Thomas 2008; Winning & Beverley 2003) but have found them lacking. A review conducted by a group of librarians within the North West; examined methods of evaluating clinical librarian services as well as providing an update of the literature on effectiveness (Brettle et al 2011). This report describes a follow up study to the North West systematic review which seeks to put its recommendations into practice and aims to:•Undertake a rigorous mixed methods evaluation study on the impact of Clinical Librarian services in the North West health region.Objectives•To use a framework that ensures consistent and robust data is collected across all NHS Trusts, providing an increased body of evidence.•To test the use of the MAP (Making Alignment a Priority) Toolkit in ensuring that evaluations meet organisational objectives.•To build research capacity amongst a group of clinical librariansMethodsThis evaluation study was based on best available evidence on how to conduct evaluations in this field (Brettle et al 2011). The services provided by Clinical librarians (CLs) are considered a complex intervention made up of a number of elements and wide ranging potential outcomes which are affected by other factors within the organisation. An experimental design to ascertain their effectiveness and impact is inappropriate and would be compromised by a wide range of confounding variables. This study is therefore based on the premise that CLs contribute to a range of outcomes and organisational objectives. A critical incident technique (CIT) was therefore used to understand and collect data on these contributions and their impact using a mixed methods approach.A regionwide survey linked to organisational outcomes was used to collect data on all uses of the CL service over a 6 month period. This was followed by structured interviews with service users from the subsequent 6 month period to triangulate, illustrate, and illuminate the questionnaire findings.Built into the design of the study was a capacity building element to improve research and evaluation skills in a group of clinical librarians. The research was undertaken with the librarians who participated in a number of ways e.g. questionnaire design, conducting interviews, analysing data, presenting results, receiving training and using standardised tools as appropriate throughout.ResultsA total of 10 librarians took part, representing 16 Trusts. They sent out 779 questionnaires over a 6 month period (all users of the service in this time). Then 24 interviews were conducted with a purposive sample which covered a range of Trusts and professionals who had used the service in the subsequent 6 month period. Over 340 critical incidents were collected which demonstrated that CLs contribute to a wide range of outcomes. The outcomes were separated into 6 categories which reflected NHS priorities and objectives: Decision making and evidence based practice; Patient centred care and health outcomes; Quality of care; Service development; Continuing professional development (CPD); Efficiency, financial or risk management. Within each of these categories, data on more specific outcomes were collected.The 10 most reported impacts and the number of times they were reported are listed in the chart below.In line with the services traditionally provided by NHS library services the majority of these fall within the Continuing Professional Development and the Decision Making and Evidence Based Practice categories of outcomes. However, it is of significant note that based on responses to the question “Did the service provided contribute to…”:•1/3 incidents demonstrated that CLs contribute directly to patient outcomes such as diagnosis and choice of intervention or test.•1/4 incidents demonstrated that CLs contribute directly to improvements in quality of life, increased patient involvement in decision making and improved access to patient information.•1/4 incidents demonstrated that CLs contribute to cost savings and risk management and more specifically 20% in avoiding tests, referrals and readmissions and 14% in reducing length of stay (LoS).The questionnaires also provided evidence on what outcomes the CLs “may contribute to in the future”. The responses to these were even higher, with the interviews suggesting that the reason for this is that much of the information provided will contribute to outcomes over the long term, e.g. guideline development.The interviews illustrated the complexity of the incidents and the wide range of outcomes to which the CLs contribute from one incident. In addition, the interviews illuminated how these contributions are made.The questionnaire proved to be a useful tool for collecting outcome data, but feedback from participants and data from the interviews demonstrated that some refinements need to be made.The study was successful in further developing the research skills of the clinical librarians involved in the project. ConclusionsClinical librarians contribute to a wide range of outcomes including those which affect direct patient care and save money within NHS organisations.The multi-method approach was successful in aligning CL contributions to organisational outcomes and providing more detail about the CL contribution than previous studies.Recommendations for a revised questionnaire and a common data set are made. Future evaluations are urged to use this approach and collect data on the same outcomes which will further add to the evidence base about the effectiveness and impact of clinical librarians

Management of Fecal Incontinence in Older People With Dementia Resident in Care Homes: A Realist Synthesis-The FINCH Study.

This document is the Accepted Manuscript version of the Editorial to Journal of the American Medical Directors Association, Vol. 198 (9):750-751. Under embargo. Embargo end date: 21 July 2018. The published version is available online at doi: https://doi.org/10.1016/j.jamda.2017.06.001. Crown Copyright © 2017 Published by Elsevier Inc. on behalf of AMDA - The Society for Post-Acute and Long-Term Care Medicine.Peer reviewe