Ireland and Brexit: Modelling the impact of deal and no-deal scenarios. Quarterly Economic Commentary Special Article, Spring 2019.

This Article attempts to quantify the macroeconomic impact of Brexit on the Irish economy. Given both the political and economic uncertainty, we consider a range of alternative scenarios. We focus on the most well understood channels through which Brexit will affect Ireland, namely though lower trade, incorporating the impact of tariff and non-tariff measures, and the potentially positive impact of FDI diversion to Ireland. Our approach, and the main contribution of this paper, is to build up estimates of each of these channels from a range of recent micro-economic studies, so our estimates are anchored in the empirical literature. We then use these micro-estimates to calibrate macro scenarios; specifically we generate alternative paths for the UK and international economy using the NiGEM global model and assess the impact on Ireland using the COSMO model. Overall, in each scenario, the level of Irish output is permanently below where it otherwise would have been were the UK to decide to remain in the EU

The prohibitin-repressive interaction with E2F1 is rapidly inhibited by androgen signalling in prostate cancer cells

Prohibitin (PHB) is a tumour suppressor molecule with pleiotropic activities across several cellular compartments including mitochondria, cell membrane and the nucleus. PHB and the steroid-activated androgen receptor (AR) have an interplay where AR downregulates PHB, and PHB represses AR. Additionally, their cellular locations and chromatin interactions are in dynamic opposition. We investigated the mechanisms of cell cycle inhibition by PHB and how this is modulated by AR in prostate cancer. Using a prostate cancer cell line overexpressing PHB, we analysed the gene expression changes associated with PHB-mediated cell cycle arrest. Over 1000 gene expression changes were found to be significant and gene ontology analysis confirmed PHB-mediated repression of genes essential for DNA replication and synthesis, for example, MCMs and TK1, via an E2F1 regulated pathway-agreeing with its G1/S cell cycle arrest activity. PHB is known to inhibit E2F1-mediated transcription, and the PHB:E2F1 interaction was seen in LNCaP nuclear extracts, which was then reduced by androgen treatment. Upon two-dimensional western blot analysis, the PHB protein itself showed androgen-mediated charge differentiation (only in AR-positive cells), indicating a potential dephosphorylation event. Kinexus phosphoprotein array analysis indicated that Src kinase was the main interacting intracellular signalling hub in androgen-treated LNCaP cells, and that Src inhibition could reduce this AR-mediated charge differentiation. PHB charge change may be associated with rapid dissociation from chromatin and E2F1, allowing the cell cycle to proceed. The AR and androgens may deactivate the repressive functions of PHB upon E2F1 leading to cell cycle progression, and indicates a role for AR in DNA replication licensing

Biocytin Recovery and 3D Reconstructions of Filled Hippocampal CA2 Interneurons

How cortical network activity processes information is of importance to a large number of basic 26 and clinical scientific questions. The protocol described here identifies the basic building blocks 27 of this circuitry. The in-depth studies of cortical regions will ultimately provide other scientists 28 with the circuit components needed for an understanding of how the brain acquires, processes 29 and stores information and what goes wrong in disease, while the electrophysiological and morphological data are widely used by computational neuroscientists in the construction of model networks that explore information processing. The protocol outlined here describes how biocytin-filled cells recorded in the CA2 region of the hippocampus are recovered and then reconstructed in 3D. Additionally, the protocol describes the demonstration of calcium binding protein or peptide content in recorded interneurons

Structural Changes Observed in the Piriform Cortex in a Rat Model of Pre-motor Parkinson’s Disease

Early diagnosis of Parkinson’s disease (PD) offers perhaps, the most promising route to a successful clinical intervention, and the use of an animal model exhibiting symptoms comparable to those observed in PD patients in the early stage of the disease, may facilitate screening of novel therapies for delaying the onset of more debilitating motor and behavioral abnormalities. In this study, a rat model of pre-motor PD was used to study the etiology of hyposmia, a non-motor symptom linked to the early stage of the disease when the motor symptoms have yet to be experienced. The study focussed on determining the effect of a partial reduction of both dopamine and noradrenaline levels on the olfactory cortex. Neuroinflammation and striking structural changes were observed in the model. These changes were prevented by treatment with a neuroprotective drug, a glucagon-like peptide-1 (GLP1) receptor agonist, exendin-4 (EX-4)

Sostdc1 deficiency accelerates fracture healing by promoting the expansion of periosteal mesenchymal stem cells

Loss of Sostdc1, a growth factor paralogous to Sost, causes the formation of ectopic incisors, fused molars, abnormal hair follicles, and resistance to kidney disease. Sostdc1 is expressed in the periosteum, a source of osteoblasts, fibroblasts and mesenchymal progenitor cells, which are critically important for fracture repair. Here, we investigated the role of Sostdc1 in bone metabolism and fracture repair. Mice lacking Sostdc1 (Sostdc1−/−) had a low bone mass phenotype associated with loss of trabecular bone in both lumbar vertebrae and in the appendicular skeleton. In contrast, Sostdc1−/− cortical bone measurements revealed larger bones with higher BMD, suggesting that Sostdc1 exerts differential effects on cortical and trabecular bone. Mid-diaphyseal femoral fractures induced in Sostdc1−/− mice showed that the periosteal population normally positive for Sostdc1 rapidly expands during periosteal thickening and these cells migrate into the fracture callus at 3 days post fracture. Quantitative analysis of mesenchymal stem cell (MSC) and osteoblast populations determined that MSCs express Sostdc1, and that Sostdc1−/− 5 day calluses harbor > 2-fold more MSCs than fractured wildtype controls. Histologically a fraction of Sostdc1-positive cells also expressed nestin and α-smooth muscle actin, suggesting that Sostdc1 marks a population of osteochondral progenitor cells that actively participate in callus formation and bone repair. Elevated numbers of MSCs in D5 calluses resulted in a larger, more vascularized cartilage callus at day 7, and a more rapid turnover of cartilage with significantly more remodeled bone and a thicker cortical shell at 21 days post fracture. These data support accelerated or enhanced bone formation/remodeling of the callus in Sostdc1−/− mice, suggesting that Sostdc1 may promote and maintain mesenchymal stem cell quiescence in the periosteum

The impact of COVID-19 public health restrictions on particulate matter pollution measured by a validated low-cost sensor network in Oxford, UK

Emergency responses to the COVID-19 pandemic led to major changes in travel behaviours and economic activities with arising impacts upon urban air quality. To date, these air quality changes associated with lockdown measures have typically been assessed using limited city-level regulatory monitoring data, however, low-cost air quality sensors provide capabilities to assess changes across multiple locations at higher spatial-temporal resolution, thereby generating insights relevant for future air quality interventions. The aim of this study was to utilise high-spatial resolution air quality information utilising data arising from a validated (using a random forest field calibration) network of 15 low-cost air quality sensors within Oxford, UK to monitor the impacts of multiple COVID-19 public heath restrictions upon particulate matter concentrations (PM10, PM2.5) from January 2020 to September 2021. Measurements of PM10 and PM2.5 particle size fractions both within and between site locations are compared to a pre-pandemic related public health restrictions baseline. While average peak concentrations of PM10 and PM2.5 were reduced by 9–10 μg/m3 below typical peak levels experienced in recent years, mean daily PM10 and PM2.5 concentrations were only ∼1 μg/m3 lower and there was marked temporal (as restrictions were added and removed) and spatial variability (across the 15-sensor network) in these observations. Across the 15-sensor network we observed a small local impact from traffic related emission sources upon particle concentrations near traffic-oriented sensors with higher average and peak concentrations as well as greater dynamic range, compared to more intermediate and background orientated sensor locations. The greater dynamic range in concentrations is indicative of exposure to more variable emission sources, such as road transport emissions. Our findings highlight the great potential for low-cost sensor technology to identify highly localised changes in pollutant concentrations as a consequence of changes in behaviour (in this case influenced by COVID-19 restrictions), generating insights into non-traffic contributions to PM emissions in this setting. It is evident that additional non-traffic related measures would be required in Oxford to reduce the PM10 and levels to within WHO health-based guidelines and to achieve compliance with PM2.5 targets developed under the Environment Act 2021

Conditional Deletion of Sost in MSC‐derived lineages Identifies Specific Cell Type Contributions to Bone Mass and B Cell Development

Sclerostin (Sost) is a negative regulator of bone formation and blocking its function via antibodies has shown great therapeutic promise by increasing both bone mass in humans and animal models. Sclerostin deletion in Sost knockout mice (Sost‐/‐) causes high bone mass (HBM) similar to Sclerosteosis patients. Sost‐/‐ mice have been shown to display an up to 300% increase in bone volume/total volume (BV/TV), relative to aged matched controls, and it has been postulated that the main source of skeletal Sclerostin is the osteocyte. To understand the cell‐type specific contributions to the HBM phenotype described in Sost‐/‐ mice, as well as to address the endocrine and paracrine mode of action of sclerostin, we examined the skeletal phenotypes of conditional Sost loss‐of‐function (SostiCOIN/iCOIN) mice with specific deletions in (1) the limb mesenchyme (Prx1‐Cre; targets osteoprogenitors and their progeny); (2) mid‐stage osteoblasts and their progenitors (Col1‐Cre); (3) mature osteocytes (Dmp1‐Cre) and (4) hypertrophic chondrocytes and their progenitors (ColX‐Cre). All conditional alleles resulted in significant increases in bone mass in trabecular bone in both the femur and lumbar vertebrae, but only Prx1‐Cre deletion fully recapitulated the amplitude of the HBM phenotype in the appendicular skeleton and the B cell defect described in the global knockout. Despite wildtype expression of Sost in the axial skeleton of Prx1‐Cre deleted mice, these mice also had a significant increase in bone mass in the vertebrae, but the Sclerostin released in circulation by the axial skeleton did not affect bone parameters in the appendicular skeleton. Also, both Col1 and Dmp1 deletion resulted in a similar 80% significant increase in trabecular bone mass, but only Col1 and Prx1 deletion resulted in a significant increase in cortical thickness. We conclude that several cell types within the Prx1‐osteoprogenitor derived lineages contribute significant amounts of Sclerostin protein to the paracrine pool of Sost, in bone