Defective monocyte plasticity and altered cAMP pathway characterize USB1-mutated poikiloderma with neutropenia Clericuzio type.

Poikiloderma with neutropenia (PN) Clericuzio type (OMIM #604173) is a rare disease with areas of skin hyper- and hypopigmentation caused by biallelic USB1 variants. The current study was spurred by poor healing of a perianal tear wound in one affected child homozygous for c.266-1G>A (p.E90Sfster8) mutation, from a family reported previously. Treatment with G-CSF/CSF3 or GM-CSF/CSF2 transiently increased neutrophil/monocytes count with no effect on wound healing. Analysis of peripheral blood revealed a lack of non-classical (CD14+/- CD16+ ) monocytes, associated with a systemic inflammatory cytokine profile, in the two affected brothers. Importantly, despite normal expression of cognate receptors, monocytes from PN patients did not respond to M-CSF or IL-34 in vitro, as determined by cytokine secretion or CD16 expression. RNAseq of monocytes showed 293 differentially expressed genes, including significant downregulation of GATA2, AKAP6 and PDE4DIP that are associated with leucocyte differentiation and cyclic adenosine monophosphate (cAMP) signalling. Notably, the plasma cAMP was significantly low in the PN patients. Our study revealed a novel association of PN with a lack of non-classical monocyte population. The defects in monocyte plasticity may contribute to disease manifestations in PN and a defective cAMP signalling may be the primary effect of the splicing errors caused by USB1 mutation.

Senescence-associated secretory proteins induced in lung adenocarcinoma by extended treatment with dexamethasone enhance migration and activation of lymphocytes.

There is a need to improve response rates of immunotherapies in lung adenocarcinoma (AC). Extended (7-14 days) treatment of high glucocorticoid receptor (GR) expressing lung AC cells with dexamethasone (Dex) induces an irreversible senescence phenotype through chronic induction of p27. As the senescence-associated secretory phenotype (SASP) may have either tumor supporting or antitumor immunomodulatory effects, it was interest to examine the effects of Dex-induced senescence of lung AC cells on immune cells. Dex-induced senescence resulted in sustained production of CCL2, CCL4, CXCL1 and CXCL2, both in vitro and in vivo. After Dex withdrawal, secretion of these chemokines by the senescent cells attracted peripheral blood monocytes, T-cells, and NK cells. Following treatment with Dex-induced SASP protein(s), the peripheral blood lymphocytes exhibited higher cell count and tumor cytolytic activity along with enhanced Ki67 and perforin expression in T and NK cells. This cytolytic activity was partially attributed to NKG2D, which was upregulated in NK cells by SASP while its ligand MICA/B was upregulated in the senescent cells. Enhanced infiltrations of T and NK cells were observed in human lung AC xenografts in humanized NSG mice, following treatment with Dex. The findings substantiate the idea that induction of irreversible senescence in high-GR expressing subpopulations of lung AC tumors using Dex pretreatment enhances tumor immune infiltration and may subsequently improve the clinical outcome of current immunotherapies.

Effect of Retirement on Cognition: Evidence From the Irish Marriage Bar.

This study empirically investigates the relationship between retirement duration and cognition among older Irish women using microdata collected in the third wave of The Irish Longitudinal Study on Ageing. Ordinary least squares (OLS) regression estimates indicate that the longer an individual has been retired, the lower the cognitive functioning, with other factors thought to affect cognition held constant (e.g., age, education, and early-life socioeconomic conditions). However, retirement is potentially endogenous with respect to cognition because cognition may affect decisions relating to retiring. If so, the OLS estimates will be biased. To test for this possibility, instrumental variable (IV) estimation is used. This method requires an IV that is highly correlated with retirement duration but not correlated with cognition. The instrument used in this study is based on the so-called marriage bar, the legal requirement that women leave paid employment upon getting married, which took effect in Ireland in the 1930s and was abolished only in the 1970s. The IV regression estimates, along with formal statistical tests, provide no evidence in support of the view that cognition affects retirement decisions. The finding of a small negative effect of retirement duration on cognition is robust to alternative empirical specifications. These findings are discussed in the wider context of the effects of work-like and work-related activities on cognition.

Targeting ABCG1 and SREBP-2 mediated cholesterol homeostasis ameliorates Zika virus-induced ocular pathology.

Zika virus (ZIKV) infection during pregnancy causes severe neurological and ocular abnormalities in infants, yet no vaccine or antivirals are available. Our transcriptomic analysis of ZIKV-infected retinal pigment epithelial (RPE) cells revealed alterations in the cholesterol pathway. Thus, we investigated the functional roles of ATP binding cassette transporter G1 (ABCG1) and sterol response element binding protein 2 (SREPB-2), two key players in cholesterol metabolism, during ocular ZIKV infection. Our in vitro data showed that increased ABCG1 activity via liver X receptors (LXRs), reduced ZIKV replication, while ABCG1 knockdown increased replication with elevated intracellular cholesterol. Conversely, inhibiting SREBP-2 or its knockdown reduced ZIKV replication by lowering cholesterol levels. In vivo, LXR agonist or SREBP-2 inhibitor treatment mitigated ZIKV-induced chorioretinal lesions in mice, concomitant with decreased expression of inflammatory mediators and increased activation of antiviral response genes. In summary, our study identifies ABCG1's antiviral role and SREBP-2's proviral effects in ocular ZIKV infection, offering cholesterol metabolism as a potential target to develop antiviral therapies.

National and international graduate migration flows.

This article examines the nature of national and international graduate migration flows in the UK. Migration equations are estimated with microdata from a matched dataset of Students and Destinations of Leavers from Higher Education, information collected by the Higher Education Statistical Agency. The probability of migrating is related to a set of observable characteristics using multinomial logit regression. The analysis suggests that migration is a selective process with graduates with certain characteristics having considerably higher probabilities of migrating, both to other regions of the UK and abroad.

Supraclavicular approach to brachial plexus block using fluoroscopic anatomic landmarks and nerve stimulation.

Irritation of neural structures, specifically the brachial plexus outside of the cervical spine is capable of producing pain in the upper extremity. These pain patterns may be similar to pain originating from the cervical spine, presenting a diagnostic challenge. Brachial plexus block is performed at multiple levels, including interscalene, supraclavicular, infraclavicular, and axillary. Interscalene block is frequently utilized by interventional pain management physicians for diagnostic and therapeutic purposes to isolate and manage the brachial plexus as a pain generator. The traditional methods employed in performing interscalene or supraclavicular brachial plexus blocks are associated with multiple disadvantages. A new technique is described to meet five essential requirements encompassing safety, specificity, consistency, reproducibility and a high success rate. Relevant anatomy and proposed technique of brachial plexus block is described. The procedure is performed under fluoroscopy with contrast injection. It is concluded that the proposed technique of brachial plexus block is useful for brachial plexus blockade providing precision and specificity with minimal complications.

Estimating the economic value of improvements in river ecology using choice experiments: an application to the water framework directive.

The Water Framework Directive is a major regulatory reform of water resources management within the European Union. Integrated catchment management plans must be prepared for all river basins, in order to achieve 'good ecological status' in all EU waters. Ecological status is a broader measure of water quality than the chemical and biological measures that were previously dominant. The Directive calls for a consideration of the economic costs and benefits of improvements to ecological status. In this paper, we use the choice experiment method to estimate the value of improvements in three components of ecological status. Given the high resource cost of valuation studies, benefits transfer methods will be needed in implementing the Directive. We thus also test the ability of choice experiments for benefits transfer across two very similar rivers in the UK.