Differentiated Human Midbrain-Derived Neural Progenitor Cells Express Excitatory Strychnine-Sensitive Glycine Receptors Containing α2β Subunits

BACKGROUND: Human fetal midbrain-derived neural progenitor cells (NPCs) may deliver a tissue source for drug screening and regenerative cell therapy to treat Parkinson's disease. While glutamate and GABA(A) receptors play an important role in neurogenesis, the involvement of glycine receptors during human neurogenesis and dopaminergic differentiation as well as their molecular and functional characteristics in NPCs are largely unknown. METHODOLOGY/PRINCIPAL FINDINGS: Here we investigated NPCs in respect to their glycine receptor function and subunit expression using electrophysiology, calcium imaging, immunocytochemistry, and quantitative real-time PCR. Whole-cell recordings demonstrate the ability of NPCs to express functional strychnine-sensitive glycine receptors after differentiation for 3 weeks in vitro. Pharmacological and molecular analyses indicate a predominance of glycine receptor heteromers containing α2β subunits. Intracellular calcium measurements of differentiated NPCs suggest that glycine evokes depolarisations mediated by strychnine-sensitive glycine receptors and not by D-serine-sensitive excitatory glycine receptors. Culturing NPCs with additional glycine, the glycine-receptor antagonist strychnine, or the Na(+)-K(+)-Cl(-) co-transporter 1 (NKCC1)-inhibitor bumetanide did not significantly influence cell proliferation and differentiation in vitro. CONCLUSIONS/SIGNIFICANCE: These data indicate that NPCs derived from human fetal midbrain tissue acquire essential glycine receptor properties during neuronal maturation. However, glycine receptors seem to have a limited functional impact on neurogenesis and dopaminergic differentiation of NPCs in vitro

Metabolic inactivation of estrogens in breast tissue by UDP-glucuronosyltransferase enzymes: an overview

The breast tissue is the site of major metabolic conversions of estradiol (E(2)) mediated by specific cytochromes P450 hydroxylations and methylation by catechol-O-methytransferase. In addition to E(2 )itself, recent findings highlight the significance of 4-hydroxylated estrogen metabolites as chemical mediators and their link to breast cancer development and progression, whereas, in opposition, 2-methoxylated estrogens appear to be protective. Recent data also indicate that breast tissue possesses enzymatic machinery to inactivate and eliminate E(2 )and its oxidized and methoxylated metabolites through conjugation catalyzed by UDP-glucuronosyltransferases (UGTs), which involves the covalent addition of glucuronic acid. In opposition to other metabolic pathways of estrogen, the UGT-mediated process leads to the formation of glucuronides that are devoid of biologic activity and are readily excreted from the tissue into the circulation. This review addresses the most recent findings on the identification of UGT enzymes that are responsible for the glucuronidation of E(2 )and its metabolites, and evidence regarding their potential role in breast cancer

The impact of viral mutations on recognition by SARS-CoV-2 specific T cells.

We identify amino acid variants within dominant SARS-CoV-2 T cell epitopes by interrogating global sequence data. Several variants within nucleocapsid and ORF3a epitopes have arisen independently in multiple lineages and result in loss of recognition by epitope-specific T cells assessed by IFN-γ and cytotoxic killing assays. Complete loss of T cell responsiveness was seen due to Q213K in the A∗01:01-restricted CD8+ ORF3a epitope FTSDYYQLY207-215; due to P13L, P13S, and P13T in the B∗27:05-restricted CD8+ nucleocapsid epitope QRNAPRITF9-17; and due to T362I and P365S in the A∗03:01/A∗11:01-restricted CD8+ nucleocapsid epitope KTFPPTEPK361-369. CD8+ T cell lines unable to recognize variant epitopes have diverse T cell receptor repertoires. These data demonstrate the potential for T cell evasion and highlight the need for ongoing surveillance for variants capable of escaping T cell as well as humoral immunity.This work is supported by the UK Medical Research Council (MRC); Chinese Academy of Medical Sciences(CAMS) Innovation Fund for Medical Sciences (CIFMS), China; National Institute for Health Research (NIHR)Oxford Biomedical Research Centre, and UK Researchand Innovation (UKRI)/NIHR through the UK Coro-navirus Immunology Consortium (UK-CIC). Sequencing of SARS-CoV-2 samples and collation of data wasundertaken by the COG-UK CONSORTIUM. COG-UK is supported by funding from the Medical ResearchCouncil (MRC) part of UK Research & Innovation (UKRI),the National Institute of Health Research (NIHR),and Genome Research Limited, operating as the Wellcome Sanger Institute. T.I.d.S. is supported by a Well-come Trust Intermediate Clinical Fellowship (110058/Z/15/Z). L.T. is supported by the Wellcome Trust(grant number 205228/Z/16/Z) and by theUniversity of Liverpool Centre for Excellence in Infectious DiseaseResearch (CEIDR). S.D. is funded by an NIHR GlobalResearch Professorship (NIHR300791). L.T. and S.C.M.are also supported by the U.S. Food and Drug Administration Medical Countermeasures Initiative contract75F40120C00085 and the National Institute for Health Research Health Protection Research Unit (HPRU) inEmerging and Zoonotic Infections (NIHR200907) at University of Liverpool inpartnership with Public HealthEngland (PHE), in collaboration with Liverpool School of Tropical Medicine and the University of Oxford.L.T. is based at the University of Liverpool. M.D.P. is funded by the NIHR Sheffield Biomedical ResearchCentre (BRC – IS-BRC-1215-20017). ISARIC4C is supported by the MRC (grant no MC_PC_19059). J.C.K.is a Wellcome Investigator (WT204969/Z/16/Z) and supported by NIHR Oxford Biomedical Research Centreand CIFMS. The views expressed are those of the authors and not necessarily those of the NIHR or MRC

Effects of closed circuit television surveillance on crime

Closed circuit television (CCTV) surveillance cameras serve many functions and are used in both public and private settings. The prevention of personal and property crime is among the primary objectives in public space, which is the main focus of this review. CCTV is viewed as a technique of “formal surveillance” and in this regard it is seen to enhance or take the place of security personnel. Results of this review indicate that CCTV has a modest but significant desirable effect on crime, is most effective in reducing crime in car parks, is most effective when targeted at vehicle crimes (largely a function of the successful car park schemes), and is more effective in reducing crime in the United Kingdom than in other countries. These results lend support for the continued use of CCTV to prevent crime in public space, but suggest that it be more narrowly targeted than its present use would indicate. Future CCTV schemes should employ high-quality evaluation designs with long follow-up periods

Identifying change over time in small area socio-economic deprivation

The measurement of area level deprivation is the subject of a wide and ongoing debate regarding the appropriateness of the geographical scale of analysis, the input indicator variables and the method used to combine them into a single figure index. Whilst differences exist, there are strong correlations between schemes. Many policy-related and academic studies use deprivation scores calculated cross-sectionally to identify areas in need of regeneration and to explain variations in health outcomes. It would be useful then to identify whether small areas have changed their level of deprivation over time and thereby be able to: monitor the effect of industry closure; assess the impact of area-based planning initiatives; or determine whether a change in the level of deprivation leads to a change in health. However, the changing relationship with an outcome cannot be judged if the ‘before’ and ‘after’ situations are based on deprivation measures which use different, often time-point specific variables, methods and geographies. Here, for the whole of the UK, inputs to the Townsend index obtained from the 1991 and 2001 Censuses have been harmonised in terms of variable detail and with the 1991 data converted to the 2001 Census ward geography. Deprivation has been calculated so that the 1991 scores are directly comparable with those for 2001. Change over time can be then identified. Measured in this way, deprivation is generally shown to have eased due to downward trends in levels of lack of access to a car, non-home ownership, household overcrowding but most particularly, to reductions in levels of unemployment. Despite these trends, not all locations became less deprived with gradients of deprivation largely persisting within the UK’s constituent countries and in different area types. For England, Wales and Scotland, the calculation of Townsend scores can readily be backdated to incorporate data from the 1971 and 1981 Censuses to create a 1971–2001 set of comparable deprivation scores. The approach can also be applied to the Carstairs index. Due to differences in data availability prior to 1991, incorporating small areas in Northern Ireland would be challenging

Host testing, establishment and biology of the gorse soft shoot moth, Agonopterix umbellana (Fabricius) (Lepidoptera: Oecophoridae), a potential biological control agent for gorse, Ulex europaeus L. (Fabaceae), in Australia

Host specificity tests on over 250 species or cultivars of plants including 37 Australian native and introduced plant species or cultivars showed that the gorse soft shoot moth, Agonopterix umbellana, would be unlikely to survive on any plant other than gorse in Australia. The first field release was at Jericho, Tasmania during spring 2007. By the summer of 2013 high larval densities of A. umbellana were evident at the release point, with dispersal recorded to a maximum of 200 m over ca. 2 ha. Recoveries at other release sites in Tasmania as well as in South Australia and Victoria suggest that the species will eventually establish across south-eastern Australia. The life cycle of A. umbellana is closely synchronised with gorse phenology. Population increase and dispersal is expected to be slow as a consequence of its univoltine life cycle incorporating the narrow larval feeding period of 3 months when gorse is a suitable food source. At Jericho, oviposition commenced in late winter which enabled hatching to coincide with the presence of new gorse growth for developing larvae. Larvae fed over a 3 month period on new growth available from mid-October to mid-January passing through six instars before pupation. The first adults were recorded in early February emerging in an obligate reproductive diapause which was completed by late July. Controlled temperature cabinets held at 12, 15, 18, 21 and 24 Celsius degree were used to estimate lower development thresholds (LDT) and thermal constants. The LDT for eggs larvae, pupae and total development were 8.7, 7.5, 7.9 and 7.9 Celsius degree, respectively and the thermal constants were 143.0 , 526.3 , 278.0 and 971.0 degree days respectively. In the long term, it is hoped that A. umbellana will contribute to the biological control of gorse in Australia. This will be in combination with the gorse seed weevil, Exapion ulicis, the gorse spider mite, Tetranychus lintearius and the gorse thrips, Sericothips staphylinus, even though earlier studies have shown these other agents are constrained either by predation in the case of T. lintearius or the effects of gorse phenology in the case of S. staphylinus and E. ulicis