Functional characterisation of the human S1P₄G protein-coupled receptor

The human G protein-coupled receptor (GPCR) S1P4 (formerly named Edg6) was identified as an orphan receptor and assigned to the Edg family on the basis of sequence similarity with other Edg receptors. S1P4 was recently shown to couple to Gαi and Gα12/13 G proteins in response to stimulation by the lysophospholipid, sphingosine-1-phosphate (S1P). This thesis describes functional characterisation of the S1P4 receptor using a modified [35S]GTPγS binding assay. CHO-K1 cells were stably transfected to express S1P4, or a fusion protein between S1P4 and a pertussis toxin-resistant form of Gαi1. S1P4 exhibited significant constitutive activity and treatment with SIP or phytoSIP further stimulated the receptor in a dose-dependent manner. Pertussis toxin treatment demonstrated that both S1P4 constitutive activity and the effects of SIP were transduced via endogenous Gαi G proteins, whilst the SlP4-Gαi1 fusion signalled via the tethered, pertussis toxin-insensitive G protein. Residue was shown to be important in governing S1P4 ligand selectivity; mutation of the naturally occurring glutamic acid to glutamine attenuated the ability of the receptor to respond to S1P and conferred sensitivity to the related compound, lysophosphatidic acid. Since most cell types express endogenous S1P and LPA family receptors, the profile of Edg family receptor expression in CHO-K1 cells was investigated. Transcripts for S1P1,2,4 and LPA1 receptors were detected using RT-PCR with species-specific oligonucleotides. Further investigations into S1P4 constitutive activity, which were undertaken using an inducible expression system, demonstrated direct correlation between S1P4 expression and constitutive activity. This suggested that S1P4 constitutive activity represents an inherent property of this receptor. In common with other naturally constitutively active GPCRs, S1P4 lacks a generally conserved cysteine residue within the first extracellular loop. It is proposed that this may account for S1P4 constitutive activity and may be relevant to the in vivo function of this receptor

How online sexual health services could work; generating theory to support development.

BACKGROUND: Online sexual health services are an emerging area of service delivery. Theory of change critically analyses programmes by specifying planned inputs and articulating the causal pathways that link these to anticipated outcomes. It acknowledges the changing and contested nature of these relationships. METHODS: We developed two versions of a theory of change for an online sexual health service. The first articulated the theory presented in the original programme proposal and the second documented its development in the early stages of implementation through interviews with key programme stakeholders. RESULTS: The programme proposal described an autonomous and empowered user completing a sexual health check using a more convenient, accessible and discreet online service and a shift from clinic based to online care. The stakeholder interviews confirmed this and described new and more complex patterns of service use as the online service creates opportunities for providers to contact users outside of the traditional clinic visit and users move between online and clinic based care. They described new types of user/provider relationships which we categorised as: those influenced by an online retail culture; those influenced by health promotion outreach and surveillance and those acknowledging the need for supported access. CONCLUSIONS: This analysis of stakeholder views on the likely the impacts of online sexual health services suggests three areas for further thinking and research. 1. Co-development of clinic and online services to support complex patterns of service use. 2. Developing access to online services for those who could use them with support. 3. Understanding user experience of sexual health services as increasing user autonomy and choice in some situations; creating exclusion and a need for support in others and intrusiveness and a lack of control in still others. This work has influenced the evaluation of this programme which will focus on; mapping patterns of use to understand how users move between the online and clinic based services; barriers to use of online services among some populations and how to overcome these; understanding user perceptions of autonomy in relation to online services

Web-Based Activity Within a Sexual Health Economy: Observational Study.

BACKGROUND: Regular testing for sexually transmitted infections (STIs) is important to maintain sexual health. Self-sampling kits ordered online and delivered in the post may increase access, convenience, and cost-effectiveness. Sexual health economies may target limited resources more effectively by signposting users toward Web-based or face-to-face services according to clinical need. OBJECTIVE: The aim of this paper was to investigate the impact of two interventions on testing activity across a whole sexual health economy: (1) the introduction of open access Web-based STI testing services and (2) a clinic policy of triage and signpost online where users without symptoms who attended clinics for STI testing were supported to access the Web-based service instead. METHODS: Data on attendances at all specialist public sexual health providers in an inner-London area were collated into a single database. Each record included information on user demographics, service type accessed, and clinical activity provided, including test results. Clinical activity was categorized as a simple STI test (could be done in a clinic or online), a complex visit (requiring face-to-face consultation), or other. RESULTS: Introduction of Web-based services increased total testing activity across the whole sexual health economy by 18.47% (from 36,373 to 43,091 in the same 6-month period-2014-2015 and 2015-2016), suggesting unmet need for testing in the area. Triage and signposting shifted activity out of the clinic onto the Web-based service, with simple STI testing in the clinic decreasing from 16.90% (920/5443) to 12.25% (511/4172) of total activity, P<.001, and complex activity in the clinic increasing from 69.15% (3764/5443) to 74.86% (3123/4172) of total activity, P<.001. This intervention created a new population of online users with different demographic and clinical profiles from those who use Web-based services spontaneously. Some triage and signposted users (29.62%, 375/1266) did not complete the Web-based testing process, suggesting the potential for missed diagnoses. CONCLUSIONS: This evaluation shows that users can effectively be transitioned from face-to-face to Web-based services and that this introduces a new population to Web-based service use and changes the focus of clinic-based activity. Further development is underway to optimize the triage and signposting process to support test completion

Ethel Carnie Holdsworth: General Belinda, co-operation and the servant problem

In July 1920, ‘Belinda: The Story of a Domestic Servant’ first appeared in the co-operative periodical, the Wheatsheaf. It was penned by one of its regular short story writers, Lancashire mill-woman Ethel Carnie Holdsworth (1886-1962). Encouraged by Percy Redfern, the Wheatsheaf’s editor, Carnie Holdsworth returned to the character of Belinda over the next couple of years, and in 1924, General Belinda became her sixth published novel. General Belinda is an episodic adventure about the trials and tribulations of domestic service. Belinda is a maid-of-all work who, like P. G. Wodehouse’s Jeeves, puts her employers’ lives and affairs to right. Comedy is the striking note, but Carnie Holdsworth was adept at putting popular fiction to work for feminist-Marxist politics. This article explores the novel as a radical feminist critique of early twentieth-century domestic service and the devastation of World War One, written from the rare perspective of a working-class woman. General Belinda is also an important example of co-operative ideals. Redfern was a key proponent of consumer socialism between the wars, and Belinda shows her employers the power of consumerism as a rational force for good, preaching against debt and fiscal irresponsibility. The article illustrates how Carnie Holdsworth’s plot intersects with wider debates in interwar women’s print culture on how British women shoppers were encouraged to be good home-making citizens. Belinda shows readers how to practise domestic economy and shop for co-operative good. In doing so, she suggests a new way of conceiving of the labour of domestic service and of positive social relations post-war, based on a co-operative understanding of dignity, mutual association and self-help

Patents and Industrialisation. An Historical Overview of the British Case, 1624-1907

A Report to the Strategic Advisory Board on Intellectual Property Policy (SABIP), U

The Iceland Microcontinent and a continental Greenland-Iceland-Faroe Ridge

The breakup of Laurasia to form the Northeast Atlantic Realm was the culmination of a long period of tectonic unrest extending back to the Late Palaeozoic. Breakup was prolonged and complex and disintegrated an inhomogeneous collage of cratons sutured by cross-cutting orogens. Volcanic rifted margins formed, which are blanketed by lavas and underlain variously by magma-inflated, extended continental crust and mafic high-velocity lower crust of ambiguous and probably partly continental provenance. New rifts formed by diachronous propagation along old zones of weakness. North of the Greenland-Iceland-Faroe Ridge the newly forming rift propagated south along the Caledonian suture. South of the Greenland-Iceland-Faroe Ridge it propagated north through the North Atlantic Craton along an axis displaced ~ 150 km to the west of the northern rift. Both propagators stalled where the confluence of the Nagssugtoqidian and Caledonian orogens formed a transverse barrier. Thereafter, the ~ 400-km-wide latitudinal zone between the stalled rift tips extended in a distributed, unstable manner along multiple axes of extension that frequently migrated or jumped laterally with shearing occurring between them in diffuse transfer zones. This style of deformation continues to the present day. It is the surface expression of underlying magma-assisted stretching of ductile mid- and lower continental crust which comprises the Icelandic-type lower crust that underlies the Greenland-Iceland-Faroe Ridge. This, and probably also one or more full-crustal-thickness microcontinents incorporated in the Ridge, are capped by surface lavas. The Greenland-Iceland-Faroe Ridge thus has a similar structure to some zones of seaward-dipping reflectors. The contemporaneous melt layer corresponds to the 3–10 km thick Icelandic-type upper crust plus magma emplaced in the ~ 10–30-km-thick Icelandic-type lower crust. This model can account for seismic and gravity data that are inconsistent with a gabbroic composition for Icelandic-type lower crust, and petrological data that show no reasonable temperature or source composition could generate the full ~ 40-km thickness of Icelandic-type crust observed. Numerical modeling confirms that extension of the continental crust can continue for many tens of Myr by lower-crustal flow from beneath the adjacent continents. Petrological estimates of the maximum potential temperature of the source of Icelandic lavas are up to 1450 °C, no more than ~ 100 °C hotter than MORB source. The geochemistry is compatible with a source comprising hydrous peridotite/pyroxenite with a component of continental mid- and lower crust. The fusible petrology, high source volatile contents, and frequent formation of new rifts can account for the true ~ 15–20 km melt thickness at the moderate temperatures observed. A continuous swathe of magma-inflated continental material beneath the 1200-km-wide Greenland-Iceland-Faroe Ridge implies that full continental breakup has not yet occurred at this latitude. Ongoing tectonic instability on the Ridge is manifest in long-term tectonic disequilibrium on the adjacent rifted margins and on the Reykjanes Ridge, where southerly migrating propagators that initiate at Iceland are associated with diachronous swathes of unusually thick oceanic crust. Magmatic volumes in the NE Atlantic Realm have likely been overestimated and the concept of a monogenetic North Atlantic Igneous Province needs to be reappraised. A model of complex, piecemeal breakup controlled by pre-existing structures that produces anomalous volcanism at barriers to rift propagation and distributes continental material in the growing oceans fits other oceanic regions including the Davis Strait and the South Atlantic and West Indian oceans

Functional characterisation of the human S1Pâ‚„G protein-coupled receptor

EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Screening for child sexual exploitation in online sexual health services:An exploratory study of expert views

BACKGROUND: Sexual health services routinely screen for child sexual exploitation (CSE). Although sexual health services are increasingly provided online, there has been no research on the translation of the safeguarding function to online services. We studied expert practitioner views on safeguarding in this context. OBJECTIVE: The aim was to document expert practitioner views on safeguarding in the context of an online sexual health service. METHODS: We conducted semistructured interviews with lead professionals purposively sampled from local, regional, or national organizations with a direct influence over CSE protocols, child protection policies, and sexual health services. Interviews were analyzed by three researchers using a matrix-based analytic method. RESULTS: Our respondents described two different approaches to safeguarding. The “information-providing” approach considers that young people experiencing CSE will ask for help when they are ready from someone they trust. The primary function of the service is to provide information, provoke reflection, generate trust, and respond reliably to disclosure. The approach values online services as an anonymous space to test out disclosure without commitment. The “information-gathering” approach considers that young people may withhold information about exploitation. Therefore, services should seek out information to assess risk and initiate disclosure. This approach values face-to-face opportunities for individualized questioning and immediate referral. CONCLUSIONS: The information-providing approach is associated with confidential telephone support lines and the information-gathering approach with clinical services. The approach adopted online will depend on ethos and the range of services provided. Effective transition from online to clinic services after disclosure is an essential element of this process and further research is needed to understand and support this transition