Simulations of Biased Agonists in the β2 Adrenergic Receptor with Accelerated Molecular Dynamics

The biased agonism of the G protein-coupled receptors (GPCRs), where in addition to a traditional G protein-signalling pathway a GPCR promotes intracellular signals though ß-arrestin, is a novel paradigm in pharmacology. Biochemical and biophysical studies have suggested that a GPCR forms a distinct ensemble of conformations signalling through the G protein and ß-arrestin. Here we report on the dynamics of the ß2 adrenergic receptor bound to the ß-arrestin and G protein biased agonists and the empty receptor to further characterize the receptor conformational changes caused by biased agonists. We use conventional and accelerated molecular dynamics (aMD) simulations to explore the conformational transitions of the GPCR from the active state to the inactive state. We found that aMD simulations enable monitoring the transition within the nanosecond timescale while capturing the known microscopic characteristics of the inactive states, such as the ionic lock, the inward position of F6.44, and water clusters. Distinct conformational states are shown to be stabilized by each biased agonist. In particular, in simulations of the receptor with the ß-arrestin biased agonist, N-cyclopentylbutanepherine we observe a different pattern of motions in helix 7 when compared to simulations with the G protein biased agonist, Salbutamol that involves perturbations of the network of interactions within the NPxxY motif. Understanding the network of interactions induced by biased ligands and the subsequent receptor conformational shifts will lead to development of more efficient drugs. © 2013 American Chemical Society

Prosthodontic rehabilitation of a patient using a swing-lock lower denture after segmental mandibulectomy

A swing-lock denture is useful in partially dentate patients where the configuration of the remaining teeth means that either the retention or stability available for a conventional removable partial denture is compromised. Such removable prostheses can also prove to be extremely useful when providing prosthodontic rehabilitation following surgical resection of oral cancer. A 20 year-old patient was referred to the Restorative Department of Cork University Dental Hospital following segmental mandibulectomy to treat a calicifying epithelial odontogenic tumour (Pindborg Tumour). Initial treatment using a conventional lower partial denture failed. This paper outlines the successfully rehabilitation using a lower Cobalt-Chromium swing-lock partial denture.

Injection locked oscillator lock detector

A simple circuit that is able to indicate if an injection-locked oscillator is in the locked condition by providing a ‘high’ or ‘low’ output is presented. The detector is compatible with most injection-locked oscillators as all that is required is access to the low-frequency bias circuit, with no direct access needed to the RF/microwave signals. To prove the universal nature of the lock detector it is successfully demonstrated practically for two scenarios: (i) a 1 GHz injection-locked VCO and (ii) a 60 GHz SiGe VCO MMIC.

The Dublin Lock Hospital: Medicine, Morality, Disease and Sin

Anecdotal evidence has it that when Dublin’s venereal disease hospital closed its doors for the last time in the 1950s, its administrative staff began to burn its records, starting with the most recent. This attempt to conceal the results of sexual profligacy is perhaps understandable in the rarefied climate of mid-century Catholic Ireland. However, the sense of shame attached to this institution has been pervasive. For example, of all Dublin’s major hospitals, the lock hospital remains the only one without a dedicated history. And, throughout its two centuries of existence, the ‘lock’ had often been a site of controversy and approbation.

The institution began in the eighteenth century as the most peripatetic, poor relation of the city’s voluntary hospitals, wandering indiscriminately through a series of temporary premises before finally achieving a permanent home and official recognition as a military-sponsored medical hospital in 1792. It also gained architectural extensions by both Richard and Francis Johnston and in the following decades. This new-found status and a growing re-conceptualisation of venereal disease as a legitimate medical problem rather than a matter of morality was, however, somewhat compromised by the choice of site at Townsend Street. The institution occupied a hidden part of city, appropriating the vacated home of the Hospital for Incurables, another marginalised group whose presence in the city had been viewed through the lens of superstition and fear. For the rest of its existence, the lock hospital would share this experience occupying a nebulous position between medicine and morality; disease and sin.

Using what’s left of the hospital’s records and a series of original architectural drawings, this paper discusses the presence and role of the lock hospital in the city in the eighteenth and early nineteenth century, tracking how changes in its administration and architectural form reflected wider attitudes towards disease, sexuality and gender in Georgian Dublin.

Physical activity in deprived communities in London: examining individual and neighbourhood-level factors

Introduction: The objectives of this study were to examine relationships between neighbourhood-level and individual-level characteristics and physical activity in deprived London neighbourhoods. Methods: In 40 of the most deprived neighbourhoods in London (ranked in top 11% in London by Index of Multiple Deprivation) a cross-sectional survey (n = 4107 adults aged > = 16 years), neighbourhood audit tool, GIS measures and routine data measured neighbourhood and individual-level characteristics. The binary outcome was meeting the minimum recommended (CMO, UK) 5×30 mins moderate physical activity per week. Multilevel modelling was used to examine associations between physical activity and individual and neighbourhood-level characteristics. Results: Respondents living more than 300 m away from accessible greenspace had lower odds of achieving recommended physical activity levels than those who lived within 300 m; from 301–600 m (OR = 0.7; 95% CI 0.5–0.9) and from 601–900 m (OR = 0.6; 95% CI 0.4–0.8). There was substantial residual between-neighbourhood variance in physical activity (median odds ratio = 1.7). Other objectively measured neighbourhood-level characteristics were not associated with physical activity levels. Conclusions Distance to nearest greenspace is associated with meeting recommended physical activity levels in deprived London neighbourhoods. Despite residual variance in physical activity levels between neighbourhoods, we found little evidence for the influence of other measured neighbourhood-level characteristics.

Physical Activity in Deprived Communities in London: Examining Individual and Neighbourhood-Level Factors

Introduction The objectives of this study were to examine relationships between neighbourhood-level and individual-level characteristics and physical activity in deprived London neighbourhoods. Methods In 40 of the most deprived neighbourhoods in London (ranked in top 11% in London by Index of Multiple Deprivation) a cross-sectional survey (n = 4107 adults aged > = 16 years), neighbourhood audit tool, GIS measures and routine data measured neighbourhood and individual-level characteristics. The binary outcome was meeting the minimum recommended (CMO, UK) 5×30 mins moderate physical activity per week. Multilevel modelling was used to examine associations between physical activity and individual and neighbourhood-level characteristics. Results Respondents living more than 300 m away from accessible greenspace had lower odds of achieving recommended physical activity levels than those who lived within 300 m; from 301–600 m (OR = 0.7; 95% CI 0.5–0.9) and from 601–900 m (OR = 0.6; 95% CI 0.4–0.8). There was substantial residual between-neighbourhood variance in physical activity (median odds ratio = 1.7). Other objectively measured neighbourhood-level characteristics were not associated with physical activity levels. Conclusions Distance to nearest greenspace is associated with meeting recommended physical activity levels in deprived London neighbourhoods. Despite residual variance in physical activity levels between neighbourhoods, we found little evidence for the influence of other measured neighbourhood-level characteristics.

Second Welland Canal - Book 1, Survey Map 1 - Entrance, Lock 1 and Port Dalhousie

Survey map of the Second Welland Canal created by the Welland Canal Company showing the areas in and around Port Dalhousie and Grantham Township. Identified structures associated with the Canal include Lock 1, Lighthouse, Lighthouse Keeper's House, East and West Piers, Harbour, Waste Weir, Store House, Collector's Office, Collector Assistant Office, Lock Tender's House and the new towing path. Features of the First Welland Canal are noted in red ink and includes the old Harbour, old Lock 1, old towing path and the original bed of the Twelve Mile Creek. The surveyors' measurements and notes can be seen in red and black ink and pencil. Local area landmarks and businesses are also identified and include streets and roads (ex. Lock Street and Colonel Clark's Cattle Road), Alex Muir's Dry Dock, RandJ Laurie Flouring Mill, R. Laurie and Company Grist Mill, A. Morrison Saw Mill, Johnson's Tavern, a store and a church. Properties and property owners of note are: Concession 1 Lots 21 and 22, John Christie, John Clark, N. Pawling, William Pawling, W. Carter, G.A. Clark, J. Maven, Mrs. Wood, James Drabble and J. Woodall.

Second Welland Canal - Book 1, Survey Map 2 - Lock 1 and Port Dalhousie

Survey map of the Second Welland Canal created by the Welland Canal Company showing the areas in and around Port Dalhousie and Grantham Township. Identified structures associated with the Canal include Lock 1, East and West Piers, Collector's Office, Lock Tender's House and the new towing path. The surveyors' measurements and notes can be seen in red and black ink and pencil. Local area landmarks and businesses are also identified and include streets and roads (ex. Road to St. Catharines, Side Line, Old Road to Port Dalhousie, Road to Niagara), the Welland Railway and its structures (ex. freight sheds, wood shed, raised platform, elevator, cranes, water tank, turn table, and passenger station), G. A. Clark's Wood Yard, Clark's Wood Office, Alex Muir's Dry Dock, Donald, Andrews and Ross' Dry Dock, RandJ Laurie Flouring Mill, R. Laurie and Company Grist Mill and A. Morrison Saw Mill. A New Road to St. Catharines is featured in red ink. Properties and property owners of note are: Concession 1 Lots 19, 20 and 21, John Christie, and John Clark.

Second Welland Canal - Book 1, Survey Map 12 - St. Catharines and Lock 4

Survey map of the Second Welland Canal created by the Welland Canal Company showing the Town of St. Catharines. Identified structures associated with the Canal include Lock 4, Hydraulic Race, floating tow path, and the Canal waterway itself. The surveyors' measurements and notes can be seen in red and black ink and pencil. Local area landmarks are also identified and include streets and roads (ex. Geneva Street, St. Paul Street, Queenston Street, Niagara Street and Mill Street), C. Phelp's Grist Mill and Store House, Stinson's Distillery, and several unnamed bridges. Properties and property owners of note are: Concession 6 Lot 16, J. R. Benson, Calvin Phelps, J. Hudson, David Gray, A. Roberts, Mrs. McDonell, J. S. McDonell, T. B. Wragg, J. Donaldson, W. Barr Jr., C. L. Hall, G. Ward, Ridout Bros and Co., and the St. Catharines Grass Co.

Second Welland Canal - Book 1, Survey Map 14 - St. Catharines and Lock 5

Survey map of the Second Welland Canal created by the Welland Canal Company showing the Canal along the eastern edge of the Town of St. Catharines. Identified structures associated with the Canal include Lock 5 and the towing path. The surveyors' measurements and notes can be seen in red and black ink and pencil. Local area landmarks are also identified and include bridges, streets, and roads (ex. Queenston Street, St. Catharines Macdamized Road and Suspension Bridge), a Pond, a number of unnamed bridges, Stinson's Distillery, and R. Collier's Saw Mill. Properties and property owners of note are: Concession 6 Lots 14 and 15, R. Collier, W. Gillespie, Orson Phelps, W. Chase, M. Bryant, John Soper, Winsor Chace, John Berryman, John Boyle, J. Madigan, B. F. Reynolds, W. Smaill, F. Stinson, G. Ward and Mrs. Soper.

Second Welland Canal - Book 1, Survey Map 15 - Hydraulic Race and Aqueduct in Grantham

Survey map of the Second Welland Canal created by the Welland Canal Company showing the Canal along the eastern edge of the Town of St. Catharines. Identified structures associated with the Canal include Lock 7, Lock House Lot, and the towing path. The surveyors' measurements and notes can be seen in red and black ink and pencil. Local area landmarks are also identified and include bridges, streets, and roads (ex. Queenston Road, St. Catharines Macdamized Road and Suspension Bridge), a hydraulic race, and the Hydraulic Aqueduct. Properties and property owners of note are: Concession 7 Lots 12, 13, and 14, M. Bryant, Mrs. Soper, J. Capner, O. Phelps, P. Marren, Mrs. Parnell, J. Carty, Mrs. Ward, and J. Goodenew.

Second Welland Canal - Book 2, Survey Map 1 - Locks 5, 6 and 7 in Grantham

Survey map of the Second Welland Canal created by the Welland Canal Company showing the Grantham Township just southeast of the Town of St. Catharines. Identified structures associated with the Canal include Locks 5, 6, and 7, two Lock House Lots, Small Lock House, waste weir, and the towing path. The surveyors' measurements and notes can be seen in red and black ink and pencil. Local area landmarks are also identified and include roads (ex. Road to Thorold), Dicks Creek, R. Collier's Saw Mill, a gate yard, paper mill, grist mill, store house, and a barn. Properties and property owners of note are: Concession 7 Lots 13, 14, and 15, R. Collier, Orson Phelps, and a Mill Lot leased to Richard Collier.

Second Welland Canal - Book 2, Survey Map 3 - Locks 8, 9 and 10 in Grantham

Survey map of the Second Welland Canal created by the Welland Canal Company showing the Grantham Township between the Town of St. Catharines and Merritton. Identified structures associated with the Canal include Locks 8, 9, and 10, waste weirs, the towing path, and several floating bridges. The surveyors' measurements and notes can be seen in red and black ink and pencil. Several stones and tree stumps likely used in the measurements are identified on the map. Local area landmarks are also identified and include streets and roads(ex. Macadamized Road to Thorold), J. Hamilton's Hotel, a school house, McCoy's Farm House, Bradley's House, O. Phelps Saw Mill, Disher and Hait's Woolen Mill, Centreville Mills, a bridge, several barns, and a number of structures (possibly houses, cabins, or shops) belonging to: P. McCoy, E. McLachlan, T. Wilson, W. Wilson, M. Bradley, S. Bradley, P. Boyle, J. Bradley, E. Grant, and W. Church. Lock 12 and 15 of the original canal are also identified. Properties and property owners of note are: Concession 8 Lots 12, 13 and 14, O. J. Phelps, P. McCoy, A. Bradley, C. Bradley, T. Reed, O. Clifford, J. Bradley, W. C. Loan Company, Duffin, and T. Towers Mill Lot.

Second Welland Canal - Book 2, Survey Map 4 - Locks 11, 12, 13, 14 and 15 in Grantham

Survey map of the Second Welland Canal created by the Welland Canal Company showing the Grantham Township along the outskirts of Merritton. Identified structures associated with the Canal include Locks 11, 12, 13, 14, and 15, Lock House Lot, and the towing path. The surveyors' measurements and notes can be seen in red and black ink and pencil. Several stones likely used in the measurements are identified on the map. Local area landmarks are also identified and include streets and roads(ex. Hartzel Road and Macadamized Road), the Great Western Railroad, Swing Bridge, Thorold Station and its structures (ex. freight house, office, water tank, and wood house), Gordon and Mackay Houses, Gordon and Mackay's Cotton Mill, hydraulic race, a wharf, pond, and an unnamed bridge. Properties and property owners of note are: Concession 9 Lots 12 and 13, A. Bradley, John O'Coner, G. Grant, J. Bradley, J. Vanderburgh, O. Clifford and a parcel of land leased Gordon and Mackay.

Second Welland Canal - Book 2, Survey Map 5 - Locks 16, 17 and 18 in Grantham

Survey map of the Second Welland Canal created by the Welland Canal Company showing the Grantham Township at Merritton. Identified structures associated with the Canal include Locks 15, 16, 17, and 18, and the towing path. The surveyors' measurements and notes can be seen in red and black ink and pencil. Local area landmarks are also identified and include streets and roads (ex. Hartzel Road and Macadamized Road), Lybster Cotton Mill, St. Catharines Paper Mill, J. Brown Cotton Mills, hydraulic race, a pond, several barns, and a number of structures (likely houses or cabins) belonging to: J. McNamara, M. Moran, A. Delany, T. Joyce, J. Delany, C. Blake, F. Weaver, W. Leeson, and Mrs. Aikins. Properties of note are: Concession 10 Lots 11 and 12. A number of reserved properties exist and are outlined in blue. They include three reserved properties for lock lots, and one large property reserved for a quarry.