Crystal structure of human IPS-1/MAVS/VISA/Cardif caspase activation recruitment domain

Background: IPS-1/MAVS/VISA/Cardif is an adaptor protein that plays a crucial role in the induction of interferons in response to viral infection. In the initial stage of the intracellular antiviral response two RNA helicases, retinoic acid inducible gene-I (RIG-I) and melanoma differentiation-association gene 5 (MDA5), are independently able to bind viral RNA in the cytoplasm. The 62 kDa protein IPS-1/MAVS/VISA/Cardif contains an N-terminal caspase activation and recruitment (CARD) domain that associates with the CARD regions of RIG-I and MDA5, ultimately leading to the induction of type I interferons. As a first step towards understanding the molecular basis of this important adaptor protein we have undertaken structural studies of the IPS-1 MAVS/VISA/Cardif CARD region. Results: The crystal structure of human IPS-1/MAVS/VISA/Cardif CARD has been determined to 2.1 angstrom resolution. The protein was expressed and crystallized as a maltose-binding protein (MBP) fusion protein. The MBP and IPS-1 components each form a distinct domain within the structure. IPS-1/MAVS/VISA/Cardif CARD adopts a characteristic six-helix bundle with a Greek-key topology and, in common with a number of other known CARD structures, contains two major polar surfaces on opposite sides of the molecule. One face has a surface-exposed, disordered tryptophan residue that may explain the poor solubility of untagged expression constructs. Conclusion: The IPS-1/MAVS/VISA/Cardif CARD domain adopts the classic CARD fold with an asymmetric surface charge distribution that is typical of CARD domains involved in homotypic protein-protein interactions. The location of the two polar areas on IPS-1/MAVS/VISA/Cardif CARD suggest possible types of associations that this domain makes with the two CARD domains of MDA5 or RIG-I. The N-terminal CARD domains of RIG-I and MDA5 share greatest sequence similarity with IPS-1/MAVS/VISA/Cardif CARD and this has allowed modelling of their structures. These models show a very different charge profile for the equivalent surfaces compared to IPS-1/MAVS/VISA/Cardif CARD.Publisher PDFPeer reviewe

Structural characterization of the carbohydrate-binding module of NanA sialidase, a pneumococcal virulence factor

This research was supported by the University of St Andrews and grants provided by the Medical Research Council.Background: Streptococcus pneumoniae Neuraminidase A (NanA) is a multi-domain protein anchored to the bacterial surface. Upstream of the catalytic domain of NanA is a domain that conforms to the sialic acid-recognising CBM40 family of the CAZY (carbohydrate-active enzymes) database. This domain has been identified to play a critical role in allowing the bacterium to promote adhesion and invasion of human brain microvascular endothelial cells, and hence may play a key role in promoting bacterial meningitis. In addition, the CBM40 domain has also been reported to activate host chemokines and neutrophil recruitment during infection. Results: Crystal structures of both apo- and holo- forms of the NanA CBM40 domain (residues 121 to 305), have been determined to 1.8 angstrom resolution. The domain shares the fold of other CBM40 domains that are associated with sialidases. When in complex with alpha 2,3- or alpha 2,6-sialyllactose, the domain is shown to interact only with the terminal sialic acid. Significantly, a deep acidic pocket adjacent to the sialic acid-binding site is identified, which is occupied by a lysine from a symmetry-related molecule in the crystal. This pocket is adjacent to a region that is predicted to be involved in protein-protein interactions. Conclusions: The structural data provide the details of linkage-independent sialyllactose binding by NanA CBM40 and reveal striking surface features that may hold the key to recognition of binding partners on the host cell surface. The structure also suggests that small molecules or sialic acid analogues could be developed to fill the acidic pocket and hence provide a new therapeutic avenue against meningitis caused by S. pneumoniae.Publisher PDFPeer reviewe

Crystal structure of human IPS-1/MAVS/VISA/Cardif caspase activation recruitment domain

<p>Abstract</p> <p>Background</p> <p>IPS-1/MAVS/VISA/Cardif is an adaptor protein that plays a crucial role in the induction of interferons in response to viral infection. In the initial stage of the intracellular antiviral response two RNA helicases, retinoic acid inducible gene-I (RIG-I) and melanoma differentiation-association gene 5 (MDA5), are independently able to bind viral RNA in the cytoplasm. The 62 kDa protein IPS-1/MAVS/VISA/Cardif contains an N-terminal caspase activation and recruitment (CARD) domain that associates with the CARD regions of RIG-I and MDA5, ultimately leading to the induction of type I interferons. As a first step towards understanding the molecular basis of this important adaptor protein we have undertaken structural studies of the IPS-1 MAVS/VISA/Cardif CARD region.</p> <p>Results</p> <p>The crystal structure of human IPS-1/MAVS/VISA/Cardif CARD has been determined to 2.1Å resolution. The protein was expressed and crystallized as a maltose-binding protein (MBP) fusion protein. The MBP and IPS-1 components each form a distinct domain within the structure. IPS-1/MAVS/VISA/Cardif CARD adopts a characteristic six-helix bundle with a Greek-key topology and, in common with a number of other known CARD structures, contains two major polar surfaces on opposite sides of the molecule. One face has a surface-exposed, disordered tryptophan residue that may explain the poor solubility of untagged expression constructs.</p> <p>Conclusion</p> <p>The IPS-1/MAVS/VISA/Cardif CARD domain adopts the classic CARD fold with an asymmetric surface charge distribution that is typical of CARD domains involved in homotypic protein-protein interactions. The location of the two polar areas on IPS-1/MAVS/VISA/Cardif CARD suggest possible types of associations that this domain makes with the two CARD domains of MDA5 or RIG-I. The N-terminal CARD domains of RIG-I and MDA5 share greatest sequence similarity with IPS-1/MAVS/VISA/Cardif CARD and this has allowed modelling of their structures. These models show a very different charge profile for the equivalent surfaces compared to IPS-1/MAVS/VISA/Cardif CARD.</p

Pricing the Asian Call Option

Background material on measure-theoretic probability theory and stochastic calculus is provided in order to clarify notation and inform the reader unfamiliar with these concepts. These fields are then employed in exploring two distinct but related approaches to fair option pricing: developing a partial differential equation whose solution, given specified boundary conditions, is the desired fair option price and evaluating a riskneutral conditional expectation whose value is the fair option price. Both approaches are illustrated by example before being applied to the Asian call option. . Two results are obtained by applying the latter option pricing approach to the Asian call option. The price of an Asian call option is shown to be equal to an integral of an unknown joint distribution function. This exact formula is then made approximate by allowing one of the random variables to become a parameter of the system. This modified Asian call option is then priced explicitly, leading to a formula that is strikingly similar to the Black- Scholes-Merton formula, which prices the European call option. Finally, possible methods of generalizing the procedure to price the Asian call option both exactly and explicitly are speculated

Flamingo Vol. III N 6

Ubersax. Cover. Picture. 0. Chaparral. Untitled. Prose. 1. Don Marquis. Love Sonnet of a Caveman. Poem. 4. Sun Dial. RIPPING, WE\u27D CALL IT. Prose. 4. Burr. Untitled. Prose. 4. Whirlwind. Untitled. Prose. 4. Octopus. Untitled. Prose. 4. Voo Doo. Untitled. Prose. 4. Log. Untitled. Prose. 4. Chaparral. Untitled. Prose. 4. E.S. Untitled. Picture. 5. OLD IRONSIDES. HER THUNDERS SHOOK THE MIGHTY DEEP, AND THERE SHOULD BE HER GRAVE. Picture. 6. A.I.C. AFTER CHAUCER. Poem. 7. Anonymous. Untitled. Prose. 7. Anonymous. ODE TO A CATFISH. Poem. 7. Anonymous. Untitled. Prose. 7. Anonymous. Untitled. Prose. 7. Anonymous. Untitled. Prose. 7. Anonymous. Untitled. Prose. 7. E.T. SCENE TWO. Picture. 7. Anonymous. Untitled. Prose. 7. Anonymous. WHAT EVERY COLLEGE MAN KNOWS. Poem. 7. Anonymous. LIKE KELLY DID. Poem. 7. Anonymous. TRAINED ANATOMY. Prose. 7. Taylor, Edna B. COUTEAU ET FOURCHETTE-A Farce in One Smack. Prose. 8. Anonymous. TWO CHARMS. Poem. 9. W.A.V. Untitled. Poem. 9. Anonymous. A Tribute to Genius. Poem. 9. Anonymous. Untitled. Picture. 9. Anonymous. Untitled. Poem. 9. A.E.R. INDIFFERENCE. Poem. 9. Anonymous. Untitled. Poem. 9. W.A.V. Untitled. Poem. 9. Anonymous. CIN— IN THAT DEATH SCENE OF MINE I MOVED THEM ALL TO TEARS. EMMA— YES. THEY KNEW YOU WERE ONLY PLAYING DEAD. Picture. 10. Anonymous. PIED PIKER. Prose. 10. Anonymous. IN A HISTRIONIC SCENTS. Picture/Poem. 10. XE. Lines. Poem. 10.; Anonymous. Untitled. Prose. 10. Anonymous. Untitled. Prose. 10. Anonymous. STAGE DIRECTIONS SAME SET THROUGHOUT THE PLAY. Picture. 11. W.M.P. TALES OF THE RAZZ AGE. Prose. 11. Anonymous. BENNY\u27S BLANK VERSE. Poem. 11. Anonymous. Untitled. Prose. 11. Anonymous. Untitled. Prose. 11. Grayce. YOU ALL KNOW THAT GUY WE LOVE SO MUCH— I SWEAR WE\u27LL HAVE TO CROWN HIM YET— WHO AFTER EVERY ACT, OR SCENE, OR SUCH, GOES OUT TO HAVE HIS CIGARETTE. Picture. 11. H.K. Untitled. Picture. 11. H.G.P. UH-UH. Prose. 11. W.G.M. THE VISION OF SIR LONGFALL. Prose. 12. Anonymous. -NIGH HALF UPON THY HORSE, A GRACEFUL SEMITE TRICK. Picture. 12. Anonymous. I\u27m Preserving That Lock of Hair... Picture. 13. Anonymous. Untitled. Prose. 13. Grayce. IT\u27S A LONG JANE THAT HAS NO CRUVES. Picture. 13. Anonymous. Relativity. Prose. 13. Anonymous. STOP THIEF! Prose. 14. Anonymous. FLAMINGO PINFEATHERS. Prose. 15. Anonymous. TO WHOM IT MAY CONCERN. Prose. 15. Bridge. Denison Comics. Picture. 16. Anonymous. A STUDY OF WILD LIFE. Picture. 18. Anonymous. Names. Poem. 18. Anonymous. YOU ARE THE FIRST MAN I EVER PERMITTED TO KISS ME. AND YOU ARE THE FIRST GIRL I EVER KISSED. WILL YOU MARRY ME? I WOULDN\u27T MARRY A LIAR. I WOULD. Picture. 18. Anonymous. TECHNICAL STUFF. Prose. 18. Anonymous. Untitled. Prose. 18. Anonymous. JACK, WHEN WE ARE MARRIED, I MUST HAVE THREE SERVANTS. YOU SHALL HAVE TWENTY, DEAR, BUT NOT ALL AT ONE TIME. Picture. 18. Anonymous. Untitled. Poem. 18. Anonymous. Untitled. Prose. 18. Anonymous. THEN THIS IS FINAL? ABSOLUTELY. SHALL I RETURN YOUR LETTERS? YES, THERE\u27S SOME GOOD MATERIAL IN THEM I CAN USE. Picture. 18. Anonymous. MY BUT YOU\u27RE CONTRADICTORY TO-NIGHT \u27\u27WHY, I AM NOT. Picture. 19. Anonymous. Untitled. Prose. 19. Anonymous. Untitled. Prose. 19. Anonymous. SPRING THIS AND RUN. Prose. 19. Anonymous. Untitled. Prose. 19. Anonymous. Untitled. Prose. 19. E.S. STOP THIEF! Prose. 19. Anonymous. Untitled. Poem. 19. Anonymous. Untitled. Prose. 19. Grayce. HER REASON. Picture/Poem. 19. Anonymous. Untitled. Prose. 19. Anonymous. LIKE KELLY DID. Prose. 19. N.H.G. FAVORITE FICTION. Poem. 19. Anonymous. HARD JUVENILE LEAD: D— THAT BALL!\u27 Picture. 19. E.B. THE END—. Picture. 20. Anonymous. Untitled. Prose. 20. Anonymous. NODE 2 A BLOCK HEAD. Prose. 20. Anonymous. Untitled. Prose. 20. Anonymous. Untitled. Prose. 20. E.B. OF A PERFECT DAY. Picture. 20. Wisconsin Octopus. Sweet Kisses. Prose. 22. Log. Untitled. Prose. 22. Bean Pot. Untitled. Prose. 22. Gargoyle. EXACTLY. Prose. 22. Froth. Untitled. Prose. 22. Phoenix. Untitled. Prose. 22. Anonymous. Untitled. Prose. 23. Chaparral. Famous Hands. Prose. 24. Chaparral. WASH OUT FOR THIS. Prose. 24. Gargoyle. Untitled. Prose. 24. Goblin. Untitled. Prose. 24. Octopus. A Tragedy. Poem. 24. Froth. Untitled. Prose. 24. Juggler. Untitled. Prose. 24. Lord Jeff. THE FROSH RETORT. Prose. 25. Goblin. Untitled. Prose. 25. Green Gander. Untitled. Prose. 25. Judge. AN EXPLANATION. Prose. 25. Green Gander. Untitled. Prose. 25. Spider Web. Untitled. Prose. 25. Chapparal. Untitled. Prose. 26. Williams Purple Cow. Untitled. Prose. 26. Froth. Untitled. Prose. 26. Gargoyle. SHERIFF, DO YOUR DUTY. Prose. 26. Beanpot. Untitled. Prose. 26. Sun Dial. A WELL BALANCED SENTENCE. Prose. 26. Chapparal. Untitled. Prose. 26. Scalper. Untitled. Prose. 26. Cracker. Untitled. Prose. 27. Scalper. Untitled. Prose. 27. Burr. Untitled. Prose. 27. Lemon Punch. Untitled. prose. 27. Schmitz. Untitled. Picture. 28. Puppet. Untitled. Prose. 28. Malteaser. Untitled. Prose. 28. Jester. SO IT GOES. Poem. 29. Brown Jug. CONTRIBUTORS ATTENTION! Prose. 29. Tiger. Untitled. Prose. 29. Scalper. QUALIFIED. Prose. 29. Purple Cow. Untitled. Prose. 29. E.B. D\u27JA EVER FEEL LIKE THIS? Picture. 29. Chaparral. Untitled. Prose. 30. Tiger. Untitled. Prose. 30. Malteaser. STOP THIEF! Prose. 30. Black and Blue Jay. Untitled. Prose. 30. Yellow Jacket. Untitled. Prose. 30. Tiger. Untitled. Prose. 30. Gargoyle. RIGHTO. Prose. 30. Yale Record. Untitled. Prose. 31. Puppet. Untitled. Prose. 31. Puppet. Untitled. Poem. 31. Virginia Reel. Untitled. Prose. 31. Puppet. Untitled. Prose. 31. Virginia Reel. Untitled. Prose. 31. Phoenix. Untitled. Prose. 31. Exchange. Untitled. Prose. 31. Stone Mill. Untitled. Prose. 31. Orange Peel. Untitled. Prose. 31. Stone Mill. Untitled. Prose. 32. Puppet. A SHORT TRAGEDY. Poem. 32. Stone Mill. Untitled. Prose. 32. Ex. Untitled. Prose. 32. Anonymous. Untitled. Prose. 32. Anonymous. Untitled. Prose. 32

Flamingo Vol. III N 6

Ubersax. Cover. Picture. 0. Chaparral. Untitled. Prose. 1. Don Marquis. Love Sonnet of a Caveman. Poem. 4. Sun Dial. RIPPING, WE\u27D CALL IT. Prose. 4. Burr. Untitled. Prose. 4. Whirlwind. Untitled. Prose. 4. Octopus. Untitled. Prose. 4. Voo Doo. Untitled. Prose. 4. Log. Untitled. Prose. 4. Chaparral. Untitled. Prose. 4. E.S. Untitled. Picture. 5. OLD IRONSIDES. HER THUNDERS SHOOK THE MIGHTY DEEP, AND THERE SHOULD BE HER GRAVE. Picture. 6. A.I.C. AFTER CHAUCER. Poem. 7. Anonymous. Untitled. Prose. 7. Anonymous. ODE TO A CATFISH. Poem. 7. Anonymous. Untitled. Prose. 7. Anonymous. Untitled. Prose. 7. Anonymous. Untitled. Prose. 7. Anonymous. Untitled. Prose. 7. E.T. SCENE TWO. Picture. 7. Anonymous. Untitled. Prose. 7. Anonymous. WHAT EVERY COLLEGE MAN KNOWS. Poem. 7. Anonymous. LIKE KELLY DID. Poem. 7. Anonymous. TRAINED ANATOMY. Prose. 7. Taylor, Edna B. COUTEAU ET FOURCHETTE-A Farce in One Smack. Prose. 8. Anonymous. TWO CHARMS. Poem. 9. W.A.V. Untitled. Poem. 9. Anonymous. A Tribute to Genius. Poem. 9. Anonymous. Untitled. Picture. 9. Anonymous. Untitled. Poem. 9. A.E.R. INDIFFERENCE. Poem. 9. Anonymous. Untitled. Poem. 9. W.A.V. Untitled. Poem. 9. Anonymous. CIN— IN THAT DEATH SCENE OF MINE I MOVED THEM ALL TO TEARS. EMMA— YES. THEY KNEW YOU WERE ONLY PLAYING DEAD. Picture. 10. Anonymous. PIED PIKER. Prose. 10. Anonymous. IN A HISTRIONIC SCENTS. Picture/Poem. 10. XE. Lines. Poem. 10.; Anonymous. Untitled. Prose. 10. Anonymous. Untitled. Prose. 10. Anonymous. STAGE DIRECTIONS SAME SET THROUGHOUT THE PLAY. Picture. 11. W.M.P. TALES OF THE RAZZ AGE. Prose. 11. Anonymous. BENNY\u27S BLANK VERSE. Poem. 11. Anonymous. Untitled. Prose. 11. Anonymous. Untitled. Prose. 11. Grayce. YOU ALL KNOW THAT GUY WE LOVE SO MUCH— I SWEAR WE\u27LL HAVE TO CROWN HIM YET— WHO AFTER EVERY ACT, OR SCENE, OR SUCH, GOES OUT TO HAVE HIS CIGARETTE. Picture. 11. H.K. Untitled. Picture. 11. H.G.P. UH-UH. Prose. 11. W.G.M. THE VISION OF SIR LONGFALL. Prose. 12. Anonymous. -NIGH HALF UPON THY HORSE, A GRACEFUL SEMITE TRICK. Picture. 12. Anonymous. I\u27m Preserving That Lock of Hair... Picture. 13. Anonymous. Untitled. Prose. 13. Grayce. IT\u27S A LONG JANE THAT HAS NO CRUVES. Picture. 13. Anonymous. Relativity. Prose. 13. Anonymous. STOP THIEF! Prose. 14. Anonymous. FLAMINGO PINFEATHERS. Prose. 15. Anonymous. TO WHOM IT MAY CONCERN. Prose. 15. Bridge. Denison Comics. Picture. 16. Anonymous. A STUDY OF WILD LIFE. Picture. 18. Anonymous. Names. Poem. 18. Anonymous. YOU ARE THE FIRST MAN I EVER PERMITTED TO KISS ME. AND YOU ARE THE FIRST GIRL I EVER KISSED. WILL YOU MARRY ME? I WOULDN\u27T MARRY A LIAR. I WOULD. Picture. 18. Anonymous. TECHNICAL STUFF. Prose. 18. Anonymous. Untitled. Prose. 18. Anonymous. JACK, WHEN WE ARE MARRIED, I MUST HAVE THREE SERVANTS. YOU SHALL HAVE TWENTY, DEAR, BUT NOT ALL AT ONE TIME. Picture. 18. Anonymous. Untitled. Poem. 18. Anonymous. Untitled. Prose. 18. Anonymous. THEN THIS IS FINAL? ABSOLUTELY. SHALL I RETURN YOUR LETTERS? YES, THERE\u27S SOME GOOD MATERIAL IN THEM I CAN USE. Picture. 18. Anonymous. MY BUT YOU\u27RE CONTRADICTORY TO-NIGHT \u27\u27WHY, I AM NOT. Picture. 19. Anonymous. Untitled. Prose. 19. Anonymous. Untitled. Prose. 19. Anonymous. SPRING THIS AND RUN. Prose. 19. Anonymous. Untitled. Prose. 19. Anonymous. Untitled. Prose. 19. E.S. STOP THIEF! Prose. 19. Anonymous. Untitled. Poem. 19. Anonymous. Untitled. Prose. 19. Grayce. HER REASON. Picture/Poem. 19. Anonymous. Untitled. Prose. 19. Anonymous. LIKE KELLY DID. Prose. 19. N.H.G. FAVORITE FICTION. Poem. 19. Anonymous. HARD JUVENILE LEAD: D— THAT BALL!\u27 Picture. 19. E.B. THE END—. Picture. 20. Anonymous. Untitled. Prose. 20. Anonymous. NODE 2 A BLOCK HEAD. Prose. 20. Anonymous. Untitled. Prose. 20. Anonymous. Untitled. Prose. 20. E.B. OF A PERFECT DAY. Picture. 20. Wisconsin Octopus. Sweet Kisses. Prose. 22. Log. Untitled. Prose. 22. Bean Pot. Untitled. Prose. 22. Gargoyle. EXACTLY. Prose. 22. Froth. Untitled. Prose. 22. Phoenix. Untitled. Prose. 22. Anonymous. Untitled. Prose. 23. Chaparral. Famous Hands. Prose. 24. Chaparral. WASH OUT FOR THIS. Prose. 24. Gargoyle. Untitled. Prose. 24. Goblin. Untitled. Prose. 24. Octopus. A Tragedy. Poem. 24. Froth. Untitled. Prose. 24. Juggler. Untitled. Prose. 24. Lord Jeff. THE FROSH RETORT. Prose. 25. Goblin. Untitled. Prose. 25. Green Gander. Untitled. Prose. 25. Judge. AN EXPLANATION. Prose. 25. Green Gander. Untitled. Prose. 25. Spider Web. Untitled. Prose. 25. Chapparal. Untitled. Prose. 26. Williams Purple Cow. Untitled. Prose. 26. Froth. Untitled. Prose. 26. Gargoyle. SHERIFF, DO YOUR DUTY. Prose. 26. Beanpot. Untitled. Prose. 26. Sun Dial. A WELL BALANCED SENTENCE. Prose. 26. Chapparal. Untitled. Prose. 26. Scalper. Untitled. Prose. 26. Cracker. Untitled. Prose. 27. Scalper. Untitled. Prose. 27. Burr. Untitled. Prose. 27. Lemon Punch. Untitled. prose. 27. Schmitz. Untitled. Picture. 28. Puppet. Untitled. Prose. 28. Malteaser. Untitled. Prose. 28. Jester. SO IT GOES. Poem. 29. Brown Jug. CONTRIBUTORS ATTENTION! Prose. 29. Tiger. Untitled. Prose. 29. Scalper. QUALIFIED. Prose. 29. Purple Cow. Untitled. Prose. 29. E.B. D\u27JA EVER FEEL LIKE THIS? Picture. 29. Chaparral. Untitled. Prose. 30. Tiger. Untitled. Prose. 30. Malteaser. STOP THIEF! Prose. 30. Black and Blue Jay. Untitled. Prose. 30. Yellow Jacket. Untitled. Prose. 30. Tiger. Untitled. Prose. 30. Gargoyle. RIGHTO. Prose. 30. Yale Record. Untitled. Prose. 31. Puppet. Untitled. Prose. 31. Puppet. Untitled. Poem. 31. Virginia Reel. Untitled. Prose. 31. Puppet. Untitled. Prose. 31. Virginia Reel. Untitled. Prose. 31. Phoenix. Untitled. Prose. 31. Exchange. Untitled. Prose. 31. Stone Mill. Untitled. Prose. 31. Orange Peel. Untitled. Prose. 31. Stone Mill. Untitled. Prose. 32. Puppet. A SHORT TRAGEDY. Poem. 32. Stone Mill. Untitled. Prose. 32. Ex. Untitled. Prose. 32. Anonymous. Untitled. Prose. 32. Anonymous. Untitled. Prose. 32

Exploring the role of intermediaries in smart grid developments

Smart grid pilot projects have been initiated in a number of locations across the UK. Innovations considered in these projects include various technologies such as smart meters and electrical energy storage devices, as well as novel institutional arrangements which form the basis of commercial Demand Side Response (DSR) initiatives. This paper reports research into DSR using multiple case studies from Low Carbon Network Fund projects in the UK. The role of Aggregator companies in DSR is reported, their role of a key intermediary analysed and conceptualised using the Accessibility, Mobility and Receptivity (AMR) framework