The emergence in the United States of large-scale "megaregions" centered on major metropolitan areas is a phenomenon often taken for granted in both scholarly studies and popular accounts of ...contemporary economic geography. This paper uses a data set of more than 4,000,000 commuter flows as the basis for an empirical approach to the identification of such megaregions. We compare a method which uses a visual heuristic for understanding areal aggregation to a method which uses a computational partitioning algorithm, and we reflect upon the strengths and limitations of both. We discuss how choices about input parameters and scale of analysis can lead to different results, and stress the importance of comparing computational results with "common sense" interpretations of geographic coherence. The results provide a new perspective on the functional economic geography of the United States from a megaregion perspective, and shed light on the old geographic problem of the division of space into areal units.
This paper examines the use of the metaphorical terms ‘mosaic’ and ‘tapestry’ in conceptualizing the structure of spatial organization over more than a century of geographic thought. The duality ...between a mosaic-like, discrete geography and a tapestry-like, indiscrete geography is one of the fundamental paradoxes in spatial ontology; this paper explores how this duality has configured the commitments of geography and continues to play a role in the more recent debate between ‘territorial’ and ‘relational’ spatial metaphors. It argues for a reconciliation of incompatible metaphors, since the complexity of the phenomenal world exceeds resolution into any single descriptive system.
This paper examines the first appearance of the term 'regional planning' in the 14th edition of the Encyclopædia Britannica (1929) in order to foreground the centrality of cultural criticism in the ...first wave of regional thinking. Through an intellectual history of the work of Benton MacKaye and Lewis Mumford, the authors of the encyclopaedia entry, it is shown that the 'region' served as a device for conceptually reuniting the fractured life of modern industrialization, and not merely or even primarily as a new scalar object for the administrative state.
Angiotensin II type 1 receptor (AT1R) is a G protein-coupled receptor that serves as a primary regulator for blood pressure maintenance. Although several anti-hypertensive drugs have been developed ...as AT1R blockers (ARBs), the structural basis for AT1R ligand-binding and regulation has remained elusive, mostly due to the difficulties of growing high-quality crystals for structure determination using synchrotron radiation. By applying the recently developed method of serial femtosecond crystallography at an X-ray free-electron laser, we successfully determined the room-temperature crystal structure of the human AT1R in complex with its selective antagonist ZD7155 at 2.9-Å resolution. The AT1R-ZD7155 complex structure revealed key structural features of AT1R and critical interactions for ZD7155 binding. Docking simulations of the clinically used ARBs into the AT1R structure further elucidated both the common and distinct binding modes for these anti-hypertensive drugs. Our results thereby provide fundamental insights into AT1R structure-function relationship and structure-based drug design.
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•Crystal structure of the human Angiotensin II type 1 receptor at 2.9-Å resolution•Structure is solved by X-ray laser serial femtosecond crystallography•Antagonist ZD7155 forms critical interactions with Tyr35, Trp84 and Arg167•Docking reveals binding modes of common angiotensin receptor blockers
Structure determination of human Angiotensin II type 1 receptor bound to an antagonist using serial femtosecond crystallography with X-ray free-electron laser and docking studies of other common anti-hypertensive drugs into the structure offer insights into design of blood pressure modulators.
Whether to treat regions as distinct, bordered entities or meshes of borderless flows has long been a debate for geographers. This paper uses the methodological and conceptual insights of network ...analysis to argue for an approach to regionalisation that treats them neither as perfectly enclosed nor perfectly borderless. By comparing the many contested readings of ‘community’ in geography and the social sciences to the operational definition of a ‘community’ in graph theory, I extend historic questions about the spatial definition of human communities and describe how network analysis can offer insight about the texture of human geography. A case study, using network data about commuting in the New England region of the US, shows how these algorithmically‐detected regions are both stable and fluid at once. The paper proposes the term ‘conchoration’ to describe the ontology of emergent, functionally whole regions which are nevertheless perforated and interdependent.
Lipidic cubic phase (LCP) crystallization has proven successful for high-resolution structure determination of challenging membrane proteins. Here we present a technique for extruding gel-like LCP ...with embedded membrane protein microcrystals, providing a continuously renewed source of material for serial femtosecond crystallography. Data collected from sub-10-μm-sized crystals produced with less than 0.5 mg of purified protein yield structural insights regarding cyclopamine binding to the Smoothened receptor.
The human glucagon receptor, GCGR, belongs to the class B G-protein-coupled receptor family and plays a key role in glucose homeostasis and the pathophysiology of type 2 diabetes. Here we report the ...3.0 Å crystal structure of full-length GCGR containing both the extracellular domain and transmembrane domain in an inactive conformation. The two domains are connected by a 12-residue segment termed the stalk, which adopts a β-strand conformation, instead of forming an α-helix as observed in the previously solved structure of the GCGR transmembrane domain. The first extracellular loop exhibits a β-hairpin conformation and interacts with the stalk to form a compact β-sheet structure. Hydrogen-deuterium exchange, disulfide crosslinking and molecular dynamics studies suggest that the stalk and the first extracellular loop have critical roles in modulating peptide ligand binding and receptor activation. These insights into the full-length GCGR structure deepen our understanding of the signalling mechanisms of class B G-protein-coupled receptors.
The Smoothened receptor (SMO) belongs to the Class Frizzled of the G protein-coupled receptor (GPCR) superfamily, constituting a key component of the Hedgehog signalling pathway. Here we report the ...crystal structure of the multi-domain human SMO, bound and stabilized by a designed tool ligand TC114, using an X-ray free-electron laser source at 2.9 Å. The structure reveals a precise arrangement of three distinct domains: a seven-transmembrane helices domain (TMD), a hinge domain (HD) and an intact extracellular cysteine-rich domain (CRD). This architecture enables allosteric interactions between the domains that are important for ligand recognition and receptor activation. By combining the structural data, molecular dynamics simulation, and hydrogen-deuterium-exchange analysis, we demonstrate that transmembrane helix VI, extracellular loop 3 and the HD play a central role in transmitting the signal employing a unique GPCR activation mechanism, distinct from other multi-domain GPCRs.
This paper reflects on a digital public history project conducted by the authors in Madison, Wisconsin. It uses these reflections to show how digital methods can create new possibilities in the field ...of historic preservation, and to emphasise that new technology alone does not cut through old challenges relating to public engagement. The bias towards newness and fluidity in digital methods offers an instructive contrast to the bias towards permanence and continuity in historic preservation. Bringing these two worlds into dialogue offers the possibility of strengthening each.
Lipidic cubic phases (LCPs) have emerged as successful matrixes for the crystallization of membrane proteins. Moreover, the viscous LCP also provides a highly effective delivery medium for serial ...femtosecond crystallography (SFX) at X-ray free-electron lasers (XFELs). Here, the adaptation of this technology to perform serial millisecond crystallography (SMX) at more widely available synchrotron microfocus beamlines is described. Compared with conventional microcrystallography, LCP-SMX eliminates the need for difficult handling of individual crystals and allows for data collection at room temperature. The technology is demonstrated by solving a structure of the light-driven proton-pump bacteriorhodopsin (bR) at a resolution of 2.4 Å. The room-temperature structure of bR is very similar to previous cryogenic structures but shows small yet distinct differences in the retinal ligand and proton-transfer pathway.
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