Pro-B1X: the creator of bone

As we age, natural changes in bone and muscle occur. However, sometimes these changes can lead to diseases such as rheumatoid arthritis (RA) and osteoporosis. In the past 50 years there have been big improvements in the treatment of RA, leading to a large increase in life expectancy. However, new treatments are being developed at a slow pace and treatment strategies predominantly modify only minor features of the diseases and are not able to stop or reverse bone damage. Recently we have found a novel leukocyte transmigration peptide, agent X, which may have the ability to increase bone growth, leading to stronger, less breakable bones. Additionally, in models of disease, preliminary data has suggested that agent X is able to restore bone growth and decrease bone damage. This data advocates that in both healthy and diseased bones, agent X may have a beneficial strengthening role, providing possible therapeutic potential in reducing fracture rates in the elderly and restoring bone growth during arthritis

Monodisperse self-assembly in a model with protein-like interactions

We study the self-assembly behaviour of patchy particles with `protein-like' interactions that can be considered as a minimal model for the assembly of viral capsids and other shell-like protein complexes. We thoroughly explore the thermodynamics and dynamics of self assembly as a function of the parameters of the model and find robust assembly of all target structures considered. Optimal assembly occurs in the region of parameter space where a free energy barrier regulates the rate of nucleation, thus preventing the premature exhaustion of the supply of monomers that can lead to the formation of incomplete shells. The interactions also need to be specific enough to prevent the assembly of malformed shells, but whilst maintaining kinetic accessibility. Free-energy landscapes computed for our model have a funnel-like topography guiding the system to form the target structure, and show that the torsional component of the interparticle interactions prevents the formation of disordered aggregates that would otherwise act as kinetic traps.Comment: 11 pages; 10 figure

Point mutations in the α2 domain of HLA-A2.1 define a functionally relevant interaction with TAP

AbstractBackground: Glycoproteins encoded by the major histocompatibility complex class I region (MHC class I) present peptide antigens to cytotoxic T cells (CTLs). Peptides are delivered to the site of MHC class I assembly by the transporter associated with antigen processing (TAP), and cell lines that lack this transporter are unable to present endogenous antigens to CTLs. Although it has been shown that a fraction of newly synthesized class I molecules are in physical association with TAP, it is not known whether this interaction is functionally relevant, or where on the class I molecule the TAP binding site might be.Results C1R cells transfected with a mutant HLA-A2.1 heavy chain (HC), where threonine at position 134 in the α2 domain is changed to lysine (T134K), are unable to present endogenous antigens to CTLs. We have studied the biochemistry of this mutant in C1R cells, and found that a large pool of unstable empty class I HC–β2m (β-2 microglobulin) heterodimers exist that are rapidly transported to the cell surface. The T134K mutant seemed to bind peptide antigens and assemble with β2m as efficiently as wild-type HLA-A2.1. However, we show here that the inefficiency with which T134K presents intracellular antigen is associated with its inability to interact with the TAP heterodimer.Conclusion These experiments establish that the class I–TAP interaction is obligatory for the presentation of peptide epitopes delivered to the endoplasmic reticulum (ER) by TAP. Wild-type HLA-A2.1 molecules in TAP-deficient cells are retained in the ER, whereas T134K is rapidly released to the cell surface, but is unstable, suggesting a role for the TAP complex as an intracellular checkpoint that only affects the release of class I molecules with stably bound peptide ligands

3.6 and 4.5 μm Phase Curves and Evidence for Non-equilibrium Chemistry in the Atmosphere of Extrasolar Planet HD 189733b

We present new, full-orbit observations of the infrared phase variations of the canonical hot Jupiter HD 189733b obtained in the 3.6 and 4.5 μm bands using the Spitzer Space Telescope. When combined with previous phase curve observations at 8.0 and 24 μm, these data allow us to characterize the exoplanet's emission spectrum as a function of planetary longitude and to search for local variations in its vertical thermal profile and atmospheric composition. We utilize an improved method for removing the effects of intrapixel sensitivity variations and robustly extracting phase curve signals from these data, and we calculate our best-fit parameters and uncertainties using a wavelet-based Markov Chain Monte Carlo analysis that accounts for the presence of time-correlated noise in our data. We measure a phase curve amplitude of 0.1242% ± 0.0061% in the 3.6 μm band and 0.0982% ± 0.0089% in the 4.5 μm band, corresponding to brightness temperature contrasts of 503 ± 21 K and 264 ± 24 K, respectively. We find that the times of minimum and maximum flux occur several hours earlier than predicted for an atmosphere in radiative equilibrium, consistent with the eastward advection of gas by an equatorial super-rotating jet. The locations of the flux minima in our new data differ from our previous observations at 8 μm, and we present new evidence indicating that the flux minimum observed in the 8 μm is likely caused by an overshooting effect in the 8 μm array. We obtain improved estimates for HD 189733b's dayside planet-star flux ratio of 0.1466% ± 0.0040% in the 3.6 μm band and 0.1787% ± 0.0038% in the 4.5 μm band, corresponding to brightness temperatures of 1328 ± 11 K and 1192 ± 9 K, respectively; these are the most accurate secondary eclipse depths obtained to date for an extrasolar planet. We compare our new dayside and nightside spectra for HD 189733b to the predictions of one-dimensional radiative transfer models from Burrows et al. and conclude that fits to this planet's dayside spectrum provide a reasonably accurate estimate of the amount of energy transported to the night side. Our 3.6 and 4.5 μm phase curves are generally in good agreement with the predictions of general circulation models for this planet from Showman et al., although we require either excess drag or slower rotation rates in order to match the locations of the measured maxima and minima in the 4.5, 8.0, and 24 μm bands. We find that HD 189733b's 4.5 μm nightside flux is 3.3σ smaller than predicted by these models, which assume that the chemistry is in local thermal equilibrium. We conclude that this discrepancy is best explained by vertical mixing, which should lead to an excess of CO and correspondingly enhanced 4.5 μm absorption in this region. This result is consistent with our constraints on the planet's transmission spectrum, which also suggest excess absorption in the 4.5 μm band at the day-night terminator

The self-assembly and evolution of homomeric protein complexes

We introduce a simple "patchy particle" model to study the thermodynamics and dynamics of self-assembly of homomeric protein complexes. Our calculations allow us to rationalize recent results for dihedral complexes. Namely, why evolution of such complexes naturally takes the system into a region of interaction space where (i) the evolutionarily newer interactions are weaker, (ii) subcomplexes involving the stronger interactions are observed to be thermodynamically stable on destabilization of the protein-protein interactions and (iii) the self-assembly dynamics are hierarchical with these same subcomplexes acting as kinetic intermediates.Comment: 4 pages, 4 figure

The Species Effect:Differential Sphingosine-1-Phosphate Responses in the Bone in Human Versus Mouse

he deterioration of osteoblast-led bone formation and the upregulation of osteoclast-regulated bone resorption are the primary causes of bone diseases, including osteoporosis. Numerous circulating factors play a role in bone homeostasis by regulating osteoblast and osteoclast activity, including the sphingolipid—sphingosine-1-phosphate (S1P). However, to date no comprehensive studies have investigated the impact of S1P activity on human and murine osteoblasts and osteoclasts. We observed species-specific responses to S1P in both osteoblasts and osteoclasts, where S1P stimulated human osteoblast mineralisation and reduced human pre-osteoclast differentiation and mineral resorption, thereby favouring bone formation. The opposite was true for murine osteoblasts and osteoclasts, resulting in more mineral resorption and less mineral deposition. Species-specific differences in osteoblast responses to S1P were potentially explained by differential expression of S1P receptor 1. By contrast, human and murine osteoclasts expressed comparable levels of S1P receptors but showed differential expression patterns of the two sphingosine kinase enzymes responsible for S1P production. Ultimately, we reveal that murine models may not accurately represent how human bone cells will respond to S1P, and thus are not a suitable model for exploring S1P physiology or potential therapeutic agents

Standoff Methods for the Detection of Threat Agents: A Review of Several Promising Laser-Based Techniques

Detection of explosives, explosive precursors, or other threat agents presents a number of technological challenges for optical sensing methods. Certainly detecting trace levels of threat agents against a complex background is chief among these challenges; however, the related issues of multiple target distances (from standoff to proximity) and sampling time scales (from passive mines to rapid rate of march convoy protection) for different applications make it unlikely that a single technique will be ideal for all sensing situations. A number of methods for spanning the range of optical sensor technologies exist which, when integrated, could produce a fused sensor system possessing a high level of sensitivity to threat agents and a moderate standoff real-time capability appropriate for portal screening of personnel or vehicles. In this work, we focus on several promising, and potentially synergistic, laser-based methods for sensing threat agents. For each method, we have briefly outlined the technique and report on the current level of capability