We have identified an analgesic mechanism of linaclotide: it activates GC-C expressed on mucosal epithelial cells, resulting in the production and release of cGMP. This extracellular cGMP acts on and inhibits nociceptors, thereby reducing nociception. We also found that linaclotide reduces chronic abdominal pain in patients with IBS-C.

We have studied a series of samples of bovine serum albumin (BSA) solutions with protein concentration, c, ranging from 2 to 500 mg/mL and ionic strength, I, from 0 to 2 M by small-angle X-ray scattering (SAXS). The scattering intensity distribution was compared to simulations using an oblate ellipsoid form factor with radii of 17 x 42 x 42 A, combined with either a screened Coulomb, repulsive structure factor, SSC(q), or an attractive square-well structure factor, SSW(q). At pH = 7, BSA is negatively charged. At low ionic strength, I < 0.3 M, the total interaction exhibits a decrease of the repulsive interaction when compared to the salt-free solution, as the net surface charge is screened, and the data can be fitted by assuming an ellipsoid form factor and screened Coulomb interaction. At moderate ionic strength (0.3-0.5 M), the interaction is rather weak, and a hard-sphere structure factor has been used to simulate the data with a higher volume fraction. Upon further increase of the ionic strength (I >or= 1.0 M), the overall interaction potential was dominated by an additional attractive potential, and the data could be successfully fitted by an ellipsoid form factor and a square-well potential model. The fit parameters, well depth and well width, indicate that the attractive potential caused by a high salt concentration is weak and long-ranged. Although the long-range, attractive potential dominated the protein interaction, no gelation or precipitation was observed in any of the samples. This is explained by the increase of a short-range, repulsive interaction between protein molecules by forming a hydration layer with increasing salt concentration. The competition between long-range, attractive and short-range, repulsive interactions accounted for the stability of concentrated BSA solution at high ionic strength.

Negatively charged globular proteins in solution undergo a condensation upon adding trivalent counterions between two critical concentrations C and C, C

Background & Aims-The transient receptor potential (TRP) channel family includes transducers of mechanical and chemical stimuli for visceral sensory neurons. TRPA1 is implicated in inflammatory pain; it interacts with G-protein-coupled receptors, but little is known about its role in the gastrointestinal (GI) tract. Sensory information from the GI tract is conducted via 5 afferent subtypes along 3 pathways.

Colonic afferents with high mechanosensory thresholds contribute to inflammatory hypersensitivity, but not those with low thresholds. Pelvic afferents become involved mainly following recovery from inflammation, whereas splanchnic afferents are implicated during both inflammation and recovery.

a b s t r a c tDuring the development of a processing route for the Selective Laser Melting (SLM) powder-bed fabrication of the nickel superalloy CM247LC it has been observed that the 'island' scan-strategy used as standard by the Concept Laser M2 SLM powder-bed system strongly influences the grain structure of the material.Optical and SEM micrographs are presented to show the observed grain structure in the SLM fabricated and Hot Isostatically Pressed (HIPped) material. The repeating pattern shown in the grain structure has been linked to the overlapping of the 'island' pattern used as standard in the Concept Laser M2 powderbed facility. It is suggested that the formation of this bi-modal grain structure can be linked to the heat transfer away from the solidifying melt pool. The concept of a 'band' heating effect across each 'island' rather than 'moving point' heating has been suggested and has been supported by Electron Back Scattered Diffraction (EBSD) evidence. For comparison an EBSD map from a sample formed using a simple 'back-and-forth' strategy has also been presented and reveals a dramatically different grain structure and crystallographic orientation.MicroCT evidence, supported by SEM microscopy, shows that in the as-fabricated material the bimodal structure caused by the 'island' scan-strategy translates directly into the macroscopic pattern for the regions of extensive weld cracking associated with the SLM fabrication of c 0 hardenable materials. Similar microCT data has shown that HIPping can effectively close the internal cracks to provide a retro-fix solution.

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