Constitutively active BRS3 is a genuinely orphan GPCR in placental mammals.

G protein-coupled receptors (GPCRs) play an important role in physiology and disease and represent the most productive drug targets. Orphan GPCRs, with their endogenous ligands unknown, were considered a source of drug targets and consequently attract great interest to identify their endogenous cognate ligands for deorphanization. However, a contrary view to the ubiquitous existence of endogenous ligands for every GPCR is that there might be a significant overlooked fraction of orphan GPCRs that function constitutively in a ligand-independent manner only. Here, we investigated the evolution of the bombesin receptor-ligand family in vertebrates in which one member-bombesin receptor subtype-3 (BRS3)-is a potential orphan GPCR. With analysis of 17 vertebrate BRS3 structures and 10 vertebrate BRS3 functional data, our results demonstrated that nonplacental vertebrate BRS3 still connects to the original ligands-neuromedin B (NMB) and gastrin-releasing peptide (GRP)-because of adaptive evolution, with significantly changed protein structure, especially in three altered key residues (Q127R, P205S, and R294H) originally involved in ligand binding/activation, whereas the placental mammalian BRS3 lost the binding affinity to NMB/GRP and constitutively activates Gs/Gq/G12 signaling in a ligand-independent manner. Moreover, the N terminus of placental mammalian BRS3 underwent positive selection, exhibiting significant structural differences compared to nonplacental vertebrate BRS3, and this domain plays an important role in constitutive activity of placental mammalian BRS3. In conclusion, constitutively active BRS3 is a genuinely orphan GPCR in placental mammals, including human. To our knowledge, this study identified the first example that might represent a new group of genuinely orphan GPCRs that will never be deorphanized by the discovery of a natural ligand and provided new perspectives in addition to the current ligand-driven GPCR deorphanization

Effect of Tensile Strength on the Microstructure of Graphite Impregnated with Salt Revealed by In Situ Synchrotron-Based Two-Dimensional X‑ray Diffraction

Owing to the inhomogeneous distribution of FLiNaK salt impregnated into graphite which is observed by scanning electron microscopy and an element probe micro-analyzer, a map scan of in situ real-time tensile synchrotron-based two-dimensional X-ray diffraction (2D-XRD) at several fixed external forces was implemented to reveal the local microstructure evolution of graphite and FLiNaK salt. Notably, a stress concentration area (SCA), that is, the main interaction area between graphite and salt, was found and then transformed from one region to another region because of the unbalanced squeeze interaction between graphite and FLiNaK salt with the increase of external force. During the external stress load process, a smaller grain size, poorer crystallinity of graphite and a larger grain size, better crystallinity of FLiNaK salt appear in the SCA; meanwhile, the changes of crystallographic preferred orientation of FLiNaK salt domains in SCA imply that the external load force makes better the ordered stacking of the larger crystal grains of the FLiNaK salt impregnated into graphite. Most importantly, we have found for the first time that the fracture position of graphite impregnated with FLiNaK salt always occurs near the SCA rather than at a fixed region under the external stress load. Thus, the present study not only helps to reveal the interaction mechanism between graphite and FLiNaK salt under the external stress load but also contributes to accurately predict and analyze the stress state of components, which would have an effective impact on the design of a molten salt reactor and the reliability of the component safety assessment

Lamellar Keratoplasty Using Acellular Bioengineering Cornea (BioCorneaVet^TM) for the Treatment of Feline Corneal Sequestrum: A Retrospective Study of 62 Eyes (2018–2021)

To retrospectively evaluate the effectiveness and outcome of lamellar keratoplasty using acellular bioengineering cornea (BioCorneaVetTM) for the treatment of feline corneal sequestrum (FCS). The medical records of cats diagnosed with FCS that underwent lamellar keratoplasty with BioCorneaVetTM between 2018 and 2021 with a minimum of 3 months of follow-up were reviewed. Follow-up examinations were performed weekly for 3 months, and then optical coherence tomography (OCT) examination was performed on select patients at 0, 3, 6, and 12 months post-operatively. A total of 61 cats (30 left eyes and 32 right eyes) were included. The Persian breed was overrepresented, 48/61 (78.69%). Four different thicknesses of acellular bioengineering cornea were used (200, 300, 400, or 450 microns), and the mean graft size was 8.23 mm (range, 5.00–12.00 mm). Minor complications were composed of partial dehiscence, and protrusion of the graft occurred in 7/62 eyes (11.29%). The median postoperative follow-up was 12.00 months (range, 3–41 months). A good visual outcome was achieved in 60/62 eyes (96.77%), and a mild to moderate corneal opacification occurred in 2/62 (3.23%). No recurrence of corneal sequestrum was observed. From the results, lamellar keratoplasty using acellular bioengineering cornea (BioCorneaVetTM) is an effective treatment for FCS, providing a good tectonic support and natural collagen framework, and resulting in satisfactory visual and cosmetic effects