GPR56, an orphan G protein-coupled receptor (GPCR) from the family of adhesion GPCRs, plays an indispensable role in cortical development and lamination. Mutations in the GPR56 gene cause a malformed cerebral cortex in both humans and mice that resembles cobblestone lissencephaly, which is characterized by overmigration of neurons beyond the pial basement membrane. However, the molecular mechanisms through which GPR56 regulates cortical development remain elusive due to the unknown status of its ligand. Here we identify collagen, type III, alpha-1 (gene symbol Col3a1) as the ligand of GPR56 through an in vitro biotinylation/ proteomics approach. Further studies demonstrated that Col3a1 null mutant mice exhibit overmigration of neurons beyond the pial basement membrane and a cobblestone-like cortical malformation similar to the phenotype seen in Gpr56 null mutant mice. Functional studies suggest that the interaction of collagen III with its receptor GPR56 inhibits neural migration in vitro. As for intracellular signaling, GPR56 couples to the Gα 12/13 family of G proteins and activates RhoA pathway upon ligand binding. Thus, collagen III regulates the proper lamination of the cerebral cortex by acting as the major ligand of GPR56 in the developing brain.brain malformation | meningeal fibroblasts D uring cerebral cortical development, most cortical neurons are born deep in specialized proliferative regions near the lining of the lateral ventricles and migrate out to take up residence in the surface layer of the brain, eventually forming a highly folded sheet of six neuronal layers (1-5). Disruptions in normal neuronal migration and positioning lead to cortical disorders, one of which is cobblestone lissencephaly (6). Cobblestone lissencephaly is typically seen in three distinct human congenital muscular dystrophy syndromes: muscle-eye-brain disease, Fukuyama-type congenital muscular dystrophy, and Walker-Warburg syndrome (6). Mutant mice with deletions in some members of the integrin pathway molecules and the extracellular matrix (ECM) constituents also exhibit cortical migration defects with deficiencies in basal lamina integrity and cortical ectopias, features that resemble the human cobblestone malformation (7-12). The suggested mechanism leading to cobblestone lissencephaly has been a defective pial basement membrane (BM) (6). However, recent literature demonstrates that abnormal neuronal migration may account partially for the improper formation of the cobblestone-like cortex (13-16).GPR56 is an orphan G protein-coupled receptor (GPCR) from the family of adhesion GPCRs. Mutations in GPR56 cause a specific human brain malformation called bilateral frontoparietal polymicrogyria (BFPP), an autosomal recessively inherited developmental disorder of the brain (17)(18)(19)(20). Magnetic resonance imaging of BFPP brains shows numerous (poly) small (micro) gyri, which extend diffusely across the frontal and parietal lobes with a decreasing anterior-to-posterior gradient of severity (17)(18)(19)(20). Further studies in...

The atomic-scale details during melting of a surface-free Lennard-Jones crystal were monitored using molecular dynamics simulations. Melting occurs when the superheated crystal spontaneously generates a sufficiently large number of spatially correlated destabilized particles that simultaneously satisfy the Lindemann and Born instability criteria. The accumulation and coalescence of these internal local lattice instabilities constitute the primary mechanism for homogeneous melt nucleation inside the crystal, in lieu of surface nucleation for equilibrium melting. The vibrational and elastic lattice instability criteria as well as the homogeneous nucleation theory all coincide in determining the superheating limit.

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Atomic structures of bulk glass-forming Cu 64.5 Zr 35.5 and the eutectic composition Cu 61.8 Zr 38.2 metallic glasses ͑MGs͒ have been studied by a combination of state-of-the-art experimental techniques and computational methods. Three-dimensional atomic configuration of the Cu 64.5 Zr 35.5 MG is established. It is found that icosahedronlike clusters are dominant in both MGs. However, icosahedronlike clusters centered by Cu atoms are slightly denser packing and less distorted in Cu 64.5 Zr 35.5 , which can enhance the glass forming ability ͑GFA͒ by suppressing atomic movements and increasing the structural incompatibility with competing crystalline phases. The atomic arrangements from short to medium-range order are envisaged and compared between both MGs.

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