Are there differences in brain morphology according to handedness?

OBJECTIVE: This study aimed to investigate the differences in brain morphology according to handedness. MATERIALS AND METHODS: Forty-two healthy subjects were enrolled (21 right-handers and 21 nonright-handers). The two groups were classified according to the Edinburgh Handedness Inventory. Measures of cortical morphology, such as thickness, surface area, volume, and curvature, and the volumes of subcortical structures, such as the amygdala, caudate, hippocampus, globus pallidus, putamen, and thalamus, were compared between the groups according to handedness using whole-brain 3D T1-weighted MRI. In addition, we investigated the white matter differences between the groups using diffusion tensor imaging. Moreover, we quantified correlations between the handedness scales of the Edinburgh Handedness Inventory and each measure of different brain morphologies. RESULTS: The volumes of the right putamen and left globus pallidus in nonright-handed participants were significantly larger than those who were right-handed (0.3559 vs. 0.3155%, p = .0028; 0.1101 vs. 0.0975%, p = .0025; respectively). Moreover, the volumes of the right putamen and left globus pallidus were negatively correlated with the handedness scales of the Edinburgh Handedness Inventory (r = -.392, p = .0101; r = -.361, p = .0189; respectively). However, the cortex morphology and the other subcortical volumes were not significantly different between the two groups. In addition, we did not find any white matter differences between the groups. CONCLUSIONS: We demonstrated that there were significant differences in brain morphology between right-handers and nonright-handers, especially in the basal ganglia, which could produce differences in motor control according to handedness.

The transcription factor STAT2 enhances proteasomal degradation of RCAN1 through the ubiquitin E3 ligase FBW7.

Down syndrome is the most common genetic disorder and is characterized by three copies of chromosome 21. Regulator of calcineurin 1 (RCAN1) is located close to the Down syndrome critical region (distal part of chromosome 21), and its product functions as an endogenous inhibitor of calcineurin signaling. RCAN1 protein stability is regulated by several inflammatory signaling factors, though the underlying mechanisms remain incompletely understood. Here, we report that RCAN1 interacts with the inflammation-linked transcription factor, signal transducer and activator of transcription 2 (STAT2) in mammalian cells. STAT2 overexpression decreased levels of RCAN1 protein. Decreases in RCAN1 were blocked by a proteasome inhibitor, indicating that STAT2 regulates RCAN1 degradation via the ubiquitin-proteasome system. Co-immunoprecipitation/immunoblot analyses showed that STAT2 enhanced RCAN1 ubiquitination through the ubiquitin E3 ligase FBW7. This pathway appeared to be physiologically relevant, as treatment of cells with interferon-α reduced RCAN1 levels through the activation of STAT2 and FBW7. Together, these results suggest that STAT2 influences diverse cellular processes linked to RCAN1 by negatively affecting RCAN1 protein stability.

Methods for photocrosslinking alginate hydrogel scaffolds with high cell viability.

Methods for seeding high-viability (>85%) three-dimensional (3D) alginate-chondrocyte hydrogel scaffolds are presented that employ photocrosslinking of methacrylate-modified alginate with the photoinitiator VA-086. Comparison with results from several other photoinitiators, including Irgacure 2959, highlights the role of solvent, ultraviolet exposure, and photoinitiator cytotoxicity on process viability of bovine chondrocytes in two-dimensional culture. The radicals generated from VA-086 photodissociation are shown to be noncytotoxic at w/v concentrations up to 1.5%, enabling photocrosslinking without significant cell death. The applicability of these photoinitiators for generating 3D tissue-engineered constructs is evaluated by measuring cell viability in 3D constructs with aggregate moduli in the 10-20 kPa range. Hydrogels with encapsulated bovine chondrocytes were constructed with >85% viability using VA-086. While the commonly used Irgacure 2959 is noncytotoxic in its native state and crosslinks the alginate at weight fractions much lower than VA-086, the cytotoxicity of IRG2959's photogenerated radical leads to viabilities below 70% in the conditions tested.

Down syndrome candidate region-1 protein interacts with Tollip and positively modulates interleukin-1 receptor-mediated signaling.

BACKGROUND: The Down syndrome candidate region-1 gene (DSCR1, also known as RCAN1) is situated close to the Down Syndrome Critical Region (DSCR), which contains genes responsible for many features of Down syndrome. DSCR1 modulates calcineurin phosphatase activity, though its functional role is incompletely understood. METHODS: Here we investigated the role of DSCR1-1S isoform in IL-1 receptor (IL-1R)-mediated signaling by analyzing interaction between DSCR1-1S and the IL-1R pathway components Tollip, IRAK-1, and TRAF6. RESULTS: Co-immunoprecipitation analyses of HEK293 cells revealed that DSCR1-1S interacted with Tollip, an IRAK-1 inhibitor, leading to the dissociation of IRAK-1 from Tollip. Similarly, both DSCR1-1S and Tollip interacted with TRAF6, with DSCR1 reducing interaction between Tollip and TRAF6. DSCR1-1S also stimulated IL-1R-mediated signaling pathways, TAK1 activation, NF-kappaB transactivation, and IL-8 production, all downstream consequences of IL-1R activation. GENERAL SIGNIFICANCE: Together, these results suggest that DSCR1-1S isoform positively modulates IL-1R-mediated signaling pathways by regulating Tollip/IRAK-1/TRAF6 complex formation.

Calmodulin dynamically regulates the trafficking of the metabotropic glutamate receptor mGluR5.

Metabotropic glutamate receptors (mGluRs) 1-8 are G protein-coupled receptors (GPCRs) that modulate excitatory neurotransmission, neurotransmitter release, and synaptic plasticity. PKC regulates many aspects of mGluR function, including protein-protein interactions, Ca(2+) signaling, and receptor desensitization. However, the mechanisms by which PKC regulates mGluR function are poorly understood. We have now identified calmodulin (CaM) as a dynamic regulator of mGluR5 trafficking. We show that the major PKC phosphorylation site on the intracellular C terminus of mGluR5 is serine 901 (S901), and phosphorylation of this residue is up-regulated in response to both receptor and PKC activation. In addition, S901 phosphorylation inhibits mGluR5 binding to CaM, decreasing mGluR5 surface expression. Furthermore, blocking PKC phosphorylation of mGluR5 on S901 dramatically affects mGluR5 signaling by prolonging Ca(2+) oscillations. Thus, our data demonstrate that mGluR5 activation triggers phosphorylation of S901, thereby directly linking PKC phosphorylation, CaM binding, receptor trafficking, and downstream signaling.

Metabotropic glutamate receptors: phosphorylation and receptor signaling.

Metabotropic glutamate receptors (mGluRs) play important roles in neurotransmission, neuronal development, synaptic plasticity, and neurological disorders. Recent studies have revealed a sophisticated interplay between mGluRs and protein kinases: activation of mGluRs regulates the activity of a number of kinases, and direct phosphorylation of mGluRs affects receptor signaling, trafficking, and desensitization. Here we review the emerging literature on mGluR phosphorylation, signaling, and synaptic function.

Overexpression of DSCR1 blocks zinc-induced neuronal cell death through the formation of nuclear aggregates.

The Down syndrome (DS) candidate region gene 1 (DSCR1) is localized near DS critical region on chromosome 21 and is overexpressed in the brains of DS patients. Although DSCR1 was known for a modulator of calcineurin, the overexpression of DSCR1 is thought to play a role in neuronal cell death. Zinc, one of the most abundant transition metals in the brain, may also contribute to selective neuronal cell death when present in excessive amounts. In the present study, we investigated the effect of DSCR1 overexpression on zinc-induced cell death in hippocampal neuroprogenitor cells. The overexpression of DSCR1 caused apoptotic cell death without an apparent formation of intracellular protein inclusions. Upon exposure to zinc, soluble DSCR1 levels were significantly decreased and insoluble levels were enhanced to a similar extent, which were partially caused by the zinc-induced inhibition of proteasomal activity and a consequently diminished degradation of DSCR1. Furthermore, zinc treatment induced the formation of nuclear DSCR1 aggregates, which blocked zinc-induced cell death. These findings indicate that, although the up-regulation of DSCR1 levels exerts a cytotoxic effect, the addition of zinc leads to the formation of cytoprotective nuclear aggregates in neuronal cells.

Using nanoparticles to create self-healing composites.

The need for viable materials for optical communications, display technologies, and biomedical engineering is driving the creation of multilayer composites that combine brittle materials, such as glass, with moldable polymers. However, crack formation is a critical problem in composites where thin brittle films lie in contact with deformable polymer layers. Using computer simulations, we show that adding nanoparticles to the polymers yields materials in which the particles become localized at nanoscale cracks and effectively form "patches" to repair the damaged regions. Through micromechanics simulations, we evaluate the properties of these systems in the undamaged, damaged, and healed states and determine optimal conditions for harnessing nanoparticles to act as responsive, self-assembled "band aids" for composite materials. The results reveal situations where the mechanical properties of the repaired composites can potentially be restored to 75%-100% of the undamaged material.

Modeling the self-assembly of copolymer-nanoparticle mixtures confined between solid surfaces.

Using numerical calculations, we undertake the first morphological studies of mixtures of AB diblocks and nanoparticles that are confined between two hard walls. A complex interplay of entropic and enthalpic interactions drives the nonselective particles to localize at the hard walls and A/B interfaces, causing the mixture to spontaneously self-assemble into particle-decorated lamellae that are oriented perpendicular to the surfaces. The film reveals a periodic array of particle "nanowires" that are separated by the nanoscale polymer domains, yielding a vital material for nanodevice fabrication.

Self-assembly of a binary mixture of particles and diblock copolymers.

Using theoretical models, we undertake the first investigation into the synergy and rich phase behavior that emerges when binary particle mixtures are blended with microphase-separating copolymers. We isolate an example of spontaneous hierarchical self-assembly in such hybrid materials, where the system exhibits both nanoscopic ordering of the particles and macroscopic phase transformation in the copolymer matrix. Furthermore, the self-assembly is driven by entropic effects involving all the different components. The results reveal that entropy can be exploited to create highly ordered nanocomposites with potentially unique electronic and photonic properties.

Entropically driven formation of hierarchically ordered nanocomposites.

Using theoretical models, we undertake the first investigation into the rich behavior that emerges when binary particle mixtures are blended with microphase-separating copolymers. We isolate an example of coupled self-assembly in such materials, where the system undergoes a nanoscale ordering of the particles along with a phase transformation in the copolymer matrix. Furthermore, the self-assembly is driven by entropic effects involving all the different components. The results reveal that entropy can be exploited to create highly ordered nanocomposites with potentially unique electronic and photonic properties.

Binary hard sphere mixtures in block copolymer melts.

We perform a self-consistent-field/density-functional-theory hybrid analysis for a system of diblock copolymers mixed with polydisperse, hard, spherical particles of various chemical species. We apply this theory to study the equilibrium morphologies of two different binary sphere/diblock melts. First, we examine the case where the particles have two different sizes, but both types are preferentially wetted by one of the copolymer blocks. We find that the single-particle distributions for the two species do not track one another and that the particles show a degree of entropically generated separation based on size, due to confinement within the diblock matrix. Second, we study the case where the particles are all the same size, but are of two different chemical species. We find that, as expected, the particle distributions reveal a degree of enthalpically driven separation, due to the spheres' preferential affinities for different blocks of the copolymer.

Isolation and characterization of water-soluble intermediates of blue pigments transformed from geniposide of Gardenia jasminoides.

Gardenia blue dye was obtained through the reaction of methylamine with genipin, the aglycone of geniposide isolated from the fruits of Gardenia jasminoides. The resulting blue pigments were passed through Bio-Gel P-2 resin yielding five fractions, GM1-GM5. Four fractions (GM1-GM4) were all blue pigments, and the first eluted higher molecular weight fraction GM1 had a higher tinctorial strength than the later eluted lower molecular weight fractions, GM2-GM4. The last eluted GM5 fraction with lambda(max) of 292 nm was colorless and was confirmed as the true intermediate of the blue pigments on the basis of UV-vis spectrophotometric evidence. The GM5 fraction was composed of two epimeric isomers, and their structures were characterized by (1)H NMR, (1)H-(1)H COSY, (13)C NMR, and HMQC and HMBC spectral measurements.