Myelin inhibitors of axonal regeneration, like Nogo and MAG, block regrowth after injury to the adult CNS. While a GPI-linked receptor for Nogo (NgR) has been identified, MAG's receptor is unknown. We show that MAG inhibits regeneration by interaction with NgR. Binding of and inhibition by MAG are lost if neuronal GPI-linked proteins are cleaved. Binding of MAG to NgR-expressing cells is GPI dependent and sialic acid independent. Conversely, NgR binds to MAG-expressing cells. MAG, but not a truncated MAG that binds neurons but does not inhibit regeneration, precipitates NgR from NgR-expressing cells, DRG, and cerebellar neurons. Importantly, NgR antibody, soluble NgR, or dominant-negative NgR each prevent inhibition of neurite outgrowth by MAG. Also, MAG and Nogo66 compete for binding to NgR. These results suggest redundancy in myelin inhibitors and indicate therapies for CNS injuries.

The neuronal ubiquitin/proteasomal pathway has been implicated in the pathogenesis of Alzheimer's disease (AD). We now show that a component of the pathway, ubiquitin C-terminal hydrolase L1 (Uch-L1), is required for normal synaptic and cognitive function. Transduction of Uch-L1 protein fused to the transduction domain of HIV-transactivator protein (TAT) restores normal enzymatic activity and synaptic function both in hippocampal slices treated with oligomeric Abeta and in the APP/PS1 mouse model of AD. Moreover, intraperitoneal injections with the fusion protein improve the retention of contextual learning in APP/PS1 mice over time. The beneficial effect of the Uch-L1 fusion protein is associated with restoration of normal levels of the PKA-regulatory subunit IIalpha, PKA activity, and CREB phosphorylation.

Unlike neonatal axons, mammalian adult axons do not regenerate after injury. Likewise, myelin, a major factor in preventing regeneration in the adult, inhibits regeneration from older but not younger neurons. Identification of the molecular events responsible for this developmental loss of regenerative capacity is believed key to devising strategies to encourage regeneration in adults after injury. Here, we report that the endogenous levels of the cyclic nucleotide, cAMP, are dramatically higher in young neurons in which axonal growth is promoted both by myelin in general and by a specific myelin component, myelin-associated glycoprotein (MAG), than in the same types of neurons that, when older, are inhibited by myelin-MAG. Inhibiting a downstream effector of cAMP [protein kinase A (PKA)] prevents myelin-MAG promotion from young neurons, and elevating cAMP blocks myelin-MAG inhibition of neurite outgrowth in older neurons. Importantly, developmental plasticity of spinal tract axons in neonatal rat pups in vivo is dramatically reduced by inhibition of PKA. Thus, the switch from promotion to inhibition by myelin-MAG, which marks the developmental loss of regenerative capacity, is mediated by a developmentally regulated decrease in endogenous neuronal cAMP levels.

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Lesioning the peripheral branch of a dorsal root ganglion (DRG) neuron before injury of the central branch of the same neuron enables spontaneous regeneration of these spinal axons. This effect is cAMP and transcription dependent. Here, we show that the cytokine interleukin-6 (IL-6) is upregulated in DRG neurons after either a conditioning lesion or treatment with dibutyryl-cAMP. In culture, IL-6 allows neurons to grow in the presence of inhibitors of regeneration present in myelin. Importantly, intrathecal delivery of IL-6 to DRG neurons blocks inhibition by myelin both in vitro and in vivo, effectively mimicking the conditioning lesion. Blocking IL-6 signaling has no effect on the ability of cAMP to overcome myelin inhibitors. Consistent with this, IL-6-deficient mice respond to a conditioning lesion as effectively as wild-type mice. We conclude that IL-6 can mimic both the cAMP effect and the conditioning lesion effect but is not an essential component of either response.

Providing fresh and drinkable water is a grand challenge the world is facing today. Development in nanomaterials can create possibilities of using energy-efficient nanoporous materials for water desalination. In this work, we demonstrated that ultrathin conductive metal–organic framework (MOF) is capable of efficiently rejecting ions while giving access to high water flux. Through molecular dynamic simulation, we discovered perfect ion rejection rate by two-dimensional (2D) multilayer MOF. The naturally porous structure of 2D MOF enables significantly 3–6 orders of magnitude higher water permeation compared to that of traditional membranes. Few layers MOF membranes show 1 order of magnitude higher water flux compared to that of single-layer nanoporous graphene or molybdenum disulfide (MoS2) without the requirement of drilling pores. The excellent performance of 2D MOF membranes is supported by water permeation calculations, water density/velocity profiles at the pore, and the water interfacial diffusion near the pore. Water desalination performance of MOF offers a potential solution for energy-efficient water desalination.

Nogo receptor (NgR)-mediated control of axon growth relies on the central nervous system-specific type I transmembrane protein Lingo-1. Interactions between Lingo-1 and NgR, along with a complementary co-receptor, result in neurite and axonal collapse. In addition, the inhibitory role of Lingo-1 is particularly important in regulation of oligodendrocyte differentiation and myelination, suggesting that pharmacological modulation of Lingo-1 function could be a novel approach for nerve repair and remyelination therapies. Here we report on the crystal structure of the ligand-binding ectodomain of human Lingo-1 and show it has a bimodular, kinked structure composed of leucine-rich repeat (LRR) and immunoglobulin (Ig)-like modules. The structure, together with biophysical analysis of its solution properties, reveals that in the crystals and in solution Lingo-1 persistently associates with itself to form a stable tetramer and that it is its LRR-Ig-composite fold that drives such assembly. Specifically, in the crystal structure protomers of Lingo-1 associate in a ring-shaped tetramer, with each LRR domain filling an open cleft in an adjacent protomer. The tetramer buries a large surface area (9,200 Å 2 ) and may serve as an efficient scaffold to simultaneously bind and assemble the NgR complex components during activation on a membrane. Potential functional binding sites that can be identified on the ectodomain surface, including the site of self-recognition, suggest a model for protein assembly on the membrane.Injured neurons in mature organisms are unable to effectively regrow their axons after central nervous system damage. One of the many factors restricting axonal regeneration after injury is the growth-inhibiting components associated with damaged myelin. At least three of these components, Nogo-66, myelin-associated glycoprotein (MAG), 3 and oligodendrocyte myelin glycoprotein, either individually or collectively, have been shown to be potent inhibitors of neurite outgrowth (1, 2). All three signal inhibition through the Nogo receptor complex, composed of the ligand-binding Nogo-66 receptor (NgR) and two complementary co-receptors p75 and Lingo-1 that act as a signal-transducing pair on an axon's cell membrane (3, 4). Although both NgR and the p75 nerve growth factor receptor have well documented roles in the context of myelin inhibition, reports exploring the role of Lingo-1 are more recent.Human Lingo-1 is a central nervous system-specific transmembrane glycoprotein (Fig. 1) also known as LERN-1, which belongs to a larger family of LRR-Ig-containing proteins involved in central nervous system development and axonal growth (5). Its large extracellular or ectodomain is thought to be of functional importance in protein-protein recognition and is characterized by a tandem array of multiple LRRs and one Iglike domain. The first studies examining the role of Lingo-1 demonstrated that in cultured neurons Lingo-1 directly associates with NgR and p75 and that whenever myelin-NgR/p75-mediated growth inhibition is observe...

Water desalination technologies are extensively utilized to solve water scarcity problems in many regions of the world. Discovery and application of two-dimensional (2D) nanoporous materials provide engineers a viable solution for reducing to a large extent energy consumption during the water desalination process. In this work, we conducted a thorough comparison of the water permeability and ion rejection rate between various 2D materials, including MoS2, graphene, phosphorene, boron nitride, and MoSe2. Through molecular dynamics simulation, we demonstrated that among all 2D materials with the same pore size, single-layer MoS2 consistently performs 27% better than graphene, 38% than phosphorene, 35% than BN, and 20% than MoSe2 in terms of water permeability while maintaining a greater than 99% ion rejection rate. We further investigated how the fundamental physics behind the outstanding performance of MoS2 is a combination of water structure and dynamics near the membrane surface, energy barrier, and water packing and velocity inside the nanopore.