ObjectiveLaquinimod is an emerging oral medication for multiple sclerosis (MS) that reduces brain atrophy and progression of disability in two Phase III clinical trials. The mechanism of these effects is unclear. Persistent activation of microglia occurs in MS and contributes to injury. Thus, we investigated whether laquinimod alters properties of microglia in culture and in experimental autoimmune encephalomyelitis (EAE), and whether this reduces neurodegeneration.MethodsMicroglia were cultured from human brains. EAE was induced in mice.ResultsThe activation of human microglia increased levels of several pro- and anti-inflammatory cytokines and these elevations were attenuated by pretreatment with laquinimod. Laquinimod prevented the decline in activated microglia of miR124a, a microRNA implicated in maintaining microglia quiescence, and reduced the activity of several signaling pathways (Jun-N-terminal kinase, ribosomal S6 kinase, and AKT/protein kinase B) in activated microglia. In EAE, axonal injury correlated with accumulation of microglia/macrophages in the spinal cord. EAE mice treated with laquinimod before onset of clinical signs subsequently had reduced microglia/macrophage density and axonal injury. Remarkably, when laquinimod treatment was initiated well into the disease course, the progressive demyelination, and axonal loss was halted. Besides inflammatory molecules associated with microglia, the level of inducible nitric oxide (NO) synthase capable of producing free radical toxicity was attenuated by laquinimod in EAE mice. Finally, in coculture where microglia activation caused neuronal death, laquinimod decreased NO levels, and neurotoxicity.InterpretationLaquinimod is a novel inhibitor of microglial activation that lowers microglia-induced neuronal death in culture and axonal injury/loss in EAE.

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A one-dimensional model of filament growth in conductive-bridge memory cells is presented, in which ions are thermally excited from the anode surface into the electrolyte, pulled by the electric field through a periodic series of wells and reduced at the cathode to form a metallic filament. The voltage, temperature, and thickness dependencies of the time required to program a cell are calculated, and material parameters for Ag/GeS2/W cells are obtained by comparison to experiment. The relation of the model to recent observations of quantized conductance is highlighted, as is the need for further study of the Ag/GeS2 interface.

Human 53BP1 is primarily known as a key player in regulating DNA double strand break (DSB) repair choice; however, its involvement in other biological process is less well understood. Here, we report a previously uncharacterized function of 53BP1 at heterochromatin, where it undergoes liquid-liquid phase separation (LLPS) with the heterochromatin protein HP1α in a mutually dependent manner. Deletion of 53BP1 results in a reduction in heterochromatin centers and the de-repression of heterochromatic tandem repetitive DNA. We identify domains and residues of 53BP1 required for its LLPS, which overlap with, but are distinct from, those involved in DSB repair. Further, 53BP1 mutants deficient in DSB repair, but proficient in LLPS, rescue heterochromatin de-repression and protect cells from stress-induced DNA damage and senescence. Our study suggests that in addition to DSB repair modulation, 53BP1 contributes to the maintenance of heterochromatin integrity and genome stability through LLPS.

The ability to control the variations in IC fabrication process is rapidly diminishing as feature sizes continue towards the sub-100 nm regime. As a result, there is an increasing uncertainty in the performance of CMOS circuits. Accounting for the worst case values of all parameters will result in an unacceptably low timing yield. Design for Variability, which involves designing to achieve a given level of confidence in the performance of ICs, is fast becoming an indispensable part of IC design methodology. This paper 1 describes a method to identify certain paths in the circuit that are responsible for the spread of timing performance. The method is based on defining a disutility function of the gate and path delays, which includes both the means and variances of the delay random variables. Based on the moments of this disutility function, an algorithm is presented which selects a subset of paths (called undominated paths) as being most responsible for the variation in timing performance. Next, a statistical gate sizing algorithm is presented, which is aimed at minimizing the delay variability of the nodes in the selected paths subject to constraints on the critical path delay and the area penalty. Monte-Carlo simulations with ISCAS '85 benchmark circuits show that our statistical optimization approach results in significant improvements in timing yield over traditional deterministic sizing methods.