Oxysterols direct immune cell migration via EBI2

Epstein-Barr virus-induced gene 2 (EBI2, also known as GPR183) is a G-protein-coupled receptor that is required for humoral immune responses; polymorphisms in the receptor have been associated with inflammatory autoimmune diseases. The natural ligand for EBI2 has been unknown. Here we describe the identification of 7α,25-dihydroxycholesterol (also called 7α,25-OHC or 5-cholesten-3β,7α,25-triol) as a potent and selective agonist of EBI2. Functional activation of human EBI2 by 7α,25-OHC and closely related oxysterols was verified by monitoring second messenger readouts and saturable, high-affinity radioligand binding. Furthermore, we find that 7α,25-OHC and closely related oxysterols act as chemoattractants for immune cells expressing EBI2 by directing cell migration in vitro and in vivo. A critical enzyme required for the generation of 7α,25-OHC is cholesterol 25-hydroxylase (CH25H). Similar to EBI2 receptor knockout mice, mice deficient in CH25H fail to position activated B cells within the spleen to the outer follicle and mount a reduced plasma cell response after an immune challenge. This demonstrates that CH25H generates EBI2 biological activity in vivo and indicates that the EBI2-oxysterol signalling pathway has an important role in the adaptive immune response.     

S-nitrosylation of NADPH oxidase regulates cell death in plant immunity

Changes in redox status are a conspicuous feature of immune responses in a variety of eukaryotes, but the associated signalling mechanisms are not well understood. In plants, attempted microbial infection triggers the rapid synthesis of nitric oxide and a parallel accumulation of reactive oxygen intermediates, the latter generated by NADPH oxidases related to those responsible for the pathogen-activated respiratory burst in phagocytes. Both nitric oxide and reactive oxygen intermediates have been implicated in controlling the hypersensitive response, a programmed execution of plant cells at sites of attempted infection. However, the molecular mechanisms that underpin their function and coordinate their synthesis are unknown. Here we show genetic evidence that increases in cysteine thiols modified using nitric oxide, termed S-nitrosothiols, facilitate the hypersensitive response in the absence of the cell death agonist salicylic acid and the synthesis of reactive oxygen intermediates. Surprisingly, when concentrations of S-nitrosothiols were high, nitric oxide function also governed a negative feedback loop limiting the hypersensitive response, mediated by S-nitrosylation of the NADPH oxidase, AtRBOHD, at Cys 890, abolishing its ability to synthesize reactive oxygen intermediates. Accordingly, mutation of Cys 890 compromised S-nitrosothiol-mediated control of AtRBOHD activity, perturbing the magnitude of cell death development. This cysteine is evolutionarily conserved and specifically S-nitrosylated in both human and fly NADPH oxidase, suggesting that this mechanism may govern immune responses in both plants and animals.     

Link between spin fluctuations and electron pairing in copper oxide superconductors

Although it is generally accepted that superconductivity is unconventional in the high-transition-temperature copper oxides, the relative importance of phenomena such as spin and charge (stripe) order, superconductivity fluctuations, proximity to a Mott insulator, a pseudogap phase and quantum criticality are still a matter of debate. In electron-doped copper oxides, the absence of an anomalous pseudogap phase in the underdoped region of the phase diagram and weaker electron correlations suggest that Mott physics and other unidentified competing orders are less relevant and that antiferromagnetic spin fluctuations are the dominant feature. Here we report a study of magnetotransport in thin films of the electron-doped copper oxide La(2?-?x)Ce(x)CuO(4). We show that a scattering rate that is linearly dependent on temperature--a key feature of the anomalous normal state properties of the copper oxides--is correlated with the electron pairing. We also show that an envelope of such scattering surrounds the superconducting phase, surviving to zero temperature when superconductivity is suppressed by magnetic fields. Comparison with similar behaviour found in organic superconductors strongly suggests that the linear dependence on temperature of the resistivity in the electron-doped copper oxides is caused by spin-fluctuation scattering.     

Corridors of migrating neurons in the human brain and their decline during infancy

The subventricular zone of many adult non-human mammals generates large numbers of new neurons destined for the olfactory bulb. Along the walls of the lateral ventricles, immature neuronal progeny migrate in tangentially oriented chains that coalesce into a rostral migratory stream (RMS) connecting the subventricular zone to the olfactory bulb. The adult human subventricular zone, in contrast, contains a hypocellular gap layer separating the ependymal lining from a periventricular ribbon of astrocytes. Some of these subventricular zone astrocytes can function as neural stem cells in vitro, but their function in vivo remains controversial. An initial report found few subventricular zone proliferating cells and rare migrating immature neurons in the RMS of adult humans. In contrast, a subsequent study indicated robust proliferation and migration in the human subventricular zone and RMS. Here we find that the infant human subventricular zone and RMS contain an extensive corridor of migrating immature neurons before 18 months of age but, contrary to previous reports, this germinal activity subsides in older children and is nearly extinct by adulthood. Surprisingly, during this limited window of neurogenesis, not all new neurons in the human subventricular zone are destined for the olfactory bulb--we describe a major migratory pathway that targets the prefrontal cortex in humans. Together, these findings reveal robust streams of tangentially migrating immature neurons in human early postnatal subventricular zone and cortex. These pathways represent potential targets of neurological injuries affecting neonates.     

Jamming by shear

A broad class of disordered materials including foams, glassy molecular systems, colloids and granular materials can form jammed states. A jammed system can resist small stresses without deforming irreversibly, whereas unjammed systems flow under any applied stresses. The broad applicability of the Liu-Nagel jamming concept has attracted intensive theoretical and modelling interest but has prompted less experimental effort. In the Liu-Nagel framework, jammed states of athermal systems exist only above a certain critical density. Although numerical simulations for particles that do not experience friction broadly support this idea, the nature of the jamming transition for frictional grains is less clear. Here we show that jamming of frictional, disk-shaped grains can be induced by the application of shear stress at densities lower than the critical value, at which isotropic (shear-free) jamming occurs. These jammed states have a much richer phenomenology than the isotropic jammed states: for small applied shear stresses, the states are fragile, with a strong force network that percolates only in one direction. A minimum shear stress is needed to create robust, shear-jammed states with a strong force network percolating in all directions. The transitions from unjammed to fragile states and from fragile to shear-jammed states are controlled by the fraction of force-bearing grains. The fractions at which these transitions occur are statistically independent of the density. Jammed states with densities lower than the critical value have an anisotropic fabric (contact network). The minimum anisotropy of shear-jammed states vanishes as the density approaches the critical value from below, in a manner reminiscent of an order-disorder transition.     

An origin of the radio jet in M87 at the location of the central black hole

Powerful radio jets from active galactic nuclei are thought to be powered by the accretion of material onto the supermassive black hole (the 'central engine'). M87 is one of the closest examples of this phenomenon, and the structure of its jet has been probed on a scale of about 100 Schwarzschild radii (R(s), the radius of the event horizon). However, the location of the central black hole relative to the jet base (a bright compact radio 'core') remains elusive. Observations of other jets indicate that the central engines are located about 10(4)-10(6)R(s) upstream from the radio core. Here we report radio observations of M87 at six frequencies that allow us to achieve a positional accuracy of about 20?microarcseconds. As the jet base becomes more transparent at higher frequencies, the multifrequency position measurements of the radio core enable us to determine the upstream end of the jet. The data reveal that the central engine of M87 is located within 14-23R(s) of the radio core at 43?GHz. This implies that the site of material infall onto the black hole and the eventual origin of the jet reside in the bright compact region seen on the image at 43?GHz.