Neurite arborization and mosaic spacing in the mouse retina require DSCAM

To establish functional circuitry, retinal neurons occupy spatial domains by arborizing their processes, which requires the self-avoidance of neurites from an individual cell, and by spacing their cell bodies, which requires positioning the soma and establishing a zone within which other cells of the same type are excluded. The mosaic patterns of distinct cell types form independently and overlap. The cues that direct these processes in the vertebrate retina are not known. Here we show that some types of retinal amacrine cells from mice with a spontaneous mutation in Down syndrome cell adhesion molecule (Dscam), a gene encoding an immunoglobulin-superfamily member adhesion molecule, have defects in the arborization of processes and in the spacing of cell bodies. In the mutant retina, cells that would normally express Dscam have hyperfasciculated processes, preventing them from creating an orderly arbor. Also, their cell bodies are randomly distributed or pulled into clumps rather than being regularly spaced mosaics. Our results indicate that mouse DSCAM mediates isoneuronal self-avoidance for arborization and heteroneuronal self-avoidance within specific cell types to prevent fasciculation and to preserve mosaic spacing. These functions are analogous to those of Drosophila DSCAM (ref. 6) and DSCAM2 (ref. 7). DSCAM may function similarly in other regions of the mammalian nervous system, and this role may extend to other members of the mammalian Dscam gene family.     

Control of the electronic phase of a manganite by mode-selective vibrational excitation

Controlling a phase of matter by coherently manipulating specific vibrational modes has long been an attractive (yet elusive) goal for ultrafast science. Solids with strongly correlated electrons, in which even subtle crystallographic distortions can result in colossal changes of the electronic and magnetic properties, could be directed between competing phases by such selective vibrational excitation. In this way, the dynamics of the electronic ground state of the system become accessible, and new insight into the underlying physics might be gained. Here we report the ultrafast switching of the electronic phase of a magnetoresistive manganite via direct excitation of a phonon mode at 71 meV (17 THz). A prompt, five-order-of-magnitude drop in resistivity is observed, associated with a non-equilibrium transition from the stable insulating phase to a metastable metallic phase. In contrast with light-induced and current-driven phase transitions, the vibrationally driven bandgap collapse observed here is not related to hot-carrier injection and is uniquely attributed to a large-amplitude Mn-O distortion. This corresponds to a perturbation of the perovskite-structure tolerance factor, which in turn controls the electronic bandwidth via inter-site orbital overlap. Phase control by coherent manipulation of selected metal-oxygen phonons should find extensive application in other complex solids--notably in copper oxide superconductors, in which the role of Cu-O vibrations on the electronic properties is currently controversial.     

Reversal of the net dinitrogen gas flux in coastal marine sediments

The flux of nitrogen from land and atmosphere to estuaries and the coastal ocean has increased substantially in recent decades. The observed increase in nitrogen loading is caused by population growth, urbanization, expanding water and sewer infrastructure, fossil fuel combustion and synthetic fertilizer consumption. Most of the nitrogen is removed by denitrification in the sediments of estuaries and the continental shelf, leading to a reduction in both cultural eutrophication and nitrogen pollution of the open ocean. Nitrogen fixation, however, is thought to be a negligible process in sub-tidal heterotrophic marine systems. Here we report sediment core data from Narragansett Bay, USA, which demonstrate that heterotrophic marine sediments can switch from being a net sink to being a net source of nitrogen. Mesocosm and core incubation experiments, together with a historic data set of mean annual chlorophyll production, support the idea that a climate-induced decrease in primary production has led to a decrease in organic matter deposition to the benthos and the observed reversal of the net sediment nitrogen flux. Our results suggest that some estuaries may no longer remove nitrogen from the water column. Instead, nitrogen could be exported to the continental shelf and the open ocean and could shift the effect of anthropogenic nitrogen loading beyond the immediate coastal zone.     

Genomic profiling of drug sensitivities via induced haploinsufficiency

Lowering the dosage of a single gene from two copies to one copy in diploid yeast results in a heterozygote that is sensitized to any drug that acts on the product of this gene. This haploinsufficient phenotype thereby identifies the gene product of the heterozygous locus as the likely drug target. We exploited this finding in a genomic approach to drug-target identification. Genome sequence information was used to generate molecularly tagged heterozygous yeast strains that were pooled, grown competitively in drug and analysed for drug sensitivity using high-density oligonucleotide arrays. Individual heterozygous strain analysis verified six known drug targets. Parallel analysis identified the known target and two hypersensitive loci in a mixed culture of 233 strains in the presence of the drug tunicamycin. Our discovery that both drug target and hypersensitive loci exhibit drug-induced haploinsufficiency may have important consequences in pharmacogenomics and variable drug toxicity observed in human populations.     

Adaptation at the output of the chemotaxis signalling pathway

In the bacterial chemotaxis network, receptor clusters process input, and flagellar motors generate output. Receptor and motor complexes are coupled by the diffusible protein CheY-P. Receptor output (the steady-state concentration of CheY-P) varies from cell to cell. However, the motor is ultrasensitive, with a narrow operating range of CheY-P concentrations. How the match between receptor output and motor input might be optimized is unclear. Here we show that the motor can shift its operating range by changing its composition. The number of FliM subunits in the C-ring increases in response to a decrement in the concentration of CheY-P, increasing motor sensitivity. This shift in sensitivity explains the slow partial adaptation observed in mutants that lack the receptor methyltransferase and methylesterase and why motors show signal-dependent FliM turnover. Adaptive remodelling is likely to be a common feature in the operation of many molecular machines.     

A redox switch in angiotensinogen modulates angiotensin release

Blood pressure is critically controlled by angiotensins, which are vasopressor peptides specifically released by the enzyme renin from the tail of angiotensinogen-a non-inhibitory member of the serpin family of protease inhibitors. Although angiotensinogen has long been regarded as a passive substrate, the crystal structures solved here to 2.1?? resolution show that the angiotensin cleavage site is inaccessibly buried in its amino-terminal tail. The conformational rearrangement that makes this site accessible for proteolysis is revealed in our 4.4?? structure of the complex of human angiotensinogen with renin. The co-ordinated changes involved are seen to be critically linked by a conserved but labile disulphide bridge. Here we show that the reduced unbridged form of angiotensinogen is present in the circulation in a near 40:60 ratio with the oxidized sulphydryl-bridged form, which preferentially interacts with receptor-bound renin. We propose that this redox-responsive transition of angiotensinogen to a form that will more effectively release angiotensin at a cellular level contributes to the modulation of blood pressure. Specifically, we demonstrate the oxidative switch of angiotensinogen to its more active sulphydryl-bridged form in the maternal circulation in pre-eclampsia-the hypertensive crisis of pregnancy that threatens the health and survival of both mother and child.     

Language understanding is grounded in experiential simulations: a response to Weiskopf

Several disciplines within the cognitive sciences have advanced the idea that people comprehend the actions of others, including the linguistic meanings they communicate, through embodied simulations where they imaginatively recreate the actions they observe or hear about. This claim has important consequences for theories of mind and meaning, such as that people’s use and interpretation of language emerges as a kind of bodily activity that is an essential part of ordinary cognition. Daniel Weiskopf presents several arguments against the idea that experiential simulations play a major role in immediate language use and meaning. We offer several rebuttals to Weiskopf, in which we critique his interpretation of simulation theory, present additional psycholinguistic evidence supportive of the simulation perspective, and suggest that a more traditional theory of linguistic meaning and processing has little psychological and empirical validity.     

Whole-genome analysis of diverse Chlamydia trachomatis strains identifies phylogenetic relationships masked by current clinical typing

Chlamydia trachomatis is responsible for both trachoma and sexually transmitted infections, causing substantial morbidity and economic cost globally. Despite this, our knowledge of its population and evolutionary genetics is limited. Here we present a detailed phylogeny based on whole-genome sequencing of representative strains of C. trachomatis from both trachoma and lymphogranuloma venereum (LGV) biovars from temporally and geographically diverse sources. Our analysis shows that predicting phylogenetic structure using ompA, which is traditionally used to classify Chlamydia, is misleading because extensive recombination in this region masks any true relationships present. We show that in many instances, ompA is a chimera that can be exchanged in part or as a whole both within and between biovars. We also provide evidence for exchange of, and recombination within, the cryptic plasmid, which is another key diagnostic target. We used our phylogenetic framework to show how genetic exchange has manifested itself in ocular, urogenital and LGV C. trachomatis strains, including the epidemic LGV serotype L2b.     

Distinct roles of nerve and muscle in postsynaptic differentiation of the neuromuscular synapse

The development of chemical synapses is regulated by interactions between pre- and postsynaptic cells. At the vertebrate skeletal neuromuscular junction, the organization of an acetylcholine receptor (AChR)-rich postsynaptic apparatus has been well studied. Much evidence suggests that the nerve-derived protein agrin activates muscle-specific kinase (MuSK) to cluster AChRs through the synapse-specific cytoplasmic protein rapsyn. But how postsynaptic differentiation is initiated, or why most synapses are restricted to an 'end-plate band' in the middle of the muscle remains unknown. Here we have used genetic methods to address these issues. We report that the initial steps in postsynaptic differentiation and formation of an end-plate band require MuSK and rapsyn, but are not dependent on agrin or the presence of motor axons. In contrast, the subsequent stages of synaptic growth and maintenance require nerve-derived agrin, and a second nerve-derived signal that disperses ectopic postsynaptic apparatus.