Excitatory glycine receptors containing the NR3 family of NMDA receptor subunits

The N-methyl-D-aspartate subtype of glutamate receptor (NMDAR) serves critical functions in physiological and pathological processes in the central nervous system, including neuronal development, plasticity and neurodegeneration. Conventional heteromeric NMDARs composed of NR1 and NR2A-D subunits require dual agonists, glutamate and glycine, for activation. They are also highly permeable to Ca2+, and exhibit voltage-dependent inhibition by Mg2+. Coexpression of NR3A with NR1 and NR2 subunits modulates NMDAR activity. Here we report the cloning and characterization of the final member of the NMDAR family, NR3B, which shares high sequence homology with NR3A. From in situ and immunocytochemical analyses, NR3B is expressed predominantly in motor neurons, whereas NR3A is more widely distributed. Remarkably, when co-expressed in Xenopus oocytes, NR3A or NR3B co-assembles with NR1 to form excitatory glycine receptors that are unaffected by glutamate or NMDA, and inhibited by D-serine, a co-activator of conventional NMDARs. Moreover, NR1/NR3A or -3B receptors form relatively Ca2+-impermeable cation channels that are resistant to Mg2+, MK-801, memantine and competitive antagonists. In cerebrocortical neurons containing NR3 family members, glycine triggers a burst of firing, and membrane patches manifest glycine-responsive single channels that are suppressible by D-serine. By itself, glycine is normally thought of as an inhibitory neurotransmitter. In contrast, these NR1/NR3A or -3B 'NMDARs' constitute a type of excitatory glycine receptor.     

Three-dimensional X-ray structural microscopy with submicrometre resolution

Advanced materials and processing techniques are based largely on the generation and control of non-homogeneous microstructures, such as precipitates and grain boundaries. X-ray tomography can provide three-dimensional density and chemical distributions of such structures with submicrometre resolution; structural methods exist that give submicrometre resolution in two dimensions; and techniques are available for obtaining grain-centroid positions and grain-average strains in three dimensions. But non-destructive point-to-point three-dimensional structural probes have not hitherto been available for investigations at the critical mesoscopic length scales (tenths to hundreds of micrometres). As a result, investigations of three-dimensional mesoscale phenomena--such as grain growth, deformation, crumpling and strain-gradient effects--rely increasingly on computation and modelling without direct experimental input. Here we describe a three-dimensional X-ray microscopy technique that uses polychromatic synchrotron X-ray microbeams to probe local crystal structure, orientation and strain tensors with submicrometre spatial resolution. We demonstrate the utility of this approach with micrometre-resolution three-dimensional measurements of grain orientations and sizes in polycrystalline aluminium, and with micrometre depth-resolved measurements of elastic strain tensors in cylindrically bent silicon. This technique is applicable to single-crystal, polycrystalline, composite and functionally graded materials.     

Nitric oxide regulates the heart by spatial confinement of nitric oxide synthase isoforms

Subcellular localization of nitric oxide (NO) synthases with effector molecules is an important regulatory mechanism for NO signalling. In the heart, NO inhibits L-type Ca2+ channels but stimulates sarcoplasmic reticulum (SR) Ca2+ release, leading to variable effects on myocardial contractility. Here we show that spatial confinement of specific NO synthase isoforms regulates this process. Endothelial NO synthase (NOS3) localizes to caveolae, where compartmentalization with beta-adrenergic receptors and L-type Ca2+ channels allows NO to inhibit beta-adrenergic-induced inotropy. Neuronal NO synthase (NOS1), however, is targeted to cardiac SR. NO stimulation of SR Ca2+ release via the ryanodine receptor (RyR) in vitro, suggests that NOS1 has an opposite, facilitative effect on contractility. We demonstrate that NOS1-deficient mice have suppressed inotropic response, whereas NOS3-deficient mice have enhanced contractility, owing to corresponding changes in SR Ca2+ release. Both NOS1-/- and NOS3-/- mice develop age-related hypertrophy, although only NOS3-/- mice are hypertensive. NOS1/3-/- double knockout mice have suppressed beta-adrenergic responses and an additive phenotype of marked ventricular remodelling. Thus, NOS1 and NOS3 mediate independent, and in some cases opposite, effects on cardiac structure and function.     

Geobacter metallireducens accesses insoluble Fe(III) oxide by chemotaxis

Microorganisms that use insoluble Fe(III) oxide as an electron acceptor can have an important function in the carbon and nutrient cycles of aquatic sediments and in the bioremediation of organic and metal contaminants in groundwater. Although Fe(III) oxides are often abundant, Fe(III)-reducing microbes are faced with the problem of how to access effectively an electron acceptor that can not diffuse to the cell. Fe(III)-reducing microorganisms in the genus Shewanella have resolved this problem by releasing soluble quinones that can carry electrons from the cell surface to Fe(III) oxide that is at a distance from the cell. Here we report that another Fe(III)-reducer, Geobacter metallireducens, has an alternative strategy for accessing Fe(III) oxides. Geobacter metallireducens specifically expresses flagella and pili only when grown on insoluble Fe(III) or Mn(IV) oxide, and is chemotactic towards Fe(II) and Mn(II) under these conditions. These results suggest that G. metallireducens senses when soluble electron acceptors are depleted and then synthesizes the appropriate appendages to permit it to search for, and establish contact with, insoluble Fe(III) or Mn(IV) oxide. This approach to the use of an insoluble electron acceptor may explain why Geobacter species predominate over other Fe(III) oxide-reducing microorganisms in a wide variety of sedimentary environments.     

Complete genome sequence of the model actinomycete Streptomyces coelicolor A3(2)

Streptomyces coelicolor is a representative of the group of soil-dwelling, filamentous bacteria responsible for producing most natural antibiotics used in human and veterinary medicine. Here we report the 8,667,507 base pair linear chromosome of this organism, containing the largest number of genes so far discovered in a bacterium. The 7,825 predicted genes include more than 20 clusters coding for known or predicted secondary metabolites. The genome contains an unprecedented proportion of regulatory genes, predominantly those likely to be involved in responses to external stimuli and stresses, and many duplicated gene sets that may represent 'tissue-specific' isoforms operating in different phases of colonial development, a unique situation for a bacterium. An ancient synteny was revealed between the central 'core' of the chromosome and the whole chromosome of pathogens Mycobacterium tuberculosis and Corynebacterium diphtheriae. The genome sequence will greatly increase our understanding of microbial life in the soil as well as aiding the generation of new drug candidates by genetic engineering.     

Ocean productivity before about 1.9 Gyr ago limited by phosphorus adsorption onto iron oxides

After the evolution of oxygen-producing cyanobacteria at some time before 2.7 billion years ago, oxygen production on Earth is thought to have depended on the availability of nutrients in the oceans, such as phosphorus (in the form of orthophosphate). In the modern oceans, a significant removal pathway for phosphorus occurs by way of its adsorption onto iron oxide deposits. Such deposits were thought to be more abundant in the past when, under low sulphate conditions, the formation of large amounts of iron oxides resulted in the deposition of banded iron formations. Under these circumstances, phosphorus removal by iron oxide adsorption could have been enhanced. Here we analyse the phosphorus and iron content of banded iron formations to show that ocean orthophosphate concentrations from 3.2 to 1.9 billion years ago (during the Archaean and early Proterozoic eras) were probably only approximately 10-25% of present-day concentrations. We suggest therefore that low phosphorus availability should have significantly reduced rates of photosynthesis and carbon burial, thereby reducing the long-term oxygen production on the early Earth--as previously speculated--and contributing to the low concentrations of atmospheric oxygen during the late Archaean and early Proterozoic.