Urocortin-deficient mice show hearing impairment and increased anxiety-like behavior

Urocortin is a member of the corticotropin-releasing hormone peptide family and is found in many discrete brain regions. The distinct expression pattern of urocortin suggests that it influences such behaviors as feeding, anxiety and auditory processing. To better define the physiological roles of urocortin, we have generated mice carrying a null mutation of the urocortin gene. Urocortin-deficient mice have normal basal feeding behavior and stress responses, but show heightened anxiety-like behaviors in the elevated plus maze and open-field tests. In addition, hearing is impaired in the mutant mice at the level of the inner ear, suggesting that urocortin is involved in the normal development of cochlear sensory-cell function. These results provide the first example of a function for any peptidergic system in hearing.     

Mutation of TRPM6 causes familial hypomagnesemia with secondary hypocalcemia

Familial hypomagnesemia with secondary hypocalcemia (OMIM 602014) is an autosomal recessive disease that results in electrolyte abnormalities shortly after birth. Affected individuals show severe hypomagnesemia and hypocalcemia, which lead to seizures and tetany. The disorder has been thought to be caused by a defect in the intestinal absorption of magnesium, rather than by abnormal renal loss of magnesium. Restoring the concentrations of serum magnesium to normal values by high-dose magnesium supplementation can overcome the apparent defect in magnesium absorption and in serum concentrations of calcium. Life-long magnesium supplementation is required to overcome the defect in magnesium handling by these individuals. We previously mapped the gene locus to chromosome 9q in three large inbred kindreds from Israel. Here we report that mutation of TRPM6 causes hypomagnesemia with secondary hypocalcemia and show that individuals carrying mutations in this gene have abnormal renal magnesium excretion.     

Biological and biomedical implications of the co-evolution of pathogens and their hosts

Co-evolution between host and pathogen is, in principle, a powerful determinant of the biology and genetics of infection and disease. Yet co-evolution has proven difficult to demonstrate rigorously in practice, and co-evolutionary thinking is only just beginning to inform medical or veterinary research in any meaningful way, even though it can have a major influence on how genetic variation in biomedically important traits is interpreted. Improving our understanding of the biomedical significance of co-evolution will require changing the way in which we look for it, complementing the phenomenological approach traditionally favored by evolutionary biologists with the exploitation of the extensive data becoming available on the molecular biology and molecular genetics of host-pathogen interactions.     

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.