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.     

Nonlinear and quantum atom optics

Coherent matter waves in the form of Bose-Einstein condensates have led to the development of nonlinear and quantum atom optics - the de Broglie wave analogues of nonlinear and quantum optics with light. In nonlinear atom optics, four-wave mixing of matter waves and mixing of combinations of light and matter waves have been observed; such progress culminated in the demonstration of phase-coherent matter-wave amplification. Solitons represent another active area in nonlinear atom optics: these non-dispersing propagating modes of the equation that governs Bose-Einstein condensates have been created experimentally, and observed subsequently to break up into vortices. Quantum atom optics is concerned with the statistical properties and correlations of matter-wave fields. A first step in this area is the measurement of reduced number fluctuations in a Bose-Einstein condensate partitioned into a series of optical potential wells.     

Insights into phase transition kinetics from colloid science

Colloids display intriguing transitions between gas, liquid, solid and liquid crystalline phases. Such phase transitions are ubiquitous in nature and have been studied for decades. However, the predictions of phase diagrams are not always realized; systems often become undercooled, supersaturated, or trapped in gel-like states. In many cases the end products strongly depend on the starting position in the phase diagram and discrepancies between predictions and actual observations are due to the intricacies of the dynamics of phase transitions. Colloid science aims to understand the underlying mechanisms of these transitions. Important advances have been made, for example, with new imaging techniques that allow direct observation of individual colloidal particles undergoing phase transitions, revealing some of the secrets of the complex pathways involved.     

Spontaneous breaking of time-reversal symmetry in the pseudogap state of a high-Tc superconductor

A change in 'symmetry' is often observed when matter undergoes a phase transition-the symmetry is said to be spontaneously broken. The transition made by underdoped high-transition-temperature (high-Tc) superconductors is unusual, in that it is not a mean-field transition as seen in other superconductors. Rather, there is a region in the phase diagram above the superconducting transition temperature Tc (where phase coherence and superconductivity begin) but below a characteristic temperature T* where a 'pseudogap' appears in the spectrum of electronic excitations. It is therefore important to establish if T* is just a cross-over temperature arising from fluctuations in the order parameter that will establish superconductivity at Tc (refs 3, 4), or if it marks a phase transition where symmetry is spontaneously broken. Here we report that, for a material in the pseudogap state, left-circularly polarized photons give a different photocurrent from right-circularly polarized photons. This shows that time-reversal symmetry is spontaneously broken below T*, which therefore corresponds to a phase transition.     

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.     

Allometric cascade as a unifying principle of body mass effects on metabolism

The power function of basal metabolic rate scaling is expressed as aM(b), where a corresponds to a scaling constant (intercept), M is body mass, and b is the scaling exponent. The 3/4 power law (the best-fit b value for mammals) was developed from Kleiber's original analysis and, since then, most workers have searched for a single cause to explain the observed allometry. Here we present a multiple-causes model of allometry, where the exponent b is the sum of the influences of multiple contributors to metabolism and control. The relative strength of each contributor, with its own characteristic exponent value, is determined by the control contribution. To illustrate its use, we apply this model to maximum versus basal metabolic rates to explain the differing scaling behaviour of these two biological states in mammals. The main difference in scaling is that, for the basal metabolic rate, the O(2) delivery steps contribute almost nothing to the global b scaling exponent, whereas for the maximum metabolic rate, the O(2) delivery steps significantly increase the global b value.     

Annexin II light chain regulates sensory neuron-specific sodium channel expression

The tetrodotoxin-resistant sodium channel Na(V)1.8/SNS is expressed exclusively in sensory neurons and appears to have an important role in pain pathways. Unlike other sodium channels, Na(V)1.8 is poorly expressed in cell lines even in the presence of accessory beta-subunits. Here we identify annexin II light chain (p11) as a regulatory factor that facilitates the expression of Na(V)1.8. p11 binds directly to the amino terminus of Na(V)1.8 and promotes the translocation of Na(V)1.8 to the plasma membrane, producing functional channels. The endogenous Na(V)1.8 current in sensory neurons is inhibited by antisense downregulation of p11 expression. Because direct association with p11 is required for functional expression of Na(V)1.8, disrupting this interaction may be a useful new approach to downregulating Na(V)1.8 and effecting analgesia.     

Recombinational DNA double-strand breaks in mice precede synapsis

In Saccharomyces cerevisiae, meiotic recombination is initiated by Spo11-dependent double-strand breaks (DSBs), a process that precedes homologous synapsis. Here we use an antibody specific for a phosphorylated histone (gamma-H2AX, which marks the sites of DSBs) to investigate the timing, distribution and Spo11-dependence of meiotic DSBs in the mouse. We show that, as in yeast, recombination in the mouse is initiated by Spo11-dependent DSBs that form during leptotene. Loss of gamma-H2AX staining (which in irradiated somatic cells is temporally linked with DSB repair) is temporally and spatially correlated with synapsis, even when this synapsis is 'non-homologous'.