Structural basis for iron piracy by pathogenic Neisseria

Neisseria are obligate human pathogens causing bacterial meningitis, septicaemia and gonorrhoea. Neisseria require iron for survival and can extract it directly from human transferrin for transport across the outer membrane. The transport system consists of TbpA, an integral outer membrane protein, and TbpB, a co-receptor attached to the cell surface; both proteins are potentially important vaccine and therapeutic targets. Two key questions driving Neisseria research are how human transferrin is specifically targeted, and how the bacteria liberate iron from transferrin at neutral pH. To address these questions, we solved crystal structures of the TbpA-transferrin complex and of the corresponding co-receptor TbpB. We characterized the TbpB-transferrin complex by small-angle X-ray scattering and the TbpA-TbpB-transferrin complex by electron microscopy. Our studies provide a rational basis for the specificity of TbpA for human transferrin, show how TbpA promotes iron release from transferrin, and elucidate how TbpB facilitates this process.     

Dissociation between hand motion and population vectors from neural activity in motor cortex

The population vector hypothesis was introduced almost twenty years ago to illustrate that a population vector constructed from neural activity in primary motor cortex (MI) of non-human primates could predict the direction of hand movement during reaching. Alternative explanations for this population signal have been suggested but could not be tested experimentally owing to movement complexity in the standard reaching model. We re-examined this issue by recording the activity of neurons in contralateral MI of monkeys while they made reaching movements with their right arms oriented in the horizontal plane-where the mechanics of limb motion are measurable and anisotropic. Here we found systematic biases between the population vector and the direction of hand movement. These errors were attributed to a non-uniform distribution of preferred directions of neurons and the non-uniformity covaried with peak joint power at the shoulder and elbow. These observations contradict the population vector hypothesis and show that non-human primates are capable of generating reaching movements to spatial targets even though population vectors based on MI activity do not point in the direction of hand motion.     

Unsaturated fatty acid content in seston and tropho-dynamic coupling in lakes

Determining the factors that control food web interactions is a key issue in ecology. The empirical relationship between nutrient loading (total phosphorus) and phytoplankton standing stock (chlorophyll a) in lakes was described about 30 years ago and is central for managing surface water quality. The efficiency with which biomass and energy are transferred through the food web and sustain the production of higher trophic levels (such as fish) declines with nutrient loading and system productivity, but the underlying mechanisms are poorly understood. Here we show that in seston (fine particles in water) during summer, specific omega3-polyunsaturated fatty acids (omega3-PUFAs), which are important for zooplankton, are significantly correlated to the trophic status of the lake. The omega3-PUFAs octadecatetraenoic acid, eicosapentaenoic acid (EPA) and docosahexaenoic acid, but not alpha-linolenic acid, decrease on a double-logarithmic scale with increasing total phosphorus. By combining the empirical relationship between EPA-to-carbon content and total phosphorus with functional models relating EPA-to-carbon content to the growth and egg production of daphnids, we predict secondary production for this key consumer. Thus, the decreasing efficiency in energy transfer with increasing lake productivity can be explained by differences in omega3-PUFA-associated food quality at the plant-animal interface.     

Genome sequence of the Brown Norway rat yields insights into mammalian evolution

The laboratory rat (Rattus norvegicus) is an indispensable tool in experimental medicine and drug development, having made inestimable contributions to human health. We report here the genome sequence of the Brown Norway (BN) rat strain. The sequence represents a high-quality 'draft' covering over 90% of the genome. The BN rat sequence is the third complete mammalian genome to be deciphered, and three-way comparisons with the human and mouse genomes resolve details of mammalian evolution. This first comprehensive analysis includes genes and proteins and their relation to human disease, repeated sequences, comparative genome-wide studies of mammalian orthologous chromosomal regions and rearrangement breakpoints, reconstruction of ancestral karyotypes and the events leading to existing species, rates of variation, and lineage-specific and lineage-independent evolutionary events such as expansion of gene families, orthology relations and protein evolution.     

Doping semiconductor nanocrystals

Doping--the intentional introduction of impurities into a material--is fundamental to controlling the properties of bulk semiconductors. This has stimulated similar efforts to dope semiconductor nanocrystals. Despite some successes, many of these efforts have failed, for reasons that remain unclear. For example, Mn can be incorporated into nanocrystals of CdS and ZnSe (refs 7-9), but not into CdSe (ref. 12)--despite comparable bulk solubilities of near 50 per cent. These difficulties, which have hindered development of new nanocrystalline materials, are often attributed to 'self-purification', an allegedly intrinsic mechanism whereby impurities are expelled. Here we show instead that the underlying mechanism that controls doping is the initial adsorption of impurities on the nanocrystal surface during growth. We find that adsorption--and therefore doping efficiency--is determined by three main factors: surface morphology, nanocrystal shape, and surfactants in the growth solution. Calculated Mn adsorption energies and equilibrium shapes for several nanocrystals lead to specific doping predictions. These are confirmed by measuring how the Mn concentration in ZnSe varies with nanocrystal size and shape. Finally, we use our predictions to incorporate Mn into previously undopable CdSe nanocrystals. This success establishes that earlier difficulties with doping are not intrinsic, and suggests that a variety of doped nanocrystals--for applications from solar cells to spintronics--can be anticipated.     

Diatom carbon export enhanced by silicate upwelling in the northeast Atlantic

Diatoms are unicellular or chain-forming phytoplankton that use silicon (Si) in cell wall construction. Their survival during periods of apparent nutrient exhaustion enhances carbon sequestration in frontal regions of the northern North Atlantic. These regions may therefore have a more important role in the 'biological pump' than they have previously been attributed, but how this is achieved is unknown. Diatom growth depends on silicate availability, in addition to nitrate and phosphate, but northern Atlantic waters are richer in nitrate than silicate. Following the spring stratification, diatoms are the first phytoplankton to bloom. Once silicate is exhausted, diatom blooms subside in a major export event. Here we show that, with nitrate still available for new production, the diatom bloom is prolonged where there is a periodic supply of new silicate: specifically, diatoms thrive by 'mining' deep-water silicate brought to the surface by an unstable ocean front. The mechanism we present here is not limited to silicate fertilization; similar mechanisms could support nitrate-, phosphate- or iron-limited frontal regions in oceans elsewhere.     

LPA3-mediated lysophosphatidic acid signalling in embryo implantation and spacing

Every successful pregnancy requires proper embryo implantation. Low implantation rate is a major problem during infertility treatments using assisted reproductive technologies. Here we report a newly discovered molecular influence on implantation through the lysophosphatidic acid (LPA) receptor LPA3 (refs 2-4). Targeted deletion of LPA3 in mice resulted in significantly reduced litter size, which could be attributed to delayed implantation and altered embryo spacing. These two events led to delayed embryonic development, hypertrophic placentas shared by multiple embryos and embryonic death. An enzyme demonstrated to influence implantation, cyclooxygenase 2 (COX2) (ref. 5), was downregulated in LPA3-deficient uteri during pre-implantation. Downregulation of COX2 led to reduced levels of prostaglandins E2 and I2 (PGE2 and PGI2), which are critical for implantation. Exogenous administration of PGE2 or carbaprostacyclin (a stable analogue of PGI2) into LPA3-deficient female mice rescued delayed implantation but did not rescue defects in embryo spacing. These data identify LPA3 receptor-mediated signalling as having an influence on implantation, and further indicate linkage between LPA signalling and prostaglandin biosynthesis.     

Mutations of the catalytic subunit of RAB3GAP cause Warburg Micro syndrome

Warburg Micro syndrome (WARBM1) is a severe autosomal recessive disorder characterized by developmental abnormalities of the eye and central nervous system and by microgenitalia. We identified homozygous inactivating mutations in RAB3GAP, encoding RAB3 GTPase activating protein, a key regulator of the Rab3 pathway implicated in exocytic release of neurotransmitters and hormones, in 12 families with Micro syndrome. We hypothesize that the underlying pathogenesis of Micro syndrome is a failure of exocytic release of ocular and neurodevelopmental trophic factors.