second model, the two main conditions were parametrically modulated by the two categories, respectively (SOM, S5.1). The activation of the precuneus was higher for hard dominance-solvable games than for easy ones ( Fig. 4A and table S10). The activation of the insula was higher for the highly focal coordination games than for less focal ones ( Fig. 4B and table S11). Previous studies also found that precuneus activity increased when the number of planned moves increased (40, 41). The higher demand for memory-related imagery and memory retrieval may explain the greater precuneus activation in hard dominance-solvable games. In highly focal coordination games, the participants may have felt quite strongly that the pool students must notice the same salient feature. This may explain why insula activation correlates with NCI.Participants might have disagreed about which games were difficult. We built a third model to investigate whether the frontoparietal activation correlates with how hard a dominance-solvable game is and whether the activation in insula and ACC correlates with how easy a coordination game is. Here, the two main conditions were parametrically modulated by each participant's probability of obtaining a reward in each game (SOM, S2.2 and S5.2). We found a negative correlation between the activation of the precuneus and the participant's probability of obtaining a reward in dominance-solvable games ( Fig. 4C and table S12), which suggests that dominance-solvable games that yielded lower payoffs presented harder mental challenges. In a previous study on working memory, precuneus activity positively correlated with response times, a measure of mental effort (24). Both findings are consistent with the interpretation that subjective measures reflecting harder tasks (higher efforts) correlate with activation in precuneus. A positive correlation between insula activation and the participant's probability of obtaining a reward again suggests that coordination games with a highly salient feature strongly activated the "gut feeling" reported by many participants (Fig. 4D and table S13). A previous study found that the subjective rating of "chills intensity" in music correlates with activation of insula (42). Both findings are consistent with the interpretation that the subjective intensity of how salient a stimulus is correlates with activation in insula.As mentioned, choices were made significantly faster in coordination games than in dominancesolvable games. The results of the second and third models provide additional support for the idea that intuitive and deliberative mental processes have quite different properties. The "slow and effortful" process was more heavily taxed when the dominance-solvable games were harder. The "fast and effortless" process was more strongly activated when coordination was easy.

Schistosomiasis is a neglected tropical disease caused by blood flukes (genus Schistosoma; schistosomes) and affecting 200 million people worldwide 1 . No vaccines are available, and treatment relies on one drug, praziquantel 2 . Schistosoma haematobium has come into the spotlight as a major cause of urogenital disease, as an agent linked to bladder cancer 1,3 and as a predisposing factor for HIV/AIDS 4,5 . The parasite is transmitted to humans from freshwater snails 1 . Worms dwell in blood vessels and release eggs that become embedded in the bladder wall to elicit chronic immune-mediated disease 6 and induce squamous cell carcinoma 7 . Here we sequenced the 385-Mb genome of S. haematobium using Illumina-based technology at 74-fold coverage and compared it to sequences from related parasites 8,9 . We included genome annotation based on function, gene ontology, networking and pathway mapping. This genome now provides an unprecedented resource for many fundamental research areas and shows great promise for the design of new disease interventions.

Parasitic diseases have a devastating, long-term impact on human health, welfare and food production worldwide. More than two billion people are infected with geohelminths, including the roundworms Ascaris (common roundworm), Necator and Ancylostoma (hookworms), and Trichuris (whipworm), mainly in developing or impoverished nations of Asia, Africa and Latin America(1). In humans, the diseases caused by these parasites result in about 135,000 deaths annually, with a global burden comparable with that of malaria or tuberculosis in disability-adjusted life years(1). Ascaris alone infects around 1.2 billion people and, in children, causes nutritional deficiency, impaired physical and cognitive development and, in severe cases, death(2). Ascaris also causes major production losses in pigs owing to reduced growth, failure to thrive and mortality(2). The Ascaris-swine model makes it possible to study the parasite, its relationship with the host, and ascariasis at the molecular level. To enable such molecular studies, we report the 273 mega-base draft genome of Ascaris suum and compare it with other nematode genomes. This genome has low repeat content (4.4%) and encodes about 18,500 protein-coding genes. Notably, the A. suum secretome (about 750 molecules) is rich in peptidases linked to the penetration and degradation of host tissues, and an assemblage of molecules likely to modulate or evade host immune responses. This genome provides a comprehensive resource to the scientific community and underpins the development of new and urgently needed interventions (drugs, vaccines and diagnostic tests) against ascariasis and other nematodiases

To infect their mammalian hosts, Fasciola hepatica larvae must penetrate and traverse the intestinal wall of the duodenum, move through the peritoneum, and penetrate the liver. After migrating through and feeding on the liver, causing extensive tissue damage, the parasites move to their final niche in the bile ducts where they mature and produce eggs. Here we integrated a transcriptomics and proteomics approach to profile Fasciola secretory proteins that are involved in host-pathogen interactions and to correlate changes in their expression with the migration of the parasite. Prediction of F. hepatica secretory proteins from 14,031 expressed sequence tags (ESTs) available from the Wellcome Trust Sanger Centre using the semiautomated EST2Secretome pipeline showed that the major components of adult parasite secretions are proteolytic enzymes including cathepsin L, cathepsin B, and asparaginyl endopeptidase cysteine proteases as well as novel trypsinlike serine proteases and carboxypeptidases. Proteomics analysis of proteins secreted by infective larvae, immature flukes, and adult F. hepatica showed that these proteases are developmentally regulated and correlate with the passage of the parasite through host tissues and its encounters with different host macromolecules. Proteases such as FhCL3 and cathepsin B have specific functions in larvae activation and intestinal wall penetration, whereas FhCL1, FhCL2, and FhCL5 are required for liver penetration and tissue and blood feeding. Besides proteases, the parasites secrete an array of antioxidants that are also highly regulated according to their migration through host tissues. However, whereas the proteases of F. hepatica are secreted into the parasite gut via a classical endoplasmic reticulum/Golgi pathway, we speculate that the antioxidants, which all lack a signal sequence, are released via a non-classical trans-tegumental pathway. Fasciola hepatica is a helminth (worm) parasite with a worldwide distribution. Although traditionally regarded as a parasite of livestock, particularly sheep and cattle, that results in a large economic loss to the agricultural community it has recently emerged as an important human infection in many regions of the world, including South America, Iran, Egypt, and mainland South-East Asia (1). Dormant larvae contained within cysts adhere to vegetation and emerge as infective juveniles (newly excysted juveniles (NEJs)) 1 in the duodenum following ingestion by animals or humans. They infect their hosts by rapidly penetrating the intestinal wall and entering the peritoneal cavity where they break through the liver capsule. After 8 -12 weeks of consistent burrowing, feeding, and growth within the liver parenchyma they move to their final destination within the bile ducts where they mature and produce enormous numbers of eggs (2). The two distinct clinical phases of fasciolosis are directly related to the migration of the parasites: acute fasciolosis, which manifests as fever, abdominal pain, weight loss, and hepatomegaly, is associated with...

Reef-building corals are renowned for their brilliant colours yet the biochemical basis for the pigmentation of corals is unknown. Here, we show that these colours are due to a family of GFP-like proteins that¯uoresce under ultraviolet (UV) or visible light. Pigments from ten coral species were almost identical to pocilloporin (Dove et al. 1995) being dimers or trimers with approximately 28-kDa subunits. Degenerative primers made to common N-terminal sequences yielded a complete sequence from reef-building coral cDNA, which had 19.6% amino acid identity with green¯uo-rescent protein (GFP). Molecular modelling revealed a`b-can' structure, like GFP, with 11 b-strands and a completely solvent-inaccessible¯uorophore composed of the modi®ed residues Gln-61, Tyr-62 and Gly-63. The molecular properties of pocilloporins indicate a range of functions from the conversion of high-intensity UV radiation into photosynthetically active radiation (PAR) that can be regulated by the dino¯agellate peridininchlorophyll-protein (PCP) complex, to the shielding of the Soret and Q x bands of chlorophyll a and c from scattered high-intensity light. These properties of pocilloporin support its potential role in protecting the photosynthetic machinery of the symbiotic dino¯agel-lates of corals under high light conditions and in enhancing the availability of photosynthetic light under shade conditions.

The hookworm Necator americanus is the predominant soil-transmitted human parasite. Adult worms feed on blood in the small intestine, causing iron deficiency anaemia, malnutrition, growth and development stunting in children, and severe morbidity and mortality during pregnancy in women. Characterization of the first hookworm genome sequence (244 Mb, 19,151 genes) identified genes orchestrating the hookworm's invasion of the human host, genes involved in blood feeding and development, and genes encoding proteins that represent new potential drug targets against hookworms. N. americanus has undergone a considerable and unique expansion of immunomodulator proteins, some of which we highlight as potential novel treatments against inflammatory diseases. We also utilize a protein microarray to demonstrate a post-genomic application of the hookworm genome sequence. This genome provides an invaluable resource to boost ongoing efforts towards fundamental and applied post-genomic research, including the development of new methods to control hookworm and human immunological diseases.

Expressed sequence tag (EST) sequencing projects are underway for numerous organisms, generating millions of short, single-pass nucleotide sequence reads, accumulating in EST databases. Extensive computational strategies have been developed to organize and analyse both small- and large-scale EST data for gene discovery, transcript and single nucleotide polymorphism analysis as well as functional annotation of putative gene products. We provide an overview of the significance of ESTs in the genomic era, their properties and the applications of ESTs. Methods adopted for each step of EST analysis by various research groups have been compared. Challenges that lie ahead in organizing and analysing the ever increasing EST data have also been identified. The most appropriate software tools for EST pre-processing, clustering and assembly, database matching and functional annotation have been compiled (available online from http://biolinfo.org/EST). We propose a road map for EST analysis to accelerate the effective analyses of EST data sets. An investigation of EST analysis platforms reveals that they all terminate prior to downstream functional annotation including gene ontologies, motif/pattern analysis and pathway mapping.

An important and exciting challenge in the postgenomic era is to understand the functions of newly discovered proteins based on their structures. The main thrust is to find the common structural motifs that contribute to specific functions. Using this premise, here we report the purification, solution NMR, and functional characterization of a novel class of weak potassium channel toxins from the venom of the scorpion Heterometrus fulvipes. These toxins, -hefutoxin1 and -hefutoxin2, exhibit no homology to any known toxins. NMR studies indicate that -hefutoxin1 adopts a unique three-dimensional fold of two parallel helices linked by two disulfide bridges without any ␤؊sheets. Based on the presence of the functional diad (Tyr 5 /Lys 19 ) at a distance (6.0 ؎ 1.0 Å) comparable with other potassium channel toxins, we hypothesized its function as a potassium channel toxin. -Hefutoxin 1 not only blocks the voltage-gated K ؉ -channels, Kv1.3 and Kv1.2, but also slows the activation kinetics of Kv1.3 currents, a novel feature of -hefutoxin 1, unlike other scorpion toxins, which are considered solely pore blockers. Alanine mutants (Y5A, K19A, and Y5A/K19A) failed to block the channels, indicating the importance of the functional diad.