Nematode parasitism is a worldwide health problem resulting in malnutrition and morbidity in over 1 billion people. The molecular mechanisms governing infection are poorly understood. Here, we report that an evolutionarily conserved nuclear hormone receptor signaling pathway governs development of the stage 3 infective larvae (iL3) in several nematode parasites, including Strongyloides stercoralis, Ancylostoma spp., and Necator americanus. As in the free-living Caenorhabditis elegans, steroid hormone-like dafachronic acids induced recovery of the dauer-like iL3 in parasitic nematodes by activating orthologs of the nuclear receptor DAF-12. Moreover, administration of dafachronic acid markedly reduced the pathogenic iL3 population in S. stercoralis, indicating the potential use of DAF-12 ligands to treat disseminated strongyloidiasis. To understand the pharmacology of targeting DAF-12, we solved the 3-dimensional structure of the S. stercoralis DAF-12 ligand-binding domain cocrystallized with dafachronic acids. These results reveal the molecular basis for DAF-12 ligand binding and identify nuclear receptors as unique therapeutic targets in parasitic nematodes.dafachronic acid ͉ parasitology ͉ pharmacology ͉ X-ray crystal structure P arasitic nematodes constitute a large family of pathogens that infect hosts ranging from plants and animals to people, causing great economic loss and worldwide health threats (1, 2). One of the most problematic parasites, Strongyloides stercoralis, is estimated to infect 100-200 million people. Primary infections are often asymptomatic and clinically silent in immunocompetent individuals. However, once the immune system is compromised (e.g., by corticosteroid therapy), the parasite establishes autoinfection cycles that result in a frequently fatal disseminated strongyloidiasis (3, 4). Hookworms (Ancylostoma and Necator spp.) are other parasitic nematodes that affect Ͼ1 billion people and are the dominant cause for iron-deficient anemia worldwide (2). Oral administration of anthelmintics such as benzimidazoles (microtuble toxins) and ivermectin (a neurotoxin) is currently the preferred treatment for nematode infections (5). However, no reliable options exist for treating the more severe form of disseminated strongyloidiasis (6). Moreover, resistance to the anthelmintics has become widespread in animals and is beginning to occur in humans (2, 7). Therefore, studying the mechanisms that govern nematode life cycles is an attractive approach to identifying new therapeutic targets.Infection of hosts by parasitic nematodes is mediated by infective larvae, which in S. stercoralis and hookworm are the third stage or L3 larvae (iL3) (4, 5). Interestingly, iL3 larvae resemble the dauer larvae of the free-living nematode Caenorhabditis elegans in that they are all nonfeeding, developmentally arrested, dormant filariform larvae with a sealed buccal capsule and thickened body wall cuticle, enabling them to survive environmental challenges (8). Like C. elegans dauer larvae, iL3 recover from their ar...

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.

Two genes controlling the purple pericarp trait in wheat, TaPpm1 and TaPpb1, are identified and the mechanism by which they co-regulate anthocyanin synthesis is proposed.

Mycotoxins are produced by fungi and are potentially toxic to pigs. Yeast cell wall extract (YCWE) is known to adsorb mycotoxins and improve gut health in pigs. One hundred and twenty growing (56 kg; experiment 1) and 48 nursery piglets (6 kg; experiment 2) were assigned to four dietary treatments in a 2 × 2 factorial design for 35 and 48 days, respectively. Factors were mycotoxins (no addition versus experiment 1: 180 μg/kg aflatoxins and 14 mg/kg fumonisins; or experiment 2: 180 μg/kg aflatoxins and 9 mg/kg fumonisins, and 1 mg/kg deoxynivalenol) and YCWE (0% versus 0.2%). Growth performance, blood, gut health and microbiome, and apparent ileal digestibility (AID) data were evaluated. In experiment 1, mycotoxins reduced ADG and G:F, and duodenal IgG, whereas in jejunum, YCWE increased IgG and reduced villus width. In experiment 2, mycotoxins reduced BW, ADG, and ADFI. Mycotoxins reduced ADG, which was recovered by YCWE. Mycotoxins reduced the AID of nutrients evaluated and increased protein carbonyl, whereas mycotoxins and YCWE increased the AID of the nutrients and reduced protein carbonyl. Mycotoxins reduced villus height, proportion of Ki-67-positive cells, and increased IgA and the proportion of bacteria with mycotoxin-degrading ability, whereas YCWE tended to increase villus height and reduced IgA and the proportion of pathogenic bacteria in jejunum. The YCWE effects were more evident in promoting gut health and growth in nursery pigs, which showed higher susceptibility to mycotoxin effects.