Targeting C-reactive protein for the treatment of cardiovascular disease

Complement-mediated inflammation exacerbates the tissue injury of ischaemic necrosis in heart attacks and strokes, the most common causes of death in developed countries. Large infarct size increases immediate morbidity and mortality and, in survivors of the acute event, larger non-functional scars adversely affect long-term prognosis. There is thus an important unmet medical need for new cardioprotective and neuroprotective treatments. We have previously shown that human C-reactive protein (CRP), the classical acute-phase protein that binds to ligands exposed in damaged tissue and then activates complement, increases myocardial and cerebral infarct size in rats subjected to coronary or cerebral artery ligation, respectively. Rat CRP does not activate rat complement, whereas human CRP activates both rat and human complement. Administration of human CRP to rats is thus an excellent model for the actions of endogenous human CRP. Here we report the design, synthesis and efficacy of 1,6-bis(phosphocholine)-hexane as a specific small-molecule inhibitor of CRP. Five molecules of this palindromic compound are bound by two pentameric CRP molecules, crosslinking and occluding the ligand-binding B-face of CRP and blocking its functions. Administration of 1,6-bis(phosphocholine)-hexane to rats undergoing acute myocardial infarction abrogated the increase in infarct size and cardiac dysfunction produced by injection of human CRP. Therapeutic inhibition of CRP is thus a promising new approach to cardioprotection in acute myocardial infarction, and may also provide neuroprotection in stroke. Potential wider applications include other inflammatory, infective and tissue-damaging conditions characterized by increased CRP production, in which binding of CRP to exposed ligands in damaged cells may lead to complement-mediated exacerbation of tissue injury.     

Molecular characterization of Ph1 as a major chromosome pairing locus in polyploid wheat

The foundation of western civilization owes much to the high fertility of bread wheat, which results from the stability of its polyploid genome. Despite possessing multiple sets of related chromosomes, hexaploid (bread) and tetraploid (pasta) wheat both behave as diploids at meiosis. Correct pairing of homologous chromosomes is controlled by the Ph1 locus. In wheat hybrids, Ph1 prevents pairing between related chromosomes. Lack of Ph1 activity in diploid relatives of wheat suggests that Ph1 arose on polyploidization. Absence of phenotypic variation, apart from dosage effects, and the failure of ethylmethane sulphonate treatment to yield mutants, indicates that Ph1 has a complex structure. Here we have localized Ph1 to a 2.5-megabase interstitial region of wheat chromosome 5B containing a structure consisting of a segment of subtelomeric heterochromatin that inserted into a cluster of cdc2-related genes after polyploidization. The correlation of the presence of this structure with Ph1 activity in related species, and the involvement of heterochromatin with Ph1 (ref. 6) and cdc2 genes with meiosis, makes the structure a good candidate for the Ph1 locus.     

Environment: whale-call response to masking boat noise

Background noise can interfere with the detection and discrimination of crucial signals among members of a species. Here we investigate the vocal behaviour in the presence and absence of whale-watcher boat traffic of three social groups (pods) of killer whales (Orcinus orca) living in the nearshore waters of Washington state. We find longer call durations in the presence of boats for all three pods, but only in recent recordings made following a period of increasing boat traffic. This result indicates that these whales adjust their behaviour to compensate for anthropogenic noise once it reaches a threshold level.     

Tonks-Girardeau gas of ultracold atoms in an optical lattice

Strongly correlated quantum systems are among the most intriguing and fundamental systems in physics. One such example is the Tonks-Girardeau gas, proposed about 40 years ago, but until now lacking experimental realization; in such a gas, the repulsive interactions between bosonic particles confined to one dimension dominate the physics of the system. In order to minimize their mutual repulsion, the bosons are prevented from occupying the same position in space. This mimics the Pauli exclusion principle for fermions, causing the bosonic particles to exhibit fermionic properties. However, such bosons do not exhibit completely ideal fermionic (or bosonic) quantum behaviour; for example, this is reflected in their characteristic momentum distribution. Here we report the preparation of a Tonks-Girardeau gas of ultracold rubidium atoms held in a two-dimensional optical lattice formed by two orthogonal standing waves. The addition of a third, shallower lattice potential along the long axis of the quantum gases allows us to enter the Tonks-Girardeau regime by increasing the atoms' effective mass and thereby enhancing the role of interactions. We make a theoretical prediction of the momentum distribution based on an approach in which trapped bosons acquire fermionic properties, finding that it agrees closely with the measured distribution.     

C. elegans ORFeome version 1.1: experimental verification of the genome annotation and resource for proteome-scale protein expression

To verify the genome annotation and to create a resource to functionally characterize the proteome, we attempted to Gateway-clone all predicted protein-encoding open reading frames (ORFs), or the 'ORFeome,' of Caenorhabditis elegans. We successfully cloned approximately 12,000 ORFs (ORFeome 1.1), of which roughly 4,000 correspond to genes that are untouched by any cDNA or expressed-sequence tag (EST). More than 50% of predicted genes needed corrections in their intron-exon structures. Notably, approximately 11,000 C. elegans proteins can now be expressed under many conditions and characterized using various high-throughput strategies, including large-scale interactome mapping. We suggest that similar ORFeome projects will be valuable for other organisms, including humans.