Crystal structure of the human angiotensin-converting enzyme-lisinopril complex

Angiotensin-converting enzyme (ACE) has a critical role in cardiovascular function by cleaving the carboxy terminal His-Leu dipeptide from angiotensin I to produce a potent vasopressor octapeptide, angiotensin II. Inhibitors of ACE are a first line of therapy for hypertension, heart failure, myocardial infarction and diabetic nephropathy. Notably, these inhibitors were developed without knowledge of the structure of human ACE, but were instead designed on the basis of an assumed mechanistic homology with carboxypeptidase A. Here we present the X-ray structure of human testicular ACE and its complex with one of the most widely used inhibitors, lisinopril (N2-[(S)-1-carboxy-3-phenylpropyl]-L-lysyl-L-proline; also known as Prinivil or Zestril), at 2.0 A resolution. Analysis of the three-dimensional structure of ACE shows that it bears little similarity to that of carboxypeptidase A, but instead resembles neurolysin and Pyrococcus furiosus carboxypeptidase--zinc metallopeptidases with no detectable sequence similarity to ACE. The structure provides an opportunity to design domain-selective ACE inhibitors that may exhibit new pharmacological profiles.     

Yeast genome duplication was followed by asynchronous differentiation of duplicated genes

Gene redundancy has been observed in yeast, plant and human genomes, and is thought to be a consequence of whole-genome duplications. Baker's yeast, Saccharomyces cerevisiae, contains several hundred duplicated genes. Duplication(s) could have occurred before or after a given speciation. To understand the evolution of the yeast genome, we analysed orthologues of some of these genes in several related yeast species. On the basis of the inferred phylogeny of each set of genes, we were able to deduce whether the gene duplicated and/or specialized before or after the divergence of two yeast lineages. Here we show that the gene duplications might have occurred as a single event, and that it probably took place before the Saccharomyces and Kluyveromyces lineages diverged from each other. Further evolution of each duplicated gene pair-such as specialization or differentiation of the two copies, or deletion of a single copy--has taken place independently throughout the evolution of these species.     

An exceptionally preserved Lower Cretaceous ecosystem

Fieldwork in the Early Cretaceous Jehol Group, northeastern China has revealed a plethora of extraordinarily well-preserved fossils that are shaping some of the most contentious debates in palaeontology and evolutionary biology. These discoveries include feathered theropod dinosaurs and early birds, which provide additional, indisputable support for the dinosaurian ancestry of birds, and much new evidence on the evolution of feathers and flight. Specimens of putative basal angiosperms and primitive mammals are clarifying details of the early radiations of these major clades. Detailed soft-tissue preservation of the organisms from the Jehol Biota is providing palaeobiological insights that would not normally be accessible from the fossil record.     

An NS3 protease inhibitor with antiviral effects in humans infected with hepatitis C virus

Hepatitis C virus (HCV) infection is a serious cause of chronic liver disease worldwide with more than 170 million infected individuals at risk of developing significant morbidity and mortality. Current interferon-based therapies are suboptimal especially in patients infected with HCV genotype 1, and they are poorly tolerated, highlighting the unmet medical need for new therapeutics. The HCV-encoded NS3 protease is essential for viral replication and has long been considered an attractive target for therapeutic intervention in HCV-infected patients. Here we identify a class of specific and potent NS3 protease inhibitors and report the evaluation of BILN 2061, a small molecule inhibitor biologically available through oral ingestion and the first of its class in human trials. Administration of BILN 2061 to patients infected with HCV genotype 1 for 2 days resulted in an impressive reduction of HCV RNA plasma levels, and established proof-of-concept in humans for an HCV NS3 protease inhibitor. Our results further illustrate the potential of the viral-enzyme-targeted drug discovery approach for the development of new HCV therapeutics.     

The evolutionary inheritance of elemental stoichiometry in marine phytoplankton

Phytoplankton is a nineteenth century ecological construct for a biologically diverse group of pelagic photoautotrophs that share common metabolic functions but not evolutionary histories. In contrast to terrestrial plants, a major schism occurred in the evolution of the eukaryotic phytoplankton that gave rise to two major plastid superfamilies. The green superfamily appropriated chlorophyll b, whereas the red superfamily uses chlorophyll c as an accessory photosynthetic pigment. Fossil evidence suggests that the green superfamily dominated Palaeozoic oceans. However, after the end-Permian extinction, members of the red superfamily rose to ecological prominence. The processes responsible for this shift are obscure. Here we present an analysis of major nutrients and trace elements in 15 species of marine phytoplankton from the two superfamilies. Our results indicate that there are systematic phylogenetic differences in the two plastid types where macronutrient (carbon:nitrogen:phosphorus) stoichiometries primarily reflect ancestral pre-symbiotic host cell phenotypes, but trace element composition reflects differences in the acquired plastids. The compositional differences between the two plastid superfamilies suggest that changes in ocean redox state strongly influenced the evolution and selection of eukaryotic phytoplankton since the Proterozoic era.     

Environmentally mediated synergy between perception and behaviour in mobile robots

The notion that behaviour influences perception seems self-evident, but the mechanism of their interaction is not known. Perception and behaviour are usually considered to be separate processes. In this view, perceptual learning constructs compact representations of sensory events, reflecting their statistical properties, independently of behavioural relevance. Behavioural learning, however, forms associations between perception and action, organized by reinforcement, without regard for the construction of perception. It is generally assumed that the interaction between these two processes is internal to the agent, and can be explained solely in terms of the neuronal substrate. Here we show, instead, that perception and behaviour can interact synergistically via the environment. Using simulated and real mobile robots, we demonstrate that perceptual learning directly supports behavioural learning and so promotes a progressive structuring of behaviour. This structuring leads to a systematic bias in input sampling, which directly affects the organization of the perceptual system. This external, environmentally mediated feedback matches the perceptual system to the emerging behavioural structure, so that the behaviour is stabilized.     

Programmable computing with a single magnetoresistive element

The development of transistor-based integrated circuits for modern computing is a story of great success. However, the proved concept for enhancing computational power by continuous miniaturization is approaching its fundamental limits. Alternative approaches consider logic elements that are reconfigurable at run-time to overcome the rigid architecture of the present hardware systems. Implementation of parallel algorithms on such 'chameleon' processors has the potential to yield a dramatic increase of computational speed, competitive with that of supercomputers. Owing to their functional flexibility, 'chameleon' processors can be readily optimized with respect to any computer application. In conventional microprocessors, information must be transferred to a memory to prevent it from getting lost, because electrically processed information is volatile. Therefore the computational performance can be improved if the logic gate is additionally capable of storing the output. Here we describe a simple hardware concept for a programmable logic element that is based on a single magnetic random access memory (MRAM) cell. It combines the inherent advantage of a non-volatile output with flexible functionality which can be selected at run-time to operate as an AND, OR, NAND or NOR gate.