Objective analysis of the topological organization of the primate cortical visual system.

The primate cortical visual system is composed of many structurally and functionally distinct areas, each receiving and sending about 10 projections from and to other cortical areas. The visual cortex is thus served by many cortico-cortical connections to form a network of considerable complexity. Thus the gross organization of this cortical processing system presents a formidable topological problem: although the spatial position of the areas in the brain is reasonably well established, the gross 'processing architecture' defined by the connections, is less well understood. Here I report an optimization approach that gives both qualitative and quantitative insight into the connectional topology of the primate cortical visual system. This approach supports suggestions that the system is divided into a dorsal 'stream' and a ventral 'stream' with limited cross-talk, that these two streams reconverge in the region of the principal sulcus (area 46) and in the superior temporal polysensory areas, that the system is hierarchically organized, and that the majority of the connections are from 'nearest-neighbour' and 'next-door-but-one' areas.     

Molecular and genetic damage in humans from environmental pollution in Poland.

Extreme environmental pollution such as that found in the highly industrialized Silesian region of Poland has been associated with increased risk of cancer and adverse reproductive outcomes. Among the most prevalent carcinogenic and mutagenic air pollutants in Silesia are the polycyclic aromatic hydrocarbons (PAH) which are largely produced by industrial and residential combustion of coal. Molecular epidemiology aims to prevent disease by using biological markers to identify risks well before clinical onset to allow effective intervention. Here, we use a battery of biological markers to measure molecular and genetic damage in peripheral blood samples from residents of Silesia and from persons living in a rural, less polluted area of Poland. The results show that their exposure to environmental pollution is associated with significant increases in carcinogen-DNA adducts (PAH-DNA and aromatic adducts), in sister chromatid exchange including high-frequency cells, and in chromosomal aberrations as well as a doubling in the frequency of ras oncogene overexpression. We found that aromatic adducts on DNA were significantly correlated with chromosomal mutation, providing us with a molecular link between environmental exposure and a genetic alteration relevant to cancer and reproductive risk.     

Structure of the catalytic domain of human phosphodiesterase 5 with bound drug molecules

Phosphodiesterases (PDEs) are a superfamily of enzymes that degrade the intracellular second messengers cyclic AMP and cyclic GMP. As essential regulators of cyclic nucleotide signalling with diverse physiological functions, PDEs are drug targets for the treatment of various diseases, including heart failure, depression, asthma, inflammation and erectile dysfunction. Of the 12 PDE gene families, cGMP-specific PDE5 carries out the principal cGMP-hydrolysing activity in human corpus cavernosum tissue. It is well known as the target of sildenafil citrate (Viagra) and other similar drugs for the treatment of erectile dysfunction. Despite the pressing need to develop selective PDE inhibitors as therapeutic drugs, only the cAMP-specific PDE4 structures are currently available. Here we present the three-dimensional structures of the catalytic domain (residues 537-860) of human PDE5 complexed with the three drug molecules sildenafil, tadalafil (Cialis) and vardenafil (Levitra). These structures will provide opportunities to design potent and selective PDE inhibitors with improved pharmacological profiles.     

Homozygotes for Huntington's disease

Careful comparison of symptomatic individuals with normal controls has revealed the primary biochemical abnormality in many human genetic diseases, particularly recessive disorders. This strategy has proved less successful for most human disorders which are not recessive, and where a single copy of the aberrant gene has clinically significant effects even though the normal gene product is present. An alternative approach that eliminates the impediment of a normal protein in affected individuals is to study homozygotes for the mutant allele. For virtually all dominant human disorders in which homozygotes have been described, symptoms have been significantly more severe in the homozygote than in the heterozygote. Thus, these disorders do not conform to the classical definition of dominance which states that homozygotes and heterozygotes for a defect are phenotypically indistinguishable. Instead, they display incomplete dominance, indicating that the normal allele may play a role in ameliorating the disease process. The D4S10 locus, defined by the probe G8 and linked to the gene for Huntington's disease (HD), has permitted us to identify individuals with a high probability of being homozygous for this autosomal dominant neurodegenerative disorder. These homozygotes do not differ in clinical expression or course from typical HD heterozygotes. HD appears to be the first human disease of genetically documented homozygosity that displays complete phenotypic dominance.     

An exceptional Devonian fish from Australia sheds light on tetrapod origins

The transition from fishes to tetrapods was one of the most dramatic events in the evolution of vertebrates, but many pivotal fossils are incomplete, resulting in gaps in the data that are used for phylogenetic reconstruction. Here we present new observations from the most complete, acid-prepared Devonian tetrapodomorph fish yet discovered, Gogonasus, which was previously placed just crownward of Kenichthys and rhizodontids, the most primitive taxa on the tetrapod lineage. Unexpectedly, Gogonasus shows a mosaic of plesiomorphic and derived tetrapod-like features. Whereas the braincase and dermal cranial skeleton exhibit generalized morphologies with respect to Eusthenopteron or Panderichthys, taxa that are traditionally considered to be phyletically close to tetrapods, the presence of a deeply invaginated, wide spiracle, advanced internal spiracular architecture and near-horizontal hyomandibula are specialized features that are absent from Eusthenopteron. Furthermore, the pectoral fin skeleton of Gogonasus shares several features with that of Tiktaalik, the most tetrapod-like fish. A new phylogenetic analysis places Gogonasus crownward of Eusthenopteron as the sister taxon to the Elpistostegalia. Aspects of the basic tetrapod limb skeleton and middle ear architecture can now be traced further back within the tetrapodomorph radiation.     

Retroviral invasion of the koala genome

Endogenous retroviruses are a common ancestral feature of mammalian genomes with most having been inactivated over time through mutation and deletion. A group of more intact endogenous retroviruses are considered to have entered the genomes of some species more recently, through infection by exogenous viruses, but this event has never been directly proved. We have previously reported koala retrovirus (KoRV) to be a functional virus that is associated with neoplasia. Here we show that KoRV also shows features of a recently inserted endogenous retrovirus that is vertically transmitted. The finding that some isolated koala populations have not yet incorporated KoRV into their genomes, combined with its high level of activity and variability in individual koalas, suggests that KoRV is a virus in transition between an exogenous and endogenous element. This ongoing dynamic interaction with a wild species provides an exciting opportunity to study the process and consequences of retroviral endogenization in action, and is an attractive model for studying the evolutionary event in which a retrovirus invades a mammalian genome.