MDC1 is coupled to activated CHK2 in mammalian DNA damage response pathways

Forkhead-homology-associated (FHA) domains function as protein-protein modules that recognize phosphorylated serine/threonine motifs. Interactions between FHA domains and phosphorylated proteins are thought to have essential roles in the transduction of DNA damage signals; however, it is unclear how FHA-domain-containing proteins participate in mammalian DNA damage responses. Here we report that a FHA-domain-containing protein-mediator of DNA damage checkpoint protein 1 (MDC1; previously known as KIAA0170)--is involved in DNA damage responses. MDC1 localizes to sites of DNA breaks and associates with CHK2 after DNA damage. This association is mediated by the MDC1 FHA domain and the phosphorylated Thr 68 of CHK2. Furthermore, MDC1 is phosphorylated in an ATM/CHK2-dependent manner after DNA damage, suggesting that MDC1 may function in the ATM-CHK2 pathway. Consistent with this hypothesis, suppression of MDC1 expression results in defective S-phase checkpoint and reduced apoptosis in response to DNA damage, which can be restored by the expression of wild-type MDC1 but not MDC1 with a deleted FHA domain. Suppression of MDC1 expression results in decreased p53 stabilization in response to DNA damage. These results suggest that MDC1 is recruited through its FHA domain to the activated CHK2, and has a critical role in CHK2-mediated DNA damage responses.     

Precise dating of Dansgaard-Oeschger climate oscillations in western Europe from stalagmite data

The signature of Dansgaard-Oeschger events--millennial-scale abrupt climate oscillations during the last glacial period--is well established in ice cores and marine records. But the effects of such events in continental settings are not as clear, and their absolute chronology is uncertain beyond the limit of (14)C dating and annual layer counting for marine records and ice cores, respectively. Here we present carbon and oxygen isotope records from a stalagmite collected in southwest France which have been precisely dated using 234U/230Th ratios. We find rapid climate oscillations coincident with the established Dansgaard-Oeschger events between 83,000 and 32,000 years ago in both isotope records. The oxygen isotope signature is similar to a record from Soreq cave, Israel, and deep-sea records, indicating the large spatial scale of the climate oscillations. The signal in the carbon isotopes gives evidence of drastic and rapid vegetation changes in western Europe, an important site in human cultural evolution. We also find evidence for a long phase of extremely cold climate in southwest France between 61.2 +/- 0.6 and 67.4 +/- 0.9 kyr ago.     

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.     

Independent rate and temporal coding in hippocampal pyramidal cells

In the brain, hippocampal pyramidal cells use temporal as well as rate coding to signal spatial aspects of the animal's environment or behaviour. The temporal code takes the form of a phase relationship to the concurrent cycle of the hippocampal electroencephalogram theta rhythm. These two codes could each represent a different variable. However, this requires the rate and phase to vary independently, in contrast to recent suggestions that they are tightly coupled, both reflecting the amplitude of the cell's input. Here we show that the time of firing and firing rate are dissociable, and can represent two independent variables: respectively the animal's location within the place field, and its speed of movement through the field. Independent encoding of location together with actions and stimuli occurring there may help to explain the dual roles of the hippocampus in spatial and episodic memory, or may indicate a more general role of the hippocampus in relational/declarative memory.