Structure-based models of cadherin-mediated cell adhesion: the evolution continues

Cadherins are glycoproteins that are responsible for homophilic, Ca²⁺-dependent cell-cell adhesion and play crucial roles in many cellular adhesion processes ranging from embryogenesis to the formation of neuronal circuits in the central nervous system. Many different experimental approaches have been used to unravel the molecular basis for cadherin-mediated adhesion. In particular, several high-resolution structures have provided models for cadherin-cadherin interactions that are illuminative in many respects yet contradictory in others. This review gives an overview of the structural studies of cadherins over the past decade while focusing on recent developments that reconcile some of the earlier findings.Received 7 January 2004; received after revision 24 February 2004; accepted 4 March 2004     

A humid climate state during the Palaeocene/Eocene thermal maximum

An abrupt climate warming of 5 to 10 degrees C during the Palaeocene/Eocene boundary thermal maximum (PETM) 55 Myr ago is linked to the catastrophic release of approximately 1,050-2,100 Gt of carbon from sea-floor methane hydrate reservoirs. Although atmospheric methane, and the carbon dioxide derived from its oxidation, probably contributed to PETM warming, neither the magnitude nor the timing of the climate change is consistent with direct greenhouse forcing by the carbon derived from methane hydrate. Here we demonstrate significant differences between marine and terrestrial carbon isotope records spanning the PETM. We use models of key carbon cycle processes to identify the cause of these differences. Our results provide evidence for a previously unrecognized discrete shift in the state of the climate system during the PETM, characterized by large increases in mid-latitude tropospheric humidity and enhanced cycling of carbon through terrestrial ecosystems. A more humid atmosphere helps to explain PETM temperatures, but the ultimate mechanisms underlying the shift remain unknown.     

BAG-6, a jack of all trades in health and disease

BCL2-associated athanogene 6 (BAG-6) (also Bat-3/Scythe) was discovered as a gene product of the major histocompatibility complex class III locus. The Xenopus ortholog Scythe was first identified to act as an anti-apoptotic protein. Subsequent studies unraveled that the large BAG-6 protein contributes to a number of cellular processes, including apoptosis, gene regulation, protein synthesis, protein quality control, and protein degradation. In this context, BAG-6 acts as a multifunctional chaperone, which interacts with its target proteins for shuttling to distinct destinations. Nonetheless, as anticipated from its genomic localization, BAG-6 is involved in a variety of immunological pathways such as macrophage function and T_H1 response. Most recently, BAG-6 was identified on the plasma membrane of dendritic cells and malignantly transformed cells where it serves as cellular ligand for the activating natural killer (NK) cell receptor NKp30 triggering NK cell cytotoxicity. Moreover, target cells were found to secrete soluble variants of BAG-6 and release BAG-6 on the surface of exosomes, which inhibit or activate NK cell cytotoxicity, respectively. These data suggest that the BAG-6 antigen is an important target to shape a directed immune response or to overcome tumor-immune escape strategies established by soluble BAG-6. This review summarizes the currently known functions of BAG-6, a fascinating multicompetent protein, in health and disease.     

Observation of squeezed light from one atom excited with two photons

Single quantum emitters such as atoms are well known as non-classical light sources with reduced noise in the intensity, capable of producing photons one by one at given times. However, the light field emitted by a single atom can exhibit much richer dynamics. A prominent example is the predicted ability of a single atom to produce quadrature-squeezed light, which has fluctuations of amplitude or phase that are below the shot-noise level. However, such squeezing is much more difficult to observe than the emission of single photons. Squeezed beams have been generated using macroscopic and mesoscopic media down to a few tens of atoms, but despite experimental efforts, single-atom squeezing has so far escaped observation. Here we generate squeezed light with a single atom in a high-finesse optical resonator. The strong coupling of the atom to the cavity field induces a genuine quantum mechanical nonlinearity, which is several orders of magnitude larger than in typical macroscopic media. This produces observable quadrature squeezing, with an excitation beam containing on average only two photons per system lifetime. In sharp contrast to the emission of single photons, the squeezed light stems from the quantum coherence of photon pairs emitted from the system. The ability of a single atom to induce strong coherent interactions between propagating photons opens up new perspectives for photonic quantum logic with single emitters.     

Genetic variation in DLG5 is associated with inflammatory bowel disease

Crohn disease and ulcerative colitis are two subphenotypes of inflammatory bowel disease (IBD), a complex disorder resulting from gene-environment interaction. We refined our previously defined linkage region for IBD on chromosome 10q23 and used positional cloning to identify genetic variants in DLG5 associated with IBD. DLG5 encodes a scaffolding protein involved in the maintenance of epithelial integrity. We identified two distinct haplotypes with a replicable distortion in transmission (P = 0.000023 and P = 0.004 for association with IBD, P = 0.00012 and P = 0.04 for association with Crohn disease). One of the risk-associated DLG5 haplotypes is distinguished from the common haplotype by a nonsynonymous single-nucleotide polymorphism 113G-->A, resulting in the amino acid substitution R30Q in the DUF622 domain of DLG5. This mutation probably impedes scaffolding of DLG5. We stratified the study sample according to the presence of risk-associated CARD15 variants to study potential gene-gene interaction. We found a significant difference in association of the 113A DLG5 variant with Crohn disease in affected individuals carrying the risk-associated CARD15 alleles versus those carrying non-risk-associated CARD15 alleles. This is suggestive of a complex pattern of gene-gene interaction between DLG5 and CARD15, reflecting the complex nature of polygenic diseases. Further functional studies will evaluate the biological significance of DLG5 variants.     

Convergence across biomes to a common rain-use efficiency

Water availability limits plant growth and production in almost all terrestrial ecosystems. However, biomes differ substantially in sensitivity of aboveground net primary production (ANPP) to between-year variation in precipitation. Average rain-use efficiency (RUE; ANPP/precipitation) also varies between biomes, supposedly because of differences in vegetation structure and/or biogeochemical constraints. Here we show that RUE decreases across biomes as mean annual precipitation increases. However, during the driest years at each site, there is convergence to a common maximum RUE (RUE(max)) that is typical of arid ecosystems. RUE(max) was also identified by experimentally altering the degree of limitation by water and other resources. Thus, in years when water is most limiting, deserts, grasslands and forests all exhibit the same rate of biomass production per unit rainfall, despite differences in physiognomy and site-level RUE. Global climate models predict increased between-year variability in precipitation, more frequent extreme drought events, and changes in temperature. Forecasts of future ecosystem behaviour should take into account this convergent feature of terrestrial biomes.