Lack of effect of neurotransmitters on cyclic AMP phosphodiesterase activity in an insect CNS.

The inhibition of cyclic nucleotide phosphodiesterase from the nerve cord of Manduca sexta was studied using theophylline as a model compound. 11 putative neurotransmitters had no effect on enzyme activity.     

Development and differentiation of the intestinal epithelium

The gastrointestinal tract develops from a simple tube to a complex organ with patterns of differentiation along four axes of asymmetry. The organ is composed of all three germ layers signaling to each other during development to form the adult structure. The gut epithelium is a constitutively developing tissue, constantly differentiating from a stem cell in a progenitor pool throughout the life of the organism. Signals from the adjacent mesoderm and between epithelial cells are required for normal orderly development/differentiation, homeostasis, and apoptosis. Embryonically important patterning factors are used during adult stages for these processes. Such critical pathways as the hedgehog, bone morphogenetic protein, Notch, Sox, and Wnt systems are used both in embryologic and adult times of gut development. We focus on and review the roles of these factors in gut epithelial cell development and differentiation.Received 18 October 2002; received after revision 18 December 2002; accepted 18 December 2002     

Engineering evolution to study speciation in yeasts

The Saccharomyces 'sensu stricto' yeasts are a group of species that will mate with one another, but interspecific pairings produce sterile hybrids. A retrospective analysis of their genomes revealed that translocations between the chromosomes of these species do not correlate with the group's sequence-based phylogeny (that is, translocations do not drive the process of speciation). However, that analysis was unable to infer what contribution such rearrangements make to reproductive isolation between these organisms. Here, we report experiments that take an interventionist, rather than a retrospective approach to studying speciation, by reconfiguring the Saccharomyces cerevisiae genome so that it is collinear with that of Saccharomyces mikatae. We demonstrate that this imposed genomic collinearity allows the generation of interspecific hybrids that produce a large proportion of spores that are viable, but extensively aneuploid. We obtained similar results in crosses between wild-type S. cerevisiae and the naturally collinear species Saccharomyces paradoxus, but not with non-collinear crosses. This controlled comparison of the effect of chromosomal translocation on species barriers suggests a mechanism for the generation of redundancy in the S. cerevisiae genome.     

Evolution of complex life cycles in helminth parasites

The fundamental question of how complex life cycles--where there is typically more than one host-evolve in host--parasite systems remains largely unexplored. We suggest that complex cycles in helminths without penetrative infective stages evolve by two essentially different processes, depending on where in the cycle a new host is inserted. In 'upward incorporation', a new definitive host, typically higher up a food web and which preys on the original definitive host, is added. Advantages to the parasite are avoidance of mortality due to the predator, greater body size at maturity and higher fecundity. The original host typically becomes an intermediate host, in which reproduction is suppressed. In 'downward incorporation', a new intermediate host is added at a lower trophic level; this reduces mortality and facilitates transmission to the original definitive host. These two processes should also apply in helminths with penetrative infective stages, although the mathematical conditions differ.     

Further evidence for small-bodied hominins from the Late Pleistocene of Flores, Indonesia

Homo floresiensis was recovered from Late Pleistocene deposits on the island of Flores in eastern Indonesia, but has the stature, limb proportions and endocranial volume of African Pliocene Australopithecus. The holotype of the species (LB1), excavated in 2003 from Liang Bua, consisted of a partial skeleton minus the arms. Here we describe additional H. floresiensis remains excavated from the cave in 2004. These include arm bones belonging to the holotype skeleton, a second adult mandible, and postcranial material from other individuals. We can now reconstruct the body proportions of H. floresiensis with some certainty. The finds further demonstrate that LB1 is not just an aberrant or pathological individual, but is representative of a long-term population that was present during the interval 95-74 to 12 thousand years ago. The excavation also yielded more evidence for the depositional history of the cave and for the behavioural capabilities of H. floresiensis, including the butchery of Stegodon and use of fire.     

A RING-type ubiquitin ligase family member required to repress follicular helper T cells and autoimmunity

Despite the sequencing of the human and mouse genomes, few genetic mechanisms for protecting against autoimmune disease are currently known. Here we systematically screen the mouse genome for autoimmune regulators to isolate a mouse strain, sanroque, with severe autoimmune disease resulting from a single recessive defect in a previously unknown mechanism for repressing antibody responses to self. The sanroque mutation acts within mature T cells to cause formation of excessive numbers of follicular helper T cells and germinal centres. The mutation disrupts a repressor of ICOS, an essential co-stimulatory receptor for follicular T cells, and results in excessive production of the cytokine interleukin-21. sanroque mice fail to repress diabetes-causing T cells, and develop high titres of autoantibodies and a pattern of pathology consistent with lupus. The causative mutation is in a gene of previously unknown function, roquin (Rc3h1), which encodes a highly conserved member of the RING-type ubiquitin ligase protein family. The Roquin protein is distinguished by the presence of a CCCH zinc-finger found in RNA-binding proteins, and localization to cytosolic RNA granules implicated in regulating messenger RNA translation and stability.