Notch signalling in the regulation of peripheral T-cell function

The Notch signalling pathway plays a highly-conserved role in regulating the cellular differentiation and proliferation events that characterise pattern formation in the embryo. As cells in the embryo respond to environmental signals, similarly T-cells in the peripheral immune system must monitor their environment for antigens and respond accordingly by entering one of several potential differentiation pathways. Recent studies have identified a role for the Notch pathway in regulating the responses of T-cells in the periphery. In this review, we discuss these findings in the context of the Notch signalling pathway's role as an orchestrator of cellular differentiation, and propose a central role for Notch as a regulator of immune system function.     

Animal models of anxiety and their molecular dissection

Genetic approaches to psychiatric illness need appropriate animal models both for investigating how genetic variants give rise to behavioural disorder and for identifying genes that may be important in human conditions. Yet the relevance of many animal models to psychiatric illness is often not clear. Here I discuss how genetic approaches can be used to validate animal models of anxiety, an approach which is applicable to other animal models. One drawback of genetic validation is the difficulty inherent in identifying the molecular variants that influence the phenotype. I review genetic approaches that have the potential to overcome this problem.     

Assessment of cognitive and motor deficits in a marmoset model of stroke

The Stroke Therapy Academic Industry Roundtable noted the need for standardized, well-accepted primate models of stroke to help develop both neuroprotective and restorative therapies. One primate model has been developed using the marmoset, a small New World species of monkey, in which long-term functional deficits can be assessed. The surgery and postoperative care of the animals is described, as well as the behavioral tests used to quantify the postoperative disability. The types of deficits seen are illustrated by reference to some of the findings with neuroprotective treatments. Nevertheless, the long-term nature and consistency of the motor deficits make this model ideal for assessing the worth of restorative therapies.     

EEG-based communication and control: speed-accuracy relationships

People can learn to control mu (8–12 Hz) or beta (18–25 Hz) rhythm amplitude in the EEG recorded over sensorimotor cortex and use it to move a cursor to a target on a video screen. In our current EEG-based brain–computer interface (BCI) system, cursor movement is a linear function of mu or beta rhythm amplitude. In order to maximize the participant's control over the direction of cursor movement, the intercept in this equation is kept equal to the mean amplitude of recent performance. Selection of the optimal slope, or gain, which determines the magnitude of the individual cursor movements, is a more difficult problem. This study examined the relationship between gain and accuracy in a 1-dimensional EEG-based cursor movement task in which individuals select among 2 or more choices by holding the cursor at the desired choice for a fixed period of time (i.e., the dwell time). With 4 targets arranged in a vertical column on the screen, large gains favored the end targets whereas smaller gains favored the central targets. In addition, manipulating gain and dwell time within participants produces results that are in agreement with simulations based on a simple theoretical model of performance. Optimal performance occurs when correct selection of targets is uniform across position. Thus, it is desirable to remove any trend in the function relating accuracy to target position. We evaluated a controller that is designed to minimize the linear and quadratic trends in the accuracy with which participants hit the 4 targets. These results indicate that gain should be adjusted to the individual participants, and suggest that continual online gain adaptation could increase the speed and accuracy of EEG-based cursor control.     

Haplotype blocks and linkage disequilibrium in the human genome

There is great interest in the patterns and extent of linkage disequilibrium (LD) in humans and other species. Characterizing LD is of central importance for gene-mapping studies and can provide insights into the biology of recombination and human demographic history. Here, we review recent developments in this field, including the recently proposed 'haplotype-block' model of LD. We describe some of the recent data in detail and compare the observed patterns to those seen in simulations.     

Use of a random coefficient regression (RCR) model to estimate growth parameters

We used a random coefficient regression (RCR) model to estimate growth parameters for the time series of observed serum glucose levels in the Replicate 1 of the Genetic Analysis Workshop 13 simulated data. For comparison, a two time-point interval was also selected and the slope between these two observations was calculated. This process yielded four phenotypes: the RCR growth phenotype, a two time-point slope phenotype, and Time 1 and Time 2 serum glucose level phenotypes. These four phenotypes were used for linkage analyses on simulated chromosomes 5, 7, 9, and 21, those chromosomes that contained loci affecting the growth course for serum glucose levels. The linkage analysis of the RCR-derived phenotype showed overwhelming evidence for linkage at one locus (LOD 65.78 on chromosome 5), while showing elevated but nonsignificant LOD scores for two other loci (LOD 1.25 on chromosome 7, LOD 1.10 on chromosome 9), and no evidence of linkage for the final locus. The two time-point slope phenotype showed evidence for linkage at one locus (LOD 4.16 on chromosome 5) but no evidence for linkage at any of the other loci. A parallel cross-sectional approach, using as input phenotypes the endpoints of the two-point slope phenotype, gave strong linkage results for the major locus on chromosome 5 (maximal LOD scores of 17.90 and 27.24 for Time 1 and Time 2, respectively) while showing elevated but nonsignificant linkage results on chromosome 7 (maximal LOD scores of 1.71 and 1.48) and no evidence for linkage at the two remaining loci. The RCR growth parameter showed more power to detect linkage to the major locus than either the cross-sectional or two-point slope approach, but the cross-sectional approach gave a higher maximal LOD score for one of the minor loci.     

The influence of environment,sex, and innate timing mechanisms on body temperature patterns of free-ranging black-tailed prairie dogs (Cynomys ludovicianus)

Mechanisms that influence body temperature patterns in black-tailed prairie dogs are not well understood. Previous research on both free-ranging and laboratory populations of black-tailed prairie dogs (Cynomys ludovicianus) has suggested that reductions in ambient temperature and food and water deprivation are the primary factors that stimulate torpor in this species. In other species, however, torpor has been shown to be influenced by a multitude of factors, including innate circadian and circannual timing mechanisms, energy status, and reproductive behaviors. Our objective was to clarify the influence of weather, sex, and intrinsic timing mechanisms on the body temperature patterns of free-ranging black-tailed prairie dogs. We monitored body temperatures of eight adult (>1 yr) prairie dogs from November 1999 to June 2000. Prairie dogs showed distinct daily and seasonal body temperature patterns, which reflected changes in ambient temperatures that occurred during these periods. These patterns of daily and seasonal heterothermy suggest that body temperature patterns of black-tailed prairie dogs may be driven by an innate timing mechanism. All prairie dogs entered torpor intermittently throughout winter and spring. Torpor bouts appeared to be influenced by precipitation and reductions in ambient temperature. Our results also suggest that reproductive behaviors and circadian timing may influence torpor in this species.     

Virulence factors of the human opportunistic pathogen Serratia marcescens identified by in vivo screening

The human opportunistic pathogen Serratia marcescens is a bacterium with a broad host range, and represents a growing problem for public health. Serratia marcescens kills Caenorhabditis elegans after colonizing the nematode's intestine. We used C.elegans to screen a bank of transposon-induced S.marcescens mutants and isolated 23 clones with an attenuated virulence. Nine of the selected bacterial clones also showed a reduced virulence in an insect model of infection. Of these, three exhibited a reduced cytotoxicity in vitro, and among them one was also markedly attenuated in its virulence in a murine lung infection model. For 21 of the 23 mutants, the transposon insertion site was identified. This revealed that among the genes necessary for full in vivo virulence are those that function in lipopolysaccharide (LPS) biosynthesis, iron uptake and hemolysin production. Using this system we also identified novel conserved virulence factors required for Pseudomonas aeruginosa pathogenicity. This study extends the utility of C.elegans as an in vivo model for the study of bacterial virulence and advances the molecular understanding of S.marcescens pathogenicity.