Notch 1 inhibits photoreceptor production in the developing mammalian retina

The transmembrane receptor Notch1 plays a role in development and homeostasis in vertebrates and invertebrates. The mammalian retina is an excellent tissue in which to dissect the precise role of Notch signaling in regulating cell fate and proliferation. However, a systematic analysis has been limited by the early embryonic lethality of Notch1-null mice. Here, Notch1 was conditionally removed from the murine retina either early or late in development. Removal of Notch1 early led to a reduction in the size of the retina as well as aberrant morphology. A decrease in the number of progenitor cells and premature neurogenesis accounted for the reduction in size. Unexpectedly, ablation of Notch1 in early progenitor cells led to enhanced cone photoreceptor production, and ablation of Notch1 at later points led to an almost exclusive production of rod photoreceptor cells. These data suggest that Notch1 not only maintains the progenitor state, but is required to inhibit the photoreceptor fate. These cone enriched mutant mice should prove to be a valuable resource for the study of this relatively rare mammalian photoreceptor cell type.     

An interactive power analysis tool for microarray hypothesis testing and generation

MOTIVATION: Human clinical projects typically require a priori statistical power analyses. Towards this end, we sought to build a flexible and interactive power analysis tool for microarray studies integrated into our public domain HCE 3.5 software package. We then sought to determine if probe set algorithms or organism type strongly influenced power analysis results. RESULTS: The HCE 3.5 power analysis tool was designed to import any pre-existing Affymetrix microarray project, and interactively test the effects of user-defined definitions of alpha (significance), beta (1-power), sample size and effect size. The tool generates a filter for all probe sets or more focused ontology-based subsets, with or without noise filters that can be used to limit analyses of a future project to appropriately powered probe sets. We studied projects from three organisms (Arabidopsis, rat, human), and three probe set algorithms (MAS5.0, RMA, dChip PM/MM). We found large differences in power results based on probe set algorithm selection and noise filters. RMA provided high sensitivity for low numbers of arrays, but this came at a cost of high false positive results (24% false positive in the human project studied). Our data suggest that a priori power calculations are important for both experimental design in hypothesis testing and hypothesis generation, as well as for the selection of optimized data analysis parameters. AVAILABILITY: The Hierarchical Clustering Explorer 3.5 with the interactive power analysis functions is available at www.cs.umd.edu/hcil/hce or www.cnmcresearch.org/bioinformatics. CONTACT: jseo@cnmcresearch.org     

Contrasting demographies and persistence of rare annual plants in highly variable environments

Spatial and temporal variation in critical life history traits differ markedly between two co-occurring, rare and endangered annual plants, Gilia tenuiflora arenaria and Chorizanthe pungens pungens, that have restricted, but overlapping geographic distributions in coastal habitats of central California, USA. Environmental variation was extreme during the 6-year study (1997–2002), with the greatest differences between an intense wet, warm El Niño year (1998), followed by a very dry, cool La Niña (1999). Both species have similar increases in adult survival and seed set with wetter, warmer weather in spring, but they differed in other traits: more Gilia germinated in years with high rainfall and temperature, while more Chorizanthe germinated in dry, cooler years; Gilia abundance increased with the number of years since the previous large El Niño event, while Chorizanthe abundance declined; and Gilia abundance was independent of the previous year’s seed set, while Chorizanthe density was directly related to the previous year’s seed set. The strong negative associations of Chorizanthe abundance with warm, wet weather and with time since the previous El Niño probably reflect the particular sequence of annual weather patterns from 1997 through 2002, especially the extremes in 1998 and 1999. Since it germinates readily in most years under a wide range of winter conditions and does not develop a long-lived seed bank, Chorizanthe seedling abundance reflects recent additions and depletions of its seed bank, rather than prevailing weather, per se. In contrast, Gilia seeds may remain in the seed bank for many years, until relatively rare winter conditions trigger significant germination. These species-specific demographies enhance persistence and coexistence of these species, but the mechanisms differ from each other and from those described for annuals in other highly variable environments.     

The Influence of Previous Mountain Pine Beetle (Dendroctonus ponderosae) Activity on the 1988 Yellowstone Fires

We examined the historical record of mountain pine beetle (Dendroctonus ponderosae Hopkins) activity within Yellowstone National Park, Wyoming, for the 25-years period leading up to the 1988 Yellowstone fires (1963–86) to determine how prior beetle activity and the resulting tree mortality affected the spatial pattern of the 1988 Yellowstone fires. To obtain accurate estimates of our model parameters, we used a Markov chain Monte Carlo method to account for the high degree of spatial autocorrelation inherent to forest fires. Our final model included three statistically significant variables: drought, aspect, and sustained mountain pine beetle activity in the period 1972–75. Of the two major mountain pine beetle outbreaks that preceded the 1988 fires, the earlier outbreak (1972–75) was significantly correlated with the burn pattern, whereas the more recent one (1980–83) was not. Although regional drought and high winds were responsible for the large scale of this event, the analysis indicates that mountain pine beetle activity in the mid-1970s increased the odds of burning in 1988 by 11% over unaffected areas. Although relatively small in magnitude, this effect, combined with the effects of aspect and spatial variation in drought, had a dramatic impact on the spatial pattern of burned and unburned areas in 1988.     

Antibiotic efficacy and microbial virulence during space flight

Human space flight is a complex undertaking that entails numerous technological and biomedical challenges. Engineers and scientists endeavor, to the extent possible, to identify and mitigate the ensuing risks. The potential for an outbreak of an infectious disease in a spacecraft presents one such concern, which is compounded by several components unique to an extraterrestrial environment. Various factors associated with the space flight environment have been shown to potentially compromise the immune system of astronauts, increase microbial proliferation and microflora exchange, alter virulence and decrease antibiotic effectiveness. An acceptable resolution of the above concerns must be achieved to ensure safe and efficient space habitation. To help bring this about, scientists are employing advances in biotechnology to better characterize the relevant variables and establish appropriate solutions. Because many of these clinical concerns are also relevant in terrestrial society, this research will have reciprocal benefits back on Earth.     

Worker honey bee ovary development: seasonal variation and the influence of larval and adult nutrition

We examined the effect of larval and adult nutrition on worker honey bee (Apis mellifera L.) ovary development. Workers were fed high or low-pollen diets as larvae, and high or low-protein diets as adults. Workers fed low-protein diets at both life stages had the lowest levels of ovary development, followed by those fed high-protein diets as larvae and low- quality diets as adults, and then those fed diets poor in protein as larvae but high as adults. Workers fed high-protein diets at both life stages had the highest levels of ovary development. The increases in ovary development due to improved dietary protein in the larval and adult life stages were additive. Adult diet also had an effect on body mass. The results demonstrate that both carry-over of larval reserves and nutrients acquired in the adult life stage are important to ovary development in worker honey bees. Carry-over from larval development, however, appears to be less important to adult fecundity than is adult nutrition. Seasonal trends in worker ovary development and mass were examined throughout the brood rearing season. Worker ovary development was lowest in spring, highest in mid-summer, and intermediate in fall.     

Selective loss of synaptic proteins in Alzheimer's disease: evidence for an increased severity with APOE varepsilon4

A pathological feature of Alzheimer's disease (AD) is an area-specific neuronal loss that may be caused by excitotoxicity-related synaptic dysfunction. Relative expression levels of synaptophysin, dynamin I, complexins I and II, N-cadherin, and alphaCaMKII were analysed in human brain tissue from AD cases and controls in hippocampus, and inferior temporal and occipital cortices. Synaptophysin and dynamin I are presynaptic terminal proteins not specific to any neurotransmitter system whereas complexin II, N-cadherin, and alphaCaMKII are specific for excitatory synapses. Complexin I is a presynaptic protein localised to inhibitory synapses. There were no significant differences in synaptophysin, dynamin I, N-cadherin, or alphaCaMKII protein levels between AD cases and controls. The complexin proteins were both markedly lower in AD cases than in controls (P < 0.01). Cases were also categorised by APOE genotype. Averaged across areas there was a 36% lowering of presynaptic proteins in AD cases carrying at least one epsilon4 allele compared with in AD cases lacking the epsilon4 allele. We infer that synaptic protein level is not indicative of neuronal loss, but the synaptic dysfunction may result from the marked relative loss of the complexins in AD, and lower levels of presynaptic proteins in AD cases with the APOE epsilon4 allele.     

Unconditional hospitality: HIV, ethics and the refugee 'problem'

Refugees, as forced migrants, have suffered displacement under conditions not of their own choosing. In 2000 there were thought to be 22 million refugees of whom 6 million were HIV positive. While the New Zealand government has accepted a number of HIV positive refugees from sub-Saharan Africa, this hospitality is under threat due to negative public and political opinion. Epidemic conditions raise the social stakes attached to sexual exchanges, contagion becomes a major figure in social relationships and social production, and the fears of the contagious nature of those 'just off the plane' connect refugees to an equally deep-seated fear of racial miscegenation. Jacques Derrida's notion of unconditional hospitality is a dream of a democracy which would have a cosmopolitan form. This means that one cannot decide in advance which refugees one might choose to resettle. This paper will use Derrida's notion of unconditional hospitality to emphasise the fragility of HIV positive refugees' position, caught between becoming newly made New Zealand subjects while at the same time having that subjecthood threatened. For Derrida, both ethics and politics demand both an action and a need for a thoughtful response (a questioning without limit).     

Distinct action of the retinoblastoma pathway on the DNA replication machinery defines specific roles for cyclin-dependent kinase complexes in prereplication complex assembly and S-phase progression

The retinoblastoma (RB) and p16ink4a tumor suppressors are believed to function in a linear pathway that is functionally inactivated in a large fraction of human cancers. Recent studies have shown that RB plays a critical role in regulating S phase as a means for suppressing aberrant proliferation and controlling genome stability. Here, we demonstrate a novel role for p16ink4a in replication control that is distinct from that of RB. Specifically, p16ink4a disrupts prereplication complex assembly by inhibiting mini-chromosome maintenance (MCM) protein loading in G1, while RB was found to disrupt replication in S phase through attenuation of PCNA function. This influence of p16ink4a on the prereplication complex was dependent on the presence of RB and the downregulation of cyclin-dependent kinase (CDK) activity. Strikingly, the inhibition of CDK2 activity was not sufficient to prevent the loading of MCM proteins onto chromatin, which supports a model wherein the composite action of multiple G1 CDK complexes regulates prereplication complex assembly. Additionally, p16ink4a attenuated the levels of the assembly factors Cdt1 and Cdc6. The enforced expression of these two licensing factors was sufficient to restore the assembly of the prereplication complex yet failed to promote S-phase progression due to the continued absence of PCNA function. Combined, these data reveal that RB and p16ink4a function through distinct pathways to inhibit the replication machinery and provide evidence that stepwise regulation of CDK activity interfaces with the replication machinery at two discrete execution points.     

Dissimilation of C3-sulfonates

Cysteate and sulfolactate are widespread natural products in the environment, while propanesulfonate, 3-aminopropanesulfonate and propane-1,3-disulfonate are xenobiotics. While some understanding of the bacterial assimilation of cysteate sulfur has been achieved, details of the dissimilation of cysteate and sulfolactate by microbes together with information on the degradation of the xenobiotics have only recently become available. This minireview centres on bacterial catabolism of the carbon moiety in these C₃-sulfonates and on the fate of the sulfonate group. Three mechanisms of desulfonation have been established. Firstly, cysteate is converted via sulfopyruvate to sulfolactate, which is desulfonated to pyruvate and sulfite; the latter is oxidized to sulfate by a sulfite dehydrogenase and excreted as sulfate in Paracoccus pantotrophus NKNCYSA. Secondly, sulfolactate can be converted to cysteate, which is cleaved in a pyridoxal 5′-phosphate-coupled reaction to pyruvate, sulfite and ammonium ions; in Silicibacter pomeroyi DSS-3, the sulfite is excreted largely as sulfite. Both desulfonation reactions seem to be widespread. The third desulfonation mechanism is oxygenolysis of, e.g. propanesulfonate(s), about which less is known.