The p53 Codon 72 PRO/PRO Genotype May Be Associated with Initial Central Visual Field Defects in Caucasians with Primary Open Angle Glaucoma

Background

Loss of vision in glaucoma is due to apoptotic retinal ganglion cell loss. While p53 modulates apoptosis, gene association studies between p53 variants and glaucoma have been inconsistent. In this study we evaluate the association between a p53 variant functionally known to influence apoptosis (codon 72 Pro/Arg) and the subset of primary open angle glaucoma (POAG) patients with early loss of central visual field.

Methods

Genotypes for the p53 codon 72 polymorphism (Pro/Arg) were obtained for 264 POAG patients and 400 controls from the U.S. and in replication studies for 308 POAG patients and 178 controls from Australia (GIST). The glaucoma patients were divided into two groups according to location of initial visual field defect (either paracentral or peripheral). All cases and controls were Caucasian with European ancestry.

Results

The p53-PRO/PRO genotype was more frequent in the U.S. POAG patients with early visual field defects in the paracentral regions compared with those in the peripheral regions or control group (p = 2.7×10⁻⁵). We replicated this finding in the GIST cohort (p  = 7.3×10⁻³, and in the pooled sample (p = 6.6×10⁻⁷) and in a meta-analysis of both the US and GIST datasets (1.3×10⁻⁶, OR 2.17 (1.58–2.98 for the PRO allele).

Conclusions

These results suggest that the p53 codon 72 PRO/PRO genotype is potentially associated with early paracentral visual field defects in primary open-angle glaucoma patients.     

How often are invasion-induced ecological impacts missed?

Managers and policy makers depend on empirical research to guide and support biosecurity measures that mitigate introduced species’ impacts. Research contributing to this knowledge base generally uses null hypothesis significance testing to determine the significance of data patterns. However, reliance on traditional statistical significance testing methods, combined with small effect and sample size and large variability inherent to many impact studies, may obscure effects on native species, communities or ecosystems. This may result in false certainty of no impact. We investigated potential Type II error rates and effect sizes for 31 non-significant empirical evaluations of impact for introduced algal and crustacean species. We found low power consistently led to acceptance of Type II errors at rates 5.6–19 times greater than Type I errors (despite moderate to large effect sizes). Our results suggest that introduced species for which impact studies have statistically non-significant outcomes (often interpreted as “no impact”) may potentially have large impacts that are missed due to small sample or effect sizes and/or high variation. This alarming willingness to “miss” impacts has severe implications for conservation efforts, including under-managing species’ impacts and discounting the costs of Type II errors.     

Seed size and shade-tolerance: a comparative analysis of North American temperate trees

Large seed size is a trait associated with plant species of mature, closed habitats, and is thought to supply an ample nutrient reserve necessary for seedling establishment. While this relationship has been shown for annuals and short-lived perennials, it is poorly documented for trees. A comparative method was used to determine whether North American temperate tree species which typically establish in shady conditions have larger seeds than those requiring more open conditions. Both angiosperms (hardwoods) and gymnosperms (conifers) were involved in the study. A significant relationship was found between large seed mass and shade-tolerance for angiosperms, but not for gymnosperms. These contrasting results seem to relate to unique evolutionary opportunities or constraints in different taxa. The absence of a relationship for gymnosperms is discussed in terms of character traits which might prevent seed size selection in response to shade. The finding for angiosperms underlines the importance of the regeneration niche in promoting coexistence among temperate hardwood species through seed size differentiation. Received: 18 March 1997 / Accepted: 26 November 1997     

Determining effects of suspended sediment on condition of a suspension feeding bivalve (Atrina zelandica): results of a survey, a laboratory experiment and a field transplant experiment

The horse mussel Atrina zelandica (Gray) is a large, suspension feeding pinnid bivalve, common in coastal and estuarine areas of northern New Zealand. As a suspension feeder, Atrina is likely to be influenced by suspended sediment loads. We conducted a laboratory experiment to determine the effect of short-term elevations in turbidity levels, such as those commonly recorded during storms, on the physiological condition and clearance rates of Atrina. We also conducted a field survey and a 3-month transplant experiment at multiple sites along a gradient of increasing suspended sediment load in a New Zealand estuary. Laboratory clearance rates of Atrina declined above a threshold suspended sediment concentration, and Atrina physiological condition at the end of this experiment was lower in high cf. low turbidity treatments. Decreases in Atrina condition were detected after exposure to elevated levels for only 3 days. The field survey and transplant experiment provided empirical evidence of a strong, negative effect of increasing suspended sediment flux on the physiological condition of Atrina. We suggest that relationships between the physiological condition of suspension feeders and sediment settling flux could provide a link between sediment inputs, which commonly occur as a result of catchment runoff during rainfall events, and the ecological health of estuarine and shallow coastal areas. Our study also demonstrated that Atrina have a natural distribution limit controlled by suspended sediment load. Thus, there is potential for larger-scale functional and structural effects on benthic communities in estuarine and coastal areas with high rates of sedimentation.     

Ligand binding to distinct states diverts aggregation of an amyloid-forming protein

Although small molecules that modulate amyloid formation in vitro have been identified, significant challenges remain in determining precisely how these species act. Here we describe the identification of rifamycin SV as a potent inhibitor of β(2) microglobulin (β(2)m) fibrillogenesis when added during the lag time of assembly or early during fibril elongation. Biochemical experiments demonstrate that the small molecule does not act by a colloidal mechanism. Exploiting the ability of electrospray ionization-ion mobility spectrometry-mass spectrometry (ESI-IMS-MS) to resolve intermediates of amyloid assembly, we show instead that rifamycin SV inhibits β(2)m fibrillation by binding distinct monomeric conformers, disfavoring oligomer formation and diverting the course of assembly to the formation of spherical aggregates. The results demonstrate the power of ESI-IMS-MS to identify specific protein conformers as targets for intervention in fibrillogenesis using small molecules and reveal a mechanism of action in which ligand binding diverts unfolded protein monomers toward alternative assembly pathways.     

Mitochondrial oxidative phosphorylation compensation may preserve vision in patients with OPA1-linked autosomal dominant optic atrophy

Autosomal Dominant Optic Atrophy (ADOA) is the most common inherited optic atrophy where vision impairment results from specific loss of retinal ganglion cells of the optic nerve. Around 60% of ADOA cases are linked to mutations in the OPA1 gene. OPA1 is a fission-fusion protein involved in mitochondrial inner membrane remodelling. ADOA presents with marked variation in clinical phenotype and varying degrees of vision loss, even among siblings carrying identical mutations in OPA1. To determine whether the degree of vision loss is associated with the level of mitochondrial impairment, we examined mitochondrial function in lymphoblast cell lines obtained from six large Australian OPA1-linked ADOA pedigrees. Comparing patients with severe vision loss (visual acuity [VA]<6/36) and patients with relatively preserved vision (VA>6/9) a clear defect in mitochondrial ATP synthesis and reduced respiration rates were observed in patients with poor vision. In addition, oxidative phosphorylation (OXPHOS) enzymology in ADOA patients with normal vision revealed increased complex II+III activity and levels of complex IV protein. These data suggest that OPA1 deficiency impairs OXPHOS efficiency, but compensation through increases in the distal complexes of the respiratory chain may preserve mitochondrial ATP production in patients who maintain normal vision. Identification of genetic variants that enable this response may provide novel therapeutic insights into OXPHOS compensation for preventing vision loss in optic neuropathies.     

Ecological correlates and phylogenetic signal of host use in North American unionid mussels

Mussels in the order Unionoida comprise ～75% of the world’s freshwater bivalve species and are free-living apart from a brief larval stage that parasitizes fish. We investigated the relationships among species of North American unionid mussels and their known host fishes from a macroevolutionary perspective to test whether and how ecological and evolutionary factors correlate with patterns of host use. A subset of 69 mussel species was chosen based on data availability regarding their fish host repertoires, phylogenetic relationships, and ecology. Despite the brevity of their parasitic life stages, the mussels conformed to the right-skewed distribution of host specificity typical of parasitic taxa, in which most species are specialists and a few are generalists. Phylogenetic least squares regression models identified affinity for low-gradient and riffle habitats, and colonization of post-glacial watersheds as the best predictors for the number of fish host species per mussel. However, the second-best model identified citation number as a predictor of the number of hosts, implying that many mussel–host interactions still remain to be identified. A Multiple Regression Mantel test was performed to identify factors associated with the proportion of hosts shared between pairs of mussel species. Range overlap, citations, genetic distance, and similarity in host infection strategy were significantly correlated with the proportion of hosts shared, yet total variation as explained by the best model was low (R²?=?0.14). There was evidence of a topological association between mussels and their hosts (P?=?0.001) and a significant phylogenetic signal of host specificity (λ?=?0.81, P?=?0.003), indicating closely related mussels that overlap in range are more likely to be competing for hosts. Our results provide an initial macroevolutionary framework for studying the evolution of host infection strategies in these mussels but also highlights gaps still remaining in our fundamental ecological knowledge of this endangered clade.     

Sink Metabolism in Tomato Fruit : II. Phloem Unloading and Sugar Uptake

Analysis of [³H]-(fructosyl)-sucrose translocation in tomato (Lycopersicon esculentum Mill.) indicates that phloem unloading in the fruit occurs, at least in part, to the apoplast followed by extracellular hydrolysis. Apoplastic sucrose, glucose, and fructose concentrations were estimated as 1 to 7, 12 to 49, and 8 to 63 millimolar, respectively in the tomato fruit pericarp tissue. Hexose concentrations were at least four-fold greater than sucrose at all developmental stages. Short-term uptake of [¹⁴C]sucrose, -glucose, and -fructose in tomato pericarp disks showed first order kinetics over the physiologically relevant concentration range. The uptake rate of [¹⁴C]-(glucosyl)-1′-fluorosucrose was identical to the rate of [¹⁴C]sucrose uptake, suggesting sucrose may be taken up directly without prior extracellular hydrolysis. Short-term uptake of all three sugars was insensitive to 10 micromolar carbonyl cyanide m-chlorophenylhydrazone and to 10 micromolar p-chloromercuribenzene sulfonic acid. However, long-term accumulation of glucose was sensitive to carbonyl cyanide m-chlorophenylhydrazone. Together these results suggest that although sucrose is at least partially hydrolyzed in the apoplast, sucrose may enter the metabolic carbohydrate pool directly. In addition, sugar uptake across the plasma membrane does not appear to be energy dependent, suggesting that sugar accumulation in the tomato fruit is driven by subsequent intracellular metabolism and/or active uptake at the tonoplast.