Comparison of multimarker logistic regression models, with application to a genomewide scan of schizophrenia

Background

Imprinted genes show expression from one parental allele only and are important for development and behaviour. This extreme mode of allelic imbalance has been described for approximately 56 human genes. Imprinting status is often disrupted in cancer and dysmorphic syndromes. More subtle variation of gene expression, that is not parent-of-origin specific, termed 'allele-specific gene expression' (ASE) is more common and may give rise to milder phenotypic differences. Using two allele-specific high-throughput technologies alongside bioinformatics predictions, normal term human placenta was screened to find new imprinted genes and to ascertain the extent of ASE in this tissue.

Results

Twenty-three family trios of placental cDNA, placental genomic DNA (gDNA) and gDNA from both parents were tested for 130 candidate genes with the Sequenom MassArray system. Six genes were found differentially expressed but none imprinted. The Illumina ASE BeadArray platform was then used to test 1536 SNPs in 932 genes. The array was enriched for the human orthologues of 124 mouse candidate genes from bioinformatics predictions and 10 human candidate imprinted genes from EST database mining. After quality control pruning, a total of 261 informative SNPs (214 genes) remained for analysis. Imprinting with maternal expression was demonstrated for the lymphocyte imprinted gene ZNF331 in human placenta. Two potential differentially methylated regions (DMRs) were found in the vicinity of ZNF331. None of the bioinformatically predicted candidates tested showed imprinting except for a skewed allelic expression in a parent-specific manner observed for PHACTR2, a neighbour of the imprinted PLAGL1 gene. ASE was detected for two or more individuals in 39 candidate genes (18%).

Conclusions

Both Sequenom and Illumina assays were sensitive enough to study imprinting and strong allelic bias. Previous bioinformatics approaches were not predictive of new imprinted genes in the human term placenta. ZNF331 is imprinted in human term placenta and might be a new ubiquitously imprinted gene, part of a primate-specific locus. Demonstration of partial imprinting of PHACTR2 calls for re-evaluation of the allelic pattern of expression for the PHACTR2-PLAGL1 locus. ASE was common in human term placenta.     

Augmentation of partially regenerated nerves by end-to-side side-to-side grafting neurotization: experience based on eight late obstetric brachial plexus cases

Objective

The effect of end-to-side neurotization of partially regenerated recipient nerves on improving motor power in late obstetric brachial plexus lesions, so-called nerve augmentation, was investigated.

Methods

Eight cases aged 3 – 7 years were operated upon and followed up for 4 years (C5,6 rupture C7,8T1 avulsion: 5; C5,6,7,8 rupture T1 avulsion:1; C5,6,8T1 rupture C7 avulsion:1; C5,6,7 ruptureC8 T1 compression: one 3 year presentation after former neurotization at 3 months). Grade 1–3 muscles were neurotized. Grade0 muscles were neurotized, if the electromyogram showed scattered motor unit action potentials on voluntary contraction without interference pattern. Donor nerves included: the phrenic, accessory, descending and ascending loops of the ansa cervicalis, 3^rd and 4^th intercostals and contralateral C7.

Results

Superior proximal to distal regeneration was observed firstly. Differential regeneration of muscles supplied by the same nerve was observed secondly (superior supraspinatus to infraspinatus regeneration). Differential regeneration of antagonistic muscles was observed thirdly (superior biceps to triceps and pronator teres to supinator recovery). Differential regeneration of fibres within the same muscle was observed fourthly (superior anterior and middle to posterior deltoid regeneration). Differential regeneration of muscles having different preoperative motor powers was noted fifthly; improvement to Grade 3 or more occurred more in Grade2 than in Grade0 or Grade1 muscles. Improvements of cocontractions and of shoulder, forearm and wrist deformities were noted sixthly. The shoulder, elbow and hand scores improved in 4 cases.

Limitations

The sample size is small. Controls are necessary to rule out any natural improvement of the lesion. There is intra- and interobserver variability in testing muscle power and cocontractions.

Conclusion

Nerve augmentation improves cocontractions and muscle power in the biceps, pectoral muscles, supraspinatus, anterior and lateral deltoids, triceps and in Grade2 or more forearm muscles. As it is less expected to improve infraspinatus power, it should be associated with a humeral derotation osteotomy and tendon transfer. Function to non improving Grade 0 or 1 forearm muscles should be restored by muscle transplantation.

Level of evidence

Level IV, prospective case series.     

Chaperone-like activity of alpha-crystallin toward aldose reductase oxidatively stressed by copper ion

The protective action of alpha-crystallin against copper-induced protein stress is studied using bovine lens aldose reductase (ALR2) as protein model. The oxidative inactivation of ALR2 induced by CuCl2 at the stoichiometric Cu2+/ALR2 ratio of 2/1 [I. Cecconi, M. Moroni, P.G. Vilardo, M. Dal Monte, P. Borella, G. Rastelli, L. Costantino, D. Garland, D. Carper, J.M. Petrash, A. Del Corso, U. Mura, Biochemistry 37 (1998) 14167-14174] is accompanied by protein aggregation phenomena when the metal ion concentration is increased (Cu2+/ALR2>3). Protein oxidation precedes protein precipitation. Both inactivation and precipitation of ALR2 are prevented by alpha-crystallin in a concentration-dependent manner. The rationale for the stabilization of ALR2 exerted by alpha-crystallin at low metal concentration is given on the basis of the ability of alpha-crystallin to chelate copper. However, the overall protective action exerted by alpha-crystallin at higher copper concentration may be explained invoking the contribution of the special features of alpha-crystallin to easily interact with target proteins undergoing structural rearrangement.     

Reproduction Strategy of the Deep-sea Hermit Crabs Pagurus alatus and Pagurus excavatus of the Central-Western Mediterranean Sea

Some aspects of the reproductive biology of two hermit crabs Pagurus alatus (Fabricius, 1775) and P. excavatus (Herbst, 1791) were studied. Specimens were collected monthly from April 2000 to March 2001 on the continental shelf and the upper-middle slope off the Southwestern coasts of Sardinia, in the central-western Mediterranean Sea. Crab size (minimum and maximum shield length) was 1.7 and 9.5 mm for 1150 females of P. alatus; 4.0 and 10.4 mm for 347 females of P. excavatus, respectively. Females of P. alatus with ripe ovaries were only found in February-April and ovigerous females were observed throughout the year except in March, with the highest incidence in summer. Females of P. excavatus with fully developed ovaries were collected during all months of the year reaching a peak from April to June. Ovigerous females of P. excavatus occurred throughout the year and the main spawning period occurred in March and April. Fecundity of both species was calculated to assess seasonal variation of reproductive intensity and was positively correlated with the size of the individuals. Monthly fecundity did not reveal significant differences in P. alatus ovigerous females, whereas P. excavatus exhibited significant differences in monthly fecundity depending on the time of year. Difference in fecundity among P. alatus and P. excavatus can be related to the size of the ovigerous females and species of hermit crab, but their different reproductive strategies suggest that they are specifically related to different environmental conditions.     

Ratio-dependent parasitism with Trissolcus basalis (Wollaston) (Hymenoptera: Scelionidae) on egg rafts of Nezara viridula (Linnaeus) (Hemiptera: Pentatomidae): effect of experimental variables and compatibility of 'ratio' and 'Holling' models

Abstract Egg rafts of Nezara viridula were exposed to the parasitoid wasp Trissolcus basalis in experimental arenas to establish the relationship of the rates of attack and parasitism to various combinations of arena size, parasitoid density, host density and parasitoid-to-host ratio. Arena sizes were varied in the ratio 1:9:63, with the largest having a search area of 1.44 m². Parasitoid and host densities were varied over a 27-fold range. The parasitoid-to-host ratios used were 1:1, 3:1 and 6:1. Finding time was related to a constant factor (flight propensity), rather than to the difficulty of finding (density of hosts). Initial attack rates were therefore related only to parasitoid numbers (or density), even at the lower densities and ratios. Parasitism rates (a function of attack rate per host) were thus also strongly related to parasitoid to host ratio, regardless of densities used and arena sizes. Even reducing host density, while keeping time and parasitoid density constant, increased the parasitism rate. A ratio model for parasitism rate was therefore compatible with the data but the more explicit Holling 'disc' equation was also compatible because handling time was sufficiently large to make it sensitive to the ratio of parasitoids to hosts for the densities used. We conclude that the two models would predict different results if the density of host egg rafts was in a range below one per square metre.     

ER Stress Induced by Tunicamycin Triggers α-Synuclein Oligomerization,Dopaminergic Neurons Death and Locomotor Impairment: a New Model of Parkinson’s Disease

Parkinson’s disease (PD) is a neurodegenerative disorder characterized by progressive death of dopaminergic neurons of the substantia nigra pars compacta (SNpc), leading to the major clinical abnormalities that characterize this disease. Although PD’s etiology is unknown, α-synuclein aggregation plays a pivotal role in PD pathogenesis, which could be associated to some pathological processes such as oxidative stress, endoplasmic reticulum (ER) stress, impaired protein degradation, and mitochondrial dysfunction. Increasing experimental evidence indicates that ER stress is involved in PD, however most of the described results employed cultured cell lines and genetically modified animal models. In this study, we developed a new ER stress rat model employing the well-known ER stressor tunicamycin (Tm). To evaluate if ER stress was able to induce PD features, we performed an intranigral injection of Tm (0.1 μg/cerebral hemisphere) and animals (male Wistar rats) were analyzed 7 days post injection. The classical 6-OHDA neurotoxin model (1 μg/cerebral hemisphere) was used as an established positive control for PD. We show that Tm injection induced locomotor impairment, dopaminergic neurons death, and activation of astroglia. In addition, we observed an extensive α-synuclein oligomerization in SNpc of Tm-injected animals when compared with DMSO-injected controls. Finally, both Tm and 6-OHDA treated animals presented increased levels of ER stress markers. Taken together, these findings show for the first time that the ER stressor Tm recapitulates some of the phenotypic characteristics observed in rodent models of PD, reinforcing the concept that ER stress could be an important contributor to the pathophysiology of PD. Therefore, we propose the intranigral Tm injection as a new ER stress-based model for the study of PD in vivo.     

<Emphasis Type="Italic">Chirocephalus sarpedonis</Emphasis> sp. nov. (Branchiopoda,Anostraca, Chirocephalidae) from Turkey questions the monophyly of the traditional <Emphasis Type="Italic">Chirocephalus</Emphasis> species-groups

Here we test for the possible coupling of two kairomone-induced, anti-fish defences in Daphnia, life-history changes (LHC) and diel vertical migration (DVM) mediated by the environmental factor light. A gradient of five different light intensities that represents naturally occurring intensities in the lake water column was used in life-history experiments, and we show that LHC of a single Daphnia clone are inversely coupled to the ambient light intensity. Furthermore, we could show that the light intensity has to exceed a threshold to induce the LHC. We also observed an effect of the light intensity on the fish kairomone-mediated expression of a candidate gene (actin 3) in a way that the gene response differs between groups of low and high light intensities. We argue that the ambient light intensity an individual is exposed to and that is dependent on the position in the water column of a lake inversely determines the degree of LHC. These findings suggest a plastic coupling of these two anti-fish defences in Daphnia (LHC and DVM), which allows for an adjustment to fluctuating environments of standing freshwater ecosystems.     

Molecular and morphological data suggest weak phylogeographic structure in the fairy shrimp <Emphasis Type="Italic">Streptocephalus torvicornis</Emphasis> (Branchiopoda,Anostraca)

Lake Tanganyika has undergone substantial climate-driven lake level fluctuations that have repeatedly changed the distribution and extent of habitat for endemic fishes. Here we consider whether patterns of population genetic structure and phenotypic divergence within the cichlid fish Telmatochromis temporalis have been affected by changing lake levels. The species has a large-bodied rock-living ecomorph and a small-bodied shell-living ecomorph, and both are found in close proximity in littoral habitats. Using mtDNA sequences we found that geographically distant (>50 km) populations within the southern lake region diverged approximately 130,000–230,000 years ago, suggesting that the regional genetic structure persisted through a low stand of over 400 m ~106,000 years ago that ended with a rise to present levels ~100,000 years ago. We also found signatures of large population expansions since this rise across the study region, suggesting that the populations positively responded to new habitat as lake levels rose to present levels. Finally, we found that geographically adjacent (<10 km) ecomorphs exhibit both significant genetic differentiation and signatures of gene flow after the lake level rise. The results suggest that local ecomorph divergence progressed with gene flow after the last major rise in lake level ~100,000, potentially facilitated by new ecological opportunities.