Sensitivity of methods for estimating breeding values using genetic markers to the number of QTL and distribution of QTL variance

The objective of this simulation study was to compare the effect of the number of QTL and distribution of QTL variance on the accuracy of breeding values estimated with genomewide markers (MEBV). Three distinct methods were used to calculate MEBV: a Bayesian Method (BM), Least Angle Regression (LARS) and Partial Least Square Regression (PLSR). The accuracy of MEBV calculated with BM and LARS decreased when the number of simulated QTL increased. The accuracy decreased more when QTL had different variance values than when all QTL had an equal variance. The accuracy of MEBV calculated with PLSR was affected neither by the number of QTL nor by the distribution of QTL variance. Additional simulations and analyses showed that these conclusions were not affected by the number of individuals in the training population, by the number of markers and by the heritability of the trait. Results of this study show that the effect of the number of QTL and distribution of QTL variance on the accuracy of MEBV depends on the method that is used to calculate MEBV.     

Design, synthesis, and biological activity of novel factor Xa inhibitors: 4-aryloxy substituents of 2,6-diphenoxypyridines

A novel series of triaryloxypyridines have been designed to inhibit factor Xa, a serine protease strategically located in the coagulation cascade. Inhibitor 5e has a K(I) against factor Xa of 0.12nM and is greater than 8000- and 2000-fold selective over two related serine proteases, thrombin and trypsin, respectively. The 4-position of the central pyridine has been identified as a site that tolerates various substitutions without deleterious effects on potency and selectivity. This suggests that the 4-position of the pyridine ring is an ideal site for chemical modifications to identify inhibitors with improved pharmacokinetic characteristics. This investigation has resulted in inhibitor 5d, which has an oral availability of 6% in dogs. The synthesis, in vitro activity, and in vivo profile of this class of inhibitors is outlined.     

Valid and reliable instruments for arm-hand assessment at ICF activity level in persons with hemiplegia: a systematic review

Background

Loss of arm-hand performance due to a hemiparesis as a result of stroke or cerebral palsy (CP), leads to large problems in daily life of these patients. Assessment of arm-hand performance is important in both clinical practice and research. To gain more insight in e.g. effectiveness of common therapies for different patient populations with similar clinical characteristics, consensus regarding the choice and use of outcome measures is paramount. To guide this choice, an overview of available instruments is necessary. The aim of this systematic review is to identify, evaluate and categorize instruments, reported to be valid and reliable, assessing arm-hand performance at the ICF activity level in patients with stroke or cerebral palsy.

Methods

A systematic literature search was performed to identify articles containing instruments assessing arm-hand skilled performance in patients with stroke or cerebral palsy. Instruments were identified and divided into the categories capacity, perceived performance and actual performance. A second search was performed to obtain information on their content and psychometrics.

Results

Regarding capacity, perceived performance and actual performance, 18, 9 and 3 instruments were included respectively. Only 3 of all included instruments were used and tested in both patient populations. The content of the instruments differed widely regarding the ICF levels measured, assessment of the amount of use versus the quality of use, the inclusion of unimanual and/or bimanual tasks and the inclusion of basic and/or extended tasks.

Conclusions

Although many instruments assess capacity and perceived performance, a dearth exists of instruments assessing actual performance. In addition, instruments appropriate for more than one patient population are sparse. For actual performance, new instruments have to be developed, with specific focus on the usability in different patient populations and the assessment of quality of use as well as amount of use. Also, consensus about the choice and use of instruments within and across populations is needed.     

Response to genomic selection: The Bulmer effect and the potential of genomic selection when the number of phenotypic records is limiting

Background

Over the last ten years, genomic selection has developed enormously. Simulations and results on real data suggest that breeding values can be predicted with high accuracy using genetic markers alone. However, to reach high accuracies, large reference populations are needed. In many livestock populations or even species, such populations cannot be established when traits are difficult or expensive to record, or when the population size is small. The value of genomic selection is then questionable.

Methods

In this study, we compare traditional breeding schemes based on own performance or progeny information to genomic selection schemes, for which the number of phenotypic records is limiting. Deterministic simulations were performed using selection index theory. Our focus was on the equilibrium response obtained after a few generations of selection. Therefore, we first investigated the magnitude of the Bulmer effect with genomic selection.

Results

Results showed that the reduction in response due to the Bulmer effect is the same for genomic selection as for selection based on traditional BLUP estimated breeding values, and is independent of the accuracy of selection. The reduction in response with genomic selection is greater than with selection based directly on phenotypes without the use of pedigree information, such as mass selection. To maximize the accuracy of genomic estimated breeding values when the number of phenotypic records is limiting, the same individuals should be phenotyped and genotyped, rather than genotyping parents and phenotyping their progeny. When the generation interval cannot be reduced with genomic selection, large reference populations are required to obtain a similar response to that with selection based on BLUP estimated breeding values based on own performance or progeny information. However, when a genomic selection scheme has a moderate decrease in generation interval, relatively small reference population sizes are needed to obtain a similar response to that with selection on traditional BLUP estimated breeding values.

Conclusions

When the trait of interest cannot be recorded on the selection candidate, genomic selection schemes are very attractive even when the number of phenotypic records is limited, because traditional breeding requires progeny testing schemes with long generation intervals in those cases.     

lemmingA encodes the Apc11 subunit of the APC/C in Drosophila melanogaster that forms a ternary complex with the E2-C type ubiquitin conjugating enzyme, Vihar and Morula/Apc2

Background

The spindle assembly checkpoint (SAC) inhibits anaphase progression in the presence of insufficient kinetochore-microtubule attachments, but cells can eventually override mitotic arrest by a process known as mitotic slippage or adaptation. This is a problem for cancer chemotherapy using microtubule poisons.

Results

Here we describe mitotic slippage in yeast bub2?? mutant cells that are defective in the repression of precocious telophase onset (mitotic exit). Precocious activation of anaphase promoting complex/cyclosome (APC/C)-Cdh1 caused mitotic slippage in the presence of nocodazole, while the SAC was still active. APC/C-Cdh1, but not APC/C-Cdc20, triggered anaphase progression (securin degradation, separase-mediated cohesin cleavage, sister-chromatid separation and chromosome missegregation), in addition to telophase onset (mitotic exit), during mitotic slippage. This demonstrates that an inhibitory system not only of APC/C-Cdc20 but also of APC/C-Cdh1 is critical for accurate chromosome segregation in the presence of insufficient kinetochore-microtubule attachments.

Conclusions

The sequential activation of APC/C-Cdc20 to APC/C-Cdh1 during mitosis is central to accurate mitosis. Precocious activation of APC/C-Cdh1 in metaphase (pre-anaphase) causes mitotic slippage in SAC-activated cells. For the prevention of mitotic slippage, concomitant inhibition of APC/C-Cdh1 may be effective for tumor therapy with mitotic spindle poisons in humans.     

Rapid learning of shelter position in an intertidal fish, the shanny Lipophrys pholis L.

The homing ability of an intertidal fish, the shanny Lipophrys pholis , was investigated using two experiments that were based on the shanny's natural propensity to home to a refuge. A displacement experiment demonstrated that the fish were able to accurately locate the previous position of a refuge once the shelter itself had been removed so that it could not be used as a cue to directly signal the goal location. This shows that the shanny can encode information about its familiar surroundings into a spatial map and use this information to home. A second experiment in which the cues internal and external to the experimental tank were put in conflict with one another suggested that the shanny can encode cues that are both intra- and external-tank cues in its representation of space, but that there is individual variation in the type of cues that are used, or memorized.     

Impact of Postovulatory Food Deprivation on the Ova Transport, Hormonal Profiles and Metabolic Changes in Sows

The effect of food deprivation on ova transport, hormonal profiles and metabolic changes was studied in 20 crossbred multiparous sows during their second oestrus after weaning. To determine the time of ovulation, transrectal ultrasonographic examination was performed. The sows were divided into 2 groups, one control group (C-group), which was fed according to Swedish standards, and one experimental group (E-group). The E-group sows were deprived of food from the first morning meal after ovulation until slaughter. Blood samples were collected every second hour from about 12 h before expected ovulation in the second oestrus after weaning until slaughter and were analysed for progesterone, prostaglandin F_2α-metabolite, insulin, glucose, free fatty acids and triglycerides. All sows were slaughtered approximately 48 h after ovulation and the genital tract was recovered. The isthmic part of the oviduct was divided into 3 equally long segments and flushed separately with phosphate buffered saline (PBS). Uterine horns were also flushed with PBS. A significantly greater number of ova were found in the first and second part of the isthmus in the E-group (p = 0.05) while in the C-group most of the ova were found in the third part of the isthmus or the uterus (p = 0.01). The level of prostaglandin F_2α-metabolite was significantly higher in the E-group compared with the C-group. The concentration of progesterone increased in both groups after ovulation but there were no significant differences between the groups. The other blood parameters showed that the food-deprived sows were in a catabolic state. The 48 h period of fasting results, directly or indirectly in an delayed ova transport, which may be due to a delayed relaxation in the smooth circular muscle layer of the isthmus.     

Autoantibody systems in rheumatoid arthritis: specificity, sensitivity and diagnostic value

This review focuses on the mechanisms of stress response in the synovial tissue of rheumatoid arthritis. The major stress factors, such as heat stress, shear stress, proinflammatory cytokines and oxidative stress, are discussed and reviewed, focusing on their potential to induce a stress response in the synovial tissue. Several pathways of stress signalling molecules are found to be activated in the synovial membrane of rheumatoid arthritis; of these the most important examples are heat shock proteins, mitogen-activated protein kinases, stress-activated protein kinases and molecules involved in the oxidative stress pathways. The expression of these pathways in vitro and in vivo as well as the consequences of stress signalling in the rheumatoid synovium are discussed. Stress signalling is part of a cellular response to potentially harmful stimuli and thus is essentially involved in the process of synovitis. Stress signalling pathways are therefore new and promising targets of future anti-rheumatic therapies.     

Mechanisms of visually mediated site recognition by the homing pigeon

The recognition of familiar areas by homing pigeons, Columba livia, is now known to depend at least in part on visual cues. Birds allowed a 5-min preview of the surrounding landscape prior to release home faster than those denied access to such cues, suggesting that recognition is visually mediated. We examined this phenomenon further by asking how memory generated through prior experience with a site is used in recognition. We provided a group of homing pigeons with training experience in which they viewed, through a single transparent vertical face of an otherwise opaque release box, an approximately 140° segment of the landscape for 5 min before release. Training previews were always given from consistent locations and orientations within a release site. Test releases that followed were used to ascertain whether subsequent site recognition necessitated previewing from this already familiar angle and distance, or whether the skill could be extended to novel, nonoverlapping lateral views of the landscape. The results suggested that homing performance was better after presentation of the view recapitulating that seen during training than after showing a novel alternative view. Pigeons may have been using a template of the arrangement of familiar landmarks around the release site as the cue for recognition. The effect, however, disappeared after repeated training, suggesting that repeated release from a site may allow for more extensive visual survey and the memorization of detailed features of the landscape or the extraction of site-specific general features that aid recognition even when a novel view is presented. Copyright 2003 The Association for the Study of Animal Behaviour. Published by Elsevier Science Ltd. All rights reserved.