CRF-based models of protein surfaces improve protein-protein interaction site predictions

Background

The identification of protein-protein interaction sites is a computationally challenging task and important for understanding the biology of protein complexes. There is a rich literature in this field. A broad class of approaches assign to each candidate residue a real-valued score that measures how likely it is that the residue belongs to the interface. The prediction is obtained by thresholding this score.Some probabilistic models classify the residues on the basis of the posterior probabilities. In this paper, we introduce pairwise conditional random fields (pCRFs) in which edges are not restricted to the backbone as in the case of linear-chain CRFs utilized by Li et al. (2007). In fact, any 3D-neighborhood relation can be modeled. On grounds of a generalized Viterbi inference algorithm and a piecewise training process for pCRFs, we demonstrate how to utilize pCRFs to enhance a given residue-wise score-based protein-protein interface predictor on the surface of the protein under study. The features of the pCRF are solely based on the interface predictions scores of the predictor the performance of which shall be improved.

Results

We performed three sets of experiments with synthetic scores assigned to the surface residues of proteins taken from the data set PlaneDimers compiled by Zellner et al. (2011), from the list published by Keskin et al. (2004) and from the very recent data set due to Cukuroglu et al. (2014). That way we demonstrated that our pCRF-based enhancer is effective given the interface residue score distribution and the non-interface residue score are unimodal.Moreover, the pCRF-based enhancer is also successfully applicable, if the distributions are only unimodal over a certain sub-domain. The improvement is then restricted to that domain. Thus we were able to improve the prediction of the PresCont server devised by Zellner et al. (2011) on PlaneDimers.

Conclusions

Our results strongly suggest that pCRFs form a methodological framework to improve residue-wise score-based protein-protein interface predictors given the scores are appropriately distributed. A prototypical implementation of our method is accessible at http://ppicrf.informatik.uni-goettingen.de/index.html.     

Using multiple templates to improve quality of homology models in automated homology modeling

When researchers build high-quality models of protein structure from sequence homology, it is today common to use several alternative target-template alignments. Several methods can, at least in theory, utilize information from multiple templates, and many examples of improved model quality have been reported. However, to our knowledge, thus far no study has shown that automatic inclusion of multiple alignments is guaranteed to improve models without artifacts. Here, we have carried out a systematic investigation of the potential of multiple templates to improving homology model quality. We have used test sets consisting of targets from both recent CASP experiments and a larger reference set. In addition to Modeller and Nest, a new method (Pfrag) for multiple template-based modeling is used, based on the segment-matching algorithm from Levitt's SegMod program. Our results show that all programs can produce multi-template models better than any of the single-template models, but a large part of the improvement is simply due to extension of the models. Most of the remaining improved cases were produced by Modeller. The most important factor is the existence of high-quality single-sequence input alignments. Because of the existence of models that are worse than any of the top single-template models, the average model quality does not improve significantly. However, by ranking models with a model quality assessment program such as ProQ, the average quality is improved by approximately 5% in the CASP7 test set.     

Mechanical dissociation of bronchi from parenchyma in the immature piglet lung.

Previous studies of isolated piglet lungs suggested that local distending forces around bronchi might be relatively weak before postnatal growth and maturation. The present study used tantalum bronchograms to compare pressure-diameter relationships of bronchi in situ and after excision from the parenchyma in immature (3- to 7-day-old) and mature (3-mo-old) piglets. The mature group reproduced behavior that is well established in mature lungs from other species; i.e., bronchial diameters maintained a constant relationship to the parenchyma as the lungs were deflated from maximum to minimum volume. In sharp contrast, diameters failed to change until the immature lungs were deflated to <5 cmH(2)O transpulmonary pressure. Total percent change in bronchial diameter was then only 24% in the immature lungs compared with 47% in the mature lungs (P < 0.002). Total elastances of mature generation 3-8 bronchi did not change when they were excised from the parenchyma. However, in the same generations of immature bronchi, total elastances were lower after than before (1.06 vs. 1.60 cmH(2)O/%, P < 0.05) excision from the parenchyma. Elastances of the excised immature and mature bronchi were then the same (1.06 vs. 1.03 cmH(2)O/%, not significant). Because elastic moduli of the lung parenchyma are also similar in the two age groups, it was concluded that local features of airway-parenchyma coupling limited the generation of local parenchymal recoil around bronchi in the immature lungs.     

Review: How to improve genomic predictions in small dairy cattle populations

This paper reviews strategies and methods to improve accuracies of genomic predictions from the perspective of a numerically small population. Improvements are realized by influencing one or both of the main factors: (1) improve or increase genomic connections to phenotypic records in training data. (2) Models and strategies to focus genomic predictions on markers closer to the causative variants. Combining populations into a joint reference population results in high improvements when combining populations of the same breed and diminishes as the genetic distance between populations increases. For distantly related breeds sophisticated Bayesian variable selection models in combination with denser markers sets or functional subsets of markers is needed. This is expected to be further improved by the efficient use of sequence information. In addition predictions can be improved by the use of phenotypes of genotyped and non-genotyped cows directly. For a small population the optimal approach will combine the above components.     

Effects of spatial scale and foraging efficiency on the predictions made by spatially-explicit models of fish growth rate potential

Synopsis Spatially-explicit modeling of fish growth rate potential is a relatively new approach that uses physical and biological properties of aquatic habitats to map spatial patterns of fish growth rate potential. Recent applications of spatially-explicit models have used an arbitrary spatial scale and have assumed a fixed foraging efficiency. We evaluated the effects of spatial scale, predator foraging efficiency (combined probabilities of prey recognition, attack, capture, and ingestion), and predator spatial distribution on estimates of mean growth rate potential of chinook salmon,Oncorhynchus tshawytscha. We used actual data on prey densities and water temperatures taken from Lake Ontario during the summer, as well as, simulated data assuming binomial distribution of prey. Results show that a predator can compensate for low foraging efficiency by inhabiting the most profitable environments (regions of high growth rate potential). Differences exist in predictions of growth rate potential across spatial scales of observation and a single scale may not be adequate for interpreting model results across seasons. Continued refinements of this modeling approach must focus on the assumptions of stationary distributions of predator and prey populations and predator foraging tactics.     

Using multiple data types and integrated population models to improve our knowledge of apex predator population dynamics

Current management of large carnivores is informed using a variety of parameters, methods, and metrics; however, these data are typically considered independently. Sharing information among data types based on the underlying ecological, and recognizing observation biases, can improve estimation of individual and global parameters. We present a general integrated population model (IPM), specifically designed for brown bears (Ursus arctos), using three common data types for bear (U. spp.) populations: repeated counts, capture–mark–recapture, and litter size. We considered factors affecting ecological and observation processes for these data. We assessed the practicality of this approach on a simulated population and compared estimates from our model to values used for simulation and results from count data only. We then present a practical application of this general approach adapted to the constraints of a case study using historical data available for brown bears on Kodiak Island, Alaska, USA. The IPM provided more accurate and precise estimates than models accounting for repeated count data only, with credible intervals including the true population 94% and 5% of the time, respectively. For the Kodiak population, we estimated annual average litter size (within one year after birth) to vary between 0.45 [95% credible interval: 0.43; 0.55] and 1.59 [1.55; 1.82]. We detected a positive relationship between salmon availability and adult survival, with survival probabilities greater for females than males. Survival probabilities increased from cubs to yearlings to dependent young ≥2 years old and decreased with litter size. Linking multiple information sources based on ecological and observation mechanisms can provide more accurate and precise estimates, to better inform management. IPMs can also reduce data collection efforts by sharing information among agencies and management units. Our approach responds to an increasing need in bear populations’ management and can be readily adapted to other large carnivores.     

Fear responses of Japanese monkeys to scale models

This study investigated fear responses of Japanese monkeys (Macaca fuscata) to scale models. Fear responses of participants were assessed using rating scores assigned by judges. In Experiment 1, participants were presented with scale models of objects in furniture, vehicle, and mammal categories. Overall, the participants expressed stronger fear responses to mammal objects as compared to the other two kinds. In Experiment 2, participants were presented with scale models of furniture, new mammals, and animals composed of insects, birds, fish, and reptiles. As a whole, the participants showed stronger fear responses to the new mammal and animal objects than to furniture objects. Fear responses to mammal and animal objects were comparable. These results suggest that Japanese monkeys show stronger fear responses to objects possessing perceptual properties of animals, as opposed to objects that do not possess such properties.     

Unpacking the mechanisms captured by a correlative species distribution model to improve predictions of climate refugia

Climate refugia are regions that animals can retreat to, persist in and potentially then expand from under changing environmental conditions. Most forecasts of climate change refugia for species are based on correlative species distribution models (SDMs) using long‐term climate averages, projected to future climate scenarios. Limitations of such methods include the need to extrapolate into novel environments and uncertainty regarding the extent to which proximate variables included in the model capture processes driving distribution limits (and thus can be assumed to provide reliable predictions under new conditions). These limitations are well documented; however, their impact on the quality of climate refugia predictions is difficult to quantify. Here, we develop a detailed bioenergetics model for the koala. It indicates that range limits are driven by heat‐induced water stress, with the timing of rainfall and heat waves limiting the koala in the warmer parts of its range. We compare refugia predictions from the bioenergetics model with predictions from a suite of competing correlative SDMs under a range of future climate scenarios. SDMs were fitted using combinations of long‐term climate and weather extremes variables, to test how well each set of predictions captures the knowledge embedded in the bioenergetics model. Correlative models produced broadly similar predictions to the bioenergetics model across much of the species' current range – with SDMs that included weather extremes showing highest congruence. However, predictions in some regions diverged significantly when projecting to future climates due to the breakdown in correlation between climate variables. We provide unique insight into the mechanisms driving koala distribution and illustrate the importance of subtle relationships between the timing of weather events, particularly rain relative to hot‐spells, in driving species–climate relationships and distributions. By unpacking the mechanisms captured by correlative SDMs, we can increase our certainty in forecasts of climate change impacts on species.     

Development of multiple QSAR models for consensus predictions and unified mechanistic interpretations of the free-radical scavenging activities of chromone derivatives

Antioxidants are important defenders of the human body against nocive free radicals, which are the causative agents of most life-threatening diseases. The immense biomedicinal utility of antioxidants necessitates the development and design of new synthetic antioxidant molecules. The present report deals with the modeling of a series of chromone derivatives, which was done to provide detailed insight into the main structural fragments that impart antioxidant activity to these molecules. Four different quantitative structure–property relationship (QSAR) techniques, namely 3D pharmacophore mapping, comparative molecular similarity indices analysis (CoMSIA 3D-QSAR), hologram QSAR (HQSAR), and group-based QSAR (G-QSAR) techniques, were employed to obtain statistically significant models with encouraging external predictive potentials. Moreover, the visual contribution maps obtained for the different models signify the importance of different structural features in specific regions of the chromone nucleus. Additionally, the G-QSAR models determine the composite influence of pairs of substituent fragments on the overall antioxidant activity profiles of the molecules. Multiple models with different strategies for assessing structure–activity relationships were applied to reach a unified conclusion regarding the antioxidant mechanism and to provide consensus predictions, which are more reliable than values derived from a single model. The structural information obtained from the various QSAR models developed in the present work can thus be effectively utilized to design and predict the activities of new molecules belonging to the class of chromone derivatives.     

关于生物学研究模型教学的一点思考

如何利用现有的资源提高生物学教学效果.应该补充现代生物学发展历史和生物研究多样化模型两方面的知识.提供了学生应该掌握的研究历史和研究模型方面的基本脉络.     

Using optimality models to improve the efficacy of parasitoids in biological control programmes

Biological control of insect pests relies on the ability of natural enemies to limit pest populations. The behaviours expressed by natural enemies against their prey or hosts are modulated by a number of factors and a better understanding of these factors is key to obtaining more efficacious pest control. We propose here that optimality models based upon a behavioural ecology approach can provide a framework that should enable optimisation of biological control practices. We limit our discussion to parasitoid natural enemies and review the factors known to influence the behaviour of these insects. The most important areas that have been studied extensively in the behavioural ecology of insect parasitoids are addressed here: (1) residence time in a host patch, (2) clutch size, (3) sex ratio, (4) host and patch marking, and (5) diet choice. We discuss the implications of the incorporation of these optimality models into efficacious biological control practices and suggest areas where a better knowledge of the behavioural ecology of these insects could improve the efficacy of parasitoid‐based pest control.     

Early piglet mortality in loose-housed sows related to sow and piglet behaviour and to the progress of parturition

The aim of the present study was to identify characteristics of sow behaviour and parturition related to early piglet mortality in loose-housed farrowing sows. Data from 152 farrowings that originated from three different herds with loose-housed sows during parturition were used. Graphical chain models were used to model the relationships between perinatal behaviour, periparturient individual conditions (time of day of parturition, rectal temperature 1–3 days postpartum) and causes of early piglet mortality. Modelling was based on the correlation between variables within herd and farrowing batch.The analysis showed that different causes of mortality were linked to different behavioural variables during the periparturient period and that they grouped into three independent categories. The first category was associated with stillbirth and death due to other causes. Stillbirth was positively related to the variation of the inter-birth interval and negatively related to the percentage of piglets that suckled during the first 8 h after birth of first piglet (BFP). Death due to other causes was negatively related to the suckling activity during the post-partal period (9–24 h after BFP). The second category was associated with piglet crushing, which was positively related to much lateral lying the last 4 h before BFP. Finally, the third category was associated with death due to lack of colostrums ingestion of colostrum, which was linked to the time of parturition and sow rectal temperature on days 1 and 2 after farrowing. Sows that gave birth during the morning compared to evening/night had more dead piglets due to lack of colostrums ingestion. Death due to lack of colostrums ingestion was also higher in sows with high rectal temperature on the day after BFP. The results further showed that litter size not only influenced mortality but also behavioural variables. High litter size was related to high nest building activity before BFP, low but more variable inter-birth intervals, and much lateral lying after BFP. The study points towards several areas of interest for further research that can help understand early piglet mortality. These include causes of variation in the progress of parturition, causes of individual differences in sow activity and responsiveness to piglets, and early management of farrowing. In addition, the study suggests possible indicators of problematic farrowings rendering liveborn piglets at risk. These include prepartum lateral lying in the sow, low suckling activity and rate of stillbirth.     

Patterns of male fitness conform to predictions of evolutionary models of late life

We studied lifetime male virility, a male fitness component, in five populations of Drosophila melanogaster. Virility was measured as the number of females, of eight total, that a male could fertilize in 24 h. Individual males were measured at weekly intervals until they died. Virility declined in an approximately linear fashion for the first 3 weeks of adult life. It then stayed low but relatively constant for another 3 weeks, exhibiting a clear plateau. These observations are consistent with the evolutionary theories of late life. The results were not consistent with a simple heterogeneity theory of late life. This is the first demonstration of a late-life plateau for a male fitness component. We also found that the virility of males that were within 7 days of death was significantly lower than that of similarly aged males that were not about to die. This rapid deterioration of virility prior to death, or death spiral, is similar to a decline in fecundity that we had previously documented.