Integrative modeling of protein-protein interactions with pyDock for the new docking challenges

The seventh CAPRI edition imposed new challenges to the modeling of protein-protein complexes, such as multimeric oligomerization, protein-peptide, and protein-oligosaccharide interactions. Many of the proposed targets needed the efficient integration of rigid-body docking, template-based modeling, flexible optimization, multiparametric scoring, and experimental restraints. This was especially relevant for the multimolecular assemblies proposed in the CASP12-CAPRI37 and CASP13-CAPRI46 joint rounds, which were described and evaluated elsewhere. Focusing on the purely CAPRI targets of this edition (rounds 38-45), we have participated in all 17 assessed targets (considering heteromeric and homomeric interfaces in T125 as two separate targets) both as predictors and as scorers, by using integrative modeling based on our docking and scoring approaches: pyDock, IRaPPA, and LightDock. In the protein-protein and protein-peptide targets, we have also participated with our webserver (pyDockWeb). On these 17 CAPRI targets, we submitted acceptable models (or better) within our top 10 models for 10 targets as predictors, 13 targets as scorers, and 4 targets as servers. In summary, our participation in this CAPRI edition confirmed the capabilities of pyDock for the scoring of docking models, increasingly used within the context of integrative modeling of protein interactions and multimeric assemblies.     

Outcomes of a ‘One Health’ Monitoring Approach to a Five-Year Beaver (Castor fiber) Reintroduction Trial in Scotland

Recent advances in noninvasive detection methods for mycobacterial infection in primates create new opportunities for exploring the epidemiology of tuberculosis in free-living species. Chimpanzees (Pan troglodytes schweinfurthii) and baboons (Papio anubis) in Gombe National Park, Tanzania, were screened for infection with pathogens of the Mycobacterium tuberculosis Complex using Fecal IS6110 PCR; none was positive. This study demonstrates the feasibility of large-scale mycobacterial screening in wild primates.     

Harvesting of males delays female breeding in a socially monogamous mammal; the beaver

Human exploitation may skew adult sex ratios in vertebrate populations to the extent that males become limiting for normal reproduction. In polygynous ungulates, females delay breeding in heavily harvested populations, but effects are often fairly small. We would expect a stronger effect of male harvesting in species with a monogamous mating system, but no such study has been performed. We analysed the effect of harvesting males on the timing of reproduction in the obligate monogamous beaver (Castor fiber). We found a negative impact of harvesting of adult males on the timing of parturition in female beavers. The proportion of normal breeders sank from over 80%, when no males had been shot in the territories of pregnant females, to under 20%, when three males had been shot. Harvesting of males in monogamous mammals can apparently affect their normal reproductive cycle.     

Crystal structure of the vertebrate NADP(H)-dependent alcohol dehydrogenase (ADH8)

The amphibian enzyme ADH8, previously named class IV-like, is the only known vertebrate alcohol dehydrogenase (ADH) with specificity towards NADP(H). The three-dimensional structures of ADH8 and of the binary complex ADH8-NADP(+) have been now determined and refined to resolutions of 2.2A and 1.8A, respectively. The coenzyme and substrate specificity of ADH8, that has 50-65% sequence identity with vertebrate NAD(H)-dependent ADHs, suggest a role in aldehyde reduction probably as a retinal reductase. The large volume of the substrate-binding pocket can explain both the high catalytic efficiency of ADH8 with retinoids and the high K(m) value for ethanol. Preference of NADP(H) appears to be achieved by the presence in ADH8 of the triad Gly223-Thr224-His225 and the recruitment of conserved Lys228, which define a binding pocket for the terminal phosphate group of the cofactor. NADP(H) binds to ADH8 in an extended conformation that superimposes well with the NAD(H) molecules found in NAD(H)-dependent ADH complexes. No additional reshaping of the dinucleotide-binding site is observed which explains why NAD(H) can also be used as a cofactor by ADH8. The structural features support the classification of ADH8 as an independent ADH class.     

Time budgets and sex differences in the Eurasian beaver

The Eurasian beaver, Castor fiber, is one of the few obligate monogamous mammal species known, and nothing is known about the time budget of the mated pair. We investigated whether mated adult Eurasian beavers would display sex differences in time budgets. Using radiotracking, we obtained behavioural data on six mated pairs of adult beaver during 2000 and 2001 on two rivers in southeast Norway. Time budgets for males and females were compared in total and over the seasons, along with temperature data collected throughout the study. The three main behaviours of both males and females were travelling, foraging and being in the lodge, accounting for 92.0 and 93.2%, respectively, of each sex's overall time budgets. Time budgets did not differ between the sexes except that males allocated more time to travel. Time budgets for each sex did not vary with season, and water and air temperature data were positively correlated with time spent travelling for both sexes. These results support the hypothesis that male and female time budgets are similar, except for the time that males and females allocated to travel. We suggest that the similarities in behaviour result because parental care by both parents is essential to the successful rearing of offspring, leading to reduced behavioural sexual dimorphism; nevertheless, some differences still occur, perhaps relating to the male's indirect parental care. Copyright 2003 The Association for the Study of Animal Behaviour. Published by Elsevier Ltd. All rights reserved.      

Spectroscopic properties of a mitochondrial cytochrome C with a single thioether bond to the heme prosthetic group

The yeast iso-1-cytochrome c variant Cys14Ser has been prepared in which one of the two thioether bonds by which the heme prosthetic group is normally bound to the protein has been eliminated. Comparison of the properties of this variant with those of the wild-type cytochrome provides insight into the role of this covalent attachment of the heme group to the apo-protein toward the functional properties of the wild-type cytochrome. Although NMR and EPR spectra indicate that the Cys14Ser variant ferricytochrome adopts the native conformation characteristic of the wild-type protein with His18 and Met80 coordinated to the heme iron (Met80 epsilon-CH -23.6 ppm; g(z), g(y), g(x), at 3.01, 2.29, approximately 1.3, respectively), the electronic spectrum of the variant does not exhibit the 695 nm CT band that is characteristic of native ferricytochromes c with these axial ligands. Chromatographic and spectropolarimetric comparison of the variant and wild-type ferricytochromes suggests that the structure of the variant is more disordered, particularly in the region of the sole tryptophanyl residue (Trp59). Upon reduction, the electronic spectrum of the variant exhibits a symmetrically broadened alpha-band that is shifted approximately 3 nm to the ultraviolet relative to its position in the spectrum in the wild-type protein. In the MCD spectrum, a band appears above 390 nm that is more intense than the Soret A-term which is also shifted to lower energy.     

Analysis of Personal and Family Factors in the Persistence of Attention Deficit Hyperactivity Disorder: Results of a Prospective Follow-Up Study in Childhood

Objectives

To study the course of ADHD during childhood and analyze possible personal and family predictor variables of the results.

Method

Sixty-one children with ADHD who were between 6 and 12 years old at the baseline assessment were evaluated 30 months later (mean age at baseline: 8.70 ± 1.97; mean age at follow-up: 10.98 ± 2.19). Status of ADHD in follow-up was identified as persistent (met DSM-IV-TR criteria according to parents’ and teachers’ ratings), contextually persistent (met ADHD criteria according to one informant, and there was functional impairment) and remitted ADHD (with subthreshold clinical symptomatology). Associated psychological disorders of the three groups were analyzed in the follow-up with the Conners'' Rating Scales. The groups were compared on ADHD characteristics (symptoms of ADHD and impairment), child psychopathology, executive functioning (EF; inhibition, working memory) and parenting characteristics (parental stress and discipline styles) at baseline.

Results

At the follow-up, 55.7% of the children continued to meet the DSM-IV-TR criteria for ADHD, 29.5% showed contextual persistence, and 14.8% presented remission of the disorder. The persistent and contextually persistent ADHD groups showed more associated psychological disorders. Inattention, oppositional problems, cognitive problems and impairment at baseline distinguished the remitted ADHD children from the persistent and contextually persistent ADHD children. Moreover, the persistent groups had significantly more emotional liability and higher parental stress than the group in remission, while no differences in EF where found among the groups.

Conclusions

ADHD children continue to present symptoms, as well as comorbid psychological problems, during adolescence and early adulthood. These findings confirm that persistence of ADHD is associated with child psychopathology, parental stress and impairment in childhood.     

Enrichment of ultraconserved elements among genomic imbalances causing mental delay and congenital anomalies

Background

In translational cancer research, gene expression data is collected together with clinical data and genomic data arising from other chip based high throughput technologies. Software tools for the joint analysis of such high dimensional data sets together with clinical data are required.

Results

We have developed an open source software tool which provides interactive visualization capability for the integrated analysis of high-dimensional gene expression data together with associated clinical data, array CGH data and SNP array data. The different data types are organized by a comprehensive data manager. Interactive tools are provided for all graphics: heatmaps, dendrograms, barcharts, histograms, eventcharts and a chromosome browser, which displays genetic variations along the genome. All graphics are dynamic and fully linked so that any object selected in a graphic will be highlighted in all other graphics. For exploratory data analysis the software provides unsupervised data analytics like clustering, seriation algorithms and biclustering algorithms.

Conclusions

The SEURAT software meets the growing needs of researchers to perform joint analysis of gene expression, genomical and clinical data.