PocketMatch: A new algorithm to compare binding sites in protein structures

Background: Recognizing similarities and deriving relationships among protein molecules is a fundamental
requirement in present-day biology. Similarities can be present at various levels which can be detected through comparison of protein sequences or their structural folds. In some cases similarities obscure at these levels could be present merely in the substructures at their binding sites. Inferring functional similarities between protein molecules by comparing their binding sites is still largely exploratory and not as yet a routine protocol. One of
the main reasons for this is the limitation in the choice of appropriate analytical tools that can compare binding sites with high sensitivity. To benefit from the enormous amount of structural data that is being rapidly accumulated, it is essential to have high throughput tools that enable large scale binding site comparison.

Results: Here we present a new algorithm PocketMatch for comparison of binding sites in a frame invariant
manner. Each binding site is represented by 90 lists of sorted distances capturing shape and chemical nature of the site. The sorted arrays are then aligned using an incremental alignment method and scored to obtain PMScores for pairs of sites. A comprehensive sensitivity analysis and an extensive validation of the algorithm have been carried out. Perturbation studies where the geometry of a given site was retained but the residue types were changed randomly, indicated that chance similarities were virtually non-existent. Our analysis also demonstrates that shape information alone is insufficient to discriminate between diverse binding sites, unless
combined with chemical nature of amino acids.

Conclusions: A new algorithm has been developed to compare binding sites in accurate, efficient and
high-throughput manner. Though the representation used is conceptually simplistic, we demonstrate that along
with the new alignment strategy used, it is sufficient to enable binding comparison with high sensitivity. Novel methodology has also been presented for validating the algorithm for accuracy and sensitivity with respect to geometry and chemical nature of the site. The method is also fast and takes about 1/250th second for one comparison on a single processor. A parallel version on BlueGene has also been implemented

Acute WNT signalling activation perturbs differentiation within the adult stomach and rapidly leads to tumour formation

A role for WNT signalling in gastric carcinogenesis has been suggested due to two major observations. First, patients with germline mutations in adenomatous polyposis coli (APC) are susceptible to stomach polyps and second, in gastric cancer, WNT activation confers a poor prognosis. However, the functional significance of deregulated WNT signalling in gastric homoeostasis and cancer is still unclear. In this study we have addressed this by investigating the immediate effects of WNT signalling activation within the stomach epithelium. We have specifically activated the WNT signalling pathway within the mouse adult gastric epithelium via deletion of either glycogen synthase kinase 3 (GSK3) or APC or via expression of a constitutively active β-catenin protein. WNT pathway deregulation dramatically affects stomach homoeostasis at very short latencies. In the corpus, there is rapid loss of parietal cells with fundic gland polyp (FGP) formation and adenomatous change, which are similar to those observed in familial adenomatous polyposis. In the antrum, adenomas occur from 4 days post-WNT activation. Taken together, these data show a pivotal role for WNT signalling in gastric homoeostasis, FGP formation and adenomagenesis. Loss of the parietal cell population and corresponding FGP formation, an early event in gastric carcinogenesis, as well as antral adenoma formation are immediate effects of nuclear β-catenin translocation and WNT target gene expression. Furthermore, our inducible murine model will permit a better understanding of the molecular changes required to drive tumourigenesis in the stomach

Spatial heterogeneity of habitat suitability for Rift Valley fever occurrence in Tanzania: an ecological niche modelling approach

Despite the long history of Rift Valley fever (RVF) in Tanzania, extent of its suitable habitat in the country remains unclear. In this study we investigated potential effects of temperature, precipitation, elevation, soil type, livestock density, rainfall pattern, proximity to wild animals, protected areas and forest on the habitat suitability for RVF occurrence in Tanzania. Presence-only records of 193 RVF outbreak locations from 1930 to 2007 together with potential predictor variables were used to model and map the suitable habitats for RVF occurrence using ecological niche modelling. Ground-truthing of the model outputs was conducted by comparing the levels of RVF virus specific antibodies in cattle, sheep and goats sampled from locations in Tanzania that presented different predicted habitat suitability values. Habitat suitability values for RVF occurrence were higher in the northern and central-eastern regions of Tanzania than the rest of the regions in the country. Soil type and precipitation of the wettest quarter contributed equally to habitat suitability (32.4% each), followed by livestock density (25.9%) and rainfall pattern (9.3%). Ground-truthing of model outputs revealed that the odds of an animal being seropositive for RVFV when sampled from areas predicted to be most suitable for RVF occurrence were twice the odds of an animal sampled from areas least suitable for RVF occurrence (95% CI: 1.43, 2.76, p < 0.001). The regions in the northern and central-eastern Tanzania were more suitable for RVF occurrence than the rest of the regions in the country. The modelled suitable habitat is characterised by impermeable soils, moderate precipitation in the wettest quarter, high livestock density and a bimodal rainfall pattern. The findings of this study should provide guidance for the design of appropriate RVF surveillance, prevention and control strategies which target areas with these characteristics

Interactions between the Nse3 and Nse4 Components of the SMC5-6 Complex Identify Evolutionarily Conserved Interactions between MAGE and EID Families

The SMC5-6 protein complex is involved in the cellular response to DNA damage. It is composed of 6-8 polypeptides, of which Nse1, Nse3 and Nse4 form a tight sub-complex. MAGEG1, the mammalian ortholog of Nse3, is the founding member of the MAGE (melanoma-associated antigen) protein family and Nse4 is related to the EID (E1A-like inhibitor of differentiation) family of transcriptional repressors.Using site-directed mutagenesis, protein-protein interaction analyses and molecular modelling, we have identified a conserved hydrophobic surface on the C-terminal domain of Nse3 that interacts with Nse4 and identified residues in its N-terminal domain that are essential for interaction with Nse1. We show that these interactions are conserved in the human orthologs. Furthermore, interaction of MAGEG1, the mammalian ortholog of Nse3, with NSE4b, one of the mammalian orthologs of Nse4, results in transcriptional co-activation of the nuclear receptor, steroidogenic factor 1 (SF1). In an examination of the evolutionary conservation of the Nse3-Nse4 interactions, we find that several MAGE proteins can interact with at least one of the NSE4/EID proteins.We have found that, despite the evolutionary diversification of the MAGE family, the characteristic hydrophobic surface shared by all MAGE proteins from yeast to humans mediates its binding to NSE4/EID proteins. Our work provides new insights into the interactions, evolution and functions of the enigmatic MAGE proteins

Patient-centric trials for therapeutic development in precision oncology

An enhanced understanding of the molecular pathology of disease gained from genomic studies is facilitating the development of treatments that target discrete molecular subclasses of tumours. Considerable associated challenges include how to advance and implement targeted drug-development strategies. Precision medicine centres on delivering the most appropriate therapy to a patient on the basis of clinical and molecular features of their disease. The development of therapeutic agents that target molecular mechanisms is driving innovation in clinical-trial strategies. Although progress has been made, modifications to existing core paradigms in oncology drug development will be required to realize fully the promise of precision medicine

Tales from the pit: moshing in the metal scene

What would become known as Moshing began in the early 1980s in the punk scene. It’s a violent and aggressive form of dancing that can involve flailing, pushing, kicking, and hitting other dancers. Moshing has made headlines in the news when fans have died in these aggressive concerts. However, this aggressive dance also harbors social bonding, a code of ethics, and comradery that give life to concerts. As moshing spreads to more genres such as rap and electronic dance music, it becomes increasingly important to understand its role and function in live performance. This paper uses neo-tribal theory to analyze site observations and in-depth interviews with moshers to understand how moshers turn the space in a venue into a place for creating meaning and belonging

Teacher professional development : a plan for multi-agency collaboration

The problem on which this study focused was the improvement of teacher professional development. The study had two focal points: a review of existing programs of multi-agency collaborative efforts and the development of a plan of collaboration for teacher professional development which involves local school districts, higher education, and state departments of public instruction. Five procedures were used in this study: a review of significant literature in the area of collaborative programs involving local school districts, higher education, and state departments of public instruction; a description and analysis of selected collaborative programs, an analysis of common characteristics found in collaborative programs, the development of a plan for multi-agency collaboration for teacher professional development, and the submission of the plan to leading authorities

The scope of nutrition education by selected primigravidas with emphasis on the role of their obstetricians

It was the purpose of this study to determine the type and amount of nutrition education received by selected primigravidas from their obstetricians and from other sources, to investigate the attitudes of the pregnant women and their doctors toward nutrition, and to determine the knowledge of the women about selected aspects of maternal nutrition. The subjects were thirty women in the sixth to eighth month of their first pregnancies who were patients of seven obstetricians in two group practices in Greensboro, North Carolina. The obstetricians also participated in the study. One nurse from each obstetrical group selected the patients to participate in the study. The data were collected using four instruments devised by the researcher. These were: 1) Women's Attitude Scale, 2) Nutrition Knowledge Quiz, 3) Women's Interview Schedule, and 4) Obstetricians' Questionnaire. Results indicated that 56% of the women felt that the nutrition information they had received during pregnancy had caused them to improve their eating habits. Sixty percent of the women, however, felt that most pregnant women do not have a good knowledge of nutrition. Scores on the nutrition knowledge quiz were low

The effects of a parent implemented infant signing intervention on communication skills for young hearing children with diagnosed language delays

Being able to communicate one’s wants and needs is an essential step in typical language development. However, children with diagnosed language delays, which constitute approximately 5–10% of children under three years, may reach this step later than typically developing children. According to Rossetti (2001), communication skills are the most highly correlated to future school performance than any other. The use of infant signing, a form of intentional symbolic gesturing, has been shown to support children’s development in multiple domains for both typically developing children and children with disabilities (e.g., DiCarlo et al., 2001; Goodwyn et al., 2000; Thompson et al., 2007). However, there is limited research showing the effects of infant signs on young hearing children’s communication skills (Vallotton, 2011c; Wijkamp, Gerritsen, Bonder, Haisma, &amp; van der Schans, 2010). The current study examined the potential effects of an infant signing intervention program on children’s communication skills, both verbal and sign usage. The researcher conducted a single subject, multiple probe research design across three children (ages 12 to 36 months) with diagnosed language delays to study their communication skills before and after the signing intervention. A pre- and post-study child language inventory supported with qualitative data collection methods was used as well. Results suggest an increase in communication attempts via both spoken and manually signed words after a primary caregiver-implemented infant signing intervention. Implications of these results are also discussed