RAPID: Fast and accurate sequence-based prediction of intrinsic disorder content on proteomic scale

Recent research in the protein intrinsic disorder was stimulated by the availability of accurate computational predictors. However, most of these methods are relatively slow, especially considering proteome-scale applications, and were shown to produce relatively large errors when estimating disorder at the protein- (in contrast to residue-) level, which is defined by the fraction/content of disordered residues. To this end, we propose a novel support vector Regression-based Accurate Predictor of Intrinsic Disorder (RAPID). Key advantages of RAPID are speed (prediction of an average-size eukaryotic proteome takes < 1 h on a modern desktop computer); sophisticated design (multiple, complementary information sources that are aggregated over an input chain are combined using feature selection); and high-quality and robust predictive performance. Empirical tests on two diverse benchmark datasets reveal that RAPID's predictive performance compares favorably to a comprehensive set of state-of-the-art disorder and disorder content predictors. Drawing on high speed and good predictive quality, RAPID was used to perform large-scale characterization of disorder in 200 + fully sequenced eukaryotic proteomes. Our analysis reveals interesting relations of disorder with structural coverage and chain length, and unusual distribution of fully disordered chains. We also performed a comprehensive (using 56000+ annotated chains, which doubles the scope of previous studies) investigation of cellular functions and localizations that are enriched in the disorder in the human proteome. RAPID, which allows for batch (proteome-wide) predictions, is available as a web server at http://biomine.ece.ualberta.ca/RAPID/.     

Can the condition of the cell microenvironment of mediastinal lymph nodes help predict the risk of metastases in non-small cell lung cancer?

Background: The aim of this study was to analyze the properties of the immune cell microenvironment of regional lymph nodes (LNs) positive for lung cancer. Methods: Twenty-four patients operated on for stages T1 and T2 of the NSCLC, were enrolled in the study. Peripheral blood and LN tissue were obtained from different lymph node sites and levels. As a control, LN tissue was taken from patients diagnosed with emphysema or pneumothorax. The cells from randomly chosen LN were tested by multi-color flow cytometry. Separate portions of LN were snap-frozen and examined for the presence of cytokeratin positive cells (CK). Propensity for apoptosis, level of TCR zeta chain expression of T cells and the number and maturation status of dendritic cells were confronted with the presence of CK-positive cells. Results: The presence of metastases correlated with the downregulation of TCR zeta, especially CD8(+) T cells. The most striking feature was the reduction in the number of myeloid CD11c(+) dendritic cells in the LN of patients with LN metastases. This could be a reflection of the immunodeficient state observed in lung cancer patients. Even in the absence of metastases in the regional LN, the same type of changes in the LN microenvironment were observed in those LN located nearer the primary tumor. Conclusions: The preliminary results of this study suggest that this approach may be helpful as an independent tumor staging factor. It is also worth noting that part of the staging process could also be based on features describing the immune cells in the peripheral blood.     

Mobile genetic elements mediate the mixotrophic evolution of novel Alicyclobacillus species for acid mine drainage adaptation

Alicyclobacillus species inhabit diverse environments and have adapted to broad ranges of pH and temperature. However, their adaptive evolutions remain elusive, especially regarding the role of mobile genetic elements (MGEs). Here, we characterized the distributions and functions of MGEs in Alicyclobacillus species across five environments, including acid mine drainage (AMD), beverages, hot springs, sediments, and soils. Nine Alicyclobacillus strains were isolated from AMD and possessed larger genome sizes and more genes than those from other environments. Four AMD strains evolved to be mixotrophic and fell into distinctive clusters in phylogenetic tree. Four types of MGEs including genomic island (GI), insertion sequence (IS), prophage, and integrative and conjugative element (ICE) were widely distributed in Alicyclobacillus species. Further, AMD strains did not possess CRISPR-Cas systems, but had more GI, IS, and ICE, as well as more MGE-associated genes involved in the oxidation of iron and sulfide and the resistance of heavy metal and low temperature. These findings highlight the differences in phenotypes and genotypes between strains isolated from AMD and other environments and the important role of MGEs in rapid environment niche expansions.     

Temperature elevation reduces the sensitivity of invasive cladoceran Daphnia lumholtzi to filamentous cyanobacterium Raphidiopsis raciborskii

1. Exotic cladoceran Daphnia lumholtzi is a highly invasive species in the north and south American continents and can potentially also invade European freshwaters and outcompete native Daphnia populations. However, European waterbodies are frequently dominated by less edible filamentous cyanobacteria including also invaders such as Raphidiopsis raciborskii, which might affect the fitness of D. lumholtzi. Furthermore, temperature may influence the sensitivity of D. lumholtzi to R. raciborskii filaments.
2. In this study, we determined whether the presence of R. raciborskii could obstruct the invasion of Europe by D. lumholtzi, through reducing its fitness, and whether this depends on temperature. We compared the population growth rate (r) and the somatic growth rate of D. lumholtzi maintained at two temperatures (20 or 26°C) and fed with two diets: green microalgae alone or green microalgae mixed with filaments of R. raciborskii. Three clones of D. lumholtzi were used to evaluate potential variation in response to the treatments among different clones.
3. At 20°C, the population growth rate of D. lumholtzi fed with cyanobacterial filaments declined sharply. This reduction was caused by increased egg abortion, egg degeneration, and mortality of newborn daphnids. At 26°C, R. raciborskii lost its harmful effect on the population growth of D. lumholtzi. The presence of cyanobacteria did reduce the somatic growth rate of D. lumholtzi at both temperatures and in all three clones except for one that had a similar somatic growth rate on both diets at 26°C.
4. The presence of filamentous cyanobacteria does affect growth in D. lumholtzi and may thereby substantially reduce its invasive potential, but only at lower temperatures. Therefore, the presence of filamentous cyanobacteria may not present an obstacle to the invasion of Europe by D. lumholtzi in a warmer future climate.

     

Determination of amyloid core structure using chemical shifts

Amyloid fibrils are the pathological hallmark of a large variety of neurodegenerative disorders. The structural characterization of amyloid fibrils, however, is challenging due to their non‐crystalline, heterogeneous, and often dynamic nature. Thus, the structure of amyloid fibrils of many proteins is still unknown. We here show that the structure calculation program CS‐Rosetta can be used to obtain insight into the core structure of amyloid fibrils. Driven by experimental solid‐state NMR chemical shifts and taking into account the polymeric nature of fibrils CS‐Rosetta allows modeling of the core of amyloid fibrils. Application to the Y145X stop mutant of the human prion protein reveals a left‐handed β‐helix     

Impaired leptin activity in New Zealand Obese mice: model of angiogenesis

Leptin is prompt to drive angiogenesis, effecting proper vascularisation. Tissue remodeling (including adipose organ) is associated with the angiogenic response. The aim of this study was to investigate the effect of hyperleptinemia on angiogenesis in subcutaneous (s.c.) in vivo matrigel model in mice on a high fat (HF) diet. HF promoted adipose tissue accumulation and biochemical changes resembling metabolic syndrome. However, the impact of this dietary treatment on angiogenesis, measured in s.c. matrigel model was not significant. Changes in leptin concentration were not accompanied by significant angiogenic response. This lack of leptin activity and impaired signal transduction at the molecular level suggests malfunction of the leptin receptor in NZO mice.     

Sequence based residue depth prediction using evolutionary information and predicted secondary structure

Background  

Residue depth allows determining how deeply a given residue is buried, in contrast to the solvent accessibility that differentiates between buried and solvent-exposed residues. When compared with the solvent accessibility, the depth allows studying deep-level structures and functional sites, and formation of the protein folding nucleus. Accurate prediction of residue depth would provide valuable information for fold recognition, prediction of functional sites, and protein design.