Study designs for identification of rare disease variants in complex diseases: the utility of family-based designs

The recent progress in sequencing technologies makes possible large-scale medical sequencing efforts to assess the importance of rare variants in complex diseases. The results of such efforts depend heavily on the use of efficient study designs and analytical methods. We introduce here a unified framework for association testing of rare variants in family-based designs or designs based on unselected affected individuals. This framework allows us to quantify the enrichment in rare disease variants in families containing multiple affected individuals and to investigate the optimal design of studies aiming to identify rare disease variants in complex traits. We show that for many complex diseases with small values for the overall sibling recurrence risk ratio, such as Alzheimer's disease and most cancers, sequencing affected individuals with a positive family history of the disease can be extremely advantageous for identifying rare disease variants. In contrast, for complex diseases with large values of the sibling recurrence risk ratio, sequencing unselected affected individuals may be preferable.     

The effect of calcium and magnesium on the interaction between β‐lactoglobulin and carotenoids from sea buckthorn berries

β‐Lactoglobulin has been shown to interact with carotenoids from sea buckthorn berries. However, previously, no studies have taken into account the effect of calcium and magnesium on the β‐lactoglobulin–carotenoids complex. This study aims to determine the effect of calcium and magnesium on the interaction between β‐lactoglobulin and carotenoids from sea buckthorn berries extract, during heating from the perspective of deepening interaction mechanisms as prerequisites for micro‐ and nanoencapsulation. Phase diagram, intrinsic fluorescence spectra, quenching experiments and synchronous spectra were employed to acquire information regarding the conformation of protein in the presence of calcium chloride and magnesium chloride. Intrinsic fluorescence data showed that, between 25°C and 60°C, the presence of calcium chloride in the complex favoured the movement of tryptophan residues to domains located at the protein–water interface, while magnesium chloride favoured the burial of tryptophan residues. Higher temperatures generated blue shifts regardless of which salt was present, suggesting exposure of tryptophan residues to the hydrophobic core of the protein. Extrinsic fluorescence intensity of the non‐heat‐treated complex with magnesium chloride was significantly higher (P < 0.01) than of the complex with calcium chloride, suggesting that 1‐anilino‐8‐naphtalenesulphonic acid was bound to a higher proportion of the β‐lactoglobulin–carotenoids complex. Calcium chloride increased extrinsic fluorescence to a greater extent than magnesium chloride at temperatures above 70°C and was related to small structural changes induced by preheating β‐lactoglobulin.     

Host carbon sources modulate cell wall architecture, drug resistance and virulence in a fungal pathogen

The survival of all microbes depends upon their ability to respond to environmental challenges. To establish infection, pathogens such as Candida albicans must mount effective stress responses to counter host defences while adapting to dynamic changes in nutrient status within host niches. Studies of C. albicans stress adaptation have generally been performed on glucose‐grown cells, leaving the effects of alternative carbon sources upon stress resistance largely unexplored. We have shown that growth on alternative carbon sources, such as lactate, strongly influence the resistance of C. albicans to antifungal drugs, osmotic and cell wall stresses. Similar trends were observed in clinical isolates and other pathogenic Candida species. The increased stress resistance of C. albicans was not dependent on key stress (Hog1) and cell integrity (Mkc1) signalling pathways. Instead, increased stress resistance was promoted by major changes in the architecture and biophysical properties of the cell wall. Glucose‐ and lactate‐grown cells displayed significant differences in cell wall mass, ultrastructure, elasticity and adhesion. Changes in carbon source also altered the virulence of C. albicans in models of systemic candidiasis and vaginitis, confirming the importance of alternative carbon sources within host niches during C. albicans infections.     

Scan-statistic approach identifies clusters of rare disease variants in LRP2, a gene linked and associated with autism spectrum disorders, in three datasets

Cluster-detection approaches, commonly used in epidemiology and astronomy, can be applied in the context of genetic sequence data for the identification of genetic regions significantly enriched with rare disease-risk variants (DRVs). Unlike existing association tests for sequence data, the goal of cluster-detection methods is to localize significant disease mutation clusters within a gene or region of interest. Here, we focus on a chromosome 2q replicated linkage region that is associated with autism spectrum disorder (ASD) and that has been sequenced in three independent datasets. We found that variants in one gene, LRP2, residing on 2q are associated with ASD in two datasets (the combined variable-threshold-test p value is 1.2 × 10(-5)). Using a cluster-detection method, we show that in the discovery and replication datasets, variants associated with ASD cluster preponderantly in 25 kb windows (adjusted p values are p(1) = 0.003 and p(2) = 0.002), and the two windows are highly overlapping. Furthermore, for the third dataset, a 25 kb region similar to those in the other two datasets shows significant evidence of enrichment of rare DRVs. The region implicated by all three studies is involved in ligand binding, suggesting that subtle alterations in either LRP2 expression or LRP2 primary sequence modulate the uptake of LRP2 ligands. BMP4 is a ligand of particular interest given its role in forebrain development, and modest changes in BMP4 binding, which binds to LRP2 near the mutation cluster, might subtly affect development and could lead to autism-associated phenotypes.     

Ferruginous microstromatolites related to Middle Jurassic condensed sequences and hardgrounds (Bucegi Mountains, Southern Carpathians, Romania)

Integrated analyses of ferruginous laminated crusts and macro-oncoids associated with Middle Jurassic (Bathonian-Callovian) hardgrounds and condensed horizons cropping out in the Bucegi Mountains (Southern Carpathians) allowed an assessment of their microbial origin and the paleoenvironmental context of their genesis. The ferruginous microstromatolites reveal different morphological types (or macrofabrics): ferruginous microstromatolites representing the hardgrounds crusts, ferruginous endostromatolites and oncoidal ferruginous microstromatolites. The last are associated with ooidal bioclastic grainstone, ooidal bioclastic grainstone-packstone, bioclastic ooidal packstone-grainstone, oncoidal floatstone and rudstone, stromatolitic bindstone, bioclastic wackestone-packstone and bioclastic wackestone microfacies. The host mineral of the ferruginous microbialites is calcite, but microbially induced iron oxyhydroxides (goethite and magnetite) prevail in the ferruginous laminae. Petrographical and scanning electron microscope (SEM) investigations revealed that these ferruginous microstromatolites were formed by the activity of microbial mats dominated by putative bacterial and fungal filaments. Locations with reduced or no sedimentation, in relatively deep-water, open-marine shelf environments, below fair-weather wave base or near to storm wave base, within the deep euphotic zone, were favorable for the hardening of the seafloor and the development of the microbial mats. The scarcity of an autochthonous benthic fauna and of burrowing, as well as the presence of framboidal pyrite suggest dysaerobic conditions. In such an environment, iron would have been in its soluble state (Fe²⁺) and the activity of micro-aerophylic iron-oxidizing bacteria appears to have been particularly intensive at the dysoxic-anoxic interface, inducing the precipitation of iron oxyhydroxides and the formation of diverse ferruginous microstromatolites.     

Temporal Ordering of Cancer Microarray Data through a Reinforcement Learning Based Approach

Temporal modeling and analysis and more specifically, temporal ordering are very important problems within the fields of bioinformatics and computational biology, as the temporal analysis of the events characterizing a certain biological process could provide significant insights into its development and progression. Particularly, in the case of cancer, understanding the dynamics and the evolution of this disease could lead to better methods for prediction and treatment. In this paper we tackle, from a computational perspective, the temporal ordering problem, which refers to constructing a sorted collection of multi-dimensional biological data, collection that reflects an accurate temporal evolution of biological systems. We introduce a novel approach, based on reinforcement learning, more precisely, on Q-learning, for the biological temporal ordering problem. The experimental evaluation is performed using several DNA microarray data sets, two of which contain cancer gene expression data. The obtained solutions are correlated either to the given correct ordering (in the cases where this is provided for validation), or to the overall survival time of the patients (in the case of the cancer data sets), thus confirming a good performance of the proposed model and indicating the potential of our proposal.     

The Impact of Chemical Compounds on Benthic Invertebrates from the Danube and Danube Delta Systems

The aim of this study is to assess freshwater sediment in terms of biological and preliminary toxicological control linked to a series of variables along the Danube River and Danube Delta systems. The research is focused on eight points of the Romanian sector in the summer to autumn of 2012. Results show a high concentration of metals, pesticides, and petroleum products in sediment samples in the monitored period. The survey is designed to gauge the total chemical pollution effects on the composition, living, and growth of benthic organisms. To assess the toxic hazard of contaminated sediment samples, a microbiotest with meiobenthic ostracods Heterocypris incongruens was performed with evaluation of mortality and growth-inhibition percentages. The preliminary results showed an increase of sediment toxicity, in terms of growth inhibition (>80%), especially at Murighiol and Ivancea. The chemical pressures alongside the temporal conditions were important variables which affected benthic communities. Low benthic diversity was found in the Isaccea–St. Gheorghe Branch sector of the Danube River. In terms of ecological status, the study reveals that the Danube and Danube Delta ecosystem are eutrophic systems equilibrated for good ecological status.