Localization of the gene for congenital dyserythropoietic anemia type I to a <1-cM interval on chromosome 15q15.1-15.3.

Congenital dyserythropoietic anemias (CDA) are a rare group of red-blood-cell disorders of unknown etiology that are characterized by ineffective erythropoiesis, pathognomonic cytopathology of the nucleated red blood cells in the bone marrow, and secondary hemochromatosis. In CDA type I, bone-marrow electron microscopy reveals characteristic findings in erythroid precursors, including spongy heterochromatin and enlarged nuclear pores. Since the genetic basis of CDA type I is not evident, we used homozygosity and linkage mapping to localize the genetic defect responsible for CDA type I in 25 Bedouins from four large consanguineous families. We report the linkage of this disease to markers on chromosome 15 located at q15. 1-q15.3. Fourteen markers within a 12-cM interval were typed in the relevant family members. Nine of the markers yielded maximum LOD scores of 1.625-12.928 at a recombination fraction of .00. Linkage disequilibrium was found only with marker D15S779. Haplotype analysis revealed eight different carrier haplotypes and highlighted the existence of a founder haplotype. Identification of historical crossover events further narrowed the gene location to between D15S779 and D15S778. The data suggest localization of the CDA type I gene within a 0.5-cM interval. The founder mutation probably occurred >/= 400 years ago. Sequence analysis of the coding region of protein 4.2, the only known erythroid-specific gene in the locus, did not reveal any change in the CDA type I patients. Future analysis of this locus may lead to the identification of a gene essential to normal erythropoiesis.     

Risk-Based Zoning Strategy for Soil Remediation at an Industrial Site

After determining at an early stage of the project that the future land use of this New Jersey chemical manufacturing site remain industrial in nature, the site was zoned according to risk. The chemicals of concern (COCs) at the site included relatively low levels of mono- and polynuclear aromatic hydrocarbons, chlorinated aliphatics, as well as other volatile and semivolatile compounds. Direct human exposure scenarios were the key to the mitigation of risks related to soils because the groundwater migration pathway was already interrupted using groundwater recovery. A focused remedial strategy was developed to ensure that the exposure pathways (inhalation, ingestion, and dermal contact) are alleviated and the remedial measures are protective to the workers operating and/or maintaining the site. The risk evaluation process included a preliminary risk assessment (Tier 1) based on a comparison with pertinent soil cleanup criteria, a prioritization analysis to rank zones, chemicals and pathways of concern, and an application of the Risk Based Corrective Action (RBCA) approach (Tier 2) for construction worker exposure scenario. The risk assessment identified selected areas that would benefit from remedial actions. Prioritization Analysis classified the site into five high-priority (comprising 97% of the total health-based risk), three medium-priority (contributing to remaining 2 to 3% of the risk), and adequately protected areas. The boundaries and volumes of affected areas were delineated based on confirmatory soil sampling and statistical analyses. The remedial technologies selected for the site have achieved appropriate reduction in risk to comply with all State regulations and include (in addition to the institutional controls): ??Capping the site where only immobilesemivolatile contaminants are present ??Excavation and on-site treatment of the soils impacted by volatile organic com pounds through ex situ low temperature desorption, or alternative “biopile” treatment and natural attenuation, and ??Excavation and off-site disposal of limited volumes of soils This risk-based, integral approach helped identify the real significance of contamination present at the site and facilitated the development of suitable and adequate remedies. Had not it been for this approach, the mere comparison with soil cleanup criteria would have unnecessarily resulted in denoting all areas as nuisance contributors, and thus requiring some actions. New Jersey Department of Environmental Protection (NJDEP) has approved this approach and contributed to its accomplishment.     

A phenome-guided drug repositioning through a latent variable model

Background

The phenome represents a distinct set of information in the human population. It has been explored particularly in its relationship with the genome to identify correlations for diseases. The phenome has been also explored for drug repositioning with efforts focusing on the search space for the most similar candidate drugs. For a comprehensive analysis of the phenome, we assumed that all phenotypes (indications and side effects) were inter-connected with a probabilistic distribution and this characteristic may offer an opportunity to identify new therapeutic indications for a given drug. Correspondingly, we employed Latent Dirichlet Allocation (LDA), which introduces latent variables (topics) to govern the phenome distribution.

Results

We developed our model on the phenome information in Side Effect Resource (SIDER). We first developed a LDA model optimized based on its recovery potential through perturbing the drug-phenotype matrix for each of the drug-indication pairs where each drug-indication relationship was switched to “unknown” one at the time and then recovered based on the remaining drug-phenotype pairs. Of the probabilistically significant pairs, 70% was successfully recovered. Next, we applied the model on the whole phenome to narrow down repositioning candidates and suggest alternative indications. We were able to retrieve approved indications of 6 drugs whose indications were not listed in SIDER. For 908 drugs that were present with their indication information, our model suggested alternative treatment options for further investigations. Several of the suggested new uses can be supported with information from the scientific literature.

Conclusions

The results demonstrated that the phenome can be further analyzed by a generative model, which can discover probabilistic associations between drugs and therapeutic uses. In this regard, LDA serves as an enrichment tool to explore new uses of existing drugs by narrowing down the search space.

Electronic supplementary material

The online version of this article (doi:10.1186/1471-2105-15-267) contains supplementary material, which is available to authorized users.     

Antiproliferative activities of isolated flavone glycosides and fatty acids from Stachys byzantina

From the aerial parts of Stachys byzanthina C. Koch., a new flavone glycoside, was isolated for the first time in addition to known two flavone glycosides. Structures were established by conventional methods of analysis and confirmed by ¹H, ¹³C NMR and mass spectral analysis. Antiproliferative activities of isolated compounds, crude extract and fractions, fatty acids (extracts of hexane and hexane:ethyl acetate, 9:1) of aerial parts of S. byzantina were investigated against Vero (African green monkey kidney), HeLa (human uterus carcinoma) and C6 (rat brain tumor) cells in vitro and compared with 5-fluorouracil (5-FU). Antiproliferative effect of the extract, isolated flavonoids and fatty acids were tested at 100, 250, 500 and 1000 μg/mL using BrdU cell proliferation ELISA.     

Paradigm of Tunable Clustering Using Binarization of Consensus Partition Matrices (Bi-CoPaM) for Gene Discovery

Clustering analysis has a growing role in the study of co-expressed genes for gene discovery. Conventional binary and fuzzy clustering do not embrace the biological reality that some genes may be irrelevant for a problem and not be assigned to a cluster, while other genes may participate in several biological functions and should simultaneously belong to multiple clusters. Also, these algorithms cannot generate tight clusters that focus on their cores or wide clusters that overlap and contain all possibly relevant genes. In this paper, a new clustering paradigm is proposed. In this paradigm, all three eventualities of a gene being exclusively assigned to a single cluster, being assigned to multiple clusters, and being not assigned to any cluster are possible. These possibilities are realised through the primary novelty of the introduction of tunable binarization techniques. Results from multiple clustering experiments are aggregated to generate one fuzzy consensus partition matrix (CoPaM), which is then binarized to obtain the final binary partitions. This is referred to as Binarization of Consensus Partition Matrices (Bi-CoPaM). The method has been tested with a set of synthetic datasets and a set of five real yeast cell-cycle datasets. The results demonstrate its validity in generating relevant tight, wide, and complementary clusters that can meet requirements of different gene discovery studies.     

The Effects of Levosimendan Exposure on Oxidant/Antioxidant Status and Trace Element Levels in the Pulmonary Artery of Rats

We investigated both the effect of levosimendan and the role of oxidant/antioxidant status and trace element levels in the pulmonary artery of rats. Fourteen male Wistar albino rats were randomly divided into two groups of seven animals each. Group 1 was not exposed to levosimendan and served as a control. Levosimendan (12 μg/kg) diluted in 10 ml 0.9 % NaCl was administered intraperitoneally to group 2. Animals of both groups were killed after 3 days, and their pulmonary arteries were harvested to determine changes in tissue oxidant/antioxidant status and trace element levels. The animals in both groups were killed 72 h after the levosimendan exposure treatment, and pulmonary arteries were harvested to determine levels of the lipid peroxidation product MDA and the antioxidant GSH as well as the decreased activity of antioxidant enzymes such as SOD, GSH-Px and CAT. It was found that MDA levels increased in pulmonary artery tissues of rats after levosimendan administration. The GSH level decreased in the pulmonary artery of rats after levosimendan treatment. Co, Mn, Fe, Cd and Pb levels were significantly higher (P < 0.001) and Mg, Zn and Cu levels significantly lower (P < 0.001) in the levosimendan group compared to the control group. These results suggest that levosimendan treatment caused an increase in free radical production and a decrease in antioxidant enzyme activity in the pulmonary artery of levosimendan-treated rats. It also caused a decrease or increase in the levels of many minerals in the pulmonary artery, which is an undesirable condition for normal pharmacological function.