Genetic syndromes caused by mutations in epigenetic genes

The orchestrated organization of epigenetic factors that control chromatin dynamism, including DNA methylation, histone marks, non-coding RNAs (ncRNAs) and chromatin-remodeling proteins, is essential for the proper function of tissue homeostasis, cell identity and development. Indeed, deregulation of epigenetic profiles has been described in several human pathologies, including complex diseases (such as cancer, cardiovascular and neurological diseases), metabolic pathologies (type 2 diabetes and obesity) and imprinting disorders. Over the last decade it has become increasingly clear that mutations of genes involved in epigenetic mechanism, such as DNA methyltransferases, methyl-binding domain proteins, histone deacetylases, histone methylases and members of the SWI/SNF family of chromatin remodelers are linked to human disorders, including Immunodeficiency Centromeric instability Facial syndrome 1, Rett syndrome, Rubinstein–Taybi syndrome, Sotos syndrome or alpha-thalassemia/mental retardation X-linked syndrome, among others. As new members of the epigenetic machinery are described, the number of human syndromes associated with epigenetic alterations increases. As recent examples, mutations of histone demethylases and members of the non-coding RNA machinery have recently been associated with Kabuki syndrome, Claes-Jensen X-linked mental retardation syndrome and Goiter syndrome. In this review, we describe the variety of germline mutations of epigenetic modifiers that are known to be associated with human disorders, and discuss the therapeutic potential of epigenetic drugs as palliative care strategies in the treatment of such disorders.     

2-(1H-Pyrazol-4-yl)acetic acids as CRTh2 antagonists

High throughput screening identified the pyrazole-4-acetic acid substructure as CRTh2 receptor antagonists. Optimisation of the compounds uncovered a tight SAR but also identified some low nanomolar inhibitors.     

On the use of weighting in LCA: translating decision makers’ preferences into weights via linear programming

Purpose

The main goal of any life cycle assessment (LCA) study is to identify solutions leading to environmental savings. In conventional LCA studies, practitioners select from some alternatives the one which better matches their preferences. This task is sometimes simplified by ranking these alternatives using an aggregated indicator defined by attaching weights to impacts. We address here the inverse problem. That is, given an alternative, we aim to determine the weights for which that solution becomes optimal.

Methods

We propose a method based on linear programming (LP) that determines, for a given alternative, the ranges within which the weights attached to a set of impact metrics must lie so that when a weighting combination of these impacts is optimized, the alternative can be optimal, while if the weights fall outside this range, it is guaranteed that the solution will be suboptimal. A large weight value implies that the corresponding LCA impact is given more importance, while a low value implies the converse. Furthermore, we provide a rigorous mathematical analysis on the implications of using weighting schemes in LCA, showing that this practice guides decision-making towards the adoption of some specific alternatives (those lying on the convex envelope of the resulting trade-off curve).

Results and discussion

A case study based on the design of hydrogen infrastructures is taken as a test bed to illustrate the capabilities of the approach presented. Given are a set of production and storage technologies available to produce and deliver hydrogen, a final demand, and cost and environmental data. A set of designs, each achieving a unique combination of cost and LCA impact, is considered. For each of them, we calculate the minimum and maximum weight to be given to every LCA impact so that the alternative can be optimal among all the candidate designs. Numerical results show that solutions with lower impact are selected when decision makers are willing to pay larger monetary penalties for the environmental damage caused.

Conclusions

LP can be used in LCA to translate the decision makers’ preferences into weights. This information is rather valuable, particularly when these weights represent economic penalties, as it allows screening and ranking alternatives on the basis of a common economic basis. Our framework is aimed at facilitating decision making in LCA studies and defines a general framework for comparing alternatives that show different performance in a wide variety of impact metrics.     

Polymorphisms in DNA-Repair Genes in a Cohort of Prostate Cancer Patients from Different Areas in Spain: Heterogeneity between Populations as a Confounding Factor in Association Studies

Background

Differences in the distribution of genotypes between individuals of the same ethnicity are an important confounder factor commonly undervalued in typical association studies conducted in radiogenomics.

Objective

To evaluate the genotypic distribution of SNPs in a wide set of Spanish prostate cancer patients for determine the homogeneity of the population and to disclose potential bias.

Design, Setting, and Participants

A total of 601 prostate cancer patients from Andalusia, Basque Country, Canary and Catalonia were genotyped for 10 SNPs located in 6 different genes associated to DNA repair: XRCC1 (rs25487, rs25489, rs1799782), ERCC2 (rs13181), ERCC1 (rs11615), LIG4 (rs1805388, rs1805386), ATM (rs17503908, rs1800057) and P53 (rs1042522). The SNP genotyping was made in a Biotrove OpenArray® NT Cycler.

Outcome Measurements and Statistical Analysis

Comparisons of genotypic and allelic frequencies among populations, as well as haplotype analyses were determined using the web-based environment SNPator. Principal component analysis was made using the SnpMatrix and XSnpMatrix classes and methods implemented as an R package. Non-supervised hierarchical cluster of SNP was made using MultiExperiment Viewer.

Results and Limitations

We observed that genotype distribution of 4 out 10 SNPs was statistically different among the studied populations, showing the greatest differences between Andalusia and Catalonia. These observations were confirmed in cluster analysis, principal component analysis and in the differential distribution of haplotypes among the populations. Because tumor characteristics have not been taken into account, it is possible that some polymorphisms may influence tumor characteristics in the same way that it may pose a risk factor for other disease characteristics.

Conclusion

Differences in distribution of genotypes within different populations of the same ethnicity could be an important confounding factor responsible for the lack of validation of SNPs associated with radiation-induced toxicity, especially when extensive meta-analysis with subjects from different countries are carried out.     

Middle Pleistocene Steppe Lion Remains from Grotte de la Carrière (Têt Valley,Eastern Pyrenees)

Journal of Mammalian Evolution - Late Pleistocene cave lions are one of the most iconic species of Northern Hemisphere Quaternary taphocoenoses. Despite their often-scarce record in cave...