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Naked mole rat (NMR) is the long-lived and tumor-resistant rodent. NMRs possess multiple adaptations that may contribute to longevity and cancer-resistance. However, whether NMRs have more efficient DNA repair have not been directly tested. Here we compared base excision repair (BER) and nucleotide excision repair (NER) systems in extracts from NMR and mouse fibroblasts after UVC irradiation. Transcript levels of the key repair enzymes demonstrated in most cases higher inducibility in the mouse vs the NMR cells. Ratios of repair enzymes activities in the extracts somewhat varied depending on post-irradiation time. NMR cell extracts were 2–3-fold more efficient at removing the bulky lesions, 1.5–3-fold more efficient at removing uracil, and about 1.4-fold more efficient at cleaving the AP-site than the mouse cells, while DNA polymerase activities being as a whole higher in the mouse demonstrate different patterns of product distribution. The level of poly(ADP-ribose) synthesis was 1.4–1.8-fold higher in the NMR cells. Furthermore, NMR cell extracts displayed higher binding of PARP1 to DNA probes containing apurinic/apyrimidinic site or photo-reactive DNA lesions. Cumulatively, our results suggest that the NMR has more efficient excision repair systems than the mouse, which may contribute to longevity and cancer resistance of this species.

A vast amount of SNPs derived from genome-wide association studies are represented by non-coding ones, therefore exacerbating the need for effective identification of regulatory SNPs (rSNPs) among them. However, this task remains challenging since the regulatory part of the human genome is annotated much poorly as opposed to coding regions. Here we describe an approach aggregating the whole set of ENCODE ChIP-seq data in order to search for rSNPs, and provide the experimental evidence of its efficiency. Its algorithm is based on the assumption that the enrichment of a genomic region with transcription factor binding loci (ChIP-seq peaks) indicates its regulatory function, and thereby SNPs located in this region are more likely to influence transcription regulation. To ensure that the approach preferably selects functionally meaningful SNPs, we performed enrichment analysis of several human SNP datasets associated with phenotypic manifestations. It was shown that all samples are significantly enriched with SNPs falling into the regions of multiple ChIP-seq peaks as compared with the randomly selected SNPs. For experimental verification, 40 SNPs falling into overlapping regions of at least 7 TF binding loci were selected from OMIM. The effect of SNPs on the binding of the DNA fragments containing them to the nuclear proteins from four human cell lines (HepG2, HeLaS3, HCT-116, and K562) has been tested by EMSA. A radical change in the binding pattern has been observed for 29 SNPs, besides, 6 more SNPs also demonstrated less pronounced changes. Taken together, the results demonstrate the effective way to search for potential rSNPs with the aid of ChIP-seq data provided by ENCODE project.

BackgroundThe progress of medicine, science, technology, education, and culture improves, year by year, quality of life and life expectancy of the populace. The modern human has a chance to further improve the quality and duration of his/her life and the lives of his/her loved ones by bringing their lifestyle in line with their sequenced individual genomes. With this in mind, one of genome-based developments at the junction of personalized medicine and bioinformatics will be considered in this work, where we used two Web services: (i) SNP_TATA_Comparator to search for alleles with a single nucleotide polymorphism (SNP) that alters the affinity of TATA-binding protein (TBP) for the TATA boxes of human gene promoters and (ii) PubMed to look for retrospective clinical reviews on changes in physiological indicators of reproductive potential in carriers of these alleles.ResultsA total of 126 SNP markers of female reproductive potential, capable of altering the affinity of TBP for gene promoters, were found using the two above-mentioned Web services. For example, 10 candidate SNP markers of thrombosis (e.g., rs563763767) can cause overproduction of coagulation inducers. In pregnant women, Hughes syndrome provokes thrombosis with a fatal outcome although this syndrome can be diagnosed and eliminated even at the earliest stages of its development. Thus, in women carrying any of the above SNPs, preventive treatment of this syndrome before a planned pregnancy can reduce the risk of death. Similarly, seven SNP markers predicted here (e.g., rs774688955) can elevate the risk of myocardial infarction. In line with Bowles’ lifespan theory, women carrying any of these SNPs may modify their lifestyle to improve their longevity if they can take under advisement that risks of myocardial infarction increase with age of the mother, total number of pregnancies, in multiple pregnancies, pregnancies under the age of 20, hypertension, preeclampsia, menstrual cycle irregularity, and in women smokers.ConclusionsAccording to Bowles’ lifespan theory—which links reproductive potential, quality of life, and life expectancy—the above information was compiled for those who would like to reduce risks of diseases corresponding to alleles in own sequenced genomes. Candidate SNP markers can focus the clinical analysis of unannotated SNPs, after which they may become useful for people who would like to bring their lifestyle in line with their sequenced individual genomes.Electronic supplementary materialThe online version of this article (10.1186/s12864-018-4478-3) contains supplementary material, which is available to authorized users.

институт цитологии и генетики сибирского отделения российской академии наук, новосибирск, россия 2 Университет ла-верна, ла-верна, Калифорния, сШа 3 новосибирский национальный исследовательский государственный университет, новосибирск, россия

The food-borne liver trematode Opisthorchis felineus is an emerging source of biliary tract diseases on the territory of the former Soviet Union and Eastern Europe. This parasite along with trematodes Opisthorchis viverrini and Clonorchis sinensis belong to the triad of epidemiologically important liver flukes of the Opisthorchiidae family. It is known that O. viverrini and C. sinensis are the main risk factors of cholangiocarcinoma (CCA) in the endemic regions. The carcinogenic potential of O. felineus has not been well researched because of the absence of systematic pathomorphological, clinical, and epidemiological studies on O. felineus opisthorchiasis. In the present study, we show the results of detailed histopathological analysis and comprehensive evaluation of inflammation, bile duct dysplasia, periductal fibrosis, bile duct hyperplasia, bile duct proliferation, egg granuloma, cysts, cholangiofibrosis, and CCA from 10 to 30 weeks following infection of Syrian hamsters with O. felineus accompanied by oral administration of dimethylnitrosamine (DMN). The results revealed that O. felineus contributes to bile duct cancer development in the hamster model. During the combined action of O. felineus and DMN, morphological features of the liver underwent dramatic changes at the cellular and organ levels. Already in the early stages of the experiment, we observed extensive periductal fibrosis, active inflammation, proliferation of the bile duct, bile duct dysplasia and egg granulomas. Later, against the background of all these changes, cholangiofibrosis and CCA were found. Our work is the first step in the study of carcinogenic potential of O. felineus. Obtained data indicate the risk of CCA of patients having chronic O. felineus opisthorchiasis, and underscore the need for the development of programs for control of this helminthiasis.

Hypertensive heart disease is a major contributor to cardiovascular mortality. Endothelin is a potent vasoconstrictive and profibrotic mediator produced by the endothelin-converting enzyme (ECE), whereas natriuretic peptides, degraded by the neutral endopeptidase (NEP), have diuretic, vasodilatory, and antifibrotic properties. Thus, combined ECE/NEP inhibition may halt hypertensive cardiac remodeling. This study examined effects of SLV338, a novel ECE/NEP inhibitor, on cardiac protection in experimental renovascular hypertension (2-kidney, 1-clip [2K1C]). Male rats were allocated to 5 groups: sham-operated rats, untreated animals with 2K1C, 2K1C animals treated with oral SLV338 (30 and 100 mg/kg per day), and 2K1C animals treated with oral losartan (20 mg/kg per day). Treatment duration was 12 weeks. Blood pressure was assessed every 4 weeks. At study end, hearts were taken for histology/computer-aided histomorphometry/immunohistochemistry. Pharmacological properties of SLV338 are described. SLV338 is a dual ECE/NEP inhibitor, as demonstrated both in vitro and in vivo. In the 2K1C study, losartan lowered blood pressure by ≤46 mm Hg, whereas both dosages of SLV338 had no effect. However, SLV338 (both dosages) completely normalized cardiac interstitial fibrosis, perivascular fibrosis, myocyte diameter, and media:lumen ratio of cardiac arteries, as did losartan. Cardiac transforming growth factor-β1 expression was significantly enhanced in untreated 2K1C rats versus controls, whereas treatment with SLV338 and losartan prevented this effect. Taken together, dual ECE/NEP inhibitor SLV338 prevents cardiac remodeling to the same extent as losartan, but in a blood pressure-independent manner, in a rat model of renovascular hypertension. This effect is at least partially mediated via suppression of cardiac transforming growth factor-β1 expression.

BackgroundAggressiveness in humans is a hereditary behavioral trait that mobilizes all systems of the body—first of all, the nervous and endocrine systems, and then the respiratory, vascular, muscular, and others—e.g., for the defense of oneself, children, family, shelter, territory, and other possessions as well as personal interests. The level of aggressiveness of a person determines many other characteristics of quality of life and lifespan, acting as a stress factor. Aggressive behavior depends on many parameters such as age, gender, diseases and treatment, diet, and environmental conditions. Among them, genetic factors are believed to be the main parameters that are well-studied at the factual level, but in actuality, genome-wide studies of aggressive behavior appeared relatively recently. One of the biggest projects of the modern science—1000 Genomes—involves identification of single nucleotide polymorphisms (SNPs), i.e., differences of individual genomes from the reference genome. SNPs can be associated with hereditary diseases, their complications, comorbidities, and responses to stress or a drug. Clinical comparisons between cohorts of patients and healthy volunteers (as a control) allow for identifying SNPs whose allele frequencies significantly separate them from one another as markers of the above conditions. Computer-based preliminary analysis of millions of SNPs detected by the 1000 Genomes project can accelerate clinical search for SNP markers due to preliminary whole-genome search for the most meaningful candidate SNP markers and discarding of neutral and poorly substantiated SNPs.ResultsHere, we combine two computer-based search methods for SNPs (that alter gene expression) {i} Web service SNP_TATA_Comparator (DNA sequence analysis) and {ii} PubMed-based manual search for articles on aggressiveness using heuristic keywords. Near the known binding sites for TATA-binding protein (TBP) in human gene promoters, we found aggressiveness-related candidate SNP markers, including rs1143627 (associated with higher aggressiveness in patients undergoing cytokine immunotherapy), rs544850971 (higher aggressiveness in old women taking lipid-lowering medication), and rs10895068 (childhood aggressiveness-related obesity in adolescence with cardiovascular complications in adulthood).ConclusionsAfter validation of these candidate markers by clinical protocols, these SNPs may become useful for physicians (may help to improve treatment of patients) and for the general population (a lifestyle choice preventing aggressiveness-related complications).Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-016-3353-3) contains supplementary material, which is available to authorized users.