Integrating transposable elements in the 3D genome

Chromosome organisation is increasingly recognised as an essential component of genome regulation, cell fate and cell health. Within the realm of transposable elements (TEs) however, the spatial information of how genomes are folded is still only rarely integrated in experimental studies or accounted for in modelling. Whilst polymer physics is recognised as an important tool to understand the mechanisms of genome folding, in this commentary we discuss its potential applicability to aspects of TE biology. Based on recent works on the relationship between genome organisation and TE integration, we argue that existing polymer models may be extended to create a predictive framework for the study of TE integration patterns. We suggest that these models may offer orthogonal and generic insights into the integration profiles (or "topography") of TEs across organisms. In addition, we provide simple polymer physics arguments and preliminary molecular dynamics simulations of TEs inserting into heterogeneously flexible polymers. By considering this simple model, we show how polymer folding and local flexibility may generically affect TE integration patterns. The preliminary discussion reported in this commentary is aimed to lay the foundations for a large-scale analysis of TE integration dynamics and topography as a function of the three-dimensional host genome

On the residual opening of hydraulic fractures

Hydraulic stimulation technologies are widely applied across resource and power generation industries to increase the productivity of oil/gas or hot water reservoirs. These technologies utilise pressurised water, which is applied inside the well to initiate and drive fractures as well as to open a network of existing natural fractures. To prevent the opened fractures from complete closure during production stage, small particles (proppants) are normally injected with the pressurised fluid. These particles are subjected to confining stresses when the fluid pressure is removed, which leads to a partial closure of the stimulated fractures. The residual fracture openings are the main outcome of such hydraulic stimulations as these openings significantly affect the permeability of the reservoirs and, subsequently, the well productivity. Past research was largely focused on the assessment of conditions and characteristics of fluid driven fractures as well as proppant placement techniques. Surprisingly, not much work was devoted to the assessment of the residual fracture profiles. In this work we develop a simplified non-linear mathematical model of residual closure of a plane crack filled with deformable particles and subjected to a remote compressive stress. It is demonstrated that the closure profile is significantly influenced by the distribution and compressibility of the particles, which are often ignored in the current evaluations of well productivity. © 2013 Springer Science+Business Media Dordrecht.Luiz Bortolan Neto, Andrei Kotouso

Genetic polymorphisms of DNA double strand break gene Ku70 and gastric cancer in Taiwan

<p>Abstract</p> <p>Background and aim</p> <p>The DNA repair gene <it>Ku70</it>, an important member of non-homologous end-joining repair system, is thought to play an important role in the repairing of DNA double strand breaks. It is known that defects in double strand break repair capacity can lead to irreversible genomic instability. However, the polymorphic variants of <it>Ku70</it>, have never been reported about their association with gastric cancer susceptibility.</p> <p>Methods</p> <p>In this hospital-based case-control study, the associations of <it>Ku70 </it>promoter T-991C (rs5751129), promoter G-57C (rs2267437), promoter A-31G (rs132770), and intron 3 (rs132774) polymorphisms with gastric cancer risk in a Taiwanese population were investigated. In total, 136 patients with gastric cancer and 560 age- and gender-matched healthy controls recruited from the China Medical Hospital in Taiwan were genotyped.</p> <p>Results</p> <p>As for <it>Ku70 </it>promoter T-991C, the ORs after adjusted by age and gender of the people carrying TC and CC genotypes were 2.41 (95% CI = 1.53-3.88) and 3.21 (95% CI = 0.96-9.41) respectively, compared to those carrying TT wild-type genotype. The <it>P </it>for trend was significant (<it>P </it>< 0.0001). In the dominant model (TC plus CC versus TT), the association between <it>Ku70 </it>promoter T-991C polymorphism and the risk for gastric cancer was also significant (adjusted OR = 2.48, 95% CI = 1.74-3.92). When stratified by age and gender, the association was restricted to those at the age of 55 or elder of age (TC vs TT: adjusted OR = 2.52, 95% CI = 1.37-4.68, <it>P </it>= 0.0139) and male (TC vs TT: adjusted OR = 2.58, 95% CI = 1.33-4.47, <it>P </it>= 0.0085). As for the other three polymorphisms, there was no difference between both groups in the distributions of their genotype frequencies.</p> <p>Conclusion</p> <p>In conclusion, the <it>Ku70 </it>promoter T-991C (rs5751129), but not the <it>Ku70 </it>promoter C-57G (rs2267437), promoter A-31G (rs132770) or intron 3 (rs132774), is associated with gastric cancer susceptibility. This polymorphism may be a novel useful marker for gastric carcinogenesis.</p

Expression of ezrin is associated with invasion and dedifferentiation of hepatitis B related hepatocellular carcinoma

<p>Abstract</p> <p>Background</p> <p>Hepatocellular carcinoma (HCC) is the fifth most common malignancy in the world and constitutes the leading cause of cancer-related death among men, and second among women in Taiwan. Liver cirrhosis and HCC are relatively prevalent, and 80% to 85% of the patients with these conditions have positive results for hepatitis B surface antigen in Taiwan. Only 5% of the general population is seronegative for all hepatititis B virus (HBV) markers. This is the first study to determine the role of ezrin upon HBV HCC cell and patients with HBV HCC undergoing hepatectomy</p> <p>Methods</p> <p>Immunohistochemical study with ezrin in 104 human HBV-HCC cases were carried out to investigate its association with the clinicopathological features and the outcomes of 104 HBV-HCC patients undergoing hepatetomy. In addition, DNA constructs including the wild type ezrin (wt-ezrin) and mutant ezrin Tyr353 (Y353) were transfected into Hep3B cell to study its role in tumor invasion and differentiation.</p> <p>Results</p> <p>HBV HCC patients with ezrin over-expression independently have smaller tumor size, cirrhotic liver background, poor tumor differentiation, and more vascular invasion. Ezrin expression status has no impact on survival for HBV-HCC patients undergoing hepatectomy. The in vitro assay showed that wt-ezrin Hep3B cells have a significant higher level of AFP secretion and higher invasion ability as compared with the control and Y353- ezrin Hep3B cells.</p> <p>Conclusion</p> <p>Ezrin over-expression contributed to de-differentiation and invasion of HBV-HCC cell. HBV-HCC patients with ezrin over-expression were independently associated with tumor with smaller size, cirrhotic liver background, poor differentiation, and vascular invasion.</p

Two Major Medicinal Honeys Have Different Mechanisms of Bactericidal Activity

Honey is increasingly valued for its antibacterial activity, but knowledge regarding the mechanism of action is still incomplete. We assessed the bactericidal activity and mechanism of action of Revamil® source (RS) honey and manuka honey, the sources of two major medical-grade honeys. RS honey killed Bacillus subtilis, Escherichia coli and Pseudomonas aeruginosa within 2 hours, whereas manuka honey had such rapid activity only against B. subtilis. After 24 hours of incubation, both honeys killed all tested bacteria, including methicillin-resistant Staphylococcus aureus, but manuka honey retained activity up to higher dilutions than RS honey. Bee defensin-1 and H2O2 were the major factors involved in rapid bactericidal activity of RS honey. These factors were absent in manuka honey, but this honey contained 44-fold higher concentrations of methylglyoxal than RS honey. Methylglyoxal was a major bactericidal factor in manuka honey, but after neutralization of this compound manuka honey retained bactericidal activity due to several unknown factors. RS and manuka honey have highly distinct compositions of bactericidal factors, resulting in large differences in bactericidal activity

ATM haplotypes and breast cancer risk in Jewish high-risk women

While genetic factors clearly play a role in conferring breast cancer risk, the contribution of ATM gene mutations to breast cancer is still unsettled. To shed light on this issue, ATM haplotypes were constructed using eight SNPs spanning the ATM gene region (142 kb) in ethnically diverse non-Ashkenazi Jewish controls (n=118) and high-risk (n=142) women. Of the 28 haplotypes noted, four were encountered in frequencies of 5% or more and accounted for 85% of all haplotypes. Subsequently, ATM haplotyping of high-risk, non-Ashkenazi Jews was performed on 66 women with breast cancer and 76 asymptomatic. One SNP (rs228589) was significantly more prevalent among breast cancer cases compared with controls (P=4 × 10−9), and one discriminative ATM haplotype was significantly more prevalent among breast cancer cases (33.3%) compared with controls (3.8%), (P⩽10−10). There was no significant difference in the SNP and haplotype distribution between asymptomatic high-risk and symptomatic women as a function of disease status. We conclude that a specific ATM SNP and a specific haplotype are associated with increased breast cancer risk in high-risk non-Ashkenazi Jews

An investigation into aripiprazole's partial D(2) agonist effects within the dorsolateral prefrontal cortex during working memory in healthy volunteers

Rationale: Working memory impairments in schizophrenia have been attributed to dysfunction of the dorsolateral prefrontal cortex (DLPFC) which in turn may be due to low DLPFC dopamine innervation. Conventional antipsychotic drugs block DLPFC D2 receptors, and this may lead to further dysfunction and working memory impairments. Aripiprazole is a D2 receptor partial agonist hypothesised to enhance PFC dopamine functioning, possibly improving working memory. Objectives: We probed the implications of the partial D2 receptor agonist actions of aripiprazole within the DLPFC during working memory. Investigations were carried out in healthy volunteers to eliminate confounds of illness or medication status. Aripiprazole’s prefrontal actions were compared with the D2/5-HT2A blocker risperidone to separate aripiprazole’s unique prefrontal D2 agonist actions from its serotinergic and striatal D2 actions that it shares with risperidone. Method: A double-blind, placebo-controlled, parallel design was implemented. Participants received a single dose of either 5 mg aripiprazole, 1 mg risperidone or placebo before performing the n-back task whilst undergoing fMRI scanning. Results: Compared with placebo, the aripiprazole group demonstrated enhanced DLPFC activation associated with a trend for improved discriminability (d’) and speeded reaction times. In contrast to aripiprazole’s neural effects, the risperidone group demonstrated a trend for reduced DLPFC recruitment. Unexpectedly, the risperidone group demonstrated similar effects to aripiprazole on d’ and additionally had reduced errors of commission compared with placebo. Conclusion: Aripiprazole has unique DLPFC actions attributed to its prefrontal D2 agonist action. Risperidone’s serotinergic action that results in prefrontal dopamine release may have protected against any impairing effects of its prefrontal D2 blockade

Metastatic canine mammary carcinomas can be identified by a gene expression profile that partly overlaps with human breast cancer profiles

<p>Abstract</p> <p>Background</p> <p>Similar to human breast cancer mammary tumors of the female dog are commonly associated with a fatal outcome due to the development of distant metastases. However, the molecular defects leading to metastasis are largely unknown and the value of canine mammary carcinoma as a model for human breast cancer is unclear. In this study, we analyzed the gene expression signatures associated with mammary tumor metastasis and asked for parallels with the human equivalent.</p> <p>Methods</p> <p>Messenger RNA expression profiles of twenty-seven lymph node metastasis positive or negative canine mammary carcinomas were established by microarray analysis. Differentially expressed genes were functionally characterized and associated with molecular pathways. The findings were also correlated with published data on human breast cancer.</p> <p>Results</p> <p>Metastatic canine mammary carcinomas had 1,011 significantly differentially expressed genes when compared to non-metastatic carcinomas. Metastatic carcinomas had a significant up-regulation of genes associated with cell cycle regulation, matrix modulation, protein folding and proteasomal degradation whereas cell differentiation genes, growth factor pathway genes and regulators of actin organization were significantly down-regulated. Interestingly, 265 of the 1,011 differentially expressed canine genes are also related to human breast cancer and, vice versa, parts of a human prognostic gene signature were identified in the expression profiles of the metastatic canine tumors.</p> <p>Conclusions</p> <p>Metastatic canine mammary carcinomas can be discriminated from non-metastatic carcinomas by their gene expression profiles. More than one third of the differentially expressed genes are also described of relevance for human breast cancer. Many of the differentially expressed genes are linked to functions and pathways which appear to be relevant for the induction and maintenance of metastatic progression and may represent new therapeutic targets. Furthermore, dogs are in some aspects suitable as a translational model for human breast tumors in order to identify prognostic molecular signatures and potential therapeutic targets.</p

Spt2p Defines a New Transcription-Dependent Gross Chromosomal Rearrangement Pathway

Large numbers of gross chromosomal rearrangements (GCRs) are frequently observed in many cancers. High mobility group 1 (HMG1) protein is a non-histone DNA-binding protein and is highly expressed in different types of tumors. The high expression of HMG1 could alter DNA structure resulting in GCRs. Spt2p is a non-histone DNA binding protein in Saccharomyces cerevisiae and shares homology with mammalian HMG1 protein. We found that Spt2p overexpression enhances GCRs dependent on proteins for transcription elongation and polyadenylation. Excess Spt2p increases the number of cells in S phase and the amount of single-stranded DNA (ssDNA) that might be susceptible to cause DNA damage and GCR. Consistently, RNase H expression, which reduces levels of ssDNA, decreased GCRs in cells expressing high level of Spt2p. Lastly, high transcription in the chromosome V, the location at which GCR is monitored, also enhanced GCR formation. We propose a new pathway for GCR where DNA intermediates formed during transcription can lead to genomic instability