Inhibition of TXNIP expression in vivo blocks early pathologies of diabetic retinopathy

Evidence is mounting that proinflammatory and proapoptotic thioredoxin-interacting protein (TXNIP) has a causative role in the development of diabetes. However, there are no studies investigating the role of TXNIP in diabetic retinopathy (DR). Here, we show that, in diabetic rats, TXNIP expression and hexosamine biosynthesis pathway (HBP) flux, which regulates TXNIP, are elevated in the retina and correlates well with the induction of inflammatory cyclooxygenase 2 (Cox-2) and sclerotic fibronectin (FN). We blocked the expression of TXNIP in diabetic rat retinas by: (i) inhibiting HBP flux; (ii) inducing post-transcriptional gene silencing (PTGS) for TXNIP mRNA; and (iii) performing an in vivo transcriptional gene silencing (TGS) approach for TXNIP knockdown by promoter-targeted small interfering RNAs and cell-penetrating peptides as RNA interference (RNAi) transducers. Each of these methods is efficient in downregulating TXNIP expression, resulting in blockade of its target genes, Cox-2 and FN, demonstrating that TXNIP has a causative role in aberrant gene induction in early DR. RNAi TGS of TXNIP abolishes diabetes-induced retinal gliosis and ganglion injury. Thus, TXNIP has a critical role in inflammation and retinal injury in early stages of DR. The successful employment of TXNIP TGS and amelioration of its pathological effects open the way for novel therapeutic strategies aimed to block disease onset and progression of DR

Stress related epigenetic changes may explain opportunistic success in biological invasions in Antipode mussels

Different environmental factors could induce epigenetic changes, which are likely involved in the biological invasion process. Some of these factors are driven by humans as, for example, the pollution and deliberate or accidental introductions and others are due to natural conditions such as salinity. In this study, we have analysed the relationship between different stress factors: time in the new location, pollution and salinity with the methylation changes that could be involved in the invasive species tolerance to new environments. For this purpose, we have analysed two different mussels’ species, reciprocally introduced in antipode areas: the Mediterranean blue mussel Mytilus galloprovincialis and the New Zealand pygmy mussel Xenostrobus securis, widely recognized invaders outside their native distribution ranges. The demetylathion was higher in more stressed population, supporting the idea of epigenetic is involved in plasticity process. These results can open a new management protocols, using the epigenetic signals as potential pollution monitoring tool. We could use these epigenetic marks to recognise the invasive status in a population and determine potential biopollutants

CAG Repeat Variants in the POLG1 Gene Encoding mtDNA Polymerase-Gamma and Risk of Breast Cancer in African-American Women

The DNA polymerase-gamma (POLG) gene, which encodes the catalytic subunit of enzyme responsible for directing mitochondrial DNA replication in humans, contains a polyglutamine tract encoded by CAG repeats of varying length. The length of the CAG repeat has been associated with the risk of testicular cancer, and other genomic variants that impact mitochondrial function have been linked to breast cancer risk in African-American (AA) women. We evaluated the potential role of germline POLG-CAG repeat variants in breast cancer risk in a sample of AA women (100 cases and 100 age-matched controls) who participated in the Women's Circle of Health Study, an ongoing multi-institutional, case-control study of breast cancer. Genotyping was done by fragment analysis in a blinded manner. Results from this small study suggest the possibility of an increased risk of breast cancer in women with minor CAG repeat variants of POLG, but no statistically significant differences in CAG repeat length were observed between cases and controls (multivariate-adjusted odds ratio 1.74; 95% CI, 0.49–6.21). Our study suggests that POLG-CAG repeat length is a potential risk factor for breast cancer that needs to be explored in larger population-based studies

Replication Pauses of the Wild-Type and Mutant Mitochondrial DNA Polymerase Gamma: A Simulation Study

The activity of polymerase γ is complicated, involving both correct and incorrect DNA polymerization events, exonuclease activity, and the disassociation of the polymerase:DNA complex. Pausing of pol-γ might increase the chance of deletion and depletion of mitochondrial DNA. We have developed a stochastic simulation of pol-γ that models its activities on the level of individual nucleotides for the replication of mtDNA. This method gives us insights into the pausing of two pol-γ variants: the A467T substitution that causes PEO and Alpers syndrome, and the exonuclease deficient pol-γ (exo−) in premature aging mouse models. To measure the pausing, we analyzed simulation results for the longest time for the polymerase to move forward one nucleotide along the DNA strand. Our model of the exo− polymerase had extremely long pauses, with a 30 to 300-fold increase in the time required for the longest single forward step compared to the wild-type, while the naturally occurring A467T variant showed at most a doubling in the length of the pauses compared to the wild-type. We identified the cause of these differences in the polymerase pausing time to be the number of disassociations occurring in each forward step of the polymerase

Dr. PIAS: an integrative system for assessing the druggability of protein-protein interactions

<p>Abstract</p> <p>Background</p> <p>The amount of data on protein-protein interactions (PPIs) available in public databases and in the literature has rapidly expanded in recent years. PPI data can provide useful information for researchers in pharmacology and medicine as well as those in interactome studies. There is urgent need for a novel methodology or software allowing the efficient utilization of PPI data in pharmacology and medicine.</p> <p>Results</p> <p>To address this need, we have developed the 'Druggable Protein-protein Interaction Assessment System' (Dr. PIAS). Dr. PIAS has a meta-database that stores various types of information (tertiary structures, drugs/chemicals, and biological functions associated with PPIs) retrieved from public sources. By integrating this information, Dr. PIAS assesses whether a PPI is druggable as a target for small chemical ligands by using a supervised machine-learning method, support vector machine (SVM). Dr. PIAS holds not only known druggable PPIs but also all PPIs of human, mouse, rat, and human immunodeficiency virus (HIV) proteins identified to date.</p> <p>Conclusions</p> <p>The design concept of Dr. PIAS is distinct from other published PPI databases in that it focuses on selecting the PPIs most likely to make good drug targets, rather than merely collecting PPI data.</p

Ethnic variations in duration of untreated psychosis: report from the CRIS-FEP study

Objectives:  There is inconsistent evidence on the influence of ethnicity on duration of untreated psychosis (DUP). We investigated ethnic differences in DUP in a large epidemiological dataset of first episode psychosis patients in an inner city area of south London, UK. Methods:  We analysed data on 558 first episode psychosis patients at the South London and Maudsley NHS Trust, between 2010 and 2012. We performed multivariable logistic regression to estimate the odds of a short DUP (≤ 6 months) by ethnic group, controlling for confounders. Results:  There was no evidence that ethnicity is associated with duration of untreated psychosis. However, we found evidence that a short DUP was strongly associated with age, living circumstances, and pathways to care variables (involuntary admission, out of office hour contact, accident and emergency referral, criminal justice agency referral and family involvement in help-seeking). Conversely, a long DUP was associated with report of social isolation, living alone, being single and General Practitioner referral. Conclusion:  Our findings suggest that indicators of social isolation were associated with long DUP. Our data also show that pathways into care characteristics play significant role in DUP. Thus, the challenge of tackling the issue of timely access to EI under the new Access and Waiting Time standard for psychosis requires a multilevel approach, including joint working with communities, public awareness of psychosis, less restrictive referral pathways and adequate resourcing of early intervention for psychosis services. These will go a long way in addressing patients’ needs rather than be determined by service structures

Making Informed Choices about Microarray Data Analysis

This article describes the typical stages in the analysis of microarray data for non-specialist researchers in systems biology and medicine. Particular attention is paid to significant data analysis issues that are commonly encountered among practitioners, some of which need wider airing. The issues addressed include experimental design, quality assessment, normalization, and summarization of multiple-probe data. This article is based on the ISMB 2008 tutorial on microarray data analysis. An expanded version of the material in this article and the slides from the tutorial can be found at http://www.people.vcu.edu/~mreimers/OGMDA/index.html

The effects of multi-domain versus single-domain cognitive training in non-demented older people: a randomized controlled trial

<p>Abstract</p> <p>Background</p> <p>Whether healthy older people can benefit from cognitive training (CogTr) remains controversial. This study explored the benefits of CogTr in community dwelling, healthy, older adults and compared the effects of single-domain with multi-domain CogTr interventions.</p> <p>Methods</p> <p>A randomized, controlled, 3-month trial of CogTr with double-blind assessments at baseline and immediate, 6-month and 12-month follow-up after training completion was conducted. A total of 270 healthy Chinese older people, 65 to 75 years old, were recruited from the Ganquan-area community in Shanghai. Participants were randomly assigned to three groups: multi-domain CogTr, single-domain CogTr, and a wait-list control group. Twenty-four sessions of CogTr were administrated to the intervention groups over a three-month period. Six months later, three booster training sessions were offered to 60% of the initial training participants. The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS, Form A), the Color Word Stroop test (CWST), the Visual Reasoning test and the Trail Making test (TMT) were used to assess cognitive function.</p> <p>Results</p> <p>Multi-domain CogTr produced statistically significant training effects on RBANS, visual reasoning, and immediate and delayed memory, while single-domain CogTr showed training effects on RBANS, visual reasoning, word interference, and visuospatial/constructional score (all <it>P </it>< 0.05). At the 12-month posttest, the multi-domain CogTr showed training effects on RBANS, delayed memory and visual reasoning, while single-domain CogTr only showed effects on word interference. Booster training resulted in effects on RBANS, visual reasoning, time of trail making test, and visuospatial/constructional index score.</p> <p>Conclusions</p> <p>Cognitive training can improve memory, visual reasoning, visuospatial construction, attention and neuropsychological status in community-living older people and can help maintain their functioning over time. Multi-domain CogTr enhanced memory proficiency, while single-domain CogTr augmented visuospatial/constructional and attention abilities. Multi-domain CogTr had more advantages in training effect maintenance.</p> <p>Clinical Trial Registration</p> <p>Chinese Clinical Trial Registry. Registration number: ChiCTR-TRC-09000732.</p

Interfering RNA and HIV: Reciprocal Interferences

In this review, a quick presentation of what interfering RNA (iRNA) are—small RNA able to exert an inhibition on gene expression at a posttranscriptional level, based on sequence homology between the iRNA and the mRNA—will be given. The many faces of the interrelations between iRNA and viruses, particularly HIV, will be reviewed. Four kinds of interactions have been described: i) iRNA of viral origin blocking viral RNA, ii) iRNA of viral origin downregulating cellular mRNA, iii) iRNA of cellular origin (microRNA) targeting viral RNA, and iv) microRNA downregulating cellular mRNA encoding cell proteins used by the virus for its replication. Next, HIV strategies to manipulate these interrelations will be considered: suppression of iRNA biosynthesis by Tat, trapping by the HIV TAR sequence of a cell component, TRBP, necessary for iRNA production and action, and induction by the virus of some microRNA together with suppression of others. Then, we will discuss the putative effects of these mutual influences on viral replication as well as on viral latency, immune response, and viral cytopathogenicity. Finally, the potential consequences on the human infection of genetic polymorphisms in microRNA genes and the therapeutic potential of iRNA will be presented

Predictive Value of POSSUM and ACPGBI Scoring in Mortality and Morbidity of Colorectal Resection: A Case–Control Study

Contains fulltext : 97239.pdf (publisher's version ) (Open Access)BACKGROUND: Preoperative risk prediction to assess mortality and morbidity may be helpful to surgical decision making. The aim of this study was to compare mortality and morbidity of colorectal resections performed in a tertiary referral center with mortality and morbidity as predicted with physiological and operative score for enumeration of mortality and morbidity (POSSUM), Portsmouth POSSUM (P-POSSUM), and colorectal POSSUM (CR-POSSUM). The second aim of this study was to analyze the accuracy of different POSSUM scores in surgery performed for malignancy, inflammatory bowel diseases, and diverticulitis. POSSUM scoring was also evaluated in colorectal resection in acute vs. elective setting. In procedures performed for malignancy, the Association of Coloproctology of Great Britain and Ireland (ACPGBI) score was assessed in the same way for comparison. METHODS: POSSUM, P-POSSUM, and CR-POSSUM predictor equations for mortality were applied in a retrospective case-control study to 734 patients who had undergone colorectal resection. The total group was assessed first. Second, the predictive value of outcome after surgery was assessed for malignancy (n = 386), inflammatory bowel diseases (n = 113), diverticulitis (n = 91), and other indications, e.g., trauma, endometriosis, volvulus, or ischemia (n = 144). Third, all subgroups were assessed in relation to the setting in which surgery was performed: acute or elective. In patients with malignancy, the ACPGBI score was calculated as well. In all groups, receiver operating characteristic (ROC) curves were constructed. RESULTS: POSSUM, P-POSSUM, and CR-POSSUM have a significant predictive value for outcome after colorectal surgery. Within the total population as well as in all four subgroups, there is no difference in the area under the curve between the POSSUM, P-POSSUM, and CR-POSSUM scores. In the subgroup analysis, smallest areas under the ROC curve are seen in operations performed for malignancy, which is significantly worse than for diverticulitis and in operations performed for other indications. For elective procedures, P-POSSUM and CR-POSSUM predict outcome significantly worse in patients operated for carcinoma than in patients with diverticulitis. In acute surgical interventions, CR-POSSUM predicts mortality better in diverticulitis than in patients operated for other indications. The ACPGBI score has a larger area under the curve than any of the POSSUM scores. Morbidity as predicted by POSSUM is most accurate in procedures for diverticulitis and worst when the indication is malignancy. CONCLUSION: The POSSUM scores predict outcome significantly better than can be expected by chance alone. Regarding the indication for surgery, each POSSUM score predicts outcome in patients operated for diverticulitis or other indications more accurately than for malignancy. The ACPGBI score is found to be superior to the various POSSUM scores in patients who have (elective) resection of colorectal malignancy