Intimal Hyperplasia in Balloon Dilated Coronary Arteries is Reduced by Local Delivery of the NO Donor, SIN-1 Via a cGMP-Dependent Pathway

<p>Abstract</p> <p>Background</p> <p>To elucidate the mechanism by which local delivery of 3-morpholino-sydnonimine (SIN-1) affects intimal hyperplasia after percutaneous transluminal coronary angioplasty (PTCA).</p> <p>Methods</p> <p>Porcine coronary arteries were treated with PTCA and immediately afterwards locally treated for 5 minutes, with a selective cytosolic guanylate cyclase inhibitor, 1 H-(1,2,4)oxadiazole(4,3-alpha)quinoxaline-1-one (ODQ) + SIN-1 or only SIN-1 using a drug delivery-balloon. Arteries were angiographically depicted, morphologically evaluated and analyzed after one and eight weeks for actin, myosin and intermediate filaments (IF) and nitric oxide synthase (NOS) contents.</p> <p>Results</p> <p>Luminal diameter after PCI in arteries treated with SIN-1 alone and corrected for age-growth was significantly larger as compared to ODQ + SIN-1 or to controls (p < 0.01). IF/actin ratio after one week in SIN-1 treated segments was not different compared to untreated segments, but was significantly reduced compared to ODQ + SIN-1 treated vessels (p < 0.05). Expression of endothelial NADPH diaphorase activity was significantly lower in untreated segments and in SIN-1 treated segments compared to controls and SIN-1 + ODQ treated arteries (p < 0.01). Restenosis index (p < 0.01) and intimal hyperplasia (p < 0.01) were significantly reduced while the residual lumen was increased (p < 0.01) in SIN-1 segments compared to controls and ODQ + SIN-1 treated vessels.</p> <p>Conclusions</p> <p>After PTCA local delivery of high concentrations of the NO donor SIN-1 for 5 minutes inhibited injury induced neointimal hyperplasia. This favorable effect was abolished by inhibition of guanylyl cyclase indicating mediation of a cyclic guanosine 3',5'-monophosphate (cGMP)-dependent pathway. The momentary events at the time of injury play crucial role in the ensuring development of intimal hyperplasia.</p

Can visco-elastic phase separation, macromolecular crowding and colloidal physics explain nuclear organisation?

BACKGROUND: The cell nucleus is highly compartmentalized with well-defined domains, it is not well understood how this nuclear order is maintained. Many scientists are fascinated by the different set of structures observed in the nucleus to attribute functions to them. In order to distinguish functional compartments from non-functional aggregates, I believe is important to investigate the biophysical nature of nuclear organisation. RESULTS: The various nuclear compartments can be divided broadly as chromatin or protein and/or RNA based, and they have very different dynamic properties. The chromatin compartment displays a slow, constrained diffusional motion. On the other hand, the protein/RNA compartment is very dynamic. Physical systems with dynamical asymmetry go to viscoelastic phase separation. This phase separation phenomenon leads to the formation of a long-lived interaction network of slow components (chromatin) scattered within domains rich in fast components (protein/RNA). Moreover, the nucleus is packed with macromolecules in the order of 300 mg/ml. This high concentration of macromolecules produces volume exclusion effects that enhance attractive interactions between macromolecules, known as macromolecular crowding, which favours the formation of compartments. In this paper I hypothesise that nuclear compartmentalization can be explained by viscoelastic phase separation of the dynamically different nuclear components, in combination with macromolecular crowding and the properties of colloidal particles. CONCLUSION: I demonstrate that nuclear structure can satisfy the predictions of this hypothesis. I discuss the functional implications of this phenomenon

Alexithymia may explain the relationship between autistic traits and eating disorder psychopathology

Background: Autistic people are disproportionately vulnerable to anorexia nervosa and other eating disorders (ED), and within the general population, autistic traits correlate with ED psychopathology. A putative mechanism which may underpin this heightened risk is alexithymia, a difficulty identifying and describing emotional states which is observed in both autism and ED. In two experiments with independent non-clinical samples, we explored whether alexithymia might mediate the heightened risk of eating psychopathology in individuals high in autistic traits. Methods: Our first experiment used the PROCESS macro for SPSS to examine relationships between alexithymia (measured by the Toronto Alexithymia Scale (TAS-20)), autistic traits (autism quotient (AQ)), and eating psychopathology (Eating Attitudes Test (EAT-26)) in 121 participants. Our second experiment (n = 300) replicated and furthered this analysis by examining moderating effects of sex and controlling for anxiety and depression as covariates. We also included an additional performance-based measure of alexithymia, the Levels of Emotional Awareness Scale (LEAS). Results: Study 1 suggested that TAS-20 scores mediated the relationship between heightened autistic traits and eating psychopathology. Replication and further scrutiny of this finding, in study 2, revealed that this mediation effect was partial and specific to the female participants in this sample. The mediation effect appeared to be carried by the difficulty identifying feelings subscale of the TAS-20, even when depression and anxiety were controlled for. LEAS scores, however, were not significantly related to autistic traits or eating psychopathology. Limitations: Cross-sectional data prevents any conclusions around the direction and causality of relationships between alexithymia, autistic traits, and eating psychopathology (alongside depression and anxiety), necessitating longitudinal research. Our non-clinical sample was predominantly Caucasian undergraduate students, so it remains to be seen if these results would extrapolate to clinical and/or autistic samples. Divergence between the TAS-20 and LEAS raises crucial questions regarding the construct validity of these measures. Conclusions: Our findings with respect to autistic traits suggest that alexithymia could partially explain the prevalence of ED in autistic people and may as such be an important consideration in the pathogenesis and treatment of ED in autistic and non-autistic people alike. Further research with clinical samples is critical to explore these ideas. Differences between men and women, furthermore, emphasize the importance of looking for sexspecific as well as generic risk factors in autistic and non-autistic men and women

The Human Sweet Tooth

Humans love the taste of sugar and the word "sweet" is used to describe not only this basic taste quality but also something that is desirable or pleasurable, e.g., la dolce vita. Although sugar or sweetened foods are generally among the most preferred choices, not everyone likes sugar, especially at high concentrations. The focus of my group's research is to understand why some people have a sweet tooth and others do not. We have used genetic and molecular techniques in humans, rats, mice, cats and primates to understand the origins of sweet taste perception. Our studies demonstrate that there are two sweet receptor genes (TAS1R2 and TAS1R3), and alleles of one of the two genes predict the avidity with which some mammals drink sweet solutions. We also find a relationship between sweet and bitter perception. Children who are genetically more sensitive to bitter compounds report that very sweet solutions are more pleasant and they prefer sweet carbonated beverages more than milk, relative to less bitter-sensitive peers. Overall, people differ in their ability to perceive the basic tastes, and particular constellations of genes and experience may drive some people, but not others, toward a caries-inducing sweet diet. Future studies will be designed to understand how a genetic preference for sweet food and drink might contribute to the development of dental caries

Competitive Tendering In The Netherlands: Central Planning Or Functional Specifications?

Institute of Transport and Logistics Studies. Faculty of Economics and Business. The University of Sydne

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency–Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research