A general modeling and visualization tool for comparing different members of a group: application to studying tau-mediated regulation of microtubule dynamics

<p>Abstract</p> <p>Background</p> <p>Innumerable biological investigations require comparing collections of molecules, cells or organisms to one another with respect to one or more of their properties. Almost all of these comparisons are performed manually, which can be susceptible to inadvertent bias as well as miss subtle effects. The development and application of computer-assisted analytical and interpretive tools could help address these issues and thereby dramatically improve these investigations.</p> <p>Results</p> <p>We have developed novel computer-assisted analytical and interpretive tools and applied them to recent studies examining the ability of 3-repeat and 4-repeat tau to regulate the dynamic behavior of microtubules in vitro. More specifically, we have developed an automated and objective method to define growth, shortening and attenuation events from real time videos of dynamic microtubules, and demonstrated its validity by comparing it to manually assessed data. Additionally, we have used the same data to develop a general strategy of building different models of interest, computing appropriate dissimilarity functions to compare them, and embedding them on a two-dimensional plot for visualization and easy comparison. Application of these methods to assess microtubule growth rates and growth rate distributions established the validity of the embedding procedure and revealed non-linearity in the relationship between the tau:tubulin molar ratio and growth rate distribution.</p> <p>Conclusion</p> <p>This work addresses the need of the biological community for rigorously quantitative and generally applicable computational tools for comparative studies. The two-dimensional embedding method retains the inherent structure of the data, and yet markedly simplifies comparison between models and parameters of different samples. Most notably, even in cases where numerous parameters exist by which to compare the different samples, our embedding procedure provides a generally applicable computational strategy to detect subtle relationships between different molecules or conditions that might otherwise escape manual analyses.</p

Breast cancer stroma frequently recruits fetal derived cells during pregnancy

Breast carcinomas associated with pregnancy display a high frequency of inflammatory types, multifocal lesions and lymph node metastasis. Because pregnancy results in transfer to mothers of foetal stem cells that can migrate and differentiate into various tissues, we addressed the issue of whether such cells are present in breast carcinoma associated with pregnancy

Variants in genes encoding small GTPases and association with epithelial ovarian cancer susceptibility

Epithelial ovarian cancer (EOC) is the fifth leading cause of cancer mortality in American women. Normal ovarian physiology is intricately connected to small GTP binding proteins of the Ras superfamily (Ras, Rho, Rab, Arf, and Ran) which govern processes such as signal transduction, cell proliferation, cell motility, and vesicle transport. We hypothesized that common germline variation in genes encoding small GTPases is associated with EOC risk. We investigated 322 variants in 88 small GTPase genes in germline DNA of 18,736 EOC patients and 26,138 controls of European ancestry using a custom genotype array and logistic regression fitting log-additive models. Functional annotation was used to identify biofeatures and expression quantitative trait loci that intersect with risk variants. One variant, ARHGEF10L (Rho guanine nucleotide exchange factor 10 like) rs2256787, was associated with increased endometrioid EOC risk (OR=1.33, p=4.46 x 10-6). Other variants of interest included another in ARHGEF10L, rs10788679, which was associated with invasive serous EOC risk (OR=1.07, p=0.00026) and two variants in AKAP6 (A-kinase anchoring protein 6) which were associated with risk of invasive EOC (rs1955513, OR=0.90, p=0.00033; rs927062, OR =0.94, p=0.00059). Functional annotation revealed that the two ARHGEF10L variants were located in super-enhancer regions and that AKAP6 rs927062 was associated with expression of GTPase gene ARHGAP5 (Rho GTPase activating protein 5). Inherited variants in ARHGEF10L and AKAP6, with potential transcriptional regulatory function and association with EOC risk, warrant investigation in independent EOC study populations

Contrasting effects of defaunation on aboveground carbon storage across the global tropics

Defaunation is causing declines of large-seeded animal-dispersed trees in tropical forests worldwide, but whether and how these declines will affect carbon storage across this biome is unclear. Here we show, using a pan-tropical dataset, that simulated declines of large-seeded animal-dispersed trees have contrasting effects on aboveground carbon stocks across Earth’s tropical forests. In our simulations, African, Neotropical and South Asian forests which have high proportions of animal-dispersed species consistently show carbon losses (2-12%), but Southeast Asian and Australian forests where there are more abiotically-dispersed species show little to no carbon losses or marginal gains (±1%). These patterns result primarily from changes in wood volume, and are underlain by consistent relationships in our empirical data (~2100 species), wherein, large-seeded animal-dispersed species are larger as adults than small-seeded animal-dispersed species, but are smaller than abiotically-dispersed species. Thus, floristic differences and distinct dispersal mode-seed size-adult size combinations can drive contrasting regional responses to defaunation

Depression and 5-year mortality in patients with acute myocardial infarction: Analysis of the IDACC database

Objective: Symptoms of depression are highly prevalent and persistent following myocardial infarction (MI). Whether depression is a risk factor for long-term mortality following MI remains controversial. The present study aimed to determine whether depression during hospitalisation for acute MI (AMI) predicted 5-year all-cause or cardiac mortality. Method: This study utilised the Identifying Depression as a Comorbid Condition (IDACC) database of 337 hospitalised patients with AMI. Depressive symptoms were assessed using the Center for Epidemiologic Studies Depression scale (CES-D). Data were linked to a government administrative death registry to determine 5-year mortality. Survival data were analysed using Cox’s proportional hazards model. Results: The mean age during AMI hospitalisation was 59 years ± 12, 74% of patients were men and depression (CES-D ≥ 16) was present in 132 patients (39.3%). The 5-year all-cause mortality rate was 10.4% (35 deaths) and the cardiac mortality rate was 6.5% (22 deaths). When depression was defined as a dichotomous variable, moderate to severe depression (defined by CES-D ≥ 27) at the time of AMI was associated with all-cause mortality (hazard ratio 2.54, 95% confidence interval 1.03 to 6.28; p = 0.04) but not cardiac mortality. However, when depression was defined by three categories (no depression CES-D < 16, mild depression CES-D 16–26, moderate to severe depression CES-D ≥ 27), it was not found to predict mortality. In addition, perceived social support was a predictor of all-cause and cardiac mortality in AMI patients. Conclusions: Our results indicate that the relationship between mortality and depression severity is not linear and that the association only becomes evident when the severity reaches a threshold level of CES-D ≥ 27, consistent with major depression. Low power may have influenced the finding of a lack of association between depression and cardiac mortality.Alexis Wheeler, John Beltrame, Graeme Tucker, Tracy Air, Liang-Han Ling and Geoffrey Schrade

Sociodemographic predictors and reasons for participation in an outpatient cardiac rehabilitation programme following percutaneous coronary intervention

Evidence-based guidelines recommend participation in cardiac rehabilitation (CR) to reduce subsequent cardiovascular events following percutaneous coronary intervention (PCI). The objective of this study was to investigate the reasons for the demographic characteristics of patients who participate in CR Programmes following PCI in a single metropolitan setting in Australia. Logistic regression models were used to examine the data obtained using self-reports through mailed questionnaires from 202 patients 12-24 months following the index PCI. Thirty-five percent of subjects reported to have participated in CR programmes, of whom less than a quarter were female. In this sample the main reason for programme participation was a recommendation given by the general practitioner (GP). The likelihood of participating in a CR programme decreased with age and absence of a partner. Additional research on determinants of participation in CR programmes among this cohort of patients could assist in the development of new strategies to encourage healthy behaviours and reduce the risk of further cardiac events