QSAR study of quinolinediones with inhibitory activity of endothelium-dependent vasorelaxation by CoMSIA

The 3D-QSAR study of quinolinediones which showed potent inhibitory effect on the acetylcholine induced vasorelaxation of rat aorta with the endothelium was conducted by CoMSIA. The statistical result, cross-validated q(2) (0.741) and r(2) (0.960) values, gave reliability to the prediction of inhibitory activity of this series.     

Improved RSA accuracy with DLT and balanced calibration marker distributions with an assessment of initial-calibration

Roentgen stereophotogrammetric analysis (RSA) has been used for over 25 years for accurate micromotion measurement in a wide variety of orthopaedic applications. This study investigated two possible improvements to the method. First, direct linear transformation (DLT) was compared to the traditional RSA reconstruction algorithm. The two methods were considered with respect to standard extrapolation and interpolation calibration cages. Matlab simulations showed that reconstruction accuracy was greatly improved (>60%) by combining DLT with an even distribution of enclosing calibration markers. Second, a benchtop study using phantoms translated at 0.0254-mm intervals showed initial-calibration, followed by removal of the interpolation cage for subsequent exposures, was potentially twice as accurate as self-calibration with an extrapolation cage. These results showed optimizations for the application of RSA when unobstructed space is required.     

External Validation and Evaluation of Reliability and Validity of the S-ReSC Scoring System to Predict Stone-Free Status after Percutaneous Nephrolithotomy

Objectives

The Seoul National University Renal Stone Complexity (S-ReSC) scoring system was developed to predict the stone-free rate (SFR) after single-tract percutaneous nephrolithotomy (PCNL). This study is an external validation of this scoring system.

Materials and methods

A retrospective review included 327 patients who underwent PCNL at 2 tertiary referral centers. The S-ReSC score was assigned from 1 to 9 based on the number of sites involved. The stone free status was defined as either complete clearance or clinically insignificant residual fragments <4 mm in size at 1 month follow-up imaging. Inter-observer and test-retest reliabilities were evaluated. The statistical performance of the prediction model was assessed by its predictive accuracy, predictive probability, and clinical usefulness.

Results

The overall SFR was 65.4%. SFRs were 83.9%, 47.6%, and 21.4% in low (1–2), intermediate (3–4), and high (5–9) score groups, respectively, with significant differences (P<0.001). Inter-observer and test-retest reliabilities revealed almost perfect agreements. External validation of the S-ReSC scoring system revealed an AUC of 0.731 (95% CI 0.675–0.788). The AUC of 3-titered S-ReSC score groups was 0.691 (95% CI, 0.629–0.753). The calibration plot showed that the predicted probability of SFR had a concordance comparable to that of the observed frequency. The Hosmer–Lemeshow goodness-of-fit statistic revealed an adequate performance of the predictive model (P = 0.10). Inter-observer and test-retest reliability showed a good level of agreement.

Conclusions

The S-ReSC scoring system is useful in predicting the post-PCNL SFR and in describing the complexity of renal stones.     

MicroRNA-5p and -3p co-expression and cross-targeting in colon cancer cells

Background

Two mature miRNA species may be generated from the 5’ and 3’ arms of a pre-miRNA precursor. In most cases, only one species remains while the complementary species is degraded. However, co-existence of miRNA-5p and -3p species is increasingly being reported. In this work, we aimed to systematically investigate co-expression of miRNA-5p/3p in colon cancer cells in a genome-wide analysis, and to examine cross-targeting of the dysregulated miRNAs and 5p/3p species.

Results

Four colon cancer cell lines were examined relative to two normal colon tissues. Of the 1,190 miRNAs analyzed, 92 and 36 were found to be up- or down-regulated, respectively, in cancer cells. Nineteen co-expressed miRNA-5p/3p pairs were further identified suggesting frequent 5p/3p co-accumulation in colon cancer cells. Of these, 14 pairs were co-up-regulated and 3 pairs were co-down-regulated indicating concerted 5p/3p dysregulation. Nine dysregulated miRNA pairs fell into three miRNA gene families, namely let-7, mir-8/200 and mir-17, which showed frequent cross-targeting in the metastasis process. Focusing on the let-7d-5p/3p pair, the respectively targeted IGF1R and KRAS were shown to be in a reverse relationship with expression of the respective miRNA, which was confirmed in transient transfection assays using let-7d mimic or inhibitor. Targeting of KRAS by let-7d was previous reported; targeting of IGF1R by let-7d-5p was confirmed in luciferase assays in this study. The findings of let-7d-5p/3p and multiple other miRNAs targeting IGF1R, KRAS and other metastasis-related factors suggest that 5p/3p miRNAs contribute to cross-targeting of multiple cancer-associated factors and processes possibly to evade functional abolishment when any one of the crucial factors are inactivated.

Conclusions

miRNA-5p/3p species are frequently co-expressed and are coordinately regulated in colon cancer cells. In cancer cells, multiple cross-targeting by the miRNAs, including the co-existing 5p/3p species, frequently occurs in an apparent safe-proof scheme of miRNA regulation of important tumorigenesis processes. Further systematic analysis of co-existing miRNA-5p/3p pairs in clinical tissues is important in elucidating 5p/3p contributions to cancer pathogenesis.

Electronic supplementary material

The online version of this article (doi:10.1186/s12929-014-0095-x) contains supplementary material, which is available to authorized users.     

Non-Invasive Clinical Parameters for the Prediction of Urodynamic Bladder Outlet Obstruction: Analysis Using Causal Bayesian Networks

Purpose

To identify non-invasive clinical parameters to predict urodynamic bladder outlet obstruction (BOO) in patients with benign prostatic hyperplasia (BPH) using causal Bayesian networks (CBN).

Subjects and Methods

From October 2004 to August 2013, 1,381 eligible BPH patients with complete data were selected for analysis. The following clinical variables were considered: age, total prostate volume (TPV), transition zone volume (TZV), prostate specific antigen (PSA), maximum flow rate (Qmax), and post-void residual volume (PVR) on uroflowmetry, and International Prostate Symptom Score (IPSS). Among these variables, the independent predictors of BOO were selected using the CBN model. The predictive performance of the CBN model using the selected variables was verified through a logistic regression (LR) model with the same dataset.

Results

Mean age, TPV, and IPSS were 6.2 (±7.3, SD) years, 48.5 (±25.9) ml, and 17.9 (±7.9), respectively. The mean BOO index was 35.1 (±25.2) and 477 patients (34.5%) had urodynamic BOO (BOO index ≥40). By using the CBN model, we identified TPV, Qmax, and PVR as independent predictors of BOO. With these three variables, the BOO prediction accuracy was 73.5%. The LR model showed a similar accuracy (77.0%). However, the area under the receiver operating characteristic curve of the CBN model was statistically smaller than that of the LR model (0.772 vs. 0.798, p = 0.020).

Conclusions

Our study demonstrated that TPV, Qmax, and PVR are independent predictors of urodynamic BOO.     

Effects of temperature on the production of hydrogen peroxide and volatile halocarbons by brackish-water algae

Marine algae produce volatile halocarbons, which have an ozone-depleting potential. The formation of these compounds is thought to be related to oxidative stress, involving H2O2 and algal peroxidases. In our study we found strong correlations between the releases of H2O2 and brominated and some iodinated compounds to the seawater medium, but no such correlation was found for CHCl3, suggesting the involvement of other formation mechanisms as well. Little is known about the effects of environmental factors on the production of volatile halocarbons by algae and in the present study we focused on the influence of temperature. Algae were sampled in an area of the brackish Baltic Sea that receives thermal discharge, allowing us to collect specimens of the same species that were adapted to different field temperature regimes. We exposed six algal species (the diatom Pleurosira laevis, the brown alga Fucus vesiculosus and four filamentous green algae, Cladophora glomerata, Enteromorpha ahlneriana, E. flexuosa and E. intestinalis) to temperature changes of 0-11 degrees C under high irradiation to invoke oxidative stress. The production rates, as well as the quantitative composition of 16 volatile halocarbons, were strongly species-dependent and different types of responses to temperature were recorded. However, no response patterns to temperature change were found that were consistent for all species or for all halocarbons. We conclude that the production of certain halocarbons may increase with temperature in certain algal species, but that the amount and composition of the volatile halocarbons released by algal communities are probably more affected by temperature-associated species shifts. These results may have implications for climatic change scenarios.     

Human Embryonic Stem Cell Technology: Large Scale Cell Amplification and Differentiation

Embryonic stem cells (ESC) hold the promise of overcoming many diseases as potential sources of, for example, dopaminergic neural cells for Parkinson’s Disease to pancreatic islets to relieve diabetic patients of their daily insulin injections. While an embryo has the innate capacity to develop fully functional differentiated tissues; biologists are finding that it is much more complex to derive singular, pure populations of primary cells from the highly versatile ESC from this embryonic parent. Thus, a substantial investment in developing the technologies to expand and differentiate these cells is required in the next decade to move this promise into reality. In this review we document the current standard assays for characterising human ESC (hESC), the status of ‘defined’ feeder-free culture conditions for undifferentiated hESC growth, examine the quality controls that will be required to be established for monitoring their growth, review current methods for expansion and differentiation, and speculate on the possible routes of scaling up the differentiation of hESC to therapeutic quantities.     

Hydrogen metabolism in Shewanella oneidensis MR-1

Shewanella oneidensis MR-1 is a facultative sediment microorganism which uses diverse compounds, such as oxygen and fumarate, as well as insoluble Fe(III) and Mn(IV) as electron acceptors. The electron donor spectrum is more limited and includes metabolic end products of primary fermenting bacteria, such as lactate, formate, and hydrogen. While the utilization of hydrogen as an electron donor has been described previously, we report here the formation of hydrogen from pyruvate under anaerobic, stationary-phase conditions in the absence of an external electron acceptor. Genes for the two S. oneidensis MR-1 hydrogenases, hydA, encoding a periplasmic [Fe-Fe] hydrogenase, and hyaB, encoding a periplasmic [Ni-Fe] hydrogenase, were found to be expressed only under anaerobic conditions during early exponential growth and into stationary-phase growth. Analyses of DeltahydA, DeltahyaB, and DeltahydA DeltahyaB in-frame-deletion mutants indicated that HydA functions primarily as a hydrogen-forming hydrogenase while HyaB has a bifunctional role and represents the dominant hydrogenase activity under the experimental conditions tested. Based on results from physiological and genetic experiments, we propose that hydrogen is formed from pyruvate by multiple parallel pathways, one pathway involving formate as an intermediate, pyruvate-formate lyase, and formate-hydrogen lyase, comprised of HydA hydrogenase and formate dehydrogenase, and a formate-independent pathway involving pyruvate dehydrogenase. A reverse electron transport chain is potentially involved in a formate-hydrogen lyase-independent pathway. While pyruvate does not support a fermentative mode of growth in this microorganism, pyruvate, in the absence of an electron acceptor, increased cell viability in anaerobic, stationary-phase cultures, suggesting a role in the survival of S. oneidensis MR-1 under stationary-phase conditions.