Iron regulatory protein 1 (IRP-1) is a bifunctional protein involved in iron homeostasis and metabolism. In one state, it binds to specific sequences in the mRNA's of several proteins involved in iron and energy metabolism, thereby influencing their expression post-transcriptionally. In another state it contains a [4Fe-4S] iron-sulfur cofactor and displays aconitase activity in the cytosol. We have shown that this protein binds and hydrolyzes ATP, with kinetic and thermodynamic equilibrium constants that predict saturation with ATP, favouring a non-RNA-binding form at normal cellular ATP levels, and thus pointing to additional function(s) of the protein. Here we show for the first time that the RNA-binding and aconitase forms of IRP-1 can undergo interconversion dependent on the density of cells growing in culture. Thus, in high density confluent cultures, compared with low density, actively proliferating cultures, cytosolic aconitase activity is increased whereas RNA binding activity is diminished. This is accompanied by a decrease in transferrin receptor expression in confluent cells, possibly due to loss of the transcript-stabilizing activity of bound IRP-1. In high density HepG2 cultures, cytosolic glutamate and the ratio of reduced-to-oxidized glutathione were increased. We propose that increased cytosolic aconitase activity in confluent cultures may divert cytosolic citrate away from the fatty acid/membrane synthetic pathways required by dividing cells, into a glutamate-dependent maintenance of cellular macromolecular synthesis. In addition, this may confer additional protection from oxidative stress due to down-regulation of iron acquisition from transferrin and increased glutamate for glutathione synthesis.

BACKGROUND: Accurate assessment of right ventricular (RV) size (RVS) and RV systolic function (RVSF) is vital in the management of various conditions, but their assessment is challenging using echocardiography. The aim of this study was to determine the accuracy and interobserver concordance of qualitative and quantitative RV echocardiography. METHODS: Fifteen readers evaluated RV function in 12 patients (360 readings) who underwent echocardiography and cardiac magnetic resonance for RV assessment. Readers qualitatively estimated RVS and RVSF as normal, mild, moderate, or severe and then reassessed quantitatively by adding RV dimensions, fractional area change, S', tricuspid annular plane systolic excursion, and RV index of myocardial performance. Cardiac magnetic resonance was used as the reference standard for grading RVS and RVSF. RESULTS: Quantitative measurements increased accuracy and interreader agreement compared to qualitative assessment alone, especially in normal categories. Readers' accuracy for diagnosing normal and severe RVS increased from 38% to 78%(P =.001) and from 70% to 97%(P =.018), and readers' accuracy for diagnosing normal and mild RVSF increased from 52% to 84%(P <.001) and from 36% to 56%(P =.001). Interreader agreement for classification of the subjects as normal or abnormal improved from a κ value of 0.40 to 0.77 (fair to good agreement) for RVS and from 0.43 to 0.66 (moderate to good agreement) for RVSF. CONCLUSIONS: Visual estimation of RVS and RVSF is inaccurate and has wide interobserver variability. Quantitation improves accuracy and reliability, especially in distinction of normal and abnormal. The reliability of mild and moderate grades remains inadequate, and further guidance is needed for the classification of abnormal categories.

The blood vessels of cancerous tumours are leaky and poorly organized. This can increase the interstitial fluid pressure inside tumours and reduce blood supply to them, which impairs drug delivery. Anti-angiogenic therapies-which 'normalize' the abnormal blood vessels in tumours by making them less leaky-have been shown to improve the delivery and effectiveness of chemotherapeutics with low molecular weights, but it remains unclear whether normalizing tumour vessels can improve the delivery of nanomedicines. Here, we show that repairing the abnormal vessels in mammary tumours, by blocking vascular endothelial growth factor receptor-2, improves the delivery of smaller nanoparticles (diameter, 12 nm) while hindering the delivery of larger nanoparticles (diameter, 125 nm). Using a mathematical model, we show that reducing the sizes of pores in the walls of vessels through normalization decreases the interstitial fluid pressure in tumours, thus allowing small nanoparticles to enter them more rapidly. However, increased steric and hydrodynamic hindrances, also associated with smaller pores, make it more difficult for large nanoparticles to enter tumours. Our results further suggest that smaller (∼12 nm) nanomedicines are ideal for cancer therapy due to their superior tumour penetration.

OBJECTIVE We sought to compare image quality, contrast enhancement, and radiation dose in patients undergoing ECG-triggered high-pitch helical CT or non-ECG-synchronized helical CT of the thoracoabdominal aorta. MATERIALS AND METHODS We retrospectively assessed data from 101 consecutive patients (81 men, 20 women; mean age, 71 ± 11 [SD] years) undergoing clinically indicated CT angiography (CTA) of the thoracoabdominal aorta on a dual-source scanner using either the ECG-triggered high-pitch helical mode (group 1, n = 52) or non-ECG-synchronized standard-pitch helical mode (group 2, n = 49) during the arterial phase. Two independent readers assessed image quality, noise, and contrast enhancement throughout the thoracoabdominal aorta. Scanner-reported dose-length product values were used to estimate effective dose values. RESULTS Image quality at the root-proximal ascending level was higher in group 1 (mean ± SD, 2.81 ± 0.40) than in group 2 (1.22 ± 0.47; p < 0.0001), with similar quality for both groups noted at other levels. Group 1 scans displayed higher image noise at all levels. The groups received a similar volume of contrast material (p = 0.77), and similar percentages of cases with acceptable contrast enhancement (> 250 HU) were noted in the two groups. The estimated radiation burden was significantly lower in group 1 (mean ± SD, 5.4 ± 1.8 mSv) than in group 2 (14.4 ± 5.1 mSv; p < 0.0001). CONCLUSION Imaging of the thoracoabdominal aorta with ECG-triggered high-pitch CTA provides higher quality images of the aortic root and ascending aorta with sufficient contrast enhancement and decreased estimated radiation dose compared with non-ECG-synchronized standard-pitch helical CT.

The phonon properties of CoSb(2) have been investigated by Raman scattering spectroscopy and lattice dynamics calculations. Sixteen out of eighteen Raman active modes predicted by factor-group analysis are experimentally observed and assigned. The calculated and measured phonon energies at the Γ point are in very good agreement. The temperature dependence of the A(g) symmetry modes is well represented by phonon-phonon interactions without contribution from any other phonon or electron related interactions.

Thrombospondin-4 (TSP-4) expression increases dramatically in hypertrophic and failing hearts in rodent models and in humans. The aim of this study was to address the function of TSP-4 in the heart. TSP-4-knockout (Thbs4(-)(/)(-)) and wild-type (WT) mice were subjected to transverse aortic constriction (TAC) to increase left ventricle load. After 2 wk, Thbs4(-)(/)(-) mice had a significantly higher heart weight/body weight ratio than WT mice. The additional increase in the heart weight in TAC Thbs4(-)(/)(-) mice was due to increased deposition of extracellular matrix (ECM). The levels of interstitial collagens were higher in the knockout mice, but the size of cardiomyocytes and apoptosis in the myocardium was unaffected by TSP-4 deficiency, suggesting that increased reactive fibrosis was the primary cause of the higher heart weight. The increased ECM deposition in Thbs4(-)(/)(-) mice was accompanied by changes in functional parameters of the heart and decreased vessel density. The expression of inflammatory and fibrotic genes known to be influential in myocardial remodeling changed as a result of TSP-4 deficiency in vivo and as a result of incubation of cells with recombinant TSP-4 in vitro. Thus, TSP-4 is involved in regulating the adaptive responses of the heart to pressure overload, suggesting its important role in myocardial remodeling. Our study showed a direct influence of TSP-4 on heart function and to identify the mechanism of its effects on heart remodeling.-Frolova, E. G., Sopko, N., Blech, L., Popović, Z. B., Li, J., Vasanji, A., Drumm, C., Krukovets, I., Jain, M. K., Penn, M. S., Plow, E. F., Stenina, O. I. Thrombospondin-4 regulates fibrosis and remodeling of the myocardium in response to pressure overload.