Left ventricular torsional mechanics and myocardial iron load in beta-thalassaemia major: a potential role of titin degradation

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Dynamic dyssynchrony and impaired contractile reserve of the left ventricle in beta-thalassaemia major: an exercise echocardiographic study

BACKGROUND: Performance of the left ventricle during exercise stress in thalassaemia patients is uncertain. We aimed to explore the phenomenon of dynamic dyssynchrony and assess contractile reserve in patients with beta-thalassaemia major and determine their relationships with myocardial iron load. METHODS AND RESULTS: Thirty-two thalassaemia patients (16 males), aged 26.8+/-6.9 years, without heart failure and 17 healthy controls were studied. Their left ventricular (LV) volumes, ejection fraction, systolic dyssynchrony index (SDI), and myocardial acceleration during isovolumic LV contraction (IVA) were determined at rest and during submaximal bicycle exercise testing using 3-dimensional and tissue Doppler echocardiography. Myocardial iron load as assessed by T2* cardiac magnetic resonance in patients were further related to indices of LV dyssynchrony and contractile reserve. At rest, patients had significantly greater LV SDI (p4.6%, control+2SD) increased from baseline 25% to 84% in patients. Delta SDI(exercise-baseline) correlated with exercise-baseline differences in LV ejection fraction (p<0.001) and stroke volume (p = 0.006). Compared with controls, patients had significantly less exercise-induced increase in LV ejection fraction, cardiac index, and IVA (interaction, all p<0.05) and had impaired contractile reserve as reflected by the gentler IVA-heart rate slope (p = 0.018). Cardiac T2* in patients correlated with baseline LV SDI (r = -0.44, p = 0.011) and IVA-heart rate slope (r = 0.36, p = 0.044). CONCLUSIONS: Resting LV dyssynchrony is associated with myocardial iron load. Exercise stress further unveils LV dynamic dyssynchrony and impaired contractile reserve in patients with beta-thalassaemia major.published_or_final_versio

Fitness Ranking of Individual Mutants Drives Patterns of Epistatic Interactions in HIV-1

This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

A novel class of microRNA-recognition elements that function only within open reading frames.

MicroRNAs (miRNAs) are well known to target 3' untranslated regions (3' UTRs) in mRNAs, thereby silencing gene expression at the post-transcriptional level. Multiple reports have also indicated the ability of miRNAs to target protein-coding sequences (CDS); however, miRNAs have been generally believed to function through similar mechanisms regardless of the locations of their sites of action. Here, we report a class of miRNA-recognition elements (MREs) that function exclusively in CDS regions. Through functional and mechanistic characterization of these 'unusual' MREs, we demonstrate that CDS-targeted miRNAs require extensive base-pairing at the 3' side rather than the 5' seed; cause gene silencing in an Argonaute-dependent but GW182-independent manner; and repress translation by inducing transient ribosome stalling instead of mRNA destabilization. These findings reveal distinct mechanisms and functional consequences of miRNAs that target CDS versus the 3' UTR and suggest that CDS-targeted miRNAs may use a translational quality-control-related mechanism to regulate translation in mammalian cells

A Brief Update on the CMZoom Survey

The inner few hundred parsecs of the Milky Way, the Central Molecular Zone (CMZ), is our closest laboratory for understanding star formation in the extreme environments (hot, dense, turbulent gas) that once dominated the universe. We present an update on the first large-area survey to expose the sites of star formation across the CMZ at high-resolution in submillimeter wavelengths: the CMZoom survey with the Submillimeter Array (SMA). We identify the locations of dense cores and search for signatures of embedded star formation. CMZoom is a three-year survey in its final year and is mapping out the highest column density regions of the CMZ in dust continuum and a variety of spectral lines around 1.3 mm. CMZoom combines SMA compact and subcompact configurations with single-dish data from BGPS and the APEX telescope, achieving an angular resolution of about 4" (0.2 pc) and good image fidelity up to large spatial scales

Star formation in a high-pressure environment: An SMA view of the Galactic centre dust ridge

The star formation rate in the Central Molecular Zone (CMZ) is an order of magnitude lower than predicted according to star formation relations that have been calibrated in the disc of our own and nearby galaxies. Understanding how and why star formation appears to be different in this region is crucial if we are to understand the environmental dependence of the star formation process. Here, we present the detection of a sample of high-mass cores in the CMZ's "dust ridge" that have been discovered with the Submillimeter Array as part of the CMZoom survey. These cores range in mass from ~ 50 - 2150 Msun within radii of 0.1 - 0.25 pc. All appear to be young (pre-UCHII), meaning that they are prime candidates for representing the initial conditions of high-mass stars and sub-clusters. We report that at least two of these cores ('c1' and 'e1') contain young, high-mass protostars. We compare all of the detected cores with high-mass cores in the Galactic disc and find that they are broadly similar in terms of their masses and sizes, despite being subjected to external pressures that are several orders of magnitude greater - ~ 10^8 K/cm^3, as opposed to ~ 10^5 K/cm^3. The fact that > 80% of these cores do not show any signs of star-forming activity in such a high-pressure environment leads us to conclude that this is further evidence for an increased critical density threshold for star formation in the CMZ due to turbulence

A new conceptual approach for systematic error correction in CNC machine tools minimizing worst case prediction error

A new artifact-based method to identify the systematic errors in multi-axis CNC machine tools minimizing the worst case prediction error is presented. The closed loop volumetric error is identified by simultaneously moving the axes of the machine tool. The physical artifact is manufactured on the machine tool and later measured on a coordinate measuring machine. The artifact consists of a set of holes in the machine tool workspace at locations that minimize the worst case prediction error for a given bounded measurement error. The number of holes to be drilled depends on the degree of the polynomials used to model the systematic error and the number of axes of the machine tool. The prediction error is also function of the number and location of the holes. The feasibility of the method is first investigated for a two-axis machine to find the best experimental setting. Finally based on the two-axis case study, we extend the results to machine tools with any number of axes. The obtained results are very promising and require only a short time to produce the artifac

Gravitational Waves from Gravitational Collapse

Gravitational wave emission from the gravitational collapse of massive stars has been studied for more than three decades. Current state of the art numerical investigations of collapse include those that use progenitors with realistic angular momentum profiles, properly treat microphysics issues, account for general relativity, and examine non--axisymmetric effects in three dimensions. Such simulations predict that gravitational waves from various phenomena associated with gravitational collapse could be detectable with advanced ground--based and future space--based interferometric observatories.Comment: 68 pages including 13 figures; revised version accepted for publication in Living Reviews in Relativity (http://www.livingreviews.org

Novel facultative Methylocella strains are active methane consumers at terrestrial natural gas seeps

Natural gas seeps contribute to global climate change by releasing substantial amounts of the potent greenhouse gas methane and other climate-active gases including ethane and propane to the atmosphere. However, methanotrophs, bacteria capable of utilising methane as the sole source of carbon and energy, play a significant role in reducing the emissions of methane from many environments. Methylocella-like facultative methanotrophs are a unique group of bacteria that grow on other components of natural gas (i.e. ethane and propane) in addition to methane but a little is known about the distribution and activity of Methylocella in the environment. The purposes of this study were to identify bacteria involved in cycling methane emitted from natural gas seeps and, most importantly, to investigate if Methylocella-like facultative methanotrophs were active utilisers of natural gas at seep sites

Molecular Interactions of Prodiginines with the BH3 Domain of Anti-Apoptotic Bcl-2 Family Members

Prodigiosin and obatoclax, members of the prodiginines family, are small molecules with anti-cancer properties that are currently under preclinical and clinical trials. The molecular target(s) of these agents, however, is an open question. Combining experimental and computational techniques we find that prodigiosin binds to the BH3 domain in some BCL-2 protein families, which play an important role in the apoptotic programmed cell death. In particular, our results indicate a large affinity of prodigiosin for MCL-1, an anti-apoptotic member of the BCL-2 family. In melanoma cells, we demonstrate that prodigiosin activates the mitochondrial apoptotic pathway by disrupting MCL-1/BAK complexes. Computer simulations with the PELE software allow the description of the induced fit process, obtaining a detailed atomic view of the molecular interactions. These results provide new data to understand the mechanism of action of these molecules, and assist in the development of more specific inhibitors of anti-apoptotic BCL-2 proteins.Spanish government and the European Union (FIS-PI10/00338) and from the ERC-2009-Adg 25027-PELE European project