Pilot study using 3D–longitudinal strain computation in a multi-parametric approach for best selecting responders to cardiac resynchronization therapy

Background

Almost all attempts to improve patient selection for cardiac resynchronization therapy (CRT) using echo-derived indices have failed so far. We sought to assess: the performance of homemade software for the automatic quantification of integral 3D regional longitudinal strain curves exploring left ventricular (LV) mechanics and the potential value of this tool to predict CRT response.

Methods

Forty-eight heart failure patients in sinus rhythm, referred for CRT-implantation (mean age: 65 years; LV-ejection fraction: 26%; QRS-duration: 160 milliseconds) were prospectively explored. Thirty-four patients (71%) had positive responses, defined as an LV end-systolic volume decrease ≥15% at 6-months. 3D–longitudinal strain curves were exported for analysis using custom-made algorithms. The integrals of the longitudinal strain signals (I _L,peak) were automatically measured and calculated for all 17 LV-segments.

Results

The standard deviation of longitudinal strain peak (SDI _L,peak ) for all 17 LV-segments was greater in CRT responders than non-responders (1.18% s^?1 [0.96; 1.35] versus 0.83% s^?1 [0.55; 0.99], p = 0.007). The optimal cut-off value of SDI _L,peak to predict response was 1.037%.s^?1. In the 18-patients without septal flash, SDI _L,peak was significantly higher in the CRT-responders.

Conclusions

This new automatic software for analyzing 3D longitudinal strain curves is avoiding previous limitations of imaging techniques for assessing dyssynchrony and then its value will have to be tested in a large group of patients.

     

Trehalose 6‐phosphate is involved in triggering axillary bud outgrowth in garden pea (Pisum sativum L.)

Trehalose 6‐phosphate (Tre6P) is a signal of sucrose availability in plants, and has been implicated in the regulation of shoot branching by the abnormal branching phenotypes of Arabidopsis (Arabidopsis thaliana) and maize (Zea mays) mutants with altered Tre6P metabolism. Decapitation of garden pea (Pisum sativum) plants has been proposed to release the dormancy of axillary buds lower down the stem due to changes in sucrose supply, and we hypothesized that this response is mediated by Tre6P. Decapitation led to a rapid and sustained rise in Tre6P levels in axillary buds, coinciding with the onset of bud outgrowth. This response was suppressed by simultaneous defoliation that restricts the supply of sucrose to axillary buds in decapitated plants. Decapitation also led to a rise in amino acid levels in buds, but a fall in phosphoenolpyruvate and 2‐oxoglutarate. Supplying sucrose to stem node explants in vitro triggered a concentration‐dependent increase in the Tre6P content of the buds that was highly correlated with their rate of outgrowth. These data show that changes in bud Tre6P levels are correlated with initiation of bud outgrowth following decapitation, suggesting that Tre6P is involved in the release of bud dormancy by sucrose. Tre6P might also be linked to a reconfiguration of carbon and nitrogen metabolism to support the subsequent growth of the bud into a new shoot.     

Multiple functions of insulin-degrading enzyme: a metabolic crosslight?

Insulin-degrading enzyme (IDE) is a ubiquitous zinc peptidase of the inverzincin family, which has been initially discovered as the enzyme responsible for insulin catabolism; therefore, its involvement in the onset of diabetes has been largely investigated. However, further studies on IDE unraveled its ability to degrade several other polypeptides, such as β-amyloid, amylin, and glucagon, envisaging the possible implication of IDE dys-regulation in the “aggregopathies” and, in particular, in neurodegenerative diseases. Over the last decade, a novel scenario on IDE biology has emerged, pointing out a multi-functional role of this enzyme in several basic cellular processes. In particular, latest advances indicate that IDE behaves as a heat shock protein and modulates the ubiquitin–proteasome system, suggesting a major implication in proteins turnover and cell homeostasis. In addition, recent observations have highlighted that the regulation of glucose metabolism by IDE is not merely based on its largely proposed role in the degradation of insulin in vivo. There is increasing evidence that improper IDE function, regulation, or trafficking might contribute to the etiology of metabolic diseases. In addition, the enzymatic activity of IDE is affected by metals levels, thus suggesting a role also in the metal homeostasis (metallostasis), which is thought to be tightly linked to the malfunction of the “quality control” machinery of the cell. Focusing on the physiological role of IDE, we will address a comprehensive vision of the very complex scenario in which IDE takes part, outlining its crucial role in interconnecting several relevant cellular processes.     

Multi-trait genomic prediction for nitrogen response indices in tropical maize hybrids

In maize breeding, genomic prediction may be an efficient tool for selecting single-crosses evaluated under abiotic stress conditions. In addition, a promising strategy is applying multiple-trait genomic prediction using selection indices (SIs), increasing genetics gains and reducing time per cycles. In this study, we aimed (i) to compare accuracy of single- and multi-trait genomic prediction (STGP; MTGP) in two maize datasets, (ii) to evaluate prediction of four selection indices that could contribute to the selection of tropical maize hybrids under contrasting nitrogen conditions, and (iii) to compare the use of linear (GBLUP) and nonlinear (RKHS/GK) kernels in STGP and MTGP analyses. For either single-trait GBLUP and RKHS analyses, the highest values obtained for accuracy were 0.40 and 0.41 using harmonic mean (HM), respectively. From multi-trait GBLUP and GK, using the combination of selection indices in MTGP seems to be suitable, increasing the accuracy. Adding grain yield and plant height in MTGP showed a slight improvement in accuracy compared to STGP. In general, there was a modest benefit of using single-trait RKHS and GK multi-trait, rather than GBLUP.     

A yeast-based genetic screening to identify human proteins that increase homologous recombination

To identify new human proteins implicated in homologous recombination (HR), we set up 'a papillae assay' to screen a human cDNA library using the RS112 strain of Saccharomyces cerevisiae containing an intrachromosomal recombination substrate. We isolated 23 cDNAs, 11 coding for complete proteins and 12 for partially deleted proteins that increased HR when overexpressed in yeast. We characterized the effect induced by the overexpression of the complete human proteasome subunit beta 2, the partially deleted proteasome subunits alpha 3 and beta 8, the ribosomal protein L12, the brain abundant membrane signal protein (BASP1) and the human homologue to v-Ha-RAS (HRAS), which elevated HR by 2-6.5-fold over the control. We found that deletion of the RAD52 gene, which has a key role in most HR events, abolished the increase of HR induced by the proteasome subunits and HRAS; by contrast, the RAD52 deletion did not affect the high level of HR due to BASP1 and RPL12. This suggests that the proteins stimulated yeast HR via different mechanisms. Overexpression of the complete beta 2 human proteasome subunit or the partially deleted alpha 3 and beta 8 subunits increased methyl methanesulphonate (MMS) resistance much more in the rad52 Delta mutant than in the wild-type. Overexpression of RPL12 and BASP1 did not affect MMS resistance in both the wild-type and the rad52 Delta mutant, whereas HRAS decreased MMS resistance in the rad52 Delta mutant. The results indicate that these proteins may interfere with the pathway(s) involved in the repair of MMS-induced DNA damage. Finally, we provide further evidence that yeast is a helpful tool to identify human proteins that may have a regulatory role in HR.     

Tumor cell phenotype is sustained by selective MAPK oxidation in mitochondria

Mitochondria are major cellular sources of hydrogen peroxide (H(2)O(2)), the production of which is modulated by oxygen availability and the mitochondrial energy state. An increase of steady-state cell H(2)O(2) concentration is able to control the transition from proliferating to quiescent phenotypes and to signal the end of proliferation; in tumor cells thereby, low H(2)O(2) due to defective mitochondrial metabolism can contribute to sustain proliferation. Mitogen-activated protein kinases (MAPKs) orchestrate signal transduction and recent data indicate that are present in mitochondria and regulated by the redox state. On these bases, we investigated the mechanistic connection of tumor mitochondrial dysfunction, H(2)O(2) yield, and activation of MAPKs in LP07 murine tumor cells with confocal microscopy, in vivo imaging and directed mutagenesis. Two redox conditions were examined: low 1 microM H(2)O(2) increased cell proliferation in ERK1/2-dependent manner whereas high 50 microM H(2)O(2) arrested cell cycle by p38 and JNK1/2 activation. Regarding the experimental conditions as a three-compartment model (mitochondria, cytosol, and nuclei), the different responses depended on MAPKs preferential traffic to mitochondria, where a selective activation of either ERK1/2 or p38-JNK1/2 by co-localized upstream kinases (MAPKKs) facilitated their further passage to nuclei. As assessed by mass spectra, MAPKs activation and efficient binding to cognate MAPKKs resulted from oxidation of conserved ERK1/2 or p38-JNK1/2 cysteine domains to sulfinic and sulfonic acids at a definite H(2)O(2) level. Like this, high H(2)O(2) or directed mutation of redox-sensitive ERK2 Cys(214) impeded binding to MEK1/2, caused ERK2 retention in mitochondria and restricted shuttle to nuclei. It is surmised that selective cysteine oxidations adjust the electrostatic forces that participate in a particular MAPK-MAPKK interaction. Considering that tumor mitochondria are dysfunctional, their inability to increase H(2)O(2) yield should disrupt synchronized MAPK oxidations and the regulation of cell cycle leading cells to remain in a proliferating phenotype.     

Lagrangian description of zooplankton swimming trajectories

Three-dimensional swimming, in 20 trajectories of Daphnia pulex,was characterized in terms of its kinematic properties. Resultsshow that the random component was stronger than the deterministiccomponent at time scales >1–2 s. Such random movementsmay have evolved to outwit potential predators and prey.     

Calix[4]arene decorated with four Tn antigen glycomimetic units and P3CS immunoadjuvant: synthesis, characterization, and anticancer immunological evaluation

A novel anticancer vaccine candidate built on a nonpeptidic scaffold has been synthesized. Four S-Tn tumor-associated glycomimetic antigens have been clustered onto a calix[4]arene scaffold bearing an immunoadjuvant moiety (P3CS). The immunogenicity of the synthetic construct has been investigated by immunization of mice in vivo. ELISA assay has evidenced that the tetravalent construct stimulates a higher production of anti-Tn antigen IgG antibodies when compared to an analogous monovalent compound. This result is ascribable to an antigen cluster effect and makes the reported vaccine candidate a good mimic of the natural motifs present on the mucine surface.     

Comparing the catalytic efficiency of some mediators of laccase

The mechanism of oxidation of non-phenolic substrates by laccase/mediators systems has been investigated. Oxidation of 4-methoxybenzyl alcohol (1), taken as a benchmark reaction, enabled us to compare and to rank the relative ability of twelve mediators: TEMPO proved most effective, and a ionic mechanism is suggested for its action. Data on intermolecular selectivity of substrate oxidation are in favour of an electron transfer (ET) mechanism in the case of ABTS-mediated oxidations, and of a radical mechanism in HBT- and HPI-mediated reactions. Investigation by cyclic voltammetry (CV) of some of the mediators revealed that an important role in determining the mechanism of substrate oxidation may be played by the stability of the oxidised form of the mediator, as well as by its redox potential.