MicroRNAs in the stressed heart: Sorting the signal from the noise

The short noncoding RNAs, known as microRNAs, are of undisputed importance in cellular signaling during differentiation and development, and during adaptive and maladaptive responses of adult tissues, including those that comprise the heart. Cardiac microRNAs are regulated by hemodynamic overload resulting from exercise or hypertension, in the response of surviving myocardium to myocardial infarction, and in response to environmental or systemic disruptions to homeostasis, such as those arising from diabetes. A large body of work has explored microRNA responses in both physiological and pathological contexts but there is still much to learn about their integrated actions on individual mRNAs and signaling pathways. This review will highlight key studies of microRNA regulation in cardiac stress and suggest possible approaches for more precise identification of microRNA targets, with a view to exploiting the resulting data for therapeutic purposes

Internal and External Triggers for Action

When the self paced preparation of an action is interrupted by a stimulus prompting the same motor response there is an increase in the reaction time to the stimulus as compared to an external or simple reaction time (SRT) condition (Obhi & Haggard, 2004). Previous studies have suggested that this cost is not attributable to perceptual or attentional factors. Therefore, to investigate the source of this RT cost we varied the motor demands of movements in Experiments one and two. Results indicated that the level of motor programming demands did not influence the RT cost in these experiments. While RTs for more demanding movements (i.e., bimanual or serial key presses) were slower than those for simple one finger actions (i.e., single key presses), the RT cost was not significantly different for both response types. That is, the RT cost did not increase as a function of motor programming demands. In a control experiment (experiment three), we assimilated the external and truncation conditions through the creation of the external-subvocal condition, to investigate if the source of the RT cost was reflective of the dual task of subvocalization. The results revealed that although the RT cost was reduced, counting subvocally did not eliminate the RT cost. Simply, the RT cost is not explained by the dual task of subvocalization. The ability to modify planned actions is fundamental to everyday life, thus we investigated the time course of modifying planned actions on the basis of an external cue in experiment four. Reaction times to produce modified actions were significantly greater than those to produce unmodified actions. Additionally, it took significantly longer to produce modified actions requiring one less effector than to produce modified actions requiring one more effector. We suggest that two time-consuming processes are involved in switching between internally generated and externally triggered actions that are modified or unmodified: a trigger switch cost when the same action has to be produced in response to an external trigger as opposed to an internal trigger, and a switch cost reflecting changes in the pattern of executed motor commands when modification is necessary. It is suggested that such processes may be mediated by regions of the frontal lobes. Finally, we conducted two experiments to investigate the time course of cancelling a planned action on the basis of an environmental prompt. It was found that an internally prepared action can be cancelled with 300ms, regardless of the motor demands associated with the prepared action, suggesting that we are cancelling the prospective “when” component of the action

Paper Session III-B - Developing a Customer-Centered Organization: Customer Advocacy at the Cape Canaveral Spaceport

The customer is the business. Peter Drucker established this paradigm when he described how to approach business challenges to maximize economic performance. Other leading quality and management experts agree. The Malcolm Baldrige National Quality Award, administered by the National Institute of Standards and Technology, allocates 20% of the total available points to customer and market knowledge and performance. And, the stock of Baldrige winners has collectively outperformed the S&P 500 stock average by 400-500%

Bcl-2 and Bax immunoreactivity in placentas from pregnancies complicated with intrauterine growth restriction and hypertension

Because placental apoptosis associated protein imbalance is thought to contribute to the pathogenesis of intrauterine growth restriction (IUGR) and preeclampsia (PE), morphological features and expression of Bcl-2 and Bax were studied on samples from 10 human placentas from pregnancies complicated with IUGR and PE and 10 placentas from uncomplicated term pregnancies. In 9/10 placentas from the IUGR/PE group, the findings were consistent with hypoxic damage and in 1/10 placentas chronic villitis was found. In both groups Bax showed strong diffuse expression (3+) in amnionic epithelium, blood vessel wall and endothelium in the chorionic plate and placental villi and the villous stroma in all placentas. The extravillous trophoblast (EVT) in the basal decidua showed 3+ Bax expression in 8/10 placentas and 2+ expression in 2/10 placentas in both groups. In the IUGR/PE group the Bax expression in both cyto (CT) and syncytiotrophoblast (ST), was 3+ in 8/10 placentas, and 2+ in 2/10 placentas. In the control group Bax expression was 3+ in both CT and ST in all 10 placentas. The 3+ Bcl-2 expression in both groups was found only in CT and ST. The syncytial knots in both groups showed 3+ positivity for Bax and Bcl-2. These findings do not confirm other authors’ findings about the increased expression of proapoptotic factors in the third trimester placentas with IUGR/PE, and the conclusion is that for the pathogenesis of IUGR and PE, the attention should be shifted to inappropriate apoptosis during the process of implantation

Postnatal β-cell maturation is associated with islet-specific microRNA changes induced by nutrient shifts at weaning.

Glucose-induced insulin secretion is an essential function of pancreatic β-cells that is partially lost in individuals affected by Type 2 diabetes. This unique property of β-cells is acquired through a poorly understood postnatal maturation process involving major modifications in gene expression programs. Here we show that β-cell maturation is associated with changes in microRNA expression induced by the nutritional transition that occurs at weaning. When mimicked in newborn islet cells, modifications in the level of specific microRNAs result in a switch in the expression of metabolic enzymes and cause the acquisition of glucose-induced insulin release. Our data suggest microRNAs have a central role in postnatal β-cell maturation and in the determination of adult functional β-cell mass. A better understanding of the events governing β-cell maturation may help understand why some individuals are predisposed to developing diabetes and could lead to new strategies for the treatment of this common metabolic disease

Procedures for Trace Analysis of Dissolved Inorganic and Organic Constituents in Water

A study of different solvent systems for the atomic absorption determination of cobalt revealed that acetone results in best sensitivity. Acetone is the solvent of choice for the sensitive measurement of several metals. Hence, methods were investigated for the separation of acetone from water by salting out so that possible solvent extraction of metal chelates into this solvent could be performed. About two-thirds saturated calcium chloride proved to be the best system for salting out of the acetone. It is essentially a neutral salt and is in general a weakly complexing salt, resulting in minimum interference in solvent extractions. Solvent extraction of several elements as dithizone or APDC chelates into acetone was successful. A new anodic stripping voltammetric method was developed for stability studies of the poorly characterized APDC chelates. The method allows the study of highly insoluble chelates. Over sixty elements were successfully measured by flame emission spectroscopy using the nitrous oxide-acetylene flame. Optimum instrumental and flame parameters and detection limits for each element were determined. High concentrations of neutral salts have, been shown to enhance titration curve breaks of weak bases titrated in either aqueous or nonaqueous solutions. This allowed the coulometric titration of microequivalent quantities of bases with Kb values as small as 4 x 10-12. Volumetric titration of bases with Kb values of 10-14 was possible in nonaqueous solvents

Mitochondrial genome linearization is a causative factor for cardiomyopathy in mice and Drosophila

Aims: Mitofusin (Mfn)2 redundantly promotes mitochondrial outer membrane tethering and organelle fusion with Mfn1, and uniquely functions as the mitochondrial receptor for Parkin during PTEN-induced putative kinase 1 (PINK1)-Parkin-mediated mitophagy. Selective deletion of Mfn2 with retention of Mfn1 preserves mitochondrial fusion while rendering damaged mitochondria resistant to normal quality control culling mechanisms. Consequently, neuron and cardiomyocyte-specific Mfn2 gene ablation is associated with accumulation of damaged mitochondria and organ dysfunction. Here, we determined how mitochondrial DNA (mtDNA) damage contributes to cardiomyopathy in Mfn2-deficient hearts. Results: RNA sequencing of Mfn2-deficient hearts revealed increased expression of some nuclear-encoded mitochondrial genes, but mitochondrial-encoded transcripts were not upregulated in parallel and mtDNA content was decreased. Ultra-deep sequencing of mtDNA showed no increase in single nucleotide mutations, but copy number variations representing insertion–deletion (in–del) mutations were induced over time by cardiomyocyte-specific Mfn2 deficiency. Double-strand mtDNA breaks in the form of in–dels were confirmed by polymerase chain reaction, and in the form of linear mitochondrial genomes were identified by southern blot analysis. Linearization of Drosophila cardiomyocyte mtDNA using conditional cardiomyocyte-specific expression of mitochondrial targeted XhoI recapitulated the cardiomyopathy of Mfn2-deficient mouse hearts. Innovation: This is the first description of mitochondrial genome linearization as a causative factor in cardiomyopathy. Conclusion: One of the consequences of interrupting mitochondrial culling by the PINK1-Mfn2-Parkin mechanism is an increase in mtDNA double-stranded breaks, which adversely impact mitochondrial function and DNA replication. Antioxid. Redox Signal. 21, 1949–1959