Metabolic Syndrome Mediates ROS-miR-193b-NFYA-Dependent Downregulation of Soluble Guanylate Cyclase and Contributes to Exercise-Induced Pulmonary Hypertension in Heart Failure With Preserved Ejection Fraction.

BACKGROUND: Many patients with heart failure with preserved ejection fraction have metabolic syndrome and develop exercise-induced pulmonary hypertension (EIPH). Increases in pulmonary vascular resistance in patients with heart failure with preserved ejection fraction portend a poor prognosis; this phenotype is referred to as combined precapillary and postcapillary pulmonary hypertension (CpcPH). Therapeutic trials for EIPH and CpcPH have been disappointing, suggesting the need for strategies that target upstream mechanisms of disease. This work reports novel rat EIPH models and mechanisms of pulmonary vascular dysfunction centered around the transcriptional repression of the soluble guanylate cyclase (sGC) enzyme in pulmonary artery (PA) smooth muscle cells. METHODS: We used obese ZSF-1 leptin-receptor knockout rats (heart failure with preserved ejection fraction model), obese ZSF-1 rats treated with SU5416 to stimulate resting pulmonary hypertension (obese+sugen, CpcPH model), and lean ZSF-1 rats (controls). Right and left ventricular hemodynamics were evaluated using implanted catheters during treadmill exercise. PA function was evaluated with magnetic resonance imaging and myography. Overexpression of nuclear factor Y α subunit (NFYA), a transcriptional enhancer of sGC ß1 subunit (sGCß1), was performed by PA delivery of adeno-associated virus 6. Treatment groups received the SGLT2 inhibitor empagliflozin in drinking water. PA smooth muscle cells from rats and humans were cultured with palmitic acid, glucose, and insulin to induce metabolic stress. RESULTS: Obese rats showed normal resting right ventricular systolic pressures, which significantly increased during exercise, modeling EIPH. Obese+sugen rats showed anatomic PA remodeling and developed elevated right ventricular systolic pressure at rest, which was exacerbated with exercise, modeling CpcPH. Myography and magnetic resonance imaging during dobutamine challenge revealed PA functional impairment of both obese groups. PAs of obese rats produced reactive oxygen species and decreased sGCß1 expression. Mechanistically, cultured PA smooth muscle cells from obese rats and humans with diabetes or treated with palmitic acid, glucose, and insulin showed increased mitochondrial reactive oxygen species, which enhanced miR-193b-dependent RNA degradation of nuclear factor Y α subunit (NFYA), resulting in decreased sGCß1-cGMP signaling. Forced NYFA expression by adeno-associated virus 6 delivery increased sGCß1 levels and improved exercise pulmonary hypertension in obese+sugen rats. Treatment of obese+sugen rats with empagliflozin improved metabolic syndrome, reduced mitochondrial reactive oxygen species and miR-193b levels, restored NFYA/sGC activity, and prevented EIPH. CONCLUSIONS: In heart failure with preserved ejection fraction and CpcPH models, metabolic syndrome contributes to pulmonary vascular dysfunction and EIPH through enhanced reactive oxygen species and miR-193b expression, which downregulates NFYA-dependent sGCß1 expression. Adeno-associated virus-mediated NFYA overexpression and SGLT2 inhibition restore NFYA-sGCß1-cGMP signaling and ameliorate EIPH.

When underadditivity of factor effects in the Psychological Refractory Period paradigm implies a bottleneck: evidence from psycholinguistics.

The Psychological Refractory Period (PRP) paradigm is a dual-task procedure that can be used to examine the resource demands of specific cognitive processes. Inferences about the underlying processes are typically based on performance in the second of two speeded tasks. If the effect of a factor manipulated in Task 2 decreases as the stimulus onset asynchrony (SOA) between tasks decreases (underadditivity), the normative inference is that the effect of this factor occurs prior to a limited-capacity central processing mechanism. In contrast, if the effect of a factor is additive with SOA then the inference is that this indexes a process that either uses a limited-capacity central processing mechanism or occurs after some process that uses this mechanism. A heretofore unidentified exception to this logic arises when Task 2 involves two separate processes that operate in parallel, but compete. Interference with one process in Task 2 because of work on Task 1 will eliminate or reduce competition within Task 2 and is hence manifest as an underadditive interaction with decreasing SOA. This is illustrated here by reference to a PRP experiment in which the ubiquitous effect of spelling-to-sound regularity on reading aloud time is eliminated at a short SOA and by consideration of three converging lines of investigation in the PRP paradigm when Task 2 involves reading aloud.

Hiding and finding: the relationship between visual concealment and visual search.

As an initial step toward developing a theory of visual concealment, we assessed whether people would use factors known to influence visual search difficulty when the degree of concealment of objects among distractors was varied. In Experiment 1, participants arranged search objects (shapes, emotional faces, and graphemes) to create displays in which the targets were in plain sight but were either easy or hard to find. Analyses of easy and hard displays created during Experiment 1 revealed that the participants reliably used factors known to influence search difficulty (e.g., eccentricity, target-distractor similarity, presence/absence of a feature) to vary the difficulty of search across displays. In Experiment 2, a new participant group searched for the targets in the displays created by the participants in Experiment 1. Results indicated that search was more difficult in the hard than in the easy condition. In Experiments 3 and 4, participants used presence versus absence of a feature to vary search difficulty with several novel stimulus sets. Taken together, the results reveal a close link between the factors that govern concealment and the factors known to influence search difficulty, suggesting that a visual search theory can be extended to form the basis of a theory of visual concealment.

The development of a theoretical framework and design tool for process usability assessment.

The purpose of usability engineering is to facilitate the deployment of new products by decreasing development costs and improving the quality of systems. This paper will discuss the development and delivery of a unique, theoretically based software tool that provides engineers and designers with easy access to the most recent advances in human-machine interface design. This research combines several theoretical views of the interaction process into a hybrid model. Based on this model, a software tool was produced that allows engineers to model the human interaction process within their design. The system then provides feedback on the interaction process through items such as: the amount of mental effort required by a user, the degree to which the system conforms to human capabilities, the expected time to complete the interaction, where potential human error may occur, as well as potential misunderstandings or points of confusion to the users. The designer may then use this information to improve the design of the system. Validation of this technique indicates that the hybrid model produces accurate predictions of usability attributes and that the technique transfers from the laboratory to the real world.