BackgroundIn contrast to systemic hypertension, the significance of arterial waves in pulmonary hypertension (PH) is not well understood. We hypothesized that arterial wave energy and wave reflection are augmented in PH and that wave behavior differs between patients with pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH).Methods and ResultsRight heart catheterization was performed using a pressure and Doppler flow sensor–tipped catheter to obtain simultaneous pressure and flow velocity measurements in the pulmonary artery. Wave intensity analysis was subsequently applied to the acquired data. Ten control participants, 11 patients with PAH, and 10 patients with CTEPH were studied. Wave speed and wave power were significantly greater in PH patients compared with controls, indicating increased arterial stiffness and right ventricular work, respectively. The ratio of wave power to mean right ventricular power was lower in PAH patients than CTEPH patients and controls. Wave reflection index in PH patients (PAH: ≈25%; CTEPH: ≈30%) was significantly greater compared with controls (≈4%), indicating downstream vascular impedance mismatch. Although wave speed was significantly correlated to disease severity, wave reflection indexes of patients with mildly and severely elevated pulmonary pressures were similar.ConclusionsWave reflection in the pulmonary artery increased in PH and was unrelated to severity, suggesting that vascular impedance mismatch occurs early in the development of pulmonary vascular disease. The lower wave power fraction in PAH compared with CTEPH indicates differences in the intrinsic and/or extrinsic ventricular load between the 2 diseases.

SUMMARYLong terminal repeat (LTR) retrotransposons are closely related to retroviruses, and their activities shape eukaryotic genomes. Here, we present a complete Lotus japonicus insertion mutant collection generated by identification of 640 653 new insertion events following de novo activation of the LTR element Lotus retrotransposon 1 (LORE1) (http://lotus.au.dk). Insertion preferences are critical for effective gene targeting, and we exploit our large dataset to analyse LTR element characteristics in this context. We infer the mechanism that generates the consensus palindromes typical of retroviral and LTR retrotransposon insertion sites, identify a short relaxed insertion site motif, and demonstrate selective integration into CHG-hypomethylated genes. These characteristics result in a steep increase in deleterious mutation rate following activation, and allow LORE1 active gene targeting to approach saturation within a population of 134 682 L. japonicus lines. We suggest that saturation mutagenesis using endogenous LTR retrotransposons with germinal activity can be used as a general and cost-efficient strategy for generation of non-transgenic mutant collections for unrestricted use in plant research.

Temporal lobe epilepsy is the most common drug-resistant form of epilepsy in adults. The reorganization of neural networks and the gene expression landscape underlying pathophysiologic network behavior in brain structures such as the hippocampus has been suggested to be controlled, in part, by microRNAs. To systematically assess their significance, we sequenced Argonaute-loaded microRNAs to define functionally engaged microRNAs in the hippocampus of three different animal models in two species and at six time points between the initial precipitating insult through to the establishment of chronic epilepsy. We then selected commonly up-regulated microRNAs for a functional in vivo therapeutic screen using oligonucleotide inhibitors. Argonaute sequencing generated 1.44 billion small RNA reads of which up to 82% were microRNAs, with over 400 unique microRNAs detected per model. Approximately half of the detected microRNAs were dysregulated in each epilepsy model. We prioritized commonly up-regulated microRNAs that were fully conserved in humans and designed custom antisense oligonucleotides for these candidate targets. Antiseizure phenotypes were observed upon knockdown of miR-10a-5p, miR-21a-5p, and miR-142a-5p and electrophysiological analyses indicated broad safety of this approach. Combined inhibition of these three microRNAs reduced spontaneous seizures in epileptic mice. Proteomic data, RNA sequencing, and pathway analysis on predicted and validated targets of these microRNAs implicated derepressed TGF-β signaling as a shared seizure-modifying mechanism. Correspondingly, inhibition of TGF-β signaling occluded the antiseizure effects of the antagomirs. Together, these results identify shared, dysregulated, and functionally active microRNAs during the pathogenesis of epilepsy which represent therapeutic antiseizure targets.

This paper aims to summarize and map contemporary views on some contentious aspects of arterial hemodynamics that have remained unresolved despite years of research. These were discussed during a workshop entitled Arterial hemodynamics: past, present and future held in London on June 14 and 15, 2016. To do this we formulated a list of potential consensus statements informed by discussion at the meeting in London and quantified the degree of agreement and invited comments from the participants of the workshop. Overall the responses and comments show a high measure of quantitative agreement with the various proposed 'consensus' statements. Taken together, these statements seem a useful basis for proceeding with a more detailed and comprehensive consensus document on the current understanding and approaches to analysis of the pulse waveform. Future efforts should be directed at identifying remaining areas of dispute and future topics for research.

Plants contain various factors that transiently interact with subunits or intermediates of the thylakoid multiprotein complexes, promoting their stable association and integration. Hence, assembly factors are essential for chloroplast development and the transition from heterotrophic to phototrophic growth. Snowy cotyledon 2 (SCO2) is a DNAJ-like protein involved in thylakoid membrane biogenesis and interacts with the light-harvesting chlorophyll-binding protein LHCB1. In Arabidopsis thaliana, SCO2 function was previously reported to be restricted to cotyledons. Here we show that disruption of SCO2 in Lotus japonicus results not only in paler cotyledons but also in variegated true leaves. Furthermore, smaller and pale-green true leaves can also be observed in A. thaliana sco2 (atsco2) mutants under short-day conditions. In both species, SCO2 is required for proper accumulation of PSII-LHCII complexes. In contrast to other variegated mutants, inhibition of chloroplastic translation strongly affects L. japonicus sco2 mutant development and fails to suppress their variegated phenotype. Moreover, inactivation of the suppressor of variegation AtClpR1 in the atsco2 background results in an additive double-mutant phenotype with variegated true leaves. Taken together, our results indicate that SCO2 plays a distinct role in PSII assembly or repair and constitutes a novel factor involved in leaf variegation.

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High wave speed and large wave reflection in the pulmonary artery have previously been reported in patients with chronic thromboembolic pulmonary hypertension (CTEPH). We assessed the impact of pulmonary endarterectomy (PEA) on pulmonary arterial wave propagation and reservoir function in patients with CTEPH. Right heart catheterization was performed using a combined pressure and Doppler flow sensor-tipped guidewire to obtain simultaneous pressure and flow velocity measurements in the pulmonary artery in eight patients with CTEPH before and 3 mo after PEA. Wave intensity and reservoir-excess pressure analyses were then performed. Following PEA, mean pulmonary arterial pressure (PAPm; ∼49 vs. ∼32 mmHg), pulmonary vascular resistance (PVR; ∼11.1 vs. ∼5.1 Wood units), and wave speed (∼16.5 vs. ∼8.1 m/s), i.e., local arterial stiffness, markedly decreased. The changes in the intensity of the reflected arterial wave and wave reflection index (pre: ∼28%; post: ∼22%) were small, and patients post-PEA with and without residual pulmonary hypertension (i.e., PAPm ≥ 25 mmHg) had similar wave reflection index (∼20 vs. ∼23%). The reservoir and excess pressure decreased post-PEA, and the changes were associated with improved right ventricular afterload, function, and size. In conclusion, although PVR and arterial stiffness decreased substantially following PEA, large wave reflection persisted, even in patients without residual pulmonary hypertension, indicating lack of improvement in vascular impedance mismatch. This may continue to affect the optimal ventriculoarterial interaction, and further studies are warranted to determine whether this contributes to persistent symptoms in some patients. NEW & NOTEWORTHY We performed wave intensity analysis in the pulmonary artery in patients with chronic thromboembolic pulmonary hypertension before and 3 mo after pulmonary endarterectomy. Despite substantial reduction in pulmonary arterial pressures, vascular resistance, and arterial stiffness, large pulmonary arterial wave reflection persisted 3 mo postsurgery, even in patients without residual pulmonary hypertension, suggestive of lack of improvement in vascular impedance mismatch.

Mean pulmonary arterial pressure and pulmonary vascular resistance (PVR) remain the most common haemodynamic measures to evaluate the severity and prognosis of pulmonary hypertension. However, PVR only captures the non-oscillatory component of the right ventricular hydraulic load and neglects the dynamic compliance of the pulmonary arteries and the contribution of wave transmission. Wave intensity analysis offers an alternative way to assess the pulmonary vasculature in health and disease. Wave speed is a measure of arterial stiffness, and the magnitude and timing of wave reflection provide information on the degree of impedance mismatch between the proximal and distal circulation. Studies in the pulmonary artery have demonstrated distinct differences in arterial wave propagation between individuals with and without pulmonary vascular disease. Notably, greater wave speed and greater wave reflection are observed in patients with pulmonary hypertension and in animal models exposed to hypoxia. Studying wave propagation makes a valuable contribution to the assessment of the arterial system in pulmonary hypertension, and here, we briefly review the current state of knowledge of the methods used to evaluate arterial waves in the pulmonary artery.