Transcriptomic-based analysis to identify candidate genes for blue color rose breeding.

KEY MESSAGE: Analysis of the flower color formation mechanism of 'Rhapsody in Blue' by BF and WF transcriptomes reveals that RhF3'H and RhGT74F2 play a key role in flower color formation. Rosa hybrida has colorful flowers and a high ornamental value. Although rose flowers have a wide range of colors, no blue roses exist in nature, and the reason for this is unclear. In this study, the blue-purple petals (BF) of the rose variety 'Rhapsody in Blue' and the white petals (WF) of its natural mutant were subjected to transcriptome analysis to find genes related to the formation of the blue-purple color. The results showed that the anthocyanin content was significantly higher in BF than in WF. A total of 1077 differentially expressed genes (DEGs) were detected by RNA-Seq analysis, of which 555 were up-regulated and 522 were down-regulated in the WF vs. BF petals. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses of the DEGs revealed that a single gene up-regulated in BF was related to multiple metabolic pathways including metabolic process, cellular process, protein-containing complex, etc. Additionally, the transcript levels of most of the structural genes related to anthocyanin synthesis were significantly higher in BF than in WF. Selected genes were analyzed by qRT-PCR and the results were highly consistent with the RNA-Seq results. The functions of RhF3'H and RhGT74F2 were verified by transient overexpression analyses, and the results confirmed that both affect the accumulation of anthocyanins in 'Rhapsody in Blue'. We have obtained comprehensive transcriptome data for the rose variety 'Rhapsody in Blue'. Our results provide new insights into the mechanisms underlying rose color formation and even blue rose formation.

Chronic Right Heart Failure: Expanding Prevalence and Challenges in Outpatient Management.

Right heart failure is caused by right heart dysfunction resulting in suboptimal stroke volume to supply the pulmonary circulation. Therapeutic developments mean that patients with acute right heart failure survive to hospital discharge and live with chronic right heart failure. Chronic right heart failure management aims to reduce afterload, optimize preload, and support contractility, with the best evidence available in vascular targeted therapy for pulmonary arterial hypertension. However, the management of chronic right heart failure relies on adapting therapies for left ventricular heart failure to the right. We review right heart failure management in the ambulatory setting and its challenges.

[Ratio of transcription factor PHF10 splice variants in lymphocytes as a molecular marker of Parkinson's disease].

Parkinson's disease (PD) is the second most common neurodegenerative disorder and causes degeneration of dopaminergic neurons in the nigrostriatal system of the brain. PHF10 is one of the most important regulatory subunits of the SWI/SNF chromatin-remodeling protein complex, which controls the gene function and chromatin state in neurons. Two alternative RHF10 isoforms, PHF10-P and PHF10-S, replace each other in the complex to change the target gene pattern. Expression of the PHF10-P and PHF10-S transcripts in the nigrostriatal system and their ratio in blood lymphocytes were found to change in a mouse model of early clinical stage of PD as compared with control mice. Changes in PHF10-S level were also observed in peripheral blood lymphocytes from patients with early clinical stage of PD. A ratio of the PHF10-P and PHF10-S transcripts in peripheral blood cells was assumed to provide a potential marker of early stage PD.

Farnesoid-X-receptor expression in monocrotaline-induced pulmonary arterial hypertension and right heart failure.

OBJECTIVE: The farnesoid-X-receptor (FXR) is a metabolic nuclear receptor superfamily member that is highly expressed in enterohepatic tissue and is also expressed in the cardiovascular system. Multiple nuclear receptors, including FXR, play a pivotal role in cardiovascular disease (CVD). Pulmonary arterial hypertension (PAH) is an untreatable cardiovascular system disease that leads to right heart failure (RHF). However, the potential physiological/pathological roles of FXR in PAH and RHF are unknown. We therefore compared FXR expression in the cardiovascular system in PAH, RHF and a control. METHODS AND RESULTS: Hemodynamic parameters and morphology were assessed in blank solution-exposed control, monocrotaline (MCT)-exposed PAH (4 weeks) and RHF (7 weeks) Sprague-Dawley rats. Real-time reverse transcription polymerase chain reaction (real-time RT-PCR), Western blot (WB), immunohistochemistry (IHC) analysis and immunofluorescence (IF) analysis were performed to assess FXR levels in the lung and heart tissues of MCT-induced PAH and RHF rats. In normal rats, low FXR levels were detected in the heart, and nearly no FXR was expressed in rat lungs. However, FXR expression was significantly elevated in PAH and RHF rat lungs but reduced in PAH and RHF rat right ventricular (RV) tissues. FXR expression was reduced only in RHF rat left ventricular (LV) tissues. CONCLUSIONS: The differential expression of FXR in MCT-induced PAH lungs and heart tissues in parallel with PAH pathophysiological processes suggests that FXR contributes to PAH.

A P450 fusion library of heme domains from Rhodococcus jostii RHA1 and its evaluation for the biotransformation of drug molecules.

The actinomycete Rhodococcus jostii RHA1 contains a multitude of oxygenase enzymes, consonant with its remarkable activities in the catabolism of hydrophobic xenobiotic compounds. In the interests of identifying activities for the transformation of drug molecules, we have cloned genes encoding 23 cytochrome P450 heme domains from R. jostii and expressed them as fusions with the P450 reductase domain (RhfRED) of cytochrome P450Rhf from Rhodococcus sp. NCIMB 9784. Fifteen of the fusions were expressed in the soluble fraction of Escherichia coli Rosetta (DE3) cells. Strains expressing the fusions of RhfRED with genes ro02604, ro04667, ro11069, ro11320, ro11277, ro08984 and ro04671 were challenged with 48 commercially available drugs revealing many different activities commensurate with P450-catalyzed hydroxylation and demethylation reactions. One recombinant strain, expressing the fusion of P450 gene ro11069 (CYP257A1) with RhfRED, and named Ro07-RhfRED, catalyzed the N-demethylation of diltiazem and imipramine. This observation was in accord with previous reports of this enzyme's activity as a demethylase of alkaloid substrates. Ro07-RhfRED was purified and characterised, and applied in cell-free biotransformations of imipramine (7 µM) giving a 63% conversion to the N-desmethyl product.

The modified Rajan's heart failure risk score predicts all-cause mortality in patients hospitalized for heart failure with reduced ejection fraction: a retrospective cohort study.

Background: The dimensionless Rajan's heart failure (R-hf) risk score was proposed to predict all-cause mortality in patients hospitalized with chronic heart failure (HF) and reduced ejection fraction (EF) (HFrEF). Purpose: To examine the association between the modified R-hf risk score and all-cause mortality in patients with HFrEF. Methods: Retrospective cohort study included adults hospitalized with HFrEF, as defined by clinical symptoms of HF with biplane EF less than 40% on transthoracic echocardiography, at a tertiary centre in Dalian, China, between 1 November 2015, and 31 October 2019. All patients were followed up until 31 October 2020. A modified R-hf risk score was calculated by substituting brain natriuretic peptide (BNP) for N-terminal prohormone of BNP (NT-proBNP) using EF× estimated glomerular filtration rate (eGFR)× haemoglobin (Hb))/BNP. The patients were stratified into tertiles according to the R-hf risk score. The measured outcome was all-cause mortality. The score performance was assessed using C-statistics. Results: A total of 840 patients were analyzed (70.2% males; mean age, 64±14 years; median (interquartile range) follow-up 37.0 (27.8) months). A lower modified R-hf risk score predicted a higher risk of all-cause mortality, independent of sex and age [1st tertile vs. 3rd tertile: adjusted hazard ratio (aHR), 3.46; 95% CI: 2.11-5.67; P<0.001]. Multivariate Cox regression analysis indicated that a lower modified R-hf risk score was associated with increased cumulative all-cause mortality [univariate: (1st tertile vs. 3rd tertile: aHR, 3.45; 95% CI: 2.11-5.65; P<0.001) and multivariate: (1st tertile vs. 3rd tertile: aHR 2.21, 95% CI: 1.29-3.79; P=0.004)]. The performance of the model, as reported by C-statistic was 0.67 (95% CI: 0.62-0.72). Conclusion: The modified R-hf risk score predicted all-cause mortality in patients hospitalized with HFrEF. Further validation of the modified R-hf risk score in other cohorts of patients with HFrEF is needed before clinical application.

Monitoring of the right ventricular responses to pressure overload: prognostic value and usefulness of echocardiography for clinical decision-making.

Regardless of whether pulmonary hypertension (PH) results from increased pulmonary venous pressure in left-sided heart diseases or from vascular remodeling and/or obstructions in pre-capillary pulmonary vessels, overload-induced right ventricular (RV) dysfunction and its final transition into right-sided heart failure is a major cause of death in PH patients. Being particularly suited for non-invasive monitoring of the right-sided heart, echocardiography has become a useful tool for optimizing the therapeutic decision-making and evaluation of therapy results in PH. The review provides an updated overview on the pathophysiological insights of heart-lung interactions in PH of different etiology, as well as on the diagnostic and prognostic value of echocardiography for monitoring RV responses to pressure overload. The article focuses particularly on the usefulness of echocardiography for predicting life-threatening aggravation of RV dysfunction in transplant candidates with precapillary PH, as well as for preoperative prediction of post-operative RV failure in patients with primary end-stage left ventricular (LV) failure necessitating heart transplantation or a LV assist device implantation. In transplant candidates with refractory pulmonary arterial hypertension, a timely prediction of impending RV decompensation can contribute to reduce both the mortality risk on the transplant list and the early post-transplant complications caused by severe RV dysfunction, and also to avoid combined heart-lung transplantation. The review also focuses on the usefulness of echocardiography for monitoring the right-sided heart in patients with acute respiratory distress syndrome, particularly in those with refractory respiratory failure requiring extracorporeal membrane oxygenation support. Given the pathophysiologic particularity of severe acute respiratory syndrome coronavirus (SARS-CoV-2) infection to be associated with a high incidence of thrombotic microangiopathy-induced increase in the pulmonary resistance, echocardiography can improve the selection of temporary mechanical cardio-respiratory support strategies and can therefore contribute to the reduction of mortality rates. On the whole, the review aims to provide a theoretical and practical basis for those who are or intend in the future to be engaged in this highly demanding field.

Formula selection for management of children with cow's milk allergy influences the rate of acquisition of tolerance: a prospective multicenter study.

OBJECTIVES: To prospectively evaluate the effect of different dietary management strategies on the rate of acquisition of tolerance in children with cow's milk allergy (CMA). STUDY DESIGN: Otherwise healthy children (aged 1-12 months) diagnosed with CMA were prospectively evaluated. The study population was divided into 5 groups based upon the formula used for management: (1) extensively hydrolyzed casein formula ([EHCF], n = 55); (2) EHCF + Lactobacillus rhamnosus GG [LGG], n = 71); (3) hydrolyzed rice formula (RHF, n = 46); (4) soy formula (n = 55); and (5) amino acid based formula (n = 33). A food challenge was performed after 12 months to assess acquisition of tolerance. RESULTS: Two hundred sixty children were evaluated (167 male, 64.2%; age 5.92 months, 95% CI 5.48-6.37; body weight 6.66 kg, 95% CI 6.41-6.91; IgE-mediated CMA 111, 42.7%). The rate of children acquiring oral tolerance after 12 months was significantly higher (P < .05) in the groups receiving EHCF (43.6%) or EHCF + LGG (78.9%) compared with the other groups: RHF (32.6%), soy formula (23.6%), and amino acid based formula (18.2%). Binary regression analysis coefficient (B) revealed that the rate of patients acquiring tolerance at the end of the study was influenced by 2 factors: (1) IgE-mediated mechanism (B -2.05, OR 0.12, 95% CI 0.06-0.26; P < .001); and (2) formula choice, such that those receiving either EHCF (B 1.48, OR 4.41, 95% CI 1.44-13.48; P = .009) or EHCF + LGG (B 3.35, OR 28.62, 95% CI 8.72-93.93; P < .001). CONCLUSIONS: EHCF accelerates tolerance acquisition in children with CMA if compared with other dietetic choices. This effect is augmented by LGG.

Early stroke after left ventricular assist device implantation: role of right heart failure.

Background: Both stroke and right heart failure (RHF) are common and serious complications after left ventricular assist device (LVAD) implantation. The objective of this study was to evaluate relation between stroke and RHF early after LVAD implantation. Methods: This is a retrospective observational cohort study. From January 2012 to December 2020, patients who underwent LVAD implantation in a single-center were enrolled. Patients with a non-dischargeable LVAD or without follow-up data were excluded. Early stroke was defined as a stroke event within 6 months after implantation. Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) definition was used for the diagnosis of RHF. Results: A total of 70 patients underwent LVAD implantation. Sixty-seven patients (95.7%) were successfully discharged and 16 patients (22.9%) died during follow-up. 14 patients (20.0%) experienced a stroke within 6 months after implantation, and 0.28 stroke events per patient-year occurred during follow-up. Postoperative RHF was more common in the stroke group (64.3% vs. 23.2%, P=0.008) and the median time from implantation to RHF was 1 day. In the Cox multivariable analysis, postoperative RHF [hazard ratio (HR): 5.063; 95% confidence interval (CI): 1.682-15.245; P=0.004], and cerebral perfusion pressure (CPP) on postoperative day (POD) 1 (HR: 0.923; 95% CI: 0.858-0.992; P=0.030) were independent predictors for early stroke. A CPP of 62 mmHg (sensitivity, 71.4%; specificity, 59.3%) was the cutoff value for early stroke according to the receiver operating characteristic (ROC) analysis. Conclusions: RHF after LVAD implantation may be a risk factor for early stroke. Prevention and management of postoperative RHF with adequate CPP could prevent early stroke after LVAD implantation.

Sex-based considerations for implementation of ventricular assist device therapy.

Women with advanced heart failure receive advanced surgical therapies such as durable left ventricular assist device (LVAD) implantation or heart transplantation at a rate much lower compared to males. Reasons for this discrepancy remain largely unknown. Much of what is understood reflects outcomes of those patients who ultimately receive device implant or heart transplantation. Females have been shown to have a higher mortality following LVAD implantation and experience higher rates of bleeding and clotting phenomena and right ventricular failure. Beyond outcomes, the literature is limited in the identification of pre-operative factors that drive lower than expected LVAD implant rates in this population. More focused research is needed to define the disparities in advance heart failure therapy delivery in women and other underserved populations.

Validation of R-hf risk score for risk stratification in ischemic heart failure patients: A prospective cohort study.

Background: The aim of this study was to validate R-heart failure (R-hf) risk score in ischemic heart failure patients. Methods: We prospectively recruited a cohort of 179 ischemic and 107 non-ischemic heart failure patients. This study mainly focused on ischemic heart failure patients. Non-ischemic heart failure patients were included for the purpose of validation of the risk score in various heart failure groups. Patients were stratified in high risk, moderate risk and low risk groups according to R-hf risk score. Results: A total of 179 participants with ischemic heart failure were included. Based on R-hf risk score, 82 had high risk, 50 had moderate risk and 47 had low risk heart failure scores. More than half of the patients having R-hf score of <5 had renal failure (n = 91, 50.8%) and anemia (n = 99, 55.3%). Notably, HFrEF was more prevalent in patients with high risk score (74, 90.2%). Patients with high risk score had significantly higher creatinine (2.63 ± 1.96, p < 0.001), Troponin-T HS (59.9 ± 38.0, p < 0.001) and PRO BNP (17842 ± 6684, p < 0.001) when compared to patients with low and moderate risk score. Patients with low risk score had significantly higher Hb (13.2 ± 1.85, p < 0.001), Albumin (3.69 ± 0.42, p < 0.001) and GFR (90.0 ± 8.04, p < 0.001). A R-hf score of <5 was a significant predictor of mortality in ischemic (OR = 50.34; 95% CI [16.94-194.00, p < 0.001) and non-ischemic (OR = 46.34; 95% CI [12.97-225.39], p < 0.001) heart failure patients. Conclusions: Lower R-hf risk score is a significant predictor of mortality in ischemic and non-ischemic heart failure patients. Risk score can be accessed at https://www.hfriskcalc.in.

The "Right" Definition for Post-Left Ventricular Assist Device Right Heart Failure: The More We Learn, the Less We Know.

Right heart failure is a major cause of morbidity and mortality following left ventricular assist device implantation. Over the past few decades, the definition proposed by the Interagency Registry of Mechanical Circulatory Support and Society of Thoracic Surgeons has continually evolved to better identify this complex pathology. We propose that the latest definition proposed by the Mechanical Circulatory Support Academic Research Consortium in 2020 will increase our recognition and understanding of this complex disease phenomenon.

Right Heart Failure in Mice Upon Pressure Overload Is Promoted by Mitochondrial Oxidative Stress.

We sought to unravel pathomechanisms of the transition of maladaptive right ventricular (RV) remodeling to right heart failure (RHF) upon pressure overload. Exposure of C57BL/6J and C57BL/6N mice to pulmonary artery banding disclosed a tight relation of structural remodeling with afterload, but a dissociation from RV systolic function. Reduced release of mitochondrial reactive oxygen species in C57BL/6J mice prevented the development of RHF. In patients with left heart failure, increased oxidative damage in RV sections was associated with severely impaired RV function. In conclusion, reactive oxygen species are involved in the transition of maladaptive RV remodeling to RHF.

Pulmonary vasodilator use in continuous-flow left ventricular assist device management.

Pulmonary hypertension (PH) due to left heart disease is the most common etiology for PH. PH in patients with heart failure with reduced fraction (HFrEF) is associated with reduced functional capacity and increased mortality. PH-HFrEF can be isolated post-capillary or combined pre- and post-capillary PH. Chronic elevation of left-sided filling pressures may lead to reverse remodeling of the pulmonary vasculature with development of precapillary component of PH. Untreated PH in patients with HFrEF results in predominant right heart failure (RHF) with irreversible end-organ dysfunction. Management of PH-HFrEF includes diuretics, vasodilators like angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers or angiotensin-receptor blocker-neprilysin inhibitors, hydralazine and nitrates. There is no role for pulmonary vasodilator use in patients with PH-HFrEF due to increased mortality in clinical trials. In patients with end-stage HFrEF and fixed PH unresponsive to vasodilator challenge, implantation of continuous-flow left ventricular assist device (cfLVAD) results in marked improvement in pulmonary artery pressures within 6 months due to left ventricular (LV) mechanical unloading. The role of pulmonary vasodilators in management of precapillary component of PH after cfLVAD is not well-defined. The purpose of this review is to discuss the pharmacologic management of PH after cfLVAD implantation.

Coronary Dissection and Right Heart Failure Salvaged by PCI With Percutaneous Intraluminal Microaxial RV-Assist Support.

Right heart failure is a dreaded sequelae of proximal right coronary artery occlusion that can complicate an angiogram or percutaneous coronary intervention. This case illustrates the use of a percutaneous intraluminal microaxial right ventricular assist device for high-risk percutaneous coronary intervention of an ostial right coronary artery dissection in refractory right heart failure. (Level of Difficulty: Advanced.).

Direct Percutaneous Transthoracic Cardiac Access for Recanalization of Longstanding Branch Pulmonary Artery Atresia.

We describe the use of direct percutaneous cardiac access to recanalize an atretic right pulmonary artery in an adolescent with complex congenital heart disease and right heart failure. This case highlights the problems associated with loss of central venous access and potential advantages of a direct cardiac approach to catheterization. (Level of Difficulty: Intermediate.).

Trapidil determines the fate of RHF rats through inhibition of ER stress.

Pulmonary arterial hypertension is a fatal disease, especially when it causes right heart failure (RHF). However, it is difficult to treat. It has been reported that trapidil (Tra) can improve the redox balance and cardiac conditions. In this study, we investigated the effect of Tra on RHF induced by monocrotaline (MCT) in rats. Male Wistar rats were treated with MCT or Tra. Treatment lasted 28 days, then rats were euthanized after echocardiography and catheterization. Subsequently, lungs and right ventricular myocardia were evaluated by hematoxylin and eosin, Masson, and TUNEL staining. Protein expression was detected by western blotting. We found remarkably expanded right ventricle end-diastolic volume, decreased partial pressure of oxygen (PaO2), increased partial pressure of carbon dioxide (PaCO2), right ventricular systolic pressure, mean pulmonary arterial pressure, lung/body weight, and liver/body weight in the RHF rat group, as well as increases in the apoptosis rate and the expression of endoplasmic reticulum stress (ERS)-related proteins. However, these changes were significantly inhibited by Tra. Our data suggested that inhibition of ERS is essential for improving RHF, and that therapeutic intervention of Tra in RHF rats works by reducing ERS.

Emerging therapies for right ventricular dysfunction and failure.

Therapeutic options for right ventricular (RV) dysfunction and failure are strongly limited. Right heart failure (RHF) has been mostly addressed in the context of pulmonary arterial hypertension (PAH), where it is not possible to discern pulmonary vascular- and RV-directed effects of therapeutic approaches. In part, opposing pathomechanisms in RV and pulmonary vasculature, i.e., regarding apoptosis, angiogenesis and proliferation, complicate addressing RHF in PAH. Therapy effective for left heart failure is not applicable to RHF, e.g., inhibition of adrenoceptor signaling and of the renin-angiotensin system had no or only limited success. A number of experimental studies employing animal models for PAH or RV dysfunction or failure have identified beneficial effects of novel pharmacological agents, with most promising results obtained with modulators of metabolism and reactive oxygen species or inflammation, respectively. In addition, established PAH agents, in particular phosphodiesterase-5 inhibitors and soluble guanylate cyclase stimulators, may directly address RV integrity. Promising results are furthermore derived with microRNA (miRNA) and long non-coding RNA (lncRNA) blocking or mimetic strategies, which can target microvascular rarefaction, inflammation, metabolism or fibrotic and hypertrophic remodeling in the dysfunctional RV. Likewise, pre-clinical data demonstrate that cell-based therapies using stem or progenitor cells have beneficial effects on the RV, mainly by improving the microvascular system, however clinical success will largely depend on delivery routes. A particular option for PAH is targeted denervation of the pulmonary vasculature, given the sympathetic overdrive in PAH patients. Finally, acute and durable mechanical circulatory support are available for the right heart, which however has been tested mostly in RHF with concomitant left heart disease. Here, we aim to review current pharmacological, RNA- and cell-based therapeutic options and their potential to directly target the RV and to review available data for pulmonary artery denervation and mechanical circulatory support.

[Training disability resource, a new disability inclusion scheme]. / La ressource handicap formation, une nouvelle piste inclusive.

Accessibility to training is necessary to improve the inclusion of people with a disability. Beyond the current or future legal obligations, the RHF (training disability resource) scheme helps training providers improve their understanding of these students' specific needs and to support them in their learning.

Vasopressin antagonism for decompensated right-sided heart failure.

BACKGROUND: Targeted treatment for decompensated right heart failure (RHF) with or without left heart failure is lacking. Vasopressin antagonists (vaptans) may offer an option by increasing urine output and fluid mobilization when used in acute decompensated RHF without impacting blood pressure or renal function, both common complications of loop diuretics. METHODS AND RESULTS: We searched electronic medical records from 2 institutions over 4 years for patients with RHF treated with vaptans. Urine output, creatinine, BUN and sodium, 1 day pre- versus 1 day post-vaptan initiation were compared. Baseline (admission) pre-vaptan values for patients with RHF who met inclusion criteria (n = 112) were RAP, median (interquartile range) = 19 (13-24) mmHg; cardiac index, mean ±â€¯standard deviation = 1.8 ±â€¯0.4 L/min/m2; BNP, 1078 (523-1690) pg/ml; creatinine clearance of 51 (39-69) ml/min, BUN, 37 (26-54) mg/dl, and serum [Na+] 132 (126-135) mEq/L. Most patients (n = 103/112) received intravenous inotrope (prior to vaptan, n = 91). Overall length of stay was 27 (16-43) days. Vaptan treatment (90% tolvaptan, 10% conivaptan) was associated with increased 24 h urine output, 1517 (906-2394) vs 2337 (1425-3744) mL, p = 0.005, and [Na+], 127 (124-130) vs 130 (126-135) mEq/L, p = 0.001, without significant change in Cr or BUN. Furosemide IV dose equivalent decreased or remained unchanged in 75% of patients at 24 h and 64% at 72 h compared to the 24 h prior to vaptan use. CONCLUSION: Vaptans were associated with a significant increase in urine output and serum sodium with an apparent reduction or stabilization of furosemide equivalent dosing in the early treatment period in patients with decompensated RHF. Vaptans may offer a management option for patients failing conventional diuretic-based treatment.