Output information-based intermittent optimal control for continuous-time nonlinear systems with unmatched uncertainties via adaptive dynamic programming.

Intermittent control stands as a valuable strategy for resource conservation and cost reduction across diverse systems. Nonetheless, prevailing research is intractable to address the challenges posed by robust optimal intermittent control of nonlinear input-affine systems with unmatched uncertainties. This paper aims to fill this gap. Initially, we introduce an enhanced finite-time intermittent control approach to ensure stability within nonlinear dynamic systems harboring bounded errors. A neural networks (NNs) state observer is constructed to estimate system information. Subsequently, an optimal intermittent controller that operates within a finite time span, guaranteeing system stability by employing the Hamilton-Jacobi-Bellman (HJB) methodology. Furthermore, we devise an output information-based event-triggered intermittent (ETI) approach rooted in the robust adaptive dynamic programming (ADP) algorithm, furnishing an optimal intermittent control law. In this process, a critic NNs is introduced to estimate the cost function and optimal intermittent controller. Simulation results show that our proposed method is superior to existing intermittent control strategies.

A sham-controlled randomised trial of pulmonary artery denervation for Group 1 pulmonary arterial hypertension: one-year outcomes of the PADN-CFDA trial.

BACKGROUND: Long-term clinical outcomes after pulmonary artery denervation (PADN) in patients with Group 1 pulmonary arterial hypertension (PAH) have not been reported. AIMS: We aimed to investigate the effect of PADN on 1-year outcomes in patients with PAH. METHODS: In the multicentre PADN-CFDA trial, 128 patients with Group 1 PAH were randomly assigned to PADN plus a phosphodiesterase-5 inhibitor (PDE-5i) versus a sham PADN procedure plus a PDE-5i. The principal endpoint of interest for the present study was clinical worsening at 1 year after randomisation, the composite of worsening of PAH (increase in WHO functional class, need for additional PAH treatments or PAH-related hospitalisation), atrial septostomy, listing for lung transplantation, or all-cause death. RESULTS: One-year clinical follow-up was available in all patients. At 1 year, clinical worsening had occurred in 3 (4.8%) patients in the PADN plus PDE-5i group and in 15 patients (23.1%) in the sham plus PDE-5i group (adjusted hazard ratio: 0.17; 95% confidence interval [CI]: 0.05-0.60; p=0.006), driven by significantly increased rates of PAH-related hospitalisations, worsening functional class and the requirement for additional PAH treatments in the sham group. Results were consistent in high-risk, intermediate-risk and low-risk patients (pinteraction=0.186). Patients treated with PADN plus PDE-5i had an improvement in the between-group change in the six-minute walking distance (6MWD) from baseline to 1 year of 81.2 m (95% CI: 50.3-112.2; p<0.001) compared with PDE-5i treatment alone. CONCLUSIONS: In this multicentre sham-controlled randomised trial, PADN treatment for Group 1 PAH significantly reduced clinical worsening and improved the 6MWD during 1-year follow-up in patients treated with a PDE-5i.

Treatment effects of pulmonary artery denervation for pulmonary arterial hypertension stratified by REVEAL risk score: Results from PADN-CFDA trial.

BACKGROUND: The differential treatment effect of pulmonary artery denervation (PADN) in pulmonary arterial hypertension (PAH) patients with different risk burdens remains unclear. This study aimed to determine the effectiveness of PADN in low vs intermediate-high-risk PAH patients. METHODS: In total, 128 patients with treatment naive PAH included in the PADN-CFDA trial were categorized into low-risk and intermediate-high-risk patients. The primary endpoint was the between-group difference in the change in 6-min walk distance (6 MWD) from baseline to 6 months. RESULTS: In the intermediate-high-risk group, those treated with PADN and PDE-5i had a greater improvement in 6 MWD from baseline to 6 months as compared to those treated with sham plus PDE-5i. From baseline to 6 months, pulmonary vascular resistance (PVR) was reduced by -6.1 ± 0.6 and -2.0 ± 0.7 Wood units following PADN plus PDE-5i and sham plus PDE-5i, respectively, along with the significant reduction of NT-proBNP in the intermediate-high-risk group. However, there were no significant differences in 6 MWD, PVR, and NT-proBNP between the PADN plus PDE-5i and sham plus PDE-5i groups among low-risk patients. Moreover, the right ventricular function was equally improved by PADN treatment across the low-, intermediate-, and high-risk groups. Clinical worsening was less with PADN plus PDE-5i treatment during the 6-month follow-up. CONCLUSIONS: In patients with pulmonary arterial hypertension, pulmonary artery denervation plus PDE-5i improved exercise capacity, NT-proBNP, hemodynamic, and clinical outcomes during the 6-month follow-up among intermediate-high risk patients.

Safety and Efficacy of Drug-Coated Balloons in Patients with Acute Coronary Syndromes and Vulnerable Plaque.

BACKGROUND: Percutaneous coronary intervention (PCI) is the main treatment option for acute coronary syndromes (ACS) often related to the progression and rupture of vulnerable plaques. While drug-eluting stents (DES) are now routinely used in PCI, drug-coated balloons (DCB) are a new strategy to PCI and their practice in the treatment of ACS with vulnerable plaques has not been reported. This study aimed to evaluate the safety and efficacy of DCB in ACS complicated with vulnerable plaque lesions. METHODS: 123 patients were retrospectively analyzed and diagnosed with ACS and given PCI in our Cardiology Department from December 2020 to July 2022. Vulnerable plaques were confirmed by intravenous ultrasound (IVUS) in all patients. According to individual treatment plan, patients were entered into either DCB (n = 55) or DES (n = 68) groups. The results of coronary angiography and IVUS before and immediately after percutaneous coronary intervention were analyzed. The occurrence of major adverse cardiovascular events (MACE) and the results of coronary angiography were also evaluated during follow-up. RESULTS: There were no significant differences in baseline clinical characteristics, preoperative minimal luminal diameter (MLD), and preoperative diameter stenosis (DS) between the two groups. Also, there were no differences in IVUS plaque burden (PB), vessel area, and lumen area in the two groups before and immediately after PCI. The efficacy analysis showed that immediately after PCI, the DCB group had smaller MLD and higher degrees of lumen stenosis than the DES group (P < 0.05). However, during follow-up, no significant differences in MLD and DS were seen in two groups; relatively, late loss in luminal diameter（LLL）in the DCB group was smaller (P＜0.05). Safety analysis showed that during follow-up, 9 patients developed restenosis after DCB implantation while restenosis occurred in 10 patients with DES treatment, no statistical difference in the incidence of restenosis in the two groups. Besides, there was no statistical difference in the incidence of major adverse cardiac events（MACE）during hospitalization and follow-up in the DCB group (7.3% (4/55)) and the DES group (8.8% (6/68)). CONCLUSION: DCB is safe and effective for ACS complicated with vulnerable plaque and has an advantage over DES in LLL.

Pulmonary Artery Denervation for Pulmonary Arterial Hypertension: A Sham-Controlled Randomized PADN-CFDA Trial.

BACKGROUND: World Health Organization (WHO) group 1 pulmonary arterial hypertension (PAH) is a progressive, debilitating disease. Previous observational studies have demonstrated that pulmonary artery denervation (PADN) reduces pulmonary artery pressures in PAH. However, the safety and effectiveness of PADN have not been established in a randomized trial. OBJECTIVES: The aim of this study was to determine the treatment effects of PADN in patients with group 1 PAH. METHODS: Patients with WHO group 1 PAH not taking PAH-specific drugs for at least 30 days were enrolled in a multicenter, sham-controlled, single-blind, randomized trial. Patients were assigned to receive PADN plus a phosphodiesterase-5 inhibitor or a sham procedure plus a phosphodiesterase-5 inhibitor. The primary endpoint was the between-group difference in the change in 6-minute walk distance from baseline to 6 months. RESULTS: Among 128 randomized patients, those treated with PADN compared with sham had a greater improvement in 6-minute walk distance from baseline to 6 months (mean adjusted between-group difference 33.8 m; 95% CI: 16.7-50.9 m; P < 0.001). From baseline to 6 months, pulmonary vascular resistance was reduced by -3.0 ± 0.3 WU after PADN and -1.9 ± 0.3 WU after sham (adjusted difference -1.4; 95% CI: -2.6 to -0.2). PADN also improved right ventricular function, reduced tricuspid regurgitation, and decreased N-terminal pro-brain natriuretic peptide. Clinical worsening was less (1.6% vs 13.8%; OR: 0.11; 95% CI: 0.01-0.87), and a satisfactory clinical response was greater (57.1% vs 32.3%; OR: 2.79; 95% CI: 1.37-5.82) with PADN treatment during 6-month follow-up. CONCLUSIONS: In patients with WHO group 1 PAH, PADN improved exercise capacity, hemodynamic status, and clinical outcomes during 6-month follow-up. (Safety and Efficacy of Pulmonary Artery Denervation in Patients With Pulmonary Arterial Hypertension [PADN-CFDA]; NCT03282266).

The Drug Coated Balloon-Only Strategy for Treatment of de Novo Left Main Coronary Artery Bifurcation Lesion: Stentless Strategy.

The study aimed to evaluate the efficacy and safety of drug coated balloon-only strategy (DCB-only) in the treatment of de novo left main coronary artery (LM) bifurcation lesions. 85 patients were enrolled in this study and classified them into two groups: DCB-only group (n = 36) and DES group (n = 49). The MLD of target vessels was measured before and immediately after percutaneous coronary intervention (PCI) and late luminal loss (LLL) were also calculated. And the occurrence of major adverse cardiovascular events (MACE) was also evaluated. Compared with that before PCI, the MLD of target lesions significantly increased immediately after PCI (P < .05) and no MACE was recorded during the perioperative period both in two groups. The MLD at follow-up was significantly higher than that before both DCB and DES treatment. Compared with the DES group, the MLD of the DCB group was smaller than immediately after PCI in the LM and LAD (P < .05). The LLL of LAD in DCB group was smaller than that in DES group (P < .05). There was no significant difference in the incidence of luminal restenosis at the target lesion between the two groups, and no significant difference in the incidence of MACE (P > .05). The use of DCB-only to treat de novo LM bifurcation lesions is effective and relatively safe, which provides new ideas for the treatment of LM coronary artery bifurcation lesions in the future.

Long-term mortality after pulmonary artery denervation stratified by baseline functional class in patients with pulmonary arterial hypertension: Long-term mortality after PADN stratified by functional class.

Aims: This study aimed to assess the long-term effects of pulmonary artery denervation (PADN) on mortality in patients with pulmonary arterial hypertension (PAH). Methods and results: Between March 2012 and March 2018, a total of 120 patients with PAH, who underwent PADN treatment and were prospectively followed up, were analysed. Patients were classified into World Health Organization (WHO) Functional Class I and II (FC 1-2; n=46) and Functional Class III and IV (FC 3-4; n=74) according to their FC prior to PADN. The primary endpoint was lung transplantation-free mortality until March 2021. The secondary endpoint was a change in the six-minute walk distance (6MWD). During the median of 4.8 years of follow-up, 23 (19.2%) patients died, predominantly from the FC 3-4 group (25.7%), compared to 8.7% in the FC 1-2 group (p=0.034). The mortality rate at one year (2.2% vs 12.2%, p=0.087) and three years (6.5% vs 17.6%, p=0.102) was numerically low in the FC 1-2 group versus the FC 3-4 group, respectively. The median net increase of 6MWD was +29 m in the FC 1-2 group, compared to +60.5 m in the FC 3-4 group (p=0.037). Conclusions: PADN results in significant improvements in survival at long-term follow-up, especially in patients with PAH in FC 3-4. This study was the continuation of the PADN-1 study which was registered at URL: http://www.chictr.trc.com.cn. Unique identifier: chiCTR-ONC-12002085.

Analysis of the Correlation Between the Ratio of Monocytes to High-Density Lipoprotein Cholesterol and in-Stent Restenosis in Patients with Premature Coronary Heart Disease.

BACKGROUND: High-density lipoprotein cholesterol (HDL-C) and monocytes are associated with coronary artery disease, and the ratio of monocytes to high-density lipoprotein (MHR) is associated with long-term adverse outcomes and the recurrence of atrial fibrillation. Currently, the trend of coronary heart disease proned to young people is becoming prominent. However, the relationship between MHR and in-stent restenosis (ISR) in patients with premature coronary heart disease (PCHD) has not been investigated. Therefore, we aimed to assess the relationship between MHR and ISR in patients with PCHD. METHODS: We retrospectively included 257 patients (men ≤ 55 years old, women ≤ 65 years old) with PCHD who underwent drug-eluting stent implantation and follow-up coronary angiography at the First Affiliated Hospital of Zhengzhou University from September 2016 to September 2019. Patients were divided into ISR and non-ISR groups depending on their follow-up coronary angiography results. Relative clinical information was recorded and analyzed. A receiver operating characteristic curve analysis was used to determine the optimum pre-procedural MHR cutoff value to predict ISR. RESULTS: Logistic regression analysis showed that MHR, smoking history, and fibrinogen were independent risk factors for ISR in patients with PCHD. The area under the receiver operating characteristic curve (AUC) of MHR was 0.750 (95% confidence interval, 0.695-0.820; P < .001), the cutoff value was 546.88, and the specificity and sensitivity were 65.2% and 78%, while the AUC of monocytes was 0.631 (95% confidence interval, 0.638-0.794; P < .001), the cutoff value was 590, and the specificity and sensitivity were 77.1% and 60.0%. CONCLUSION: MHR is an independent risk factor for ISR in patients with PCHD and showed a certain predictive value.

Improved Outcomes of Combined Main Branch Stenting and Side Branch Drug-Coated Balloon versus Two-Stent Strategy in Patients with Left Main Bifurcation Lesions.

BACKGROUND: Drug-eluting stent (DES) plus drug-coated balloon (DCB) is a safe and effective treatment strategy for coronary artery bifurcation lesions, but there is no report about this strategy being used for left main (LM) bifurcation lesions. We aim to explore the efficacy and safety of DES plus DCB in the treatment of LM bifurcation lesions. METHODS: A total of 100 patients diagnosed with LM bifurcation lesions by coronary angiography were retrospectively enrolled at our center from January 2018 to December 2019. They received either a two-stent strategy or a main branch (MB) stenting plus side branch (SB) DCB strategy and were accordingly divided into the 2-DES group and the DES + DCB group. Patients treated with DES + DCB were compared with a cohort of matched patients treated with a 2-DES strategy. Clinical data was collected and quantitative coronary analysis was performed. RESULTS: For immediate postoperative angiography, though the two groups had no differences in the minimal luminal diameter (MLD) and luminal stenosis of MB, the DES + DCB group had significantly lower SB ostial MLD and a higher degree of residual lumen stenosis than the 2-DES group (P < 0.05). At the time of follow-up, the SB ostial MLD of the DES + DCB group was higher than that of the 2-DES group, but lumen stenosis, late lumen loss (LLL), and LLL at the distal end of the left MB were all smaller than those of the 2-DES group (Ps < 0.05). Furthermore, the incidence of lumen restenosis and MACE between the two groups had no significance. CONCLUSION: The combination of DES and DCB is relatively safe and effective for the treatment of LM bifurcation lesions, and this strategy seems to have advantages in reducing LLL at the SB ostium.

Overexpression of Ubiquitin-Specific Protease 2 (USP2) in the Heart Suppressed Pressure Overload-Induced Cardiac Remodeling.

Ubiquitin-specific protease 2 (USP2) is an important member of the deubiquitination system. GEO dataset revealed that USP2 was downregulated in the hearts under pressure overload. However, the cardiomyocyte-specific function of USP2 in the setting of pressure overload is unknown. In the current study, a mouse model of pressure overload was induced by transverse aortic constriction (TAC, 2 weeks). Overexpression of USP2 in the heart was conducted by AAV9 infection. Changes in heart histology were detected by Masson's trichrome staining and hematoxylin-eosin staining (H&E). Echocardiography was used to assess cardiac function. The size of cardiomyocytes was examined by wheat germ agglutinin (WGA) staining. Cardiac oxidative stress was detected by dihydroethidine staining. Our results showed that USP2 was downregulated in the cardiomyocytes following 2 weeks of TAC. Overexpression of cardiac USP2 preserved ventricular function following 2 weeks of TAC. Overexpression of cardiac USP2 inhibited TAC-induced cardiac remodeling, by suppressing cardiac hypertrophy, inhibiting inflammatory responses and fibrosis, and attenuating oxidative stress. Our findings reveal a previously unrecognized role of USP2 in regulating pressure overload-induced cardiac remodeling.

The protective role of DPP4 inhibitors in atherosclerosis.

Diabetes is a chronic non-communicable disease whose incidence continues to grow rapidly, and it is one of the most serious and critical public health problems. Diabetes complications, especially atherosclerosis-related chronic vascular complications, are a serious threat to human life and health. Growing evidence suggests that dipeptidyl peptidase 4 (DPP4) inhibitors, beyond their role in improving glycemic control, are helpful in ameliorating endothelial dysfunction in humans and animal models of T2DM. In fact, DPP4 inhibitors have been shown by successive studies to play a protective effect against vascular complications. On one hand, in addition to their hypoglycemic effects, DPP4 inhibitors participate in the control of atherosclerotic risk factors by regulating blood lipids and lowering blood pressure. On the other hand, DPP4 inhibitors exert anti-atherosclerotic effects directly through multiple mechanisms, including improving endothelial cell dysfunction, increasing circulating endothelial progenitor cell (EPCs) levels, regulating mononuclear macrophages and smooth muscle cells, inhibiting inflammation and oxidative stress and improving plaque instability. Herein, we review the beneficial roles of DPP4 inhibitors in atherosclerosis as detailed.

NLRP3 inflammasome mediate palmitate-induced endothelial dysfunction.

AIMS: Free fatty acids (FFA) is a key contributor to insulin resistance and endothelial dysfunction. However, the precise mechanism underlying the role of FFA remains elusive. This study aimed to investigate the role of NLRP3 (NOD-like receptor pyrin domain containing-3) inflammasome in FFA induced endothelial dysfunction. MAIN METHODS: HUVECs were transfected with NLRP3 siRNA and then stimulated with LPS and palmitate. C57 BL/6 J mice transfected with NLRP3 Lenti-Virus were fed with a high-fat diet (HFD). The levels of NLRP3 inflammasome, AMPKα (AMP-activated protein kinase), endothelial nitric oxide synthase (eNOS) and the activity of the insulin signal pathway, in endothelial cells were determined via Western blotting. Endothelial function was determined by measuring the level of endothelium-dependent vasodilatation. KEY FINDINGS: FFA could activate NLRP3 inflammasome and induce IL-1ß release both in vitro. and in vivo. Using siRNA and Lenti-Virus to inhibit NLRP3 abolished palmitate-induced IL-1ß release and restored impaired phosphorylation of IRS-1 (Tyr), Akt (Ser473) and eNOS (Ser1177) and ACh-mediated endothelium-dependent vasorelaxation induced by palmitate. AMPKα activator AICAR(5-aminoimidazole-4-carbox-amide-1-ß-d-ribofuranoside) inhibited NLRP3 inflammasome activation and decreased IL-1ß release and restored impaired insulin signal pathway induced by palmitate. SIGNIFICANCE: NLRP3 inflammasome activation via AMPKα inactivation mediated palmitate-induced endothelial dysfunction through involves IL-1ß-induced insulin signal pathway.

TRPM7 channel inhibition exacerbates pulmonary arterial hypertension through MEK/ERK pathway.

The increased proliferation and apoptosis resistance of pulmonary artery smooth muscle cells (PASMCs) drive the progression of pulmonary arterial hypertension (PAH). The transient receptor potential melastatin 7 (TRPM7) is an endogenous magnesium channel reported to promote the proliferation of SMCs. However, whether TRPM7 is associated with PAH pathogenesis remains uncharacterized. We found that TRPM7 was downregulated in PASMCs from PAH human and Sprague-Dawley rats with hypoxia-induced PAH. Similar results were reproduced in PASMCs treated with PAH stimuli in vitro. Additionally, the TRPM7 currents and intracellular magnesium level in PASMCs were also reduced by PAH stimuli. Functionally, TRPM7 inhibition with waixenicin A or knockdown promoted, and reversely, its overexpression inhibited the proliferation and apoptosis resistance of PASMCs. Moreover, waixenicin A exacerbated hypoxia-induced PAH features in rats. Furthermore, TRPM7 inhibition activated MEK/ERK pathway, and the effects of TRPM7 inhibition were drastically attenuated by pathway specific inhibitor U0126, thus suggesting that activating MEK/ERK pathway is a predominant mechanism through which TRPM7 inhibition exacerbates PAH. In summary, these results may identify TRPM7 as a novel negative regulator in PAH pathogenesis, and suggest that improving its function may represent an antagonistic strategy to modify PAH progression.

C1qTNF-related protein 1 attenuates doxorubicin-induced cardiac injury via activation of AKT.

AIMS: The clinical use of doxorubicin (Dox) is limited due to a degenerative irreversible cardiac toxicity, but the precise mechanisms that contribute to this pathological response are not understood. C1q/TNF-related protein 1 (CTRP1), which is a conserved protein of the C1q family, has notable metabolic and cardiovascular functions. However, whether CTRP1 can attenuate Dox-induced cardiac injury remains unclear. Our study aimed to investigate the effect of CTRP1 on Dox-induced cardiotoxicity and assessed the mechanisms of this effect. MATERIALS AND METHODS: We manipulated CTRP1 expression in the heart using in vivo gene delivery system. Two weeks after gene delivery, the mice received a single intraperitoneal injection of Dox (20 mg/kg) to induce cardiac injury. KEY FINDINGS: Cardiac CTRP1 protein levels were decreased in DOX-treated mice. CTRP1 overexpression reduced plasma cardiac troponin I, restored cardiac function and attenuated cardiomyocyte apoptosis in Dox-treated mice. CTRP1 also improved cell viability and reduced lactate dehydrogenase release in vitro. Dox resulted in the decreased the protein kinase B (PKB/AKT) phosphorylation, which were restored by CTRP1 overexpression. AKT inhibition offset the inhibitory effects of CTRP1 on myocyte apoptosis in vitro. CTRP1 lost its protection against Dox-induced cardiac injury in mice with AKT deficiency. Furthermore, infusion of recombinant CTRP1 protein could reverse pre-established injury in heart induced by Dox treatment. SIGNIFICANCE: In conclusion, CTRP1 protected against Dox-induced cardiotoxicity via activation of AKT. CTRP1 has the therapeutic potential to treat Dox-induced cardiotoxicity.

The association between an endothelial nitric oxide synthase gene polymorphism and coronary heart disease in young people and the underlying mechanism.

With the development of molecular biological technology, the association between genes and diseases has drawn increasing attention of researchers; the endothelial nitric oxide synthase (eNOS) gene has been reported to be a candidate gene for cardiovascular disease (CHD). The present study aimed to investigate the association between a polymorphism of eNOS and the risk of CHD in young people (≤40 years old), in addition to the underlying mechanism. A total of 234 cases of CHD in young individuals were collected as the CHD group and 228 cases of healthy individuals as the control group. Peripheral blood was collected and the genotype of the eNOS G894T polymorphism was identified by polymerase chain reaction-restriction fragment length polymorphism, the gene frequency was calculated and the distributions of genotype and allele frequency between the two groups were compared. Bioinformatics tools were employed to analyze the differences in the local protein structures of the eNOS G894T polymorphism and the biological mechanism was preliminary discussed. The results demonstrated that there were significant differences in the distribution of genotype frequency and allele frequency of the eNOS G894T gene polymorphism between the CHD group and control group (P<0.05). The risk of CHD in GT and TT genotypes were higher compared with the GG genotype (P<0.05). The G894T polymorphism led to Glu298Asp mutation of encoded protein, which is within the active site of eNOS, and partial structures of the protein were converted from random coil to α­helix. In conclusion, the eNOS G894T gene polymorphism was associated with the occurrence and development of CHD in young people. The potential mechanism is that the G894T polymorphism leads to altered protein structure, which affects the function of eNOS in generating nitric oxide and cardiovascular diastole. The results of the present study suggested a potential target gene for the prevention and treatment of CHD in young people (≤40 years old).

Allelic variations at four major maturity E genes and transcriptional abundance of the E1 gene are associated with flowering time and maturity of soybean cultivars.

The time to flowering and maturity are ecologically and agronomically important traits for soybean landrace and cultivar adaptation. As a typical short-day crop, long day conditions in the high-latitude regions require soybean cultivars with photoperiod insensitivity that can mature before frost. Although the molecular basis of four major E loci (E1 to E4) have been deciphered, it is not quite clear whether, or to what degree, genetic variation and the expression level of the four E genes are associated with the time to flowering and maturity of soybean cultivars. In this study, we genotyped 180 cultivars at E1 to E4 genes, meanwhile, the time to flowering and maturity of those cultivars were investigated at six geographic locations in China from 2011 to 2012 and further confirmed in 2013. The percentages of recessive alleles at E1, E2, E3 and E4 loci were 38.34%, 84.45%, 36.33%, and 7.20%, respectively. Statistical analysis showed that allelic variations at each of four loci had a significant effect on flowering time as well as maturity. We classified the 180 cultivars into eight genotypic groups based on allelic variations of the four major E loci. The genetic group of e1-nf representing dysfunctional alleles at the E1 locus flowered earliest in all the geographic locations. In contrast, cultivars in the E1E2E3E4 group originated from the southern areas flowered very late or did not flower before frost at high latitude locations. The transcriptional abundance of functional E1 gene was significantly associated with flowering time. However, the ranges of time to flowering and maturity were quite large within some genotypic groups, implying the presence of some other unknown genetic factors that are involved in control of flowering time or maturity. Known genes (e.g. E3 and E4) and other unknown factors may function, at least partially, through regulation of the expression of the E1 gene.