Integrative multiomics profiling of passion fruit reveals the genetic basis for fruit color and aroma.

Passion fruit (Passiflora edulis) possesses a complex aroma and is widely grown in tropical and subtropical areas. Here, we conducted the de novo assembly, annotation, and comparison of PPF (P. edulis Sims) and YPF (P. edulis f. flavicarpa) reference genomes using PacBio, Illumina, and Hi-C technologies. Notably, we discovered evidence of recent whole-genome duplication events in P. edulis genomes. Comparative analysis revealed 7.6∼8.1 million single nucleotide polymorphisms, 1 million insertions/deletions, and over 142 Mb presence/absence variations among different P. edulis genomes. During the ripening of yellow passion fruit, metabolites related to flavor, aroma, and color were substantially accumulated or changed. Through joint analysis of genomic variations, differentially expressed genes, and accumulated metabolites, we explored candidate genes associated with flavor, aroma, and color distinctions. Flavonoid biosynthesis pathways, anthocyanin biosynthesis pathways, and related metabolites are pivotal factors affecting the coloration of passion fruit, and terpenoid metabolites accumulated more in PPF. Finally, by heterologous expression in yeast (Saccharomyces cerevisiae), we functionally characterized 12 terpene synthases. Our findings revealed that certain TPS homologs in both YPF and PPF varieties produce identical terpene products, while others yield distinct compounds or even lose their functionality. These discoveries revealed the genetic and metabolic basis of unique characteristics in aroma and flavor between the 2 passion fruit varieties. This study provides resources for better understanding the genome architecture and accelerating genetic improvement of passion fruits.

A Novel Creatinine-Based Equation to Estimate Glomerular Filtration Rate in Chinese Population With Chronic Kidney Disease: Implications for DOACs Dosing in Atrial Fibrillation Patients.

Background: Over/under-estimating renal function may increase inappropriate dosing strategy associated adverse outcomes; however, previously reported equations to estimate renal function have limited accuracy in chronic kidney disease (CKD) patients. Consequently, we intended to develop a novel equation to precisely estimate renal function and subsequently guide clinical treatment for CKD patients. Methods: A novel approach, Xiangya-s equation, to estimate renal function for CKD patients was derived by linear regression analysis and validated in 1885 patients with measured glomerular filtration rate (mGFR) < 60 ml/min/1.73 m2 by renal dynamic imaging at three representative hospitals in China, with the performance evaluated by accuracy, bias and precision. In the meanwhile, 2,165 atrial fibrillation (AF) patients who initiated direct oral anticoagulants (DOACs) between December 2015 and December 2018 were identified and renal function was assessed by estimated creatinine clearance (eCrCl). Events per 100 patient-years was calculated. Cox proportional hazards regression was applied to compare the incidence of outcomes of each group. Results: Xiangya-s equation demonstrated higher accuracy, lower bias and improved precision when compared with 12 creatinine-based and 2 CysC-based reported equations to estimate GFR in multi-ethnic Chinese CKD patients. When we applied Xiangya-s equation to patients with AF and CKD prescribed DOACs, wide variability was discovered in eCrCl calculated by the Cockcroft-Gault (CG), Modification of Diet in Renal Disease Study (MDRD), Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI), Xiangya equation which we had developed for generally patients and Xiangya-s equations, which persisted after grouping by different renal function stages. Equation choice affected drug-dosing adjustments, with the formulas agreeing for only 1.19%, 5.52%, 33.22%, 26.32%, and 36.61% of potentially impacted patients for eCrCl cutoffs of <15, <30, 15-49, 30-49, ≥50 ml/min, respectively. Relative to CG equation, accordance in DOACs dosage was 81.08%, 88.54%, 62.25%, and 47.68% for MDRD, CKD-EPI, Xiangya and Xiangya-s equations for patients with CrCl < 50 ml/min (eCrCl cutoffs of <30, 30-49, ≥50 ml/min), respectively. Reclassification of renal function stages by Xiangya-s equation was significantly associated with stroke or systemic embolism, non-major clinically relevant bleeding and any bleeding events. Conclusion: Xiangya-s equation provides more accurate GFR estimates in Chinese CKD patients who need consecutive monitoring of renal function, which may assist clinicians in choosing appropriate drug dosages.

Protective Effects of Amlodipine Pretreatment on Contrast-Induced Acute Kidney Injury And Overall Survival In Hypertensive Patients.

BACKGROUD: Contrast-induced acute kidney injury (CI-AKI) is the most common adverse reaction caused by contrast media, which has been reported to prolong hospitalization and increase mortality and morbidity. The hypertensive population has proved susceptible to CI-AKI. Unfortunately, no therapeutic has been shown to prevent and cure CI-AKI effectively. A few studies have shown the protection of amlodipine on renal function, but the relationship between amlodipine and CI-AKI in hypertensive group is unknown, we aimed to study the effects of amlodipine on CI-AKI and overall survival in a large Chinese hypertensive cohort. METHODS: A retrospective, matched, cohort study was conducted among adults hospitalized at the Third Xiangya Hospital of Central South University from October 2007 to May 2017. CI-AKI was the primary end point of the trial, time-related all-cause mortality (including in-hospital) and length of hospital stay were the secondary end points. Propensity Score Matching was used to reduce the effect of selection bias and potential confounding. RESULTS: 868 patients with and 1,798 ones without amlodipine before contrast administration were included. The incidence of CI-AKI was 10.50%. The unadjusted, adjusted, and propensity-score matched incidence of CI-AKI were lower in patients treated with amlodipine (OR, 0.650; P = 0 .003; OR, 0.577; P = 0.007; OR, 0.687; P = 0.015, respectively), and the same results were found in the subgroups of diabetes, chronic kidney disease (CKD), non-CKD, low-osmolar, and elderly. Moreover, amlodipine reduced hospital stay, whether matched or not (7.08 ± 7.28 vs 7.77 ± 7.82, P = 0.027, before matching; vs 7.81 ± 7.58, P = 0.040, after matching). 1,046 patients finished follow-up including 343 amlodipine users and 703 non-users. The overall mortality was significantly lower among amlodipine users (10.79%) than controls (16.07%), the significant difference was found in survival between them (P = 0.024, log-rank test), amlodipine was associated with longer overall survival [HR, 0.623; 95% CI (0.430-0.908), P = 0.014]. CONCLUSION: In conclusion, we first found amlodipine treatment before contrast exposure played a role in protecting hypertensive patients from CI-AKI and prolonging survival.

A novel rat model of contrast-induced nephropathy based on dehydration.

BACKGROUND: Contrast-induced nephropathy (CIN) is a frequent cause of hospital-acquired acute kidney injury. Previous animal models developed to explore the pathogenesis of CIN were based primarily on surgery or indomethacin treatment. Thus, we sought to explore a novel CIN rat model comparable to the human CIN. METHODS AND RESULTS: Both serum creatinine and tubular injury score were used to assess the successful establishment of the present model. In our study, dehydration duration and the iohexol dosage were found to be the two most important factors to develop a rat CIN model. And, dehydration for 3 days plus furosemide (10 mL/kg) injection before iohexol (15 mL/kg) administration was demonstrated the optimal strategy. Renal injury induced by 15 mL/kg iohexol was almost twice more severe than 10 mL/kg. Moreover, significant renal function decrease, morphological damage and mitochondrial dysfunction occurred as early as 6 h after iohexol injection, not 24 h as previous studies reported. Unexpectedly, we firstly discovered that dehydration after iohexol administration did not increase the extent of renal damage, indicating that hydration after contrast media exposure may be ineffective. CONCLUSIONS: A novel CIN rat model based on dehydration and iohexol exposure was established and validated to assist in understanding and preventing CIN.

Thymic Stromal Lymphopoietin-Related Allergic Pathway in Patients With Vernal Keratoconjunctivitis.

PURPOSE: To investigate the expression of thymic stromal lymphopoietin (TSLP) and the relevant signaling pathways in the giant papillae obtained from patients with vernal keratoconjunctivitis (VKC) and to study the potential functional role and molecular mechanism of TSLP. METHODS: Giant papillae from VKC patients and control samples were used to perform immunohistochemical staining and analyze the mRNA expression of TSLP and related pathway by real-time polymerase chain reaction. RESULTS: TSLP was markedly expressed in the epithelial cells and some inflammatory cells of giant papillae, but not in the control conjunctival tissue. TSLP mRNA expression in the giant papillae of VKC was increased by 9.63 ± 0.99 (mean ± SD) fold compared with controls (P < 0.01). CD11c and OX40L immunoreactive cells largely infiltrated the giant papillae as observed by immunohistochemical staining. CD4Th2 cell infiltration was observed through high immunoreactivity of CD4. Th2 cytokines (IL-4, IL-5 and IL-13) and OX40 in the VKC specimens showed increased expression. Augmented gene expression levels of CD4 (6.88 ± 1.84), OX40L (7.60 ± 1.79), OX40 (7.25 ± 1.38), IL-4 (6.89 ± 1.46), IL-5 (8.42 ± 1.55), and IL-13 (9.69 ± 1.94) were significantly different from controls (P < 0.05). CONCLUSIONS: Our observations provide strong evidence that TSLP may be a crucial factor that contributes to the development and progression of allergic conjunctivitis. The results also demonstrated that TSLP activates dendritic cells to prime CD4T cells to differentiate into Th2 type and triggers Th2-dominant allergic inflammation through the TSLP/OX40L/OX40 signaling as part of immunopathogenesis of VKC.

Erythropoietin protects retinal pigment epithelial cells from oxidative damage.

Oxidative damage from reactive oxygen species (ROS) has been implicated in many diseases, including age-related macular degeneration, in which the retinal pigment epithelium (RPE) is considered a primary target. The aim of this study was to determine whether erythropoietin (EPO) protects cultured human RPE cells against oxidative damage and to identify the pathways that may mediate protection. EPO (1 IU/ml) significantly increased the viability of oxidant-treated RPE cells, decreased the release of the inflammatory cytokines tumor necrosis factor-alpha and interleukin-1beta, recovered the RPE cells' barrier integrity disrupted by oxidative stress, prevented oxidant-induced cell DNA fragmentation and membrane phosphatidylserine exposure, and also reduced the levels of oxidant-induced intracellular ROS and restored cellular antioxidant potential, total antioxidant capacity, glutathione peroxidase, and superoxide dismutase and decreased malondialdehyde, the end product of lipid peroxidation. EPO inhibited caspase-3-like activity. Protection by EPO was partly dependent on the activation of Akt1 and the maintenance of the mitochondrial membrane potential. No enhanced or synergistic protection was observed during application of Z-DEVD-FMK (caspase-3 inhibitor) combined with EPO compared with cultures exposed to EPO and H(2)O(2) alone. Together, these results suggest that EPO could protect against oxidative injury-induced cell death and mitochondrial dysfunction in RPE cells through modulation of Akt1 phosphorylation, mitochondrial membrane potential, and cysteine protease activity.