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.

Imatinib adherence prediction using machine learning approach in patients with gastrointestinal stromal tumor.

BACKGROUND: Nonadherence to imatinib is common in patients with gastrointestinal stromal tumor (GIST), which is associated with poor prognosis and financial burden. The primary aim of this study was to investigate the adherence rate in patients with GIST and subsequently develop a model based on machine learning (ML) and deep learning (DL) techniques to identify the associated factors and predict the risk of imatinib nonadherence. METHODS: All eligible patients completed four sections of questionnaires. After the data set was preprocessed, statistically significance variables were identified and further processed to modeling. Six ML and four DL algorithms were applied for modeling, including eXtreme gradient boosting, light gradient boosting machine (LGBM), categorical boosting, random forest, support vector machine, artificial neural network, multilayer perceptron, NaiveBayes, TabNet, and Wide&Deep. The optimal ML model was used to identify potential factors for predicting adherence. RESULTS: A total of 397 GIST patients were recruited. Nonadherence was observed in 185 patients (53.4%). LGBM exhibited superior performance, achieving a mean f1_score of 0.65 and standard deviation of 0.12. The predominant indicators for nonadherent prediction of imatinib were cognitive functioning, whether to perform therapeutic drug monitoring (if_TDM), global health status score, social support, and gender. CONCLUSIONS: This study represents the first real-world investigation using ML techniques to predict risk factors associated with imatinib nonadherence in patients with GIST. By highlighting the potential factors and identifying high-risk patients, the multidisciplinary medical team can devise targeted strategies to effectively address the daily challenges of treatment adherence.

Validation of pre-operative risk scores of contrast-induced acute kidney injury in a Chinese cohort.

BACKGROUND: Pre-operative risk scores are more valuable than post-procedure risk scores because of lacking effective treatment for contrast-induced acute kidney injury (CI-AKI). A number of pre-operative risk scores have been developed, but due to lack of effective external validation, most of them are also difficult to apply accurately in clinical practice. It is necessary to review and validate the published pre-operative risk scores for CI-AKI. MATERIALS AND METHODS: We systematically searched PubMed and EMBASE databases for studies of CI-AKI pre-operative risk scores and assessed their calibration and discriminatory in a cohort of 2669 patients undergoing coronary angiography or percutaneous coronary intervention (PCI) from September 2007 to July 2017. The definitions of CI-AKI may affect the validation results, so three definition were included in this study, CI-AKI broad1 was defined as an increase in serum creatinine (Scr) of 44.2 µmol/L or 25%; CI-AKI broad2, an increase in Scr of 44.2 µmol/L or 50%; and CI-AKI-narrow, an increase in Scr of 44.2 µmol/L. The calibration of the model was assessed with the Hosmer-Lemeshow test and the discriminatory capacity was identified by C-statistic. RESULTS: Of the 8 pre-operative risk scores for CI-AKI identified, 7 were single-center study and only 1 was based on multi-center study. In addition, 7 of the scores were just validated internally and only Chen score was externally validated. In the validation cohort of 2669 patients, the incidence of CI-AKI ranged from 3.0%(Liu) to 16.4%(Chen) for these scores. Furthermore, the incidence of CI-AKI was 6.59% (178) for CI-AKI broad1, 1.44% (39) for CI-AKI broad2, and 0.67% (18) for CI-AKI-narrow. For CI-AKI broads, C-statistics varied from 0.44 to 0.57. For CI-AKI-narrow, the Maioli score had the best discrimination and calibration, what's more, the C-statistics of Maioli, Chen, Liu and Ghani was ≥0.7. CONCLUSION: Most pre-operative risk scores were established based on single-center studies and most of them lacked external validation. For CI-AKI broads, the prediction accuracy of all risk scores was low. The Maioli score had the best discrimination and calibration, when using the CI-AKI-narrow definition.

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.

Isolation and identification of 3-bromocarbazole-degrading bacteria.

In this study, a bacterial strain, CH-1, capable of degrading 3-bromocarbazole (3-BCZ) was isolated from a polluted soil. Based on its physio-biochemical characteristics and 16S rRNA genes, strain CH-1 was identified as a Stenotrophomonas sp. Strain CH-1 was able to degrade 70% of 50 mg/L 3-BCZ within 8 d at pH 7.0 and 30°C in mineral salt medium (MSM). During the process, the main intermediate metabolite was identified as (2E, 4Z)-6-(2-amino-5-bromophenyl)-2-hydroxy-6-oxhexa-2, 4-dienoic by gas (2E, 4Z)-6-(2-amino-5-bromophenyl)-2-hydroxy-6-oxhexa-2,4-dienoic via gas chromatograph-mass spectrometry (GC-MS) analysis. The metabolite disappeared after 14 d, suggesting that the metabolite can also be degraded by strain CH-1. 3-BCZ is a new persistent organic pollutant. This is the first report of the biodegradation of 3-BCZ. The results indicated that strain CH-1 may be a promising bacterial candidate for the bioremediation of environments polluted with polyhalogenated carbazoles (PHCs).

Untargeted metabolomics analysis reveals the potential mechanism of imatinib-induced skin rash in patients with gastrointestinal stromal tumor.

Imatinib-induced skin rash poses a significant challenge for patients with gastrointestinal stromal tumor, often resulting in treatment interruption or discontinuation and subsequent treatment failure. However, the underlying mechanism of imatinib-induced skin rashes in gastrointestinal stromal tumor patients remains unclear. A total of 51 patients (27 with rash and 24 without rash) were enrolled in our study. Blood samples were collected concomitantly with the onset of clinical manifestations of rashes, and simultaneously collecting clinical relevant information. The imatinib concentration and untargeted metabolomics were performed by ultra-high-performance liquid chromatography-tandem mass spectrometry. There were no significant differences in age, gender, imatinib concentration and white blood cells count between the rash group and the control group. However, the rash group exhibited a higher eosinophil count (P<0.05) and lower lymphocyte count (P<0.05) compared to the control group. Untargeted metabolomics analysis found that 105 metabolites were significantly differentially abundant. The univariate analysis highlighted erucamide, linoleoylcarnitine, and valine betaine as potential predictive markers (AUC≥0.80). Further enriched pathway analysis revealed primary metabolic pathways, including sphingolipid signaling pathway, sphingolipid metabolism, cysteine and methionine metabolism, biosynthesis of unsaturated fatty acids, arginine and proline metabolism, and biosynthesis of amino acids. These findings suggest that the selected differential metabolites could serve as a foundation for the prediction and management of imatinib-induced skin rash in gastrointestinal stromal tumor patients.

Enantioselective effects of methamidophos on the coelomocytes lysosomal membrane stability of Eisenia fetida.

Many of organophosphorous insecticides are chiral compounds. In this study, the enantioselective effects of organophosphate insecticide methamidophos on the coelomocytes lysosomal membrane stability of earthworm Eisenia fetida were studied: (1) The enantiomers of methamidophos were absolutely separated by high-performance liquid chromatography with a commercial chiral column; (2) The neutral red retention assay was used to judge the lysosomal membrane stability. The results showed that with the concentration increasing, lysosomal membranes have been significantly destroyed by individual stereoisomers and racemate of methamidophos. The neutral red retention times were significantly descended from 76.88 to 29.78 min. Both (+)- and (-)-methamidophos showed more prone to destroy the integrity of the lysosomal membrane than the racemate. However, the different effect between stereoisomers is slight.

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.

Spectral blueshift of biophotonic activity and transmission in the ageing mouse brain.

The brain is considered to be a complex system with extremely low energy consumption and high-efficiency information transmission and processing, and this system has not been replicated by any artificial systems so far. Several studies indicate that the activity and transmission of biophotons in neural circuits may play an important role in neural information communication, while the biophotonic spectral redshift from lower to higher in animals may be related to the evolution of intelligence. The ageing processes of higher organisms are often accompanied by a decline in brain functions; however, the underlying mechanisms are unclear. Combining an ultraweak biophoton imaging system with the improved biophoton spectral analysis device, we compared and analyzed the spectra of glutamate-induced biophotonic emissions in mouse brain slices at different ages (newborn, 1, 3, 6, 12, 15, and 18 months). We found that the glutamate-induced biophotonic emissions presented a spectral blueshift from young to old mice, suggesting that the brain may transform to use relatively high-energy biophotons for neural information transmission and processing during the ageing process. Such a change may lead to a gradual decrease in the efficiency of the nervous system and provide a new biophysical mechanism for explaining the ageing-related changes in cognitive functions.

CaMKII as a key regulator of contrast-induced nephropathy through mPTP opening in HK-2 cells.

Contrast-induced nephropathy (CIN), refers to acute kidney injury observed after administration of contrast media during angiographic or other medical procedures such as urography, and accounting for 12% of all causes of acute renal failure, but no specific prevention or treatment strategy exists for its obscure pathophysiology. The aim of our study was to explore the influence of calcium/calmodulin-dependent protein kinase II (CaMKII) in CIN by using HK-2 cells. Knockdown of CypD was achieved by lentivirus, and CaMKII overexpression by transfection with the plasmid. In this study, we have demonstrated that CypD-mediated mPTP opening triggered mitochondrial dysfunction and tubule cells apoptosis in CIN. We also found that iohexol treatment was associated with mitochondrial ROS overloading, ATP depletion and LDH release. Inhibition of CypD with the pharmacologic inhibitor or knockdown of CypD abrogated mPTP opening, oxidative stress, mitochondria damage, and cell apoptosis induced by iohexol. In addition, we found that inhibition of the CaMKII activity alleviated iohexol-induced CypD expression, whereas also decreased mPTP opening, oxidative stress, mitochondria damage, and cell apoptosis, similarly to the inhibition of CypD did. Moreover, CaMKII overexpression enhanced iohexol-induced mPTP opening, mitochondrial damage and renal tubular epithelial cells apoptosis. These findings first identified the novel role of CaMKII in iohexol-induced tubular cells apoptosis and delineated the CaMKII-CypD/mPTP pathway during contrast-induced tubular cell damage. Hence, these results could provide a new strategy for CIN protection.

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.

Enantioselectivity in aquatic toxicity of synthetic pyrethroid insecticide fenvalerate.

Synthetic pyrethroids (SPs) are a family of chiral insecticides with a large number of stereoisomers. Fenvalerate (FV) is one of the most potent pyrethroid insecticides, controlling a wide range of insect pests in agricultural fields, public health situations and animal houses. FV contains two chiral centers. In this study, four stereoisomers of FV were absolutely separated by high-performance liquid chromatography with a commercial chiral column, CHIRALCEL OJ-H, using n-hexane containing 1,2-dichloroethane and ethanol as mobile phase. Toxicity assays of each isomer and racemate of FV were performed using Daphnia magna (D. magna), zebrafish (Danio rerio) and zebrafish embryo-larval. In the acute toxicity of D. magna, significant differences were observed: the 24h EC(50) of alphaS-2S-FV was 51 times more toxic than the alphaR-2R-FV, and the 48 h LC(50) results showed that the alphaS-2S-FV was 99 times more toxic than alphaR-2R-FV. In the toxicity assay of D. rerio, dramatic differences were also found: the LC(50) value of alphaS-2S-FV was 17, 22, 39 and 56 times more toxic than the alphaR-2R-FV at 24, 48, 72 and 96 h, respectively. The assays of 4-day-old zebrafish embryo-larval showed that the exposure to FV enantioselectively induced crooked body, yolk sac edema and pericardial edema and that the alphaS-2S-FV was 3.8 times stronger than the other isomers in 96-h mortality. The results indicate that the enantiomeric differences should be taken into consideration in assessing the ecological effects of SPs.

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.