By using the thiazolo5,4-dthiazole (TzTz) moiety as the core of a proton acceptor, compounds 2,2′-(thiazolo5,4-dthiazole-2,5-diyl)bis(4-tert-butylphenol) ( t -HTTH) and ...4-tert-butyl-2-(5-(5-tert-butyl-2-methoxyphenyl)thiazolo5,4-dthiazol-2-yl)phenol ( t -MTTH) have been strategically designed and synthesized. Upon photoexcitation, both t -HTTH and t -MTTH undergo a reversible type excited-state intramolecular proton transfer (ESIPT), the underlying mechanism of which has been verified by femtosecond early relaxation dynamics in various solvents. The pre-equilibrium in the excited state leads to both normal (∼440 nm) and proton-transfer tautomer (∼560 nm) emissions, for which the intensity ratio is dependent on both the molecular structure and the polarity of surrounding media. As a result, the emission can be widely tuned from blue to yellow via white-light luminescence. On the basis of t -MTTH, a white organic light emitting diode (WOLED) was successfully fabricated, which achieved external quantum efficiency (ηext) of 1.70% with Commission Internationale de L’Eclairage coordinates of (0.29, 0.33). More importantly, the electroluminescent spectra show superior color stability that is independent of luminance. The result demonstrates for the first time a credible WOLED based on a unimolecular ESIPT reaction, which may have far-reaching implications for practical application.
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IJS, KILJ, NUK, PNG, UL, UM
Background
In pancreatic cancer, methods to predict early recurrence (ER) and identify patients at increased risk of relapse are urgently required.
Purpose
To develop a radiomic nomogram based on MR ...radiomics to stratify patients preoperatively and potentially improve clinical practice.
Study Type
Retrospective.
Population
We enrolled 303 patients from two medical centers. Patients with a disease‐free survival ≤12 months were assigned as the ER group (n = 130). Patients from the first medical center were divided into a training cohort (n = 123) and an internal validation cohort (n = 54). Patients from the second medical center were used as the external independent validation cohort (n = 126).
Field Strength/Sequence
3.0T axial T1‐weighted (T1‐w), T2‐weighted (T2‐w), contrast‐enhanced T1‐weighted (CET1‐w).
Assessment
ER was confirmed via imaging studies as MRI or CT. Risk factors, including clinical stage, CA19‐9, and radiomic‐related features of ER were assessed. In addition, to determine the intra‐ and interobserver reproducibility of radiomic features extraction, the intra‐ and interclass correlation coefficients (ICC) were calculated.
Statistical Tests
The area under the receiver‐operator characteristic (ROC) curve (AUC) was used to evaluate the predictive accuracy of the radiomic signature in both the training and test groups. The results of decision curve analysis (DCA) indicated that the radiomic nomogram achieved the most net benefit.
Results
The AUC values of ER evaluation for the radiomics signature were 0.80 (training cohort), 0.81 (internal validation cohort), and 0.78 (external validation cohort). Multivariate logistic analysis identified the radiomic signature, CA19‐9 level, and clinical stage as independent parameters of ER. A radiomic nomogram was then developed incorporating the CA19‐9 level and clinical stage. The AUC values for ER risk evaluation using the radiomic nomogram were 0.87 (training cohort), 0.88 (internal validation cohort), and 0.85 (external validation cohort).
Data Conclusion
The radiomic nomogram can effectively evaluate ER risks in patients with resectable pancreatic cancer preoperatively, which could potentially improve treatment strategies and facilitate personalized therapy in pancreatic cancer.
Level of Evidence: 4
Technical Efficacy: Stage 4
J. Magn. Reson. Imaging 2020;52:231–245.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Background and Purpose
Colorectal cancer is the third most common cancer worldwide. HER2 and HER3 are two members of human epidermal receptor family of tyrosine kinase receptors (RTKs) and associated ...with poor survival in colorectal cancer. They have been observed as important therapeutic targets in various types of cancer. Corosolic acid, a natural pentacyclic triterpene, has been demonstrated to have a significant anti‐cancer activity. However, the target of corosolic acid has not yet been explored. This study aimed to reveal the direct targets of corosolic acid underlying its anti‐cancer activities.
Experimental Approach
The targets of corosolic acid were revealed by the phospho‐RTK array, bio‐layer interferometry, co‐immunoprecipitation, and proximity ligation assay. The inhibitory action of corosolic acid on HER2/HER3 heterodimerization and related downstream signalling were investigated in HCT116 and SW480 cells. In addition, the chemo‐preventive effects of corosolic acid were validated in both HCT116 xenograft model and AOM/DSS model.
Key Results
Our results demonstrated that corosolic acid could prevent NRG1‐induced HER2/HER3 heterodimerization and suppress the phosphorylation of both HER2 and HER3. Furthermore, HER2 and HER3 could regulate the downstream signalling pathways of RalA/RalBP1/CDK1 and PI3K/Akt/PKA, respectively, resulting in the changes in phosphorylation of Drp1 and mitochondrial dynamics. corosolic acid exhibited anti‐cancer activity in both HCT116 xenograft model and AOM/DSS model.
Conclusions and Implications
Collectively, our results demonstrated corosolic acid directly targeted HER2 and HER3 heterodimerization and inhibited mitochondrial fission via regulating RalA/RalBP1/CDK1 and PI3K/Akt/PKA pathways, revealing a novel mechanism underlying the beneficial effects of corosolic acid on colorectal cancer.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Dysregulated maternal nutrition, such as vitamin deficiencies and excessive levels of glucose and fatty acids, increases the risk for congenital heart disease (CHD) in the offspring. However, the ...association between maternal amino‐acid levels and CHD is unclear. Here, it is shown that increased leucine levels in maternal plasma during the first trimester are associated with elevated CHD risk in the offspring. High levels of maternal leucine increase embryonic lysine‐leucylation (K‐Leu), which is catalyzed by leucyl‐tRNA synthetase (LARS). LARS preferentially binds to and catalyzes K‐Leu modification of lysine 339 within T‐box transcription factor TBX5, whereas SIRT3 removes K‐Leu from TBX5. Reversible leucylation retains TBX5 in the cytoplasm and inhibits its transcriptional activity. Increasing embryonic K‐Leu levels in high‐leucine‐diet fed or Sirt3 knockout mice causes CHD in the offspring. Targeting K‐Leu using the leucine analogue leucinol can inhibit LARS activity, reverse TBX5 K‐Leu modification, and decrease the occurrence of CHD in high‐leucine‐diet fed mice. This study reveals that increased maternal leucine levels increases CHD risk in the offspring through inhibition of embryonic TBX5 signaling, indicating that leucylation exerts teratogenic effects during heart development and may be an intervening target of CHD.
Increased gestational leucine levels are significantly associated with risk for congenital heart disease (CHD) in offspring. Increased embryonic lysine‐leucylation (K‐Leu), generated via maternal high‐leucine‐chow feeding, or Sirt3 knockout, causes CHD in the offspring of mice, through elevating embryonic K‐Leu of TBX5 and inhibiting TBX5 activity. Targeting K‐Leu via leucinol reverses K‐Leu modifications and lowers the occurrence of CHD in mice.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
SUMMARY
Slow development has been shown to be a general mechanism to restore the fertility of thermo‐sensitive and photoperiod‐sensitive genic male sterile (TGMS and PGMS) lines in Arabidopsis. rpg1 ...is a TGMS line defective in primexine, which is essential for pollen wall pattern formation. Here, we showed that RPG1‐GFP was highly expressed in microsporocytes, microspores, and pollen grains but not in the tapetum in the complemented transgenic line, suggesting that microsporocytes are the main sporophytic cells for primexine formation. Further cytological observations showed that primexine formation in rpg1 was partially restored under slow growth conditions, leading to its fertility restoration. RPG2 is the homolog of RPG1 in Arabidopsis. We revealed that the fertility recovery of rpg1 rpg2 was significantly reduced compared with that of rpg1 under low temperature. The RPG2‐GFP protein was also expressed in microsporocytes in the RPG2‐GFP (WT) transgenic line. These results suggest that RPG2 plays a redundant role in rpg1 fertility restoration. rpg1 plants were male sterile at the early growth stage, while their fertility was partially restored at the late developmental stage. The fertility of the rpg1 lateral branches was also partially restored. Further growth analysis showed that slow growth at the late reproductive stage or on the lateral branches led to fertility restoration. This work reveals the importance of gene redundancy in fertility restoration for TGMS lines and provides further insight into pollen wall pattern formation.
Significance Statement
This work reveals the importance of gene redundancy in fertility restoration for TGMS lines. Slow development at the late developmental stage or on the lateral branch can restore the fertility in TGMS lines.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
N-doped carbon materials have been proven to be effective catalysts for activating peroxymonosulfate (PMS). Marine algae biomass is rich in nitrogenous substances , which can reduce the cost of ...N-doping process and can obtain excellent N-doped catalysts cheaply and easily. In this study, kelp biomass was selected to prepare N-doped kelp biochar (KB) materials. The high defect degree, high specific surface area, and participation of graphite N make KB have excellent catalytic degradation ability. The KB degraded 40 mg/L ofloxacin (OFL) close to 100% within 60 min, applied with PMS. Through quenching experiments and electron paramagnetic resonance spectroscopy, the degradation process dominated by non-radical pathways was determined. At the same time, O2·- and 1O2 were closely related, and a significant impact of quenching O2·- on the reaction was observed. The non-radical approach made the system excellent performance over a wide pH range and in the presence of multiple anions. The experiments of reusability confirmed the stability of the material. Its catalytic performance was restored after low-temperature pyrolysis. This research supports the use of endogenous nitrogen in biomass. It provides more options for advanced oxidation process application and marine resource development.
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•Kelp biochar catalysts show excellent peroxymonosulfate catalytic performance.•pH and co-occurring anions have limited influence on the degradation process.•Metal components don't participate in catalysis.•Synergistic action of radical pathway and non-radical pathway.•The catalyst maintains strong catalytic degradation ability after three cycles.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPUK, ZAGLJ, ZRSKP
The Allium genus is cultivated globally as vegetables, condiments, or medicinal plants and is characterized by large genomes and strong pungency. However, the genome evolution and genomic basis ...underlying their unique flavor formation remain poorly understood. Herein, we report an 11.27-Gb chromosome-scale genome assembly for bunching onion (A. fistulosum). The uneven bursts of long-terminal repeats contribute to diversity in genome constituents, and dispersed duplication events largely account for gene expansion in Allium genomes. The extensive duplication and differentiation of alliinase and lachrymatory factor synthase manifest as important evolutionary events during flavor formation in Allium crops. Furthermore, differential selective preference for flavor-related genes likely lead to the variations in isoalliin content in bunching onions. Moreover, we reveal that China is the origin and domestication center for bunching onions. Our findings provide insights into Allium genome evolution, flavor formation and domestication history and enable future genome-assisted breeding of important traits in these crops.
A systemic treatment strategy is urgently demanded to suppress the rapid growth and easy metastasis characteristics of breast cancer. In this work, a chimeric peptide‐engineered self‐delivery ...nanomedicine (designated as ChiP‐CeR) for photodynamic‐triggered breast cancer immunotherapy by macrophage polarization. Among these, ChiP‐CeR is composed of the photosensitizer of chlorine e6 (Ce6) and the TLR7/8 agonist of lmiquimod (R837), which is further modified with tumor matrix targeting peptide (Fmoc‐K(Fmoc)‐PEG8‐CREKA. ChiP‐CeR is preferred to actively accumulate at the tumor site via specific recognition of fibronectin, which can eradicate primary tumor growth through photodynamic therapy (PDT). Meanwhile, the destruction of primary tumors would trigger immunogenic cell death (ICD) effects to release high‐mobility group box‐1(HMGB1) and expose calreticulin (CRT). Moreover, ChiP‐CeR can also polarize M2‐type tumor‐associated macrophages (TAMs) into M1‐type TAMs, which can activate T cell antitumor immunity in combination with ICD. Overall, ChiP‐CeR possesses superior antitumor effects against primary and lung metastatic tumors, which provide an applicable nanomedicine and a feasible strategy for the systemic management of metastatic breast cancer.
A chimeric peptide‐engineered self‐delivery nanomedicine (designated as ChiP‐CeR) based on matrix tumor‐targeting peptide (designated as ChiP), photosensitizer (Ce6), and immune adjuvant (R837) is developed for photodynamic therapy and immunotherapy. ChiP‐CeR possess superior antitumor effects against primary and lung metastatic tumor, which provide an applicable nanomedicine and a feasible strategy for the systemic management of metastatic breast cancer.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Negative therapeutic feedback of inflammation would extensively attenuate the antitumor effect of photodynamic therapy (PDT). In this work, tumor homing chimeric peptide rhomboids (designated as ...NP‐Mel) are fabricated to improve photodynamic performance by inhibiting PDT‐upregulated cyclooxygenase‐2 (COX‐2). The hydrophobic photosensitizer of protoporphyrin IX (PpIX) and palmitic acid are conjugated onto the neuropilin receptors (NRPs) targeting peptide motif (CGNKRTR) to obtain tumor homing chimeric peptide (Palmitic‐K(PpIX)CGNKRTR), which can encapsulate the COX‐2 inhibitor of meloxicam. The well dispersed NP‐Mel not only improves the drug stability and reactive oxygen species (ROS) production ability, but also increase the breast cancer targeted drug delivery to intensify the PDT effect. In vitro and in vivo studies verify that NP‐Mel will decrease the secretion of prostaglandin E2 (PGE2) after PDT treatment, inducing the downregulation of IL‐6 and TNF‐α expressions to suppress PDT induced inflammation. Ultimately, an improved PDT performance of NP‐Mel is achieved without inducing obvious systemic toxicity, which might inspire the development of sophisticated nanomedicine in consideration of the feedback induced therapeutic resistance.
Tumor homing chimeric peptide rhomboids (designated as NP‐Mel) are developed to promote the targeting delivery of drugs to breast cancer overexpressing neuropilin receptors (NRPs). NP‐Mel decrease the secretion of prostaglandin E2 (PGE2) after photodynamic therapy (PDT), inducing the downregulation of pro‐inflammatory cytokines to reverse PDT induced inflammation for enhanced breast cancer treatment.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
In this paper, we provide a model to handle multiple replenishment cycles and the cross-selling of multiple major items with one minor item, while allowing partial late delivery. The optimization ...analytic expression of the model is finally obtained by utilizing the convexity of cost function for F and using the first-order conditions in optimization theory. Numerical examples and sensitivity analysis demonstrate the effectiveness of the model and algorithm, which offers a competent solution for practical applications.
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