Fresh fruit and vegetables are sources of vitamins, minerals, and dietary fiber; however, due to their short postharvest life, a large portion of the produce is lost ...
Macrophages are plastic and, in response to different local stimuli, can polarize toward multi-dimensional spectrum of phenotypes, including the pro-inflammatory M1-like and the anti-inflammatory ...M2-like states. Using a high-throughput phenotypic screen in a library of ~4000 FDA-approved drugs, bioactive compounds and natural products, we find ~300 compounds that potently activate primary human macrophages toward either M1-like or M2-like state, of which ~30 are capable of reprogramming M1-like macrophages toward M2-like state and another ~20 for the reverse repolarization. Transcriptional analyses of macrophages treated with 34 non-redundant compounds identify both shared and unique targets and pathways through which the tested compounds modulate macrophage activation. One M1-activating compound, thiostrepton, is able to reprogram tumor-associated macrophages toward M1-like state in mice, and exhibit potent anti-tumor activity. Our compound-screening results thus help to provide a valuable resource not only for studying the macrophage biology but also for developing therapeutics through modulating macrophage activation.
The 186 aa truncated protein produced by the tomato spontaneous non-ripening (nor) mutant enters the nucleus and combines with the promoters of its target genes, resulting in a gain of function.
...Abstract
The tomato non-ripening (nor) mutant generates a truncated 186-amino-acid protein (NOR186) and has been demonstrated previously to be a gain-of-function mutant. Here, we provide more evidence to support this view and answer the open question of whether the NAC-NOR gene is important in fruit ripening. Overexpression of NAC-NOR in the nor mutant did not restore the full ripening phenotype. Further analysis showed that the truncated NOR186 protein is located in the nucleus and binds to but does not activate the promoters of 1-aminocyclopropane-1-carboxylic acid synthase2 (SlACS2), geranylgeranyl diphosphate synthase2 (SlGgpps2), and pectate lyase (SlPL), which are involved in ethylene biosynthesis, carotenoid accumulation, and fruit softening, respectively. The activation of the promoters by the wild-type NOR protein can be inhibited by the mutant NOR186 protein. On the other hand, ethylene synthesis, carotenoid accumulation, and fruit softening were significantly inhibited in CR-NOR (CRISPR/Cas9-edited NAC-NOR) fruit compared with the wild-type, but much less severely affected than in the nor mutant, while they were accelerated in OE-NOR (overexpressed NAC-NOR) fruit. These data further indicated that nor is a gain-of-function mutation and NAC-NOR plays a significant role in ripening of wild-type fruit.
Powering marine distributed buoys sustainably and cost-efficiently has always been challenging in the ocean environment. Triboelectric nanogenerators (TENG), thanks to their robustness, high ...efficiency and low cost in energy harvesting, has provided a novel solution to the long-term electrical power supply for a series of distributed systems (including buoys). In this study, a wave energy harvesting sandwich-like TENG (S-TENG) has been proposed. In the on-land forced motion experiments, the S-TENG yields much superior performances compared to previous tower-like TENG in terms of the power density. The studies also reveal that the electrical output increases linearly even with larger number of parallel connected S-TENG layers. Consequently, a buoy integrated with 7 parallel connected S-TENGs is studied through systematic wave basin experiments and the relevance of most hydrodynamic parameters (including wave height, frequency, direction as well as mooring system) have been revealed. The presented wave basin experiments are original in wave energy harvesting TENG research practice and prove to be very helpful in that they simulate the most close-to-real ocean environments in the lab. The studies are concluded with a 12 W high-brightness LED lit up on a navigation supporting buoy. This study has set a benchmark of achieving self-powered buoy with TENG, which can be extended to other marine distributed systems such as sensors and small robotics.
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•Sandwich structure boosting output power density of triboelectric nanogenerators.•Accessible power promotion through parallel nanogenerators in layers.•First time triboelectric nanogenerator tested in an advanced wave basin.•Self-powered navigation buoy achieved by triboelectric nanogenerator integration.
Background and aims
A single immune checkpoint inhibitor (ICI) regimen has limited value in treating advanced bile tract cancer (BTC); therefore, ICI combination therapy is often applied. This ...meta-analysis aimed to evaluate the effectiveness and safety of ICI combination therapy for advanced BTC.
Methods
The study protocol was registered on PROSPERO (CRD42023452422). Data on the median progression-free survival (PFS), median overall survival (OS), objective response rate (ORR), disease control rate (DCR), and grade ≥3 adverse events (AEs) reported in relevant studies were pooled and analyzed to determine the efficacy and safety of ICI combination therapy.
Results
In total, 15 studies with 665 patients were included in this meta-analysis. The overall ORR and DCR were 34.6% and 77.6%, respectively. The overall median PFS and OS were 6.06 months 95% confidence interval (CI): 4.91–7.21 and 12.11 months (95% CI: 10.66–13.55), respectively. Patients receiving ICI combination therapy in addition to other therapies had a considerably prolonged median PFS and OS (z=9.69,
p
<0.001 and z=16.17,
p
<0.001). Patients treated as first-line treatment had a substantially longer median PFS and OS compared to patients treated as non-first-line treatment (z=11.19,
p
<0.001 and z=49.17,
p
<0.001). The overall pooled grade ≥3 AEs rate was 38.2% (95% CI: 0.268–0.497) and was not influenced by whether ICI therapy was combined with other treatments or not or the treatment line.
Conclusion
Advanced BTC patients may benefit from ICI combination treatment without additional AEs. However, concurrent chemotherapy or radiotherapy is still needed to achieve better outcomes.
Systematic review registration
https://www.crd.york.ac.uk/prospero/
, identifier CRD42023452422.
Anticancer drugs have been developed with expectations to provide long-term or at least short-term survival benefits for patients with cancer. Unfortunately, drug therapy tends to provoke malignant ...biological and clinical behaviours of cancer cells relating not only to the evolution of resistance to specific drugs but also to the enhancement of their proliferation and metastasis abilities. Thus, drug therapy is suspected to impair long-term survival in treated patients under certain circumstances. The paradoxical therapeutic effects could be described as 'quenching thirst with poison', where temporary relief is sought regardless of the consequences. Understanding the underlying mechanisms by which tumours react on drug-induced stress to maintain viability is crucial to develop rational targeting approaches which may optimize survival in patients with cancer. In this review, we describe the paradoxical adverse effects of anticancer drugs, in particular how cancer cells complete resistance evolution, enhance proliferation, escape from immune surveillance and metastasize efficiently when encountered with drug therapy. We also describe an integrative therapeutic framework that may diminish such paradoxical effects, consisting of four main strategies: (1) targeting endogenous stress response pathways, (2) targeting new identities of cancer cells, (3) adaptive therapy- exploiting subclonal competition of cancer cells, and (4) targeting tumour microenvironment.
Summary
Chloroplast development and chlorophyll(Chl)metabolism in unripe tomato contribute to the growth and quality of the fruit, however these mechanisms are poorly understood. In this study, we ...initially investigated seven homeobox‐containing transcription factors (TFs) with specific ripening‐associated expression patterns using virus‐induced gene silencing (VIGS) technology and found that inhibiting the expression of one of these TFs, BEL1‐LIKE HOMEODOMAIN11 (SlBEL11), significantly increased Chl levels in unripe tomato fruit. This enhanced Chl accumulation was further validated by generating stable RNA interference (RNAi) transgenic lines. RNA sequencing (RNA‐seq) of RNAi‐SlBEL11 fruit at the mature green (MG) stage showed that 48 genes involved in Chl biosynthesis, photosynthesis and chloroplast development were significantly upregulated compared with the wild type (WT) fruit. Genomic global scanning for Homeobox TF binding sites combined with RNA‐seq differential gene expression analysis showed that 22 of these 48 genes were potential target genes of SlBEL11 protein. These genes included Chl biosynthesis‐related genes encoding for protochlorophyllide reductase (POR), magnesium chelatase H subunit (CHLH) and chlorophyllide a oxygenase (CAO), and chloroplast development‐related genes encoding for chlorophyll a/b binding protein (CAB), homeobox protein knotted 2 (TKN2) and ARABIDOPSIS PSEUDO RESPONSE REGULATOR 2‐LIKE (APRR2‐like). Electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation quantitative polymerase chain reaction (PCR) (ChIP‐qPCR) assays were employed to verify that SlBEL11 protein could bind to the promoters for TKN2, CAB and POR. Taken together, our findings demonstrated that SlBEL11 plays an important role in chloroplast development and Chl synthesis in tomato fruit.
Significance Statement
The roles of a BEL1‐LIKE HOMEODOMAIN11 transcription factor (SlBEL11) associated with specific ripening‐associated expression patterns in tomato fruit were investigated. Results demonstrate that SlBEL11 plays an important role in chloroplast development and Chl synthesis in tomato fruits.
Cholecystectomy is a standard surgery for patients suffering from gallbladder diseases, while the causal effects of cholecystectomy on colorectal cancer (CRC) and other complications are still ...unknown.
We obtained genetic variants associated with cholecystectomy at a genome-wide significant level ( P value <5 × 10 -8 ) as instrumental variables (IVs) and performed Mendelian randomization (MR) to identify the complications of cholecystectomy. Furthermore, the cholelithiasis was also treated as the exposure to compare its causal effects to those of cholecystectomy, and multivariable MR analysis was carried out to judge whether the effect of cholecystectomy was independent of cholelithiasis. The study was reported based on Strengthening the Reporting of Observational Studies in Epidemiology Using Mendelian Randomization guidelines.
The selected IVs explained 1.76% variance of cholecystectomy. Our MR analysis suggested that cholecystectomy cannot elevate the risk of CRC (odds ratio OR =1.543, 95% confidence interval CI: 0.607-3.924). Also, it was not significant in either colon or rectum cancer. Intriguingly, cholecystectomy might decrease the risk of Crohn's disease (OR = 0.078, 95% CI: 0.016-0.368) and coronary heart disease (OR = 0.352, 95% CI: 0.164-0.756). However, it might increase the risk of irritable bowel syndrome (IBS) (OR = 7.573, 95% CI: 1.096-52.318). Cholelithiasis could increase the risk of CRC in the largest population (OR = 1.041, 95% CI: 1.010-1.073). The multivariable MR analysis suggested that genetic liability to cholelithiasis could increase the risk of CRC in the largest population (OR = 1.061, 95% CI: 1.002-1.125) after adjustment of cholecystectomy.
The study indicated that cholecystectomy might not increase the risk of CRC, but such a conclusion needs further proving by clinical equivalence. Additionally, it might increase the risk of IBS, which should be paid attention to in clinical practice.
•Melatonin treatment ameliorated chilling injury in cold-stored guava fruit.•Melatonin treatment reduced cell membrane permeability and weight loss in guava fruit.•Melatonin treatment retained higher ...TSS, total sugar, sucrose and vitamin C in guava.•The optimal concentration of melatonin for postharvest guava fruit was 100 μmol/L.•Melatonin displayed a great potential application for postharvest guava fruit.
The influence of melatonin treatment on the quality and chilling injury of guavas during storage at 4 ± 1 °C were evaluated. Compared with control group, fruit of guava cv. Xiguahong exposed to various concentrations (50, 100, 150, and 200 μmol/L) of melatonin showed a significantly lower fruit respiration rate, weight loss, cell membrane permeability, and chilling injury index, but a higher commercially acceptable fruit rate, higher peel L*, h° value, and chlorophyll content. Melatonin treatment also delayed the decreases of fruit firmness, sucrose, total soluble sugar, vitamin C, titratable acidity, and total soluble solids. These data indicate that melatonin treatment could increase chilling tolerance and retain quality of cold-stored guavas. Among various concentrations of melatonin treatment, 100 μmol/L melatonin-treated guavas showed the preferable quality properties and lowest chilling injury index. Thus, melatonin may be a novel method of postharvest handling to enhance cold resistance and extend storage-life of cold-stored guava fruit.
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•H2O2 down-regulated expression of ROS scavenging-related genes in longan pulp.•H2O2 reduced activities of ROS scavenging enzymes (SOD, CAT, APX) in longan pulp.•H2O2 reduced ROS ...scavenging capacity and raised O2–. generation rate in longan pulp.•H2O2 promoted lipid peroxidation of cell membrane in pulp of harvested longan fruit.•H2O2-reduced ROS scavenging capacity led to H2O2-stimulated pulp breakdown of longans.
The influence of hydrogen peroxide (H2O2) on the ROS metabolism and its relationship to pulp breakdown of fresh longan cv. Fuyan during storage was evaluated. Contrasted to control fruit, H2O2-treated samples manifested a higher index of pulp breakdown, an enhanced rate of O2–. generation, and an increased amount of MDA, but lower APX, CAT and SOD activities, reduced expressions of DlAPX, DlCAT and DlSOD, and lower concentrations of total phenolics, flavonoid, AsA, and GSH as well as lower levels of free radicals scavenging capacity. These data revealed that H2O2-induced pulp breakdown of longan was because H2O2 reduced ability of removing ROS but increased ROS generation and accumulation, which promoted peroxidation of cell membrane lipid, and subsequently led to damaging cell membrane structure and breakdown occurrence in pulp of postharvest fresh longan.
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