Summary
Arabidopsis histone H3 lysine 4 (H3K4) demethylases play crucial roles in several developmental processes, but their involvement in seedling establishment remain unexplored.
Here, we show ...that Arabidopsis JUMONJI DOMAIN‐CONTAINING PROTEIN17 (JMJ17), an H3K4me3 demethylase, is involved in cotyledon greening during seedling establishment. Dark‐grown seedlings of jmj17 accumulated a high concentration of protochlorophyllide, an intermediate metabolite in the tetrapyrrole biosynthesis (TPB) pathway that generates chlorophyll (Chl) during photomorphogenesis. Upon light irradiation, jmj17 mutants displayed decreased cotyledon greening and reduced Chl level compared with the wild‐type; overexpression of JMJ17 completely rescued the jmj17‐5 phenotype.
Transcriptomics analysis uncovered that several genes encoding key enzymes involved in TPB were upregulated in etiolated jmj17 seedlings. Consistently, chromatin immunoprecipitation‐quantitative PCR revealed elevated H3K4me3 level at the promoters of target genes. Chromatin association of JMJ17 was diminished upon light exposure. Furthermore, JMJ17 interacted with PHYTOCHROME INTERACTING FACTOR1 in the yeast two‐hybrid assay.
JMJ17 binds directly to gene promoters to demethylate H3K4me3 to suppress PROTOCHLOROPHYLLIDE OXIDOREDUCTASE C expression and TPB in the dark. Light results in de‐repression of gene expression to modulate seedling greening during de‐etiolation. Our study reveals a new role for histone demethylase JMJ17 in controlling cotyledon greening in etiolated seedlings during the dark‐to‐light transition.
See also the Commentary on this article by Woodson, 231: 907–909.
•The proposed model integrates several advanced MCDM methods.•We use the modified ITARA and the PCIM-MADM to determine the supplier’s performance index.•The integrated sustainable supplier selection ...and transportation planning problem is solved by the FMOLP.•A multinational smart audio manufacturing company is used as a case study to demonstrate our proposed methodology.
Supplier selection and transportation planning are essential tasks in managing supply chain networks (SCNs). The choice of a supplier has a significant influence on the transportation planning of SCNs, as the transportation routes will change. A limited number of studies in the literature have addressed the supplier selection and transportation planning issues simultaneously. This study proposes a two-stage multi-criteria decision-making (MCDM) approach for sustainable supplier evaluation and transportation planning in multi-level SCNs. Initially, a supplier evaluation framework is proposed using the modified indifference threshold-based attribute ratio analysis (ITARA) and the performance calculation technique of the integrated multiple multi-attribute decision-making (PCIM-MADM) to determine the supplier’s performance index. Subsequently, a multi-level SCN model is established, and the sustainable supplier selection and transportation planning problem is solved by the fuzzy multi-objective linear programming (FMOLP) method. A set of real-world data provided by a smart audio manufacturing company has been used to demonstrate the proposed approach. Decision-makers understand the importance of criteria through the weights constructed by the modified ITARA. Moreover, the results of the PCIM-MADM can effectively determine the supplier’s ranking and provide improving strategies for underperforming suppliers. The augmented max–min technique of the FMOLP can produce a single optimal solution of the transportation allocation. The results show that our approach can effectively evaluate sustainable supplier performance and optimize transportation planning in SCNs.
Background
No evidence is currently available to estimate the outcomes of intensity‐modulated radiation therapy (IMRT) and surgery for patients with early oral cavity squamous cell carcinoma ...(E‐OCSCC).
Methods
We recruited patients from the Taiwan Cancer Registry Database who had received a diagnosis of E‐OCSCC. Propensity score matching was performed, and Cox proportional hazards model was used to analyze all‐cause mortality.
Results
In the multivariate Cox regression analyses, the adjusted hazard ratio (aHR) (95% confidence interval CI) for surgery compared with definitive IMRT, T2N0M0 compared with T1N0M0, and male patients compared with female patients were 0.303 (0.245, 0.375), 1.340 (1.077, 1.668), and 2.012 (1.432, 2.826), respectively. The aHRs (95% CIs) for age 61 to 70, 71 to 80, and ≧81 years compared with <40 years were 2.984 (1.43, 4.225), 3.353 (2.578, 4.112), and 4.277 (4.104, 5.679), respectively.
Conclusions
For patients with E‐OCSCC, surgery may be considered the first option rather than definitive IMRT.
Epithelial–mesenchymal transition (EMT) has been implicated in fibrogenesis and carcinogenesis; however, the exact role of EMT‐inducer Slug in the progression of precancerous oral submucous fibrosis ...(OSF) has not been investigated. In the current study, we showed that the expression of Slug was upregulated in OSF tissues and associated with various myofibroblast markers. After silence of Slug in fibrotic buccal mucosal fibroblasts (fBMFs), the elevated myofibroblast activities and fibrosis markers were all downregulated. Our data revealed that arecoline, an areca nut alkaloid, increased the expression of Slug in normal BMFs, and inhibition of Slug successfully prevented the arecoline‐induced myofibroblast activation. Additionally, overexpression of Slug in BMFs stimulated the activities of myofibroblasts, indicating that upregulation of Slug by arecoline contributes to the myofibroblast transdifferentiation. Most importantly, Slug was able to bind to the E‐box of type I collagen, leading to increased expression of type I collagen. Altogether, this study demonstrated the abnormal elevation of Slug in OSF and its significance in arecoline‐induced fibrogenesis. Moreover, downregulation of Slug could be a potential target for OSF remedy via suppression of myofibroblast activities and type I collagen.
In normal BMFs, arecoline stimulation will elevate the expression of Slug, which directly binds to the promotor of type I collagen, leading to increased collagen deposition and myofibroblasts transdifferentiation. In fibrotic BMFs, inhibition of Slug will reduce the expression of the myofibroblast marker, α‐SMA, and the myofibroblast activities as well as downregulate the ECM accumulation, which may relieve the fibrotic condition.
Human ubiquinol-cytochrome c reductase core protein 1 (UQCRC1) is an evolutionarily conserved core subunit of mitochondrial respiratory chain complex III. We recently identified the ...disease-associated variants of UQCRC1 from patients with familial parkinsonism, but its function remains unclear. Here we investigate the endogenous function of UQCRC1 in the human neuronal cell line and the Drosophila nervous system. Flies with neuronal knockdown of uqcrc1 exhibit age-dependent parkinsonism-resembling defects, including dopaminergic neuron reduction and locomotor decline, and are ameliorated by UQCRC1 expression. Lethality of uqcrc1-KO is also rescued by neuronally expressing UQCRC1, but not the disease-causing variant, providing a platform to discern the pathogenicity of this mutation. Furthermore, UQCRC1 associates with the apoptosis trigger cytochrome c (cyt-c), and uqcrc1 deficiency increases cyt-c in the cytoplasmic fraction and activates the caspase cascade. Depleting cyt-c or expression of the anti-apoptotic p35 ameliorates uqcrc1-mediated neurodegeneration. Our findings identify a role for UQCRC1 in regulating cyt-c-induced apoptosis.
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•Neuronal reduction of uqcrc1, the ETC complex III subunit, causes PD-like symptoms•uqcrc1 regulates DA neuronal maintenance and locomotor activity in flies•The disease-associated uqcrc1 variant fails to bind cytochrome c, triggering apoptosis•Targeting cytochrome c, but not ROS, ameliorates uqcrc1-mediated neurodegeneration
Point mutations in human UQCRC1 associate with familial parkinsonism, but the underlying mechanisms remain unclear. Using the fruit fly as a model, Hung et al. show that the disease variant fails to retain apoptosis trigger cyt-c in mitochondria, resulting in apoptotic neurodegeneration.
While mechanisms for metastasis were extensively studied in cancer cells from patients with detectable tumors, pathways underlying metastatic dissemination from early lesions before primary tumors ...appear are poorly understood. Her2 promotes breast cancer early dissemination by suppressing p38, but how Her2 downregulates p38 is unclear. Here, we demonstrate that in early lesion breast cancer models, Her2 inhibits p38 by inducing Skp2 through Akt-mediated phosphorylation, which promotes ubiquitination and proteasomal degradation of Tpl2, a p38 MAP3K. The early disseminating cells are Her2
Skp2
Tpl2
p-p38
E-cadherin
in the MMTV-Her2 breast cancer model. In human breast carcinoma, high Skp2 and low Tpl2 expression are associated with the Her2
status; Tpl2 expression positively correlates with that of activated p38; Skp2 expression negatively correlates with that of Tpl2 and activated p38. Moreover, the Her2-Akt-Skp2-Tpl2-p38 axis plays a key role in the disseminating phenotypes in early lesion breast cancer cells; inhibition of Tpl2 enhances early dissemination in vivo. These findings identify the Her2-Akt-Skp2-Tpl2-p38 cascade as a novel mechanism mediating breast cancer early dissemination and a potential target for novel therapies targeting early metastatic dissemination.
Lipotoxicity leads to numerous metabolic disorders such as nonalcoholic steatohepatitis. Luteolin, apigenin, and chrysin are three flavones with known antioxidant and anti‐inflammatory properties, ...but whether they inhibit lipotoxicity‐mediated NLRP3 inflammasome activation was unclear. To address this question, we used J774A.1 macrophages and Kupffer cells stimulated with 100 μM palmitate (PA) in the presence or absence of 20 μM of each flavone. PA increased p‐PERK, p‐IRE1α, p‐JNK1/2, CHOP, and TXNIP as well as p62 and LC3‐II expression and induced autophagic flux damage. Caspase‐1 activation and IL‐1β release were also noted after 24 h of exposure to PA. In the presence of the PERK inhibitor GSK2656157, PA‐induced CHOP and TXNIP expression and caspase‐1 activation were mitigated. Compared with PA treatment alone, Bcl‐2 coupled to beclin‐1 was elevated and autophagy was reversed by the JNK inhibitor SP600125. With luteolin, apigenin, and chrysin treatment, PA‐induced ROS production, ER stress, TXNIP expression, autophagic flux damage, and apoptosis were ameliorated. Moreover, TXNIP binding to NLRP3 and IL‐1β release in response to LPS/PA challenge were reduced. These results suggest that luteolin, apigenin, and chrysin protect hepatic macrophages against PA‐induced NLRP3 inflammasome activation and autophagy damage by attenuating endoplasmic reticulum stress.
Advanced glycation end products (AGEs), which are highly reactive molecules resulting from persistent high‐glucose levels, can lead to the generation of oxidative stress and cardiac complications. ...The carboxyl terminus of HSP70 interacting protein (CHIP) has been demonstrated to have a protective role in several diseases, including cardiac complications; however, the role in preventing AGE‐induced cardiac damages remains poorly understood. Here, we found that elevated AGE levels impaired cardiac CHIP expression in streptozotocin‐induced diabetes and high‐fat diet‐administered animals, representing AGE exposure models. We used the TUNEL assay, hematoxylin and eosin, Masson′s trichrome staining, and western blotting to prove that cardiac injuries were induced in diabetic animals and AGE‐treated cardiac cells. Interestingly, our results collectively indicated that CHIP overexpression significantly rescued the AGE‐induced cardiac injuries and promoted cell survival. Moreover, CHIP knockdown‐mediated stabilization of nuclear factor κB (NFκB) was attenuated by overexpressing CHIP in the cells. Furthermore, co‐immunoprecipitation and immunoblot assay revealed that CHIP promotes the ubiquitination and proteasomal degradation of AGE‐induced NFκB. Importantly, fluorescence microscopy, a luciferase reporter assay, electrophoretic mobility shift assay, and subcellular fractionation further demonstrated that CHIP overexpression inhibits AGE‐induced NFκB nuclear translocation, reduced its binding ability with the promoter sequences of the receptor of AGE, consequently inhibiting the translocation of the receptor AGE to the cell membrane for its proper function. Overall, our current study findings suggest that CHIP can target NFκB for ubiquitin‐mediated proteasomal degradation, and thereby potentially rescue AGE‐induced cardiac damages.
The current study findings suggest that CHIP can target NF κB for ubiquitin‐mediated proteasomal degradation, and thereby potentially rescue AGE‐induced cardiac damages.
The strength of SERS signal depends on the amount of analyte adsorbed onto the hotspots of a SERS substrate immersed in solution. This adsorption is a dynamic process and can be described by the ...Langmuir adsorption model, in which the adsorption is influenced by several factors such as the temperature and the immersion time. By varying the immersion time and immersion volume of a gold nanostructure array SERS substrate in malachite green solution, we find that the required immersion time to reach the equilibrium adsorption coverage increases with decreasing analyte concentration and volume. For a 6.5 mm × 6.5 mm SERS substrate immersed in 15 ml of 1.5 ppb malachite solution, it takes more than 7 days of immersion time for it to reach 63% of the equilibrium coverage in ambient environment. Furthermore, at low concentration and immersion volume, the solution concentration decreases during the adsorption process and causes deviation from the prediction of Langmuir isotherm. In this work, we demonstrate that for quantitative SERS measurement in low analyte concentration, it is critical to take the immersion volume and time into consideration and ensure the equilibrium adsorption coverage or SERS intensity is reached for accurate concentration determination.
The strength of SERS signal depends on the amount of analyte adsorbed onto the hotspots of a SERS substrate immersed in solution. This adsorption is a dynamic process and can be described by the Langmuir adsorption model. We demonstrate that for low analyte concentration and immersion volume, the time to reach equilibrium adsorption coverage can take many days and deviates from the Langmuir model prediction. It is therefore critical to take the immersion volume and time into consideration for quantitative SERS determination.
Oxidized cysteine residues are highly reactive and can form functional covalent conjugates, of which the allosteric redox switch formed by the lysine-cysteine NOS bridge is an example. Here, we ...report a noncanonical FAD-dependent enzyme Orf1 that adds a glycine-derived N-formimidoyl group to glycinothricin to form the antibiotic BD-12. X-ray crystallography was used to investigate this complex enzymatic process, which showed Orf1 has two substrate-binding sites that sit 13.5 Å apart unlike canonical FAD-dependent oxidoreductases. One site could accommodate glycine and the other glycinothricin or glycylthricin. Moreover, an intermediate-enzyme adduct with a NOS-covalent linkage was observed in the later site, where it acts as a two-scissile-bond linkage facilitating nucleophilic addition and cofactor-free decarboxylation. The chain length of nucleophilic acceptors vies with bond cleavage sites at either N-O or O-S accounting for N-formimidoylation or N-iminoacetylation. The resultant product is no longer sensitive to aminoglycoside-modifying enzymes, a strategy that antibiotic-producing species employ to counter drug resistance in competing species.
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