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Cancer stem cells (CSCs) are inherently resistant to chemotherapy, and CSCs in chemotherapy-failed recurrent tumors are enriched; however, the cellular origin of chemotherapy-induced CSC enrichment remains unclear. Communication with stromal fibroblasts may induce cancer cell dedifferentiation into CSCs through secreted factors. We recently demonstrated that fibroblast-derived exosomes promote chemoresistance in colorectal cancer (CRC). Here, we report that fibroblasts confer CRC chemoresistance via exosome-induced reprogramming (dedifferentiation) of bulk CRC cells to phenotypic and functional CSCs. At the molecular level, we provided evidence that the major reprogramming regulators in fibroblast-exosomes are Wnts. Exosomal Wnts were found to increase Wnt activity and drug resistance in differentiated CRC cells, and inhibiting Wnt release diminished this effect in vitro and in vivo. Together, our results indicate that exosomal Wnts derived from fibroblasts could induce the dedifferentiation of cancer cells to promote chemoresistance in CRC, and suggest that interfering with exosomal Wnt signaling may help to improve chemosensitivity and the therapeutic window.

General strategies for the chemical synthesis of organic compounds, especially of architecturally complex natural products, are not easily identified. Here we present a method to establish a strategy for such syntheses, which uses network analysis. This approach has led to the identification of a versatile synthetic intermediate that facilitated syntheses of the diterpenoid alkaloids weisaconitine D and liljestrandinine, and the core of gomandonine. We also developed a web-based graphing program that allows network analysis to be easily performed on molecules with complex frameworks. The diterpenoid alkaloids comprise some of the most architecturally complex and functional-group-dense secondary metabolites isolated. Consequently, they present a substantial challenge for chemical synthesis. The synthesis approach described here is a notable departure from other single-target-focused strategies adopted for the syntheses of related structures. Specifically, it affords not only the targeted natural products, but also intermediates and derivatives in the three subfamilies of diterpenoid alkaloids (C-18, C-19 and C-20), and so provides a unified synthetic strategy for these natural products. This work validates the utility of network analysis as a starting point for identifying strategies for the syntheses of architecturally complex secondary metabolites. WebNetwork analysis to determine the maximally bridged ring (or rings) of molecules is used as part of a strategy for the syntheses of architecturally complex natural chemicals; this strategy is demonstrated via the synthesis of the diterpenoid alkaloids weisaconitine D and liljestrandinine. To complex molecules via network analysis Rich Sarpong and colleagues have developed a unified strategy for the synthesis of multiple members of the diterpenoid alkaloid family using a development of the 'network analysis' approach formalized by E. J. Corey in the 1970s. The authors used this framework to identify a versatile synthetic intermediate that facilitates syntheses of weisaconitine D and liljestrandinine, as well as the core of gomandonine. The web-based deterministic graphing program developed for this work has the potential to be more generally applicable to the analysis and synthesis of other architecturally challenging molecules.

Let H be a real or complex Hilbert space with the dimension greater than one and B ( H ) the algebra of all bounded linear operators on H . Assume that δ is a linear mapping from B ( H ) into itself which is Jordan derivable at a given element Ω ∈ B ( H ) , in the sense that δ ( A ∘ B ) = δ ( A ) ∘ B + A ∘ δ ( B ) holds for all A , B ∈ B ( H ) with A ∘ B = Ω , where ∘ denotes the Jordan product A ∘ B = A B + B A . In this paper, we show that if Ω is an arbitrary but fixed nonzero operator, then δ is a derivation; if Ω is a zero operator, then δ is a generalized derivation.

Notch-1 inhibits apoptosis in some transformed cells through incompletely understood mechanisms. Notch-1 can increase nuclear factor-kappa B (NF-κB) activity through a variety of mechanisms. Overexpression of cleaved Notch-1 in T-cell acute lymphoblastic leukemia cells activates NF-κB via interaction with the I kappa B kinase (IKK) signalosome. Concomitant activation of the Notch and NF-κB pathways has been described in a large series of cervical cancer specimens. Here, we show that wild-type, spontaneously expressed Notch-1 stimulates NF-κB activity in CaSki cervical cancer cells by associating with the IKK signalosome through IKKα. A significant fraction of tumor necrosis factor (TNF)-α-stimulated IκB kinase activity in CaSki cells is Notch-1-dependent. In addition, Notch-1 is found in the nucleus in association with IKKα at IKKα-stimulated promoters and is required for association of IKKα with these promoters under basal and TNF-α-stimulated conditions. Notch-1–IKKα complexes are found in normal human keratinocytes as well, suggesting that IKK regulation is a physiological function of Notch-1. Both Notch-1 and IKKα knockdown sensitize CaSki cells to cisplatin-induced apoptosis to equivalent extents. Our data indicate that Notch-1 regulates NF-κB in cervical cancer cells at least in part via cytoplasmic and nuclear IKK-mediated pathways.

Solar radiation is one of the most important factors affecting climate and environment, and its long-term variation is of much concern in climate change studies. In the light of the limited number of radiation stations with reliable long-term time series observations, this paper presents a new evaluation of the long-term variation of surface solar radiation over China by combining quality-controlled observed data and two radiation models. One is the ANN-based (Artificial Neutral Network) model and the other is a physical model. The two models produce radiation trends comparable to the observed ones at a few validation stations possessing reliable and continuous data. Then, the trend estimate is extended by the ANN-based model to all 96 radiation stations and furthermore extended by the physical model to all 716 China Meteorological Administration (CMA) routine stations. The new trend estimate is different from previous ones in two aspects. First, the magnitude of solar radiation over China decreased by about −0.23 W m−2 yr−1 between 1961 and 2000, which is greatly less in magnitude than trend slopes estimated in previous studies (ranging over −0.41 ~ −0.52 W m−2 yr−1). Second, the \"From Dimming to Brightening\" transition in China during the late 1980s ~ the early 1990s was addressed in previous studies, but this study indicates the solar radiation reached a stable level since the 1990s and the transition is not noticeable. These differences indicate the importance of data-quality control and analysis approaches. Finally, an obvious transition from brightening to dimming around 1978 is found over the Tibetan Plateau, where aerosol loads are very low, indicating that the importance of cloud changes in altering solar radiation may be comparable to that of the aerosol changes.

The next core-collapse supernova in the Milky Way or its satellites will represent a once-in-a-generation opportunity to obtain detailed information about the explosion of a star and provide significant scientific insight for a variety of fields because of the extreme conditions found within. Supernovae in our galaxy are not only rare on a human timescale but also happen at unscheduled times, so it is crucial to be ready and use all available instruments to capture all possible information from the event. The first indication of a potential stellar explosion will be the arrival of a bright burst of neutrinos. Its observation by multiple detectors worldwide can provide an early warning for the subsequent electromagnetic fireworks, as well as signal to other detectors with significant backgrounds so they can store their recent data. The supernova early warning system (SNEWS) has been operating as a simple coincidence between neutrino experiments in automated mode since 2005. In the current era of multi-messenger astronomy there are new opportunities for SNEWS to optimize sensitivity to science from the next galactic supernova beyond the simple early alert. This document is the product of a workshop in June 2019 towards design of SNEWS 2.0, an upgraded SNEWS with enhanced capabilities exploiting the unique advantages of prompt neutrino detection to maximize the science gained from such a valuable event.

Qin J, Fan G, Lv Y, et al. Int J Nanomedicine. 2025;20:3861-3875. The authors have advised there is an error in Scheme 1 on page 3863. Specifically, a boron atom was incorrectly depicted as a nitrogen atom. The correct Scheme 1 is shown below. Scheme 1 Schematic illustration of the formation and mechanism of the LIP-C/I. The authors apologize for this error.

Numerous studies indicate that p300 acts as a key transcriptional cofactor in vivo , at least, in part, by modulating activities of p53 by acetylation. Nevertheless, the regulation of the p53-p300 interplay is not completely understood. Here, we have identified the DEAD (Asp-Glu-Ala-Asp) box RNA helicase 24 (DDX24) as a novel regulator of the p300-p53 axis. We found that DDX24 interacts with p300, and this interaction leads to suppression of p300-mediated acetylation of p53. Notably, RNA interference-mediated knockdown of endogenous DDX24 significantly increases the acetylation levels of endogenous p53 in human cancer cells and subsequently promotes p53-mediated activation of its transcriptional targets such as p21 and p53 upregulated modulator of apoptosis (PUMA). In contrast, DDX24 expression inhibits the p300-p53 interaction and suppresses p300-mediated acetylation of p53. Moreover, DDX24 is overexpressed in human cancer cells and reduction of DDX24 protein levels by RNA interference induces cell cycle arrest and senescence in a p53-dependent manner. These results reveal DDX24 as an important regulator of p300 and suggest that the modulation of the p53-p300 interplay by DDX24 is critical in controlling p53 activities in human cancer cells.

Summary Estrogen receptor (ER) in ovariectomy-induced osteoporotic fracture was reported to exhibit delayed expression. Mechanical stimulation enhanced ER-α expression in osteoporotic fracture callus at the tissue level. ER was also found to be required for the effectiveness of vibrational mechanical stimulation treatment in osteoporotic fracture healing. Introduction Estrogen receptor(ER) is involved in mechanical signal transduction in bone metabolism. Its expression was reported to be delayed in osteoporotic fracture healing. The purpose of this study was to investigate the roles played by ER during osteoporotic fracture healing enhanced with mechanical stimulation. Methods Ovariectomy-induced osteoporotic SD rats that received closed femoral fractures were divided into five groups, (i) SHAM, (ii) SHAM-VT, (iii) OVX, (iv) OVX-VT, and (v) OVX-VT-ICI, where VT stands for whole-body vibration treatment and ICI for ER antagonization by ICI 182,780. Callus formation and gene expression were assessed at 2, 4, and 8 weeks postfracture. In vitro osteoblastic differentiation, mineralization, and ER-α expression were assessed. Results The delayed ER expression was found to be enhanced by vibration treatment. Callus formation enhancement was shown by callus morphometry and micro-CT analysis. Enhancement effects by vibration were partially abolished when ER was modulated by ICI 182,780, in terms of callus formation capacity at 2–4 weeks and ER gene and protein expression at all time points. In vitro, ER expression in osteoblasts was not enhanced by VT treatment, but osteoblastic differentiation and mineralization were enhanced under estrogen-deprived condition. When osteoblastic cells were modulated by ICI 182,780, enhancement effects of VT were eliminated. Conclusions Vibration was able to enhance ER expression in ovariectomy-induced osteoporotic fracture healing. ER was essential in mechanical signal transduction and enhancement in callus formation effects during osteoporotic fracture healing enhanced by vibration. The enhancement of ER-α expression by mechanical stimulation was not likely to be related to the increased expression in osteoblastic cells but rather to the systemic enhancement in recruitment of ER-expressing progenitor cells through increased blood flow and neo-angiogenesis. This finding might explain the observed difference in mechanical sensitivity of osteoporotic fracture to mechanical stimulation.

Mulberry is an important industrial crop and medicinal plant with a history of thousands of years. Glycosylation catalysed by glycosyltransferase (GT) is one of the most important modification reactions necessary to maintain metabolic homeostasis in plant cellular processes and is often involved in the biosynthesis of secondary metabolites. Mulberry contains a large number of active glycosylated products, especially flavonoids and stilbenes, while their biosynthesis has not been fully elucidated. In this study, a total of 121 GT encoding genes were identified in the genome of Morus alba L., and their gene structures, chromosomal locations, and expression levels were analysed. Phylogenetic analysis suggested that MaUGT89AS1 might recognize the 7-OH site of flavonoid substrates. In vitro enzymatic activity analysis showed that MaUGT89AS1 was able to glycosylate kaempferol at both 7-OH and 3-OH to form kaempferol-7-O-β-D-glucopyranoside and kaempferol-3-O-β-D-glucopyranoside. In addition, it had glycosylation activity towards 7-OH of other flavonoids such as quercetin. The optimum reaction temperature and pH of MaUGT89AS1 were 40°C and 8.0, respectively. Molecular docking elucidated the binding conformations and interactions for MaUGT89AS1 to recognize different glycosylation sites. Site-directed mutagenesis proved the essential role of His16 and Asp119 catalytic dichotomies in glycosylation reaction. This work will provide molecular resources for heterologous synthesis of flavonoid glycoside compounds with important medicinal activities.