Enriched PD-L1 expression in cancer stem-like cells (CSCs) contributes to CSC immune evasion. However, the mechanisms underlying PD-L1 enrichment in CSCs remain unclear. Here, we demonstrate that ...epithelial-mesenchymal transition (EMT) enriches PD-L1 in CSCs by the EMT/β-catenin/STT3/PD-L1 signaling axis, in which EMT transcriptionally induces N-glycosyltransferase STT3 through β-catenin, and subsequent STT3-dependent PD-L1 N-glycosylation stabilizes and upregulates PD-L1. The axis is also utilized by the general cancer cell population, but it has much more profound effect on CSCs as EMT induces more STT3 in CSCs than in non-CSCs. We further identify a non-canonical mesenchymal-epithelial transition (MET) activity of etoposide, which suppresses the EMT/β-catenin/STT3/PD-L1 axis through TOP2B degradation-dependent nuclear β-catenin reduction, leading to PD-L1 downregulation of CSCs and non-CSCs and sensitization of cancer cells to anti-Tim-3 therapy. Together, our results link MET to PD-L1 stabilization through glycosylation regulation and reveal it as a potential strategy to enhance cancer immunotherapy efficacy.
Summary
The Orchidaceae is a diverse and ecologically important plant family. Approximately 69% of all orchid species are epiphytes, which provide diverse microhabitats for many small animals and ...fungi in the canopy of tropical rainforests. Moreover, many orchids are of economic importance as food flavourings or ornamental plants. Phalaenopsis aphrodite, an epiphytic orchid, is a major breeding parent of many commercial orchid hybrids. We provide a high‐quality chromosome‐scale assembly of the P. aphrodite genome. The total length of all scaffolds is 1025.1 Mb, with N50 scaffold size of 19.7 Mb. A total of 28 902 protein‐coding genes were identified. We constructed an orchid genetic linkage map, and then anchored and ordered the genomic scaffolds along the linkage groups. We also established a high‐resolution pachytene karyotype of P. aphrodite and completed the assignment of linkage groups to the 19 chromosomes using fluorescence in situ hybridization. We identified an expansion in the epiphytic orchid lineage of FRS5‐like subclade associated with adaptations to the life in the canopy. Phylogenetic analysis further provides new insights into the orchid lineage‐specific duplications of MADS‐box genes, which might have contributed to the variation in labellum and pollinium morphology and its accessory structure. To our knowledge, this is the first orchid genome to be integrated with a SNP‐based genetic linkage map and validated by physical mapping. The genome and genetic map not only offer unprecedented resources for increasing breeding efficiency in horticultural orchids but also provide an important foundation for future studies in adaptation genomics of epiphytes.
Understanding the magnetic and ferroelectric ordering of magnetoelectric multiferroic materials at the nanoscale necessitates a versatile imaging method with high spatial resolution. Here, soft X‐ray ...ptychography is employed to simultaneously image the ferroelectric and antiferromagnetic domains in an 80 nm thin freestanding film of the room‐temperature multiferroic BiFeO3 (BFO). The antiferromagnetic spin cycloid of period 64 nm is resolved by reconstructing the corresponding resonant elastic X‐ray scattering in real space and visualized together with mosaic‐like ferroelectric domains in a linear dichroic contrast image at the Fe L3 edge. The measurements reveal a near perfect coupling between the antiferromagnetic and ferroelectric ordering by which the propagation direction of the spin cycloid is locked orthogonally to the ferroelectric polarization. In addition, the study evinces both a preference for in‐plane propagation of the spin cycloid and changes of the ferroelectric polarization by 71° between multiferroic domains in the epitaxial strain‐free, freestanding BFO film. The results provide a direct visualization of the strong magnetoelectric coupling in BFO and of its fine multiferroic domain structure, emphasizing the potential of ptychographic imaging for the study of multiferroics and non‐collinear magnetic materials with soft X‐rays.
The ferroelectric and magnetic structure of a freestanding thin film of multiferroic bismuth ferrite are imaged with soft x‐ray ptychography at the Fe L‐edge. This scanning coherent diffractive imaging technique directly visualizes the strong magnetoelectric coupling between the antiferromagnetic spin cycloid and ferroelectric domains on the nanoscale.
Spatiotemporal regulation of cell migration is crucial for animal development and organogenesis. Compared to spatial signals, little is known about temporal signals and the mechanisms integrating the ...two. In the Caenorhabditis elegans hermaphrodite, the stereotyped migration pattern of two somatic distal tip cells (DTCs) is responsible for shaping the gonad. Guidance receptor UNC-5 is necessary for the dorsalward migration of DTCs. We found that BLMP-1, similar to the mammalian zinc finger transcription repressor Blimp-1/PRDI-BF1, prevents precocious dorsalward turning by inhibiting precocious unc-5 transcription and is only expressed in DTCs before they make the dorsalward turn. Constitutive expression of blmp-1 when BLMP-1 would normally disappear delays unc-5 transcription and causes turn retardation, demonstrating the functional significance of blmp-1 down-regulation. Correct timing of BLMP-1 down-regulation is redundantly regulated by heterochronic genes daf-12, lin-29, and dre-1, which regulate the temporal fates of various tissues. DAF-12, a steroid hormone receptor, and LIN-29, a zinc finger transcription factor, repress blmp-1 transcription, while DRE-1, the F-Box protein of an SCF ubiquitin ligase complex, binds to BLMP-1 and promotes its degradation. We have therefore identified a gene circuit that integrates the temporal and spatial signals and coordinates with overall development of the organism to direct cell migration during organogenesis. The tumor suppressor gene product FBXO11 (human DRE-1 ortholog) also binds to PRDI-BF1 in human cell cultures. Our data suggest evolutionary conservation of these interactions and underscore the importance of DRE-1/FBXO11-mediated BLMP-1/PRDI-BF1 degradation in cellular state transitions during metazoan development.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The inhibitory effect of melatonin on cancer cell dissemination is well established, yet the functional involvement of lncRNAs in melatonin signaling remains poorly understood. In this study, we ...identified a melatonin‐attenuated lncRNA acting as a potential melatonin‐regulated oral cancer stimulator (MROS‐1). Downregulation of MROS‐1 by melatonin suppressed TPA‐induced oral cancer migration through replenishing the protein expression of prune homolog 2 (PRUNE2), which functioned as a tumor suppressor in oral cancer. Melatonin‐mediated MROS‐1/PRUNE2 expression and cell motility in oral cancer were regulated largely through the activation of JAK‐STAT pathway. In addition, MROS‐1, preferentially localized in the nuclei, promoted oral cancer migration in an epigenetic mechanism in which it modulates PRUNE2 expression by interacting with a member of the DNA methylation machinery, DNA methyltransferase 3A (DNMT3A). Higher methylation levels of PRUNE2 promoter were associated with nodal metastases and inversely correlated with PRUNE2 expression in head and neck cancer. Collectively, these findings suggest that MROS‐1, serving as a functional mediator of melatonin signaling, could predispose patients with oral cancer to metastasize and may be implicated as a potential target for antimetastatic therapies.
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•High dosage of SO42− (>10meq/L) stabilized ZnO NPs by inverting surface potential.•The electrolyte-driven aggregation of ZnO NPs was inhibited by 10mg/L SRHA.•ZnO NPs kept stable in ...a wastewater with high TOC and even high ionic strength.•High TOC and low pH compromised high ionic strength on the dissolution of ZnO NPs.
Zinc oxide nanoparticles (ZnO NPs) are widely used nanomaterials and their environmental impacts have received increasing attention. The fate and toxicity of ZnO NPs in the environment are determined by their stability and dissolution. In this study, the influence of water chemistry on aggregation, sedimentation, and dissolution of ZnO NPs was investigated. The stabilized ZnO NPs aggregated and precipitated when the aqueous pH closed to their zero point of charge (pHzpc). Counter-ions neutralized the surface charge of NPs and promoted their destabilization. However, a high concentration of counter-ion (SO42−, >10meq/L) made the NPs more stable because of the inverted surface potential. The stability of ZnO NPs was maintained by high concentration of Suwannee River humic acid (SRHA, 10mg/L) even the concentration of electrolytes was high. The influence of water chemistry on the stability and dissolution of ZnO NPs was further demonstrated in different wastewaters. In one wastewater sample, ZnO NPs was unexpectedly stable and with a high dissolution, which was due to the effects of pH value, organic matter concentration, as well as the concentration of counter ions. Our findings facilitate the predictions of the fate of stabilized ZnO NPs in the environment.
A new “single‐flask” method was developed for the synthesis of imidazolidines and pyrrolidines with high stereoselectivity. First, a Schiff base was arylated with an aryne. Second, an intramolecular ...proton transfer took place from the methylene position to the anionic aryne ring. Third, the resultant ylide reacted with a second equivalent of the same Schiff base in situ or an electron‐deficient alkene through a (3+2) cycloaddition. These sequential tandem 1,2‐addition/(3+2) cycloaddition reactions led to the desired heterocycles in 63–88 % yields.
Two steps in one flask: A sequence of arylation of a Schiff base, an intramolecular proton transfer from the methylene position to the anionic aryne ring, and reaction of the resulting ylide with either a second equivalent of Schiff base or an electron‐deficient alkene in a (3+2) cycloaddition generates imidazolidines and pyrrolidines in high stereoselectivity and 63–88 % yields.
Real-time reverse transcription-PCR (RT-PCR) is currently the most sensitive method to detect severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that causes coronavirus disease 2019 ...(COVID-19). However, the correlation between detectable viral RNA and culturable virus in clinical specimens remains unclear. Here, we performed virus culture for 60 specimens that were confirmed to be positive for SARS-CoV-2 RNA by real-time RT-PCR. The virus could be successfully isolated from 12 throat and nine nasopharyngeal swabs and two sputum specimens. The lowest copy number required for virus isolation was determined to be 5.4, 6.0, and 5.7 log
genome copies/ml sample for detecting the
,
, and
genes, respectively. We further examined the correlation of genome copy number and virus isolation in different regions of the viral genome, demonstrating that culturable specimens are characterized by high copy numbers with a linear correlation observed between copy numbers of amplicons targeting structural and nonstructural regions. Overall, these results indicate that in addition to the copy number, the integrity of the viral genome should be considered when evaluating the infectivity of clinical SARS-CoV-2 specimens.
Deoxyshikonin (DSK), a phytochemical constituent, has been documented to elicit various oncostatic properties alone or in combination with established therapeutics. However, its role in restraining ...oral squamous cell carcinoma (OSCC) is mostly unclear. Here, we examined the tumor-suppressive effect of DSK and explored the molecular mechanisms underlying DSK’s activities on controlling oral cancer. Our results showed that DSK dose-dependently lessened the cell viability of tongue cancer cell lines, involving induction of cell cycle arrest at the sub-G1 phase and apoptotic cell death. Moreover, a unique signature of apoptosis-related proteins, including augmented nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) expression and caspase activation, was observed in DSK-treated tongue cancer cell lines. Furthermore, DSK-mediated upregulation of HO-1 and cleavage of caspase-9 and -3 were significantly inhibited by pharmacological blockage of p38 kinase. Collectively, these data revealed that DSK halted cell cycle progression and elicited cell apoptosis in tongue cancer cell lines, reshaping a p38-dependent profile of apoptotic proteome. Our findings provided novel insights into the therapeutic implications of a natural compound on the management of OSCC.
Bisphenol A (BPA) is a sealant and flux of plastic materials and has been determined to be an endocrine-disrupting chemical. Prenatal exposure to BPA can lead to substantial adverse effects on fetal ...growth and development. This study was conducted to assess BPA concentration in pregnant women and umbilical cord blood, and to investigate whether maternal BPA exposure affected fetal outcomes including lower birth weight (LBW), smaller size for gestational age (SGA), and high leptin (HLP) and low adiponectin (LAD) secretion.
We measured the BPA levels of maternal blood (n = 97) and umbilical cord blood (n = 97) with a high-performance liquid chromatography/UV detector. The protein secretion of leptin and adiponectin were separately determined using enzyme-linked immunosorbent assay. A logistic regression was performed to estimate the effects of maternal exposure to BPA on LBW, SGA, and adverse action of adipokines in newborns.
The geometric means of BPA concentration in maternal blood and fetal cord blood were 2.5 ng/ml and 0.5 ng/ml, respectively. Elevated risks of LBW (OR 2.42, 95% confidence interval (CI) 1.72-3.36), SGA (OR 2.01, 95% CI 1.39-3.01), and adverse action of leptin (OR 1.67, 95% CI 1.12-2.25) and adiponectin (OR 1.25, 95% CI 1.52-3.97) were observed in male neonates in the highest quartile of maternal BPA exposure.
Elevated prenatal BPA exposure increased the risk of LBW, SGA, and adverse actions of adipokines in neonates, especially in male infants. These results provide further evidence that maternal exposure is correlated with adverse birth outcomes.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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