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"J Xu"
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Twist1 promotes breast cancer invasion and metastasis by silencing Foxa1 expression
The heterogeneous breast cancers can be classified into different subtypes according to their histopathological characteristics and molecular signatures. Foxa1 expression is linked with luminal breast cancer (LBC) with good prognosis, whereas Twist1 expression is associated with basal-like breast cancer (BLBC) with poor prognosis owing to its role in promoting epithelial-to-mesenchymal transition (EMT), invasiveness and metastasis. However, the regulatory and functional relationships between Twist1 and Foxa1 in breast cancer progression are unknown. In this study, we demonstrate that in the estrogen receptor (ERα)-positive LBC cells Twist1 silences Foxa1 expression, which has an essential role in relieving Foxa1-arrested migration, invasion and metastasis of breast cancer cells. Mechanistically, Twist1 binds to
Foxa1
proximal promoter and recruits the NuRD transcriptional repressor complex to de-acetylate H3K9 and repress RNA polymerase II recruitment. Twist1 also silences
Foxa1
promoter by inhibiting AP-1 recruitment. Twist1 expression in MCF7 cells silenced Foxa1 expression, which was concurrent with the induction of EMT, migration, invasion and metastasis of these cells. Importantly, restored Foxa1 expression in these cells largely inhibited Twist1-promoted migration, invasion and metastasis. Restored Foxa1 expression did not change the Twist1-induced mesenchymal cellular morphology and the expression of Twist1-regulated E-cadherin, β-catenin, vimentin and Slug, but it partially rescued Twist1-silenced ERα and cytokeratin 8 expression and reduced Twist1-induced integrin α5, integrin β1 and MMP9 expression. In a xenografted mouse model, restored Foxa1 also increased Twist1-repressed LBC markers and decreased Twist1-induced BLBC markers. Furthermore, Twist1 expression is negatively correlated with Foxa1 in the human breast tumors. The tumors with high Twist1 and low Foxa1 expressions are associated with poor distant metastasis-free survival. These results demonstrate that Twist1’s silencing effect on Foxa1 expression is largely responsible for Twist1-induced migration, invasion and metastasis, but less responsible for Twist1-induced mesenchymal morphogenesis and expression of certain EMT markers.
Journal Article
No pulsed radio emission during a bursting phase of a Galactic magnetar
Fast radio bursts (FRBs) are millisecond-duration radio transients of unknown physical origin observed at extragalactic distances
1
–
3
. It has long been speculated that magnetars are the engine powering repeating bursts from FRB sources
4
–
13
, but no convincing evidence has been collected so far
14
. Recently, the Galactic magnetar SRG 1935+2154 entered an active phase by emitting intense soft γ-ray bursts
15
. One FRB-like event with two peaks (FRB 200428) and a luminosity slightly lower than the faintest extragalactic FRBs was detected from the source, in association with a soft γ-ray/hard-X-ray flare
18
–
21
. Here we report an eight-hour targeted radio observational campaign comprising four sessions and assisted by multi-wavelength (optical and hard-X-ray) data. During the third session, 29 soft-γ-ray repeater (SGR) bursts were detected in γ-ray energies. Throughout the observing period, we detected no single dispersed pulsed emission coincident with the arrivals of SGR bursts, but unfortunately we were not observing when the FRB was detected. The non-detection places a fluence upper limit that is eight orders of magnitude lower than the fluence of FRB 200428. Our results suggest that FRB–SGR burst associations are rare. FRBs may be highly relativistic and geometrically beamed, or FRB-like events associated with SGR bursts may have narrow spectra and characteristic frequencies outside the observed band. It is also possible that the physical conditions required to achieve coherent radiation in SGR bursts are difficult to satisfy, and that only under extreme conditions could an FRB be associated with an SGR burst.
An 8-hour radio observational campaign of the Galactic magnetar SGR 1935+2154, assisted by multi-wavelength data, indicates that associations between fast radio bursts and soft γ-ray bursts are rare.
Journal Article
Glycolysis gatekeeper PDK1 reprograms breast cancer stem cells under hypoxia
Glycolysis is critical for cancer stem cell reprogramming; however, the underlying regulatory mechanisms remain elusive. Here, we show that pyruvate dehydrogenase kinase 1 (PDK1) is enriched in breast cancer stem cells (BCSCs), whereas depletion of PDK1 remarkably diminishes ALDH
+
subpopulations, decreases stemness-related transcriptional factor expression, and inhibits sphere-formation ability and tumor growth. Conversely, high levels of PDK1 enhance BCSC properties and are correlated with poor overall survival. In mouse xenograft tumor, PDK1 is accumulated in hypoxic regions and activates glycolysis to promote stem-like traits. Moreover, through screening hypoxia-related long non-coding RNAs (lncRNAs) in PDK1-positive tissue, we find that lncRNA H19 is responsible for glycolysis and BCSC maintenance. Furthermore,
H19
knockdown decreases PDK1 expression in hypoxia, and ablation of
PDK1
counteracts H19-mediated glycolysis and self-renewal ability
in vitro
and
in vivo
. Accordingly, H19 and PDK1 expression exhibits strong correlations in primary breast carcinomas. H19 acting as a competitive endogenous RNA sequesters miRNA let-7 to release Hypoxia-inducible factor 1α, leading to an increase in PDK1 expression. Lastly, aspirin markedly attenuates glycolysis and cancer stem-like characteristics by suppressing both H19 and PDK1. Thus, these novel findings demonstrate that the glycolysis gatekeeper PDK1 has a critical role in BCSC reprogramming and provides a potential therapeutic strategy for breast malignancy.
Journal Article
Gastric cancer and gene copy number variation: emerging cancer drivers for targeted therapy
Gastric cancer (GC) is among the most common malignancy in the world with poor prognosis and limited treatment options. It has been established that gastric carcinogenesis is caused by a complex interaction between host and environmental factors. Copy number variation (CNV) refers to a form of genomic structural variation that results in abnormal gene copy numbers, including gene amplification, gain, loss and deletion. DNA CNV is an important influential factor for the expression of both protein-coding and non-coding genes, affecting the activity of various signaling pathways. CNV arises as a result of preferential selection that favors cancer development, and thus, targeting the amplified 'driver genes' in GC may provide novel opportunities for personalized therapy. The detection of CNVs in chromosomal or mitochondrial DNA from tissue or blood samples may assist the diagnosis, prognosis and targeted therapy of GC. In this review, we discuss the recent CNV discoveries that shed light on the molecular pathogenesis of GC, with a specific emphasis on CNVs that display diagnostic, prognostic or therapeutic significances in GC.
Journal Article
Potential and electric double-layer effect in electrocatalytic urea synthesis
Electrochemical synthesis is a promising way for sustainable urea production, yet the exact mechanism has not been fully revealed. Herein, we explore the mechanism of electrochemical coupling of nitrite and carbon dioxide on Cu surfaces towards urea synthesis on the basis of a constant-potential method combined with an implicit solvent model. The working electrode potential, which has normally overlooked, is found influential on both the reaction mechanism and activity. The further computational study on the reaction pathways reveals that *CO-NH and *NH-CO-NH as the key intermediates. In addition, through the analysis of turnover frequencies under various potentials, pressures, and temperatures within a microkinetic model, we demonstrate that the activity increases with temperature, and the Cu(100) shows the highest efficiency towards urea synthesis among all three Cu surfaces. The electric double-layer capacitance also plays a key role in urea synthesis. Based on these findings, we propose two essential strategies to promote the efficiency of urea synthesis on Cu electrodes: increasing Cu(100) surface ratio and elevating the reaction temperature.
Electrochemical urea synthesis presents a promising alternative to conventional synthesis methods, yet the elusive mechanism hindered its development. Here, the authors take copper as an example to explore the potential and electric double-layer effect in electrocatalytic urea synthesis, and reveal two essential strategies to promote the efficiency of urea synthesis.
Journal Article
Cavin-1 is essential for the tumor-promoting effect of caveolin-1 and enhances its prognostic potency in pancreatic cancer
Caveolin-1 exhibits a stage-dependent, functional fluctuation during pancreatic cancer development, but the underlying mechanisms remain unclear. Here, we report that cavin-1, a structural protein of caveolae, modulates the oncogenic function of caveolin-1 and cooperates with caveolin-1 to enhance pancreatic cancer aggressiveness. Cavin-1 expression is associated with caveolin-1 in pancreatic cancer tissue samples and cell lines, and predicts the metastatic potential of pancreatic cancer. Interactome analyses further revealed the physical interaction of cavin-1 and caveolin-1 and their colocalization in pancreatic cancer cells. Cavin-1 stabilizes caveolin-1 expression or activity by inhibiting its internalization and subsequent lysosomal degradation. More in-depth functional experiments showed that caveolin-1-enhanced aggressiveness of pancreatic cancer cells is dependent on the presence of cavin-1. In contrast, cavin-1 depletion inhibited the invasion and metastasis of pancreatic cancer cells, which could not be restored by caveolin-1-rescue construct. Tissue microarray analyses in two independent clinic cohorts also supported the augment of cavin-1 on the prognostic potency of caveolin-1, and showed that combination of cavin-1 with caveolin-1 predicted worse survival in pancreatic cancer patients. Of note, the phenotypes because of cavin-1 could not be achieved by other cavins such as cavin-2, and the tumor-promoting role of cavin-1 in pancreatic cancer was found to be largely dependent on caveolin-1 expression, which highlights the critical role of cavin-1/caveoin-1 in pancreatic cancer progression, and suggests that the interruption of cavin-1/caveolin-1 interaction is a promising therapeutic strategy for pancreatic cancer.
Journal Article
Spin-polarized oxygen evolution reaction under magnetic field
The oxygen evolution reaction (OER) is the bottleneck that limits the energy efficiency of water-splitting. The process involves four electrons’ transfer and the generation of triplet state O
2
from singlet state species (OH
-
or H
2
O). Recently, explicit spin selection was described as a possible way to promote OER in alkaline conditions, but the specific spin-polarized kinetics remains unclear. Here, we report that by using ferromagnetic ordered catalysts as the spin polarizer for spin selection under a constant magnetic field, the OER can be enhanced. However, it does not applicable to non-ferromagnetic catalysts. We found that the spin polarization occurs at the first electron transfer step in OER, where coherent spin exchange happens between the ferromagnetic catalyst and the adsorbed oxygen species with fast kinetics, under the principle of spin angular momentum conservation. In the next three electron transfer steps, as the adsorbed O species adopt fixed spin direction, the OER electrons need to follow the Hund rule and Pauling exclusion principle, thus to carry out spin polarization spontaneously and finally lead to the generation of triplet state O
2
. Here, we showcase spin-polarized kinetics of oxygen evolution reaction, which gives references in the understanding and design of spin-dependent catalysts.
Here, authors demonstrate the ferromagnetic catalyst to facilitate spin polarization in water oxidation reaction. They find the ferromagnetic-exchange-like behaviour between the ferromagnetic catalyst and the adsorbed oxygen species.
Journal Article
Well-posedness of the Prandtl equation in Sobolev spaces
We develop a new approach to study the well-posedness theory of the Prandtl equation in Sobolev spaces by using a direct energy method under a monotonicity condition on the tangential velocity field instead of using the Crocco transformation. Precisely, we firstly investigate the linearized Prandtl equation in some weighted Sobolev spaces when the tangential velocity of the background state is monotonic in the normal variable. Then to cope with the loss of regularity of the perturbation with respect to the background state due to the degeneracy of the equation, we apply the Nash-Moser-Hörmander iteration to obtain a well-posedness theory of classical solutions to the nonlinear Prandtl equation when the initial data is a small perturbation of a monotonic shear flow.
Journal Article
Tuning of lattice oxygen reactivity and scaling relation to construct better oxygen evolution electrocatalyst
Developing efficient and low-cost electrocatalysts for oxygen evolution reaction is crucial in realizing practical energy systems for sustainable fuel production and energy storage from renewable energy sources. However, the inherent linear scaling relation for most catalytic materials imposes a theoretical overpotential ceiling, limiting the development of efficient electrocatalysts. Herein, using modeled Na
x
Mn
3
O
7
materials, we report an effective strategy to construct better oxygen evolution electrocatalyst through tuning both lattice oxygen reactivity and scaling relation via alkali metal ion mediation. Specifically, the number of Na
+
is linked with lattice oxygen reactivity, which is determined by the number of oxygen hole in oxygen lone-pair states formed by native Mn vacancies, governing the barrier symmetry between O–H bond cleavage and O–O bond formation. On the other hand, the presence of Na
+
could have specific noncovalent interaction with pendant oxygen in *OOH to overcome the limitation from linear scaling relation, reducing the overpotential ceiling. Combining in situ spectroscopy-based characterization with first-principles calculations, we demonstrate that an intermediate level of Na
+
mediation (NaMn
3
O
7
) exhibits the optimum oxygen evolution activity. This work provides a new rational recipe to develop highly efficient catalyst towards water oxidation or other oxidative reactions through tuning lattice oxygen reactivity and scaling relation.
While water-splitting provides a renewable means to generate fuel, the water-oxidation half-reaction is considered a bottleneck process. Here, authors tune lattice oxygen reactivity and scaling relations via alkali metal ion mediation in NaMn
3
O
7
for oxygen evolution electrocatalysis.
Journal Article