The molecular mechanisms underlying estrogen receptor (ER)‐positive breast carcinogenesis and endocrine therapy resistance remain incompletely understood. Here, we report that circPVT1, a circular ...RNA generated from the lncRNA PVT1, is highly expressed in ERα‐positive breast cancer cell lines and tumor samples and is functionally important in promoting ERα‐positive breast tumorigenesis and endocrine therapy resistance. CircPVT1 acts as a competing endogenous RNA (ceRNA) to sponge miR‐181a‐2‐3p, promoting the expression of ESR1 and downstream ERα‐target genes and breast cancer cell growth. Furthermore, circPVT1 directly interacts with MAVS protein to disrupt the RIGI–MAVS complex formation, inhibiting type I interferon (IFN) signaling pathway and anti‐tumor immunity. Anti‐sense oligonucleotide (ASO)‐targeting circPVT1 inhibits ERα‐positive breast cancer cell and tumor growth, re‐sensitizing tamoxifen‐resistant ERα‐positive breast cancer cells to tamoxifen treatment. Taken together, our data demonstrated that circPVT1 can work through both ceRNA and protein scaffolding mechanisms to promote cancer. Thus, circPVT1 may serve as a diagnostic biomarker and therapeutic target for ERα‐positive breast cancer in the clinic.
Synopsis
Estrogen receptor (ER)α, encoded by ESR1, promotes mammary malignancies and is targeted in cancer therapy; however, resistance arises frequently. This study reports a novel circRNA, termed circPVT1, with dual mechanisms to enhance ER‐positive breast tumorigenesis, suggesting therapeutic opportunities.
CircPVT1 is highly expressed in ERα‐positive breast tumor patients.
CircPVT1 sponges miR‐181a‐2‐3p to stabilize ESR1 mRNA, activating the expression of estrogen/ERα‐target genes.
CircPVT1 interacts with MAVS protein to disrupt RIGI–MAVS complex formation, repressing the expression of type I IFN and interferon‐stimulated genes.
ASO‐targeting circPVT1 suppresses ERα‐positive breast cancer cell and tumor growth.
Circular RNA circPVT1 has dual function in aggravating ER+ mammary gland malignancies.
The structure–property relationship in 0.06C–5.5Mn steel subjected to different annealing temperatures and time was studied. Mn played a stronger effect on stabilizing austenite in comparison with ...Ni, and low-C medium-Mn steel possessed excellent hardenability. The reverse transformation of martensite to austenite occurred during intercritical annealing, and the volume fraction was first increased and then decreased on increasing annealing temperature or prolonging annealing time, indicative of change in thermal stability by element partitioning and coarsening of grain size. Correspondingly, the elongation was first increased and then decreased, consistent with the variation in the stability of reverted austenite. The yield strength was gradually decreased because of several factors, including recrystallization of
α
′ martensite, decreased stability of reverted austenite, and coarse grain size. The maximum product of strength and ductility was obtained on annealing at 650 °C for 10 min, which was attributed to the optimal stability of reverted austenite rather than the highest volume fraction, and tensile strength and elongation were 1120 MPa and 23.3%. The strain partitioning behavior of two phases was elucidated by analyzing Lüders straining and continuous work hardening after yield point elongation, and the deformation mechanism was strongly related to the stability of reverted austenite.
The use of unmanned aerial vehicles (UAVs) for target searching in complex environments has increased considerably in recent years. The numerous studies on UAV search methods have been reported, but ...few have been conducted on collaborative human-UAV search which is common in many applications. In this paper, we present a problem of collaborative human-UAV search for escaped criminals, the aim of which is to minimize the expected time of capture rather than detection. We show that our problem is much more complex than the problem of pure UAV search. The difficulty of our problem is further increased by the fact that criminals will attempt to avoid detection and capture. To solve the problem, we propose a hybrid evolutionary algorithm (EA) that uses three evolutionary operators, namely, comprehensive learning, variable mutation, and local search, to efficiently explore the solution space. The experimental results demonstrate that the proposed method outperforms some well-known EAs and other popular UAV search methods on test instances. An application of our method to a real-world operation took 311 min to capture a criminal who had escaped for over three days, validating its practicability and performance advantage. This paper provides a good basis for promoting the application of EAs to a wider class of man-machine collaboration scheduling problems.
Individual free fatty acids (FAs) play important roles in metabolic homeostasis, many through engagement with more than 40G protein-coupled receptors. Searching for receptors to sense beneficial ...omega-3 FAs of fish oil enabled the identification of GPR120, which is involved in a spectrum of metabolic diseases. Here, we report six cryo-electron microscopy structures of GPR120 in complex with FA hormones or TUG891 and G
or G
trimers. Aromatic residues inside the GPR120 ligand pocket were responsible for recognizing different double-bond positions of these FAs and connect ligand recognition to distinct effector coupling. We also investigated synthetic ligand selectivity and the structural basis of missense single-nucleotide polymorphisms. We reveal how GPR120 differentiates rigid double bonds and flexible single bonds. The knowledge gleaned here may facilitate rational drug design targeting to GPR120.
Building a better scaffold: Low loadings (0.2–1 mol %) of new double axially chiral phosphoric acid catalysts 1 based on bis‐binol scaffold were used for asymmetric transfer hydrogenation. 2‐Aryl‐ ...and 2‐alkyl‐substituted quinolines gave tetrahydroquinolines in excellent yields and with up to 98 % ee and 2,3‐disubstituted tetrahydroquinolines were prepared in high diastereo‐ and enantioselectivities (up to >20:1 and 92 % ee).
The ultra-low carbon medium Mn steel was subjected to quenching and intercritical tempering process. The 650°C tempering route led to 15% volume fraction of austenite with combination of high yield ...strength of 650MPa, low yield ratio of 0.86, and excellent elongation of ∼31%. The impact energy at −20°C was enhanced more than twenty times from 10J to 213J. The formation of reversed transformation austenite during the intercritical tempering process contributed to the observed superior mechanical properties.
Adhesion G-protein-coupled receptors (aGPCRs) are important for organogenesis, neurodevelopment, reproduction and other processes
. Many aGPCRs are activated by a conserved internal (tethered) ...agonist sequence known as the Stachel sequence
. Here, we report the cryogenic electron microscopy (cryo-EM) structures of two aGPCRs in complex with G
: GPR133 and GPR114. The structures indicate that the Stachel sequences of both receptors assume an α-helical-bulge-β-sheet structure and insert into a binding site formed by the transmembrane domain (TMD). A hydrophobic interaction motif (HIM) within the Stachel sequence mediates most of the intramolecular interactions with the TMD. Combined with the cryo-EM structures, biochemical characterization of the HIM motif provides insight into the cross-reactivity and selectivity of the Stachel sequences. Two interconnected mechanisms, the sensing of Stachel sequences by the conserved 'toggle switch' W
and the constitution of a hydrogen-bond network formed by Q
/Y
and the P
/V
φφG
motif (φ indicates a hydrophobic residue), are important in Stachel sequence-mediated receptor activation and G
coupling. Notably, this network stabilizes kink formation in TM helices 6 and 7 (TM6 and TM7, respectively). A common G
-binding interface is observed between the two aGPCRs, and GPR114 has an extended TM7 that forms unique interactions with G
. Our structures reveal the detailed mechanisms of aGPCR activation by Stachel sequences and their G
coupling.
We compile the radio-optical-X-ray spectral energy distributions (SEDs) of 65 knots and 29 hotspots in 41 active galactic nucleus jets to examine their high-energy radiation mechanisms. Their SEDs ...can be fitted with the single-zone leptonic models, except for the hotspot of Pictor A and six knots of 3C 273. The X-ray emission of 1 hotspot and 22 knots is well explained as synchrotron radiation under the equipartition condition; they usually have lower X-ray and radio luminosities than the others, which may be due to a lower beaming factor. An inverse Compton (IC) process is involved for explaining the X-ray emission of the other SEDs. Without considering the equipartition condition, their X-ray emission can be attributed to the synchrotron-self-Compton process, but the derived jet powers (Pjet) are not correlated with Lk and most of them are larger than Lk, with more than three orders of magnitude, where Lk is the jet kinetic power estimated with their radio emission. Under the equipartition condition, the X-ray emission is well interpreted with the IC process for the cosmic microwave background photons (IC/CMB). In this scenario, the derived Pjet of knots and hotspots are correlated with and comparable to Lk. These results suggest that the IC/CMB model may be a promising interpretation of the X-ray emission. In addition, a tentative knot-hotspot sequence in the synchrotron peak-energy-peak-luminosity plane is observed, similar to the blazar sequence, which may be attributed to the different cooling mechanisms of electrons.
The resource utilization of spent alkaline Zn–Mn batteries (S-AZMB) has always been a hot issue in the field of energy regeneration and environmental protection. The cumbersome and complicated ...purification process is the reason for their limited recycling. Not long ago, we proved that unpurified S-AZMB can be used directly: construct a Z-scheme photocatalytic system by combining with commercial TiO2 through high-temperature calcination. In order for this finding to be truly adopted by the application market, the high energy consumption calcination process needs to be improved urgently. In this work, we explore the temperature dependence of performance for the composite photocatalyst (TiO2@S-AZMB). A series of experimental results confirm that lowering the calcination temperature not only conducive to improving the separation efficiency of photogenerated electron-hole pairs, but also can significantly improve the environmental adaptability of the catalyst. Specifically, the catalyst synthesized by calcination temperature at 200 °C exhibits higher toluene removal efficiency than that at 500 °C under different initial concentration of pollutants, relative humidity, light intensity and oxygen content. This study not only further improves the photocatalytic performance of the composite catalyst, but also accords with the idea of energy saving and emission reduction, which provides more space for the possibility of recycling S-AZMB.
•A series of composite photocatalysts using unpurified S-AZMB as a raw material were synthesized.•The calcination temperature dependence of the photodegradation toluene properties was explored.•A lower calcination temperature beneficial to expand the environmental adaptability of the catalyst.•Catalysts synthesized at low calcined temperature showed excellent structural and performance stability.
Endocrine therapy is the frontline treatment for estrogen receptor (ER) positive breast cancer patients. However, the primary and acquired resistance to endocrine therapy drugs remain as a major ...challenge in the clinic. Here, this work identifies an estrogen‐induced lncRNA, LINC02568, which is highly expressed in ER‐positive breast cancer and functional important in cell growth in vitro and tumorigenesis in vivo as well as endocrine therapy drug resistance. Mechanically, this work demonstrates that LINC02568 regulates estrogen/ERα‐induced gene transcriptional activation in trans by stabilizing ESR1 mRNA through sponging miR‐1233‐5p in the cytoplasm. Meanwhile, LINC02568 contributes to tumor‐specific pH homeostasis by regulating carbonic anhydrase CA12 in cis in the nucleus. The dual functions of LINC02568 together contribute to breast cancer cell growth and tumorigenesis as well as endocrine therapy drug resistance. Antisense oligonucleotides (ASO) targeting LINC02568 significantly inhibits ER‐positive breast cancer cell growth in vitro and tumorigenesis in vivo. Furthermore, combination treatment with ASO targeting LINC02568 and endocrine therapy drugs or CA12 inhibitor U‐104 exhibits synergistic effects on tumor growth. Taken together, the findings reveal the dual mechanisms of LINC02568 in regulating ERα signaling and pH homeostasis in ER‐positive breast cancer, and indicated that targeting LINC02568 might represent a potential therapeutic avenue in the clinic.
Estrogen/ERα‐induced LINC02568 acts as a ceRNA to sponge miR‐1233‐5p to regulate the expression of ESR1 in the cytosol, in turn promoting the activation of ERα‐target gene program. LINC02568 also regulates its adjacent coding gene CA12 in cis to regulate cellular pH. LINC02568‐regulated ERα‐target gene activation and cellular pH both contribute to the development and drug resistance of ER+ breast cancer.
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