Notch receptors (Notch1-4) play critical roles in tumorigenesis and metastasis of malignant tumors, including breast cancer. Although abnormal Notch activation is related to various tumors, the ...importance of single receptors and their mechanism of activation in distinct breast cancer subtypes are still unclear. Previous studies by our group demonstrated that Notch3 may inhibit the emergence and progression of breast cancer. PTEN is a potent tumor suppressor, and its loss of function is sufficient to promote the occurrence and progression of tumors. Intriguingly, numerous studies have revealed that Notch1 is involved in the regulation of PTEN through its binding to CBF-1, a Notch transcription factor, and the PTEN promoter. In this study, we found that Notch3 and PTEN levels correlated with the luminal phenotype in breast cancer cell lines. Furthermore, we demonstrated that Notch3 transactivated PTEN by binding CSL-binding elements in the PTEN promoter and, at least in part, inhibiting the PTEN downstream AKT-mTOR pathway. Notably, Notch3 knockdown downregulated PTEN and promoted cell proliferation and tumorigenesis. In contrast, overexpression of the Notch3 intracellular domain upregulated PTEN and inhibited cell proliferation and tumorigenesis in vitro and in vivo. Moreover, inhibition or overexpression of PTEN partially reversed the promotion or inhibition of cell proliferation induced by Notch3 alterations. In general, Notch3 expression positively correlated with elevated expression of PTEN, ER, lower Ki-67 index, and incidence of involved node status and predicted better recurrence-free survival in breast cancer patients. Therefore, our findings demonstrate that Notch3 inhibits breast cancer proliferation and suppresses tumorigenesis by transactivating PTEN expression.
Deuterium water (D2O) is a strategic material that is widely used in and scientific research and has applications in fields such as nuclear energy generation. However, its content in natural water is ...extremely low. Therefore, the development of a room‐temperature technology for achieving simple, efficient, and low‐cost separation of D2O from natural water is challenging. In this study, porous graphene (PG) nanosheets with “crater‐like” pores are sandwiched between two layers of graphene oxide (GO) membranes to prepare a GO/PG/GO membrane with a macroscopic heterostructure, which can be used to separate D2O and H2O by pressure‐driven filtration. At 25 °C, the rejection rate of D2O is ≈97%, the selectivity of H2O/D2O is ≈35.2, and the excellent performance can be attributed to the difference of transmembrane resistance and flow state of H2O and D2O in the confinement state. In addition, the D2O concentration in natural water is successfully enriched from 0.013% to 0.059% using only one stage, and the membrane exhibits excellent structural and cycling stability. Therefore, this method does not require ultralow temperatures, high energy supplies, complex separation equipment, or the introduction of toxic chemicals. Thus, it can be directly applied to the large‐scale industrial production and removal of D2O.
A graphene oxide/porous graphene/graphene oxide (GO/PG/GO) membrane separation technology by pressure‐driven filtration is reported and it is applied in isotope separation at room temperature. It shows an excellent structural, long‐term stability, ultralow energy consumption, and ultrahigh selectivity for deuterium water, including rejection rate of ≈97%, the selectivity of ≈35.2 as well.
•Late Triassic bimodal igneous rocks are identified in Northeast China.•Late Triassic igneous rocks formed in an extensional environment.•The subduction of Paleo-Pacific Plate beneath Eurasia ...happened after Late Triassic.
This paper reports new zircon LA–ICP–MS and SIMS U–Pb ages and Hf isotope data, and whole-rock major and trace element data for Late Triassic igneous rocks of eastern Heilongjiang Province, NE China. These data provide new insights into the timing of the initiation of subduction of the Paleo-Pacific Plate beneath the Eurasian continent. The zircon U–Pb age data indicate that a suite of Late Triassic (228–202Ma) igneous rocks is present within the Songnen–Zhangguangcai Range Massif and within the western margin of the Khanka Massif. The Late Triassic igneous rocks within the Songnen–Zhangguangcai Range Massif consist of basalts, basaltic andesites, gabbro-diabases, and rhyolites, whereas coeval igneous rocks in the western margin of the Khanka Massif consist of hornblende gabbros and syenogranitic porphyries. These Late Triassic rocks constitute a geochemically bimodal igneous rock association that contains mafic rocks enriched in light rare earth elements (LREE) and large ion lithophile elements (LILE), and depleted in heavy rare earth elements (HREE) and high field strength elements (HFSE) such as Nb, Ta, Zr, Hf, and Ti. Zircons from these mafic rocks have εHf (t) values and TDM1 ages of +2.8 to +9.8 and 477–733Ma, respectively, suggesting that they formed from a primary magma generated by the partial melting of depleted lithospheric mantle material that had been previously modified by subduction-related fluids. The coeval felsic rocks are characterized by enrichments in LREEs and LILEs, and depletions in HREEs and HFSEs (including Nb, Ta, and Ti), and their zircons have εHf (t) values and TDM2 ages of +0.6 to +7.9 and 766 to 1461Ma, respectively, implying that these rocks were generated during the partial melting of juvenile crustal material. The Late Triassic bimodal igneous rocks in eastern Heilongjiang Province, combined with the regional geologic information, therefore record a post-orogenic extensional environment related to the final late Permian–Early Triassic closure of the Paleo-Asian Ocean. In addition, the presence of Late Triassic bimodal igneous rocks within the eastern margin of the Eurasian continent suggests that the subduction of the Paleo-Pacific Plate beneath the Eurasian continent began after the Late Triassic.
Abstract
Long-duration GRB 200829A was detected by Fermi-GBM and Swift-BAT/XRT, and then rapidly observed by other ground-based telescopes. It has a weak
γ
-ray emission in the very early phase and ...is followed by a bright spiky
γ
-ray emission pulse. The radiation spectrum of the very early emission is best fitted by a power-law function with index ∼−1.7. However, the bright spiky
γ
-ray pulse, especially the time around the peak, exhibits a distinct two-component radiation spectrum, i.e., Band function combined with a blackbody radiation spectrum. We infer the photospheric properties and reveal a medium magnetization at a photospheric position by adopting the initial size of the outflow as
r
0
= 10
9
cm. It implies that the Band component in this pulse may be formed during the dissipation of the magnetic field. The power-law radiation spectra found in the very early prompt emission may imply the external-shock origination of this phase. Then, we perform the Markov Chain Monte Carlo method fitting on the light curves of this burst, where the jet corresponding to the
γ
-ray pulse at around 20 s is used to refresh the external shock. It is shown that the light curves of the very early phase and X-ray afterglow after 40 s, involving the X-ray bump at around 100 s, can be well modeled in the external-shock scenario. For the obtained initial outflow, we estimate the minimum magnetization factor of the jet based on the fact that the photospheric emission of this jet is missed in the very early phase.
LA-ICP-MS zircon U–Pb dating and geochemical data have been obtained from five representative mafic–ultramafic intrusions in the Lesser Xing'an–Zhangguangcai Range, NE China, with the aim of ...improving our understanding of the Mesozoic tectonic evolution in the region, and in particular, determining the time of initiation of the circum-Pacific tectonic system. The selected zircons exhibit striped absorption in cathodoluminescence (CL) images and have high Th/U ratios (0.20–3.16), indicating a magmatic origin. The zircon U–Pb dates indicate that most of these magmatic zircons (other than a few relics that were captured and entrained in the magma) formed in the late Early Jurassic (186–182Ma), and not as previously supposed in the Middle Caledonian. The five mafic–ultramafic plutons are composed of olivine-gabbro, hornblendite, gabbro, hornblende-gabbro, and gabbro–diorite. The olivine-gabbro and hornblendite display cumulate textures, implying that fractional crystallization of olivine and plagioclase took place during magma evolution. These mafic–ultramafic igneous rocks have SiO2=37.3%–55.7%, MgO=3.05%–13.3%, Al2O3=11.8%–23.8%, Mg#=42–69 Mg#=100Mg/(Mg+Fe2+total), and δEu=0.88–1.32, and they display three types of rare earth element (REE) distribution patterns: right-slipped, flat patterns, or dome-like. The trace element spider diagrams show that the rocks are enriched in large ion lithophile elements (LILEs) such as Ba, K, and Sr, and depleted in high field strength elements (HFSEs) such as Nb, Ta, Zr, and Hf. The zircons have εHf (186–182Ma)=+2.7 to +12.0, and TDM1=366–732Ma. The geochemical data indicate that the Early Jurassic mafic magma originated in an extensional environment from the partial melting of a depleted mantle wedge that had been metasomatized by fluids released from a fossil subducted slab. These data, combined with information on the spatial variation of coeval igneous rocks, indicate that the formation of the Early Jurassic mafic–ultramafic rocks in the Lesser Xing'an–Zhangguangcai Range was related to the subduction of the Paleo-Pacific Plate beneath the Eurasian continent, and this event would mark the beginning of the circum-Pacific tectonic system.
► The mafic–ultramafic intrusive rocks are studied in NE China. ► The mafic–ultramafic intrusive rocks formed in Early Jurassic. ► They were derived from partial melting of a depleted mantle wedge within a fossil subduction zone. ► Early Jurassic mafic magmatism marks the beginning of the circum-Pacific tectonic system.
Alzheimer's disease (AD) is associated with high incidence of cardiovascular events but the mechanism remains elusive. Our previous study reveals a tight correlation between cardiac dysfunction and ...low mitochondrial aldehyde dehydrogenase (ALDH2) activity in elderly AD patients. In the present study we investigated the effect of ALDH2 overexpression on cardiac function in APP/PS1 mouse model of AD. Global ALDH2 transgenic mice were crossed with APP/PS1 mutant mice to generate the ALDH2-APP/PS1 mutant mice. Cognitive function, cardiac contractile, and morphological properties were assessed. We showed that APP/PS1 mice displayed significant cognitive deficit in Morris water maze test, myocardial ultrastructural, geometric (cardiac atrophy, interstitial fibrosis) and functional (reduced fractional shortening and cardiomyocyte contraction) anomalies along with oxidative stress, apoptosis, and inflammation in myocardium. ALDH2 transgene significantly attenuated or mitigated these anomalies. We also noted the markedly elevated levels of lipid peroxidation, the essential lipid peroxidation enzyme acyl-CoA synthetase long-chain family member 4 (ACSL4), the transcriptional regulator for ACLS4 special protein 1 (SP1) and ferroptosis, evidenced by elevated NCOA4, decreased GPx4, and SLC7A11 in myocardium of APP/PS1 mutant mice; these effects were nullified by ALDH2 transgene. In cardiomyocytes isolated from WT mice and in H9C2 myoblasts in vitro, application of Aβ (20 μM) decreased cell survival, compromised cardiomyocyte contractile function, and induced lipid peroxidation; ALDH2 transgene or activator Alda-1 rescued Aβ-induced deteriorating effects. ALDH2-induced protection against Aβ-induced lipid peroxidation was mimicked by the SP1 inhibitor tolfenamic acid (TA) or the ACSL4 inhibitor triacsin C (TC), and mitigated by the lipid peroxidation inducer 5-hydroxyeicosatetraenoic acid (5-HETE) or the ferroptosis inducer erastin. These results demonstrate an essential role for ALDH2 in AD-induced cardiac anomalies through regulation of lipid peroxidation and ferroptosis.
Abstract
Knowledge about the Lorentz factor and its evolution of relativistic jets in gamma-ray bursts (GRBs) is crucial to understand their physics. An exact value of the bulk Lorentz factor can be ...estimated based on a high-energy spectral cutoff, which may appear in the GRBs’ prompt emission owing to the absorption of photon–photon pair production. In this work, we focus on an investigation of the bulk Lorentz factor evolution of jets in an individual burst. Based on Fermi observations, we search for bursts with multiple GRB pulses characterized by a high-energy spectral cutoff, and nine GRBs are obtained. Together with the estimation of the pulse duration and radiation spectrum, the Lorentz factor of jets corresponding to different pulses in an individual GRB is estimated. It is shown that the Lorentz factor of jets in an individual GRB fluctuates within a certain range and without a general trend in these nine GRBs. In addition, the Lorentz factors of the jets in GRBs 130821A, 160509A, and 160625B seem to increase with time. We also study the relations among
L
iso
,
E
p,z
, and Γ for the pulses in our sample, which are found to be consistent with those found in previous works.
We investigate strong field ionization of an atomic gas in a plasmonically enhanced field resulting from the illumination of a nanometer-sized structure with ultrafast laser pulse. We use ...perturbation theory to derive an approximate solution for electron’s motion following ionization. These analytical estimates are corroborated by the time-dependent Schrödinger equation and classical trajectory Monte Carlo simulations. Notably, our approach can be used to obtain electron energy spectra without having to rely on numerical simulations. This allows for a deeper study of the dependence of electron energy spectrum on the properties of the near-field, suggesting electric field sensor applications. We derive an analytical expression for the location of the peak of the higher-energy structure (HES) as a function of laser parameters and near-field decay length. We find a particularly strong dependence of the energy peak on laser frequency, with lower frequencies causing a significant upward shift in the final electron energies. Combined with control of the width of the HES, which can be done by changing the size of the nanostructure, this points to the possibility of using nanotips as sources of ultrashort electron beams of tunable energy.
Quasi‐2D layered organometal halide perovskites have recently emerged as promising candidates for solar cells, because of their intrinsic stability compared to 3D analogs. However, relatively low ...power conversion efficiency (PCE) limits the application of 2D layered perovskites in photovoltaics, due to large energy band gap, high exciton binding energy, and poor interlayer charge transport. Here, efficient and water‐stable quasi‐2D perovskite solar cells with a peak PCE of 18.20% by using 3‐bromobenzylammonium iodide are demonstrated. The unencapsulated devices sustain over 82% of their initial efficiency after 2400 h under relative humidity of ≈40%, and show almost unchanged photovoltaic parameters after immersion into water for 60 s. The robust performance of perovskite solar cells results from the quasi‐2D perovskite films with hydrophobic nature and a high degree of electronic order and high crystallinity, which consists of both ordered large‐bandgap perovskites with the vertical growth in the bottom region and oriented small‐bandgap components in the top region. Moreover, due to the suppressed nonradiative recombination, the unencapsulated photovoltaic devices can work well as light‐emitting diodes (LEDs), exhibiting an external quantum efficiency of 3.85% and a long operational lifetime of ≈96 h at a high current density of 200 mA cm−2 in air.
High‐crystallinity quasi‐2D perovskite films with oriented structure are fabricated by using 3‐bromobenzylammonium iodide, leading to perovskite solar cells with a high efficiency of 18.20%. Moreover, the unencapsulated devices exhibit excellent moisture resistance, retaining 82% of the initial efficiency after 2400 h under ambient conditions. Even after immersion into water for 60 s, the unsealed device shows little decay.
Impaired activation and regulation of the extinction of inflammatory cells and molecules in injured neuronal tissues are key factors in the development of epilepsy. SerpinA3N is mainly associated ...with the acute phase response and inflammatory response. In our current study, transcriptomics analysis, proteomics analysis, and Western blotting showed that the expression level of Serpin clade A member 3N (SerpinA3N) is significantly increased in the hippocampus of mice with kainic acid (KA)-induced temporal lobe epilepsy, and this molecule is mainly expressed in astrocytes. Notably, in vivo studies using gain- and loss-of-function approaches revealed that SerpinA3N in astrocytes promoted the release of proinflammatory factors and aggravated seizures. Mechanistically, RNA sequencing and Western blotting showed that SerpinA3N promoted KA-induced neuroinflammation by activating the NF-κB signaling pathway. In addition, co-immunoprecipitation revealed that SerpinA3N interacts with ryanodine receptor type 2 (RYR2) and promotes RYR2 phosphorylation. Overall, our study reveals a novel SerpinA3N-mediated mechanism in seizure-induced neuroinflammation and provides a new target for developing neuroinflammation-based strategies to reduce seizure-induced brain injury.
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