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.
Aims/hypothesis
Arctigenin is a natural compound that had never been previously demonstrated to have a glucose-lowering effect. Here it was found to activate AMP-activated protein kinase (AMPK), and ...the mechanism by which this occurred, as well as the effects on glucose and lipid metabolism were investigated.
Methods
2-Deoxyglucose uptake and AMPK phosphorylation were examined in L6 myotubes and isolated skeletal muscle. Gluconeogenesis and lipid synthesis were evaluated in rat primary hepatocytes. The acute and chronic effects of arctigenin on metabolic abnormalities were observed in C57BL/6J and
ob
/
ob
mice. Changes in mitochondrial membrane potential were measured using the J-aggregate-forming dye, JC-1. Analysis of respiration of L6 myotubes or isolated mitochondria was conducted in a channel oxygen system.
Results
Arctigenin increased AMPK phosphorylation and stimulated glucose uptake in L6 myotubes and isolated skeletal muscles. In primary hepatocytes, it decreased gluconeogenesis and lipid synthesis. The enhancement of glucose uptake and suppression of hepatic gluconeogenesis and lipid synthesis by arctigenin were prevented by blockade of AMPK activation. The respiration of L6 myotubes or isolated mitochondria was inhibited by arctigenin with a specific effect on respiratory complex I. A single oral dose of arctigenin reduced gluconeogenesis in C57BL/6J mice. Chronic oral administration of arctigenin lowered blood glucose and improved lipid metabolism in
ob
/
ob
mice.
Conclusions/interpretation
This study demonstrates a new role for arctigenin as a potent indirect activator of AMPK via inhibition of respiratory complex I, with beneficial effects on metabolic disorders in
ob
/
ob
mice. This highlights the potential value of arctigenin as a possible treatment of type 2 diabetes.
Alloy design based on single-principal-element systems has approached its limit for performance enhancements. A substantial increase in strength up to gigapascal levels typically causes the premature ...failure of materials with reduced ductility. Here, we report a strategy to break this trade-off by controllably introducing high-density ductile multicomponent intermetallic nanoparticles (MCINPs) in complex alloy systems. Distinct from the intermetallic-induced embrittlement under conventional wisdom, such MCINP-strengthened alloys exhibit superior strengths of 1.5 gigapascals and ductility as high as 50% in tension at ambient temperature. The plastic instability, a major concern for high-strength materials, can be completely eliminated by generating a distinctive multistage work-hardening behavior, resulting from pronounced dislocation activities and deformation-induced microbands. This MCINP strategy offers a paradigm to develop next-generation materials for structural applications.
There are few data on the molecular epidemiology of cryptococcosis in China. Here we investigated the species distribution, molecular types and antifungal susceptibilities of 312 Cryptococcus ...neoformans species complex isolates from ten hospitals over 5 years. Isolates were identified by internal transcribed spacer (ITS) sequencing and by two matrix-assisted laser desorption–ionization time-of-flight mass spectrometry (MALDI-TOF MS) systems. Multilocus sequence typing (MLST) was used to verify species/variety and to designate molecular types. Susceptibility to six antifungal drugs was determined by the Sensititre YeastOne™ method. Cryptococcus neoformans was the predominant species (305/312 isolates (97.8%), all were ITS type 1, serotype A), of which 89.2% (272/305) were C. neoformans var. grubii MLST sequence type (ST) 5 and 6.2% (19/305) were ST31. Other C. neoformans var. grubii STs were rare but included six novel STs. Only two strains were C. neoformans var. neoformans (both serotype AD). Cryptococcus gattii was uncommon (n = 7, four ITS types) and comprised five MLST STs including one novel ST. For C. neoformans var. grubii, the proportion of isolates with non-wild-type MICs to fluconazole significantly rose in the fourth study year (from 0% (0/56 isolates) in the first year to 23.9% (17/71) in the fourth year), including five isolates with fluconazole MICs of ≥32 mg/L. The study has provided useful data on the species epidemiology and their genetic diversity and antifungal susceptibility. The proportional increase in isolates with non-wild-type MICs to fluconazole is noted.
Abstract
Spin-valley locking in monolayer transition metal dichalcogenides has attracted enormous interest, since it offers potential for valleytronic and optoelectronic applications. Such an exotic ...electronic state has sparsely been seen in bulk materials. Here, we report spin-valley locking in a Dirac semimetal BaMnSb
2
. This is revealed by comprehensive studies using first principles calculations, tight-binding and effective model analyses, angle-resolved photoemission spectroscopy measurements. Moreover, this material also exhibits a stacked quantum Hall effect (QHE). The spin-valley degeneracy extracted from the QHE is close to 2. This result, together with the Landau level spin splitting, further confirms the spin-valley locking picture. In the extreme quantum limit, we also observed a plateau in the
z
-axis resistance, suggestive of a two-dimensional chiral surface state present in the quantum Hall state. These findings establish BaMnSb
2
as a rare platform for exploring coupled spin and valley physics in bulk single crystals and accessing 3D interacting topological states.
In order to understand the aging and processing of organic aerosols (OA), an intensive field campaign (Campaign of Air Pollution at Typical Coastal Areas IN Eastern China, CAPTAIN) was conducted ...March–April at a receptor site (a Changdao island) in central eastern China. Multiple fast aerosol and gas measurement instruments were used during the campaign, including a high resolution time-of-flight aerosol mass spectrometer (HR-ToF-AMS) that was applied to measure mass concentrations and non-refractory chemical components of submicron particles (PM1nr). The average mass concentration of PM1(PM1nr+black carbon) was 47 ± 36 μg m−3 during the campaign and showed distinct variation, depending on back trajectories and their overlap with source regions. Organic aerosol (OA) is the largest component of PM1 (30%), followed by nitrate (28%), sulfate (19%), ammonium (15%), black carbon (6%), and chloride (3%). Four OA components were resolved by positive matrix factorization (PMF) of the high-resolution spectra, including low-volatility oxygenated organic aerosol (LV-OOA), semi-volatile oxygenated OA (SV-OOA), hydrocarbon-like OA (HOA) and a coal combustion OA (CCOA). The mass spectrum of CCOA had high abundance of fragments from polycyclic aromatic hydrocarbons (PAHs) (m/z 128, 152, 178, etc.). The average atomic ratio of oxygen to carbon in OA (O / C) at Changdao was 0.59, which is comparable to other field studies reported at locations downwind of large pollution sources, indicating the oxidized nature of most OA during the campaign. The evolution of OA elemental composition in the van Krevelen diagram (H / C vs. O / C) showed a slope of −0.63; however, the OA influenced by coal combustion exhibits a completely different evolution that appears dominated by physical mixing. The aging of organic aerosols vs. photochemical age was investigated. It was shown that OA / ΔCO, as well as LV-OOA / ΔCO and SV-OOA / ΔCO, positively correlated with photochemical age. LV-OOA accounted for 73% of the OA secondary formation (SOA) in the oldest plumes (photochemical age of 25 h). The kOH at Changdao, by assuming SOA formation and aging as a first-order process proportional to OH, was calculated to be 5.2 × 10−12 cm3 molec.−1 s−1, which is similar to those determined in recent studies of polluted air in other continents.
The extension of the cosmic-ray spectrum beyond 1 petaelectronvolt (PeV; 10
electronvolts) indicates the existence of the so-called PeVatrons-cosmic-ray factories that accelerate particles to PeV ...energies. We need to locate and identify such objects to find the origin of Galactic cosmic rays
. The principal signature of both electron and proton PeVatrons is ultrahigh-energy (exceeding 100 TeV) γ radiation. Evidence of the presence of a proton PeVatron has been found in the Galactic Centre, according to the detection of a hard-spectrum radiation extending to 0.04 PeV (ref.
). Although γ-rays with energies slightly higher than 0.1 PeV have been reported from a few objects in the Galactic plane
, unbiased identification and in-depth exploration of PeVatrons requires detection of γ-rays with energies well above 0.1 PeV. Here we report the detection of more than 530 photons at energies above 100 teraelectronvolts and up to 1.4 PeV from 12 ultrahigh-energy γ-ray sources with a statistical significance greater than seven standard deviations. Despite having several potential counterparts in their proximity, including pulsar wind nebulae, supernova remnants and star-forming regions, the PeVatrons responsible for the ultrahigh-energy γ-rays have not yet been firmly localized and identified (except for the Crab Nebula), leaving open the origin of these extreme accelerators.
A phase field model of discontinuous dynamic recrystallization (PF-DDRX) was employed to investigate grain structure evolution and its impact on mechanical response during thermomechanical processing ...of magnesium alloys. A set of isothermal compression experiments were conducted by thermo-mechanical simulator and used to calibrate the PF-DDRX model parameters such as the critical stress of recrystallization, the activation energy coefficient of dislocation, grain boundary mobility and recrystallization grain nucleation. The grain structure features of polycrystalline magnesium alloys were used to generate the initial grain structure for DDRX simulations. Simulation results show that 1) the ‘necklace’ microstructures, which are often observed in DDRX, form at the earlier stage of recrystallization; and 2) both predicted grain structure and mechanical response are in a reasonable agreement with experimental data. More importantly, the results demonstrate that the proposed methods enable one to establish the relationships between PF-DDRX model parameters and material properties for quantitative prediction and design of grain microstructures and material properties with thermomechanical processes.
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•A PF-DDRX model involving dislocation activities, nucleation and boundary migration has been developed.•Rate sensitive and nucleation activation energy were determined by analyzing experimental flow characteristics.•Actual microstructure details were reproduced by PF model and used as initial grain structure for DRX modeling.•Mechanical response and grain structure can be well predicted for given temperature and strain rate.
Background
Thymic stromal lymphopoietin (TSLP), IL‐25, and IL‐33 system contribute to the initiation and development of Th2 responses. This study aimed to explore the involvement of TSLP, IL‐25, ...IL‐33, and their receptors in type 2 T‐helper (Th) responses in chronic rhinosinusitis with nasal polyps (CRSwNPs) and their cross‐regulation in human nasal epithelial cells (HNECs).
Methods
Immunohistochemistry, quantitative RT‐PCR, ELISA, Bio‐Plex assay, and flow cytometry were used to detect the expression of TSLP/common γ‐like TSLP receptor (TSLPR)/IL‐7 receptor α (IL‐7Rα), IL‐25/IL‐17B receptor (IL‐17RB), and IL‐33/membrane‐bound ST2 (ST2L)/soluble ST2 (sST2) in sinonasal mucosa and HNECs. HNECs cultured at an air–liquid interface were used to explore the expression in regulation of these cytokine systems.
Results
Compared with controls and noneosinophilic CRSwNP, the expression of TSLP/TSLPR/IL‐7Rα and ST2L/sST2 was significantly increased in eosinophilic CRSwNP, predominantly in epithelial cells. In contrast, the expression of IL‐33 and IL‐25/IL‐17RB was enhanced in epithelial cells in both eosinophilic and noneosinophilic CRSwNP compared to controls. The expression of TSLP, TSLPR, and ST2L was positively correlated with symptom and computer tomography scan scores in eosinophilic CRSwNP and with Th2 cytokine expression in sinonasal mucosa. The expression of ST2L was correlated with TSLP and its receptor expression. TSLP could induce ST2L expression that promoted IL‐33‐induced TSLP expression in HNECs. In addition, TSLP/TSLPR/IL‐7Rα and ST2L could be induced by Th2 cytokines, while IL‐25/IL‐17RB and IL‐33 could be upregulated by Th1/Th17 cytokines, in HNECs.
Conclusions
The positive feedback loop between TSLP, IL‐33 and their receptors, and Th2 cytokines may facilitate Th2‐skewed inflammation in eosinophilic CRSwNP.
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