Gasdermin E (GSDME) has an important role in inducing secondary necrosis/pyroptosis. Upon apoptotic stimulation, it can be cleaved by activated caspase-3 to generate its N-terminal fragment ...(GSDME-NT), which executes pyroptosis by perforating the plasma membrane. GSDME is expressed in many human lung cancers including A549 cells. Paclitaxel and cisplatin are two representative chemotherapeutic agents for lung cancers, which induce apoptosis via different action mechanisms. However, it remains unclear whether they can induce GSDME-mediated secondary necrosis/pyroptosis in lung A549 cancer cells. Here we showed that both paclitaxel and cisplatin evidently induced apoptosis in A549 cells as revealed by the activation of multiple apoptotic markers. Notably, some of the dying cells displayed characteristic morphology of secondary necrosis/pyroptosis, by blowing large bubbles from the cellular membrane accompanied by caspase-3 activation and GSDME-NT generation. But the ability of cisplatin to induce this phenomenon was much stronger than that of paclitaxel. Consistent with this, cisplatin triggered much higher activation of caspase-3 and generation of GSDME-NT than paclitaxel, suggesting that the levels of secondary necrosis/pyroptosis correlated with the levels of active caspase-3 and GSDME-NT. Supporting this, caspase-3 specific inhibitor (Ac-DEVD-CHO) suppressed cisplatin-induced GSDME-NT generation and concurrently reduced the secondary necrosis/pyroptosis. Besides, GSDME knockdown significantly inhibited cisplatin- but not paclitaxel-induced secondary necrosis/pyroptosis. These results indicated that cisplatin induced higher levels of secondary necrosis/pyroptosis in A549 cells than paclitaxel, suggesting that cisplatin may provide additional advantages in the treatment of lung cancers with high levels of GSDME expression.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Light-up luminescence sensors have been employed in real-time in situ visual detection of target molecules including volatile organic compounds (VOCs). However, currently employed light-up sensors, ...which are generally based on the aggregation-induced emission (AIE) or solvent-induced energy transfer effect, exhibit limited sensitivity for light-up detection and poor recycling performances thereby significantly hindering their industrial applications. Inspired by the low-temperature enhanced luminescence phenomenon, we herein propose and show that a guest-lock-induced luminescence enhancement mechanism can be used to realize the ultrafast light-up detection of target VOCs. Through introduction of chlorinated hydrocarbons to lock the molecular vibrations within a designed Cu4I4-based metal–organic framework (MOF), luminescence intensity could be enhanced significantly at room temperature. This guest-lock-induced luminescence enhancement is brought about by weak supramolecular interactions between the host framework and the guest molecules, allowing highly sensitive and specific detection of the guest vapor with ultrafast response time (<1 s). Single-crystal X-ray diffraction (SCXRD) analysis of guest molecules-loaded MOFs and density functional theory (DFT) calculations were employed to investigate the host–guest interactions involved in this phenomenon. Moreover, the above MOF sensor successfully achieved real-time detection of a toxic chloroaromatic molecule, chlorobenzene. The guest-lock-induced light-up mechanism opens up a route to discovering high-performance ultrafast light-up luminescent sensors for real-time detection applications.
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IJS, KILJ, NUK, PNG, UL, UM
Quantum anomalous Hall goes intrinsicQuantum anomalous Hall effect—the appearance of quantized Hall conductance at zero magnetic field—has been observed in thin films of the topological insulator ...Bi2Se3 doped with magnetic atoms. The doping, however, introduces inhomogeneity, reducing the temperature at which the effect occurs. Two groups have now observed quantum anomalous Hall effect in intrinsically magnetic materials (see the Perspective by Wakefield and Checkelsky). Serlin et al. did so in twisted bilayer graphene aligned to hexagonal boron nitride, where the effect enabled the switching of magnetization with tiny currents. In a complementary work, Deng et al. observed quantum anomalous Hall effect in the antiferromagnetic layered topological insulator MnBi2Te4.Science, this issue p. 900, p. 895; see also p. 848In a magnetic topological insulator, nontrivial band topology combines with magnetic order to produce exotic states of matter, such as quantum anomalous Hall (QAH) insulators and axion insulators. In this work, we probe quantum transport in MnBi2Te4 thin flakes—a topological insulator with intrinsic magnetic order. In this layered van der Waals crystal, the ferromagnetic layers couple antiparallel to each other; atomically thin MnBi2Te4, however, becomes ferromagnetic when the sample has an odd number of septuple layers. We observe a zero-field QAH effect in a five–septuple-layer specimen at 1.4 kelvin, and an external magnetic field further raises the quantization temperature to 6.5 kelvin by aligning all layers ferromagnetically. The results establish MnBi2Te4 as an ideal arena for further exploring various topological phenomena with a spontaneously broken time-reversal symmetry.
Anhedonia is the inability to experience pleasure from rewarding or enjoyable activities and is a core symptom of depression in humans. Here, we describe a protocol for the measurement of anhedonia ...in mice, in which anhedonia is measured by a sucrose preference test (SPT) based on a two-bottle choice paradigm. A reduction in the sucrose preference ratio in experimental relative to control mice is indicative of anhedonia. To date, inconsistent and variable results have been reported following the use of the SPT by different groups, probably due to the use of different protocols and equipment. In this protocol, we describe how to set up a clearly defined apparatus for SPT and provide a detailed protocol to ensure greater consistency when carrying out SPT. This optimized protocol is highly sensitive, reliable, and adaptable for evaluation of chronic stress-related anhedonia, as well as morphine-induced dependence. The whole SPT, including adaptation, baseline measurement, and testing, takes 8 d.
Objective
Induction of secondary necrosis/pyroptosis contributes to the toxicity of chemotherapeutic drugs, in which gasdermin E (GSDME) plays critical roles. This study aimed to explore whether ...GSDME is involved in mediating the cytotoxic effects of cisplatin and doxorubicin on mouse macrophages.
Methods
RAW 264.7 cells and bone marrow‐derived macrophages (BMDMs) were treated with cisplatin or doxorubicin. Propidium iodide staining was used to assay necrosis, and immunoblotting was performed to detect protein expression. GSDME was knocked down by using small interfering RNA. Mice were injected intraperitoneally to evaluate toxicity to macrophages in vivo. Flow cytometry and immunofluorescence microscopy were adopted to analyse phenotypes of peritoneal cells. Cytokine levels were assayed by cytometric bead array.
Results
Both cisplatin and doxorubicin dose‐dependently induced necrosis in mouse RAW 264.7 macrophages and BMDMs. Accompanying this, multiple caspases were activated, concomitant with the cleavage of poly (ADP‐ribose) polymerase. Consistent with caspase‐3 activation, GSDME was cleaved to generate its N‐terminal fragment (GSDME‐NT), thus leading to secondary necrosis/pyroptosis. Inhibition of caspase‐3 significantly attenuated the generation of GSDME‐NT concurrently with decreased necrosis in macrophages. GSDME knockdown also evidently decreased the necrosis in RAW 264.7 and BMDMs. Besides, cisplatin administration depleted peritoneal macrophages in mice, which was associated with caspase‐3 activation and GSDME‐NT generation. Consistent with the macrophage depletion, cisplatin administration significantly decreased survival of mice with bacterial infection.
Conclusion
Chemotherapeutic cisplatin and doxorubicin exerted their cytotoxicity on macrophages partly by inducing caspase‐3/GSDME‐mediated secondary necrosis.
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DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Rumination is a repetitive self-referential thinking style that is often interpreted as an expression of abnormalities of the default mode network (DMN) observed during “resting-state” in major ...depressive disorder (MDD). Recent evidence has demonstrated that the DMN is not unitary but can be further divided into 3 functionally heterogenous subsystems, although the subsystem mechanistically underlying rumination remains unclear. Due to the unconstrained and indirect correlational nature of previous resting-state fMRI studies on rumination's network underpinnings, a paradigm allowing direct investigation of network interactions during active rumination is needed. Here, with a modified continuous state-like paradigm, we induced healthy participants to ruminate or imagine objective scenarios (distraction, as a control condition) on 3 different MRI scanners. We compared functional connectivities (FC) of the DMN and its 3 subsystems between rumination and distraction states. Results yielded a highly reproducible and dissociated pattern. During rumination, within-DMN FC was generally decreased as compared to the distraction state. At the subsystem level, we found increased FC between the core and medial temporal lobe (MTL) subsystem as well as decreased FC between the core and dorsal medial prefrontal cortex (DMPFC) subsystem and within the MTL subsystem. Finally, subjects’ behavioral measures of rumination and brooding were negatively correlated with FC between the core and DMPFC subsystems. These results suggest active rumination involves enhanced constraint by the core subsystem on the MTL subsystem and decreased coupling between the core and DMPFC subsystem, allowing for more information exchange among those involved DMN components. Furthermore, the reproducibility of our findings provides a rigorous evaluation of their validity and significance.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The NLRP3 inflammasome is a multi-molecular complex that acts as a molecular platform to mediate caspase-1 activation, leading to IL-1β/IL-18 maturation and release in cells stimulated by various ...pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs). This inflammasome plays an important role in the innate immunity as its activation can further promote the occurrence of inflammation, enhance the ability of host to remove pathogens, and thus facilitate the repair of injured tissues. But if the inflammasome activation is dysregulated, it will cause the development of various inflammatory diseases and metabolic disorders. Therefore, under normal conditions, the activation of inflammasome is tightly regulated by various positive and negative signaling pathways to respond to the stimuli without damaging the host itself while maintaining homeostasis. In this review, we summarize recent advances in the major signaling pathways (including TLRs, MAPK, mTOR, autophagy, PKA, AMPK, and IFNR) that regulate NLRP3 inflammasome activation, providing a brief view of the molecular network that regulates this inflammasome as a theoretical basis for therapeutic intervention of NLRP3 dysregulation-related diseases.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
With the development and application of thermotropic shape memory polymer materials in the biomedical field, it is very crucial for these materials to improve their thermal conductivity efficiency ...and shape memory recovery rate by endowing them a high thermal conductivity. In our work, a PLA/NR/T‐ZnOw/GR shape memory composite was prepared by melt blending with tetrapod zinc oxide whisker (T‐ZnOw) and graphene (GR) as the double inorganic fillers and polylactic acid (PLA) and natural rubber (NR) as the polymer matrix. The synergism of T‐ZnOw and GR constructs a three‐dimensional (3D) thermal conductive network, making the thermal conductivity of PLA/NR/5wt%T‐ZnOw/2.5wt%GR increase to 1.215 W∙(m∙K)−1. The addition of T‐ZnOw reduces the agglomeration of GR in the PLA/NR matrix and the interfacial thermal resistance between the fillers and the matrix. It also improves the heat transfer rate, resulting in an excellent shape memory of PLA/NR/T‐ZnOw/GR with a morphology recovery rate of ca. 96%, a fixed rate of 95% and high thermal stability. The presented biodegradable shape memory composite with the 3D thermal conductive network is promising in the fields of medical treatment and intelligent sensors.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Mechanically bonded amphiphiles (MBAs), also known as mechanically interlocked molecules (MIMs), have emerged as an important kind of functional building block for the construction of artificial ...molecular machines and soft materials. Herein, a novel MBA, i.e., bistable 2rotaxane H2 was designed and synthesized. In the solution state, H2 demonstrated pH and metal ion-responsive emissions due to the presence of a distance-dependent photoinduced electron transfer (PET) process and the fluorescence resonance energy transfer (FRET) process, respectively. Importantly, the amphiphilic feature of H2 has endowed it with unique self-assembly capability, and nanospheres were obtained in a mixed H2O/CH3CN solvent. Moreover, the morphology of H2 aggregates can be tuned from nanospheres to vesicles due to the pH-controlled shuttling motion-induced alternation of H2 amphiphilicity. Interestingly, larger spheres with novel pearl-chain-like structures from H2 were observed after adding stoichiometric Zn2+. In particular, H2 shows pH-responsive emissions in its aggregation state, allowing the visualization of the shuttling movement by just naked eyes. It is assumed that the well-designed 2rotaxane, and particularly the proposed concept of MBA shown here, will further enrich the families of MIMs, offering prospects for synthesizing more MIMs with novel assembly capabilities and bottom-up building dynamic smart materials with unprecedented functions.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
•Holistic thinking and analytic thinking are advanced modes of thinking, which neural mechanisms have not been fully explored.•We used the frame-line task and the triad task, with multivariate ...pattern analysis (MVPA).•We mapped the fundamental neural substrates of holistic thinking and analytic thinking.•We provided a new method to explore the neural representation of cultural constructs.
Holistic and analytic thinking are two distinct modes of thinking used to interpret the world with relative preferences varying across cultures. While most research on these thinking styles has focused on behavioral and cognitive aspects, a few studies have utilized functional magnetic resonance imaging (fMRI) to explore the correlations between brain metrics and self-reported scale scores. Other fMRI studies used single holistic and analytic thinking tasks. As a single task may involve processing in spurious low-level regions, we used two different holistic and analytic thinking tasks, namely the frame-line task and the triad task, to seek convergent brain regions to distinguish holistic and analytic thinking using multivariate pattern analysis (MVPA). Results showed that brain regions fundamental to distinguish holistic and analytic thinking include the bilateral frontal lobes, bilateral parietal lobes, bilateral precentral and postcentral gyrus, bilateral supplementary motor areas, bilateral fusiform, bilateral insula, bilateral angular gyrus, left cuneus, and precuneus, left olfactory cortex, cingulate gyrus, right caudate and putamen. Our study maps brain regions that distinguish between holistic and analytic thinking and provides a new approach to explore the neural representation of cultural constructs. We provide initial evidence connecting culture-related brain regions with language function to explain the origins of cultural differences in cognitive styles.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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