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The basic principle of quantum mechanics1 guarantees the unconditional security of quantum key distribution (QKD)2–6 at the cost of forbidding the amplification of a quantum state. As a result, and despite remarkable progress in worldwide metropolitan QKD networks7,8 over the past decades, a long-haul fibre QKD network without a trusted relay has not yet been achieved. Here, through the sending-or-not-sending protocol9, we achieve twin-field QKD10 and distribute secure keys without any trusted repeater over a 511 km long-haul fibre trunk that links two distant metropolitan areas. The fibre trunk contains 12 fibres in the cable, three of which are used for the quantum channel, optical synchronization and frequency locking, respectively. The remaining nine are used for classical fibre communication. Our secure key rate is around three orders of magnitude greater than that expected if the previous QKD field-test system was applied over the same length. Efficient quantum-state transmission and stable single-photon interference over such a long-haul deployed fibre pave the way to large-scale fibre quantum networks.A field test of twin-field quantum key distribution was implemented through a 511 km optical fibre. To this end, precise wavelength control of remote independent laser sources and fast time- and phase-compensation systems are developed.

The outbreak of white spot syndrome (WSS) is a looming challenge, due to dramatic losses to the crustacean aquaculture industry. However, at present, there are no prophylactic or therapeutic means to control this infectious viral disease. Here, we screened fifteen medicinal plants for their inhibitory activity on the white spot syndrome virus (WSSV), using red swamp crayfish (Procambarus clarkii) as a model species. The results showed that the crude extracts of Pinellia ternata (Thunb.) Breit. had the highest inhibitory effect (91.59%, 100 mg/kg) on WSSV proliferation, and its main component, beta-sitosterol, showed a much higher activity (95.79%, 50 mg/kg). Further, beta-sitosterol potently reduced (p < 0.01) viral loads and viral gene transcription levels in a concentration-dependent fashion, and significantly promoted the survival rate of WSSV-challenged crayfish (57.14%, 50 mg/kg). The co-incubation assay indicated that beta-sitosterol did not influence the infectivity of WSSV particles. Both pre- and post-treatment of beta-sitosterol exerted a significant inhibitory effect (p < 0.01) on the viral load in vivo. Mechanistically, beta-sitosterol not only interfered with the expression of viral genes (immediate early gene 1, ie1; DNA polymerase, DNApol) that are important in initiating WSSV transcription, but it also attenuated the hijacking of innate immune signaling pathways (Toll, IMD, and JAK/STAT pathways) by viral genes to block WSSV replication. Moreover, the expression of several antiviral immune, antioxidant, pro-inflammatory, and apoptosis-related genes changed significantly in beta-sitosterol-treated crayfish. Beta-sitosterol is a potent WSSV inhibitor and has the potential to be developed as an effective anti-WSSV agent against a WSS outbreak in crustacean aquaculture.

Background The failure of novel therapies effective in preclinical animal models largely reflects the fact that current models do not really mimic the pathological/therapeutic features of glioblastoma (GBM), in which the most effective temozolomide chemoradiotherapy (RT/TMZ) regimen can only slightly extend survival. How to improve RT/TMZ efficacy remains a major challenge in clinic. Methods Syngeneic G422 TN -GBM model mice were subject to RT/TMZ, surgery, piperlongumine (PL), αPD1, glutathione. Metabolomics or transcriptomics data from G422 TN -GBM and human GBM were used for gene enrichment analysis and estimation of ROS generation/scavenging balance, oxidative stress damage, inflammation and immune cell infiltration. Overall survival, bioluminescent imaging, immunohistochemistry, and immunofluorescence staining were used to examine therapeutic efficacy and mechanisms of action. Results Here we identified that glutathione metabolism was most significantly altered in metabolomics analysis upon RT/TMZ therapies in a truly refractory and reliable mouse triple-negative GBM (G422 TN ) preclinical model. Consistently, ROS generators/scavengers were highly dysregulated in both G422 TN -tumor and human GBM. The ROS-inducer PL synergized surgery/TMZ, surgery/RT/TMZ or RT/TMZ to achieve long-term survival (LTS) in G422 TN -mice, but only one LTS-mouse from RT/TMZ/PL therapy passed the rechallenging phase (immune cure). Furthermore, the immunotherapy of RT/TMZ/PL plus anti-PD-1 antibody (αPD1) doubled LTS (50%) and immune-cured (25%) mice. Glutathione completely abolished PL-synergistic effects. Mechanistically, ROS reduction was associated with RT/TMZ-resistance. PL restored ROS level (mainly via reversing Duox2/Gpx2), activated oxidative stress/inflammation/immune responses signature genes, reduced cancer cell proliferation/invasion, increased apoptosis and CD3 + /CD4 + /CD8 + T-lymphocytes in G422 TN -tumor on the basis of RT/TMZ regimen. Conclusion Our findings demonstrate that PL reverses RT/TMZ-reduced ROS and synergistically resets tumor microenvironment to cure GBM. RT/TMZ/PL or RT/TMZ/PL/αPD1 exacts effective immune cure in refractory GBM, deserving a priority for clinical trials.

Glioblastoma multiforme (GBM), a highly invasive brain tumor, is severely restricted in T-cell infiltration and anti-tumor activity due to its immunosuppressive microenvironment. However, commonly used preclinical GBM mouse models cannot fully recapitulate the refractoriness of human GBM or effectively distinguish therapeutic efficacy. In this study, we evaluated the efficacy and mechanisms of therapies based on the novel sesquiterpene lactone small-molecule compound, ACT001, using the refractory G422 TN -GBM mouse model. ACT001 alone exerted evident anti-G422 TN -GBM effects in vivo and in vitro , but it only slightly prolonged animal survival. ACT001 combined with concurrent radiotherapy and temozolomide (RT/TMZ) exerted synergistic effects by suppressing tumor progression and extending animal survival. Importantly, the RT/TMZ/ACT001 regimen could achieve cure (long-term survival, >100 d, 26.7%) and immune cure (passing the tumor-rechallenge assay, >100 d, 12.5%) in G422 TN mice. However, combining the anti-PD-1 antibody (αPD-1) with RT/TMZ/ACT001 did not further improve survival. Mechanistically, RT/TMZ/ACT001 substantially activated the tumor necrosis factor (TNF) pathway, inducing tumor cells and stromal cells in the microenvironment to express the chemokine C-X-C motif chemokine 10 (CXCL10), thereby promoting T-cell infiltration, especially CD8 + T cell, into the tumor site. Pharmacological inhibition of the TNF signaling pathway with R-7050 completely abolished the synergistic efficacy of RT/TMZ/ACT001. Taken together, our results demonstrate that ACT001 combined with RT/TMZ can overcome the immunosuppressive barrier of GBM to achieve immune cure in GBM via TNF-CXCL10-CD8 + signaling, strongly suggesting the priority of combining ACT001 with RT/TMZ rather than with αPD-1 in clinical trials.

The Ras and Rab interactor 1 (RIN1) is a multifunctional signaling protein that has been implicated in the regulation of tumor cell migration and proliferation. Here we found that RIN1 was abundant in the dorsal root ganglia (DRG) neurons positive for transient receptor potential vanilloid 1 (TRPV1), a critical mediator of pain sensitization in patients with metastatic bone cancer. Our data showed that RIN1 interacted with TRPV1 and induced the endocytosis of TRPV1 through its guanine nucleotide exchange factor activity toward small GTPase Ras-related protein 5 (Rab5). This process limited the duration and magnitude of TRPV1-dependent acute pain responses in intact male mice. Conditioned knockout of RIN1 in the DRG neurons enhanced TRPV1 activity and led to the reflexive nociceptive sensitization and aversive pain behaviors. In mice with the bone cancer pain, we found a significant reduction of RIN1 protein level in the DRG neurons, which correlated with TRPV1 accumulation on the plasma membrane. Special rescue of RIN1 expression in the DRG neurons repressed the surface TRPV1 distribution and alleviated both the reflexive-defensive and affective-motivational aspects of bone cancer pain. Our data thus revealed an important role of RIN1 in the negative control over TRPV1-dependent pain behaviors.

DPY30 belongs to the core subunit of components of the histone lysine methyltransferase complex, which is implicated in tumorigenesis, cell senescence, and other biological events. However, its contribution to colorectal carcinoma (CRC) progression and metastasis has yet to be elucidated. Therefore, this study aimed to investigate the biological function of DPY30 in CRC metastasis both in vitro and in vivo. Herein, our results revealed that DPY30 overexpression is significantly positively correlated with positive lymph nodes, epithelial-mesenchymal transition (EMT), and CRC metastasis. Moreover, DPY30 knockdown in HT29 and SW480 cells markedly decreased EMT progression, as well as the migratory and invasive abilities of CRC cells in vitro and lung tumor metastasis in vivo. Mechanistically, DPY30 increased histone H3K4me3 level and promoted EMT and CRC metastasis by upregulating the transcriptional expression of ZEB1. Taken together, our findings indicate that DPY30 may serve as a therapeutic target and prognostic marker for CRC. Graphical Abstract

Glioblastoma (GBM) is immunologically cold and responds poorly to immune‐based therapies owing to its highly heterogeneous and immunosuppressive tumor microenvironment (TME). However, strategies to achieve a cold‐to‐hot transition remain elusive, and suitable research models are still lacking. Here, TME profiling classifies our refractory G422 TN ‐GBM model as the TME Med (heterogeneous immune populations, “cold”) subtype of human GBM, which can be shifted toward the TME High (immune‐high, “hot”) subtype by inhibiting TGF‐β signaling. In the multi‐drug regimen, only αTGF‐β combining temozolomide chemoradiotherapy and αPD‐1 achieves immune‐cure (ICu, passing tumor rechallenge, 12.5%). ICu screening reveals a newly identified Csmd3 + microglial subset with innate immune memory potential, which likely initiates durable anti‐GBM immune memory and closely associates with effective GBM therapy and favorable prognosis. MG OE• Csmd3 , BV2 ( Csmd3 ‐overexpressed microglial BV2) elicit robust anti‐GBM effects and achieve a notably 100% tumor rechallenge success in G422 TN ‐GBM mice via promoting TME Med ‐to‐TME High remodeling. Taken together, our findings identify an immunologically cold TME Med GBM mouse model and provide a proof‐of‐concept for microglia‐based TME reprogramming and cell therapy in GBM.

In the last decade, considerable advances have been made in the investigation of dipolar quantum gases. Previous theoretical investigations of a rotating binary dipolar Bose-Einstein condensate, where only one component possesses dipole moment, were mainly focused on two special orientations of the dipoles: perpendicular or parallel to the plane of motion. Here we study the ground-state and rotational properties of such a system for an arbitrary orientation of the dipoles. We demonstrate the ground-state vortex structures depend strongly on the relative strength between dipolar and contact interactions and the rotation frequency, as well as on the orientation of the dipoles. In the absence of rotation, the tunable dipolar interaction can be used to induce the squeezing or expansion of the cloud and to derive the phase transition between phase coexistence and separation. Under finite rotation, the system is found to exhibit exotic ground-state vortex configurations, such as kernel-shell, vortex necklace and compensating stripe vortex structures. We also check the validity of the Feynman relation and find no significant deviations from it. The obtained results open up alternate ways for the quantum control of dipolar quantum gases.

Overexpression of extracellular signal-regulated kinase ½ (ERK ½) signaling pathway leads to overproduction of reactive oxygen species (ROS) which induces oxidative stress. Coenzyme Q10 (CoQ10) scavenges ROS and protects cells against oxidative stress. The present study was designed to examine whether the protection of Coenzyme Q10 against oxidative damage in astrocytes is through regulating ERK 1/2 pathway. Ultraviolet B (UVB) irradiation was chosen as a tool to induce oxidative stress. Murine astrocytes were treated with 10 μg/ml and 25 μg/ml of CoQ10 for 24 h prior to UVB and maintained during UVB and 24 h post-UVB. Cell viability was evaluated by counting viable cells and MTT conversion assay. ROS production was measured using fluorescent probes. Levels of p-ERK 1/2, ERK 1/2, p-PKA, PKA were detected using immunocytochemistry and/or Western blotting. The results showed that UVB irradiation decreased the number of viable cells. This damaging effect was associated with accumulation of ROS and elevations of p-ERK 1/2 and p-PKA. Treatment with CoQ10 at 25 μg/ml significantly increased the number of viable cells and prevented the UVB-induced increases of ROS, p-ERK 1/2, and p-PKA. It is concluded that suppression of the PKA-ERK 1/2 signaling pathway may be one of the important mechanisms by which CoQ10 protects astrocytes from UVB-induced oxidative damage.

Soil contamination remains a global problem. Among the different kinds of remediation technologies, in situ soil thermal remediation has attracted great attention in the environmental field, representing a potential remedial alternative for contaminated soils. Soils need to be heated to a high temperature in thermal remediation, which requires a large amount of energy. For the natural gas heating system in thermal remediation, a fuzzy coordination control strategy and thermohydraulic dynamics model have been proposed in this paper. In order to demonstrate the superiority of the strategy, the other three traditional control strategies are introduced. Analysis of the temperature rise and energy consumption of soils under different control strategies were conducted. The results showed that the energy consumption of fuzzy coordination control strategy is reduced by 33.9% compared to that of the traditional control strategy I, constant natural gas flow and excess air ratio. Further, compared to the traditional control strategy II, constant excess air ratio and desired outlet temperature of wells, the strategy proposed can reduce energy consumption by 48.7%. The results illustrate the superiority of the fuzzy coordination control strategy, and the strategy can greatly reduce energy consumption, thereby reducing the cost of in situ soil thermal remediation.