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To discover new drugs to combat COVID-19, an understanding of the molecular basis of SARS-CoV-2 infection is urgently needed. Here, for the first time, we report the crucial role of cathepsin L (CTSL) in patients with COVID-19. The circulating level of CTSL was elevated after SARS-CoV-2 infection and was positively correlated with disease course and severity. Correspondingly, SARS-CoV-2 pseudovirus infection increased CTSL expression in human cells in vitro and human ACE2 transgenic mice in vivo, while CTSL overexpression, in turn, enhanced pseudovirus infection in human cells. CTSL functionally cleaved the SARS-CoV-2 spike protein and enhanced virus entry, as evidenced by CTSL overexpression and knockdown in vitro and application of CTSL inhibitor drugs in vivo. Furthermore, amantadine, a licensed anti-influenza drug, significantly inhibited CTSL activity after SARS-CoV-2 pseudovirus infection and prevented infection both in vitro and in vivo. Therefore, CTSL is a promising target for new anti-COVID-19 drug development.

Coptis chinensis is an ancient Chinese herb treating diabetes in China for thousands of years. However, its underlying mechanism remains poorly understood. Here, we report the effects of its main active component, berberine (BBR), on stimulating insulin secretion. In mice with hyperglycemia induced by a high-fat diet, BBR significantly increases insulin secretion and reduced blood glucose levels. However, in mice with hyperglycemia induced by global or pancreatic islet β-cell-specific Kcnh6 knockout, BBR does not exert beneficial effects. BBR directly binds KCNH6 potassium channels, significantly accelerates channel closure, and subsequently reduces KCNH6 currents. Consequently, blocking KCNH6 currents prolongs high glucose-dependent cell membrane depolarization and increases insulin secretion. Finally, to assess the effect of BBR on insulin secretion in humans, a randomized, double-blind, placebo-controlled, two-period crossover, single-dose, phase 1 clinical trial (NCT03972215) including 15 healthy men receiving a 160-min hyperglycemic clamp experiment is performed. The pre-specified primary outcomes are assessment of the differences of serum insulin and C-peptide levels between BBR and placebo treatment groups during the hyperglycemic clamp study. BBR significantly promotes insulin secretion under hyperglycemic state comparing with placebo treatment, while does not affect basal insulin secretion in humans. All subjects tolerate BBR well, and we observe no side effects in the 14-day follow up period. In this study, we identify BBR as a glucose-dependent insulin secretagogue for treating diabetes without causing hypoglycemia that targets KCNH6 channels. Berberine is a compound with glucose-lowering effects in mice and humans. Here, the authors show that in mice berberine has beneficial glycemic effects by promoting insulin secretion, which requires the potassium channel KCNH6 in beta cells, and that berberine can promote insulin secretion in healthy men in a phase 1 clinical trial.

The Zhuangzi Au deposit in the world-class Jiaodong gold province hosts visible natural gold, and pyrite as the main ore mineral, making it an excellent subject for deciphering the complex hydrothermal processes and mechanisms of gold precipitation. Three types of zoned pyrite crystals were distinguished based on textural and geochemical results from EPMA, SIMS sulfur isotopic analyses and NanoSIMS mapping. Py0 has irregular shapes and abundant silicate inclusions and was contemporaneous with the earliest pyrite–sericite–quartz alteration. It has low concentrations of As (0–0.3 wt.%), Au and Cu. Py1 precipitated with stage I mineralization shows oscillatory zoning with the bright bands having high As (0.4–3.9 wt.%), Au and Cu contents, whereas the dark bands have low contents of As (0–0.4 wt.%), Au and Cu. The oscillatory zoning represents pressure fluctuations and repeated local fluid phase separation around the pyrite crystal. The concentration of invisible gold in Py1 is directly proportional to the arsenic concentration. Py1 is partially replaced by Py2 which occurs with arsenopyrite, chalcopyrite and native gold in stage II. The replacement was likely the result of pseudomorphic dissolution–reprecipitation triggered by a new pulse of Au-rich hydrothermal fluids. The δ34S values for the three types of pyrite are broadly similar ranging from + 7.1 to + 8.8‰, suggesting a common sulfur source. Fluid inclusion microthermometry suggests that extensive phase separation was responsible for the gold deposition during stage II mineralization. Uranium–Pb dating of monazite constrains the age of mineralization to ca. 119 Ma coincident with a short compressional event around 120 Ma linked to an abrupt change in the drift direction of the subducting Pacific plate.

Glutamate, as one of the most important carbon sources in the TCA cycle, is central in metabolic processes that will subsequently influence tumor progression. Several factors can affect the expression of glutamate receptors, playing either a tumor-promoting or tumor-suppressor role in cancer. Thus, the activation of glutamate receptors by the ligand could play a role in tumor development as ample studies have demonstrated the expression of glutamate receptors in a broad range of tumor cells. Glutamate and its receptors are involved in the regulation of different immune cells’ development and function, as suggested by the receptor expression in immune cells. The activation of glutamate receptors can enhance the effectiveness of the effector’s T cells, or decrease the cytokine production in immunosuppressive myeloid-derived suppressor cells, increasing the antitumor immune response. These receptors are essential for the interaction between tumor and immune cells within the tumor microenvironment (TME) and the regulation of antitumor immune responses. Although the role of glutamate in the TCA cycle has been well studied, few studies have deeply investigated the role of glutamate receptors in the regulation of cancer and immune cells within the TME. Here, by a systematic review of the available data, we will critically assess the physiopathological relevance of glutamate receptors in the regulation of cancer and immune cells in the TME and provide some unifying hypotheses for futures research on the role of glutamate receptors in the immune modulation of the tumor.

CD68 plays a critical role in promoting phagocytosis; however, the function of CD68 in tumor immunity and prognosis remains unknown. We analyzed CD68 expression among 33 tumor and normal tissues from The Cancer Genome Atlas and Genotype-Tissue Expression datasets. The relationship between CD68 expression and cancer prognosis, immune infiltration, checkpoint markers, and drug response was explored. Upregulated CD68 levels were observed in various cancer types, which were verified through tumor tissue chips using immunohistochemistry. High levels of CD68 in tumor samples correlated with an adverse prognosis in glioblastoma, kidney renal clear cell carcinoma, lower-grade glioma, liver hepatocellular carcinoma, lung squamous cell carcinoma, thyroid carcinoma, and thymoma and a favorable prognosis in kidney chromophobe. The top three negatively enriched Kyoto Encyclopedia of Genes and Genomes terms in the high CD68 subgroup were chemokine signaling pathway, cytokine-cytokine receptor interaction, and cell adhesion molecule cams. The top negatively enriched HALLMARK terms included complement, allograft rejection, and inflammatory response. A series of targeted drugs and small-molecule drugs with promising therapeutic effects were predicted. The clinical prognosis and immune infiltration of high expression levels of CD68 differ across tumor types. Inhibiting CD68-dependent signaling could be a promising therapeutic strategy for immunotherapy in many tumor types.

Background Proliferative diabetic retinopathy (PDR), a sight-threatening retinopathy, is the leading cause of irreversible blindness in adults. Despite strict control of systemic risk factors, a fraction of patients with diabetes develop PDR, suggesting the existence of other potential pathogenic factors underlying PDR. This study aimed to investigate the plasma metabotype of patients with PDR and to identify novel metabolite markers for PDR. Biomarkers identified from this study will provide scientific insight and new strategies for the early diagnosis and intervention of diabetic retinopathy. Methods A total of 1024 patients with type 2 diabetes were screened. To match clinical parameters between case and control subjects, patients with PDR (PDR, n  = 21) or those with a duration of diabetes of ≥10 years but without diabetic retinopathy (NDR, n  = 21) were assigned to the present case-control study. Distinct metabolite profiles of serum were examined using liquid chromatography-mass spectrometry (LC-MS). Results The distinct metabolites between PDR and NDR groups were significantly enriched in 9 KEGG pathways ( P  < 0.05, impact > 0.1), namely, alanine, aspartate and glutamate metabolism, caffeine metabolism, beta-alanine metabolism, purine metabolism, cysteine and methionine metabolism, sulfur metabolism, sphingosine metabolism, and arginine and proline metabolism. A total of 63 altered metabolites played important roles in these pathways. Finally, 4 metabolites were selected as candidate biomarkers for PDR, namely, fumaric acid, uridine, acetic acid, and cytidine. The area under the curve for these biomarkers were 0.96, 0.95, 1.0, and 0.95, respectively. Conclusions This study suggested that impairment in the metabolism of pyrimidines, arginine and proline were identified as metabolic dysregulation associated with PDR. And fumaric acid, uridine, acetic acid, and cytidine might be potential biomarkers for PDR. Fumaric acid was firstly reported as a novel metabolite marker with no prior reports of association with diabetes or diabetic retinopathy, which might provide insights into potential new pathogenic pathways for diabetic retinopathy.

During Clonorchis sinensis ( C. sinensis ) infection, pro-inflammatory macrophages (M1 macrophages) are highly activated, yet their role in the disease remains poorly understood. Previous studies have demonstrated that extracellular vesicles from C. sinensis (CsEVs) can activate these macrophages, and inhibiting a specific miRNA (Csi-let-7a-5p) in CsEVs (InCsEVs) can reduce this activation. In the present study, liver macrophages in mice were removed using clodronate liposomes (Clodlip). Subsequently, different types of bone marrow-derived macrophages (BMDMs) were adoptively transferred into the mice lacking liver macrophages: untreated (PBS-BMDM), treated with CsEVs (CsEVs-BMDM), treated with a control (ScrCsEVs-BMDM), or treated with InCsEVs (InCsEVs-BMDM). Biliary damages were then evaluated. The results indicated that the transferred macrophages successfully repopulated the mice. CsEVs-BMDM led to significant inflammation and bile duct damage, accompanied by higher levels of inflammatory cytokines (TNF-α and IL-1β). However, when macrophages were treated with InCsEVs, the damage and inflammation were alleviated, and the levels of TNF-α and IL-1β decreased. These findings suggest that pro-inflammatory macrophages activated by CsEVs, especially through Csi-let-7a-5p, play a crucial role in biliary damage during C. sinensis infection. Although other immune cells may also be involved, this study emphasizes the significance of pro-inflammatory macrophages in clonorchiasis.

Hepatic arterial infusion chemotherapy (HAIC) using a combination of oxaliplatin, fluorouracil, and leucovorin (FOLFOX) has shown promise for hepatocellular carcinoma (HCC) patients classified under Barcelona Clinic Liver Cancer (BCLC) stage C. In China, the combined therapy of camrelizumab and apatinib is now an approved first-line approach for inoperable HCC. This study (NCT04191889) evaluated the benefit of combining camrelizumab and apatinib with HAIC-FOLFOX for HCC patients in BCLC stage C. Eligible patients were given a maximum of six cycles of HAIC-FOLFOX, along with camrelizumab and apatinib, until either disease progression or intolerable toxicities emerged. The primary outcome measured was the objective response rate (ORR) based on the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Thirty-five patients were enrolled. Based on RECIST v1.1 criteria, the confirmed ORR stood at 77.1% (95% CI: 59.9% to 89.6%), with a disease control rate of 97.1% (95% CI: 85.1% to 99.9%). The median progression-free survival was 10.38 months (95% CI: 7.79 to 12.45). Patient quality of life had a transient deterioration within four cycles of treatment, and generally recovered thereafter. The most frequent grade ≥3 or above treatment-related adverse events included reduced lymphocyte count (37.1%) and diminished neutrophil count (34.3%). The combination of camrelizumab, apatinib, and HAIC demonstrated encouraging results and manageable safety concerns for HCC at BCLC stage C.

In the present work, the effect of dephosphorization slag basicity on the dephosphorization of hot metal has been studied in the lower temperature range of 1370 °C to 1420 °C and the lower basicity of 1.26 to 2.20 with new double slag converter steelmaking process (NDSP). Based on the ion-molecule coexistence theory (IMCT), the thermodynamic model IMCT-Ni of dephosphorization slag is established. With increasing basicity from 1.26 to 2.20, the phosphorus distribution ratio LP between hot metal and slag increases. The dephosphorization ratio and the decarbonization ratio both increase, while the demanganization ratio decreases. The morphologies of P-rich phase change from long strip shape (B = 1.26-1.37) to dendritic shape (B = 1.50) and to massive shape (B = 1.71-2.20). The area of P-rich phase increases from about 4 μm2 to about 8000 μm2. The content of P2O5 in the P-rich phase increases and the value of the coefficient n in nC2S-C3P of the P-rich phase decreases from 6-20 to 1-2. The phosphorus-enrichment contribution ratio of calcium silicate is in the order of RC2S>RCS>RC3S>RC3S2. The phosphorus-enrichment degree in dephosphorization slag is enhanced mainly by C2S-C3P. With increasing basicity, the calculated results of IMCT-(pct C2S-CjP) and RC2S are well consistent with the measurement results of AP-rich phase and (pct P2O5)P-rich phase of industrial experiment, indicating that the IMCT calculated results can correctly express the phosphorus-enrichment degree of dephosphorization slag.

Quantum teleportation of single-photon qubits from a ground observatory to a satellite in low-Earth orbit via an uplink channel is achieved with a fidelity that is well above the classical limit. Quantum security in orbit The laws of quantum physics give rise to protocols for ultra-secure cryptography and quantum communications. However, to be useful in a global network, these protocols will have to function with satellites. Extending existing protocols to such long distances poses a tremendous experimental challenge. Researchers led by Jian-Wei Pan present a pair of papers in this issue that take steps toward a global quantum network, using the low-Earth-orbit satellite Micius. They demonstrate satellite-to-ground quantum key distribution, an integral part of quantum cryptosystems, at kilohertz rates over 1,200 kilometres, and report quantum teleportation of a single-photon qubit over 1,400 kilometres. Quantum teleportation is the transfer of the exact state of a quantum object from one place to another, without physical travelling of the object itself, and is a central process in many quantum communication protocols. These two experiments suggest that Micius could become the first component in a global quantum internet. An arbitrary unknown quantum state cannot be measured precisely or replicated perfectly 1 . However, quantum teleportation enables unknown quantum states to be transferred reliably from one object to another over long distances 2 , without physical travelling of the object itself. Long-distance teleportation is a fundamental element of protocols such as large-scale quantum networks 3 , 4 and distributed quantum computation 5 , 6 . But the distances over which transmission was achieved in previous teleportation experiments, which used optical fibres and terrestrial free-space channels 7 , 8 , 9 , 10 , 11 , 12 , were limited to about 100 kilometres, owing to the photon loss of these channels. To realize a global-scale ‘quantum internet’ 13 the range of quantum teleportation needs to be greatly extended. A promising way of doing so involves using satellite platforms and space-based links, which can connect two remote points on Earth with greatly reduced channel loss because most of the propagation path of the photons is in empty space. Here we report quantum teleportation of independent single-photon qubits from a ground observatory to a low-Earth-orbit satellite, through an uplink channel, over distances of up to 1,400 kilometres. To optimize the efficiency of the link and to counter the atmospheric turbulence in the uplink, we use a compact ultra-bright source of entangled photons, a narrow beam divergence and high-bandwidth and high-accuracy acquiring, pointing and tracking. We demonstrate successful quantum teleportation of six input states in mutually unbiased bases with an average fidelity of 0.80 ± 0.01, well above the optimal state-estimation fidelity on a single copy of a qubit (the classical limit) 14 . Our demonstration of a ground-to-satellite uplink for reliable and ultra-long-distance quantum teleportation is an essential step towards a global-scale quantum internet.