UBE2S promotes glycolysis in hepatocellular carcinoma by enhancing E3 enzyme-independent polyubiquitination of VHL.

Background/Aims: Ubiquitination is widely involved in the progression of hepatocellular carcinoma (HCC) by regulating various cellular processes. However, systematic strategies for screening core ubiquitin-related genes, clarifying their functions and mechanisms, and ultimately developing potential therapeutics for patients with HCC are still lacking. Methods: Cox and LASSO regression analyses were performed to construct a ubiquitin-related gene prediction model for HCC. Loss- and gain-of-function studies, transcriptomic and metabolomics analysis were used to explore the function and mechanism of UBE2S on HCC cell glycolysis and growth. Results: Based on 1423 ubiquitin-related genes, a four-gene signature was successfully constructed to evaluate the prognosis of patients with HCC. UBE2S was identified in this signature with the potential to predict the survival of patients with HCC. E2F2 transcriptionally upregulated UBE2S expression by directly binding to its promoter. UBE2S positively regulated glycolysis in a HIF-1α-dependent manner, thus promoting the proliferation of HCC cells. Mechanistically, UBE2S enhanced K11-linkage polyubiquitination at lysine residues 171 and 196 of VHL independent of E3 ligase, thereby indirectly stabilizing HIF-1α protein levels by mediating the degradation of VHL by the proteasome. In particular, the combination of cephalomannine, a small molecule compound that inhibits the expression of UBE2S, and PX-478, an inhibitor of HIF-1α, significantly improved the anti-tumor efficacy. Conclusions: UBE2S is identified as a key biomarker in HCC among the thousands of ubiquitin-related genes and promotes glycolysis by E3 enzyme-independent ubiquitination, thus serving as a therapeutic target for the treatment of HCC.

The GFPT2-O-GlcNAcylation-YBX1 axis promotes IL-18 secretion to regulate the tumor immune microenvironment in pancreatic cancer.

The immunosuppressive microenvironment caused by several intrinsic and extrinsic mechanism has brought great challenges to the immunotherapy of pancreatic cancer. We identified GFPT2, the key enzyme in hexosamine biosynthesis pathway (HBP), as an immune-related prognostic gene in pancreatic cancer using transcriptome sequencing and further confirmed that GFPT2 promoted macrophage M2 polarization and malignant phenotype of pancreatic cancer. HBP is a glucose metabolism pathway leading to the generation of uridine diphosphate N-acetylglucosamine (UDP-GlcNAc), which is further utilized for protein O-GlcNAcylation. We confirmed GFPT2-mediated O-GlcNAcylation played an important role in regulating immune microenvironment. Through cellular proteomics, we identified IL-18 as a key downstream of GFPT2 in regulating the immune microenvironment. Through CO-IP and protein mass spectrum, we confirmed that YBX1 was O-GlcNAcylated and nuclear translocated by GFPT2-mediated O-GlcNAcylation. Then, YBX1 functioned as a transcription factor to promote IL-18 transcription. Our study elucidated the relationship between the metabolic pathway of HBP in cancer cells and the immune microenvironment, which might provide some insights into the combination therapy of HBP vulnerability and immunotherapy in pancreatic cancer.

Immune persistence after different polio sequential immunization schedules in Chinese infants.

Trivalent oral poliovirus vaccine (tOPV) has been withdrawn and instead an inactivated poliovirus vaccine (IPV) and bivalent type 1 and type 3 OPV (bOPV) sequential immunization schedule has been implemented since 2016, but no immune persistence data are available for this polio vaccination strategy. This study aimed to assess immune persistence following different polio sequential immunization schedules. Venous blood was collected at 24, 36, and 48 months of age from participants who had completed sequential schedules of combined IPV and OPV in phase III clinical trials. The serum neutralizing antibody titers against poliovirus were determined, and the poliovirus-specific antibody-positive rates were evaluated. A total of 1104 participants were enrolled in this study. The positive rates of poliovirus type 1- and type 3-specific antibodies among the sequential immunization groups showed no significant difference at 24, 36, or 48 months of age. The positive rates of poliovirus type 2-specific antibody in the IPV-IPV-tOPV group at all time points were nearly 100%, which was significantly higher than the corresponding rates in other immunization groups (IPV-bOPV-bOPV and IPV-IPV-bOPV). Immunization schedules involving one or two doses of IPV followed by bOPV failed to maintain a high positive rate for poliovirus type 2-specific antibody.

Effect and Mechanism of Chinese Medicine in Treatment of Osteoporosis / 中国实验方剂学杂志

Osteoporosis （OP） is a common bone disease affecting the quality of life and causing huge medical burden to the patients and society. The occurrence of OP is mainly caused by excessive bone resorption and insufficient bone formation， which are directly influenced by external calcium ion balance. Calcium imbalance can impair bone integrity， reduce the calcium supply to the bone， and lower the calcium content in the bone， thus triggering OP. Drugs are the main anti-OP therapy in modern medicine， which， however， may cause adverse reactions and drug dependence. Chinese medicines have good clinical effects and high safety in treating OP， being suitable for long-term use. Recent studies have shown that Chinese medicines can alleviate estrogen deficiency， regulate bone cell and calcium metabolism， which is crucial for the formation and development of OP. The transient receptor potential cation channel superfamily V members 5 and 6 （TRPV5 and TRPV6， respectively） affect bone homeostasis by mediating the transmembrane calcium ion transport in the intestine （TRPV6） and kidney （TRPV5）. Therefore， TRPV5/6 is one of the key targets to understand the anti-OP mechanisms of the effective parts of Chinese medicines， which is worthy of further study. This paper summarizes the research results about the anti-OP effects of Chinese medicines in the last two decades， especially the mechanism of regulating calcium metabolism， aiming to provide new ideas for the basic research， clinical application， and drug development of OP treatment.

Mechanism of Zhishi Xiebai Guizhitang in Treating AS Based on Regulation of Cholesterol Metabolism in Foam Cells by TRPA1 / 中国实验方剂学杂志

ObjectiveTo explore the effect and mechanism of Zhishi Xiebai Guizhitang on the progression of atherosclerosis （AS） mice based on the regulation of cholesterol metabolism in foam cells by transient receptor potential channel ankyrin 1 （TRPA1）. MethodThe AS model was established on apolipoprotein E knockout （ApoE-/-） mice with a high-fat diet. The mice were randomly divided into low-dose， middle-dose， and high-dose groups of Zhishi Xiebai Guizhitang （2.97， 5.94， 11.88 g·kg-1） and simvastatin group （0.002 g·kg-1）， and the drug was administered along with a high-fat diet. C57BL/6J mice were fed an ordinary diet as a normal group. After the above process， the aorta and serum of mice were taken. The pathological changes of the aortic root were observed by hematoxylin-eosin （HE） staining. The lipid plaques in the aorta were observed by gross oil redness. Serum levels of total cholesterol （TC）， triglyceride （TG）， low density lipoprotein cholesterol （LDL-C）， and high density lipoprotein cholesterol （HDL-C） were detected， and the levels of interleukin-1β （IL-1β） and interleukin-18 （IL-18） were detected by enzyme-linked immunosorbent assay （ELISA）. Western blot and immunohistochemical method were used to analyze the expression of TRPA1， ATP-binding cassette transporter A1 （ABCA1）， ATP-binding cassette transporter G1 （ABCG1）， and mannose receptor （CD206）. ResultFrom the perspective of drug efficacy， compared with the normal group， pathological changes such as plaque， a large number of foam cells， and cholesterol crystals appeared in the aorta of the model group， and the serum levels of TC， LDL-C， IL-1β， and IL-18 were significantly increased （P<0.01）. The HDL-C level was significantly decreased （P<0.01）， and the CD206 level in aortic tissue was significantly decreased （P<0.01）. Compared with the model group， the lipid deposition in the aorta was alleviated in all drug administration groups. In addition， except for the high-dose group of Zhishi Xiebai Guizhitang， all drug administration groups could significantly decrease the levels of TC and LDL-C （P<0.01）. In terms of inflammation， except for the middle-dose group of Zhishi Xiebai Guizhitang， the levels of IL-1β and IL-18 were significantly decreased in all drug administration groups （P<0.05）. Moreover， Zhishi Xiebai Guizhitang could also up-regulate the levels of CD206， and the difference was significant in the middle-dose and high-dose groups （P<0.05）. From the perspective of mechanism， the expression levels of TRPA1， ABCA1， and ABCG1 in the aorta in the model group were lower than those in the normal group （P<0.05）. Compared with the model group， all drug administration groups significantly increased the expression of TRPA1 in the aorta （P<0.05）， and the expressions of ABCA1 and ABCG1 were increased. The differences in the middle-dose and high-dose groups and the simvastatin group were significant （P<0.05）， which was basically consistent with the trend of immunohistochemical results. ConclusionZhishi Xiebai Guizhitang can effectively reduce blood lipid and inflammation levels and inhibit the formation of aortic plaque. The mechanism may be explained as follows： the expressions of ABCA1 and ABCG1 downstream are increased through TRPA1， which promotes cholesterol outflow in foam cells， thereby regulating cholesterol metabolism， intervening in inflammation level to a certain extent， and finally treating AS.

Clinical analysis of 11 cases multisystem inflammatory syndrome associated with SARS-CoV-2 Omicron variant infection in children / 中华儿科杂志

Objective: To explore the clinical characteristics, diagnosis, treatment, and follow-up of multisystem inflammatory syndrome in children (MIS-C) related to SARS-CoV-2 Omicron variant infection. Methods: A retrospective analysis was conducted on clinical data of 11 children with MIS-C, who were admitted to the Department of Pediatrics of Peking University First Hospital from December 2022 to January 2023. Clinical characteristics, treatment, and follow-up of MIS-C were summarized in this study. Results: The 11 cases contained 7 boys and 4 girls, with an age of 4.4 (2.0, 5.5) years on admission. All the patients had fever, with a duration of 7(5, 9) days. Other clinical manifestations included rash in 7 cases, conjunctival hyperemia in 5 cases, red lips and raspberry tongue in 3 cases, lymphadenopathy in 3 cases, and swollen fingers and toes in 2 cases. There were 8 cases of digestive symptoms, 8 cases of respiratory symptoms, and 3 cases of nervous system symptoms. Eight patients had multi-system injuries, and one of them had shock presentation. All 11 patients were infected with SARS-CoV-2 Omicron BF.7 variant. The laboratory examination results showed that all cases had elevated inflammatory indicators, abnormal coagulation function and myocardial damage. Six patients had elevated white blood cell counts, 5 cases had liver function abnormalities, 3 cases had kidney function abnormalities, and 8 cases had coronary artery involvement. All 11 patients received anti-infection treatment, of which 3 cases received only 2 g/kg intravenous immunoglobulin (IVIG), while the remaining 8 cases received a combination of IVIG and 2 mg/(kg·d) methylprednisolone. Among the 8 cases with coronary artery disease, 6 cases received low molecular weight heparin anticoagulation therapy. All patients were followed up in 2 weeks after being discharged, and their inflammatory markers had returned to normal by that time. The 8 cases with coronary artery disease and 3 cases with pneumonia showed significant improvement or back to normal at the 4-week follow-up. All patients had no new complications or comorbidities during follow-up of more than 3 months. Conclusions: MIS-C may present with Kawasaki disease-like symptoms, with or without gastrointestinal, neurological, or respiratory symptoms. Elevated inflammatory markers, abnormal coagulation function, and cardiac injury contribute to the diagnosis of MIS-C. IVIG and methylprednisolone were the primary treatments for MIS-C, and a favorable short-term prognosis was observed during a follow-up period of more than 3 months.

A topochemical reaction induced the formation of Bi2S3 micro-straws from a Bi-MOF for an ultra-long Zn storage life.

Aqueous zinc ion batteries (ZIBs) are considered as promising energy storage devices in the post-lithium-ion era, due to their high energy density, low cost, high safety, and environmental benignity, however their commercialization is hindered by the sluggish diffusion kinetics of cathode materials due to the large hydrate Zn2+ radius. In this work, we propose a unique structure inheritance strategy for preparing Bi2S3 micro-straws in which a metal-organic framework (MOF) denoted as Bi-PYDC (PYDC2- = 3,5-pyridinedicarboxylate) with a string of [Bi2O2]2+ chains is judiciously selected as the structure-directing template to induce the formation of micro-straws based on a topochemical reaction. The distinctive hollow structure significantly enhances the ionic storage kinetics. Impressively, the obtained battery exhibits an ultra-long cycle life of more than 10 000 cycles at a current density of 1 A g-1 while maintaining a capacity of more than 153.4 mA h g-1. In addition, the Zn2+ insertion/extraction mechanism of Bi2S3 micro-straws is also investigated by multiple analytical methods, revealing the involvement of Zn2+ rather than H+ in the electrochemical storage process. This work may lead a new direction for constructing high performance cathodes of Zn-ion batteries through a MOF-based structure-directing template.

The Diagnostic Value of a Nomogram Based on Clinical Imaging and MRIBased Radiomic Features in Triple-Negative Breast Cancer.

OBJECTIVE: This study aimed to determine the utility of a radiomic nomogram combined with clinical imaging and radiomic features based on MRI for the diagnosis of triple-negative breast cancer. METHODS: Multi-parametric MRI images of 136 breast cancer patients were retrospectively analyzed, 95 cases were stratified into the training cohort, and 41 cases were selected for the test group. According to the pathological molecular typing, the patients were divided into 23 cases of triple-negative breast cancer and 113 cases of non-triple-negative breast cancer. ITK software was used to manually delineate the lesion volume region of interest (VOI), and the Pyradiomics package was used to extract radiomic features for screening and model building. The platform was then used to analyze the clinical and imaging risk factors of breast cancer to build a characteristic model separately. Finally, a radiomic nomogram was constructed by integrating the radiomic and independent clinical image features. The diagnostic performance of the model was assessed using ROC curves. RESULTS: Univariate and multivariate analyses showed that the menstrual cycle, glandular density, and skin thickening were risk factors for clinical imaging characteristics of triple-negative breast cancer. The Area Under the Curve (AUC) was 0.839 and 0.826 for univariate and multivariate analysis, respectively. After screening, 11 radiomic features participated in the calculation of the radiomic score, and its AUC in the test set was 0.803. Combining it further with clinical models, the AUC improved to 0.899. CONCLUSION: The radiomic nomogram developed in this study has great value in the diagnosis of triple-negative breast cancer.

An extra-erythrocyte role of haemoglobin body in chondrocyte hypoxia adaption.

Although haemoglobin is a known carrier of oxygen in erythrocytes that functions to transport oxygen over a long range, its physiological roles outside erythrocytes are largely elusive1,2. Here we found that chondrocytes produced massive amounts of haemoglobin to form eosin-positive bodies in their cytoplasm. The haemoglobin body (Hedy) is a membraneless condensate characterized by phase separation. Production of haemoglobin in chondrocytes is controlled by hypoxia and is dependent on KLF1 rather than the HIF1/2α pathway. Deletion of haemoglobin in chondrocytes leads to Hedy loss along with severe hypoxia, enhanced glycolysis and extensive cell death in the centre of cartilaginous tissue, which is attributed to the loss of the Hedy-controlled oxygen supply under hypoxic conditions. These results demonstrate an extra-erythrocyte role of haemoglobin in chondrocytes, and uncover a heretofore unrecognized mechanism in which chondrocytes survive a hypoxic environment through Hedy.

Deubiquitinating PABPC1 by USP10 upregulates CLK2 translation to promote tumor progression in pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is extremely malignant with limited treatment options. Deubiquitinases (DUBs), which cleave ubiquitin on substrates, can regulate tumor progression and are appealing therapeutic targets, but there are few related studies in PDAC. In our study, we screened the expression levels and prognostic value of USP family members based on published databases and selected USP10 as the potential interventional target in PDAC. IHC staining of the PDAC microarray revealed that USP10 expression was an adverse clinical feature of PDAC. USP10 promoted tumor growth both in vivo and in vitro in PDAC. Co-IP experiments revealed that USP10 directly interacts with PABPC1. Deubiquitination assays revealed that USP10 decreased the K27/29-linked ubiquitination level of the RRM2 domain of PABPC1. Deubiquitinated PABPC1 was able to couple more CLK2 mRNA and eIF4G1, which increased the translation efficiency. Replacing PABPC1 with a mutant that could not be ubiquitinated impaired USP10 knock-down-mediated tumor suppression in PDAC. Targeting USP10 significantly delayed the growth of cell-derived xenograft and patient-derived xenograft tumors. Collectively, our study first identified USP10 as the DUB of PABPC1 and provided a rationale for potential therapeutic options for PDAC with high USP10 expression.

Large HBV Surface Protein-Induced Unfolded Protein Response Dynamically Regulates p27 Degradation in Hepatocellular Carcinoma Progression.

Up to 50% of hepatocellular carcinoma (HCC) is caused by hepatitis B virus (HBV) infection, and the surface protein of HBV is essential for the progression of HBV-related HCC. The expression of large HBV surface antigen (LHB) is presented in HBV-associated HCC tissues and is significantly associated with the development of HCC. Gene set enrichment analysis revealed that LHB overexpression regulates the cell cycle process. Excess LHB in HCC cells induced chronic endoplasmic reticulum (ER) stress and was significantly correlated with tumor growth in vivo. Cell cycle analysis showed that cell cycle progression from G1 to S phase was greatly enhanced in vitro. We identified intensive crosstalk between ER stress and cell cycle progression in HCC. As an important regulator of the G1/S checkpoint, p27 was transcriptionally upregulated by transcription factors ATF4 and XBP1s, downstream of the unfolded protein response pathway. Moreover, LHB-induced ER stress promoted internal ribosome-entry-site-mediated selective translation of p27, and E3 ubiquitin ligase HRD1-mediated p27 ubiquitination and degradation. Ultimately, the decrease in p27 protein levels reduced G1/S arrest and promoted the progress of HCC by regulating the cell cycle.

HMMR alleviates endoplasmic reticulum stress by promoting autophagolysosomal activity during endoplasmic reticulum stress-driven hepatocellular carcinoma progression.

BACKGROUND: The mechanism of hepatitis B virus (HBV)-induced carcinogenesis remains an area of interest. The accumulation of hepatitis B surface antigen in the endoplasmic reticulum (ER) of hepatocytes stimulates persistent ER stress. Activity of the unfolded protein response (UPR) pathway of ER stress may play an important role in inflammatory cancer transformation. How the protective UPR pathway is hijacked by cells as a tool for malignant transformation in HBV-related hepatocellular carcinoma (HCC) is still unclear. Here, we aimed to define the key molecule hyaluronan-mediated motility receptor (HMMR) in this process and explore its role under ER stress in HCC development. METHODS: An HBV-transgenic mouse model was used to characterize the pathological changes during the tumor progression. Proteomics and transcriptomics analyses were performed to identify the potential key molecule, screen the E3 ligase, and define the activation pathway. Quantitative real-time PCR and Western blotting were conducted to detect the expression of genes in tissues and cell lines. Luciferase reporter assay, chromatin immunoprecipitation, coimmunoprecipitation, immunoprecipitation, and immunofluorescence were employed to investigate the molecular mechanisms of HMMR under ER stress. Immunohistochemistry was used to clarify the expression patterns of HMMR and related molecules in human tissues. RESULTS: We found sustained activation of ER stress in the HBV-transgenic mouse model of hepatitis-fibrosis-HCC. HMMR was transcribed by c/EBP homologous protein (CHOP) and degraded by tripartite motif containing 29 (TRIM29) after ubiquitination under ER stress, which caused the inconsistent expression of mRNA and protein. Dynamic expression of TRIM29 in the HCC progression regulated the dynamic expression of HMMR. HMMR could alleviate ER stress by increasing autophagic lysosome activity. The negative correlation between HMMR and ER stress, positive correlation between HMMR and autophagy, and negative correlation between ER stress and autophagy were verified in human tissues. CONCLUSIONS: This study identified the complicated role of HMMR in autophagy and ER stress, that HMMR controls the intensity of ER stress by regulating autophagy in HCC progression, which could be a novel explanation for HBV-related carcinogenesis.

Combination immunotherapy of glioblastoma with dendritic cell cancer vaccines, anti-PD-1 and poly I:C.

Glioblastoma (GBM) is a lethal cancer with limited therapeutic options. Dendritic cell (DC)-based cancer vaccines provide a promising approach for GBM treatment. Clinical studies suggest that other immunotherapeutic agents may be combined with DC vaccines to further enhance antitumor activity. Here, we report a GBM case with combination immunotherapy consisting of DC vaccines, anti-programmed death-1 (anti-PD-1) and poly I:C as well as the chemotherapeutic agent cyclophosphamide that was integrated with standard chemoradiation therapy, and the patient remained disease-free for 69 months. The patient received DC vaccines loaded with multiple forms of tumor antigens, including mRNA-tumor associated antigens (TAA), mRNA-neoantigens, and hypochlorous acid (HOCl)-oxidized tumor lysates. Furthermore, mRNA-TAAs were modified with a novel TriVac technology that fuses TAAs with a destabilization domain and inserts TAAs into full-length lysosomal associated membrane protein-1 to enhance major histocompatibility complex (MHC) class I and II antigen presentation. The treatment consisted of 42 DC cancer vaccine infusions, 26 anti-PD-1 antibody nivolumab administrations and 126 poly I:C injections for DC infusions. The patient also received 28 doses of cyclophosphamide for depletion of regulatory T cells. No immunotherapy-related adverse events were observed during the treatment. Robust antitumor CD4+ and CD8+ T-cell responses were detected. The patient remains free of disease progression. This is the first case report on the combination of the above three agents to treat glioblastoma patients. Our results suggest that integrated combination immunotherapy is safe and feasible for long-term treatment in this patient. A large-scale trial to validate these findings is warranted.

Development of a MMAE-based antibody-drug conjugate targeting B7-H3 for glioblastoma.

B7-H3 (immunoregulatory protein B7-homologue 3) is overexpressed in many cancer cells with limited expression in normal tissues, considered to be a promising target for tumor therapeutics. Clinical trials of antibody-drug conjugates (ADCs) against different targets for glioblastoma have been investigated and showed potent efficacies. In this study, we developed a homogeneous ADC 401-4 with a drug-to-antibody ratio (DAR) of 4, which was prepared by conjugation of Monomethyl auristatin E (MMAE) to a humanized anti-B7-H3 mAb 401, through a divinylsulfonamide-mediated disulfide re-bridging approach. In vitro studies, 401-4 displayed specific killing against B7-H3-expressing tumors and was more effective in cells with higher levels of B7-H3 for different glioblastoma cells. 401-4 was furthered labeled with Cy5.5 to yield a fluorescent conjugate 401-4-Cy5.5. The in vivo imaging studies showed that the conjugate accumulated in tumor regions and exhibited the ability to target-specific delivery. In addition, significant antitumor activities for 401-4 was observed against U87-derived tumor xenografts in a dose dependent manner.

Inhibition of epithelial-to-mesenchymal transition augments antitumor efficacy of nanotherapeutics in pancreatic ductal adenocarcinoma.

Intrinsic drug resistance mechanisms of tumor cells often reduce intracellular drug concentration to suboptimal levels. Epithelial-to-mesenchymal transition (EMT) is a pivotal process in tumor progression and metastasis that confers an aggressive phenotype as well as resistance to chemotherapeutics. Therefore, it is imperative to develop novel strategies and identify new targets to improve the overall efficacy of cancer treatment. We developed SN38 (active metabolite of irinotecan)-assembled glycol chitosan nanoparticles (cSN38) for the treatment of pancreatic ductal adenocarcinoma (PDAC). Furthermore, cSN38 and the TGF-ß1 inhibitor LY364947 formed composite nanoparticles upon self-assembly (cSN38 + LY), which obviated the poor aqueous solubility of LY364947 and enhanced drug sensitivity. The therapeutic efficacy of cSN38 + LY nanotherapeutics was studied in vitro and in vivo using suitable models. The cSN38 nanoparticles exhibited an antitumor effect that was significantly attenuated by TGF-ß-induced EMT. The cellular uptake of SN38 was impeded during EMT, which affected the therapeutic efficacy. The combination of LY364947 and cSN38 markedly enhanced the cellular uptake of SN38, increased cytotoxic effects, and inhibited EMT in PDAC cells in vitro. Furthermore, cSN38 + LY significantly inhibited PDAC xenograft growth in vivo. The cSN38 + LY nanoparticles increased the therapeutic efficacy of cSN38 via repressing the EMT of PDAC cells. Our findings provide a rationale for designing nanoscale therapeutics to combat PDAC.

Unveiling the unprecedented catalytic capability of micro-sized Co-ZIF-L for the thermal decomposition of RDX by 2D-structure-induced mechanism reversal.

Developing MOF-based catalysts with superior catalytic properties for the thermal decomposition of cyclotrimethylenetrinitramine (RDX) is significant for the application of novel and efficient combustion catalysts oriented to RDX-based propellants with excellent combustion performance. Herein, micro-sized Co-ZIF-L with a star-like morphology (SL-Co-ZIF-L) was found to exhibit unprecedented catalytic capability for the decomposition of RDX, which can lower the decomposition temperature of RDX by 42.9 °C and boost the heat release by 50.8%, superior to that of all the ever-reported MOFs and even ZIF-67, which has similar chemical composition but a much smaller size. In-depth mechanism study from both experimental and theoretical views reveals that the weekly interacted 2D layered structure of SL-Co-ZIF-L could activate the exothermic C-N fission pathway for the decomposition of RDX in the condensed phase, thus reversing the commonly advantageous N-N fission pathway and promoting the decomposition process in the low-temperature stage. Our study reveals the unusually superior catalytic capability of micro-sized MOF catalysts and sheds light on the rational structure design of catalysts used in micromolecule transformation reactions, typically the thermal decomposition of energetic materials.

Phenyldivinylsulfonamides for the construction of antibody-drug conjugates with controlled four payloads.

Phenyldivinylsulfonamides emerged from a series of divinylsulfonamides, demonstrating their ability to effectively re-bridge disulfide bonds. This kind of linkers was attached to monomethyl auristatin E (MMAE) and further conjugated with a model antibody, trastuzumab. After optimization, the linker 20 can deliver stable and highly homogenous DAR (Drug-to-Antibody Ratio) four antibody-drug conjugates (ADCs). The method was also applicable for other IgG1 antibodies to obtain ADCs with controlled four payloads. Moreover, the MMAE-bearing ADC is potent, selective and efficacious against target cell lines.

Raman spectra and vibrational properties of FOX-7 under pressure and temperature: First-principles calculations.

FOX-7 (1,1-diamino-2,2-dinitroethene) as one of the widely studied insensitive high explosives exists five polymorphs (α, ß, γ, α', ε) whose crystal structures have been determined by XRD (X-rays Diffraction) and which are investigated by a density functional theory (DFT) approach in this work. The calculation results show that the GGA PBE-D2 method can reproduce the experimental crystal structure of FOX-7 polymorphs better. The calculated Raman spectra of FOX-7 polymorphs were compared in detail and fully with the experimental Raman spectra data and it was found that the calculated Raman spectra frequencies have an overall red-shift in middle band (800-1700 cm-1), and that the maximum deviation does not exceed 4 % (The maximum point is the mode of CC in plane bending). The high-temperature phase transform path (α â†’ ß â†’ Î³) and the high-pressure phase transform path (α â†’ α'→ε) can be well represented in the computational Raman spectra. In addition, crystal structure of ε-FOX-7 was performed up to 70 GPa to probe Raman spectra and vibrational properties. The results showed that the NH2 Raman shift is jittering with pressure (not smooth compared to other vibrational modes) and NH2 anti-symmetry-stretching appears red-shifted. The vibration of hydrogen mixes in all of other vibrational modes. This work shows that the dispersion-corrected GGA PBE method can reproduce the experimental structure, vibrational properties and Raman spectra very well.

Meplazumab in hospitalized adults with severe COVID-19 (DEFLECT): a multicenter, seamless phase 2/3, randomized, third-party double-blind clinical trial.

Meplazumab, a humanized CD147 antibody, has shown favourable safety and efficacy in our previous clinical studies. In DEFLECT (NCT04586153), 167 patients with severe COVID-19 were enroled and randomized to receive three dosages of meplazumab and a placebo. Meplazumab at 0.12 mg/kg, compared to the placebo group, showed clinical benefits in significantly reducing mortality by 83.6% (2.4% vs. 14.6%, p = 0.0150), increasing the proportion of patients alive and discharged without supplemental oxygen (82.9% vs. 70.7%, p = 0.0337) and increasing the proportion of patients who achieved sustained clinical improvement (41.5% vs. 31.7%). The response rate in the 0.2 mg/kg group was relatively increased by 16.0% compared with the placebo group (53.7% vs. 46.3%). Meplazumab also reduced the viral loads and multiple cytokine levels. Compare with the placebo group, the 0.3 mg/kg significantly increased the virus negative rate by 40.6% (p = 0.0363) and reduced IL-8 level (p = 0.0460); the 0.2 mg/kg increased the negative conversion rate by 36.9%, and reduced IL-4 (p = 0.0365) and IL-8 levels (p = 0.0484). In this study, the adverse events occurred at a comparable rate across the four groups, with no unexpected safety findings observed. In conclusion, meplazumab promoted COVID-19 convalescence and reduced mortality, viral load, and cytokine levels in severe COVID-19 population with good safety profile.

Effects of pressure on structural, electronic, optical, and mechanical properties of nitrogen-rich energetic material: 6-azido-8-nitrotetrazolo[1,5-b]pyridazine-7-amine (3at).

CONTEXT AND RESULTS: 6-Azido-8-nitrotetrazolo[1,5-b]pyridazine-7-amine (3at) is a promising green energetic material, which meets the development requirements of environment-friendly explosives. By discussing the relationship between lattice parameters and pressure, it is found that the compression ratio indicates anisotropy of compressibility. And bond lengths get shorter under pressure, resulting in stronger intermolecular bonds. The N3 group rotates under pressure. And then, the optical properties basically change regularly with the change of pressure. As the pressure increases, the absorption range widens. In the low energy interval, it shows transparency, and then with the increase of energy and pressure, it shows better optical activity. With the increase of pressure and energy, the absorption coefficient increases, representing that the optical activity becomes high. Finally, according to the analysis of mechanical properties, 3at exhibited brittle behavior at 0 GPa and 100 GPa, while at 10 to 90 GPa, the values of ν and B/G are malleable. COMPUTATIONAL AND THEORETICAL TECHNIQUES: Based on density functional theory, the crystal parameters, electronic properties, optical properties, and elastic and mechanical properties of 3at under different pressures were studied theoretically. The GGA-PW91+OBS method was used to calculate the physical parameters under pressure, such as lattice parameters, energy band structures, dielectric function, refractive index, absorption coefficient, and elastic constants. Physical properties under (3at) pressure are predicted.