Solid-Liquid-Gas Three-Phase Indirect Electrolysis Enabled by Affinity Auxiliary Imparted Covalent Organic Frameworks.

The design of efficient heterogenous redox mediators with favorable affinity to substrate and electrolyte are much desired yet still challenging for the development of indirect electrolysis system. Herein, for the first time, we have developed a solid-liquid-gas three-phase indirect electrolysis system based on a covalent organic framework (Dha-COF-Cu) as heterogenous redox mediator for S-S coupling reaction. Dha-COF-Cu with the integration of high porosity, nanorod morphology, abundant hydroxyl groups and active Cu sites is much beneficial for the adsorption/activation of thiols, uniform dispersion and high wettability in electrolyte, and efficient interfacial electron transfer. Notably, Dha-COF-Cu as solid-phase redox mediator exhibits excellent electrocatalytic efficiency for the formation of value-added liquid-phase S-S bond product (yields up to 99%) coupling with the generation of gas-phase product of H2 (~1.40 mmol g-1 h-1), resulting in a powerful three-phase indirect electrolysis system. This is the first work about COFs that can be applied in three-phase indirect electrolysis system, which might promote the development of porous crystalline materials in this field.

Synthesis of Isotypic Giant Polymolybdate Cages for Efficient Photocatalytic C-C Coupling Reactions.

The construction of isotypic high-nuclearity inorganic cages with identical pristine parent structure and increasing nuclearity is highly important for molecular growth and structure-property relationship study, yet it still remains a great challenge. Here, we provide an in situ growth approach for successfully synthesizing a series of new giant hollow polymolybdate dodecahedral cages, Mo250, Mo260-I, and Mo260-E, whose structures are growth based on giant polymolybdate cage Mo240. Remarkably, they show two pathways of nuclear growth based on Mo240, that is, the growth of 10 and 20 Mo centers on the inner and outer surfaces to afford Mo250 and Mo260-I, respectively, and the growth of 10 Mo centers both on the inner and outer surfaces to give Mo260-E. To the best of our knowledge, this is the first study to display the internal and external nuclear growth of a giant hollow polyoxometalate cage. More importantly, regular variations in structure and nuclearity confer these polymolybdate cages with different optical properties, oxidative activities, and hydrogen atom transfer effect, thus allowing them to exhibit moderate to excellent photocatalytic performance in oxidative cross-coupling reactions between different unactivated alkanes and N-heteroarenes. In particular, Mo240 and Mo260-E with better comprehensive abilities can offer the desired coupling product with yield up to 92% within 1 h.

Constructing Functional Radiation-Resistant Thorium Clusters for Catalytic Redox Reactions.

When catalytic reactions are interfered with by radiation sources, thorium clusters are promising as potential catalysts due to their superior radiation resistance. However, there is currently very little research on the design synthesis and catalytic application of radiation-stable thorium clusters. In this work, we have elaborately engineered and fabricated three high-nuclear thorium cluster catalysts denoted as Th12L3-MA12, Th12L3-MA6-BF6, and Th12L3-Fcc12, which did not undergo any significant alterations in their molecular structures and compositions after irradiation with 690 kGy γ-rays. We systematically investigated the photocatalytic/thermocatalytic properties of these radiation-resistant thorium clusters for the first time and found that γ-rays could not alter their catalytic activities. In addition, it was found that ligand engineering could modulate the catalytic activity of thorium clusters, thus expanding the range of catalytic applications of thorium clusters, including reduction reactions (nitroarene reduction) and some oxidation reactions (N-heterocyclic oxidative dehydrogenation and diphenylmethane oxidation). Meanwhile, all of these organic transformation reactions achieved a >80% conversion and nearly 100% product selectivity. Radiation experiments combined with DFT calculations showed that the synergistic catalysis of thorium-oxo core and ligands led to the generation of specific active species (H+, O2•-, or tBuO/tBuOO•) and activation of substrate molecules, thus achieving superior catalytic performance. This work is not only the first to develop radiation-resistant thorium cluster catalysts to perform efficient redox reactions but also provides design ideas for the construction of high-nuclearity thorium clusters under mild conditions.

Air-sea exchange of PAHs in the Taiwan Strait: Seasonal dynamics and regulation mechanisms revealed by machine learning approach.

In this study, to understand the seasonal dynamics of air-sea exchange and its regulation mechanisms, we investigated polycyclic aromatic hydrocarbons (PAHs) at the air-sea interface in the western Taiwan Strait in combination with measurements and machine learning (ML) predictions. For 3-ring PAHs and most of 4- to 6-ring, volatilization and deposition fluxes were observed, respectively. Seasonal variations in air-sea exchange flux suggest the influence of monsoon transitions. Results of interpretable ML approach (XGBoost) indicated that volatilization of 3-ring PAHs was significantly controlled by dissolved PAH concentrations (contributed 24.0 %), and the gaseous deposition of 4- to 6-ring PAHs was related to more contaminated air masses originating from North China during the northeast monsoon. Henry's law constant emerged as a secondary factor, influencing the intensity of air-sea exchange, particularly for low molecular weight PAHs. Among environmental parameters, notably high wind speed emerges as the primary factor and biological pump's depletion of PAHs in surface seawater amplifies the gaseous deposition process. The distinct dynamics of exchanges at the air-water interface for PAHs in the western TWS can be attributed to variations in primary emission intensities, biological activity, and the inconsistent pathways of long-range atmospheric transport, particularly within the context of the monsoon transition.

Decreased expression of KLF6 in ectopic endometrial stromal cells contributes to endometriosis progression by targeting CTNNB1.

Despite decades of research, endometriosis remains a mysterious gynecological disease with unknown etiology and pathogenesis. Krüppel-like Factor 6 (KLF6), a transcription factor, has a wide expression profile and regulates a variety of biological processes. Here, we investigated the expression and function of KLF6 and its possible regulatory mechanisms in endometriosis. To determine the function of KLF6, knockdown and overexpression experiments were performed in eutopic endometrial stromal cells (EU-ESCs) and ectopic endometrial stromal cells (EC-ESCs), respectively. Cell viability, apoptosis, migration, invasion, and angiogenesis assays were conducted in ESCs. ChIP-sequencing and mRNA-sequencing were performed to investigate the functional mechanism of KLF6 in regulating ESCs. We found that KLF6 was highly expressed in eutopic endometrium of endometriosis patients, compared with ectopic endometrium. Similarly, the same was true in EU-ESCs, which was compared with EC-ESCs. Overexpression of KLF6 significantly suppressed EC-ESC proliferation, migration and invasion and induced cell apoptosis, while knockdown of KLF6 resulted in the opposite effects on EU-ESCs. Overexpression of KLF6 significantly inhibited EC-ESC angiogenesis. Mechanistically, the results of ChIP sequencing and mRNA sequencing revealed that CTNNB1 may be a transcriptional target regulated by KLF6. Reintroduction of KLF6 reversed the effects of KLF6 knockdown on EU-ESCs. KLF6 inhibited the proliferation, migration and angiogenesis of EC-ESCs by inhibiting the expression of CTNNB1. Our findings provided a new perspective on the role of KLF6 in endometriosis progression and inspire potential targeted therapeutic strategies.

Kallikrein-Related Peptidase 4 Promotes Proliferation, Migration, Invasion, and Pro-Angiogenesis of Endometrial Stromal Cells via Regulation of Brain-Derived Neurotrophic Factor Production in Endometriosis.

Endometriosis is a common benign gynecologic condition. Endometriosis lesions are associated with endometrial cell proliferation, migration, invasion, and neovascularization, while the specific molecular mechanisms are still elusive. Transcriptome sequencing has been used for the identification of diagnostic markers in endometriosis. Here, transcriptome profiling revealed that kallikrein-related peptidase 4 (KLK4) expression was up-regulated in ectopic endometrium (EC) tissues of patients with endometriosis. KLK4 mediates the degradation of extracellular matrix proteins, and its proteolytic activity activates many tumorigenic and metastatic pathways via tumor invasion and migration. Nevertheless, whether KLK4 serves as an important regulatory factor in endometriosis remains unclear. This study confirmed that KLK4 was highly expressed in ectopic endometrial stromal cells (EC-ESCs). KLK4 overexpression promoted proliferation and suppressed apoptosis of EC-ESCs, induced cell migration and invasion, and enhanced angiogenesis in vivo. Mechanistically, KLK4 overexpression mediated the protein cleavage of pro-brain-derived neurotrophic factor in EC-ESCs. Finally, brain-derived neurotrophic factor was a vital downstream substrate of KLK4 maintained the proliferation, metastasis, and pro-angiogenesis abilities and inhibited apoptosis of ESCs through a rescue study. Together, these findings demonstrate the promotive role of KLK4 in endometriosis development. In addition, the study provides a new insight that KLK4 might be a potential therapeutic target and prognostic marker for patients with endometriosis.

Sulfur atom-directed metal-ligand synergistic catalysis in zirconium/hafnium-oxo clusters for highly efficient amine oxidation.

The performance applications (e.g., photocatalysis) of zirconium (Zr) and hafnium (Hf) based complexes are greatly hindered by the limited development of their structures and the relatively inert metal reactivity. In this work, we constructed two ultrastable Zr/Hf-based clusters (Zr9-TC4A and Hf9-TC4A) using hydrophobic 4-tert-butylthiacalix[4]arene (H4TC4A) ligands, in which unsaturated coordinated sulfur (S) atoms on the TC4A4- ligand can generate strong metal-ligand synergy with nearby active metal Zr/Hf sites. As a result, these two functionalized H4TC4A ligands modified Zr/Hf-oxo clusters, as catalysts for the amine oxidation reaction, exhibited excellent catalytic activity, achieving very high substrate conversion (>99%) and product selectivity (>90%). Combining comparative experiments and theoretical calculations, we found that these Zr/Hf-based cluster catalysts accomplish efficient amine oxidation reactions through synergistic effect between metals and ligands: (i) The photocatalytic benzylamine (BA) oxidation reaction was achieved by the synergistic effect of the dual active sites, in which, the naked S sites on the TC4A4- ligand oxidize the BA by photogenerated hole and oxygen molecules are reduced by photogenerated electrons on the metal active sites; (ii) in the aniline oxidation reaction, aniline was adsorbed by the bare S sites on ligands to be closer to metal active sites and then oxidized by the oxygen-containing radicals activated by the metal sites, thus completing the catalytic reaction under the synergistic catalytic effect of the proximity metal-ligand. In this work, the Zr/Hf-based complexes applied in the oxidation of organic amines have been realized using active S atom-directed metal-ligand synergistic catalysis and have demonstrated very high reactivity.

Parallel perception of visual motion using light-tunable memory matrix.

Parallel perception of visual motion is of crucial significance to the development of an intelligent machine vision system. However, implementing in-sensor parallel visual motion perception using conventional complementary metal-oxide semiconductor technology is challenging, because the temporal and spatial information embedded in motion cannot be simultaneously encoded and perceived at the sensory level. Here, we demonstrate the parallel perception of diverse motion modes at the sensor level by exploiting light-tunable memory matrix in a van der Waals (vdW) heterostructure array. The optoelectronic characteristics of gate-tunable photoconductivity and light-tunable memory matrix enable devices in the array to realize simultaneous encoding and processing of incoming spatiotemporal light pattern. Furthermore, we implement a visual motion perceptron with the array capable of deciphering multiple motion parameters in parallel, including direction, velocity, acceleration, and angular velocity. Our work opens up a promising venue for the realization of an intelligent machine vision system based on in-sensor motion perception.

Analysis of the impact of the Xiaolangdi Reservoir on the runoff of the Yellow River downstream based on CEEMDAN-multiscale information entropy.

Water resources are vital to the development of human society, and mastering the law of runoff changes is the basis for achieving sustainable use of water resources. To study the impact of reservoir construction on the changes of downstream river runoff, this paper decomposes the runoff before and after reservoir construction using the CEEMDAN method based on the runoff data from the Huayuankou hydrological station. The fluctuation characteristics of each decomposition series of runoff before and after reservoir construction and the intra-annual variation pattern of runoff are also analyzed by combining multi-time information entropy and coefficient of variation. The results show that after the operation of the Xiaolangdi Reservoir, the annual runoff variation cycle tends to be flat, and the monthly runoff cycle is significantly reduced. After reservoir construction, the entropy values of each IMF and Res of runoff become larger, the complexity and randomness of runoff changes increase, and predictability decreases. Before and after the operation of the Xiaolangdi Reservoir, the coefficient of variation of runoff were 0.28-1 and 0.38-0.83, the distribution of runoff was more uniform, and the percentage of runoff in the flood season was reduced from 51.51 to 39.89%.

Occurrence of emerging contaminants in pet hair and indoor air: integrative health risk assessment using multiple ToxCast endpoints.

Indoor exposome is a growing concern, including a mixture of legacy and emerging contaminants. Recent studies suggest that indoor pollutants may accumulate in pet hair, a part of indoor exposome, increasing health risks to pet owners; however, the source and hazards of pollutants associated with pet hair are largely unknown. Here, we found that hydrophobic pollutants often had higher indoor concentrations than hydrophilic ones, and polycyclic aromatic hydrocarbons (PAHs) were the most dominant fractions (61.1%) in indoor air exposome while polycyclic musks (PCMs) had the highest concentrations among all contaminant classes in indoor dust (1559 ± 1598 ng g-1 dw) and pet hair (2831 ± 2458 ng g-1 dw). The levels of hygiene-related contaminants (PCMs, current-use pesticides (CUPs), and antibiotics) were higher in pet hair than dust due to direct contact during applications. Health risk assessment using toxicity thresholds from high-throughput screening data showed that human health risks from the five classes of indoor contaminants (PAHs, PCMs, organophosphate esters, CUPs, and antibiotics) via inhalation, ingestion, and dermal contact were within acceptable limits, but the children may be exposed to a higher risk than the adults. The thresholds estimated from the ToxCast data using endpoint sensitivity distribution make the exposome risk assessment feasible in the absence of benchmarks, which is beneficial for including a mixture of emerging pollutants in risk assessment.

Calix[4]arene-Functionalized Titanium-Oxo Compounds for Perceiving Differences in Catalytic Reactivity Between Mono- and Multimetallic Sites.

While the difference in catalytic reactivity between mono- and multimetallic sites is often attributed to more than just the number of active sites, still few catalyst model systems have been developed to explore more underlying causal factors. In this work, we have elaborately designed and constructed three stable calix[4]arene (C4A)-functionalized titanium-oxo compounds, Ti-C4A, Ti4-C4A, and Ti16-C4A, with well-defined crystal structures, increasing nuclearity, and tunable light absorption capacity and energy levels. Among them, Ti-C4A and Ti16-C4A can be taken as model catalysts to compare the differences in reactivity between mono- and multimetallic sites. Taking CO2 photoreduction as the basic catalytic reaction, both compounds can achieve CO2-to-HCOO- conversion with high selectivity (close to 100%). Moreover, the catalytic activity of multimetallic Ti16-C4A is up to 2265.5 µmol g-1 h-1, which is at least 12 times higher than that of monometallic Ti-C4A (180.0 µmol g-1 h-1), and is the best-performing crystalline cluster-based photocatalyst known to date. Catalytic characterization combined with density functional theory calculations shows that in addition to the advantage of having more metal active sites (for adsorption and activation of more CO2 molecules), Ti16-C4A can effectively reduce the activation energy required for the CO2 reduction reaction by completing the multiple electron-proton transfer process rapidly with synergistic metal-ligand catalysis, thus exhibiting superior catalytic performance to that of monometallic Ti-C4A. This work provides a crystalline catalyst model system to explore the potential factors underlying the difference in catalytic reactivity between mono- and multimetallic sites.

Microchip gas chromatography column using magnetic beads coated with polydimethylsiloxane and metal organic frameworks.

Micro gas chromatography (µGC) using microfabricated silicon columns has been developed in response to the requirement for portable on-site gas analysis. Although different stationary phases have been developed, repeatable and reliable surface coatings in these rather small microcolumns remains a challenge. Herein, a new stationary phase coating strategy using magnetic beads (MBs) as carriers for micro column is presented. MBs modified with organopolysiloxane (MBs@OV-1) and a metal organic framework (MBs@HKUST-1) are deposited in on-chip microcolumns assisted with a magnetic field with an optimized modification process. MBs@OV-1 column showed a minimum HETP of 0.074 cm (1351 plates/m) of 62 cm/s. Mixtures of volatile organic compounds are successfully separated using MBs carried stationary phase which demonstrates that this technique has good chromatographic column efficiency. This method not only provides a novel coating process, washing and characterization of the stationary phases but also establishes a straightforward strategy for testing new absorbent materials for µGC systems.

Regulation of Redox Molecular Junctions in Covalent Organic Frameworks for H2 O2 Photosynthesis Coupled with Biomass Valorization.

H2 O2 photosynthesis coupled with biomass valorization can not only maximize the energy utilization but also realize the production of value-added products. Here, a series of COFs (i.e. Cu3 -BT-COF, Cu3 -pT-COF and TFP-BT-COF) with regulated redox molecular junctions have been prepared to study H2 O2 photosynthesis coupled with furfuryl alcohol (FFA) photo-oxidation to furoic acid (FA). The FA generation efficiency of Cu3 -BT-COF was found to be 575 mM g-1 (conversion ≈100 % and selectivity >99 %) and the H2 O2 production rate can reach up to 187 000 µM g-1 , which is much higher than Cu3 -pT-COF, TFP-BT-COF and its monomers. As shown by theoretical calculations, the covalent coupling of the Cu cluster and the thiazole group can promote charge transfer, substrate activation and FFA dehydrogenation, thus boosting both the kinetics of H2 O2 production and FFA photo-oxidation to increase the efficiency. This is the first report about COFs for H2 O2 photosynthesis coupled with biomass valorization, which might facilitate the exploration of porous-crystalline catalysts in this field.

B-cell-specific checkpoint molecules that regulate anti-tumour immunity.

The role of B cells in anti-tumour immunity is still debated and, accordingly, immunotherapies have focused on targeting T and natural killer cells to inhibit tumour growth1,2. Here, using high-throughput flow cytometry as well as bulk and single-cell RNA-sequencing and B-cell-receptor-sequencing analysis of B cells temporally during B16F10 melanoma growth, we identified a subset of B cells that expands specifically in the draining lymph node over time in tumour-bearing mice. The expanding B cell subset expresses the cell surface molecule T cell immunoglobulin and mucin domain 1 (TIM-1, encoded by Havcr1) and a unique transcriptional signature, including multiple co-inhibitory molecules such as PD-1, TIM-3, TIGIT and LAG-3. Although conditional deletion of these co-inhibitory molecules on B cells had little or no effect on tumour burden, selective deletion of Havcr1 in B cells both substantially inhibited tumour growth and enhanced effector T cell responses. Loss of TIM-1 enhanced the type 1 interferon response in B cells, which augmented B cell activation and increased antigen presentation and co-stimulation, resulting in increased expansion of tumour-specific effector T cells. Our results demonstrate that manipulation of TIM-1-expressing B cells enables engagement of the second arm of adaptive immunity to promote anti-tumour immunity and inhibit tumour growth.

Electronic Tuning of CO2 Interaction by Oriented Coordination of N-Rich Auxiliary in Porphyrin Metal-Organic Frameworks for Light-Assisted CO2 Electroreduction.

The efficient CO2 electroreduction into high-value products largely relies on the CO2 adsorption/activation or electron-transfer of electrocatalysts, thus site-specific functionalization methods that enable boosted related interactions of electrocatalysts are much desired. Here, an oriented coordination strategy is reported to introduce N-rich auxiliary (i.e., hexamethylenetetramine, HMTA) into metalloporphyrin metal organic frameworks (MOFs) to synthesize a series of site-specific functionalized electrocatalysts (HMTA@MOF-545-M, M = Fe, Co, and Ni) and they are successfully applied in light-assisted CO2 electroreduction. Noteworthy, thus-obtained HMTA@MOF-545-Co presents approximately two times enhanced CO2 adsorption-enthalpy and electrochemical active surface-area with largely decreased impedance-value after modification, resulting in almost twice higher CO2 electroreduction performance than its unmodified counterpart. Besides, its CO2 electroreduction performance can be further improved under light-illumination and displays superior FECO (≈100%), high CO generation rate (≈5.11 mol m-2  h-1 at -1.1 V) and energy efficiency (≈70% at -0.7 V). Theoretical calculations verify that the oriented coordination of HMTA can increase the charge density of active sites, almost doubly enhance the CO2 adsorption energy, and largely reduce the energy barrier of rate determining step for the boosted performance improvement. This work might promote the development of modifiable porous crystalline electrocatalysts in high-efficiency CO2 electroreduction.

Head-to-head comparison of perfluorobutane contrast-enhanced US and multiparametric MRI for breast cancer: a prospective, multicenter study.

BACKGROUND: Multiparametric magnetic resonance imaging (MP-MRI) has high sensitivity for diagnosing breast cancers but cannot always be used as a routine diagnostic tool. The present study aimed to evaluate whether the diagnostic performance of perfluorobutane (PFB) contrast-enhanced ultrasound (CEUS) is similar to that of MP-MRI in breast cancer and whether combining the two methods would enhance diagnostic efficiency. PATIENTS AND METHODS: This was a head-to-head, prospective, multicenter study. Patients with breast lesions diagnosed by US as Breast Imaging Reporting and Data System (BI-RADS) categories 3, 4, and 5 underwent both PFB-CEUS and MP-MRI scans. On-site operators and three reviewers categorized the BI-RADS of all lesions on two images. Logistic-bootstrap 1000-sample analysis and cross-validation were used to construct PFB-CEUS, MP-MRI, and hybrid (PFB-CEUS + MP-MRI) models to distinguish breast lesions. RESULTS: In total, 179 women with 186 breast lesions were evaluated from 17 centers in China. The area under the receiver operating characteristic curve (AUC) for the PFB-CEUS model to diagnose breast cancer (0.89; 95% confidence interval [CI] 0.74, 0.97) was similar to that of the MP-MRI model (0.89; 95% CI 0.73, 0.97) (P = 0.85). The AUC of the hybrid model (0.92, 95% CI 0.77, 0.98) did not show a statistical advantage over the PFB-CEUS and MP-MRI models (P = 0.29 and 0.40, respectively). However, 90.3% false-positive and 66.7% false-negative results of PFB-CEUS radiologists and 90.5% false-positive and 42.8% false-negative results of MP-MRI radiologists could be corrected by the hybrid model. Three dynamic nomograms of PFB-CEUS, MP-MRI and hybrid models to diagnose breast cancer are freely available online. CONCLUSIONS: PFB-CEUS can be used in the differential diagnosis of breast cancer with comparable performance to MP-MRI and with less time consumption. Using PFB-CEUS and MP-MRI as joint diagnostics could further strengthen the diagnostic ability. Trial registration Clinicaltrials.gov; NCT04657328. Registered 26 September 2020. IRB number 2020-300 was approved in Chinese PLA General Hospital. Every patient signed a written informed consent form in each center.

Study on differentially expressed genes and participating pathways of ectopic endometrium in adenomyosis patients with different data sets.

BACKGROUND: Adenomyosis is a benign uterine disease and affected patients present with symptoms such as menorrhagia, chronic pelvic pain, abnormal uterine bleeding, and infertility. However, the specific mechanisms by which adenomyosis occurs need to be further studied. OBJECTIVE: Dataset of adenomyosis from our hospital and a public database were analyzed using bioinformatics. Corresponding differentially expressed genes (DEGs) and gene enrichment were detected to explore potential genetic adenomyosis targets. METHODS: Clinical data on adenomyosis were accessed based on the pathological specimens of patients with adenomyosis obtained from the Shengjing Hospital. R software was used to screen for DEGs, and volcano and cluster maps were drawn. Adenomyosis datasets (GSE74373) were downloaded from the GEO database. GEO2R online tool was used to screen for DEGs between adenomyosis and normal controls. Genes with P < 0.01 and |logFC| >1 were selected as DEGs. DAVID software was used for functional and pathway enrichment analyses. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed on common DEGs to obtain descriptions of the genes. The online database STRING was used for interaction gene retrieval. Moreover, Cytoscape software was used to construct a protein-protein interaction (PPI) network map for common DEGs to visualize potential gene interactions and screen the hub genes. RESULTS: A total of 845 DEGs were identified in the dataset obtained from Shengjing Hospital. A total of 175 genes were downregulated, and 670 genes were upregulated. In the GSE74373 database, 1679 genes were differentially expressed, 916 genes were downregulated, and 763 genes were upregulated. A total of 40 downregulated and 148 upregulated common DEGs showed potential gene interactions. The top ten upregulated hub genes were CDH1, EPCAM, CLDN7, ESRP1, RAB25, SPINT1, PKP3, TJP3, GRHL2, and CDKN2A. CONCLUSION: Genes involved in tight junction may be key in the development of adenomyosis and may provide a potential treatment strategy for adenomyosis.

Tislelizumab plus chemotherapy versus placebo plus chemotherapy as first-line treatment for advanced or metastatic oesophageal squamous cell carcinoma (RATIONALE-306): a global, randomised, placebo-controlled, phase 3 study.

BACKGROUND: The options for first-line treatment of advanced oesophageal squamous cell carcinoma are scarce, and the outcomes remain poor. The anti-PD-1 antibody, tislelizumab, has shown antitumour activity in previously treated patients with advanced oesophageal squamous cell carcinoma. We report interim analysis results from the RATIONALE-306 study, which aimed to assess tislelizumab plus chemotherapy versus placebo plus chemotherapy as first-line treatment for advanced or metastatic oesophageal squamous cell carcinoma. METHODS: This global, randomised, double-blind, parallel-arm, placebo-controlled, phase 3 study was conducted at 162 medical centres across Asia, Europe, Oceania, and North America. Patients (aged ≥18 years) with unresectable, locally advanced, recurrent or metastatic oesophageal squamous cell carcinoma (regardless of PD-L1 expression), Eastern Cooperative Oncology Group performance status of 0-1, and measurable or evaluable disease per Response Evaluation Criteria in Solid Tumours (version 1.1) were recruited. Patients were randomly assigned (1:1), using permuted block randomisation (block size of four) and stratified by investigator-chosen chemotherapy, region, and previous definitive therapy, to tislelizumab 200 mg or placebo intravenously every 3 weeks on day 1, together with an investigator-chosen chemotherapy doublet, comprising a platinum agent (cisplatin 60-80 mg/m2 intravenously on day 1 or oxaliplatin 130 mg/m2 intravenously on day 1) plus a fluoropyrimidine (fluorouracil [750-800 mg/m2 intravenously on days 1-5] or capecitabine [1000 mg/m2 orally twice daily on days 1-14]) or paclitaxel (175 mg/m2 intravenously on day 1). Treatment was continued until disease progression or unacceptable toxicity. Investigators, patients, and sponsor staff or designees were masked to treatment. The primary endpoint was overall survival. The efficacy analysis was done in the intention-to-treat population (ie, all randomly assigned patients) and safety was assessed in all patients who received at least one dose of study treatment. The trial is registered with ClinicalTrials.gov, NCT03783442. FINDINGS: Between Dec 12, 2018, and Nov 24, 2020, 869 patients were screened, of whom 649 were randomly assigned to tislelizumab plus chemotherapy (n=326) or placebo plus chemotherapy (n=323). Median age was 64·0 years (IQR 59·0-69·0), 563 (87%) of 649 participants were male, 86 (13%) were female, 486 (75%) were Asian, and 155 (24%) were White. 324 (99%) of 326 patients in the tislelizumab group and 321 (99%) of 323 in the placebo group received at least one dose of the study drug. As of data cutoff (Feb 28, 2022), median follow-up was 16·3 months (IQR 8·6-21·8) in the tislelizumab group and 9·8 months (IQR 5·8-19·0) in the placebo group, and 196 (60%) of 326 patients in the tislelizumab group versus 226 (70%) of 323 in the placebo group had died. Median overall survival in the tislelizumab group was 17·2 months (95% CI 15·8-20·1) and in the placebo group was 10·6 months (9·3-12·1; stratified hazard ratio 0·66 [95% CI 0·54-0·80]; one-sided p<0·0001). 313 (97%) of 324 patients in the tislelizumab group and 309 (96%) of 321 in the placebo group had treatment-related treatment-emergent adverse events. The most common grade 3 or 4 treatment-related treatment-emergent adverse events were decreased neutrophil count (99 [31%] in the tislelizumab group vs 105 [33%] in the placebo group), decreased white blood cell count (35 [11%] vs 50 [16%]), and anaemia (47 [15%] vs 41 [13%]). Six deaths in the tislelizumab group (gastrointestinal and upper gastrointestinal haemorrhage [n=2], myocarditis [n=1], pulmonary tuberculosis [n=1], electrolyte imbalance [n=1], and respiratory failure [n=1]) and four deaths in the placebo group (pneumonia [n=1], septic shock [n=1], and unspecified death [n=2]) were determined to be treatment-related. INTERPRETATION: Tislelizumab plus chemotherapy as a first-line treatment for advanced or metastatic oesophageal squamous cell carcinoma provided superior overall survival with a manageable safety profile versus placebo plus chemotherapy. Given that the interim analysis met its superiority boundary for the primary endpoint, as confirmed by the independent data monitoring committee, this Article represents the primary study analysis. FUNDING: BeiGene.

Interpenetrating 3D Covalent Organic Framework for Selective Stilbene Photoisomerization and Photocyclization.

The selective photoisomerization or photocyclization of stilbene to achieve value upgrade is of great significance in industry applications, yet it remains a challenge to accomplish both of them through a one-pot photocatalysis strategy under mild conditions. Here, a sevenfold interpenetrating 3D covalent organic framework (TPDT-COF) has been synthesized through covalent coupling between N,N,N,N-tetrakis(4-aminophenyl)-1,4-benzenediamine (light absorption and free radical generation) and 5,5'-(2,1,3-benzothiadiazole-4,7-diyl)bis[2-thiophenecarboxaldehyde] (catalytic center). The thus-obtained sevenfold interpenetrating structure presents a functional pore channel with a tunable photocatalytic ability and specific pore confinement effect that can be applied for selective stilbene photoisomerization and photocyclization. Noteworthily, it enables photogeneration of cis-stilbene or phenanthrene with >99% selectivity by simply changing the gas atmosphere under mild conditions (Ar, SeleCis. > 99%, SelePhen. < 1% and O2, SeleCis. < 1%, and SelePhen. > 99%). Theoretical calculations prove that different gas atmospheres possess varying influences on the energy barriers of reaction intermediates, and the pore confinement effect plays a synergistically catalytic role, thus inducing different product generation. This study might facilitate the exploration of porous crystalline materials in selective photoisomerization and photocyclization.

Preventing Disused Bone Loss through Inhibition of Advanced Glycation End Products.

Bone loss occurs in astronauts during long-term space flight, but the mechanisms are still unclear. We previously showed that advanced glycation end products (AGEs) were involved in microgravity-induced osteoporosis. Here, we investigated the improvement effects of blocking AGEs formation on microgravity-induced bone loss by using the AGEs formation inhibitor, irbesartan. To achieve this objective, we used a tail-suspended (TS) rat model to simulate microgravity and treated the TS rats with 50 mg/kg/day irbesartan, as well as the fluorochrome biomarkers injected into rats to label dynamic bone formation. To assess the accumulation of AGEs, pentosidine (PEN), non-enzymatic cross-links (NE-xLR), and fluorescent AGEs (fAGEs) were identified in the bone; 8-hydroxydeoxyguanosine (8-OHdG) was analyzed for the reactive oxygen species (ROS) level in the bone. Meanwhile, bone mechanical properties, bone microstructure, and dynamic bone histomorphometry were tested for bone quality assessment, and Osterix and TRAP were immunofluorescences stained for the activities of osteoblastic and osteoclastic cells. Results showed AGEs increased significantly and 8-OHdG expression in bone showed an upward trend in TS rat hindlimbs. The bone quality (bone microstructure and mechanical properties) and bone formation process (dynamic bone formation and osteoblastic cells activities) were inhibited after tail-suspension, and showed a correlation with AGEs, suggesting the elevated AGEs contributed to the disused bone loss. After being treated with irbesartan, the increased AGEs and 8-OHdG expression were significantly inhibited, suggesting irbesartan may reduce ROS to inhibit dicarbonyl compounds, thus suppressing AGEs production after tail-suspension. The inhibition of AGEs can partially alter the bone remodeling process and improve bone quality. Both AGEs accumulation and bone alterations almost occurred in trabecular bone but not in cortical bone, suggesting AGEs effects on bone remodeling under microgravity are dependent on the biological milieu.