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Background Dendritic cell (DC) vaccines for cancer therapy offer the possibility to let the patient’s own immune system kill cancer cells. However, DC vaccines have shown less efficacy than expected due to failure to induce cancer cell killing and by activating T regulatory cells. Methods We tested if inhibition of signalling via WASp and Arp2/3 using the small molecule CK666 would enhance DC-mediated killing of tumour cells in vitro and in vivo. Results Using CK666 during the ex vivo phase of antigen processing of ovalbumin (OVA), murine and human DCs showed decreased phagosomal acidification, indicating activation of the cross-presentation pathway. When compared to untreated DCs, DCs treated with CK666 during uptake and processing of OVA-induced increased proliferation of OVA-specific CD8+ OT-I T cells in vitro and in vivo. Using the aggressive B16-mOVA melanoma tumour model, we show that mice injected with CK666-treated DCs and OVA-specific CD8+ OT-I T cells showed higher rejection of B16 melanoma cells when compared to mice receiving non-treated DCs. This resulted in the prolonged survival of tumour-bearing mice receiving CK666-treated DCs. Moreover, combining CK666-treated DCs with the checkpoint inhibitor anti-PD1 further prolonged survival. Conclusion Our data suggest that the small molecule inhibitor CK666 is a good candidate to enhance DC cross-presentation for cancer therapy.

Supplementary Figure from Combination Neoantigen-Based Dendritic Cell Vaccination and Adoptive T-Cell Transfer Induces Antitumor Responses Against Recurrence of Hepatocellular Carcinoma

A high rate of recurrence after curative therapy is a major challenge for the management of hepatocellular carcinoma (HCC). Currently, no effective adjuvant therapy is available to prevent HCC recurrence. We designed a personalized neoantigen-loaded dendritic cell vaccine and neoantigen-activated T-cell therapy, and used it as adjuvant therapy to treat 10 patients with HCC who had undergone curative resection or radiofrequency ablation in the first stage of a phase II trial (NCT03067493). The primary outcomes were safety and neoantigen-specific immune response. Disease-free survival (DFS) was also evaluated. The immunotherapy was successfully administered to all the patients without unexpected delay and demonstrated a reasonable safety profile with no grade ≥3 treatment-related side effects reported. Seventy percent of patients generated de novo circulating multiclonal neoantigen-specific T-cell responses. Induced neoantigen-specific immunity was maintained over time, and epitope spreading was observed. Patients who generated immune responses to treatment exhibited prolonged DFS compared with nonresponders (P = 0.012), with 71.4% experiencing no relapse for 2 years after curative treatment. High expression of an immune stimulatory signature, enhanced immune-cell infiltration (i.e., CD8+ T cells), and upregulated expression of T-cell inflammatory gene profiles were found in the primary tumors of the responders. In addition, neoantigen depletion (immunoediting) was present in the recurrent tumors compared with the primary tumors (7/9 vs. 1/17, P = 0.014), suggesting that immune evasion occurred under the pressure of immunotherapy. Our study indicates that neoantigen-based combination immunotherapy is feasible, safe, and has the potential to reduce HCC recurrence after curative treatment.

Table S5 shows detailed information of structure variations in the six HCC patients with WGS analysis.

Fig.S1 shows flow chart of enrollment for multifocal HCC patients with anti-PD-1 therapy. Fig.S2 shows CT images of the six HCC patients with two tumors in the liver. Fig.S3 shows purity of tumor content of the six HCC patients with two tumors in the liver. Fig.S4 shows HBV integration sites in the six HCC patients with two tumors in the liver. Fig.S5 shows expression level of TERT in the six HCC patients with two tumors in the liver. Fig.S6 shows landscape of inter-chromosomal translocations and copy number alterations in small and large tumors of four cases. Fig.S7 shows number and types of chromosomal rearrangement in the six HCC patients with two tumors in the liver. Fig.S8 shows copy number aberrations in the six HCC patients with two tumors in the liver. Fig.S9 shows mutational landscape of the six HCC patients with two tumors in the liver. Fig.S10 shows non-silent mutations in the six HCC patients with two tumors in the liver. Fig.S11 shows profile of mutational cancer cell fractions of small and large tumors in the six HCC patients. Fig.S12 shows unsupervised clustering of RNA expression in tumors and adjacent normal liver tissues of 12 multifocal HCC patients. Fig.S13 shows expression level of immune functional genes in small and large tumors of 12 multifocal HCC patients. Fig.S14 shows expression level of immune stimulators in small and large tumors of 12 multifocal HCC patients. Fig.S15 shows expression level of immune inhibitors in small and large tumors of 12 multifocal HCC patients. Fig.S16 shows mutations of immune-related genes in the six HCC patients with two tumor nodules in the liver. Fig.S17 shows images of the small and large tumors before and after anti-PD-1 therapy.

Purpose:Targeted therapy and immunotherapy are transforming the treatment approach for intrahepatic cholangiocarcinoma (ICC). However, little is known about the intertumor heterogeneity (ITH) of multifocal ICC and its impacts on patient response to these treatments. We aimed to characterize the immunogenomic and epigenomic heterogeneity of multifocal ICC to guide treatment decision making.Experimental Design:We obtained 66 tumor samples from 16 patients with multifocal ICC and characterized the tumor and immune heterogeneity using whole-exome sequencing, bulk and single-cell RNA sequencing, methylation microarray, and multiplex immunostaining. Patients were divided into high- or low-ITH groups according to the median ITH index. Two independent cohorts were used to validate findings. Responses to anti-PD-1 therapy were assessed.Results:Multifocal ICC presented considerable intertumor genomic, transcriptional, and epigenomic heterogeneity within a patient in high ITH group. The immune profile among multiple tumors within a patient was relatively less heterogeneous in high- or low-ITH group, and consistent responses of multiple tumors to anti-PD-1 immunotherapy were observed. Unsupervised clustering of immune markers identified one low and one high immune subtype, with higher immune cell infiltration, closer tumor–immune cell interactions, and upregulated IFN-signature expression in high-immune subtype. Determining expression levels of CD8B and ICOS facilitated this immune classification and prediction of patient prognosis. Finally, promoter DNA methylation contributed to different immune profiles of two subtypes by regulating immune-gene expression.Conclusions:There is comprehensive heterogeneity in the genome, transcriptome, and epigenome of multifocal ICC. On the basis of the less heterogeneous immune profile of ICC, we suggest an immune classification that stratifies patients' prognosis and may support personalized immunotherapy.

Supplementary Data from Multiomic Analysis Reveals Comprehensive Tumor Heterogeneity and Distinct Immune Subtypes in Multifocal Intrahepatic Cholangiocarcinoma

Table S1 shows clinicopathologic information of 12 multifocal HCC patients. Table S2 shows PCR primers used for validation of HBV integration sites. Table S4 shows HBV integration analysis in HCC patients with WGS data. Table S8 shows P-value of pathways enrichment analysis in the small and large tumors of 12 multifocal HCC patients. Table S10 shows correlation between the number of rearrangements and immune activity. Table S11 shows detailed clinical data of eight patients with anti-PD-1 therapy.

Purpose:Immune checkpoint inhibitor therapy is emerging as the promising option for patients with advanced hepatocellular carcinoma. We aimed to investigate the heterogeneity of different tumor nodules of the same patient with multifocal hepatocellular carcinomas in response to immunotherapy and its molecular mechanisms.Experimental Design:We attained 45 surgical tumor samples including 33 small and 12 large nodules from 12 patients with multifocal hepatocellular carcinoma and evaluated genomic and immune heterogeneity among tumors through whole-genome sequencing and RNA sequencing. IHC was performed to validate the expression of immune markers. The responses to anti–programmed cell death protein-1 (PD-1) therapy in patients with multifocal hepatocellular carcinoma were evaluated.Results:The small and large tumors within the same patient presented with similar genomic characteristics, indicating their same genomic origin. We further found the small tumors had higher immune cell infiltration including more CD8+ T cells, M1 macrophages, and monocytes as compared with large tumors. Besides, the expression of interferon signature predictive of response to anti–PD-1 therapy was significantly upregulated in the small tumors. Moreover, the immune pathways were more vigorous along with less active proliferation pathways in the small tumors. In keeping with this, we found that small nodules were more sensitive to anti–PD-1 therapy than large nodules in patients with multifocal hepatocellular carcinoma.Conclusions:The small tumors in patients with multifocal hepatocellular carcinoma had higher immune cell infiltration and upregulation of immune pathways as compared with the large tumors, which can partially explain the different responses of small and large tumors in the same case to anti–PD-1 therapy.

The use of functional biodegradable wastes to treat environmental problems would create minimal extra burden to our environment. In this paper, we propose a sustainable and practical strategy to turn spent coffee ground (SCG) into a multifunctional palladium-loaded catalyst for water treatment instead of going into landfill as solid waste. Bleached delignified coffee ground (D-SCG) has a porous structure and a good capability to reduce Pd (II) to Pd (0). A large amount of nanocellulose is formed on the surface of SCG after bleaching by H2O2, which anchors and disperses the palladium nanoparticles (Pd NPs). The D-SCG loaded with Pd NPs (Pd-D-SCG) is superhydrophilic, which facilitates water transport and thus promotes efficient removal of organic pollutants dissolved in water. Pd-D-SCG exhibits excellent room temperature catalytic activity for the removal of 4-nitrophenol (4-NP) and methylene blue (MB) in water and shows good chemical stability and recyclability in water, with no obvious decrease even after five repeated cycles.

Scavenger receptors are pattern recognition receptors that recognize both foreign and self-ligands, and initiate different mechanisms of cellular activation, often as co-receptors. The function of scavenger receptor CD36 in the immune system has mostly been studied in macrophages but it is also highly expressed by innate type B cells where its function is less explored. Here we report that CD36 is involved in macro-autophagy/autophagy in B cells, and in its absence, the humoral immune response is impaired. We found that CD36-deficient B cells exhibit a significantly reduced plasma cell formation, proliferation, mitochondrial mobilization and oxidative phosphorylation. These changes were accompanied by impaired initiation of autophagy, and we found that CD36 regulated autophagy and colocalized with autophagosome membrane protein MAP1LC3/LC3 (microtubule-associated protein 1 light chain 3). When we investigated T-cell-dependent immune responses, we found that mice with CD36 deficiency, specifically in B cells, exhibited attenuated germinal center responses, class switching, and antibody production as well as autophagosome formation. These findings establish a critical role for CD36 in B cell responses and may also contribute to our understanding of CD36-mediated autophagy in other cells as well as in B cell lymphomas that have been shown to express the receptor. Abbreviations: AICDA/AID: activation-induced cytidine deaminase; ATG5: autophagy related 5; ATP: adenosine triphosphate; BCR: B-cell receptor; CPG: unmethylated cytosine-guanosine; CQ: chloroquine; DC: dendritic cells; FOB: follicular B cells; GC: germinal center; Ig: immunoglobulin; LPS: lipopolysaccharide; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; MFI: mean fluorescence intensity; MZB: marginal zone B cells; NP-CGG: 4-hydroxy-3-nitrophenylacetyl-chicken gamma globulin; OCR: oxygen consumption rate; oxLDL: oxidized low-density lipoprotein; PC: plasma cells; Rapa: rapamycin; SQSTM1/p62: sequestosome 1; SRBC: sheep red blood cells; Tfh: follicular helper T cells; TLR: toll-like receptor.

BACKGROUND: B-cell affinity maturation in germinal center relies on regulated actin dynamics for cell migration and cell-to-cell communication. Activating mutations in the cytoskeletal regulator Wiskott-Aldrich syndrome protein (WASp) cause X-linked neutropenia (XLN) with reduced serum level of IgA. OBJECTIVE: We investigated the role of B cells in XLN pathogenesis. METHODS: We examined B cells from 6 XLN patients, 2 of whom had novel R268W and S271F mutations in WASp. By using immunized XLN mouse models that carry the corresponding patient mutations, WASp L272P or WASp I296T, we examined the B-cell response. RESULTS: XLN patients had normal naive B cells and plasmablasts, but reduced IgA+ B cells and memory B cells, and poor B-cell proliferation. On immunization, XLN mice had a 2-fold reduction in germinal center B cells in spleen, but with increased generation of plasmablasts and plasma cells. In vitro, XLN B cells showed reduced immunoglobulin class switching and aberrant cell division as well as increased production of immunoglobulin-switched plasma cells. CONCLUSIONS: Overactive WASp predisposes B cells for premature differentiation into plasma cells at the expense of cell proliferation and immunoglobulin class switching. ispartof: JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY vol:149 issue:3 pages:1069-1084 ispartof: location:United States status: published

With the gradual construction of the land and space planning system and the acceleration of the urban-rural integrated development process, China’s rural land planning and preparation have ushered in substantial innovations, and at the same time, they are also facing huge challenges. Among them, the low utilization rate of rural land and cultural desertification are the crux of the lagging rural development. This paper takes Guifengshan Village in Macheng City, Hubei Province as an example. Through the analysis of the current advantages of the village, the analysis of challenges, and the evaluation of the suitability of land use, this paper proposes to promote the mutual benefit of agriculture, culture and tourism, and promote the revitalization of Guifengshan Village, forming a “agricultural industry + characteristic cultural creation + red ecology”. “Tourism” jointly develops rural planning strategies. It aims to link rural agriculture, tourism and cultural industries closely on the basis of people-oriented and ecological protection, with income generation as the goal of rural revitalization, to achieve the establishment and extension of the industrial chain, and to promote rural revitalization.

Both lncRNAs and the N6-methyladenosine (m6A) modification are key regulators of tumorigenesis and innate immunity. However, little is known about the m6A modification of lncRNAs and their clinical and immune relevance in bladder cancer. In this study, we identified m6A-related lncRNAs using Pearson correlation analysis in The Cancer Genome Atlas (TCGA) and the IMvigor210 datasets. Next, univariate Cox regression was performed using the TCGA dataset to filter prognostic m6A-related lncRNAs, which were further subjected to the least absolute shrinkage and selection operator (LASSO) Cox regression to establish a 12 m6A-related lncRNA prognostic score (m6A-LRS). The m6A-LRS was validated in the IMvigor210 dataset. In addition, high m6A-LRS tumors, characterized by decreased tumor mutation load and neoantigen load, showed poorer response to immunotherapy than those with low m6A-LRS in the IMvigor210 dataset. Further, we constructed an m6A-LRS-based nomogram that demonstrated a strong ability to predict overall survival in patients with bladder cancer. Moreover, enrichment analysis revealed that tumor-associated biological processes, oncogenic signaling, and tumor hallmarks were commonly associated with a high m6A-LRS. Gene set variation analysis also indicated that high m6A-LRS was associated with activation of canonical oncogenic signatures, such as the epithelial-to-mesenchymal transition, cell cycle regulators, and DNA replication, as well as activation of immunosuppressive signatures, such as the T-cell exhaustion and pan-fibroblast-TGF-β response signatures. Furthermore, we observed distinct tumor microenvironment cell infiltration characteristics between high- and low-risk tumors. High m6A-LRS tumors showed reduced infiltration of CD8+ T-cells and enhanced infiltration of macrophages and fibroblasts. Additionally, we established a competing endogenous RNA network based on the12 m6A-related lncRNAs. Finally, three lncRNAs (SNHG16, SBF2-AS1, and BDNF-AS) were selected for further validation. The qualitative PCR assay on 10 pairs of bladder cancer and adjacent normal control samples validated the differential expression, and methylated RNA immunoprecipitation (MeRIP) analysis demonstrated a robust m6A enrichment in T24 bladder cancer cells compared with normal uroepithelial cells (SVHUC-1). In conclusion, this study introduced an m6A-related lncRNA signature that identified a subgroup of patients with poor prognoses and suboptimal immune responses, thus providing novel approaches for treatment response prediction and patient stratification in bladder cancer.

The cumulative exposure to metals affects cardiac conduction, and the effect of polymetallic exposure on heart rate in children is unknown. To evaluate the relationship between cumulative exposure to metal mixtures and heart rate among Chinese preschoolers, the determination of urinary 24 metals was processed by high-resolution inductively coupled plasma-mass spectrometry. Heart rate was recorded when measuring blood pressure after resting 5 min or longer. As a method to compute the Environmental risk score (ERS) according to heart rate under heavy metal mixtures, adaptive elastic net (AENET) with 299 predictors which were formed by the combination of main effects, squared terms, and pairwise interactions of heavy metals with a total number of 23, 23, 253 respectively. To further assess the associations between ERS and heart rate, regression analyses were performed with complex survey designs. The construction of ERS under heart rate-related metal mixtures was returned by AENET in according to 11 main effects (tin, arsenic, zinc, iron, titanium, vanadium, nickel, manganese, cobalt, copper and chromium) and 2 squared terms (tungsten and rubidium). A high correlation was monitored between the alteration of ERS in the study population and heart rate (β = 1.030, 95% CI: 0.730 - 1.330 in 1239; β = 1.085, 95% CI: 0.777 - 1.393 in 1061). Significant associations of ERS with higher heart rates were also pointed out (Ps 0.05). Our study elucidates the association of the cumulative exposure of heavy metals as mixtures and heart rate among Chinese preschoolers. Further research is obliged to corroborate these findings in longitudinal studies.

Garnet electrolyte is a promising candidate for the development of all-solid-state Li-metal batteries, because of its safety and stability against Li metal. However, its practical application is limited by the difficulty in production of its high-density thin sheet. In this work, we have fabricated garnet thin sheet electrolytes (Li6.4La3Zr1.4Ta0.6O12, LLZTO) by tape-casting technique. By using Li2O as a liquid-phase sintering additive, a high relative density up to 99% was achieved. Electrochemical results show the LLZTO sheets have an ionic conductivity of 5.2 × 10−4 S cm−1 at 30 °C and good cycling stability against Li metal. Based on the sheets, all-solid-state Li/LLZTO/LiFePO4 batteries exhibit excellent reversible cycles at 60 °C and 0.1C with an initial discharge specific capacity of 125.8 mA h g−1 and a retention of 92.3% after 50 cycles. These results indicate that the tape-casting process demonstrated here provides an effective method of producing high-density garnet thin sheet electrolytes for high-performance all-solid-state Li-metal batteries.

Garnets are promising solid electrolytes for developing solid state Li batteries, owing to their features of relatively high conductivity and stability against lithium metal. However, they show shortcoming of Li penetration through garnets during Li plating and stripping, which limits their practice application. Herein, we present a strategy to solve such problem by coating SnO2 films on the surfaces of the Li6·4La3Zr1·4Ta0·6O12 pellets. Through conversion reaction of SnO2 with Li at 200 °C, the nanocomposite layers consisting of crosslinked LixSn and Li2O are formed between the Li and the Li6·4La3Zr1·4Ta0·6O12 electrolytes. This leads to transition from lithiophobicity to lithiophilicity, thus greatly reducing interfacial resistance from 1100 Ω cm2 to 25 Ω cm2. Furthermore, taking advantage of suppressing volume change of LixSn alloy which is about 260%, the intermediate layers maintain integrity under the current densities of 0.2 mA cm−2 for 650 h cycles. In addition, the critical current density of Li/SnO2-Li6.4La3Zr1·4Ta0·6O12-SnO2/Li can be as high as 1.15 mA cm−2. As a proof-of-concept, this effective interface modification based on conversion reaction method contributes to a useful way of solving the Li/garnet interface problem and promoting the solid state Li batteries development.

Purpose: Targeted therapy and immunotherapy are transforming the treatment approach for intrahepatic cholangiocarcinoma (ICC). However, little is known about the intertumor heterogeneity (ITH) of multifocal ICC and its impacts on patient response to these treatments. We aimed to characterize the immunogenomic and epigenomic heterogeneity of multifocal ICC to guide treatment decision making. Experimental Design: We obtained 66 tumor samples from 16 patients with multifocal ICC and characterized the tumor and immune heterogeneity using whole-exome sequencing, bulk and single-cell RNA sequencing, methylation microarray, and multiplex immunostaining. Patients were divided into high- or low-ITH groups according to the median ITH index. Two independent cohorts were used to validate findings. Responses to anti-PD-1 therapy were assessed. Results: Multifocal ICC presented considerable intertumor genomic, transcriptional, and epigenomic heterogeneity within a patient in high ITH group. The immune profile among multiple tumors within a patient was relatively less heterogeneous in high- or low-ITH group, and consistent responses of multiple tumors to anti-PD-1 immunotherapy were observed. Unsupervised clustering of immune markers identified one low and one high immune subtype, with higher immune cell infiltration, closer tumor–immune cell interactions, and upregulated IFN-signature expression in high-immune subtype. Determining expression levels of CD8B and ICOS facilitated this immune classification and prediction of patient prognosis. Finally, promoter DNA methylation contributed to different immune profiles of two subtypes by regulating immune-gene expression. Conclusions: There is comprehensive heterogeneity in the genome, transcriptome, and epigenome of multifocal ICC. On the basis of the less heterogeneous immune profile of ICC, we suggest an immune classification that stratifies patients' prognosis and may support personalized immunotherapy.

X-linked neutropenia (XLN) is caused by gain-of-function mutations in the actin regulator Wiskott-Aldrich Syndrome protein (WASp). XLN patients have reduced numbers of cytotoxic cells in peripheral blood; however, their capacity to kill tumor cells remains to be determined. Here, we examined NK and T cells from 2 patients with XLN harboring the activating WASpL270P mutation. XLN patient NK and T cells had increased granzyme B content and elevated degranulation and IFN-γ production when compared with healthy control cells. Murine WASpL272P NK and T cells formed stable synapses with YAC-1 tumor cells and anti-CD3/CD28-coated beads, respectively. WASpL272P mouse T cells had normal degranulation and cytokine response whereas WASpL272P NK cells showed an enhanced response. Imaging experiments revealed that while WASpL272P CD8+ T cells had increased accumulation of actin upon TCR activation, WASpL272P NK cells had normal actin accumulation at lytic synapses triggered through NKp46 signaling but had impaired response to lymphocyte function associated antigen-1 engagement. When compared with WT mice, WASpL272P mice showed reduced growth of B16 melanoma and increased capacity to reject MHC class I-deficient cells. Together, our data suggest that cytotoxic cells with constitutively active WASp have an increased capacity to respond to and kill tumor cells. ispartof: JCI INSIGHT vol:6 issue:6 ispartof: location:United States status: published

β-Catenin recruits BRD4 and other coregulators to protect pluripotency gene transcription against network perturbation., Mouse embryonic stem cells cultured with MEK (mitogen-activated protein kinase kinase) and GSK3 (glycogen synthase kinase 3) inhibitors (2i) more closely resemble the inner cell mass of preimplantation blastocysts than those cultured with SL [serum/leukemia inhibitory factor (LIF)]. The transcriptional mechanisms governing this pluripotent ground state are unresolved. Release of promoter-proximal paused RNA polymerase II (Pol2) is a multistep process necessary for pluripotency and cell cycle gene transcription in SL. We show that β-catenin, stabilized by GSK3 inhibition in medium with 2i, supplies transcriptional coregulators at pluripotency loci. This selectively strengthens pluripotency loci and renders them addicted to transcription initiation for productive gene body elongation in detriment to Pol2 pause release. By contrast, cell cycle genes are not bound by β-catenin, and proliferation/self-renewal remains tightly controlled by Pol2 pause release under 2i conditions. Our findings explain how pluripotency is reinforced in the ground state and also provide a general model for transcriptional resilience/adaptation upon network perturbation in other contexts.

Purpose: Immune checkpoint inhibitor therapy is emerging as the promising option for patients with advanced hepatocellular carcinoma. We aimed to investigate the heterogeneity of different tumor nodules of the same patient with multifocal hepatocellular carcinomas in response to immunotherapy and its molecular mechanisms. Experimental Design: We attained 45 surgical tumor samples including 33 small and 12 large nodules from 12 patients with multifocal hepatocellular carcinoma and evaluated genomic and immune heterogeneity among tumors through whole-genome sequencing and RNA sequencing. IHC was performed to validate the expression of immune markers. The responses to anti–programmed cell death protein-1 (PD-1) therapy in patients with multifocal hepatocellular carcinoma were evaluated. Results: The small and large tumors within the same patient presented with similar genomic characteristics, indicating their same genomic origin. We further found the small tumors had higher immune cell infiltration including more CD8+ T cells, M1 macrophages, and monocytes as compared with large tumors. Besides, the expression of interferon signature predictive of response to anti–PD-1 therapy was significantly upregulated in the small tumors. Moreover, the immune pathways were more vigorous along with less active proliferation pathways in the small tumors. In keeping with this, we found that small nodules were more sensitive to anti–PD-1 therapy than large nodules in patients with multifocal hepatocellular carcinoma. Conclusions: The small tumors in patients with multifocal hepatocellular carcinoma had higher immune cell infiltration and upregulation of immune pathways as compared with the large tumors, which can partially explain the different responses of small and large tumors in the same case to anti–PD-1 therapy.

The electrochemical conversion of the greenhouse gas, carbon dioxide (CO2), to energy fuels and value-added chemicals presents one of the most valuable approaches to harvest pollutants and produce renewable energy. However, the stable molecular structure of CO2 and the sluggish reaction kinetics make CO2 reduction reaction (CO2RR) formidably challenging to achieve reaction rate and selectivity practical in industry. Graphene and its derivatives have been considered a group of intriguing materials to develop advanced CO2RR electrocatalysts due to their large specific surface area, remarkable electron transfer ability, superior stability, and easy tunability of the structure and surface properties. Herein, we comprehensively discuss the state-of-the-art electrocatalysts constructed with graphene and derivatives for active and selective CO2RR within the recent five years, mainly including the electrocatalysts with both metal-based (e.g., noble, non-noble, or combined thereof) and non-metal (e.g., doped, modified, defected, or composited) catalytic sites. To present the versatile, high-performance metal-based CO2RR electrocatalysts constructed with graphene, we further subdivide them according to the sizes, oxidation states, metal species synergies, dimensionalities, and versatility. Finally, we provide the challenges and perspectives in this emerging area of utilising CO2 to produce various carbon-based fuels and chemicals via graphene chemistry.

Ultra-tough transparent conductive elastomers (TCEs) with self-healing performance are of great significance for research in the fields of soft robotics, optical display electronics, wearable electronic equipment and human–computer interaction. However, their limitation, such as the desolventizing process, low polymerization rate or balance between toughness and self-healing performance, cause difficulty in manufacturing by the 3D printing technique. Here, we propose a novel preparation strategy for 3D printed TCEs based on the photopolymerization of maleic acid (MA)/choline chloride (ChCl) and acrylamide (AAm)/choline chloride type polymerizable deep eutectic solvents (PDESs). PDES can polymerize into a tough and rich in hydrogen bonds poly(PDES) in a few seconds without solvent evaporation. The printed TCEs with precision of 10 µm have high transparency (95.6%) and stable electrical signals at 50% compression for 10,000 cycles. In addition, efficient self-healing performance due to the dynamic hydrogen bonds of poly(PDES) provides broad application prospects for 3D printed TCEs in long-term pressure-resistant intelligent applications.

The bookstore is an integral part of campus public service, and it is an essential place for reading, learning and spending for teachers and students. Provided the current management and development problems faced by old campus bookstores, this article takes the old campus bookstore in the Huangjiahu campus of Wuhan University of Science and Technology as a research case while uses space syntax theory, Depthmap software, and axis models to analyzes and evaluate accessibility, and then optimize campus old location and layout of bookstores. Simultaneously, by using the analytic hierarchy process, the simulated bookstore sites of selection in the campus are tested at the target level, decision level and plan level. This article aims to propose optimization methods for the management and development of old campus bookstores from the perspective of spatial location selection through qualitative quantification and provide constructive references for similar research.

Photocaged amines (PCAs) can allow a spatiotemporal control of the highly versatile and widely implemented nucleophile-catalyzed thiol-Michael addition reaction. However, a major challenge with most PCAs is that their relatively low quantum yields easily lead to low photosensitivity, especially under the radiation of light-emitting diodes (LEDs). In this paper, the phototriggered base proliferation (PBP) reaction as a powerful 365 nm LED photoclick tool is presented for the nucleophile-initiated thiol-Michael addition reaction. Compared to the PCA system, the advantages of this approach lie in its enhanced photosensitivity, increased reaction rate and elevated conversion. Finally, due to the persistent interactions of the produced longeval amine, remarkable post conversion was thus initially achieved after irradiation.