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A kind of CdS/Cd-BiOCl immobilized films photocatalyst was prepared. The optical and physicochemical properties of the CdS/Cd-BiOCl photocatalysts were analysed, and the detailed characterization revealed CdS/Cd-BiOCl films photocatalyst with good charge carrier separation effect. The reusabilities and photocatalytic properties of the samples were studied. The 15%CdS/Cd-BiOCl photocatalyst exhibited superior performance in photocatalytic degradation of tetracycline (TC) and favorable stability under visible light irradiation. As for the photodegradation rate of TC, 15%CdS/Cd-BiOCl exhibited an excellent photodegradation activity, which is 4.06 and 9.53 times higher than that of CdS/Cd and BiOCl, respectively. The results showed that dominant active species are •O2− and •OH radicals during photodegradation. The charge transfer in Z-scheme CdS/Cd-BiOCl films photocatalyst could synchronously generate conduct band (CB) electrons in BiOCl and valence band (VB) holes in CdS, and metal Cd served as electron mediator. This work can be a reference for the design of film photocatalysts and new insight for photodegradating towards contaminants.

Supplementary Table S10. p value of NOTCH2 target genes and members of its transcriptional complex that are inversely correlated to BCL6 in primary GC B-cells.

Supplementary Figure S1. BCL6 displays a specific genomic localization pattern in FL. Supplementary Figure S2. Inverse correlation between BCL6 and NOTCH2 complex genes in primary GC B-cells. Supplementary Figure S3. GC reaction is impaired in Notch2 knock-in mice. Supplementary Figure S4. GC reaction is impaired in Notch2 knock-in mice. Supplementary Figure S5. BCL6 represses NOTCH2 complex genes and Notch activity. Supplementary Figure S6. FL cells are dependent on BCL6 in a NOTCH2-dependent manner. Supplementary Figure S7. Evaluation of the in vivo potency and specificity of anti-Notch2 blockade. Supplementary Figure S8. RI-BPI suppresses FL tumors in vivo and ex vivo. Supplementary Table S5. Primers used for RT-PCR.

Supplementary Figure S1. Crebbp deficiency results in accelerated germinal center derived B-cell lymphoma development in mice. Supplementary Figure S2. Ep300 deficiency results in accelerated germinal center derived B-cell lymphoma development in mice. Supplementary Figure S3. Western blots showing the knockdown efficiency of shRNAs against human CREBBP in human DLBCL MD901 cells and H3K27ac reduction in MD901 cells transduced with shRNAs against human CREBBP, and stacked bar plot showing the genome-wide distribution of CREBBP ChIPseq peaks in OCI-Ly7 cells. Supplementary Figure S4. GSEA enrichment plots showing correlation of genes with >25% loss of H3K27ac at enhancers in VavP-Bcl2/shCrebbp tumours with ranked expression change between B220+ lymphoma cells from VavP-Bcl2/shCrebbp tumours (n=3) and VavP-Bcl2/GFP tumours (n=3). NES, normalized enrichment score. Supplementary Figure S5. Venn diagram showing the overlap of H3K4me2+H3K4me3-H3K27ac+ (active enhancer) peaks between human tonsilar IgD+ Naïve B cells (NBs) and CD77+ germinal center B cells (GCBs). Supplementary Figure S6. Pathway analysis of down-regulated genes in top 500 differentially expressed genes between murine VavP-Bcl2/shCrebbp tumours and VavP-Bcl2/GFP tumours (left panel), or between CREBBP knockdown and scramble control human DLBLC MD901 cells (right panel). Supplementary Figure S7. Pathway analysis of genes with > 25% reduction of H3K27ac reads at promoters in murine VavP-Bcl2/shCrebbp tumors. Supplementary Figure S8. UCSC read-density tracks of normalized BCL6 (purple) and SMRT (orange) ChIP-seq reads in human tonsilar GCBs, H3K27ac ChIP-seq reads in human tonsilar NBCs (red) and GCBs (blue), and H3K27ac ChIP-seq in control scramble (Scr, green) and CREBBP KD (shCREBBP, turquoise) MD901 cells at the human CIITA and CD74 loci. BCL6 and SMRT peaks determined by MACS2 are indicated by grey bars under the read density track. Supplementary Figure S9. Stacked bar plots showing the frequencies of CREBBP somatic mutations in two cohorts of FL and one cohort of DLBCL primary patient samples. Supplementary Figure S10. The proportions of the Up (up-regulated) and Down (down-regulated) genes in the top 100, 500, and 1000 most differentially expressed genes of the respective cohorts profiled in Figure 3. Supplementary Figure S11. Representative flow cytometry analysis for FAS and GL7 of whole spleens from NS-DAD wild type (wt) or mutant (mut) animals. Supplementary Figure S12. Western blots showing the knockdown efficiency of shRNAs against human HDAC3 in DLBCL cell lines OCI-Ly7 and MD901 120 hr after induction of shRNA expression. The amount of HDAC3 was quantified by using ImageJ, and the ratio of shRNA knockdown samples and the control shLuc sample was indicated below the blots. Supplementary Figure S13. BCL6 and HDAC3 ChIP-qPCR at enhancers of CD74 or HLA-DOA (primer sequences please check Supplementary Table S12) in OCI-Ly1 cells transfected with either non-target siRNA (siNT) or BCL6 siRNA (siBCL6). Supplementary Figure S14. Quantification of HLA-DR measured by flow cytometry in shCREBBP or scramble transduced lymphoma cells MD901 and OCI-Ly18 in a second biological replicate experiment.

A list of CREBBP mutations in cohorts 1 and 2.

Chromosomal instability; Lethal prostate cancer; Therapy resistance Inestabilidad cromosómica; Cáncer de próstata letal; Resistencia a la terapia Inestabilitat cromosòmica; Càncer de pròstata letal; Resistència a la teràpia Metastatic prostate cancer (PCa) inevitably acquires resistance to standard therapy preceding lethality. Here, we unveil a chromosomal instability (CIN) tolerance mechanism as a therapeutic vulnerability of therapy-refractory lethal PCa. Through genomic and transcriptomic analysis of patient datasets, we find that castration and chemotherapy-resistant tumors display the highest CIN and mitotic kinase levels. Functional genomics screening coupled with quantitative phosphoproteomics identify MASTL kinase as a survival vulnerability specific of chemotherapy-resistant PCa cells. Mechanistically, MASTL upregulation is driven by transcriptional rewiring mechanisms involving the non-canonical transcription factors androgen receptor splice variant 7 and E2F7 in a circuitry that restrains deleterious CIN and prevents cell death selectively in metastatic therapy-resistant PCa cells. Notably, MASTL pharmacological inhibition re-sensitizes tumors to standard therapy and improves survival of pre-clinical models. These results uncover a targetable mechanism promoting high CIN adaptation and survival of lethal PCa. Research was supported by NIH/NCI grants P30CA08748 (to R.C.H.); R01CA207311 and R01CA261925 (to J.D.-D.); K22CA207458 and R01CA237398 (to V.R.-B.); and funding to V.R.-B. from the Mayo Clinic Foundation, The Margaret Q. Landenberger Research Foundation, The W.W. Smith Charitable Trust, The AACR, and The Prostate Cancer Foundation (PCF).

ObjectivesTo examine whether a high positive end-expiratory pressure (PEEP ≥5 cmH2O) has a protective effect on the risk of postoperative pulmonary complications (PPCs) in a cohort of patients living at high altitudes and undergoing general anaesthesia.DesignRetrospective, observational study.SettingA tertiary hospital in China.ParticipantsAdult Tibetan patients living at high altitudes (≥3000 m) and who went to the low-altitude plain to undergo non-cardiothoracic surgery under general anaesthesia, from January 2018 to April 2020.MeasurementsThis study included 1905 patients who were divided according to the application of an intraoperative PEEP: low PEEP (2O, including 0 cmH2O) or high PEEP (≥5 cmH2O). The primary outcome was a composite of PPCs within the first 7 postoperative days. The secondary outcomes included reintubation and unplanned intensive care unit (ICU) admission within the first 7 postoperative days and total hospital stays (day).ResultsThe study included 1032 patients in the low PEEP group and 873 in the high PEEP group. There were no differences in the incidence of PPCs between the high and low PEEP groups (relative risk (RR) 0.913; 95% CI 0.716 to 1.165; p=0.465). After propensity score matching, 643 patients remained in each group, and the incidence of PPCs in the low PEEP group (18.0%) was higher than in the high PEEP group (13.7%; RR 0.720; 95% CI 0.533 to 0.974; p=0.033). There were no differences in the incidence of reintubation, unplanned ICU admission or hospital stays. The risk factors of PPCs derived from multiple regression showed that the application of >5 cmH2O PEEP during intraoperative mechanical ventilation was associated with a significantly lower risk of PPCs in patients from a high altitude (OR=0.725, 95% CI 0.530 to 0.992; p=0.044).ConclusionsThe application of PEEP ≥5 cmH2O during intraoperative mechanical ventilation in patients living at high altitudes and undergoing surgery at low altitudes may be associated with a lower risk of PPCs. Prospective longitudinal studies are needed to further investigate perioperative lung protection ventilation strategies for patients from high altitudes.Trial registration numberChinese Clinical Trial Registry (ChiCTR2100044260).

BackgroundChimeric antigen receptors (CARs) engage antigen independently of HLA and enable sustained T cell proliferation when they are endowed with both activating and costimulatory functions. While remission rates have been noticeably elevated in numerous clinical trials targeting CD19, CD22 or BCMA, relapses are common. One of the several underlying relapse mechanisms is antigen escape, which refers to a relapsing tumor that is either negative for the targeted antigen or expresses the latter at a low level. Failure to eliminate antigen-low tumors raises questions about the sensitivity of CARs and the minimum antigen density that is required for effective tumor eradication. Unlike CARs, TCRs engage antigen in an HLA-dependent manner, and they do so with high sensitivity. We hypothesized that a TCR/CD3 complex containing the same heavy and light immunoglobulin chains as a CAR will display increased sensitivity to the target antigen.MethodsWe edited the TRAC locus in human primary T cells to establish a novel antigen receptor structure, termed HLA-independent TCR or HIT receptor, by incorporating into the TCR/CD3 complex the same heavy and light chains as those of a corresponding CAR. We assessed their antigen sensitivity against a panel of cell lines expressing different antigen levels, analyzing their cytotoxicity, cytokine secretion, signaling response and degranulation activity. HIT and CAR T cells were further evaluated for their anti-tumor response using established ALL and AML mouse models.ResultsCD19-TRAC-HIT and CD19-TRAC-CAR T cells lysed wild-type NALM6 (~27,000 CD19 molecules) and NALM6 variants with 100-fold less CD19. As CD19 levels decreased further, CAR T cells no longer killed their target, in contrast to HIT T cells. HIT T cells showed increased expression of IFN-gamma, IL-2 and TNF-alpha upon exposure to NALM6 cells expressing ~20 CD19 molecules per cell, compared to CAR T cells. This increased sensitivity of HIT receptors correlated to their greater signaling response, upon exposure to the low-antigen-density NALM6. Phospho-proteomic analyses further confirmed this increased response of HIT T cells to low antigen levels. Altogether, these results confirm that HIT receptors endow T cells with greater antigen sensitivity than canonical CARs. We further showed that HIT T cells have higher in vivo anti-tumor activity compared to CAR T cells in mice bearing low-antigen-density ALL or AML.ConclusionsHIT receptors consistently afford high antigen sensitivity and mediate tumor recognition beyond what current CARs can provide. HIT receptors open new prospects for targeting cell surface antigens of low abundance.Ethics ApprovalEight- to 12-week-old NOD/SCID/IL-2Rgamma-null (NSG) male mice (Jackson Laboratory) were used under a protocol approved by the MSKCC Institutional Animal Care and Use Committee.

SUMMARYThe DNA sensor cyclic GMP-AMP synthase (cGAS) is critical in host antiviral immunity. Vaccinia virus (VACV) is a large cytoplasmic DNA virus that belongs to the poxvirus family. How vaccinia virus antagonizes the cGAS-mediated cytosolic DNA-sensing pathway is largely unknown. In this study, we screened 82 vaccinia viral genes to identify potential viral inhibitors of the cGAS/Stimulator of interferon gene (STING) pathway. We discovered that vaccinia E5 is a virulence factor and a major inhibitor of cGAS that elicits proteasome-dependent cGAS degradation. E5 localizes to the cytoplasm and nuclei of infected cells. Cytosolic E5 triggers K48-linked ubiquitination of cGAS and proteasome-dependent degradation via interacting with cGAS. E5 itself also undergoes ubiquitination and degradation. Deleting the E5R gene from the Modified vaccinia virus Ankara (MVA) genome strongly induces type I IFN production by dendritic cells (DCs) and promotes DC maturation, thereby improving the immunogenicity of the viral vector.

lncRNAs make up a majority of the human transcriptome and have key regulatory functions. Here we perform unbiased de novo annotation of transcripts expressed during the human humoral immune response to find 30% of the human genome transcribed during this process, yet 58% of these transcripts manifest striking differential expression, indicating an lncRNA phylogenetic relationship among cell types that is more robust than that of coding genes. We provide an atlas of lncRNAs in naive and GC B-cells that indicates their partition into ten functionally categories based on chromatin features, DNase hypersensitivity and transcription factor localization, defining lncRNAs classes such as enhancer-RNAs (eRNA), bivalent-lncRNAs, and CTCF-associated, among others. Specifically, eRNAs are transcribed in 8.6% of regular enhancers and 36.5% of super enhancers, and are associated with coding genes that participate in critical immune regulatory pathways, while plasma cells have uniquely high levels of circular-RNAs accounted for by and reflecting the combinatorial clonal state of the Immunoglobulin loci., Long non-coding RNAs (lncRNA) constitute a large fraction of human transcriptome, and are reported, individually, for context-specific regulatory functions. Here the authors expand our understanding by providing a systemic, unbiased annotation of lncRNA to establish an atlas of lncRNA landscape during the induction of human humoral immune responses.

Chimeric antigen receptors (CARs) are receptors for antigen that direct potent immune responses. Tumor escape associated with low target antigen expression is emerging as one potential limitation of their efficacy. Here we edit the TRAC locus in human peripheral blood T cells to engage cell-surface targets through their T cell receptor-CD3 complex reconfigured to utilize the same immunoglobulin heavy and light chains as a matched CAR. We demonstrate that these HLA-independent T cell receptors (HIT receptors) consistently afford high antigen sensitivity and mediate tumor recognition beyond what CD28-based CARs, the most sensitive design to date, can provide. We demonstrate that the functional persistence of HIT T cells can be augmented by constitutive coexpression of CD80 and 4-1BBL. Finally, we validate the increased antigen sensitivity afforded by HIT receptors in xenograft mouse models of B cell leukemia and acute myeloid leukemia, targeting CD19 and CD70, respectively. Overall, HIT receptors are well suited for targeting cell surface antigens of low abundance.

Heart disease currently, as one of the most important causes of death in the world which can take one’s life immediately, should be taken seriously. In 2019, there were almost 9 millions people died from this disease, and the mortality was still increasing. This study aims to warn people be more focus on their heart condition, and provide a further suggestion about whether they can speculate their heart disease at home. In order to test the hypothesis that the cardiac parameters examined at home can also demonstrates the correct heart condition, many different machine learning algorithms were used to predict the final heart disease accuracy by different data sets (from home and from hospital). Also, there would be spot diagram and Pierson correlation diagram to show the correlation between features and condition, and the correlation among the features. In the end, chi-square method was used to determine the influential degree of those factors which can cause the heart disease. The results of these illustrated that even though several important factors which could only be examined in the hospital rather than at home played the leading role of predicting heart disease, people could still try to predict or observe the heart condition at home, because accuracy difference of the predicting results were only 2% to 4%. Therefore, the result from home could be the reference of whether people should go to the hospital to do more advanced examinations.

The research and development and use of China’s aviation biofuels is entering into industrialization. Compared with the EU countries, China’s aviation biofuel industry is still in its infancy and its features are high cost, low production and small scale of commercial application. Through the literature review method, this paper studies the development experience of EU’s aviation biofuels from three aspects of legislative support, financial support, and technical support. By comparing the development situation of aviation biofuel industry between China and the European Union and considering the development situation of China’s economy, the paper illustrates the development situation of China’s aviation biofuels and puts forward some suggestions on the development of China’s aviation biofuels from three angles of government support, business support and scientific research support to promote low-carbon aviation development and economic sustainable development.

Although the BCL6 transcriptional repressor is frequently expressed in human follicular lymphomas (FL), its biological role in this disease remains unknown. Herein, we comprehensively identify the set of gene promoters directly targeted by BCL6 in primary human FLs. We noted that BCL6 binds and represses NOTCH2 and NOTCH pathway genes. Moreover, BCL6 and NOTCH2 pathway gene expression is inversely correlated in FL. Notably, BCL6 upregulation is associated with repression of NOTCH2 and its target genes in primary human and murine germinal center (GC) cells. Repression of NOTCH2 is an essential function of BCL6 in FL and GC B cells because inducible expression of Notch2 abrogated GC formation in mice and killed FL cells. Indeed, BCL6-targeting compounds or gene silencing leads to the induction of NOTCH2 activity and compromises survival of FL cells, whereas NOTCH2 depletion or pathway antagonists rescue FL cells from such effects. Moreover, BCL6 inhibitors induced NOTCH2 expression and suppressed growth of human FL xenografts in vivo and primary human FL specimens ex vivo. These studies suggest that established FLs are thus dependent on BCL6 through its suppression of NOTCH2. Significance: We show that human FLs are dependent on BCL6, and primary human FLs can be killed using specific BCL6 inhibitors. Integrative genomics and functional studies of BCL6 in primary FL cells point toward a novel mechanism whereby BCL6 repression of NOTCH2 drives the survival and growth of FL cells as well as GC B cells, which are the FL cell of origin. Cancer Discov; 7(5); 506–21. ©2017 AACR. This article is highlighted in the In This Issue feature, p. 443

Somatic mutations in CREBBP occur frequently in B-cell lymphoma. Here, we show that loss of CREBBP facilitates the development of germinal center (GC)–derived lymphomas in mice. In both human and murine lymphomas, CREBBP loss-of-function resulted in focal depletion of enhancer H3K27 acetylation and aberrant transcriptional silencing of genes that regulate B-cell signaling and immune responses, including class II MHC. Mechanistically, CREBBP-regulated enhancers are counter-regulated by the BCL6 transcriptional repressor in a complex with SMRT and HDAC3, which we found to bind extensively to MHC class II loci. HDAC3 loss-of-function rescued repression of these enhancers and corresponding genes, including MHC class II, and more profoundly suppressed CREBBP-mutant lymphomas in vitro and in vivo. Hence, CREBBP loss-of-function contributes to lymphomagenesis by enabling unopposed suppression of enhancers by BCL6/SMRT/HDAC3 complexes, suggesting HDAC3-targeted therapy as a precision approach for CREBBP-mutant lymphomas. Significance: Our findings establish the tumor suppressor function of CREBBP in GC lymphomas in which CREBBP mutations disable acetylation and result in unopposed deacetylation by BCL6/SMRT/HDAC3 complexes at enhancers of B-cell signaling and immune response genes. Hence, inhibition of HDAC3 can restore the enhancer histone acetylation and may serve as a targeted therapy for CREBBP-mutant lymphomas. Cancer Discov; 7(1); 38–53. ©2016 AACR. See related commentary by Höpken, p. 14. This article is highlighted in the In This Issue feature, p. 1

Summary The NRF2 transcription factor controls a cell stress program that is implicated in cancer and there is great interest in targeting NRF2 for therapy. We show that NRF2 activity depends on Fructosamine-3-kinase (FN3K)—a kinase that triggers protein de-glycation. In its absence, NRF2 is extensively glycated, unstable, and defective at binding to small MAF proteins and transcriptional activation. Moreover, the development of hepatocellular carcinoma triggered by MYC and Keap1 inactivation depends on FN3K in vivo. N-acetyl cysteine treatment partially rescues the effects of FN3K loss on NRF2 driven tumor phenotypes indicating a key role for NRF2-mediated redox balance. Mass spectrometry reveals that other proteins undergo FN3K-sensitive glycation, including translation factors, heat shock proteins, and histones. How glycation affects their functions remains to be defined. In summary, our study reveals a surprising role for the glycation of cellular proteins and implicates FN3K as targetable modulator of NRF2 activity in cancer.

The efficacy of chimeric antigen receptor (CAR) T cell therapy against poorly responding tumors can be enhanced by administering the cells in combination with immune checkpoint blockade inhibitors. Alternatively, the CAR construct has been engineered to coexpress factors that boost CAR-T cell function in the tumor microenvironment. We modified CAR-T cells to secrete PD-1-blocking single-chain variable fragments (scFv). These scFv-secreting CAR-T cells acted in both a paracrine and autocrine manner to improve the anti-tumor activity of CAR-T cells and bystander tumor-specific T cells in clinically relevant syngeneic and xenogeneic mouse models of PD-L1+ hematologic and solid tumors. The efficacy was similar to or better than that achieved by combination therapy with CAR-T cells and a checkpoint inhibitor. This approach may improve safety, as the secreted scFvs remained localized to the tumor, protecting CAR-T cells from PD-1 inhibition, which could potentially avoid toxicities associated with systemic checkpoint inhibition.

Surface roughness determined qualitatively by direct visualization can be correlated to several physical properties. However, finding a suitable method of quantifying surface roughness, until recently, has been difficult. The concept of Fractal Dimension, recently popularized by Mandelbrot(1982) has been extremely successful in quantifying surface roughness and relating it to such measurable physical properties such as; cleanability, catalytic activity, rate of corrosion, and even flavor.Atomic Force Microscopes permit direct three dimensional measurements of surface microstructure. AFM images are obtained by measuring the motion of a sharp stylus as it is scanned across a surface. Because the AFM directly measures three dimensional topograms, it is ideally suited for two dimensional and three dimensional fractal analysis. Other microscope techniques such as the scanning electron or optical microscope give only two dimensional magnification and fractal measurements are not easily made.The Atomic Force Microscope enables us to obtain the fractal dimension of surface profiles as well as surface areas. For surface profiles we use a box counting method (Mandelbrot 1986, Chesters et al. 1989).