Stilbenoids remodel the DNA methylation patterns in breast cancer cells and inhibit oncogenic NOTCH signaling through epigenetic regulation of MAML2 transcriptional activity

DNA hypomethylation was previously implicated in cancer progression and metastasis. The purpose of this study was to examine whether stilbenoids, resveratrol and pterostilbene thought to exert anticancer effects, target genes with oncogenic function for de novo methylation and silencing, leading to inactivation of related signaling pathways. Following Illumina 450K, genome-wide DNA methylation analysis reveals that stilbenoids alter DNA methylation patterns in breast cancer cells. On average, 75% of differentially methylated genes have increased methylation, and these genes are enriched for oncogenic functions, including NOTCH signaling pathway. MAML2, a coactivator of NOTCH targets, is methylated at the enhancer region and transcriptionally silenced in response to stilbenoids, possibly explaining the downregulation of NOTCH target genes. The increased DNA methylation at MAML2 enhancer coincides with increased occupancy of repressive histone marks and decrease in activating marks. This condensed chromatin structure is associated with binding of DNMT3B and decreased occupancy of OCT1 transcription factor at MAML2 enhancer, suggesting a role of DNMT3B in increasing methylation of MAML2 after stilbenoid treatment. Our results deliver a novel insight into epigenetic regulation of oncogenic signals in cancer and provide support for epigenetic-targeting strategies as an effective anticancer approach

Assessment of chemical-crosslink-assisted protein structure modeling in CASP13

International audienceWith the advance of experimental procedures obtaining chemical crosslinking information is becoming a fast and routine practice. Information on crosslinks can greatly enhance the accuracy of protein structure modeling. Here, we review the current state of the art in modeling protein structures with the assistance of experimentally determined chemical crosslinks within the framework of the 13th meeting of Critical Assessment of Structure Prediction approaches. This largest‐to‐date blind assessment reveals benefits of using data assistance in difficult to model protein structure prediction cases. However, in a broader context, it also suggests that with the unprecedented advance in accuracy to predict contacts in recent years, experimental crosslinks will be useful only if their specificity and accuracy further improved and they are better integrated into computational workflows

PD-L1 Overexpression, SWI/SNF Complex Deregulation, and Profound Transcriptomic Changes Characterize Cancer-Dependent Exhaustion of Persistently Activated CD4+ T Cells

Growing tumors avoid recognition and destruction by the immune system. During continuous stimulation of tumor-infiltrating lymphocytes (TILs) by tumors, TILs become functionally exhausted; thus, they become unable to kill tumor cells and to produce certain cytokines and lose their ability to proliferate. This collectively results in the immune escape of cancer cells. Here, we show that breast cancer cells expressing PD-L1 can accelerate exhaustion of persistently activated human effector CD4+ T cells, manifesting in high PD-1 and PD-L1 expression level son T cell surfaces, decreased glucose metabolism genes, strong downregulation of SWI/SNF chromatin remodelingcomplex subunits, and p21 cell cycle inhibitor upregulation. This results in inhibition of T cell proliferation and reduction of T cell numbers. The RNAseq analysis on exhausted CD4+ T cells indicated strong overexpression of IDO1 and genes encoding pro-inflammatory cytokines and chemokines. Some interleukins were also detected in media from CD4+ T cells co-cultured with cancer cells. The PD-L1 overexpression was also observed in CD4+ T cells after co-cultivation with other cell lines overexpressing PD-L1, which suggested the existence of a general mechanism of CD4+ T cell exhaustion induced by cancer cells. The ChIP analysis on the PD-L1 promoter region indicated that the BRM recruitment in control CD4+ T cells was replaced by BRG1 and EZH2 in CD4+ T cells strongly exhausted by cancer cells. These findings suggest that epi-drugs such as EZH2 inhibitors may be used as immunomodulators in cancer treatment

Prediction of protein assemblies, the next frontier: The CASP14-CAPRI experiment

We present the results for CAPRI Round 50, the fourth joint CASP-CAPRI protein assembly prediction challenge. The Round comprised a total of twelve targets, including six dimers, three trimers, and three higher-order oligomers. Four of these were easy targets, for which good structural templates were available either for the full assembly, or for the main interfaces (of the higher-order oligomers). Eight were difficult targets for which only distantly related templates were found for the individual subunits. Twenty-five CAPRI groups including eight automatic servers submitted ~1250 models per target. Twenty groups including six servers participated in the CAPRI scoring challenge submitted ~190 models per target. The accuracy of the predicted models was evaluated using the classical CAPRI criteria. The prediction performance was measured by a weighted scoring scheme that takes into account the number of models of acceptable quality or higher submitted by each group as part of their five top-ranking models. Compared to the previous CASP-CAPRI challenge, top performing groups submitted such models for a larger fraction (70–75%) of the targets in this Round, but fewer of these models were of high accuracy. Scorer groups achieved stronger performance with more groups submitting correct models for 70–80% of the targets or achieving high accuracy predictions. Servers performed less well in general, except for the MDOCKPP and LZERD servers, who performed on par with human groups. In addition to these results, major advances in methodology are discussed, providing an informative overview of where the prediction of protein assemblies currently stands.Cancer Research UK, Grant/Award Number: FC001003; Changzhou Science and Technology Bureau, Grant/Award Number: CE20200503; Department of Energy and Climate Change, Grant/Award Numbers: DE-AR001213, DE-SC0020400, DE-SC0021303; H2020 European Institute of Innovation and Technology, Grant/Award Numbers: 675728, 777536, 823830; Institut national de recherche en informatique et en automatique (INRIA), Grant/Award Number: Cordi-S; Lietuvos Mokslo Taryba, Grant/Award Numbers: S-MIP-17-60, S-MIP-21-35; Medical Research Council, Grant/Award Number: FC001003; Japan Society for the Promotion of Science KAKENHI, Grant/Award Number: JP19J00950; Ministerio de Ciencia e Innovación, Grant/Award Number: PID2019-110167RB-I00; Narodowe Centrum Nauki, Grant/Award Numbers: UMO-2017/25/B/ST4/01026, UMO-2017/26/M/ST4/00044, UMO-2017/27/B/ST4/00926; National Institute of General Medical Sciences, Grant/Award Numbers: R21GM127952, R35GM118078, RM1135136, T32GM132024; National Institutes of Health, Grant/Award Numbers: R01GM074255, R01GM078221, R01GM093123, R01GM109980, R01GM133840, R01GN123055, R01HL142301, R35GM124952, R35GM136409; National Natural Science Foundation of China, Grant/Award Number: 81603152; National Science Foundation, Grant/Award Numbers: AF1645512, CCF1943008, CMMI1825941, DBI1759277, DBI1759934, DBI1917263, DBI20036350, IIS1763246, MCB1925643; NWO, Grant/Award Number: TOP-PUNT 718.015.001; Wellcome Trust, Grant/Award Number: FC00100

Photocatalytical Decomposition of Contaminants οn Thin Film Gas Sensors

Gas sensing materials have been prepared in a form of $TiO_{2}-SnO_{2}$ thin films by rf reactive sputtering from $Ti:SnO_{2}$ and $Sn:TiO_{2}$ targets. Material studies have been performed by scanning electron microscopy, atomic force microscopy, X-ray diffraction at grazing incidence, Mössbauer spectroscopy, X-ray photoelectron spectroscopy and optical spectrophotometry. Dynamic gas sensing responses have been recorded as reproducible changes in the electrical resistance upon introduction of hydrogen at a partial pressure of 100-6000 ppm over a wide temperature range 473-873 K. Contamination experiments have been carried out with the motor oil (40 vol.% solution in $CCl_{4}$) in order to study the effect of UV light illumination on the gas sensor response. Optical spectroscopy has been applied to monitor the photodecomposition of the test compound, bromothymol blue. The Electronic Nose, ALPHA MOS FOX 4000 has been used in order to differentiate between different groups of motor oil vapors

TiO2: Cr nanopowders for hydrogen sensing

The aim of this research was to use nanocrystalline TiO2 and TiO2: Cr (0.1–10 at. % Cr) obtained by Flame Spray Synthesis, FSS, for hydrogen sensing. Morphological properties of nanopowders were investigated by Brunauer–Emmett–Teller, BET, adsorption isotherms, X-ray Diffraction, XRD, Scanning Electron Microscopy, SEM, and Transmission Electron Microscopy, TEM. Nanosensors were prepared in a form of circular tablets by pressing the nanopowder at the pressure of 25 MPa and heating up to 400oC. Dynamic changes in the electrical resistance ΔR/Ro upon hydrogen exposure were detected over low-to- medium concentration range of 50-3000 ppm at 200-400oC. The influence of particle size and Cr content on the sensor response was studied

Gas sensing properties of TiO2 - SnO2 nanomaterials

Nanocomposites of TiO2/SnO2 for hydrogen and ammonia detection are compared with complex oxides that belong to TiO2/SnO2 system. Nanocomposites have been prepared by mechanical mixing of nanopowders with different specific surface area SSA=159 m2/g for TiO2 and SSA=21 m2/g for SnO2 as determined from BET measurements. Complex oxides have been synthesized by sol - gel method from organic precursor of TTIP and SnCl2*2H2O. The resulting SSA=91 m2/g has turned out to be larger for 50 mol % TiO2 + 50 mol % SnO2 sol-gel sample as compared with 65 m2/g for the nanocomposite of the same nominal chemical content. Nanocomposites consist of two separate phases of larger-grain (21-28 nm) cassiterite SnO2 and smaller-grain (8-11 nm) rutile TiO2, respectively, over a full compositional range. XRD and STEM suggest that a solid solution with some precipitation of SnO2 is formed for 50 mol. % TiO2 + 50 mol. % SnO2. For nanocomposites, TEM experiments reveal the presence of small, elongated TiO2 crystals and larger SnO2 crystals of irregular shape. For 50 mol.% TiO2 + 50 mol.% SnO2 sol - gel sample, spherical, homogeneously distributed grains are seen in TEM. Sensor responses exhibit a broad maximum over the compositional range at 20 - 50 mol.% of TiO2 mixed with SnO2. The electrical resistivity of 50 mol % TiO2 + 50 mol % SnO2 sol-gel sample is less affected than that of the nanocomposite of the same composition, by the exposure to H2 and NH2 at elevated temperatures

Gas sensing properties of TiO2-SnO2 nanomaterials

Nanocomposites of TiO2/SnO2 for hydrogen detection have been prepared by mechanical mixing of TiO2 and SnO2 nanopowders with different specific surface area SSA = 150.9 m2/g (TiO2) and SSA = 18.3 m2/g (SnO2). Nanocomposites consist of two distinct components: larger - grain (21-28 nm) cassiterite SnO2 and smaller - grain (8-11 nm) rutile TiO2 as indicated by X-ray diffraction measurements and transmission electron microscope, TEM, images. Nanopowders of 50 mol% TiO2/50 mol% SnO2 are composed of small, elongated TiO2 forms mixed with larger SnO2 grains of regular shape as demonstrated by TEM. Scanning electron microscopy, SEM of gas sensing tablets, prepared by pressing nanopowders under 25 MPa at 400 °C reveal a high degree of agglomeration. Sensor responses in the electrical resistivity over a wide range of concentrations from 50 to 3000 ppm H2 at a constant temperature chosen within the interval 250-400 °C have been measured and analyzed before and after sample conditioning at 500 °C in Ar + 7% H2 atmosphere. Sensing tablets of 50 mol% TiO2/50 mol% SnO2 display the highest sensitivity to hydrogen at moderate temperatures of 250-300 °C. Kinetics of the sensor responses are improved and the recovery time is significantly reduced as a result of annealing in the reducing atmosphere