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

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

Impact of AlphaFold on structure prediction of protein complexes: The CASP15-CAPRI experiment

We present the results for CAPRI Round 54, the 5th joint CASP-CAPRI protein assembly prediction challenge. The Round offered 37 targets, including 14 homodimers, 3 homo-trimers, 13 heterodimers including 3 antibody-antigen complexes, and 7 large assemblies. On average ~70 CASP and CAPRI predictor groups, including more than 20 automatics servers, submitted models for each target. A total of 21 941 models submitted by these groups and by 15 CAPRI scorer groups were evaluated using the CAPRI model quality measures and the DockQ score consolidating these measures. The prediction performance was quantified by a weighted score based on the number of models of acceptable quality or higher submitted by each group among their five best models. Results show substantial progress achieved across a significant fraction of the 60+ participating groups. High-quality models were produced for about 40% of the targets compared to 8% two years earlier. This remarkable improvement is due to the wide use of the AlphaFold2 and AlphaFold2-Multimer software and the confidence metrics they provide. Notably, expanded sampling of candidate solutions by manipulating these deep learning inference engines, enriching multiple sequence alignments, or integration of advanced modeling tools, enabled top performing groups to exceed the performance of a standard AlphaFold2-Multimer version used as a yard stick. This notwithstanding, performance remained poor for complexes with antibodies and nanobodies, where evolutionary relationships between the binding partners are lacking, and for complexes featuring conformational flexibility, clearly indicating that the prediction of protein complexes remains a challenging problem

Spin-Wave Resonance in Magnetic Semiconductor Thin Films - Experiment

Magnetic properties of polycrystalline thin films of chromium chalcogenide spinels (CdCr$\text{}_{2}$Se$\text{}_{4}$ lightly doped with indium and CdCr$\text{}_{2x}$In$\text{}_{2-2x}$Se$\text{}_{4}$) were studied. The ferromagnetic (FMR) and spin-wave resonance (SWR) techniques were used to investigate the temperature dependences of both the spin-wave stiffness constant D and the saturation magnetization M$\text{}_{s}$. The resonance spectra were recorded in the temperature range extending from 4.2 K to 300 K. The influence of indium concentration on M$\text{}_{s}$(T) and D(T) was studied. It was shown that lightly doped samples (In/Cd < 1% at.) exhibited the ferromagnetic ordering with M$\text{}_{s}$(T) and D(T) being the linear functions of T$\text{}^{3}$ $\text{}^{/}$ $\text{}^{2}$ and T$\text{}^{5}$ $\text{}^{/}$ $\text{}^{2}$, respectively. Higher concentration of indium produced the reentrant transition and spin-glass state of magnetic ordering in CdCr$\text{}_{2x}$In$\text{}_{2-2x}$Se$\text{}_{4}$. The temperature dependence of M$\text{}_{s}$ was also found from the FMR data for these two magnetic phases

STUDIES OF MAGNETIC PROPERTIES OF THIN CdCr2Se4 FILMS - EXPERIMENT

A new preparation method of thin CdCr2Se4 : In films by vacuum evaporation technique is proposed. We report and analyse the temperature dependence of magnetization and the effect of Cr2+ and Cr+4 impurity ions on the FMR linewidth. Also the electrical transport properties of these films are studied

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

H-T Phase Diagram of Magnetic Semiconductor Thin Films - Experiment

We used the irreversibilities between the field cooled and zero field cooled dc magnetization to determine the field and composition dependence of the spin-glass freezing temperature in CdCr$\text{}_{2}$Se$\text{}_{4}$ : In (REE) and CdCr$\text{}_{2-2x}$In$\text{}_{2x}$Se$\text{}_{4}$ (0.15 ≤ x ≤ 0.35) (SG) thin films. The H-T phase diagram of samples with REE has two instability lines: the Gabay-Toulouse-type (G-T) and the De Almeida-Thouless-type (A-T) while samples in SG state are characterized by the A-T line. The A-T line of thin films was used for calculation the normalised internal magnetic field h$\text{}_{m}$ of infinite spin clusters with long range ordering