Transcriptomic profiling disclosed the role of DNA methylation and histone modifications in tumor-infiltrating myeloid-derived suppressor cell subsets in colorectal cancer

Increased numbers of myeloid-derived suppressor cells (MDSCs) are positively correlated with poor prognosis and reduced survivals of cancer patients. They play central roles in tumor immune evasion and tumor metastasis. However, limited data are available on phenotypic/transcriptomic characteristics of the different MDSCs subsets in cancer. These cells include immature (I-MDSCs), monocytic (M-MDSCs), and polymorphonuclear/granulocytic (PMN-MDSCs). Phenotypic characterization of myeloid subsets from 27 colorectal cancer (CRC) patients was assessed by flow cytometric analyses. RNA-sequencing of sorted I-MDSCs, PMN-MDSCs, and antigen-presenting cells (APCs) was also performed. We found that the levels of I-MDSCs and PMN-MDSCs were increased in tumor tissues (TT), compared with normal tissues (NT) in colorectal cancer. Our functional annotation analyses showed that genes associated with histone deacetylase (HDAC) activation- and DNA methylation-mediated transcriptional silencing were upregulated, and histone acetyl transferase (HAT)-related genes were downregulated in tumor-infiltrating I-MDSCs. Moreover, pathways implicated in cell trafficking and immune suppression, including Wnt, interleukin-6 (IL-6), and mitogen-activated protein kinase (MAPK) signaling, were upregulated in I-MDSCs. Notably, PMN-MDSCs showed downregulation in genes related to DNA methylation and HDAC binding. Using an ex vivo model, we found that inhibition of HDAC activation or neutralization of IL-6 in CRC tumor tissues downregulates the expression of genes associated with immunosuppression and myeloid cell chemotaxis, confirming the importance of HDAC activation and IL-6 signaling pathway in MDSC function and chemotaxis. This study provides novel insights into the epigenetic regulations and other molecular pathways in different myeloid cell subsets within the CRC tumor microenvironment (TME), giving opportunities to potential targets for therapeutic benefits

Structural basis for the second step of group II intron splicing

The group II intron and the spliceosome share a common active site architecture and are thought to be evolutionarily related. Here we report the 3.7 Å crystal structure of a eukaryotic group II intron in the lariat-3′ exon form, immediately preceding the second step of splicing, analogous to the spliceosomal P complex. This structure reveals the location of the intact 3′ splice site within the catalytic core of the group II intron. The 3′-OH of the 5′ exon is positioned in close proximity to the 3′ splice site for nucleophilic attack and exon ligation. The active site undergoes conformational rearrangements with the catalytic triplex having dif- ferent configurations before and after the second step of splicing. We describe a complete model for the second step of group II intron splicing that incorporates a dynamic catalytic triplex being responsible for creating the binding pocket for 3′ splice site capture

Kinetics of the Esterification Reaction between Pentanoic Acid and Methanol Catalyzed by Noncorrosive Cation Exchange Resin

Methyl pentanoate, commonly known as methyl valerate, is the methyl ester of pentanoic acid (valeric acid) with a fruity odour. Methyl pentanoate is commonly used in fragrances, beauty care, soap, laundry detergents at levels of 0.1 – 1 %. In its very pure form (purity 99.5 %) it is used as a plasticizer in the manufacture of plastics. In the present investigation, kinetics of esterification of pentanoic acid with methanol catalyzed by heterogeneous catalyst in a batch-type reactor is reported. The effect of reaction conditions such as temperature, molar ratio, catalyst loading, and initial concentration of pentanoic acid and methanol, and the inhibiting effect of water on the kinetics has been studied. The pentanoic acid conversion reached 93 % at 333.15 K at a methanol to pentanoic acid molar ratio of 10:1 with 7 % (g L–1) Amberlyst 15 as catalyst. Mass transfer effects were found to be negligible. Observed reaction rate data was fitted to the regression technique. Estimated Eley-Rideal kinetic model reaction rate constants were fitted to the Arrhenius type equation with activation energy EA 39.5 kJ mol–1 and pre exponential factor ko 1.8 · 103 L2 g–1 mol–1 h–1

Investigation of the effect of PD-L1 blockade on triple negative breast cancer cells using fourier transform infrared spectroscopy

Interactions between programmed death-1 (PD-1) with its ligand PD-L1 on tumor cells can antagonize T cell responses. Inhibiting these interactions using immune checkpoint inhibitors has shown promise in cancer immunotherapy. MDA-MB-231 is a triple negative breast cancer cell line that expresses PD-L1. In this study, we investigated the biochemical changes in MDA-MB-231 cells following treatment with atezolizumab, a specific PD-L1 blocker. Our readouts were Fourier Transform Infrared (FTIR) spectroscopy and flow cytometric analyses. Chemometrical analysis, such as principal component analysis (PCA), was applied to delineate the spectral differences. We were able to identify the chemical alterations in both protein and lipid structure of the treated cells. We found that there was a shift from random coil and ?-helical structure to ?-sheet conformation of PD-L1 on tumor cells due to atezolizumab treatment, which could hinder binding with its receptors on immune cells, ensuring sustained T cell activation for potent immune responses. This work provides novel information about the effects of atezolizumab at molecular and cellular levels. FTIR bio-spectroscopy, in combination with chemometric analyses, may expedite research and offer new approaches for cancer immunology. - 2019 by the authors. Licensee MDPI, Basel, Switzerland.Diabetes Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), P.O. Box 34110 Doha, Qatar Cancer Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), P.O. Box 34110 Doha, Qatar Department of Chemistry and Earth Sciences, Qatar University (QU), P.O. Box 2713 Doha, Qatar Qatar Computing Research Institute, Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), P.O. Box 34110 Doha, Qatar Qatar Environment & Energy Research Institute (QEERI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), P.O. Box 34110 Doha, Qatar Correspondence: [email protected] (M.H.M.A.); [email protected] (E.E.

The effect of quantum memory on quantum games

We study quantum games with correlated noise through a generalized quantization scheme. We investigate the effects of memory on quantum games, such as Prisoner's Dilemma, Battle of the Sexes and Chicken, through three prototype quantum-correlated channels. It is shown that the quantum player enjoys an advantage over the classical player for all nine cases considered in this paper for the maximally entangled case. However, the quantum player can also outperform the classical player for subsequent cases that can be noted in the case of the Battle of the Sexes game. It can be seen that the Nash equilibria do not change for all the three games under the effect of memory.Comment: 26 pages, 7 ps figure

Revival-collapse phenomenon in the fluctuations of quadrature field components of the multiphoton Jaynes-Cummings model

In this paper we consider a system consisting of a two-level atom, initially prepared in a coherent superposition of upper and lower levels, interacting with a radiation field prepared in generalized quantum states in the framework of multiphoton Jaynes-Cummings model. For this system we show that there is a class of states for which the fluctuation factors can exhibit revival-collapse phenomenon (RCP) similar to that exhibited in the corresponding atomic inversion. This is shown not only for normal fluctuations but also for amplitude-squared fluctuations. Furthermore, apart from this class of states we generally demonstrate that the fluctuation factors associated with three-photon transition can provide RCP similar to that occurring in the atomic inversion of the one-photon transition. These are novel results and their consequence is that RCP occurred in the atomic inversion can be measured via a homodyne detector. Furthermore, we discuss the influence of the atomic relative phases on such phenomenon.Comment: 17 pages, 4 figure

Ontogeny of iodothyronine deiodinases in human liver

The role of the deiodinases D1, D2, and D3 in the tissue-specific and time-dependent regulation of thyroid hormone bioactivity during fetal development has been investigated in animals but little is known about the ontogeny of these enzymes in humans. We analyzed D1, D2, and D3 activities in liver microsomes from 10 fetuses of 15-20 weeks gestation and from 8 apparently

Flexibility of habitat use in novel environments: insights from a translocation experiment with lesser black-backed gulls

Being faced with unknown environments is a concomitant challenge of species' range expansions. Strategies to cope with this challenge include the adaptation to local conditions and a flexibility in resource exploitation. The gulls of the Larus argentatus-fuscus-cachinnans group form a system in which ecological flexibility might have enabled them to expand their range considerably, and to colonize urban environments. However, on a population level both flexibility and local adaptation lead to signatures of differential habitat use in different environments, and these processes are not easily distinguished. Using the lesser black-backed gull (Larus fuscus) as a system, we put both flexibility and local adaptation to a test. We compare habitat use between two spatially separated populations, and use a translocation experiment duringwhich individuals were released into novel environment. The experiment revealed that on a population-level flexibility best explains the differences in habitat use between the two populations. We think that our results suggest that the range expansion and huge success of this species complex could be a result of its broad ecological niche and flexibility in the exploitation of resources. However, this also advises caution when using species distribution models to extrapolate habitat use across space

Differential gene expression of tumor-infiltrating CD33 + myeloid cells in advanced- versus early-stage colorectal cancer

Abstract: Colorectal cancer (CRC) has high mortality rates, especially in patients with advanced disease stages, who often do not respond to therapy. The cellular components of the tumor microenvironment are essentially responsible for dictating disease progression and response to therapy. Expansion of different myeloid cell subsets in CRC tumors has been reported previously. However, tumor-infiltrating myeloid cells have both pro- and anti-tumor roles in disease progression. In this study, we performed transcriptomic profiling of cells of myeloid lineage (CD33+) from bulk CRC tumors at varying disease stages. We identified differentially expressed genes and pathways between CRC patients with advanced stage and early stages. We found that pro-angiogenic and hypoxia-related genes were upregulated, while genes related to immune and inflammatory responses were downregulated in CD33+ myeloid cells from patients with advanced stages, implying that immune cell recruitment and activation could be compromised in advanced disease stages. Moreover, we identified a unique “poor prognosis CD33+ gene signature” by aligning top upregulated and downregulated genes in tumor-infiltrating myeloid cells from our analyses with data from The Cancer Genome Atlas. Our results showed that this gene signature is an independent prognostic indicator for disease-specific survival in CRC patients, potentially reflecting its clinical importance