A novel unconventional T cell population enriched in Crohn's disease

Objective One of the current hypotheses to explain the proinflammatory immune response in IBD is a dysregulated T cell reaction to yet unknown intestinal antigens. As such, it may be possible to identify disease-associated T cell clonotypes by analysing the peripheral and intestinal T-cell receptor (TCR) repertoire of patients with IBD and controls. Design We performed bulk TCR repertoire profiling of both the TCR alpha and beta chains using high-throughput sequencing in peripheral blood samples of a total of 244 patients with IBD and healthy controls as well as from matched blood and intestinal tissue of 59 patients with IBD and disease controls. We further characterised specific T cell clonotypes via single-cell RNAseq. Results We identified a group of clonotypes, characterised by semi-invariant TCR alpha chains, to be significantly enriched in the blood of patients with Crohn's disease (CD) and particularly expanded in the CD8+ T cell population. Single-cell RNAseq data showed an innate-like phenotype of these cells, with a comparable gene expression to unconventional T cells such as mucosal associated invariant T and natural killer T (NKT) cells, but with distinct TCRs. Conclusions We identified and characterised a subpopulation of unconventional Crohn-associated invariant T (CAIT) cells. Multiple evidence suggests these cells to be part of the NKT type II population. The potential implications of this population for CD or a subset thereof remain to be elucidated, and the immunophenotype and antigen reactivity of CAIT cells need further investigations in future studies

Investigation of terahertz radiation influence on rat glial cells

Abstract We studied an influence of continuous terahertz (THz) radiation (0.12–0.18 THz, average power density of 3.2 mW/cm²) on a rat glial cell line. A dose-dependent cytotoxic effect of THz radiation is demonstrated. After 1 minute of THz radiation exposure a relative number of apoptotic cells increased in 1.5 times, after 3 minutes it doubled. This result confirms the concept of biological hazard of intense THz radiation. Diagnostic applications of THz radiation can be restricted by the radiation power density and exposure time

Synthesis, Molecular Docking, In Vitro and In Vivo Studies of Novel Dimorpholinoquinazoline-Based Potential Inhibitors of PI3K/Akt/mTOR Pathway

A (series) range of potential dimorpholinoquinazoline-based inhibitors of the PI3K/Akt/mTOR cascade was synthesized. Several compounds exhibited cytotoxicity towards a panel of cancer cell lines in the low and sub-micromolar range. Compound 7c with the highest activity and moderate selectivity towards MCF7 cells which express the mutant type of PI3K was also tested for the ability to inhibit PI3K-(signaling pathway) downstream effectors and associated proteins. Compound 7c inhibited the phosphorylation of Akt, mTOR, and S6K at 125–250 nM. It also triggered PARP1 cleavage, ROS production, and cell death via several mechanisms. Inhibition of PI3Kα was observed at a concentration of 7b 50 µM and of 7c 500 µM and higher, that can indicate minority PI3Kα as a target among other kinases in the titled cascade for 7c. In vivo studies demonstrated an inhibition of tumor growth in the colorectal tumor model. According to the docking studies, the replacement of the triazine core in gedatolisib (8) by a quinazoline fragment, and incorporation of a (hetero)aromatic unit connected with the carbamide group via a flexible spacer, can result in more selective inhibition of the PI3Kα isoform

1.86 Ga key paleomagnetic pole from the Murmansk craton intrusions - Eastern Murman Sill Province, NE Fennoscandia: Multidisciplinary approach and paleotectonic applications

We present the first 1.86 Ga paleomagnetic key pole of Fennoscandia obtained for the dolerite sills of the Murmansk craton – Eastern Murman Sill Province, that outcrop in the northern part of the Kola Peninsula along the Barents Sea coast for a distance of 200 km (Slat = 68.5°; Slong = 37.9°; N = 16 sites; Plat = 54.7°; Plong = 234.7°; dp/dm = 4.3°/6.3°, Qv = 5). The age of the sills and their characteristic remanent magnetization (ChRM) was determined by four independent geochronometers: U-Pb – 1860 ± 4 and 1863 ± 7 Ma (ID-TIMS, baddeleyite), Sm-Nd – 1889 ± 57 Ma, Rb-Sr – 1850 Ma, Ar/Ar – 1865 ± 8 and 1857 ± 20 Ma (biotite). The primary nature of the ChRM is confirmed by the results of petrographic, geochemical, paleo- and rock magnetic studies, as well as by thermochronological data. The similarity of the petrographic and geochemical characteristics of sills from different localities indicates that these dolerite sills were formed during a single magmatic event and their cooling down to 580 °C occurred at depths of about 10 ± 2 km and lasted ∼2800 years or even faster. Paleogeographic reconstruction of Fennoscandia on the basis of the obtained paleomagnetic pole is in general agreement with the previously suggested configuration of core of the Nuna/Columbia supercontinent (Evans and Mitchell, 2011; Meert and Santosh, 2017). A new reliable Thellier-Coe paleointensity determination for this time reveals a rather low mean VDM = 1.8 (±0.1) × 1022 Am2 that supports the Proterozoic dipole low hypothesis (Biggin et al., 2009)

Expression Profile of Genes Related to Drug Metabolism in Human Brain Tumors

Background Endogenous and exogenous compounds as well as carcinogens are metabolized and detoxified by phase I and II enzymes, the activity of which could be crucial to the inactivation and hence susceptibility to carcinogenic factors. The expression of these enzymes in human brain tumor tissue has not been investigated sufficiently. We studied the association between tumor pathology and the expression profile of seven phase I and II drug metabolizing genes (CYP1A1, CYP1B1, ALDH3A1, AOX1, GSTP1, GSTT1 and GSTM3) and some of their proteins. Methods Using qRT-PCR and western blotting analysis the gene and protein expression in a cohort of 77 tumors were investigated. The major tumor subtypes were meningioma, astrocytoma and brain metastases, -the later all adenocarcinomas from a lung primary. Results Meningeal tumors showed higher expression levels for AOX1, CYP1B1, GSTM3 and GSTP1. For AOX1, GSTM and GSTP1 this could be verified on a protein level as well. A negative correlation between the WHO degree of malignancy and the strength of expression was identified on both transcriptional and translational level for AOX1, GSTM3 and GSTP1, although the results could have been biased by the prevalence of meningiomas and glioblastomas in the inevitably bipolar distribution of the WHO grades. A correlation between the gene expression and the protein product was observed for AOX1, GSTP1 and GSTM3 in astrocytomas. Conclusions The various CNS tumors show different patterns of drug metabolizing gene expression. Our results suggest that the most important factor governing the expression of these enzymes is the histological subtype and to a far lesser extent the degree of malignancy itself