Extrachromosomal circularization of DNA is an important genomic feature in cancer. However, the structure, composition and genome-wide frequency of extrachromosomal circular DNA have not yet been ...profiled extensively. Here, we combine genomic and transcriptomic approaches to describe the landscape of extrachromosomal circular DNA in neuroblastoma, a tumor arising in childhood from primitive cells of the sympathetic nervous system. Our analysis identifies and characterizes a wide catalog of somatically acquired and undescribed extrachromosomal circular DNAs. Moreover, we find that extrachromosomal circular DNAs are an unanticipated major source of somatic rearrangements, contributing to oncogenic remodeling through chimeric circularization and reintegration of circular DNA into the linear genome. Cancer-causing lesions can emerge out of circle-derived rearrangements and are associated with adverse clinical outcome. It is highly probable that circle-derived rearrangements represent an ongoing mutagenic process. Thus, extrachromosomal circular DNAs represent a multihit mutagenic process, with important functional and clinical implications for the origins of genomic remodeling in cancer.
Abstract Toll-like receptor 4 (TLR4) is one of the key immune system effectors playing the main role in recognition of viruses and bacteria. Dysregulation of the TLR4 signaling owing to single ...nucleotide polymorphisms (SNPs) may alter the ligand binding and balance between pro- and anti-inflammatory cytokines, thereby modulating the risk of chronic inflammation and cancer. TLR4 polymorphisms may be associated with at least nine types of cancer. The most intensively investigating TLR4 polymorphisms are Asp299Gly (rs4986790) and Thr399Ile (rs4986791). It seems to be that Asp299Gly and Thr399Ile are related to increased risk of precancerous gastric lesions, and, possibly, gastric cancer. Thr399Ile also may be connected with gallbladder cancer, and both of these polymorphisms apparently have no impact on risk of prostate cancer. However, the data about many SNPs and their associations with different types of cancer are conflicting, and further large, well-designed, comprehensive studies in various populations are necessary for solution of this problem. The short list of TLR4 SNPs for further investigation may include TLR4_896A/G (Asp299Gly, rs4986790), TLR4_1196C/T (Thr399Ile, rs4986791), Thr135Ala, TLR4_1859 G/A (rs11536858), TLR4_2032T/C (rs10116253), TLR4_2437A/G (rs1927914), TLR4_2856T/C (rs10759932), TLR4_3725 G/C (rs11536889), TLR4_7764 G/A (rs1927911), TLR4_11350G/C, TLR4_11912 G/T (rs2149356), TLR4_16649G/C (rs7873784), and TLR4_17050T/C (rs11536891).
We discuss interesting effects that occur when strongly focusing light with mth-order cylindrical–circular polarization. This type of hybrid polarization combines properties of the mth-order ...cylindrical polarization and circular polarization. Reluing on the Richards-Wolf formalism, we deduce analytical expressions that describe E- and H-vector components, intensity patterns, and projections of the Poynting vector and spin angular momentum (SAM) vector at the strong focus. The intensity of light in the strong focus is theoretically and numerically shown to have an even number of local maxima located along a closed contour centered at an on-axis point of zero intensity. We show that light generates 4m vortices of a transverse energy flow, with their centers located between the local intensity maxima. The transverse energy flow is also shown to change its handedness an even number of times proportional to the order of the optical vortex via a full circle around the optical axis. It is interesting that the longitudinal SAM projection changes its sign at the focus 4m times. The longitudinal SAM component is found to be positive, and the polarization vector is shown to rotate anticlockwise in the focal spot regions where the transverse energy flow rotates anticlockwise, and vice versa—the longitudinal SAM component is negative and the polarization vector rotates clockwise in the focal spot regions where the transverse energy flow rotates clockwise. This spatial separation at the focus of left and right circularly polarized light is a manifestation of the optical spin Hall effect. The results obtained in terms of controlling the intensity maxima allow the transverse mode analysis of laser beams in sensorial applications. For a demonstration of the proposed application, the metalens is calculated, which can be a prototype for an optical microsensor based on sharp focusing for measuring roughness.
The article studies the change of clavarioid mycota species richness along the longitudinal gradient of climatic continentality in the forest tundra ecotone of Eurasia and the results are discussed ...for continental and regional levels using the basic climatic variables. It was found that species richness declines, both continentally and regionally, with climate continentality increasing. The Fennoscandian sector situated in the mild maritime climate is the richest, whereas Yakutia, with an ultracontinental harsh climate is the poorest. Strong positive correlations were found between species richness and mean annual temperature and precipitation. On the other hand, spatial turnover of species, or beta diversity, has a negative correlation with the macroclimatic gradient. There are European sectors, where clavarioid mycota associating with the birch and pine-spruce open woodlands have high similarity with their boreal variants, whereas in Siberian sectors, east of the Yenisei River, where mycota is associated with larch and cedar elfin bushes, the similarities are more akin to tundra variants. At the continental scale, there is no reliable relationship between mycota diversity with the flora richness and soil pH, but the permafrost thickness is significantly correlated with the studied levels of the clavarioid mycota diversity.
•The species richness of clavarioid fungi declines with increasing climatic continentality.•A strong correlation exists between the species richness of fungi with climatic parameters.•The set of species in the European sectors are similar to the taiga, Siberian with tundra.
Oxidative stress is involved in a wide range of age-related diseases. A critical role has been proposed for mitochondrial oxidative stress in initiating or promoting these pathologies and the ...potential for mitochondria-targeted antioxidants to fight them, making their search and testing a very urgent task. In this study, the mitochondria-targeted antioxidants SkQ1, SkQ3 and MitoQ were examined as they affected isolated rat liver mitochondria and yeast cells, comparing SkQ3 with clinically tested SkQ1 and MitoQ. At low concentrations, all three substances stimulated the oxidation of respiratory substrates in state 4 respiration (no ADP addition); at higher concentrations, they inhibited the ADP-triggered state 3 respiration and the uncoupled state, depolarized the inner mitochondrial membrane, contributed to the opening of the mPTP (mitochondrial permeability transition pore), did not specifically affect ATP synthase, and had a pronounced antioxidant effect. SkQ3 was the most active antioxidant, not possessing, unlike SkQ1 or MitoQ, prooxidant activity with increasing concentrations. In yeast cells, all three substances reduced prooxidant-induced intracellular oxidative stress and cell death and prevented and reversed mitochondrial fragmentation, with SkQ3 being the most efficient. These data allow us to consider SkQ3 as a promising potential therapeutic agent to mitigate pathologies associated with oxidative stress.
Obesity results from alterations in the body's regulation of energy intake, expenditure, and storage. Recent evidence, primarily from investigations in animal models, suggests that the gut microbiota ...affects nutrient acquisition and energy regulation. Its composition has also been shown to differ in lean vs obese animals and humans. In this article, we review the published evidence supporting the potential role of the gut microbiota in the development of obesity and explore the role that modifying the gut microbiota may play in its future treatment. Evidence suggests that the metabolic activities of the gut microbiota facilitate the extraction of calories from ingested dietary substances and help to store these calories in host adipose tissue for later use. Furthermore, the gut bacterial flora of obese mice and humans include fewer Bacteroidetes and correspondingly more Firmicutes than that of their lean counterparts, suggesting that differences in caloric extraction of ingested food substances may be due to the composition of the gut microbiota. Bacterial lipopolysaccharide derived from the intestinal microbiota may act as a triggering factor linking inflammation to high-fat diet-induced metabolic syndrome. Interactions among microorganisms in the gut appear to have an important role in host energy homeostasis, with hydrogen-oxidizing methanogens enhancing the metabolism of fermentative bacteria. Existing evidence warrants further investigation of the microbial ecology of the human gut and points to modification of the gut microbiota as one means to treat people who are overweight or obese.
Reversal of cancer gene expression is predictive of therapeutic potential and can be used to find new indications for existing drugs (drug repositioning). Gene expression reversal potential is ...currently calculated, in almost all studies, by pre-aggregating all tumour samples into a single group signature or a limited number of molecular subtype signatures. Here, we investigate whether drug repositioning based on individual tumour sample gene expression signatures outperforms the use of tumour group and subtype signatures. The tumour signatures were created using 534 tumour samples and 72 matched normal samples from 530 clear cell renal cell carcinoma (ccRCC) patients. More than 20,000 drug signatures were extracted from the CMAP and LINCS databases. We show that negative enrichment of individual tumour samples correlated (Spearman's rho = 0.15) much better with the amount of differentially expressed genes in drug signatures than with the tumour group signature (Rho = 0.08) and the 4 tumour subtype signatures (Rho 0.036-0.11). Targeted drugs used against ccRCC, such as sirolimus and temsirolimus, which could not be identified with the pre-aggregated tumour signatures could be recovered using individual sample analysis. Thus, drug repositioning can be personalized by taking into account the gene expression profile of the individual's tumour sample.
We propose an accelerated density matrix purification scheme with error control. The method makes use of the scale-and-fold acceleration technique and screening of submatrix products in the ...block-sparse matrix-matrix multiplies to reduce the computational cost. An error bound and a parameter sweep are combined to select a threshold value for the screening, such that the error can be controlled. We evaluate the performance of the method in comparison to purification without acceleration and without submatrix product screening.
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