A study of the classification problem in context of information theory is presented in the paper. Current research in that field is focused on optimisation and bayesian approach. Although that gives satisfying results, they require a vast amount of data and computations to train on. Authors propose a new concept named Informational Neurobayesian Approach (INA), which allows to solve the same problems, but requires significantly less training data as well as computational power. Experiments were conducted to compare its performance with the traditional one and the results showed that capacity of the INA is quite promising.
Hypermethylation of tumor suppressors and other aberrations of DNA methylation in tumors play a significant role in cancer progression. DNA methylation can be affected by various environmental conditions including hypoxia. The response to hypoxia is mainly achieved through activation of the transcription program associated with HIF1a transcription factor. VHL inactivation by genetic or epigenetic events, which also induces aberrant activation of HIF1a, is the most common driver event for renal cancer. With whole-genome bisulfite sequencing and LC-MS, we demonstrated that VHL inactivation induced global genome hypermethylation in human kidney cancer cells under normoxic conditions. This effect was reverted by exogenous expression of wild-type VHL. We show that global genome hypermethylation in VHL mutants can be explained by transcriptional changes in MDH and L2HGDH genes that cause the accumulation of 2-hydroxyglutarate—a metabolite that inhibits DNA demethylation by Tet enzymes. Unlike the known cases of DNA hypermethylation in cancer, 2-hydroxyglutarate was accumulated in IDH wild type cells. Key points Inactivation of VHL gene leads to genome hypermethylation in kidney cancer cells. The DNA methylation phenotype can be rescued by endogenous expression of wild-type VHL. DNA hypermethylation can be attributed to the accumulation of a Tet inhibitor 2-hydroxyglutarate The accumulation of 2-hydroxyglutarate in IDH wild-type cells is explained by gene expression changes in key metabolic enzymes (malate dehydrogenase MDH and 2-hydroxyglutrarate dehydrogenase L2HGDH).
МОДЕЛЮВАННЯ В МЕДИЦИНІСмерть клеток в стареющем организме не вызывает сомнения и, по умолчанию, признается следствием старения самих клеток.Однако здесь присутствует парадокс, который не был замечен раньше: смерть клеток, которые являются постоянными структурными элементами тканей и органов, не допускается с позиции математического закона, характеризующий динамику популяционной смертности
We report a family case of type II early-onset Alzheimer's disease (AD) inherited over three generations. None of the patients in the family had mutations in the genes believed to be the major risk factors for AD, such as APP, presenilin 1 or 2. Targeted exome sequencing of 249 genes that were previously reported to be associated with AD revealed a rare mutation in hemochromatosis (HFE) gene known to be associated with hemochromotosis. Compared to previous studies, we show that HFE mutation can possess the risk of AD in transferrin-, APOE- and APP-normal patients.
Hypermethylation of tumour suppressors and other aberrations of DNA methylation in tumours play a significant role in cancer progression. DNA methylation can be affected by various environmental conditions, including hypoxia. The response to hypoxia is mainly achieved through activation of the transcriptional program associated with HIF1A transcription factor. Inactivation of Von Hippel-Lindau Tumour Suppressor gene (VHL) by genetic or epigenetic events, which also induces aberrant activation of HIF1A, is the most common driver event for renal cancer. With whole-genome bisulphite sequencing and LC-MS, we demonstrated that VHL inactivation induced global genome hypermethylation in human kidney cancer cells under normoxic conditions. This effect was reverted by exogenous expression of wild-type VHL. We showed that global genome hypermethylation in VHL mutants can be explained by transcriptional changes in MDH and L2HGDH genes that cause the accumulation of 2-hydroxyglutarate – a metabolite that inhibits DNA demethylation by TET enzymes. Unlike the known cases of DNA hypermethylation in cancer, 2-hydroxyglutarate was accumulated in the cells with the wild-type isocitrate dehydrogenases.
Abstract Error-prone mutants of polymerase epsilon (POLE*) or polymerase delta (POLD1*) induce a mutator phenotype in human cancers. Here we show that the rate of mutations introduced by POLD1* is elevated by 50%, while the rate of POLE*-induced mutations is decreased twofold, within one kilobase from replication origins. These results support a model in which POLD1 replicates both the leading and the lagging strands within a kilobase from an origin. The magnitude of the mutational bias suggests that the probability of an individual origin to initiate replication exceeds 50%, which is much higher than previous estimates. Using additional data from nascent DNA sequencing and Okazaki fragments sequencing (OK-seq) experiments, we showed that a majority of origins are firing at each replication round, but the initiated replication fork does not propagate further than 1Kb in both directions. Analyses based on mutational data and on OK-seq data concordantly suggest that only approximately a quarter of fired origins result in a processive replication fork. Taken together, our results provide a new model of replication initiation.
Here we present the application of deep neural network (DNN) ensembles trained on transcriptomic data to identify the novel markers associated with the mammalian embryonic-fetal transition (EFT). Molecular markers of this process could provide important insights into regulatory mechanisms of normal development, epimorphic tissue regeneration and cancer. Subsequent analysis of the most significant genes behind the DNNs classifier on an independent dataset of adult-derived and human embryonic stem cell (hESC)-derived progenitor cell lines led to the identification of COX7A1 gene as a potential EFT marker. COX7A1, encoding a cytochrome C oxidase subunit, was up-regulated in post-EFT murine and human cells including adult stem cells, but was not expressed in pre-EFT pluripotent embryonic stem cells or their in vitro-derived progeny. COX7A1 expression level was observed to be undetectable or low in multiple sarcoma and carcinoma cell lines as compared to normal controls. The knockout of the gene in mice led to a marked glycolytic shift reminiscent of the Warburg effect that occurs in cancer cells. The DNN approach facilitated the elucidation of a potentially new biomarker of cancer and pre-EFT cells, the embryo-onco phenotype, which may potentially be used as a target for controlling the embryonic-fetal transition.
ABSTRACT For evolutionary biology, the phenotypic consequences of epigenetic variations and their potential contribution to adaptation and diversification are pressing issues. Marine and freshwater sticklebacks represent an ideal model for studying both genetic and epigenetic components of phenotypic plasticity that allow fish to inhabit water with different salinity. Here, we applied single-cell genomics (scRNA-seq and scATAC-seq) and whole-genome bisulfite sequencing to characterize intercellular variability in transcription, the abundance of open chromatin regions, and CpG methylation level in gills of marine and freshwater stickleback morphs. We found little difference in overall transcriptional variance between the morphs but observed significant changes in chromatin openness variance. In addition, genomic divergence islands (DIs) coincided with regions of increased methylation entropy in freshwater fish. Moreover, analysis of transcription factor binding sites within DIs revealed that СTCF motifs around marker SNPs were significantly enriched within the region. Altogether, our data show that increased epigenetic variance accompanies the adaptation of marine sticklebacks to freshwater.
'/%3e%3cpath id='b' d='M658.84 441.31c-7.618 16.446-22.845 19.271-36.164 5.995 0 0 5.354-3.783 11.086-4.826-1.075-4.574 1.13-10.902 4.235-14.324 3.258 2.227 7.804 6.689 8.96 11.874 8.03-1.04 11.883 1.282 11.883 1.282z'/%3e%3cuse xlink:href='%23b' transform='rotate(9.37 700 804)'/%3e%3cuse xlink:href='%23b' transform='rotate(18.74 700 804)'/%3e%3cpath fill='none' stroke='%23f8c300' stroke-width='16' d='M603 478a340 340 0 0 1 194 0'/%3e%3cg transform='translate(700 380)'%3e%3cg transform='translate(0 -140)'%3e%3cpath id='c' d='m0-513674 301930 929245-790463-574305h977066l-790463 574305z' transform='scale(.00005)'/%3e%3c/g%3e%3cg id='d'%3e%3cuse xlink:href='%23c' transform='translate(-70 -121.244)'/%3e%3cuse xlink:href='%23c' transform='translate(-121.244 -70)'/%3e%3cuse xlink:href='%23c' transform='translate(-140)'/%3e%3c/g%3e%3cuse xlink:href='%23d' transform='scale(-1 1)'/%3e%3c/g%3e%3c/g%3e%3c/svg%3e)
