Unveiling DNA algorithms: satellite DNA sequences as iterable objects. A computational model.

Every adult male of the little roundworm Caenorhabditis elegans is always and invariably comprised of exactly 1031 somatic cells, not one more, not one less; and so it is for the adult hermaphrodite (959 somatic cells); its intestine founder cell (the ‘E’ blastomere), if isolated and cultured, undergoes the same number of divisions as in the whole embryo (Robertson et al., 2014); the zygote of Drosophila melanogaster executes 13 cycles of asynchronous cell divisions without cellularization: how are these numbers counted? Artificial Intelligence (First and Second Order Logic, Knowledge graph Engineering) infers that, to perform precise stereotypical numbers of asynchronous cell divisions, a nucleic (genomic) counter is indispensable. Made up of tandemly repeated similar monomers, satellite DNA (satDNA) corresponds to iterable objects used in programming. The purpose of this article is to show how satDNA sequences can be iterated over to count a deterministic number of cell divisions: computational models (attached for free download) are introduced that handle DNA repeated sequences as iterable counters and simulate their use in cells through an epigenetic marker (cytosine methylation) as an iterator. SatDNA, because of its propensity to remodel its structure, can also operate as a strong accelerator in the evolution of complex organs and provides a basis to control interspecific variability of shapes.

Dermatoglyphics and abdominal resistance in female children and adolescents: a cross-sectional study

Background: Dermatoglyphics is considered, in the scientific milieu, to be an epigenetic marker. The objective of this study was to analyze the presence of dermatoglyphic marks characteristic of neuromotor capacity and abdominal resistance in children and adolescents. Methods: This is a cross-sectional study. The sample consisted of 1,002 individuals, female children and adolescents between the ages of 10 and 16, from public and private schools in the city of Joaçaba, Santa Catarina, Brazil. The protocol selected for analyzing the fingerprints was dermatoglyphics, proposed by Cummins and Midlo using a Dermatoglyphic Reader. The Brazilian Sports Project Manual - PROESP 2015 was used to collect data on muscle strength motor tests. Results: The results showed the presence of a dermatoglyphic mark characteristic of abdominal motor capacity and muscle strength in females. A higher frequency of arches was identified in MET4 and whorls in MET5 and MDT4 in the Risk Zone group. In the Healthy Zone group, ulnar loop was found to be more frequent in MET4, MET5, and MDT4 fingers. Conclusions: The results demonstrated a predictive marker for abdominal motor capacity and strength in females through dermatoglyphics.

A novel epigenetic marker, TET2, is identified in the intractable epileptic brain and regulates ABCB1 in the blood-brain barrier

BackgroundDrug-resistant epilepsy (DRE) is a chronic condition derived from spontaneous changes and regulatory effects in the epileptic brain. DNA methylation, an inheritable but reversible epigenetic change, may participate in this complicated regulatory network. As demethylation factors, ten-eleven translocation (TET) family members have become a focus in recent studies of neurological disorders. Thus, we aimed to unravel their role in DRE and their function related to the possible refractory factor ABCB1 in a blood-brain barrier (BBB) model.MethodsWe quantified and localized TET1, TET2 and 5-hydroxymethylcytosine (5-hmC) in the temporal lobe cortex of DRE patients (n = 27) and traumatic brain haemorrhage controls (n = 10) by immunochemical staining. TET2 and ABCB1 expression patterns were determined in the temporal cortex and isolated brain capillaries of DRE patients using immunohistological detection and Western blot analysis, respectively. A BBB model constructed with hCMEC/D3 cells was used to verify the demethylation and regulatory effects of TET2 on ABCB1.ResultsTET2 expression was significantly increased in the temporal cortical tissue of DRE patients with or without hippocampal sclerosis (HS) compared to control patients, while TET1 and 5-hmC showed differences in expression. We also discovered that the vascular endothelium of DRE patients has a strong affinity for TET2. ABCB1 and TET2 have identical densities in the DRE temporal cortex, and they both have evidently higher expression in the vascular endothelium from the neocortex of DRE patients. In the BBB, TET2 depletion can cause attenuated expression and function of ABCB1, as well as a pattern of higher methylation in CpG islands of the ABCB1 promoter.ConclusionsThrough a cohort study performed on the temporal cortex and brain vessels of DRE patients, we identified a novel epigenetic marker, TET2. Data from experiments in a BBB model suggest that TET2 has a specific regulatory effect on ABCB1, which may serve as a potential mechanism and target in DRE and requires further research.

Comparative Study between Saffron (Crocus sativus L.) and / or Turmeric (Curcuma longa L.) Extracts on D-galactose Deleterious Brain Effects in Rats

Aims: This study was designed to investigate the active chemical constituents and antioxidant capacities of saffron stigmas and turmeric rhizomes ethanolic extracts (ESE and ETE) respectively. D- galactose deleterious brain effects as well as the role of ESE and ETE supplementation against D-galactose intoxication were evaluated on male rat’s brain. Place of study: Biochemistry and Nutrition Department, Faculty of Women for Arts, Science and Education, Ain Shams University. Methodology: Fifty adult male Sprague-Dawley rats were divided into 5 groups; 10 rats each. Group (1): Healthy control; group (2): D-galactose control; rats were intoxicated with D-galactose (250mg/kg body weight /day/subcutaneously); group (3-5): D-galactose intoxicated rats and supplemented with (30mg /kg body weight /daily orally) of ESE, ETE and (15mg /kg body weight /daily orally) from each extract respectively for six weeks. Results: Research results revealed that saffron and turmeric ethanolic extracts contain active chemical constituents including polyphenols and flavonoids that possess high antioxidant activity. Biochemical analysis of brain tissues documented that injection with D-galactose caused significant increase (p≤0.05) in oxidative stress parameters including [advanced glycation end products (AGEs), protein carbonyl group (PCG), malondialdehyde (MDA) and nitric oxide (NO) Levels], pro-inflammatory markers like [tumor necrosis factor alpha (TNF-α) and interleukin -6 (IL-6) levels] , epigenetic marker [p16INK4a content] as well as neural cell markers [metallothoenins (MTs) and serotonin (5-HT) levels].On the other hand D-galactose intoxication caused significant decrease (p≤0.05) in brain antioxidants as [total antioxidant capacity (TAC), reduced glutathione (GSH) level and catalase (CAT) activity] as well as brain acetylcholinesterase (AChE) activity. All these results were proved by the microscopic examination and apoptotic markers immunohistochemical analysis of brain tissues that revealed degenerative changes in cerebral cortex and hippocampus. Oral administration of saffron and turmeric ethanolic extracts alone or in combination decreased brain oxidants, pro-inflammatory markers, epigenetic marker and neural cell markers levels while increased the levels and activities of antioxidants as well as AChE activity associated with an improvement of brain microscopic examination and immunohistochemical analysis. The most significant improvements (p≤0.05) were recorded in the group that supplemented with both extracts. Conclusion: Study results proved that saffron and turmeric ethanolic extracts active components were able to correct deleterious brain effects induced by D-galactose and using their mixture was more efficient in ameliorating brain toxicity than using each extract alone evidenced by biochemical analysis, microscopic examination as well as immunohistochemical determination of apoptotic markers in bmrain tissues. It is advised to add saffron and turmeric to human foods and to prepare their ethanolic extracts to be available for human beings due to their ability to preserve brain functions and structure as well as their potential to inhibit and retard brain aging and neuro-degeneration.

The dynamics of N6-methyladenine RNA modification in interactions between rice and plant viruses

Background N6-methyladenosine (m6A) is the most common RNA modification in eukaryotes and has been implicated as a novel epigenetic marker that is involved in various biological processes. The pattern and functional dissection of m6A in the regulation of several major human viral diseases have already been reported. However, the patterns and functions of m6A distribution in plant disease bursting remain largely unknown. Results We analyse the high-quality m6A methylomes in rice plants infected with two devastating viruses. We find that the m6A methylation is mainly associated with genes that are not actively expressed in virus-infected rice plants. We also detect different m6A peak distributions on the same gene, which may contribute to different antiviral modes between rice stripe virus or rice black-stripe dwarf virus infection. Interestingly, we observe increased levels of m6A methylation in rice plant response to virus infection. Several antiviral pathway-related genes, such as RNA silencing-, resistance-, and fundamental antiviral phytohormone metabolic-related genes, are also m6A methylated. The level of m6A methylation is tightly associated with its relative expression levels. Conclusions We revealed the dynamics of m6A modification during the interaction between rice and viruses, which may act as a main regulatory strategy in gene expression. Our investigations highlight the significance of m6A modifications in interactions between plant and viruses, especially in regulating the expression of genes involved in key pathways.

EMBR-04. BET INHIBITION TARGETS RADIOTHERAPY RESISTANCE IN H3K27ME3-DEFICIENT GROUP 3 MEDULLOBLASTOMA

Medulloblastoma has been categorized into four subgroups based on genetic, epigenetic and transcriptional profiling. However, molecular pathways determining radiotherapy response in this tumor remain elusive. Here, we investigated the role of the EZH2-dependent histone H3K27 tri-methylation in radiotherapy response in medulloblastoma. We demonstrate that 47.2% of group 3 and 4 medulloblastoma patients have H3K27me3-deficient tumors. Loss of H3K27me3 was associated with a radioresistant phenotype, high relapse rates and poor overall survival. We show that an epigenetic switch from H3K27me3 to H3K27ac occurs at specific genomic loci in H3K27me3-deficient medulloblastoma cells altering the transcriptional profile. The resulting up-regulation of EPHA2 (ephrin type-A receptor 2) stimulates an excessive activation of the pro-survival AKT signaling pathway leading to radiotherapy resistance. We show that BET inhibition targets radiation resistance in H3K27me3-deficient medulloblastoma by suppressing H3K27ac levels, blunting EPHA2 overexpression and mitigating the excessive AKT signaling. Additionally, BET inhibition sensitizes medulloblastoma cells to radiation by enhancing apoptotic response through suppression of Bcl-XL and up-regulation of Bim expression. Our work demonstrates a novel mechanism of radiation resistance in medulloblastoma and identifies an epigenetic marker predictive of radiotherapy response. Based on these findings we propose an epigenetically guided treatment approach targeting radiotherapy resistance in medulloblastoma patients.

Plasmodium falciparum malaria drives epigenetic reprogramming of human monocytes toward a regulatory phenotype

In malaria-naïve children and adults, Plasmodium falciparum-infected red blood cells (Pf-iRBCs) trigger fever and other symptoms of systemic inflammation. However, in endemic areas where individuals experience repeated Pf infections over many years, the risk of Pf-iRBC-triggered inflammatory symptoms decreases with cumulative Pf exposure. The molecular mechanisms underlying these clinical observations remain unclear. Age-stratified analyses of uninfected, asymptomatic Malian individuals before the malaria season revealed that monocytes of adults produced lower levels of inflammatory cytokines (IL-1β, IL-6 and TNF) in response to Pf-iRBC stimulation compared to monocytes of Malian children and malaria-naïve U.S. adults. Moreover, monocytes of Malian children produced lower levels of IL-1β and IL-6 following Pf-iRBC stimulation compared to 4–6-month-old infants. Accordingly, monocytes of Malian adults produced more IL-10 and expressed higher levels of the regulatory molecules CD163, CD206, Arginase-1 and TGM2. These observations were recapitulated in an in vitro system of monocyte to macrophage differentiation wherein macrophages re-exposed to Pf-iRBCs exhibited attenuated inflammatory cytokine responses and a corresponding decrease in the epigenetic marker of active gene transcription, H3K4me3, at inflammatory cytokine gene loci. Together these data indicate that Pf induces epigenetic reprogramming of monocytes/macrophages toward a regulatory phenotype that attenuates inflammatory responses during subsequent Pf exposure. Trial Registration: ClinicalTrials.gov NCT01322581.

Rad9, a 53BP1 Ortholog of Budding Yeast, Is Insensitive to Spo11-Induced Double-Strand Breaks During Meiosis

Exogenous double-strand breaks (DSBs) induce a DNA damage response during mitosis as well as meiosis. The DNA damage response is mediated by a cascade involving Mec1/Tel1 (ATR/ATM) and Rad53 (Chk2) kinases. Meiotic cells are programmed to form DSBs for the initiation of meiotic recombination. In budding yeast, Spo11-mediated meiotic DSBs activate Mec1/Tel1, but not Rad53; however, the mechanism underlying the insensitivity of Rad53 to meiotic DSBs remains largely unknown. In this study, we found that meiotic cells activate Rad53 in response to exogenous DSBs and that this activation is dependent on an epigenetic marker, Dot1-dependent histone H3K79 methylation, which becomes a scaffold of an Rad53 mediator, Rad9, an ortholog of 53BP1. In contrast, Rad9 is insensitive to meiotic programmed DSBs. This insensitiveness of Rad9 derives from its inability to bind to the DSBs. Indeed, artificial tethering of Rad9 to the meiotic DSBs activated Rad53. The artificial activation of Rad53 kinase in meiosis decreases the repair of meiotic DSBs. These results suggest that the suppression of Rad53 activation is a key event in initiating a meiotic program that repairs programmed DSBs.