From coupled Rashba electron- and hole-gas layers to three-dimensional topological insulators

We introduce a system of stacked two-dimensional electron-and hole-gas layers with Rashba spin-orbit interaction and show that the tunnel coupling between the layers induces a strong three-dimensional (3D) topological insulator phase. At each of the two-dimensional bulk boundaries we find the spectrum consisting of a single anisotropic Dirac cone, which we show by analytical and numerical calculations. Our setup has a unit cell consisting of four tunnel coupled Rashba layers and presents a synthetic strong 3D topological insulator and is distinguished by its rather high experimental feasibility

A high-resolution RNA expression atlas of Retinitis Pigmentosa genes in the human and mouse retinas

PURPOSE. Retinitis pigmentosa (RP) is one of the leading causes of visual handicap in the world population and is characterized by high genetic heterogeneity. The study of the disease mechanisms and the development of efficient therapeutic approaches have mostly relied on the availability of animal models for this condition, so far. Nevertheless, little information is available about the RNA expression profiles of RP genes in the human retina. An expression atlas of 34 known RP genes in human and murine retinas was generated to overcome this lack of information. METHODS. Appropriate templates were retrieved for 34 RP genes that were used to perform RNA in situ hybridization studies on human and murine adult eyes. RESULTS. Most of the genes displayed similar patterns between human and mouse retina. Different expression patterns were observed for the CNGB1, USH2A, and FSCN2 genes, compared with those in previously reported profiles. In addition, different expression profiles were detected for the RPGR, CA4, PAP1, RGR, and RLBP1 genes in human and mouse retinas. CONCLUSIONS. The first gene expression atlas has been generated of RP genes in human and murine retinas. Differences observed in the expression patterns of some genes in humans and mice, will open new perspectives on the function of these genes and their putative roles in disease pathogenesis

The influence of gibberellic acid and paclobutrazol on induction of somatic embryogenesis in wild type and hairy root cultures of Centaurium erythraea Gillib.

The effects of exogenous gibberellic acid (GA3) and paclobutrazol on induction of somatic embryos in wild type and hairy root culture of Centaurium erythraea Gillib. were investigated. Both compoundswere incorperated into 1/2 MS medium at 6 concentrations (0.01, 0.03, 0.1, 0.3, 1.0 and 3.0 ìM). Wild type root and hairy root explants cultured in the presence of GA3 at all tested concentrations under 16-h photoperiod or in the darkness decreased the number of somatic embryos that were produced. Paclobutrazol (0.3 mM) induced the largest number (19.7, 16.5) of somatic embryos in wild type and hairy root cultures, respectively. Rooting of plants derived from somatic embryos as achieved on ½MSmedium. These results indicate that paclobutrazol is beneficial for somatic embryo induction and formation in wild type and hairy root culture

Supplementary material for: "New aurone epoxide and auronolignan from the heartwood of Cotinus coggygria Scop."

Table S1. HPLC program for the quantification of the main compounds from the C. coggygria CH2Cl2/MeOH extract Figure S1. UV spectra of 14 in MeOH, with addition of AlCl3, and HCl Figure S2. UV spectra of compound 14 in MeOH, with NaOAc, NaOAc+H3BO3 and with NaOMe Figure S3. 1H NMR spectrum of compound 14 Figure S4. 13C NMR spectrum of compound 14 Figure S5. Aromatic part of the COSY spectrum of 14 Figure S6. Aromatic part of the NOESY spectrum of 14 Figure S7. Aromatic part of the HSQC spectrum of 14 Figure S8. Aromatic part of the HMBC spectrum of 14 Figure S9. Key HMBC correlations of 14 Table S2. 1H, 13C NMR and HMBC data of 14 (CD3OD, δ ppm, J in Hz) Figure S10. Aromatic part of the 1H NMR spectrum of 15 Figure S11. Aliphatic part of the 1H NMR spectrum of 15 Figure S12. 13C NMR spectrum of 15 Figure S13. HSQC spectrum of 15 Figure S14. The first part of the HMBC spectrum of 15 Figure S15. The second part of the HMBC spectrum of 15 Figure S16. HMBC (4 Hz) correlation H-7''/C-4' (15) Figure S17. The first part of the NOESY spectrum of 15 Figure S18. The second part of the NOESY spectrum of 15 Table S3. 1H and 13C NMR data of 15 (CD3OD, δ ppm, J in Hz) Figure S19. 3-Aryl-propanol moiety in 15 Figure S20. Key HMBC correlations in 15 Figure S21. UV spectrum of 15 Figure S22. UV spectrum of 10This is the supplementary material for the article: Miroslav Novakovic, Iris Djordjevic, Nina Todorovic, Snezana Trifunovic, Boban Andjelkovic, Boris Mandic, Milka Jadranin, Ivan Vuckovic, Vlatka Vajs, Slobodan Milosavljevic & Vele Tesevic (2019) New aurone epoxide and auronolignan from the heartwood of Cotinus coggygria Scop, Natural Product Research, 33:19, 2837-2844, DOI: [https://dx.doi.org/10.1080/14786419.2018.1508141]Published version of the article: [https://cer.ihtm.bg.ac.rs/handle/123456789/2389

DNA methylation and differential gene regulation in photoreceptor cell death

Retinitis pigmentosa (RP) defines a group of inherited degenerative retinal diseases causing progressive loss of photoreceptors. To this day, RP is still untreatable and rational treatment development will require a thorough understanding of the underlying cell death mechanisms. Methylation of the DNA base cytosine by DNA methyltransferases (DNMTs) is an important epigenetic factor regulating gene expression, cell differentiation, cell death, and survival. Previous studies suggested an involvement of epigenetic mechanisms in RP, and in this study, increased cytosine methylation was detected in dying photoreceptors in the rd1, rd2, P23H, and S334ter rodent models for RP. Ultrastructural analysis of photoreceptor nuclear morphology in the rd1 mouse model for RP revealed a severely altered chromatin structure during retinal degeneration that coincided with an increased expression of the DNMT isozyme DNMT3a. To identify disease-specific differentially methylated DNA regions (DMRs) on a genomic level, we immunoprecipitated methylated DNA fragments and subsequently analyzed them with a targeted microarray. Genome-wide comparison of DMRs between rd1 and wild-type retina revealed hypermethylation of genes involved in cell death and survival as well as cell morphology and nervous system development. When correlating DMRs with gene expression data, we found that hypermethylation occurred alongside transcriptional repression. Consistently, motif analysis showed that binding sites of several important transcription factors for retinal physiology were hypermethylated in the mutant model, which also correlated with transcriptional silencing of their respective target genes. Finally, inhibition of DNMTs in rd1 organotypic retinal explants using decitabine resulted in a substantial reduction of photoreceptor cell death, suggesting inhibition of DNA methylation as a potential novel treatment in RP

Deceleration of Fusion–Fission Cycles Improves Mitochondrial Quality Control during Aging

Mitochondrial dynamics and mitophagy play a key role in ensuring mitochondrial quality control. Impairment thereof was proposed to be causative to neurodegenerative diseases, diabetes, and cancer. Accumulation of mitochondrial dysfunction was further linked to aging. Here we applied a probabilistic modeling approach integrating our current knowledge on mitochondrial biology allowing us to simulate mitochondrial function and quality control during aging in silico. We demonstrate that cycles of fusion and fission and mitophagy indeed are essential for ensuring a high average quality of mitochondria, even under conditions in which random molecular damage is present. Prompted by earlier observations that mitochondrial fission itself can cause a partial drop in mitochondrial membrane potential, we tested the consequences of mitochondrial dynamics being harmful on its own. Next to directly impairing mitochondrial function, pre-existing molecular damage may be propagated and enhanced across the mitochondrial population by content mixing. In this situation, such an infection-like phenomenon impairs mitochondrial quality control progressively. However, when imposing an age-dependent deceleration of cycles of fusion and fission, we observe a delay in the loss of average quality of mitochondria. This provides a rational why fusion and fission rates are reduced during aging and why loss of a mitochondrial fission factor can extend life span in fungi. We propose the ‘mitochondrial infectious damage adaptation’ (MIDA) model according to which a deceleration of fusion–fission cycles reflects a systemic adaptation increasing life span

Stochastic Drift in Mitochondrial DNA Point Mutations: A Novel Perspective Ex Silico

The mitochondrial free radical theory of aging (mFRTA) implicates Reactive Oxygen Species (ROS)-induced mutations of mitochondrial DNA (mtDNA) as a major cause of aging. However, fifty years after its inception, several of its premises are intensely debated. Much of this uncertainty is due to the large range of values in the reported experimental data, for example on oxidative damage and mutational burden in mtDNA. This is in part due to limitations with available measurement technologies. Here we show that sample preparations in some assays necessitating high dilution of DNA (single molecule level) may introduce significant statistical variability. Adding to this complexity is the intrinsically stochastic nature of cellular processes, which manifests in cells from the same tissue harboring varying mutation load. In conjunction, these random elements make the determination of the underlying mutation dynamics extremely challenging. Our in silico stochastic study reveals the effect of coupling the experimental variability and the intrinsic stochasticity of aging process in some of the reported experimental data. We also show that the stochastic nature of a de novo point mutation generated during embryonic development is a major contributor of different mutation burdens in the individuals of mouse population. Analysis of simulation results leads to several new insights on the relevance of mutation stochasticity in the context of dividing tissues and the plausibility of ROS ”vicious cycle” hypothesis

Somatic Point Mutations in mtDNA Control Region Are Influenced by Genetic Background and Associated with Healthy Aging: A GEHA Study

Tissue specific somatic mutations occurring in the mtDNA control region have been proposed to provide a survival advantage. Data on twins and on relatives of long-lived subjects suggested that the occurrence/accumulation of these mutations may be genetically influenced. To further investigate control region somatic heteroplasmy in the elderly, we analyzed the segment surrounding the nt 150 position (previously reported as specific of Leukocytes) in various types of leukocytes obtained from 195 ultra-nonagenarians sib-pairs of Italian or Finnish origin collected in the frame of the GEHA Project. We found a significant correlation of the mtDNA control region heteroplasmy between sibs, confirming a genetic influence on this phenomenon. Furthermore, many subjects showed heteroplasmy due to mutations different from the C150T transition. In these cases heteroplasmy was correlated within sibpairs in Finnish and northern Italian samples, but not in southern Italians. This suggested that the genetic contribution to control region mutations may be population specific. Finally, we observed a possible correlation between heteroplasmy and Hand Grip strength, one of the best markers of physical performance and of mortality risk in the elderly. Our study provides new evidence on the relevance of mtDNA somatic mutations in aging and longevity and confirms that the occurrence of specific point mutations in the mtDNA control region may represent a strategy for the age-related remodelling of organismal functions