Orbital Magnetism and Current Distribution of Two-Dimensional Electrons under Confining Potential

The spatial distribution of electric current under magnetic field and the resultant orbital magnetism have been studied for two-dimensional electrons under a harmonic confining potential V(\vecvar{r})=m \omega_0^2 r^2/2 in various regimes of temperature and magnetic field, and the microscopic conditions for the validity of Landau diamagnetism are clarified. Under a weak magnetic field (\omega_c\lsim\omega_0, \omega_c being a cyclotron frequency) and at low temperature (T\lsim\hbar\omega_0), where the orbital magnetic moment fluctuates as a function of the field, the currents are irregularly distributed paramagnetically or diamagnetically inside the bulk region. As the temperature is raised under such a weak field, however, the currents in the bulk region are immediately reduced and finally there only remains the diamagnetic current flowing along the edge. At the same time, the usual Landau diamagnetism results for the total magnetic moment. The origin of this dramatic temperature dependence is seen to be in the multiple reflection of electron waves by the boundary confining potential, which becomes important once the coherence length of electrons gets longer than the system length. Under a stronger field (\omega_c\gsim\omega_0), on the other hand, the currents in the bulk region cause de Haas-van Alphen effect at low temperature as T\lsim\hbar\omega_c. As the temperature gets higher (T\gsim\hbar\omega_c) under such a strong field, the bulk currents are reduced and the Landau diamagnetism by the edge current is recovered.Comment: 15 pages, 11 figure

Orbital Magnetism in the Ballistic Regime: Geometrical Effects

We present a general semiclassical theory of the orbital magnetic response of noninteracting electrons confined in two-dimensional potentials. We calculate the magnetic susceptibility of singly-connected and the persistent currents of multiply-connected geometries. We concentrate on the geometric effects by studying confinement by perfect (disorder free) potentials stressing the importance of the underlying classical dynamics. We demonstrate that in a constrained geometry the standard Landau diamagnetic response is always present, but is dominated by finite-size corrections of a quasi-random sign which may be orders of magnitude larger. These corrections are very sensitive to the nature of the classical dynamics. Systems which are integrable at zero magnetic field exhibit larger magnetic response than those which are chaotic. This difference arises from the large oscillations of the density of states in integrable systems due to the existence of families of periodic orbits. The connection between quantum and classical behavior naturally arises from the use of semiclassical expansions. This key tool becomes particularly simple and insightful at finite temperature, where only short classical trajectories need to be kept in the expansion. In addition to the general theory for integrable systems, we analyze in detail a few typical examples of experimental relevance: circles, rings and square billiards. In the latter, extensive numerical calculations are used as a check for the success of the semiclassical analysis. We study the weak-field regime where classical trajectories remain essentially unaffected, the intermediate field regime where we identify new oscillations characteristic for ballistic mesoscopic structures, and the high-field regime where the typical de Haas-van Alphen oscillations exhibit finite-size corrections. We address the comparison with experimental data obtained in high-mobility semiconductor microstructures discussing the differences between individual and ensemble measurements, and the applicability of the present model.Comment: 88 pages, 15 Postscript figures, 3 further figures upon request, to appear in Physics Reports 199

Effects of IKAP/hELP1 Deficiency on Gene Expression in Differentiating Neuroblastoma Cells: Implications for Familial Dysautonomia

Familial dysautonomia (FD) is a developmental neuropathy of the sensory and autonomous nervous systems. The IKBKAP gene, encoding the IKAP/hELP1 subunit of the RNA polymerase II Elongator complex is mutated in FD patients, leading to a tissue-specific mis-splicing of the gene and to the absence of the protein in neuronal tissues. To elucidate the function of IKAP/hELP1 in the development of neuronal cells, we have downregulated IKBKAP expression in SHSY5Y cells, a neuroblastoma cell line of a neural crest origin. We have previously shown that these cells exhibit abnormal cell adhesion when allowed to differentiate under defined culture conditions on laminin substratum. Here, we report results of a microarray expression analysis of IKAP/hELP1 downregulated cells that were grown on laminin under differentiation or non-differentiation growth conditions. It is shown that under non-differentiation growth conditions, IKAP/hELP1 downregulation affects genes important for early developmental stages of the nervous system, including cell signaling, cell adhesion and neural crest migration. IKAP/hELP1 downregulation during differentiation affects the expression of genes that play a role in late neuronal development, in axonal projection and synapse formation and function. We also show that IKAP/hELP1 deficiency affects the expression of genes involved in calcium metabolism before and after differentiation of the neuroblastoma cells. Hence, our data support IKAP/hELP1 importance in the development and function of neuronal cells and contribute to the understanding of the FD phenotype

Progress for research of grape and wine culture in Georgia, the South Caucasus

This communication will provide the latest information about the progress of the “Research Project for the Study of Georgian Grapes and Wine Culture”, managed by the National Wine Agency of Georgia since 2014. Local and foreign institutions continue to work together with the aim of stimulating multidisciplinary scientific research activity on Georgian viticulture and viniculture and to reconstruct their development from Neolithic civilizations to the present. The project is multidisciplinary in nature, merging contributions from archaeology, history, ethnography, molecular genetics, biomolecular archaeology, palaeobotany, ampelography, enology, climatology and other scientific fields

Phosphatidylserine Increases IKBKAP Levels in Familial Dysautonomia Cells

Familial Dysautonomia (FD) is an autosomal recessive congenital neuropathy that results from abnormal development and progressive degeneration of the sensory and autonomic nervous system. The mutation observed in almost all FD patients is a point mutation at position 6 of intron 20 of the IKBKAP gene; this gene encodes the IκB kinase complex-associated protein (IKAP). The mutation results in a tissue-specific splicing defect: Exon 20 is skipped, leading to reduced IKAP protein expression. Here we show that phosphatidylserine (PS), an FDA-approved food supplement, increased IKAP mRNA levels in cells derived from FD patients. Long-term treatment with PS led to a significant increase in IKAP protein levels in these cells. A conjugate of PS and an omega-3 fatty acid also increased IKAP mRNA levels. Furthermore, PS treatment released FD cells from cell cycle arrest and up-regulated a significant number of genes involved in cell cycle regulation. Our results suggest that PS has potential for use as a therapeutic agent for FD. Understanding its mechanism of action may reveal the mechanism underlying the FD disease

Olfactory Stem Cells, a New Cellular Model for Studying Molecular Mechanisms Underlying Familial Dysautonomia

International audienceBackground: Familial dysautonomia (FD) is a hereditary neuropathy caused by mutations in the IKBKAP gene, the most common of which results in variable tissue-specific mRNA splicing with skipping of exon 20. Defective splicing is especially severe in nervous tissue, leading to incomplete development and progressive degeneration of sensory and autonomic neurons. The specificity of neuron loss in FD is poorly understood due to the lack of an appropriate model system. To better understand and modelize the molecular mechanisms of IKBKAP mRNA splicing, we collected human olfactory ecto-mesenchymal stem cells (hOE-MSC) from FD patients. hOE-MSCs have a pluripotent ability to differentiate into various cell lineages, including neurons and glial cells.Methodology/Principal Findings: We confirmed IKBKAP mRNA alternative splicing in FD hOE-MSCs and identified 2 novel spliced isoforms also present in control cells. We observed a significant lower expression of both IKBKAP transcript and IKAP/hELP1 protein in FD cells resulting from the degradation of the transcript isoform skipping exon 20. We localized IKAP/hELP1 in different cell compartments, including the nucleus, which supports multiple roles for that protein. We also investigated cellular pathways altered in FD, at the genome-wide level, and confirmed that cell migration and cytoskeleton reorganization were among the processes altered in FD. Indeed, FD hOE-MSCs exhibit impaired migration compared to control cells. Moreover, we showed that kinetin improved exon 20 inclusion and restores a normal level of IKAP/hELP1 in FD hOE-MSCs. Furthermore, we were able to modify the IKBKAP splicing ratio in FD hOE-MSCs, increasing or reducing the WT (exon 20 inclusion):MU (exon 20 skipping) ratio respectively, either by producing free-floating spheres, or by inducing cells into neural differentiation.Conclusions/Significance: hOE-MSCs isolated from FD patients represent a new approach for modeling FD to better understand genetic expression and possible therapeutic approaches. This model could also be applied to other neurological genetic diseases

DNA methylation signatures of Prostate Cancer in peripheral T-cells

Abstract Background Prostate Cancer (PCa) is the second most common cancer in men where advancements have been made for early detection using imaging techniques, however these are limited by lesion size. Immune surveillance has emerged as an effective approach for early detection and to monitor disease progression. In recent studies, we have shown that host peripheral blood immune cells undergo changes in DNA methylation in liver and breast cancer. Methods In the current study, we examined the DNA methylation status of peripheral blood T cells of men with positive biopsy for PCa versus men with negative biopsy having benign prostate tissue, defined as controls. T cells DNA was isolated and subjected to Illumina Infinium methylation EPIC array and validated using Illumina amplicon sequencing and pyrosequencing platforms. Results Differential methylation of 449 CG sites between control and PCa T cell DNA showed a correlation with Gleason score (p < 0.05). Two hundred twenty-three differentially methylated CGs between control and PCa (∆ß +/− 10%, p < 0.05), were enriched in pathways involved in immune surveillance system. Three CGs which were found differentially methylated following DMP (Differentially methylated probes) analysis of ChAMP remained significant after BH (Benjamini-Hochberg) correction, of which, 2 CGs were validated. Predictive ability of combination of these 3 CGs (polygenic methylation score, PMS) to detect PCa had high sensitivity, specificity and overall accuracy. PMS also showed strong positive correlation with Gleason score and tumor volume of PCa patients. Conclusions Results from the current study provide for the first-time a potential role of DNA methylation changes in peripheral T cells in PCa. This non-invasive methodology may allow for early intervention and stratification of patients into different prognostic groups to reduce PCa associated morbidity from repeat invasive prostate biopsies and design therapeutic strategy to reduce PCa associated mortality

DNA methylation signatures of breast cancer in peripheral T-cells

Abstract Background Immune surveillance acts as a defense mechanism in cancer, and its disruption is involved in cancer progression. DNA methylation reflects the phenotypic identity of cells and recent data suggested that DNA methylation profiles of T cells and peripheral blood mononuclear cells (PBMC) are altered in cancer progression. Methods We enrolled 19 females with stage 1 and 2, nine with stage 3 and 4 and 9 age matched healthy women. T cells were isolated from peripheral blood and extracted DNA was subjected to Illumina 450 K DNA methylation array analysis. Raw data was analyzed by BMIQ, ChAMP and ComBat followed by validation of identified genes by pyrosequencing. Results Analysis of data revealed ~ 10,000 sites that correlated with breast cancer progression and established a list of 89 CG sites that were highly correlated (p  0.7, r < − 0.7) with breast cancer progression. The vast majority of these sites were hypomethylated and enriched in genes with functions in the immune system. Conclusions The study points to the possibility of using DNA methylation signatures as a noninvasive method for early detection of breast cancer and its progression which need to be tested in clinical studies