Anomalous microwave response in the dissipative regime of topological superconducting devices based on Bi2Te2.3Se0.7

Superconducting proximity junctions based on topological insulators are widely believed to harbor Majorana-like bound states. The latter serves as a paradigm non-local topological quantum computation protocols. Nowadays, a search for topological phases in different materials, perspective for a realization of topological qubits, is one of the central efforts in quantum physics. It is motivated, in particular, by recent observation of anomalous ac Josephson effect, which being a signature of Majorana physics. Its manifestations, such as a fractional Josephson frequency and the absence of the first (or several odd in more rare cases), Shapiro steps, were reported for different materials. Here we study Shapiro steps in Nb/Bi2Te2.3Se0.7/Nb junctions, based on ultrasmall single crystals of a 3D topological insulator synthesized by a physical vapor deposition (PVD) technique. We present evidence that our junctions are ballistic. When subjected to microwave radiation, the junctions exhibit Shapiro steps, but the first step is missing. Typically it is assumed that the missing first step (MFS) effect cannot be observed in the presence of quasiparticle poisoning due to suppression of the 4{\pi}-periodic component. Our findings within the context of the RSJ-model of Josephson junction dynamics show that such behaviour of samples corresponds to a specific condition, requiring a minimum of 5% of the 4{\pi}-component for disappearance of the first Shapiro step.Comment: Keywords: Shapiro step missing, Topological insulator, Superconductivity, Ballistic transport, 4{\pi}-periodic componen

ЭМИССИОННЫЕ ПРОЦЕССЫ ВЗАИМОДЕЙСТВИЯ КВАНТОВОЙ ЯМЫ С ДОНОРНЫМ ДЕЛЬТА-СЛОЕМ В pHEMT-ГЕТЕРОСТРУКТУРАХ

The paper provides experimental and theoretical study of pHEMT heterostructures with quantum well (QW) AlGaAs/InGaAs/GaAs and delta-doped layer used as active layers for fabrication of 4-18 GHz transistors. As the experimental techniques, the electrochemical capacitance-voltage (ECV) profiling and other methods of admittance spectroscopy are applied. Modernization of commercial ECV-profiling setup allows observing for the first time the concentration peak from a near-surface delta-layer of pHEMT heterostructures together with the enrichment peak from the quantum well. In order to optimize the etching speed the crater bottom control is performed by means of AFM. The electrolyte-semiconductor contact capacitance is measured with Agilent RLC-meter. The main theoretical technique used in the research is numerical modeling of nanoheterostructure key electronic features by self-consistent solution of Schrödinger and Poisson equations. The potential line-up for the conduction band bottom is obtained, and the quantized energy levels are calculated. The complex analysis of series of samples is carried out in order to understand the influence of delta-layer position on the level depth and at the carrier concentration. The optimum distance between QW and delta-layer providing the most efficient charge carrier delivery to quantum well is found. The performed research is aimed at improvement of microwave electronic devices allowing increase of the gain coefficient and the transfer characteristic of SHF-transistors.В настоящей статье проведено экспериментальное и теоретическое исследование pHEMT-гетероструктур (ГС) с квантовой ямой (КЯ) AlGaAs/InGaAs/GaAs и дельта-легированным слоем, используемых как активные области при изготовлении СВЧ-транзисторов, работающих в частотном диапазоне 4...18ГГц. В качестве экспериментальных методик применялись: электрохимическое вольт-фарадное профилирование, методы адмиттансной спектроскопии (полной проводимости). Была проведена модернизация установки ECV-Pro, что позволило впервые в эксперименте наблюдать два концентрационных пика: от приповерхностного дельта-слоя pHEMT-транзистора и пик обогащения от КЯ. Для определения оптимальной скорости травления осуществлялся контроль дна кратера в процессе травления посредством АСМ-микроскопа. Емкость контакта "электролит–полупроводник" измерялась RLCизмерителем Agilent. Основной теоретический метод исследования в работе – численное моделирование ключевых электрофизических параметров наногетероструктуры путем самосогласованного решения уравнений Шредингера и Пуассона. Были определены профили дна зоны проводимости и рассчитаны уровни размерного квантования для исследуемых образцов гетероструктуры. Проведен комплексный анализ серии образцов с целью исследования влияния положения дельта-слоя на глубину залегания уровней и концентрацию носителей в КЯ. Определено оптимальное расстояние между КЯ и дельта-слоем, обеспечивающее наиболее эффективный процесс поставки носителей заряда в квантовую яму. Проведенный цикл исследований направлен на совершенствование приборов СВЧ-электроники. Он позволяет увеличить коэффициент усиления и крутизну передаточной характеристики транзисторов

Abstract 2122: Chronic inflammatory levels of nitric oxide/reactive nitrogen species down-regulate BRCA1 protein expression and decrease homologous recombination

Abstract The link between inflammation and cancer was proposed more than 150 years ago when Virchow suggested that malignancies tend to arise at sites of chronic inflammation. Recent studies have established that elevated levels of nitric oxide/reactive nitrogen species (NO/RNS) generated in the inflammatory microenvironment are associated with several conditions critical for initiation and promotion of cancer. The BRCA1 protein contributes to cell viability in multiple ways, including DNA repair, cell cycle checkpoint control, transcription, and regulation of chromosome segregation. The BRCA1 gene mutations have been identified and associated with an increased risk of cancer. Sporadic breast carcinomas, on the other hand, rarely show mutations of this gene. Instead, BRCA1 protein expression is frequently reduced in sporadic cases. BRCA1 expression is negatively regulated at the transcriptional level by the repressive complex of retinoblastoma-like protein 2 (RBL2) and E2F4. Formation of the repression RBL2/E2F4 complex is accelerated by RBL2 dephosphorylation. Recently, protein phosphatase 2A (PP2A), an enzyme responsible for RBL2 dephosphorylation, was shown to be nitrated and activated by NO/RNS (Ohama T., et al., JBC 285, 2010). In the present investigation MCF-10A (human mammary epithelial cells) and A549 (human lung carcinoma cells) were incubated with 0.05-0.1 mM of the NO-donor SNAP, concentrations that mimic the chronic inflammation level of intracellular NO/RNS. These levels of NO/RNS induce substantial dephosphorylation of RBL2 in a PP2A dependent way. RBL2 dephosphorylation promoted a repressive RBL2/E2F4 complex formation, with accumulation of this complex into nuclei. RBL2/E2F4 inhibitory complex binds to the single E2F site in the proximal promoter of the BRCA1 gene, replaces the activator E2F1, and block BRCA1 proliferation. To measure the impact of RNS-dependent BRCA1 downregulation on the level of DNA Homologous Recombination Repair (HRR) we used DR-GFP system, which has been described by many investigators (R. S. Bindra et al., Cancer Res 65, 2005; S. E. Golding et al., JBC 279, 2004; A. J. Pierce, R. D. Johnson, L. H. Thompson, M. Jasin, Genes Dev 13, 1999). The preliminary results showed that inflammatory levels of NO/RNS significantly decreased the HRR frequency for the both types of cells. Interesting, the same concentration of SNAP also promotes MCF-10A and A549 cells proliferation. These data revealed that NO/RNS-dependent decrease in BRCA1 expression can lead to genetic instability by shifting the balance between the high-fidelity HRR and the error-prone non-homologous end-joining pathways of the DNA repair. This mechanism can play a significant role in the maintenance of genetic instability and stimulation of carcinogenesis under chronic inflammatory conditions. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2122. doi:1538-7445.AM2012-2122</jats:p

Nitric Oxide: Genomic Instability And Synthetic Lethality

Regardless of etiology, inflammatory conditions are characterized by overexpression of inducible nitric oxide synthase (iNOS) and overproduction of nitric oxide and reactive nitrogen species (NO/RNS) in epithelial and inflammatory cells at the site of carcinogenesis.NO/RNS produced in inflamed tissues can contribute to the process of carcinogenesis by different mechanisms. One of these mechanisms is NO-dependent stimulation of genomic instability by inhibiting of Breast Cancer type 1 Susceptibility protein (BRCA1) expression. Block of BRCA1 expression shifts DNA double-strand breaks (DSB) repair from error-free high-fidelity homologous recombination repair (HRR) to error-prone nonhomologous end joining (NHEJ).BRCA1 epigenetically block miRNA-155 expression via its association with HDAC2, which deacetylates histones H2A and H3 on the miRNA-155 promoter. The miRNA-155 is responsible for post-translational silencing of essential members of mismatch repair (MMR) core: MSH2, MSH6, and MLH1 proteins. They epigenetic inactivation induces DNA microsatellite instability (MSI). Recently, we demonstrated NO-dependent downregulation of MMR core proteins (MSH2, MSH6, and MLH1) through the ↓BRCA1/↑miRNA-155 signaling pathway. Hence, another NO-dependent mechanism of genomic instability is downregulation of MMR core proteins and stimulation of the DNA MSI.Loss or inhibition of Poly(ADP-ribose) polymerase 1 (PARP1) activity results in accumulation of DNA single-strand breaks, which are subsequently converted to DSB by the transcription machinery. In BRCA-positive cells, DSB are repaired by HRR, but they cannot be properly repaired in BRCA1-deficient cells, leading to genomic instability, chromosomal rearrangements, and cell death. Our data demonstrated that combination of NO-donors with PARP inhibitors significantly sensitized the BRCA1-positive cancer cells to DNA-damaging agents

Abstract 3926: Chronic inflammatory levels of nitric oxide/reactive nitrogen species downregulate BRCA1 protein expression

Abstract The link between inflammation and cancer was proposed more than 150 years ago when Virchow suggested that malignancies tend to arise at sites of chronic inflammation. Recent studies have established that elevated levels of nitric oxide/reactive nitrogen species (NO/RNS) generated in the inflammatory microenvironment are associated with several conditions critical for initiation and promotion of cancer. The BRCA1 protein contributes to cell viability in multiple ways, including DNA repair, cell cycle checkpoint control, transcription, and regulation of chromosome segregation. Hundreds of mutations in the BRCA1 gene have been identified and associated with an increased risk of cancer. Sporadic breast carcinomas, on the other hand, rarely show mutations of this gene. Instead, BRCA1 protein expression is frequently reduced in sporadic cases. As sporadic tumors account for &amp;gt;90% of the breast cancer, considerable research is directed towards the identification of mechanisms that down-regulate the function of the wild type BRCA1 and lead to genetic instability. BRCA1 expression is negatively regulated at the transcriptional level by the repressive complex of retinoblastoma-like protein 2 (RBL2) and E2F4. Formation of the repression RBL2/E2F4 complex can be accelerated by, for example, RBL2 dephosphorylation. Recently, protein phosphatase 2A (PP2A), an enzyme responsible for RBL2 dephosphorylation, was shown to be nitrated and activated by NO/RNS (Ohama T., et al., JBC 285, 8711-18, 2010). In the present investigation I demonstrate that inflammatory levels of NO/RNS induce substantial dephosphorylation of RBL2. Normal human mammary epithelial cells (MCF-10A) were incubated with 0.1 mM of the NO-donor SNAP for 6 h. This concentration of NO-donor mimics the intracellular level of NO/RNS during chronic inflammation, hypoxia, and does not induce significant DNA damage and maintains the ATM/ATR-dependent pathways intact. After 6 h incubation with SNAP, significant decrease in total amount of BRCA1 protein was observed with no apparent changes in the levels of E2F1, E2F4, and the catalytic subunit of PP2A, all involved in the regulation of BRCA1. RBL2 dephosphorylation promotes a repressive RBL2/E2F4 complex formation, which inhibits expression of BRCA1. I hypothesize that NO/RNS generated by chronic inflammatory conditions posttranslationally modify proteins involved in the regulation of BRCA1 expression and downregulate BRCA1 expression, thereby constituting a critical role in genetic instability and ultimately carcinogenesis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3926. doi:10.1158/1538-7445.AM2011-3926</jats:p

Role of nitric oxide in the radiation-induced bystander effect

AbstractCells that are not irradiated but are affected by “stress signal factors” released from irradiated cells are called bystander cells. These cells, as well as directly irradiated ones, express DNA damage-related proteins and display excess DNA damage, chromosome aberrations, mutations, and malignant transformation. This phenomenon has been studied widely in the past 20 years, since its first description by Nagasawa and Little in 1992, and is known as the radiation-induced bystander effect (RIBE). Several factors have been identified as playing a role in the bystander response. This review will focus on one of them, nitric oxide (NO), and its role in the stimulation and propagation of RIBE. The hydrophobic properties of NO, which permit its diffusion through the cytoplasm and plasma membranes, allow this signaling molecule to easily spread from irradiated cells to bystander cells without the involvement of gap junction intercellular communication. NO produced in irradiated tissues mediates cellular regulation through posttranslational modification of a number of regulatory proteins. The best studied of these modifications are S-nitrosylation (reversible oxidation of cysteine) and tyrosine nitration. These modifications can up- or down-regulate the functions of many proteins modulating different NO-dependent effects. These NO-dependent effects include the stimulation of genomic instability (GI) and the accumulation of DNA errors in bystander cells without direct DNA damage

Abstract 3633: Combination of PARP inhibitor ABT-888 with NO-donor SNAP sensitizes BRCA1 positive cancer cell lines to ionizing radiation

Abstract Loss or inhibition of Poly(ADP-ribose) polymerase 1 (PARP1) activity results in accumulation of DNA single-strand breaks, which are subsequently converted to DNA double-strand breaks (DSBs) by the cellular replication and/or transcription machinery. Breast cancer type 1 susceptibility protein (BRCA1) is essential for homologous recombination repair (HRR) of DNA DSB. In BRCA-positive cells, DSBs are repaired by HRR, but they cannot be properly repaired in BRCA-deficient cells, leading to genomic instability, chromosomal rearrangements, and cell death. The role of PARP1 in the DNA damage response promoted the development of PARP inhibitors (PARPi) as chemo- and radio-sensitizers for the treatment of cancers harboring mutations in the BRCA genes. However, inherited BRCA1 or BRCA2 mutations account for 5-10% of breast cancers and 10-15% of ovarian cancers. Hence, a low frequency of BRCA1 loss in non-hereditary tumors can limit the clinical use of this approach. Our recent work revealed significant down-regulation of BRCA1 gene expression by nitric oxide donors (NO-d) (Yakovlev, 2013). Hence, we assumed that combination of NO-d with PARP inhibitors could be effective in sensitization of the BRCA1-positive tumors to DNA-damaging therapy. We identified the optimal concentrations of PARPi ABT-888 at 20μM and NO-d SNAP at 200μM, which don't affect cell survival, but effectively block PARP1 activity or BRCA1 expression accordingly. Next, cancer cell lines were pretreated with ABT-888 or SNAP, or with they combination and irradiated. Survival curves were determined by clonogenic assay. Our preliminary data demonstrates significant radiosensitization when combining an NO-d with a PARPi in BRCA1 positive tumor cell lines (Table 1). We plan to test this drug combination on the additional cancer cell lines and on animal models for sensitization to ionizing radiation and to the different chemotherapeutic agents. Table 1.Clonogenic assay for A-549 and MDA-MB-231 cell lines: survival fraction.IR (Gy)02468A-549Control1.00±0.0380.55±0.0450.23±0.0360.09±0.0070.0242±0.004ABT-8881.00±0.0650.49±0.0310.18±0.0350.05±0.0040.0076±0.001SNAP0.97±0.0850.43±0.0450.16±0.0330.04±0.0080.0091±0.002ABT-888 + SNAP0.71±0.0750.24±0.0420.05±0.0070.01±0.0020.0014±0.0003MDA-MB-231Control1.00±0.0630.44±0.0380.15±0.0270.039±0.0070.0078±0.0007ABT-8880.85±0.0520.28±0.0170.07±0.0090.012±0.0020.0015±0.0005SNAP1.03±0.0380.3±0.0430.10±0.0080.020±0.0040.0034±0.0007ABT-888 + SNAP0.49±0.0660.12±0.0170.02±0.0070.002±0.00040.00013±0.0001 Citation Format: Aaron Wilson, Vasily A. Yakovlev. Combination of PARP inhibitor ABT-888 with NO-donor SNAP sensitizes BRCA1 positive cancer cell lines to ionizing radiation. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3633. doi:10.1158/1538-7445.AM2015-3633</jats:p