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Jan 2021 • bioRxiv

Germline polymorphisms and alternative splicing of human immunoglobulin light chain genes

Ivana Mikocziova, Ayelet Peres, Moriah Gidoni, Victor Greiff, Gur Yaari, Ludvig M Sollid

Immunoglobulin loci are rich in germline polymorphisms and identification of novel polymorphic variants can be facilitated by germline inference of B cell receptor repertoires. Germline gene inference is complicated by somatic hypermutations, errors arising from PCR amplification, and DNA sequencing as well as from the varying length of reference alleles. Inference of light chain genes is even more challenging than inference of heavy chain genes due to large gene duplication events on the kappa locus as well as absence of D genes in the rearranged light chain transcripts. Here, we analyzed the light chain cDNA sequences from naïve BCR repertoires of a Norwegian cohort of 100 individuals. We optimized light chain allele inference by tweaking parameters within TIgGER functions, extending the germline reference sequences, and establishing mismatch frequency patterns at polymorphic positions to filter out false positive candidates. As a result, we identified 48 previously unreported variants of light chain variable genes. Altogether, we selected 14 candidates for novel light chain polymorphisms for validation and successfully validated 11 by Sanger sequencing. Additional clustering of light chain 5′UTR, L-PART1 and L-PART2 revealed partial intron retention in alternative splice variants in 11 kappa and 9 lambda V alleles. The alternatively spliced transcripts were only observed in genes with low expression levels, suggesting a possible role in expression regulation. Our results provide novel insight into germline variation in human light chain immunoglobulin loci.

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Jan 2021 • Nanomaterials

Investigations of Shape, Material and Excitation Wavelength Effects on Field Enhancement in SERS Advanced Tips

Y Mandelbaum, R Mottes, Z Zalevsky, D Zitoun, A Karsenty

This article, a part of the larger research project of Surface-Enhanced Raman Scattering (SERS), describes an advanced study focusing on the shapes and materials of Tip-Enhanced Raman Scattering (TERS) designated to serve as part of a novel imager device. The initial aim was to define the optimal shape of the “probe”: tip or cavity, round or sharp. The investigations focused on the effect of shape (hemi-sphere, hemispheroid, ellipsoidal cavity, ellipsoidal rod, nano-cone), and the effect of material (Ag, Au, Al) on enhancement, as well as the effect of excitation wavelengths on the electric field. Complementary results were collected: numerical simulations consolidated with analytical models, based on solid assumptions. Preliminary experimental results of fabrication and structural characterization are also presented. Thorough analyses were performed around critical parameters, such as the plasmonic metal—Silver, Aluminium or Gold—using Rakic model, the tip geometry—sphere, spheroid, ellipsoid, nano-cone, nano-shell, rod, cavity—and the geometry of the plasmonic array: cross-talk in multiple nanostructures. These combined outcomes result in an optimized TERS design for a large number of applications. View Full-Text

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Jan 2021 • International journal of molecular sciences

Loss of Fer Jeopardizes Metabolic Plasticity and Mitochondrial Homeostasis in Lung and Breast Carcinoma Cells

Linoy Mehazri, Sally Shpungin, Shai Bel, Uri Nir

Metabolic plasticity is a hallmark of the ability of metastatic cancer cells to survive under stressful conditions. The intracellular Fer kinase is a selective constituent of the reprogramed mitochondria and metabolic system of cancer cells. In the current work, we deciphered the modulatory roles of Fer in the reprogrammed metabolic systems of metastatic, lung (H358), non-small cell lung cancer (NSCLC), and breast (MDA-MB-231), triple-negative breast cancer (TNBC), carcinoma cells. We show that H358 cells devoid of Fer (H358ΔFer), strictly depend on glucose for their proliferation and growth, and fail to compensate for glucose withdrawal by oxidizing and metabolizing glutamine. Furthermore, glucose deficiency caused increased reactive oxygen species (ROS) production and induction of a DNA damage response (DDR), accompanied by the onset of apoptosis and attenuated cell-cycle progression. Analysis of mitochondrial function revealed impaired respiratory and electron transport chain (ETC) complex 1 (comp. I) activity in the Fer-deficient H358ΔFer cells. This was manifested by decreased levels of NAD+ and ATP and relatively low abundance of tricarboxylic acid (TCA) cycle metabolites. Impaired electron transport chain comp. I activity and dependence on glucose were also confirmed in Fer-deficient, MDA-MB-231ΔFer cells. Although both H358ΔFer and MDA-MB-231ΔFer cells showed a decreased aspartate level, this seemed to be compensated by the predominance of pyrimidines synthesis over the urea cycle progression. Notably, absence of Fer significantly impeded the growth of H358ΔFer and MDA-MB-231ΔFer xenografts in mice …

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Jan 2021 • Molecules

Metal–Metal Bond in the Light of Pauling’s Rules

Elena Levi, Doron Aurbach, Carlo Gatti

About 70 years ago, in the framework of his theory of chemical bonding, Pauling proposed an empirical correlation between the bond valences (or effective bond orders (BOs)) and the bond lengths. Till now, this simple correlation, basic in the bond valence model (BVM), is widely used in crystal chemistry, but it was considered irrelevant for metal–metal bonds. An extensive analysis of the quantum chemistry data computed in the last years confirms very well the validity of Pauling’s correlation for both localized and delocalized interactions. This paper briefly summarizes advances in the application of the BVM for compounds with TM–TM bonds (TM= transition metal) and provides further convincing examples. In particular, the BVM model allows for very simple but precise calculations of the effective BOs of the TM–TM interactions. Based on the comparison between formal and effective BOs, we can easily describe steric and electrostatic effects. A possible influence of these effects on materials stability is discussed. View Full-Text

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Jan 2021 • Cells

Fer and FerT Govern Mitochondrial Susceptibility to Metformin and Hypoxic Stress in Colon and Lung Carcinoma Cells

Odeya Marciano, Linoy Mehazri, Sally Shpungin, Alexander Varvak, Eldad Zacksenhaus, Uri Nir

Aerobic glycolysis is an important metabolic adaptation of cancer cells. However, there is growing evidence that reprogrammed mitochondria also play an important metabolic role in metastatic dissemination. Two constituents of the reprogrammed mitochondria of cancer cells are the intracellular tyrosine kinase Fer and its cancer-and sperm-specific variant, FerT. Here, we show that Fer and FerT control mitochondrial susceptibility to therapeutic and hypoxic stress in metastatic colon (SW620) and non-small cell lung cancer (NSCLC-H1299) cells. Fer-and FerT-deficient SW620 and H1299 cells (SW∆ Fer/FerT and H∆ Fer/FerT cells, respectively) become highly sensitive to metformin treatment and to hypoxia under glucose-restrictive conditions. Metformin impaired mitochondrial functioning that was accompanied by ATP deficiency and robust death in SW∆ Fer/FerT and H∆ Fer/FerT cells compared to the parental SW620 and H1299 cells. Notably, selective knockout of the fer gene without affecting FerT expression reduced sensitivity to metformin and hypoxia seen in SW∆ Fer/FerT cells. Thus, Fer and FerT modulate the mitochondrial susceptibility of metastatic cancer cells to hypoxia and metformin. Targeting Fer/FerT may therefore provide a novel anticancer treatment by efficient, selective, and more versatile disruption of mitochondrial function in malignant cells. View Full-Text

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Jan 2021 • bioRxiv

Genome instability drives epistatic adaptation in the human pathogen Leishmania

Giovanni Bussotti, Laura Piel, Pascale Pescher, Malgorzata Anna Domagalska, K Shanmugha Rajan, Tirza Doniger, Disha Gajanan Hiregange, Peter J Myler, Ron Unger, Shulamit J Michaeli, Gerald Frank Spaeth

How genome instability is harnessed for fitness gain despite its potential deleterious effects is largely elusive. An ideal system to address this important open question is provided by the protozoan pathogen Leishmania that exploits frequent variations in chromosome and gene copy number to regulate expression levels. Using ecological genomics and experimental evolution approaches we provide first evidence that Leishmania adaptation relies on epistatic interactions between functionally associated gene copy number variations that can inform on pathways driving fitness gain in a given environment. We further uncover post-transcriptional regulation as a key mechanism that compensates for deleterious gene dosage effects and provides phenotypic robustness to genetically heterogenous parasite populations. Finally, we correlate dynamic variations in snoRNA gene dosage to changes in rRNA 2′-O-methylation and pseudouridylation, proposing translational control as an additional layer of parasite adaptation. Leishmania genome instability is thus harnessed for fitness gain by genome-dependent variations in gene expression, and genome-independent, compensatory mechanisms. This allows for polyclonal adaptation and maintenance of genetic heterogeneity despite strong selection. Epistatic adaptation described here needs to be considered in Leishmania epidemiology and biomarker discovery, and may be relevant to other fast evolving, eukaryotic cells that exploit genome instability for adaptation, such as fungal pathogens or cancer.

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Jan 2021 • NanoImpact

In vitro skin toxicity of CuO and ZnO nanoparticles: Application in the safety assessment of antimicrobial coated textiles

Rossella Bengalli, Alessandra Colantuoni, Ilana Perelshtein, Aharon Gedanken, Maddalena Collini, Paride Mantecca, Luisa Fiandra

In the context of nosocomial infections, there is an urgent need to develop efficient nanomaterials (NMs) with antibacterial properties for the prevention of infection diseases. Metal oxide nanoparticles (MeO-NPs) are promising candidates for the development of new antibacterial textiles. However, the direct exposure to MeO-NPs and MeO-coated NMs through skin contact could constitute a severe hazard for human health. In this work, the toxicity of copper and zinc oxide (CuO, ZnO) NPs antimicrobial-coated textiles was assessed on an in vitro reconstructed 3D model of epidermis. Thus, MeO-NPs and extracts from MeO-coated NMs were tested on EpiDerm™ skin model according to OECD TG 431 (Corrosion Test) and 439 (Irritation Test), respectively. Skin surface fluids composition is a crucial aspect to be considered in the development of NMs that have to encounter this tissue. So, for the irritation test, coated …

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Jan 2021 • Nanomaterials 11 (1), 232, 2021

Carbon Dots-Based Logic Gates

Shweta Pawar, Hamootal Duadi, Yafit Fleger, Dror Fixler

Carbon dots (CDs)-based logic gates are smart nanoprobes that can respond to various analytes such as metal cations, anions, amino acids, pesticides, antioxidants, etc. Most of these logic gates are based on fluorescence techniques because they are inexpensive, give an instant response, and highly sensitive. Computations based on molecular logic can lead to advancement in modern science. This review focuses on different logic functions based on the sensing abilities of CDs and their synthesis. We also discuss the sensing mechanism of these logic gates and bring different types of possible logic operations. This review envisions that CDs-based logic gates have a promising future in computing nanodevices. In addition, we cover the advancement in CDs-based logic gates with the focus of understanding the fundamentals of how CDs have the potential for performing various logic functions depending upon their different categories. View Full-Text

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Jan 2021 • Polymers 13 (23), 4259, 2021

Design of Magnetic Hydrogels for Hyperthermia and Drug Delivery

Sayan Ganguly, Shlomo Margel

Hydrogels are spatially organized hydrophilic polymeric systems that exhibit unique features in hydrated conditions. Among the hydrogel family, composite hydrogels are a special class that are defined as filler-containing systems with some tailor-made properties. The composite hydrogel family includes magnetic-nanoparticle-integrated hydrogels. Magnetic hydrogels (MHGs) show magneto-responsiveness, which is observed when they are placed in a magnetic field (static or oscillating). Because of their tunable porosity and internal morphology they can be used in several biomedical applications, especially diffusion-related smart devices. External stimuli may influence physical and chemical changes in these hydrogels, particularly in terms of volume and shape morphing. One of the most significant external stimuli for hydrogels is a magnetic field. This review embraces a brief overview of the fabrication of MHGs and two of their usages in the biomedical area: drug delivery and hyperthermia-based anti-cancer activity. As for the saturation magnetization imposed on composite MHGs, they are easily heated in the presence of an alternating magnetic field and the temperature increment is dependent on the magnetic nanoparticle concentration and exposure time. Herein, we also discuss the mode of different therapies based on non-contact hyperthermia heating.

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Jan 2021 • The Journal of Chemical Physics

Using quantum annealers to calculate ground state properties of molecules

Justin Copenhaver, Adam Wasserman, Birgit Wehefritz-Kaufmann

Quantum annealers are an alternative approach to quantum computing, which make use of the adiabatic theorem to efficiently find the ground state of a physically realizable Hamiltonian. Such devices are currently commercially available and have been successfully applied to several combinatorial and discrete optimization problems. However, the application of quantum annealers to problems in chemistry remains a relatively sparse area of research due to the difficulty in mapping molecular systems to the Ising model Hamiltonian. In this paper, we review two different methods for finding the ground state of molecular Hamiltonians using Ising model-based quantum annealers. In addition, we compare the relative effectiveness of each method by calculating the binding energies, bond lengths, and bond angles of the H3+ and H2O molecules and mapping their potential energy curves. We also assess the resource …

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Jan 2021 • Journal of The Electrochemical Society

Improved High-Energy Na-NCM Cathode Prepared by Ion Exchange Route via Application of Various ALD Treatments

Meital Turgeman, Miryam Fayena-Greenstein, Shaul Bublil, Netanel Shpigel, Merav Nadav Tsubery, Munseok Chae, Yuval Elias, Doron Aurbach

The application of layered oxide compounds as cathode materials for sodium-ion batteries is considered a promising direction for the development of high-energy Na-ion batteries. However, despite many efforts, practical implementation of such electrodes is still challenging, mainly due to structural and surface instabilities associated with the high operating voltage of these cathodes. One of the most effective ways to mitigate these undesirable phenomena is the use of atomic layer deposition (ALD) to form a Nano-sized protective layer on the electrode surface. Application of ALD treatment results in increased electrode stability by preventing irreversible interactions between the electrolyte and cathode material. In search of optimal coating formulations, the effect of various ALD coatings viz. sodium-aluminate, lithium-aluminate, and alumina on the electrochemical performance of Na-NCM cathode synthesized by ion …

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Jan 2021 • Polymers 13 (24), 4307, 2021

Designing Natural Polymer-Based Capsules and Spheres for Biomedical Applications—A Review

Kusha Sharma, Ze’ev Porat, Aharon Gedanken

Natural polymers, such as polysaccharides and polypeptides, are potential candidates to serve as carriers of biomedical cargo. Natural polymer-based carriers, having a core–shell structural configuration, offer ample scope for introducing multifunctional capabilities and enable the simultaneous encapsulation of cargo materials of different physical and chemical properties for their targeted delivery and sustained and stimuli-responsive release. On the other hand, carriers with a porous matrix structure offer larger surface area and lower density, in order to serve as potential platforms for cell culture and tissue regeneration. This review explores the designing of micro- and nano-metric core–shell capsules and porous spheres, based on various functions. Synthesis approaches, mechanisms of formation, general- and function-specific characteristics, challenges, and future perspectives are discussed. Recent advances in protein-based carriers with a porous matrix structure and different core–shell configurations are also presented in detail.

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Jan 2021 • Cancers

Specific Compositions of Cannabis sativa Compounds Have Cytotoxic Activity and Inhibit Motility and Colony Formation of Human Glioblastoma Cells In Vitro

Hadar Peeri, Nurit Shalev, Ajjampura C Vinayaka, Rephael Nizar, Gila Kazimirsky, Dvora Namdar, Seegehalli M Anil, Eduard Belausov, Chaya Brodie, Hinanit Koltai

Glioblastoma multiforme (GBM) is the most lethal subtype of glioma. Cannabis sativa is used for the treatment of various medical conditions. Around 150 phytocannabinoids have been identified in C. sativa, among them Δ-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) that trigger GBM cell death. However, the optimal combinations of cannabis molecules for anti-GBM activity are unknown. Chemical composition was determined using high-performance liquid chromatography (HPLC) and gas chromatography mass spectrometry (GC/MS). Cytotoxic activity was determined by XTT and lactate dehydrogenase (LDH) assays and apoptosis and cell cycle by fluorescence-activated cell sorting (FACS). F-actin structures were observed by confocal microscopy, gene expression by quantitative PCR, and cell migration and invasion by scratch and transwell assays, respectively. Fractions of a high-THC cannabis strain extract had significant cytotoxic activity against GBM cell lines and glioma stem cells derived from tumor specimens. A standard mix (SM) of the active fractions F4 and F5 induced apoptosis and expression of endoplasmic reticulum (ER)-stress associated-genes. F4 and F5 inhibited cell migration and invasion, altered cell cytoskeletons, and inhibited colony formation in 2 and 3-dimensional models. Combinations of cannabis compounds exert cytotoxic, anti-proliferative, and anti-migratory effects and should be examined for efficacy on GBM in pre-clinical studies and clinical trials. View Full-Text

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Jan 2021 • Journal of Food Science and Technology

Making salty cucumbers and honeyed apples by applying the sonochemical method

Belal Abu Salha, Nina Perkas, Aharon Gedanken

Sonochemistry was applied in the last few years for coating surfaces of various substrates for imparting desired properties to the surface. In the current paper the coating of cucumbers with NaCl nanoparticles and apples with honey nanoparticles was accomplished by applying the sonochemical method. In both coating the nanoparticles were deposited from aqueous solutions. The products were characterized by Inductively coupled plasma, Dynamic light scattering, Scanning electron microscopy, and Nuclear magnetic resonance.

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Jan 2021 • ACS nano

Electronic Tuning of Monolayer Graphene with Polymeric “Zwitterists”

James Nicolas Pagaduan, Nicholas Hight-Huf, Avdhoot Datar, Yehiel Nagar, Michael Barnes, Doron Naveh, Ashwin Ramasubramaniam, Reika Katsumata, Todd Emrick

Work function engineering of two-dimensional (2D) materials by application of polymer coatings represents a research thrust that promises to enhance the performance of electronic devices. While polymer zwitterions have been demonstrated to significantly modify the work function of both metal electrodes and 2D materials due to their dipole-rich structure, the impact of zwitterion chemical structure on work function modulation is not well understood. To address this knowledge gap, we synthesized a series of sulfobetaine-based zwitterionic random copolymers with variable substituents and used them in lithographic patterning for the preparation of negative-tone resists (i.e., “zwitterists”) on monolayer graphene. Ultraviolet photoelectron spectroscopy indicated a significant work function reduction, as high as 1.5 eV, induced by all polymer zwitterions when applied as ultrathin films (<10 nm) on monolayer graphene …

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Jan 2021 • Applied Surface Science

Analysis of fluctuations in the Raman spectra of suspended and supported graphene films

NM Yitzhak, O Girshevitz, Y Fleger, A Haran, S Katz, A Butenko, M Kaveh, I Shlimak

The repeatability of the Raman scattering (RS) spectra was analyzed in monolayer and bilayer CVD-grown graphene films. Position and width of the two main RS lines (G-line and 2D-line) together with their intensity ratio I2D/IG were measured in samples where graphene film was supported by a SiO2/Si substrate and where the film was suspended over pits in the substrate. The results are presented as histograms averaged by a Gaussian with the width W, considered as a measure of non-repeatability. Relatively large fluctuations in the I2D/IG value and linewidth were observed upon repeated measurements at the same point both in supported and suspended samples. The RS measurements in crystalline graphite and mechanically exfoliated graphene deposited on hexagonal boron nitride showed higher repeatability which means that increased W in CVD-grown films reflects the sensitivity of RS processes in …

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Jan 2021 • bioRxiv

Protein degradation analysis by affinity microfluidics

Lev Brio, Danit Wasserman, Efrat Michaely-Barbiro, Doron Gerber, Amit Tzur

Protein degradation mediated by the ubiquitin-proteasome pathway regulates signaling events in all eukaryotic cells, with implications in pathological conditions such as cancer and neurodegenerative diseases. Detection of protein degradation is an elementary need in basic and translational research. In vitro degradation assays, in particular, have been instrumental in the understanding of how cell proliferation and other fundamental cellular processes are regulated. These assays are direct, quantitative and highly informative but also laborious, typically relying on low-throughput polyacrylamide gel-electrophoresis followed by autoradiography or immunoblotting. We present protein degradation on chip (pDOC), a MITOMI-based integrated microfluidic device for discovery and analysis of ubiquitin mediated proteolysis. The platform accommodates microchambers on which protein degradation is assayed quickly and simultaneously in physiologically relevant environments, using minute amount of reagents. Essentially, pDOC provides a multiplexed, sensitive and colorimetric alternative to the conventional degradation assays, with relevance to biomedical and translational research.

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Jan 2021 • Energy Res

Na0. 44MnO2/Polyimide Aqueous Na-ion Batteries for Large Energy Storage Applications

S Maddukuri, A Nimkar, MS Chae, TR Penki, S Luski, D Aurbach

Aqueous salt batteries with high concentrations of salt or water in salt aqueous systems have received considerable attention with focus on improving working voltage range and energy density. Here, the effect of NaClO4 salt concentration on the electrochemical performance and stability of tunnel-type Na0. 44MnO2 (NMO) cathodes and organic polyimide (PI) derivative anodes was studied. High capacity retention and 100% coulombic efficiency were shown for NMO/PI full cell in saturated NaClO4 electrolyte. A high, stable capacity of 115 mAh/g was achieved for the PI anode material, and the full cell showed a stable capacity of 41 mAh/g at 2C rate for 430 cycles (calculated for the weight of NMO cathode). Even at a fast 5C rate, a discharge capacity of 33 mAh/g was maintained for 2,400 prolonged cycles with nearly 100% efficiency. The full cell device can achieve an average voltage of 1 V with energy density of 24 Wh/kg. This study highlights concentrated sodium perchlorate as a promising electrolyte solution for stabilization of electrodes and enhancement of electrochemical performance in aqueous media.

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Jan 2021 • ACS Applied Materials &amp; Interfaces

Robust Room-Temperature NO2 Sensors from Exfoliated 2D Few-Layered CVD-Grown Bulk Tungsten Di-selenide (2H-WSe2)

A Moumen, R Konar, D Zappa, E Teblum, I Perelshtein, R Lavi, ...

We report a facile and robust room-temperature NO2 sensor fabricated using bi- and multi-layered 2H variant of tungsten di-selenide (2H-WSe2) nanosheets, exhibiting high sensing characteristics. A simple liquid-assisted exfoliation of 2H-WSe2, prepared using ambient pressure chemical vapor deposition, allows smooth integration of these nanosheets on transducers. Three sensor batches are fabricated by modulating the total number of layers (L) obtained from the total number of droplets from a homogeneous 2H-WSe2 dispersion, such as ∼2L, ∼5–6L, and ∼13–17L, respectively. The gas-sensing attributes of 2H-WSe2 nanosheets are investigated thoroughly. Room temperature (RT) experiments show that these devices are specifically tailored for NO2 detection. 2L WSe2 nanosheets deliver the best rapid response compared to ∼5–6L or ∼13–17L. The response of 2L WSe2 at RT is 250, 328, and 361% to …

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Jan 2021 • AIP Advances

DNA origami based superconducting nanowires

Lior Shani, Philip Tinnefeld, Yafit Fleger, Amos Sharoni, Boris Ya Shapiro, Avner Shaulov, Oleg Gang, Yosef Yeshurun

Utilizing self-assembled DNA structures in the development of nanoelectronic circuits requires transforming the DNA strands into highly conducting wires. Toward this end, we investigate the use of DNA self-assembled nanowires as templates for the deposition of a superconducting material. Nanowires formed by the deposition of superconducting NbN exhibit thermally activated and quantum phase slips as well as exceptionally large negative magnetoresistance. The latter effect can be utilized to suppress a significant part of the low temperature resistance caused by the quantum phase slips.

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Jan 2021 • Molecules

Redox Potential and Crystal Chemistry of Hexanuclear Cluster Compounds

Elena Levi, Doron Aurbach, Carlo Gatti

Most of TM 6-cluster compounds (TM= transition metal) are soluble in polar solvents, in which the cluster units commonly remain intact, preserving the same atomic arrangement as in solids. Consequently, the redox potential is often used to characterize structural and electronic features of respective solids. Although a high lability and variety of ligands allow for tuning of redox potential and of the related spectroscopic properties in wide ranges, the mechanism of this tuning is still unclear. Crystal chemistry approach was applied for the first time to clarify this mechanism. It was shown that there are two factors affecting redox potential of a given metal couple: Lever’s electrochemical parameters of the ligands and the effective ionic charge of TM, which in cluster compounds differs effectively from the formal value due to the bond strains around TM atoms. Calculations of the effective ionic charge of TMs were performed in the framework of bond valence model, which relates the valence of a bond to its length by simple Pauling relationship. It was also shown that due to the bond strains the charge depends mainly on the atomic size of the inner ligands. View Full-Text

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