Theory of STM junctions for \pi-conjugated molecules on thin insulating films

A microscopic theory of the transport in a scanning tunnelling microscope (STM) set-up is introduced for \pi-conjugated molecules on insulating films, based on the density matrix formalism. A key role is played in the theory by the energy dependent tunnelling rates which account for the coupling of the molecule to the tip and to the substrate. In particular, we analyze how the geometrical differences between the localized tip and extended substrate are encoded in the tunnelling rate and influence the transport characteristics. Finally, using benzene as an example of a planar, rotationally symmetric molecule, we calculate the STM current voltage characteristics and current maps and analyze them in terms of few relevant angular momentum channels.Comment: 19 pages, 12 figures, minor changes to conform to published versio

Subgap features due to quasiparticle tunneling in quantum dots coupled to superconducting leads

We present a microscopic theory of transport through quantum dot set-ups coupled to superconducting leads. We derive a master equation for the reduced density matrix to lowest order in the tunneling Hamiltonian and focus on quasiparticle tunneling. For high enough temperatures transport occurs in the subgap region due to thermally excited quasiparticles, which can be used to observe excited states of the system for low bias voltages. On the example of a double quantum dot we show how subgap transport spectroscopy can be done. Moreover, we use the single level quantum dot coupled to a normal and a superconducting lead to give a possible explanation for the subgap features observed in the experiments published in Appl. Phys. Lett. 95, 192103 (2009).Comment: 18 pages, 20 figures, revised according to published versio

Lokalisation und Funktion von KDEL-Rezeptoren in Hefe- und Säugerzellen

A/B toxins such as cholera toxin, Pseudomonas exotoxin and yeast killer toxin K28 contain a KDEL-like motif at either subunit which ensures retrograde toxin transport through the secretory pathway of a target cell. Intoxication and host cell entry is initiated by toxin binding to plasma membrane (PM) receptors where the yeast KDEL receptor (KDELR) was recently identified as receptor of K28. Consistent with its function at the cell surface, electron microscopy was performed to support PM co-localization of KDELRs in yeast and mammals. To identify how a major KDELR fraction is retained in the secretory pathway, the C-terminal lysine cluster of KDELRs was confirmed to play an important role for ER retention in yeast and mammalian cells. As KDELRs function as GPCRs in the regulation of vesicle trafficking, a similar signalling function after cargo binding at the cell surface is assumed. To address such novel functions, CRISPR/Cas9-mediated KDELR knock-out (KO) cell lines were generated. While KDELR1-KO inhibited HEK293 cell survival, the generation of KDELR2- and KDELR3-KO cell lines was successful. Characterization of commercial KDELR1-KO HAP1 cells revealed a strong sensitivity under ER stress conditions and an increased secretion of PDI. Additionally, transcriptome analysis showed alterations in the expression of genes whose products are involved in developmental processes, cell adhesion and extracellular matrix functions.A/B-Toxine wie das Cholera-Toxin, Pseudomonas-Exotoxin und das Hefe-Killertoxin K28 enthalten ein KDEL-ähnliches Motiv an einer ihrer Untereinheiten, welches den retrograden Toxintransport durch den Sekretionsweg der Zielzelle ermöglicht. Ihr Eindringen wird durch die Bindung an Plasmamembran (PM)-Rezeptoren initiiert, wobei der KDEL-Rezeptor (KDELR) als PM-Rezeptor von K28 identifiziert werden konnte. Im Zusammenhang mit dieser Funktion an der Zelloberfläche wurde eine Co-Lokalisation des KDELR in der PM von Hefe- und Säugerzellen durch Elektronenmikroskopie bestätigt. Untersuchungen bezüglich der KDELR-Retention im Sekretionsweg konnten eine entscheidende Rolle des C-terminalen Lysin-Clusters in Hefe- und Säugerzellen bestärken. Da KDELRs bei der Regulation von Transportprozessen als GPCRs agieren, kann auch eine ähnliche Signalfunktion nach extrazellulärer Ligandenbindung angenommen werden. Zur Analyse solch neuer Funktionen wurden mittels CRISPR/Cas9-Technologie KDELR-KO Zelllinien hergestellt. Während die Generierung eines KDELR2- und KDELR3-KOs gelang, verhinderte der KDELR1-KO das Überleben von HEK293-Zellen. Die Charakterisierung einer kommerziellen KDELR1-KO HAP1-Zelllinie zeigte eine erhöhte Sensitivität bei ER-Stress sowie eine verstärkte PDI-Sekretion. Zusätzlich konnten mittels Transkriptomanalyse Veränderungen in Entwicklungsprozessen, Zelladhäsion sowie Komponenten der Extrazellulären Matrix nachgewiesen werden

Dust Evolution in Protoplanetary Disks

(abridged) In the core accretion scenario for the formation of planetary rocky cores, the first step toward planet formation is the growth of dust grains into larger and larger aggregates and eventually planetesimals. Although dust grains are thought to grow from the submicron sizes typical of interstellar dust to micron size particles in the dense regions of molecular clouds and cores, the growth from micron size particles to pebbles and kilometre size bodies must occur in protoplanetary disks. This step in the formation of planetary systems is the last stage of solids evolution that can be observed directly in young extrasolar systems. In this chapter we review the constraints on the physics of grain-grain collisions as they have emerged from laboratory experiments and numerical computations. We then review the current theoretical understanding of the global processes governing the evolution of solids in protoplanetary disks, including dust settling, growth, and radial transport. The predicted observational signatures are summarized. We discuss recent developments in the study of grain growth in molecular cloud cores and in collapsing envelopes of protostars as these provide the initial conditions for the dust in disks. We discuss the observational evidence for the growth of grains in young disks from mm surveys, as well as the recent evidence of radial variations of the dust properties in disks. We include a brief discussion of the constraints on the small end of the grain size distribution and on dust settling as derived from optical and IR observations. The observations are discussed in the context of global dust evolution models, in particular we focus on the emerging evidence for a very efficient early growth of grains and the radial distribution of grain sizes in disks. We also highlight the limits of current models, including the need to slow the radial drift of grains.Comment: Accepted for publication as a chapter in Protostars and Planets VI, University of Arizona Press (2014), eds. H. Beuther, R. Klessen, C. Dullemond, Th. Hennin

In-hospital safety in field conditions of Nifurtimox Eflornithine Combination Therapy (NECT) for T. B. Gambiense Sleeping Sickness

Trypanosoma brucei (T.b.) gambiense Human African trypanosomiasis (HAT; sleeping sickness) is a fatal disease. Until 2009, available treatments for 2(nd) stage HAT were complicated to use, expensive (eflornithine monotherapy), or toxic, and insufficiently effective in certain areas (melarsoprol). Recently, nifurtimox-eflornithine combination therapy (NECT) demonstrated good safety and efficacy in a randomised controlled trial (RCT) and was added to the World Health Organisation (WHO) essential medicines list (EML). Documentation of its safety profile in field conditions will support its wider use

Mechanisms of Hepatocellular Toxicity Associated with Dronedarone—A Comparison to Amiodarone

Dronedarone is a new antiarrhythmic drug with an amiodarone-like benzofuran structure. Shortly after its introduction, dronedarone became implicated in causing severe liver injury. Amiodarone is a well-known mitochondrial toxicant. The aim of our study was to investigate mechanisms of hepatotoxicity of dronedarone in vitro and to compare them with amiodarone. We used isolated rat liver mitochondria, primary human hepatocytes, and the human hepatoma cell line HepG2, which were exposed acutely or up to 24h. After exposure of primary hepatocytes or HepG2 cells for 24h, dronedarone and amiodarone caused cytotoxicity and apoptosis starting at 20 and 50µM, respectively. The cellular ATP content started to decrease at 20µM for both drugs, suggesting mitochondrial toxicity. Inhibition of the respiratory chain required concentrations of ~10µM and was caused by an impairment of complexes I and II for both drugs. In parallel, mitochondrial accumulation of reactive oxygen species (ROS) was observed. In isolated rat liver mitochondria, acute treatment with dronedarone decreased the mitochondrial membrane potential, inhibited complex I, and uncoupled the respiratory chain. Furthermore, in acutely treated rat liver mitochondria and in HepG2 cells exposed for 24h, dronedarone started to inhibit mitochondrial β-oxidation at 10µM and amiodarone at 20µM. Similar to amiodarone, dronedarone is an uncoupler and an inhibitor of the mitochondrial respiratory chain and of β-oxidation both acutely and after exposure for 24h. Inhibition of mitochondrial function leads to accumulation of ROS and fatty acids, eventually leading to apoptosis and/or necrosis of hepatocytes. Mitochondrial toxicity may be an explanation for hepatotoxicity of dronedarone in viv

Absolute Magnitudes and Colors of RR Lyrae stars in DECam Passbands from Photometry of the Globular Cluster M5

We characterize the absolute magnitudes and colors of RR Lyrae stars in the globular cluster M5 in the ugriz filter system of the Dark Energy Camera (DECam). We provide empirical Period-Luminosity (P-L) relationships in all 5 bands based on 47 RR Lyrae stars of the type ab and 14 stars of the type c. The P-L relationships were found to be better constrained for the fundamental mode RR Lyrae stars in the riz passbands, with dispersion of 0.03, 0.02 and 0.02 magnitudes, respectively. The dispersion of the color at minimum light was found to be small, supporting the use of this parameter as a means to obtain accurate interstellar extinctions along the line of sight up to the distance of the RR Lyrae star. We found a trend of color at minimum light with pulsational period that, if taken into account, brings the dispersion in color at minimum light to < 0.016 magnitudes for the (r-i), (i-z), and (r-z) colors. These calibrations will be very useful for using RR Lyrae stars from DECam observations as both standard candles for distance determinations and color standards for reddening measurements.Comment: Accepted for publication in A

Trueperella pyogenes endocarditis in a Swiss farmer: a case report and review of the literature.

BACKGROUND Trueperella pyogenes (T. pyogenes) is a bacterium that colonizes the skin and mucosal surfaces of various domestic and wild animals. It rarely leads to infections in humans, with only a few descriptions available in the literature. CASE PRESENTATION A 71-year-old Swiss farmer with a history of recurring basal cell carcinoma and metastasized pancreatic neuroendocrine tumor presented with signs of sepsis after a three-day history of general weakness, malaise and fever. Clinical and echocardiographic findings, as well as persistent bacteremia were consistent with mitral valve endocarditis caused by T. pyogenes. The patient's condition gradually improved under antibiotic treatment with piperacillin/tazobactam (empiric therapy of sepsis), and later penicillin G based on resistance testing. He was discharged after 13 days and continued outpatient antibiotic therapy with ceftriaxone, resulting in a total antibiotic treatment duration of six weeks. This is the first literature review of T. pyogenes endocarditis in humans. Among nine cases of T. pyogenes endocarditis, three patients had documented contact with farm animals and five had an underlying condition that compromised the immune system. While antibiotic resistance of T. pyogenes is an emerging concern, susceptibility to beta-lactam antibiotics seems to persist. The mortality of T. pyogenes endocarditis described in the literature was high, with 66% of patients not surviving the disease. CONCLUSIONS T. pyogenes is a rare causative organism of infectious endocarditis in humans and descriptions are mainly restricted to case reports. In our review of the literature, we found that both an impaired immune system and contact with farm animals might be risk factors. Growth of T. pyogenes in blood cultures is unlikely to be missed during routine analysis, as it shows marked beta-hemolysis on blood agar culture plates, which generally leads to further characterization of the bacteria. Susceptibility to penicillin, ceftriaxone, and macrolides seems to be retained and the reported mortality in the few patients with T. pyogenes endocarditis is high

Dynamical symmetry breaking in vibration-assisted transport through nanostructures

A theoretical model of a single molecule coupled to many vibronic modes is presented. At low energies, transport is dominated by electron-vibron processes where transfer of an electron through the dot is accompanied by the excitation/emission of quanta (vibrons). Because the frequency of the $n$th mode is taken as an $n$th multiple of the frequency of the fundamental mode, several energetically degenerate or quasi-degenerate vibronic configurations can contribute to transport. We investigate the consequences of strong electron-vibron coupling in a fully \emph{symmetric} set-up. Several striking features are predicted. In particular, a gate-asymmetry and pronounced negative differential conductance features are observed. We attribute these features to the presence of slow channels originating from the interplay of Franck-Condon suppression of transport channels and spin/orbital degeneracies.Comment: 10 pages, 11 figures, published versio

Single-cell RNA sequencing reveals developmental heterogeneity of blastomeres during major genome activation in bovine embryos

Embryonic development is initially controlled by maternal RNAs and proteins stored in the oocyte, until gene products gradually generated by the embryo itself take over. Major embryonic genome activation (EGA) in bovine embryos occurs at the eight-to 16-cell stage. Morphological observations, such as size of blastomeres and distribution of microvilli, suggested heterogeneity among individual cells already at this developmental stage. To address cell heterogeneity on the transcriptome level, we performed single-cell RNA sequencing of 161 blastomeres from 14 in vitro produced bovine embryos at Day 2 (n = 6) and Day 3 (n = 8) post fertilization. Complementary DNA libraries were prepared using the Single-Cell RNA-Barcoding and Sequencing protocol and sequenced. Non-supervised clustering of single-cell transcriptome profiles identified six clusters with specific sets of genes. Most embryos were comprised of cells from at least two different clusters. Sorting cells according to their transcriptome profiles resulted in a non-branched pseudo-time line, arguing against major lineage inclination events at this developmental stage. In summary, our study revealed heterogeneity of transcriptome profiles among single cells in bovine Day 2 and Day 3 embryos, suggesting asynchronous blastomere development during the phase of major EGA