Search query: markus müller serdes

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abstract: Advances in semiconductor manufacturing still lead to ever decreasing feature sizes and constantly allow higher degrees of integration in application specific integrated circuits (ASICs) Therefore the bandwidth requirements on the external interfaces of such systems on chips (SoC) are steadily growing. Yet, as the number of pins on these ASICs is not increasing in the same pace known as pin limitation the bandwidth per pin has to be increased. SerDes (Serializer/Deserializer) technology, which allows to transfer data serially at very high data rates of 25Gbps and more is a key technology to overcome pin limitation and exploit the computing power that can be achieved in todays SoCs. As such SerDes blocks together with the digital logic interfacing them form complex mixed signal systems, verification of performance and functional correctness is very challenging. In this thesis a novel mixed signal design methodology is proposed, which tightly couples model and implementation in order to ensure consistency throughout the design cycles and hereby accelerate the overall implementation flow. A tool flow that has been developed is presented, which integrates well into state of the art electronic design automation (EDA) environments and enables the usage of this methodology in practice. Further, the design space of todays high speed serial links is analyzed and an architecture is proposed, which pushes complexity into the digital domain in order to achieve robustness, portability between manufacturing processes and scaling with advanced node technologies. The all digital phase locked loop (PLL) and clock data recovery (CDR) which have been developed are described in detail. The developed design flow was used for the implementation of the SerDes architecture in a 28nm silicon process and proved to be indispensable for future projects.
author_names: Markus Muller
title: Digital centric multi gigabit SerDes design and verification
year: 2018

abstract: Summary The recent emergence of the novel, pathogenic SARS coronavirus 2 (SARS CoV 2) in China and its rapid national and international spread pose a global health emergency. Cell entry of coronaviruses depends on binding of the viral spike (S) proteins to cellular receptors and on S protein priming by host cell proteases. Unravelling which cellular factors are used by SARS CoV 2 for entry might provide insights into viral transmission and reveal therapeutic targets. Here, we demonstrate that SARS CoV 2 uses the SARS CoV receptor ACE2 for entry and the serine protease TMPRSS2 for S protein priming. A TMPRSS2 inhibitor approved for clinical use blocked entry and might constitute a treatment option. Finally, we show that the sera from convalescent SARS patients cross neutralized SARS 2 S driven entry. Our results reveal important commonalities between SARS CoV 2 and SARS CoV infection and identify a potential target for antiviral intervention.
author_names: Markus Hoffmann

Hannah Kleine-Weber

Simon Schroeder

Nadine Kruger

Tanja Herrler

Sandra Erichsen

Tobias S Schiergens

Georg Herrler

Nai-Huei Wu

Andreas Nitsche

Marcel Alexander Muller

Christian Drosten

Stefan Pohlmann
title: SARS CoV 2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor
venue: Cell
year: 2020

abstract: The global spread of SARS CoV 2/COVID 19 is devastating health systems and economies worldwide. Recombinant or vaccine induced neutralizing antibodies are used to combat the COVID 19 pandemic. However, the recently emerged SARS CoV 2 variants B.1.1.7 (UK) B.1.351 (South Africa) and P.1 (Brazil) harbor mutations in the viral spike (S) protein that may alter virus host cell interactions and confer resistance to inhibitors and antibodies. Here, using pseudoparticles, we show that entry of all variants into human cells is susceptible to blockade by the entry inhibitors soluble ACE2, Camostat, EK 1 and EK 1 C4. In contrast, entry of the B.1.351 and P.1 variant was partially (Casirivimab) or fully (Bamlanivimab) resistant to antibodies used for COVID 19 treatment. Moreover, entry of these variants was less efficiently inhibited by plasma from convalescent COVID 19 patients and sera from BNT162b2 vaccinated individuals. These results suggest that SARS CoV 2 may escape neutralizing antibody responses, which has important implications for efforts to contain the pandemic.
author_names: Markus Hoffmann

Prerna Arora

Rudiger Gross

Alina Seidel

Bojan F Hornich

Alexander S Hahn

Nadine Kruger

Luise Graichen

Heike Hofmann-Winkler

Amy Kempf

Martin S Winkler

Sebastian R Schulz

Hans-Martin Jack

Bernd Jahrsdorfer

Hubert Schrezenmeier

Martin Muller

Alexander Kleger

Jan Munch

Stefan Pohlmann
title: SARS CoV 2 variants B.1.351 and P.1 escape from neutralizing antibodies
venue: Cell
year: 2021

abstract: The coronavirus disease 2019 (COVID 19) pandemic, which is caused by severe acute respiratory syndrome coronavirus 2 (SARS CoV 2) has been associated with more than 780,000 deaths worldwide (as of 20 August 2020) To develop antiviral interventions quickly, drugs used for the treatment of unrelated diseases are currently being repurposed to treat COVID 19. Chloroquine is an anti malaria drug that is used for the treatment of COVID 19 as it inhibits the spread of SARS CoV 2 in the African green monkey kidney derived cell line Vero 1 3 Here we show that engineered expression of TMPRSS2, a cellular protease that activates SARS CoV 2 for entry into lung cells 4 renders SARS CoV 2 infection of Vero cells insensitive to chloroquine. Moreover, we report that chloroquine does not block infection with SARS CoV 2 in the TMPRSS2 expressing human lung cell line Calu 3. These results indicate that chloroquine targets a pathway for viral activation that is not active in lung cells and is unlikely to protect against the spread of SARS CoV 2 in and between patients. Expression of TMPRSS2 a protease that activates SARS CoV 2 for entry into cells renders SARS CoV 2 insensitive to chloroquine.
author_names: Markus Hoffmann

Kirstin Mosbauer

Heike Hofmann-Winkler

Artur Kaul

Hannah Kleine-Weber

Nadine Kruger

Nils C Gassen

Marcel Alexander Muller

Christian Drosten

Stefan Pohlmann
title: Chloroquine does not inhibit infection of human lung cells with SARS CoV 2
venue: Nature
year: 2020

abstract: Infection related diabetes can arise as a result of virus associated b cell destruction. Clinical data suggest that the severe acute respiratory syndrome coronavirus 2 (SARS CoV 2) causing the coronavirus disease 2019 (COVID 19) impairs glucose homoeostasis, but experimental evidence that SARS CoV 2 can infect pancreatic tissue has been lacking. In the present study, we show that SARS CoV 2 infects cells of the human exocrine and endocrine pancreas ex vivo and in vivo. We demonstrate that human b cells express viral entry proteins, and SARS CoV 2 infects and replicates in cultured human islets. Infection is associated with morphological, transcriptional and functional changes, including reduced numbers of insulin secretory granules in b cells and impaired glucose stimulated insulin secretion. In COVID 19 full body postmortem examinations, we detected SARS CoV 2 nucleocapsid protein in pancreatic exocrine cells, and in cells that stain positive for the b cell marker NKX6.1 and are in close proximity to the islets of Langerhans in all four patients investigated. Our data identify the human pancreas as a target of SARS CoV 2 infection and suggest that b cell infection could contribute to the metabolic dysregulation observed in patients with COVID 19.
author_names: Janis A Muller

Rudiger Gross

Carina Conzelmann

Jana Kruger

Uta Merle

Johannes Steinhart

Tatjana Weil

Lennart Koepke

Caterina Prelli Bozzo

Clarissa Read

Giorgio Fois

Tim Eiseler

Julia Gehrmann

Joanne van Vuuren

Isabel M Wessbecher

Manfred Frick

Ivan G Costa

Markus Breunig

Beate Gruner

Lynn Peters

Michael Schuster

Stefan Liebau

Thomas Seufferlein

Steffen Stenger

Albrecht Stenzinger

Patrick E MacDonald

Frank Kirchhoff

Konstantin Maria Johannes Sparrer

Paul Walther

Heiko Lickert

Thomas F E Barth

Martin Wagner

Jan Munch

Sandra Heller

Alexander Kleger
title: SARS CoV 2 infects and replicates in cells of the human endocrine and exocrine pancreas.
venue: Nature metabolism
year: 2021

abstract: BackgroundReceiver operating characteristic (ROC) curves are useful tools to evaluate classifiers in biomedical and bioinformatics applications. However, conclusions are often reached through inconsistent use or insufficient statistical analysis. To support researchers in their ROC curves analysis we developed pROC, a package for R and S+ that contains a set of tools displaying, analyzing, smoothing and comparing ROC curves in a user friendly, object oriented and flexible interface.ResultsWith data previously imported into the R or S+ environment, the pROC package builds ROC curves and includes functions for computing confidence intervals, statistical tests for comparing total or partial area under the curve or the operating points of different classifiers, and methods for smoothing ROC curves. Intermediary and final results are visualised in user friendly interfaces. A case study based on published clinical and biomarker data shows how to perform a typical ROC analysis with pROC.ConclusionspROC is a package for R and S+ specifically dedicated to ROC analysis. It proposes multiple statistical tests to compare ROC curves, and in particular partial areas under the curve, allowing proper ROC interpretation. pROC is available in two versions: in the R programming language or with a graphical user interface in the S+ statistical software. It is accessible at http:/expasy.org/tools/pROC/ under the GNU General Public License. It is also distributed through the CRAN and CSAN public repositories, facilitating its installation.
author_names: Xavier Robin

Natacha Turck

Alexandre Hainard

Natalia Tiberti

Frederique Lisacek

Jean-Charles Sanchez

Markus Muller
title: pROC: an open source package for R and S+ to analyze and compare ROC curves
venue: BMC Bioinformatics
year: 2010

abstract: Tet proteins oxidize 5 methylcytosine (mC) to generate 5 hydroxymethyl (hmC) 5 formyl (fC) and 5 carboxylcytosine (caC) The exact function of these oxidative cytosine bases remains elusive. We applied quantitative mass spectrometry based proteomics to identify readers for mC and hmC in mouse embryonic stem cells (mESC) neuronal progenitor cells (NPC) and adult mouse brain tissue. Readers for these modifications are only partially overlapping, and some readers, such as Rfx proteins, display strong specificity. Interactions are dynamic during differentiation, as for example evidenced by the mESC specific binding of Klf4 to mC and the NPC specific binding of Uhrf2 to hmC, suggesting specific biological roles for mC and hmC. Oxidized derivatives of mC recruit distinct transcription regulators as well as a large number of DNA repair proteins in mouse ES cells, implicating the DNA damage response as a major player in active DNA demethylation.
author_names: Cornelia G Spruijt

Felix A Gnerlich

Arne H Smits

Toni Pfaffeneder

Pascal W Jansen

Christina Bauer

Martin Munzel

Mirko Wagner

Markus Muller

Fariha Khan

H Christian Eberl

Anneloes Mensinga

Arie B Brinkman

Konstantin Lephikov

Udo Muller

Jorn Walter

Rolf Boelens

Hugo Ingen

Heinrich Leonhardt

Thomas Carell

Michiel Vermeulen
title: Dynamic Readers for 5 (Hydroxy)Methylcytosine and Its Oxidized Derivatives
venue: Cell
year: 2013

abstract: Abstract The oncofetal mRNA binding protein IGF2BP1 and the transcriptional regulator SRF modulate gene expression in cancer. In cancer cells, we demonstrate that IGF2BP1 promotes the expression of SRF in a conserved and N6 methyladenosine (m6A) dependent manner by impairing the miRNA directed decay of the SRF mRNA. This results in enhanced SRF dependent transcriptional activity and promotes tumor cell growth and invasion. At the post transcriptional level, IGF2BP1 sustains the expression of various SRF target genes. The majority of these SRF/IGF2BP1 enhanced genes, including PDLIM7 and FOXK1, show conserved upregulation with SRF and IGF2BP1 synthesis in cancer. PDLIM7 and FOXK1 promote tumor cell growth and were reported to enhance cell invasion. Consistently, 35 SRF/IGF2BP1 dependent genes showing conserved association with SRF and IGF2BP1 expression indicate a poor overall survival probability in ovarian, liver and lung cancer. In conclusion, these findings identify the SRF/IGF2BP1 miRNome and m6A dependent control of gene expression as a conserved oncogenic driver network in cancer.
author_names: Simon Muller

Markus Glass

Anurag Kumar Singh

Jacob Haase

Nadine Bley

Tommy Fuchs

Marcell Lederer

Andreas Dahl

Huilin Huang

Jianjun Chen

Guido Posern

Stefan Huttelmaier
title: IGF2BP1 promotes SRF dependent transcription in cancer in a m6A and miRNA dependent manner
venue: Nucleic acids research
year: 2019

abstract: 5 Hydroxymethylcytosine (hmC) was recently detected as the sixth base in mammalian tissue at so far controversial levels. The function of the modified base is currently unknown, but it is certain that the base is generated from 5 methylcytosine (mC) This fuels the hypothesis that it represents an intermediate of an active demethylation process, which could involve further oxidation of the hydroxymethyl group to a formyl or carboxyl group followed by either deformylation or decarboxylation. Here, we use an ultra sensitive and accurate isotope based LC MS method to precisely determine the levels of hmC in various mouse tissues and we searched for 5 formylcytosine (fC) 5 carboxylcytosine (caC) and 5 hydroxymethyluracil (hmU) as putative active demethylation intermediates. Our data suggest that an active oxidative mC demethylation pathway is unlikely to occur. Additionally, we show using HPLC MS analysis and immunohistochemistry that hmC is present in all tissues and cell types with highest concentrations in neuronal cells of the CNS.
author_names: Daniel Globisch

Martin Munzel

Markus Muller

Stylianos Michalakis

Mirko Wagner

Susanne F Koch

Tobias Bruckl

Martin Biel

Thomas Carell
title: Tissue Distribution of 5 Hydroxymethylcytosine and Search for Active Demethylation Intermediates
venue: PloS one
year: 2010

abstract: The control of quantum systems is of fundamental scientific interest and promises powerful applications and technologies. Impressive progress has been achieved in isolating quantum systems from the environment and coherently controlling their dynamics, as demonstrated by the creation and manipulation of entanglement in various physical systems. However, for open quantum systems, engineering the dynamics of many particles by a controlled coupling to an environment remains largely unexplored. Here we realize an experimental toolbox for simulating an open quantum system with up to five quantum bits (qubits) Using a quantum computing architecture with trapped ions, we combine multi qubit gates with optical pumping to implement coherent operations and dissipative processes. We illustrate our ability to engineer the open system dynamics through the dissipative preparation of entangled states, the simulation of coherent many body spin interactions, and the quantum non demolition measurement of multi qubit observables. By adding controlled dissipation to coherent operations, this work offers novel prospects for open system quantum simulation and computation.
author_names: Julio T Barreiro

Markus Muller

Philipp Schindler

Daniel Nigg

Thomas Monz

Michael Chwalla

Markus Hennrich

Christian F Roos

Peter Zoller

Rainer Blatt
title: An open system quantum simulator with trapped ions
venue: Nature
year: 2011